16	33439912	Circumferential resection margin (CRM) negativity and complete TME are associated with lower local and distal recurrence rates and better long-term survival.	('negativity', 'Var', (39, 49))	('TME', 'Chemical', '-', (63, 66))	('complete', 'Var', (54, 62))	('lower', 'NegReg', (87, 92))	('better', 'PosReg', (131, 137))
62	32992658	For instance, high expression of PD-L1 on immune cells infiltrating the tumor was shown to be an independent predictor of better melanoma patient outcomes following tumor resection, and a better predictor of response to PD-1 blockade than PD-L1 expression on tumor cells in immunogenic cancers such as melanoma, non-small cell lung cancer and urothelial cancer.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('PD-L1', 'Gene', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('non-small cell lung cancer', 'Disease', (312, 338))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('melanoma', 'Phenotype', 'HP:0002861', (302, 310))	('better', 'PosReg', (122, 128))	('melanoma', 'Disease', (302, 310))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('urothelial cancer', 'Disease', 'MESH:D014523', (343, 360))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (327, 338))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (312, 338))	('urothelial cancer', 'Disease', (343, 360))	('cancers', 'Phenotype', 'HP:0002664', (286, 293))	('cancers', 'Disease', (286, 293))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (316, 338))	('tumor', 'Disease', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('melanoma', 'Disease', 'MESH:D008545', (302, 310))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (312, 338))	('PD-1 blockade than PD-L1', 'Disease', 'MESH:D010300', (220, 244))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (354, 360))	('melanoma', 'Disease', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('patient', 'Species', '9606', (138, 145))	('PD-1 blockade than PD-L1', 'Disease', (220, 244))	('high expression', 'Var', (14, 29))	('tumor', 'Disease', (259, 264))	('cancers', 'Disease', 'MESH:D009369', (286, 293))
65	32992658	For instance, PD-L1 expression on immunogenic MC38 colorectal tumor cells directly suppressed CD8 T-cell cytotoxicity and was dominant in suppressing anti-tumor immunity.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('colorectal tumor', 'Disease', 'MESH:D015179', (51, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cytotoxicity', 'Disease', 'MESH:D064420', (105, 117))	('tumor', 'Disease', (62, 67))	('expression', 'Var', (20, 30))	('tumor', 'Disease', (155, 160))	('MC38', 'CellLine', 'CVCL:B288', (46, 50))	('colorectal tumor', 'Disease', (51, 67))	('CD8', 'Gene', (94, 97))	('PD-L1', 'Gene', (14, 19))	('suppressing', 'NegReg', (138, 149))	('suppressed', 'NegReg', (83, 93))	('CD8', 'Gene', '925', (94, 97))	('cytotoxicity', 'Disease', (105, 117))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
76	32992658	Anti-PD-L1 antibodies release CD80 from this sequestered form and re-instate the CD80-CD28 co-stimulatory interaction while simultaneously blocking the PD-L1-PD-1 inhibitory pathway, resulting in augmented T-cell activation upon antigen recognition (Figure 2).	('CD80', 'Gene', '397161', (30, 34))	('CD80', 'Gene', (81, 85))	('CD28', 'Gene', '940', (86, 90))	('augmented', 'PosReg', (196, 205))	('CD80', 'Gene', (30, 34))	('blocking', 'NegReg', (139, 147))	('antibodies', 'Var', (11, 21))	('Anti-PD-L1', 'Gene', (0, 10))	('PD-L1-PD-1 inhibitory pathway', 'Pathway', (152, 181))	('T-cell activation', 'biological_process', 'GO:0042110', ('206', '223'))	('CD28', 'Gene', (86, 90))	('T-cell activation', 'CPA', (206, 223))	('CD80', 'Gene', '397161', (81, 85))	('augmented T-cell activation', 'Phenotype', 'HP:0005419', (196, 223))
79	32992658	PD-L1-deficient T-cells are more susceptible to killing by cytotoxic T-cells, indicating that PD-L1 protects T-cells undergoing clonal expansion and supports optimal protective immunity.	('PD-L1', 'Var', (94, 99))	('protective immunity', 'CPA', (166, 185))	('PD-L1-deficient T-cells', 'Disease', 'MESH:D010300', (0, 23))	('PD-L1-deficient T-cells', 'Disease', (0, 23))
81	32992658	The ligation of PD-L1 expressed by T-cells can promote tumor immune escape via diverse mechanisms.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('PD-L1', 'Gene', (16, 21))	('promote', 'PosReg', (47, 54))	('tumor', 'Disease', (55, 60))	('ligation', 'Var', (4, 12))
83	32992658	This so-called "back-signaling" can promote T-helper 1 (Th1)-to-Th17 switch in CD4 T-cells, a non-responsive (anergic) phenotype in CD8 T-cells and apoptosis in activated T-cells; the ligation of PD-L1 on T-cells was as efficient as PD-1 ligation in suppressing T-cell functionality.	('suppressing', 'NegReg', (250, 261))	('ligation', 'Var', (184, 192))	('promote', 'PosReg', (36, 43))	('CD4', 'Gene', (79, 82))	('PD-L1', 'Gene', (196, 201))	('T-helper', 'CPA', (44, 52))	('CD4', 'Gene', '404704', (79, 82))	('apoptosis', 'biological_process', 'GO:0097194', ('146', '155'))	('apoptosis', 'biological_process', 'GO:0006915', ('146', '155'))	('CD8', 'Gene', (132, 135))	('T-cell functionality', 'CPA', (262, 282))	('CD8', 'Gene', '925', (132, 135))	('signaling', 'biological_process', 'GO:0023052', ('20', '29'))
98	32992658	It is unclear to what extent anti-PD-1 therapeutic antibodies directly modify the biology of PD-1-expressing TAMs, but myeloid cell-targeting therapies, especially a blockade of the colony stimulating factor 1 (CSF1) receptor signaling, potently synergize with immunotherapy in preclinical models of cancer.	('CSF1', 'Gene', (211, 215))	('CSF1', 'Gene', '1435', (211, 215))	('signaling', 'biological_process', 'GO:0023052', ('226', '235'))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('colony stimulating factor 1', 'Gene', (182, 209))	('CSF1', 'molecular_function', 'GO:0005011', ('211', '215'))	('TAMs', 'Chemical', '-', (109, 113))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('blockade', 'Var', (166, 174))	('colony stimulating factor 1', 'Gene', '1435', (182, 209))	('cancer', 'Disease', (300, 306))
109	32992658	Furthermore, anti-angiogenic therapy combined with anti-PD-1 facilitated the formation in the tumor tissue of highly specialized capillaries known as high endothelial venules (HEVs), structures normally present in lymph nodes where they serve as dedicated sites of T-cell homing, likely indicative of the development of tertiary lymphoid structures within the tumor.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('formation', 'biological_process', 'GO:0009058', ('77', '86'))	('tumor', 'Disease', (360, 365))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('facilitated', 'PosReg', (61, 72))	('tumor', 'Disease', (94, 99))	('anti-PD-1', 'Var', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (360, 365))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))
118	32992658	Copy number amplifications of 9p24.1 have been associated with increased PD-L1 expression in several cancers, and occur most commonly in mediastinal large B-cell lymphoma, classical Hodgkin's lymphoma and triple-negative breast cancer, but have also been described in ovarian, head and neck, bladder, cervical cancers, sarcomas and colorectal cancers, albeit at lower frequencies.	('lymphoma', 'Phenotype', 'HP:0002665', (162, 170))	('sarcomas', 'Phenotype', 'HP:0100242', (319, 327))	('colorectal cancers', 'Disease', (332, 350))	('cancers', 'Disease', 'MESH:D009369', (310, 317))	('sarcomas', 'Disease', (319, 327))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (155, 170))	('cancers', 'Phenotype', 'HP:0002664', (343, 350))	('colorectal cancer', 'Phenotype', 'HP:0003003', (332, 349))	('lymphoma', 'Phenotype', 'HP:0002665', (192, 200))	('cancers', 'Disease', (343, 350))	('ovarian', 'Disease', (268, 275))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (182, 200))	('breast cancer', 'Disease', 'MESH:D001943', (221, 234))	('breast cancer', 'Disease', (221, 234))	('PD-L1', 'Gene', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('expression', 'MPA', (79, 89))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (155, 170))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('increased PD', 'Phenotype', 'HP:0008151', (63, 75))	("Hodgkin's lymphoma", 'Disease', (182, 200))	('colorectal cancers', 'Disease', 'MESH:D015179', (332, 350))	('cancers', 'Phenotype', 'HP:0002664', (310, 317))	('cervical cancers', 'Disease', (301, 317))	('B-cell lymphoma', 'Disease', (155, 170))	('cervical cancers', 'Disease', 'MESH:D002583', (301, 317))	('cancers', 'Disease', (310, 317))	('cancers', 'Disease', 'MESH:D009369', (343, 350))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('Copy number amplifications', 'Var', (0, 26))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('increased', 'PosReg', (63, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))	('cancers', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('bladder', 'Disease', (292, 299))	('sarcomas', 'Disease', 'MESH:D012509', (319, 327))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (182, 200))
119	32992658	Enhanced signaling via JAK2 in cancers with 9p24.1 amplifications, contributed to mixed inflammatory and constitutive tumor-derived PD-L1 expression.	('JAK2', 'Gene', '3717', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('JAK2', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('amplifications', 'Var', (51, 65))	('tumor', 'Disease', (118, 123))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('signaling', 'MPA', (9, 18))	('cancers', 'Disease', (31, 38))	('cancers', 'Disease', 'MESH:D009369', (31, 38))	('Enhanced', 'PosReg', (0, 8))
120	32992658	In addition, tumors with CD274 genetic gains demonstrated higher mutational loads compared to non-amplified cases and responded particularly well to PD-1 blockade.	('mutational loads', 'MPA', (65, 81))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('gains', 'PosReg', (39, 44))	('genetic', 'Var', (31, 38))	('CD274', 'Gene', '29126', (25, 30))	('higher', 'PosReg', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('CD274', 'Gene', (25, 30))
121	32992658	Deletions of PD-L1 are also commonly found in melanoma and non-small cell lung cancer, and represent one of the mechanisms leading to the lack of tumor cell PD-L1 expression.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('found', 'Reg', (37, 42))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (59, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Disease', (146, 151))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (59, 85))	('PD-L1', 'Gene', (13, 18))	('non-small cell lung cancer', 'Disease', (59, 85))	('expression', 'MPA', (163, 173))	('Deletions', 'Var', (0, 9))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (63, 85))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
128	32992658	Furthermore, inactivation of the tumor suppressor TP53, which is often associated with activating RAS mutations in lung adenocarcinoma and increased mutational load due to DNA damage repair defects, drives T-cell activation and immune-mediated elevation of PD-L1 expression, translating into a strong clinical benefit of PD-1 blockade in such patients.	('drives', 'PosReg', (199, 205))	('inactivation', 'Var', (13, 25))	('expression', 'MPA', (263, 273))	('associated', 'Reg', (71, 81))	('increased', 'PosReg', (139, 148))	('lung adenocarcinoma', 'Disease', (115, 134))	('DNA', 'cellular_component', 'GO:0005574', ('172', '175'))	('activating', 'PosReg', (87, 97))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', (33, 38))	('TP53', 'Gene', (50, 54))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('patients', 'Species', '9606', (343, 351))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (115, 134))	('defects', 'Var', (190, 197))	('T-cell activation', 'biological_process', 'GO:0042110', ('206', '223'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('mutational load', 'MPA', (149, 164))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (115, 134))	('T-cell activation', 'CPA', (206, 223))	('RAS', 'Gene', (98, 101))	('TP53', 'Gene', '7157', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('elevation of PD', 'Phenotype', 'HP:0008151', (244, 259))	('PD-L1', 'Gene', (257, 262))
130	32992658	Expression of mutant EGFR was sufficient to induce PD-L1 expression in bronchial epithelial cells, while EGFR targeting reduced PD-L1 expression in EGFR-mutant tumor cells.	('induce', 'PosReg', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('EGFR', 'Gene', (105, 109))	('EGFR', 'Gene', '1956', (21, 25))	('expression', 'MPA', (57, 67))	('PD-L1', 'Gene', (128, 133))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'molecular_function', 'GO:0005006', ('105', '109'))	('reduced PD', 'Phenotype', 'HP:0032198', (120, 130))	('reduced', 'NegReg', (120, 127))	('expression', 'MPA', (134, 144))	('EGFR', 'Gene', '1956', (105, 109))	('tumor', 'Disease', (160, 165))	('EGFR', 'Gene', (21, 25))	('mutant', 'Var', (14, 20))	('EGFR', 'Gene', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('EGFR', 'molecular_function', 'GO:0005006', ('148', '152'))	('EGFR', 'molecular_function', 'GO:0005006', ('21', '25'))	('PD-L1', 'Gene', (51, 56))
132	32992658	Similarly, activating mutations in the fibroblast growth factor receptor 2 (FGFR2) in colorectal cancer activate PD-L1 expression via the JAK/STAT3 pathway.	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('fibroblast growth factor receptor 2', 'Gene', '2263', (39, 74))	('expression', 'MPA', (119, 129))	('STAT3', 'Gene', (142, 147))	('FGFR2', 'Gene', (76, 81))	('activate', 'PosReg', (104, 112))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('FGFR2', 'Gene', '2263', (76, 81))	('colorectal cancer', 'Disease', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('39', '63'))	('JAK', 'molecular_function', 'GO:0004713', ('138', '141'))	('PD-L1', 'Protein', (113, 118))	('activating mutations', 'Var', (11, 31))	('fibroblast growth factor receptor 2', 'Gene', (39, 74))	('STAT3', 'Gene', '6774', (142, 147))	('FGFR', 'molecular_function', 'GO:0005007', ('76', '80'))
140	32992658	In human non-small cell lung cancer, nuclear YAP staining on immunohistochemistry was associated with PD-L1 expression.	('non-small cell lung cancer', 'Disease', (9, 35))	('YAP', 'Gene', (45, 48))	('human', 'Species', '9606', (3, 8))	('nuclear', 'Var', (37, 44))	('associated', 'Reg', (86, 96))	('PD-L1', 'Gene', (102, 107))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (9, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (24, 35))	('expression', 'MPA', (108, 118))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (13, 35))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (9, 35))	('YAP', 'Gene', '10413', (45, 48))
142	32992658	Mechanistically, loss of the epithelial marker E-cadherin frees the E-cadherin-associated beta-catenin for cytoplasmic translocation, GSK-3beta-mediated ubiquitination and proteosomal degradation.	('frees', 'MPA', (58, 63))	('E-cadherin', 'Gene', (47, 57))	('beta-catenin', 'Gene', (90, 102))	('E-cadherin', 'Gene', '999', (47, 57))	('GSK-3beta', 'Gene', '2931', (134, 143))	('E-cadherin', 'Gene', (68, 78))	('E-cadherin', 'Gene', '999', (68, 78))	('proteosomal degradation', 'MPA', (172, 195))	('beta-catenin', 'Gene', '1499', (90, 102))	('GSK-3beta', 'Gene', (134, 143))	('loss', 'Var', (17, 21))
147	32992658	For example, demethylation of the PD-L1 promoter via TGFbeta1-dependent repression of the DNA methyltransferase DNMT1 allowed for expression of PD-L1 upon TNFalpha-mediated NF-kB activation.	('expression', 'MPA', (130, 140))	('TGFbeta1', 'Gene', '7040', (53, 61))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('TGFbeta1', 'Gene', (53, 61))	('DNMT1', 'Gene', (112, 117))	('TNFalpha', 'Gene', (155, 163))	('allowed', 'Reg', (118, 125))	('DNMT1', 'Gene', '1786', (112, 117))	('demethylation', 'biological_process', 'GO:0070988', ('13', '26'))	('demethylation', 'Var', (13, 26))	('PD-L1', 'Gene', (144, 149))	('TNFalpha', 'Gene', '7124', (155, 163))
154	32992658	Loss of IFNgamma responsiveness in tumor cells may result from inactivating mutations in JAK1/2 disrupting INFgamma signaling, leading to tumor immune escape and disease progression.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('inactivating mutations', 'Var', (63, 85))	('tumor', 'Disease', (138, 143))	('JAK1/2', 'Gene', (89, 95))	('disease progression', 'CPA', (162, 181))	('tumor', 'Disease', (35, 40))	('leading to', 'Reg', (127, 137))	('Loss', 'NegReg', (0, 4))	('INFgamma signaling', 'MPA', (107, 125))	('disrupting', 'NegReg', (96, 106))	('IFNgamma', 'Protein', (8, 16))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('JAK1/2', 'Gene', '3716;3717', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
156	32992658	Tumor cells with disrupted IFNgamma signaling had a defective PD-L1 upregulation and were efficiently controlled by the immune system in a mouse model of melanoma.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mouse', 'Species', '10090', (139, 144))	('melanoma', 'Disease', 'MESH:D008545', (154, 162))	('melanoma', 'Phenotype', 'HP:0002861', (154, 162))	('melanoma', 'Disease', (154, 162))	('disrupted', 'Var', (17, 26))	('defective', 'NegReg', (52, 61))	('IFNgamma', 'Gene', (27, 35))	('PD-L1', 'Gene', (62, 67))	('upregulation', 'PosReg', (68, 80))
158	32992658	These data also suggest that disrupted IFNgamma signaling is advantageous for tumors in the context of immunotherapy.	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('disrupted', 'Var', (29, 38))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('IFNgamma', 'Protein', (39, 47))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))
162	32992658	Hypermethylation of the PD-L1 promoter prevented PD-L1 expression, while a constitutive expression of PD-L1 in melanoma biopsies and cell lines was associated with global DNA hypomethylation patterns.	('prevented', 'NegReg', (39, 48))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('Hypermethylation', 'Var', (0, 16))	('expression', 'MPA', (55, 65))	('PD-L1', 'Gene', (49, 54))
164	32992658	Other epigenetic mechanisms such as histone deacetylation and aberrant expression of the Enhancer of zeste homolog 2 (EZH2) contribute to the control of PD-L1 expression in cancer cells by limiting transcription factor access to the PD-L1 promoter region (reviewed in).	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('PD-L1', 'Gene', (153, 158))	('cancer', 'Disease', (173, 179))	('transcription factor access', 'MPA', (198, 225))	('Enhancer of zeste homolog 2', 'Gene', (89, 116))	('transcription factor', 'molecular_function', 'GO:0000981', ('198', '218'))	('histone deacetylation', 'biological_process', 'GO:0016575', ('36', '57'))	('aberrant', 'Var', (62, 70))	('expression', 'MPA', (159, 169))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('control', 'MPA', (142, 149))	('transcription', 'biological_process', 'GO:0006351', ('198', '211'))	('EZH2', 'Gene', (118, 122))	('EZH2', 'Gene', '2146', (118, 122))	('Enhancer of zeste homolog 2', 'Gene', '2146', (89, 116))	('limiting', 'NegReg', (189, 197))
166	32992658	A number of miRs can bind to the 3'UTR of the PD-L1 gene and have been shown to directly suppress PD-L1 expression, including miR-513, miR-155, miR-17-5p, miR-33a, miR-34a and multiple others (Table 1).	('PD-L1', 'Gene', (46, 51))	('miR-33a', 'Gene', (155, 162))	('miR-17-5p', 'Gene', '406952', (144, 153))	('bind', 'Interaction', (21, 25))	('miR-17-5p', 'Gene', (144, 153))	('PD-L1', 'Gene', (98, 103))	('miR-513', 'Var', (126, 133))	('miR-34a', 'Gene', (164, 171))	('miR-155', 'Gene', '406947', (135, 142))	('miR-34a', 'Gene', '407040', (164, 171))	('expression', 'MPA', (104, 114))	('suppress', 'NegReg', (89, 97))	('miR-33a', 'Gene', '407039', (155, 162))	('miR-155', 'Gene', (135, 142))
168	32992658	miR-20b, -21 and -130b upregulated PD-L1 expression in colorectal cancer also by targeting PTEN, while miR-135 augmented PD-L1 expression in lung cancer by suppressing the ubiquitination of proteins in the JAK/STAT signaling pathway.	('PD-L1', 'Gene', (121, 126))	('signaling pathway', 'biological_process', 'GO:0007165', ('215', '232'))	('upregulated', 'PosReg', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (55, 72))	('lung cancer', 'Disease', (141, 152))	('ubiquitination of', 'MPA', (172, 189))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('suppressing', 'NegReg', (156, 167))	('expression', 'MPA', (41, 51))	('augmented', 'PosReg', (111, 120))	('miR-20b', 'Gene', '574032', (0, 7))	('PTEN', 'Gene', (91, 95))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))	('colorectal cancer', 'Disease', 'MESH:D015179', (55, 72))	('expression', 'MPA', (127, 137))	('targeting', 'Reg', (81, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('JAK', 'molecular_function', 'GO:0004713', ('206', '209'))	('JAK/STAT signaling pathway', 'Pathway', (206, 232))	('colorectal cancer', 'Disease', (55, 72))	('miR-135', 'Var', (103, 110))	('PTEN', 'Gene', '5728', (91, 95))	('proteins', 'Protein', (190, 198))	('PD-L1', 'Gene', (35, 40))	('miR-20b', 'Gene', (0, 7))
169	32992658	Nonglycosylated PD-L1 is an unstable protein that is rapidly degraded by the ubiquitin/proteasome system after being phosphorylated by glycogen synthase kinase 3beta (GSK3beta).	('degraded', 'NegReg', (61, 69))	('Nonglycosylated', 'Var', (0, 15))	('PD-L1', 'Gene', (16, 21))	('GSK3beta', 'Gene', (167, 175))	('GSK3beta', 'Gene', '2931', (167, 175))	('glycogen synthase kinase 3beta', 'Gene', '2932', (135, 165))	('glycogen synthase kinase 3beta', 'Gene', (135, 165))
170	32992658	Glycosylation improves PD-L1 stability but also creates a therapeutic vulnerability, where abnormal glycosylation such as that triggered by a commonly used anti-diabetic drug metformin results in endoplasmic reticulum-associated degradation of PD-L1 and improved immune responses.	('diabetic', 'Disease', 'MESH:D003920', (161, 169))	('endoplasmic reticulum-associated degradation', 'MPA', (196, 240))	('improved', 'PosReg', (254, 262))	('metformin', 'Chemical', 'MESH:D008687', (175, 184))	('PD-L1', 'Protein', (23, 28))	('glycosylation', 'Var', (100, 113))	('diabetic', 'Disease', (161, 169))	('stability', 'MPA', (29, 38))	('improves', 'PosReg', (14, 22))	('immune responses', 'CPA', (263, 279))	('abnormal glycosylation', 'Phenotype', 'HP:0012345', (91, 113))	('abnormal glycosylation', 'Var', (91, 113))	('PD-L1', 'Protein', (244, 249))
173	32992658	Aberrant glycosylation of PD-L1 in cancer cells may provide some insight into the validity of PD-L1 detection as a predictive biomarker of immunotherapy response.	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	('PD-L1', 'Gene', (26, 31))	('glycosylation', 'biological_process', 'GO:0070085', ('9', '22'))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('glycosylation', 'MPA', (9, 22))	('cancer', 'Disease', (35, 41))
174	32992658	demonstrated, using mass spectrometry and immunohistochemistry on 22 human melanoma samples, a discrepancy in PD-L1 expression assessed by the two methods, which the authors attributed to the aberrant PD-L1 glycosylation interfering with the antibody binding on immunohistochemistry.	('aberrant', 'Var', (192, 200))	('antibody binding', 'Interaction', (242, 258))	('PD-L1', 'Protein', (201, 206))	('human', 'Species', '9606', (69, 74))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('interfering', 'NegReg', (221, 232))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('glycosylation', 'MPA', (207, 220))
181	32992658	Thus, CDK4/6 inhibitors synergized with PD-1 blockade in mouse tumor models.	('tumor', 'Disease', (63, 68))	('CDK4/6', 'Gene', '12567;12571', (6, 12))	('inhibitors', 'Var', (13, 23))	('mouse', 'Species', '10090', (57, 62))	('CDK', 'molecular_function', 'GO:0004693', ('6', '9'))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('CDK4/6', 'Gene', (6, 12))
185	32992658	In several studies, high levels of circulating sPD-L1 were associated with poor patient outcomes in melanoma, lung and gastric cancers and lymphoma and with reduced response to PD-1 blockade in melanoma.	('PD-1 blockade in melanoma', 'Disease', 'MESH:D010300', (177, 202))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lymphoma', 'Phenotype', 'HP:0002665', (139, 147))	('lung', 'Disease', (110, 114))	('sPD-L1', 'Var', (47, 53))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('gastric cancers', 'Phenotype', 'HP:0012126', (119, 134))	('melanoma', 'Disease', (194, 202))	('poor', 'NegReg', (75, 79))	('PD-1 blockade in melanoma', 'Disease', (177, 202))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('gastric cancers and lymphoma', 'Disease', 'MESH:D013274', (119, 147))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('patient', 'Species', '9606', (80, 87))	('reduced', 'NegReg', (157, 164))
191	32992658	A similar increase in PD-L1 expression in longitudinal biopsies, combined with an immune gene expression signature, was observed in patients treated with anti-CTLA-4 antibodies.	('anti-CTLA-4', 'Var', (154, 165))	('PD-L1', 'Gene', (22, 27))	('expression', 'MPA', (28, 38))	('anti-CTLA-4', 'Gene', (154, 165))	('increase', 'PosReg', (10, 18))	('patients', 'Species', '9606', (132, 140))
200	32992658	However, inhibition of TGFbeta signaling released matrix metalloproteinase-9 by stromal fibroblasts, resulting in cleavage of PD-L1 from the surface of PD-L1-expressing cancer cells and myeloid cells and generation of soluble PD-L1, thus potentially desensitizing to anti-PD-1 treatment.	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('cancer', 'Disease', (169, 175))	('TGFbeta', 'Gene', (23, 30))	('soluble PD-L1', 'MPA', (218, 231))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('PD-L1', 'Gene', (126, 131))	('soluble', 'cellular_component', 'GO:0005625', ('218', '225'))	('cleavage', 'MPA', (114, 122))	('matrix metalloproteinase-9', 'Gene', '4318', (50, 76))	('TGFbeta', 'Gene', '7039', (23, 30))	('inhibition', 'Var', (9, 19))	('matrix metalloproteinase-9', 'Gene', (50, 76))
211	32992658	Epigenetic targeting of tumor PD-L1 expression can also improve tumor-specific antigen expression and the resulting T-cell recognition, thus creating new therapeutic vulnerabilities.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('Epigenetic targeting', 'Var', (0, 20))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (24, 29))	('improve', 'PosReg', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor PD-L1', 'Disease', 'MESH:D010300', (24, 35))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('T-cell recognition', 'CPA', (116, 134))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor PD-L1', 'Disease', (24, 35))
354	29934362	Any deregulation of this core group of enzymes often leads to cancer development.	('deregulation', 'Var', (4, 16))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('men', 'Species', '9606', (76, 79))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('leads to', 'Reg', (53, 61))
356	29934362	An exciting really interesting new gene (RING) family of E3 ubiquitin ligases, known as RNF20 and RNF40, monoubiquitinates histone H2A at K119 or H2B at K120, is known to function in transcriptional elongation, DNA double-strand break (DSB) repair processes, maintenance of chromatin differentiation, and exerting tumor suppressor activity.	('RNF40', 'Gene', (98, 103))	('K120', 'Chemical', '-', (153, 157))	('at K120', 'Var', (150, 157))	('tumor', 'Disease', (314, 319))	('H2A', 'Gene', '8337', (131, 134))	('H2B', 'Gene', (146, 149))	('function', 'Reg', (171, 179))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('DNA', 'cellular_component', 'GO:0005574', ('211', '214'))	('chromatin', 'cellular_component', 'GO:0000785', ('274', '283'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('314', '330'))	('RNF40', 'Gene', '9810', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('monoubiquitinates', 'Var', (105, 122))	('tumor suppressor', 'biological_process', 'GO:0051726', ('314', '330'))	('H2A', 'Gene', (131, 134))	('H2B', 'Gene', '8349', (146, 149))	('transcriptional elongation', 'CPA', (183, 209))	('ubiquitin', 'molecular_function', 'GO:0031386', ('60', '69'))
364	29934362	Recent advances in research and technology have identified additional inherent risk factors that may or may not be heritable, which range from cellular allelic mutations, somatic mutations, accumulating mutations such as hot spot mutation, homozygous gene deletion, or gene amplification, non-synonymous single nucleotide polymorphisms, inflammatory tumor microenvironment, angiogenesis, and epigenetic alterations in the genome of normal cells that transforms them into cancer cells with characteristic properties such as uncontrolled cell proliferation, and are associated with invasive and metastatic potential.	('epigenetic alterations', 'Var', (392, 414))	('men', 'Species', '9606', (368, 371))	('cancer', 'Phenotype', 'HP:0002664', (471, 477))	('uncontrolled cell proliferation', 'CPA', (523, 554))	('tumor', 'Disease', (350, 355))	('tumor', 'Disease', 'MESH:D009369', (350, 355))	('associated with', 'Reg', (564, 579))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))	('cancer', 'Disease', 'MESH:D009369', (471, 477))	('cancer', 'Disease', (471, 477))	('mutations', 'Var', (203, 212))
365	29934362	The epigenetic impact in cancer development is yet a largely unexplored area and it is potentially an evolving strategy to counter the development and progression of cancer.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('men', 'Species', '9606', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('men', 'Species', '9606', (39, 42))	('cancer', 'Disease', (25, 31))	('epigenetic impact', 'Var', (4, 21))
366	29934362	Several studies have indicated that cancer cells are often associated with modifications or alterations in their chromatin landscape and are associated with DNA replication and repair.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('associated', 'Reg', (59, 69))	('chromatin landscape', 'MPA', (113, 132))	('associated', 'Reg', (141, 151))	('alterations', 'Reg', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('modifications', 'Var', (75, 88))
376	29934362	Several studies have demonstrated that modifications such as addition or deletion on DNA and/or histones by methylation, acetylation, SUMOylation, ADP ribosylation, ubiquitination, phosphorylation, and several other modifications on histone serine, threonine, and lysine residues or the DNA itself by specific enzymes regulating several processes such as maintaining cell identity, cell cycle regulation, proliferation, and genome integrity.	('lysine', 'Chemical', 'MESH:D008239', (264, 270))	('ubiquitination', 'MPA', (165, 179))	('serine', 'Chemical', 'MESH:D012694', (241, 247))	('phosphorylation', 'MPA', (181, 196))	('cell cycle regulation', 'CPA', (382, 403))	('threonine', 'Chemical', 'MESH:D013912', (249, 258))	('modifications', 'Var', (39, 52))	('acetylation', 'MPA', (121, 132))	('addition', 'Var', (61, 69))	('deletion', 'Var', (73, 81))	('cell identity', 'CPA', (367, 380))	('proliferation', 'CPA', (405, 418))	('DNA', 'Gene', (85, 88))	('genome integrity', 'CPA', (424, 440))
379	29934362	Deregulated epigenetic changes have been associated with the development of several diseases including chronic inflammation-driven cancers.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('inflammation', 'biological_process', 'GO:0006954', ('111', '123'))	('Deregulated epigenetic changes', 'Var', (0, 30))	('associated', 'Reg', (41, 51))	('inflammation-driven cancers', 'Disease', 'MESH:D007249', (111, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('inflammation-driven cancers', 'Disease', (111, 138))	('men', 'Species', '9606', (68, 71))
380	29934362	In cancer cells, numerous epigenetic alterations are observed in genes regulating cell cycle, oncogenes, tumor suppressor genes, and apoptosis related genes, such as aberrant methylation or acetylation of the histones and/or DNA.	('acetylation', 'MPA', (190, 201))	('cell', 'CPA', (82, 86))	('aberrant methylation', 'Var', (166, 186))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('apoptosis related genes', 'Gene', (133, 156))	('epigenetic alterations', 'Var', (26, 48))	('cancer', 'Disease', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('histones', 'Protein', (209, 217))	('tumor', 'Disease', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
385	29934362	H2A monoubiquitination on K119 plays a role in transcriptional silencing of polycomb proteins and in genome maintenance compared with H2B, which is ubiquitinated at K120.	('H2B', 'Gene', (134, 137))	('polycomb proteins', 'Protein', (76, 93))	('H2A', 'Gene', (0, 3))	('H2B', 'Gene', '8349', (134, 137))	('K120', 'Chemical', '-', (165, 169))	('transcriptional', 'MPA', (47, 62))	('genome maintenance', 'CPA', (101, 119))	('silencing', 'NegReg', (63, 72))	('H2A', 'Gene', '8337', (0, 3))	('monoubiquitination', 'Var', (4, 22))
389	29934362	In eukaryotic cells, RNF20/RNF40 can exclusively monoubiquitinate K120 on histone H2B.	('monoubiquitinate', 'MPA', (49, 65))	('histone H2B', 'Protein', (74, 85))	('RNF40', 'Gene', (27, 32))	('RNF40', 'Gene', '9810', (27, 32))	('K120', 'Var', (66, 70))	('K120', 'Chemical', '-', (66, 70))
393	29934362	Aberrant H2Bub1 is the key to initiation of malignant transformation and directly influences chromatin structure beyond the level of the single nucleosome.	('influences', 'Reg', (82, 92))	('Aberrant', 'Var', (0, 8))	('H2Bub1', 'Gene', '8349', (9, 15))	('malignant transformation', 'CPA', (44, 68))	('chromatin structure', 'MPA', (93, 112))	('H2Bub1', 'Gene', (9, 15))
395	29934362	Deregulation in any of these process leads to the development of tumors, as evidenced with hypermethylation of RNF20 promoters in breast tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('RNF20', 'Gene', (111, 116))	('Deregulation', 'Var', (0, 12))	('breast tumor', 'Phenotype', 'HP:0100013', (130, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('hypermethylation', 'Var', (91, 107))	('breast tumor', 'Disease', 'MESH:D001943', (130, 142))	('men', 'Species', '9606', (57, 60))	('leads to', 'Reg', (37, 45))	('breast tumor', 'Disease', (130, 142))
396	29934362	Mutations in cell division cycle 73 (CDC73) lead to loss of maintenance of H2Bub1 PTM both in vitro and in vivo.	('loss', 'NegReg', (52, 56))	('H2Bub1', 'Gene', (75, 81))	('CDC73', 'Gene', (37, 42))	('CDC73', 'Gene', '79577', (37, 42))	('Mutations', 'Var', (0, 9))	('maintenance of', 'MPA', (60, 74))	('H2Bub1', 'Gene', '8349', (75, 81))
397	29934362	Abnormally regulated or mutated CDC73 has been reported in several tumors such as breast, colorectal, gastric, parathyroid, renal, and in patients with familial disorder-hyperparathyroidism jaw tumor syndrome.	('mutated', 'Var', (24, 31))	('parathyroid', 'Disease', (111, 122))	('patients', 'Species', '9606', (138, 146))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (170, 189))	('gastric', 'Disease', (102, 109))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('jaw tumor', 'Phenotype', 'HP:0030792', (190, 199))	('renal', 'Disease', (124, 129))	('breast', 'Disease', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('CDC73', 'Gene', (32, 37))	('CDC73', 'Gene', '79577', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('familial disorder-hyperparathyroidism jaw tumor syndrome', 'Disease', 'MESH:C563273', (152, 208))	('tumors', 'Disease', (67, 73))	('reported', 'Reg', (47, 55))	('colorectal', 'Disease', (90, 100))
399	29934362	Deregulated expression and hyperactivation of deubiquitination enzymes also upset the overall expression of H2Bub1.	('hyperactivation of deubiquitination', 'Disease', (27, 62))	('Deregulated', 'Var', (0, 11))	('H2Bub1', 'Gene', '8349', (108, 114))	('H2Bub1', 'Gene', (108, 114))	('deubiquitination', 'biological_process', 'GO:0016579', ('46', '62'))	('expression', 'MPA', (94, 104))	('upset', 'Reg', (76, 81))	('expression', 'MPA', (12, 22))	('hyperactivation of deubiquitination', 'Disease', 'MESH:D011504', (27, 62))
419	29934362	(2016) showed that RNF20 depletion with a concomitant reduction in H2Bub1 augments tumor necrosis factor-induced activation of NF-kappaB and its subsequent pro-inflammatory cytokine and chemokine genes.	('necrosis', 'Disease', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('augments', 'PosReg', (74, 82))	('pro-inflammatory cytokine', 'MPA', (156, 181))	('reduction', 'NegReg', (54, 63))	('tumor', 'Disease', (83, 88))	('NF-kappaB', 'Gene', '4790', (127, 136))	('RNF20', 'Gene', (19, 24))	('necrosis', 'Disease', 'MESH:D009336', (89, 97))	('men', 'Species', '9606', (77, 80))	('activation', 'PosReg', (113, 123))	('H2Bub1', 'Gene', '8349', (67, 73))	('NF-kappaB', 'Gene', (127, 136))	('depletion', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('H2Bub1', 'Gene', (67, 73))
421	29934362	In vivo RNF20+/- mice were shown to be predisposed to acute and chronic colonic inflammation and development of colorectal cancer.	('colorectal cancer', 'Disease', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('colonic inflammation', 'Disease', 'MESH:D007249', (72, 92))	('mice', 'Species', '10090', (17, 21))	('colonic inflammation', 'Disease', (72, 92))	('men', 'Species', '9606', (104, 107))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('inflammation', 'biological_process', 'GO:0006954', ('80', '92'))	('chronic colonic inflammation', 'Phenotype', 'HP:0100281', (64, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('predisposed', 'Reg', (39, 50))	('RNF20+/-', 'Var', (8, 16))
423	29934362	Genetic instability has been identified to play a critical role in the development of colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('Genetic instability', 'Var', (0, 19))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('colorectal cancer', 'Disease', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('men', 'Species', '9606', (78, 81))
424	29934362	(2008) for the first time identified five genes SMC1L1 (two independent mutations), CSPG6, NIPBL, STAG3, and RNF20 involved in sister chromatid cohesion and mutations in these genes can lead to chromosome instability in colorectal cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (220, 237))	('sister chromatid cohesion', 'biological_process', 'GO:0007062', ('127', '152'))	('CSPG6', 'Gene', (84, 89))	('chromosome instability', 'Phenotype', 'HP:0040012', (194, 216))	('chromatid', 'cellular_component', 'GO:0005694', ('134', '143'))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('SMC1L1', 'Gene', (48, 54))	('mutations', 'Var', (157, 166))	('colorectal cancers', 'Disease', (220, 238))	('SMC1L1', 'Gene', '8243', (48, 54))	('STAG3', 'Gene', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('chromatid', 'cellular_component', 'GO:0005695', ('134', '143'))	('NIPBL', 'Gene', '25836', (91, 96))	('NIPBL', 'Gene', (91, 96))	('chromosome', 'cellular_component', 'GO:0005694', ('194', '204'))	('lead to', 'Reg', (186, 193))	('chromosome instability', 'CPA', (194, 216))	('STAG3', 'Gene', '10734', (98, 103))	('SMC', 'cellular_component', 'GO:0016029', ('48', '51'))	('colorectal cancers', 'Disease', 'MESH:D015179', (220, 238))	('CSPG6', 'Gene', '9126', (84, 89))	('RNF20', 'Gene', (109, 114))
428	29934362	The RNF20/40 heterodimeric complex is a known major E3 ligase that is responsible for H2Bub1 on K120 and also facilitates H3 methylation on K4 and K79, thereby regulating transcription.	('transcription', 'MPA', (171, 184))	('regulating', 'Reg', (160, 170))	('K120', 'Chemical', '-', (96, 100))	('H2Bub1', 'Gene', '8349', (86, 92))	('facilitates', 'PosReg', (110, 121))	('H2Bub1', 'Gene', (86, 92))	('K120', 'Var', (96, 100))	('K79', 'Gene', (147, 150))	('K79', 'Gene', '338785', (147, 150))
432	29934362	Furthermore, athymic nude mice receiving MCF-7 cells infected by lentiviruses carrying empty vectors or MCF-7 cells with lentivirus-delivered Eg5, RNF20, or RNF40 knockdown, the tumor growth was significantly suppressed compared with control mice, suggesting that an RNF20/40-Eg5 axis is involved in breast carcinogenesis.	('RNF20', 'Gene', (147, 152))	('RNF40', 'Gene', '9810', (157, 162))	('tumor', 'Disease', (178, 183))	('RNF40', 'Gene', (157, 162))	('knockdown', 'Var', (163, 172))	('suppressed', 'NegReg', (209, 219))	('MCF-7', 'CellLine', 'CVCL:0031', (41, 46))	('breast carcinogenesis', 'Disease', (300, 321))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('MCF-7', 'CellLine', 'CVCL:0031', (104, 109))	('nude mice', 'Species', '10090', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('mice', 'Species', '10090', (242, 246))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (300, 321))	('mice', 'Species', '10090', (26, 30))
437	29934362	RNF20 knockdown significantly reduces H2Bub1 expression and promotes migration in both breast cancer cells and in non-transformed mammary epithelial cells.	('promotes', 'PosReg', (60, 68))	('H2Bub1', 'Gene', '8349', (38, 44))	('H2Bub1', 'Gene', (38, 44))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('expression', 'MPA', (45, 55))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('knockdown', 'Var', (6, 15))	('reduces', 'NegReg', (30, 37))	('RNF20', 'Gene', (0, 5))	('migration', 'CPA', (69, 78))
439	29934362	Silencing of RNF20 in breast cancer cells can function as a tumor promoter.	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('RNF20', 'Gene', (13, 18))	('tumor', 'Disease', (60, 65))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
440	29934362	It was found that depletion of RNF20 increased breast cancer cell proliferation and migration potential.	('RNF20', 'Gene', (31, 36))	('breast cancer', 'Disease', (47, 60))	('migration potential', 'CPA', (84, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('depletion', 'Var', (18, 27))	('increased', 'PosReg', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
441	29934362	It is of note that RNF20 promotes CpG island hypermethylation in several breast cancers and that down-regulation of H2B ubiquitination promotes tumorigenesis.	('H2B', 'Gene', (116, 119))	('down-regulation', 'NegReg', (97, 112))	('RNF20', 'Gene', (19, 24))	('ubiquitination', 'MPA', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('regulation', 'biological_process', 'GO:0065007', ('102', '112'))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('tumor', 'Disease', (144, 149))	('hypermethylation', 'Var', (45, 61))	('promotes', 'PosReg', (25, 33))	('H2B', 'Gene', '8349', (116, 119))	('breast cancers', 'Disease', 'MESH:D001943', (73, 87))	('breast cancers', 'Disease', (73, 87))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('breast cancers', 'Phenotype', 'HP:0003002', (73, 87))	('promotes', 'PosReg', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('CpG island', 'Protein', (34, 44))
442	29934362	In NIH3T3 mouse cells, RNF20 silencing up-regulated formation of colonies in soft agar, indicating neoplastic transformation of cells.	('mouse', 'Species', '10090', (10, 15))	('agar', 'Chemical', 'MESH:D000362', (82, 86))	('NIH3T3', 'CellLine', 'CVCL:0594', (3, 9))	('silencing', 'Var', (29, 38))	('colon', 'Disease', (65, 70))	('RNF20', 'Gene', (23, 28))	('up-regulated', 'PosReg', (39, 51))	('neoplastic transformation', 'CPA', (99, 124))	('colon', 'Disease', 'MESH:D015179', (65, 70))
444	29934362	The mixed-lineage leukemia (MLL) proto-oncogene MLL1 was found to be involved in chromosomal translocations occurring frequently in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), infant acute leukemia, and in patients treated with topoisomerase II inhibitors.	('ALL', 'Phenotype', 'HP:0006721', (192, 195))	('leukemia', 'Disease', 'MESH:D007938', (18, 26))	('MLL1', 'Gene', '4297', (48, 52))	('leukemia', 'Disease', (18, 26))	('chromosomal translocations', 'Var', (81, 107))	('acute leukemia', 'Phenotype', 'HP:0002488', (205, 219))	('MLL1', 'Gene', (48, 52))	('leukemia', 'Phenotype', 'HP:0001909', (182, 190))	('patients', 'Species', '9606', (228, 236))	('MLL', 'Gene', (48, 51))	('acute lymphoblastic leukemia', 'Disease', (162, 190))	('MLL', 'Gene', '4297', (48, 51))	('leukemia', 'Phenotype', 'HP:0001909', (211, 219))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (162, 190))	('acute myeloid leukemia', 'Disease', (132, 154))	('leukemia', 'Disease', 'MESH:D007938', (182, 190))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (162, 190))	('involved', 'Reg', (69, 77))	('leukemia', 'Disease', (182, 190))	('leukemia', 'Phenotype', 'HP:0001909', (146, 154))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (138, 154))	('leukemia', 'Disease', (211, 219))	('leukemia', 'Disease', 'MESH:D007938', (211, 219))	('AML', 'Disease', 'MESH:D015470', (156, 159))	('AML', 'Phenotype', 'HP:0004808', (156, 159))	('AML', 'Disease', (156, 159))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (132, 154))	('MLL', 'Gene', (28, 31))	('infant', 'Species', '9606', (198, 204))	('leukemia', 'Disease', 'MESH:D007938', (146, 154))	('MLL', 'Gene', '4297', (28, 31))	('leukemia', 'Phenotype', 'HP:0001909', (18, 26))	('leukemia', 'Disease', (146, 154))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (168, 190))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (132, 154))
445	29934362	MLL rearrangements initiate aggressive forms of acute leukemia and are associated with poor outcome.	('acute leukemia', 'Phenotype', 'HP:0002488', (48, 62))	('men', 'Species', '9606', (13, 16))	('rearrangements', 'Var', (4, 18))	('leukemia', 'Phenotype', 'HP:0001909', (54, 62))	('MLL', 'Gene', '4297', (0, 3))	('MLL', 'Gene', (0, 3))	('initiate', 'Reg', (19, 27))	('leukemia', 'Disease', (54, 62))	('leukemia', 'Disease', 'MESH:D007938', (54, 62))
448	29934362	Suppression of RNF20 slowed down leukemia progression in an in vivo animal model and was associated with down-regulation of the MLL-AF9 target gene.	('down-regulation', 'NegReg', (105, 120))	('slowed down', 'NegReg', (21, 32))	('Suppression', 'Var', (0, 11))	('MLL', 'Gene', '4297', (128, 131))	('RNF20', 'Gene', (15, 20))	('AF9', 'Gene', '4300', (132, 135))	('regulation', 'biological_process', 'GO:0065007', ('110', '120'))	('MLL', 'Gene', (128, 131))	('AF9', 'Gene', (132, 135))	('leukemia', 'Phenotype', 'HP:0001909', (33, 41))	('leukemia', 'Disease', 'MESH:D007938', (33, 41))	('leukemia', 'Disease', (33, 41))
457	29934362	Interestingly, genes encoding polycomb group protein BMI-1 and EZH2 are found to be amplified in metastatic prostate cancer, with a concomitant increase in levels of H2Aub1 and H3K27me3.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('EZH2', 'Gene', '2146', (63, 67))	('polycomb group protein BMI-1', 'Gene', (30, 58))	('prostate cancer', 'Disease', 'MESH:D011471', (108, 123))	('H3K27me3', 'Var', (177, 185))	('levels', 'MPA', (156, 162))	('prostate cancer', 'Phenotype', 'HP:0012125', (108, 123))	('EZH2', 'Gene', (63, 67))	('H2A', 'Gene', '8337', (166, 169))	('protein', 'cellular_component', 'GO:0003675', ('45', '52'))	('amplified', 'PosReg', (84, 93))	('H2A', 'Gene', (166, 169))	('polycomb group protein BMI-1', 'Gene', '648', (30, 58))	('increase', 'PosReg', (144, 152))	('prostate cancer', 'Disease', (108, 123))
459	29934362	In a previous study, it was shown that RNF20 and RNF40 interact with androgen receptor and modulate its transcritpional activity in androgen-dependent LNCaP prostate cancer cells, and depletion of RNF20 or RNF40 is strongly correlated with inhibition of LNCaP cell proliferation and a reduction in H2Bub1 levels.	('inhibition', 'NegReg', (240, 250))	('reduction', 'NegReg', (285, 294))	('RNF20', 'Var', (197, 202))	('interact', 'Interaction', (55, 63))	('modulate', 'Reg', (91, 99))	('RNF40', 'Gene', '9810', (206, 211))	('LNCaP', 'CellLine', 'CVCL:0395', (151, 156))	('cell proliferation', 'biological_process', 'GO:0008283', ('260', '278'))	('androgen receptor', 'Gene', (69, 86))	('transcritpional activity', 'MPA', (104, 128))	('androgen receptor', 'Gene', '367', (69, 86))	('RNF40', 'Gene', (49, 54))	('depletion', 'Var', (184, 193))	('H2Bub1', 'Gene', '8349', (298, 304))	('H2Bub1', 'Gene', (298, 304))	('LNCaP cell proliferation', 'CPA', (254, 278))	('RNF40', 'Gene', (206, 211))	('RNF20', 'Gene', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('LNCaP prostate cancer', 'Disease', (151, 172))	('prostate cancer', 'Phenotype', 'HP:0012125', (157, 172))	('RNF40', 'Gene', '9810', (49, 54))	('LNCaP', 'CellLine', 'CVCL:0395', (254, 259))	('LNCaP prostate cancer', 'Disease', 'MESH:D011471', (151, 172))
462	29934362	Using human lung cancer A549, H1299, and H460 cell lines, and normal lung epithelial cells, suppression of H2Bub1 by RNF20 knockdown was associated with significant decrease in H3K4 and H3K79 trimethylation.	('lung cancer A549', 'Disease', (12, 28))	('RNF20', 'Gene', (117, 122))	('human', 'Species', '9606', (6, 11))	('H3K4', 'Protein', (177, 181))	('H2Bub1', 'Gene', '8349', (107, 113))	('H460', 'CellLine', 'CVCL:0459', (41, 45))	('decrease', 'NegReg', (165, 173))	('trimethylation', 'MPA', (192, 206))	('lung cancer A549', 'Disease', 'MESH:D008175', (12, 28))	('H1299', 'CellLine', 'CVCL:0060', (30, 35))	('suppression', 'NegReg', (92, 103))	('K79', 'Gene', (188, 191))	('H2Bub1', 'Gene', (107, 113))	('K79', 'Gene', '338785', (188, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (12, 23))	('knockdown', 'Var', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
463	29934362	It was also observed that RNF20 knockdown and down-regulation of H2Bub1 affect several cellular signaling pathways and enhanced proliferation, migration, invasion, and cisplatin resistance of these cells.	('cisplatin', 'Chemical', 'MESH:D002945', (168, 177))	('affect', 'Reg', (72, 78))	('down-regulation', 'NegReg', (46, 61))	('H2Bub1', 'Gene', '8349', (65, 71))	('cisplatin resistance', 'CPA', (168, 188))	('knockdown', 'Var', (32, 41))	('cellular signaling pathways', 'Pathway', (87, 114))	('invasion', 'CPA', (154, 162))	('proliferation', 'CPA', (128, 141))	('H2Bub1', 'Gene', (65, 71))	('RNF20', 'Gene', (26, 31))	('migration', 'CPA', (143, 152))	('enhanced', 'PosReg', (119, 127))
465	29934362	The present study, has for the first time demonstrated that loss of H2Bub1 is associated with enhanced malignancy and poor differentiation of lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('poor differentiation', 'CPA', (118, 138))	('malignancy', 'Disease', 'MESH:D009369', (103, 113))	('H2Bub1', 'Gene', (68, 74))	('malignancy', 'Disease', (103, 113))	('lung adenocarcinoma', 'Disease', (142, 161))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (142, 161))	('loss', 'Var', (60, 64))	('enhanced', 'PosReg', (94, 102))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (142, 161))	('H2Bub1', 'Gene', '8349', (68, 74))
480	29934362	In addition, tumor-associated mutant p53 has been shown to bind and transcriptionally activate SREBP2 and activate the mevalonate pathway; it is highly possible that p53 and SREBPs may potentially regulate each other.	('tumor', 'Disease', (13, 18))	('mevalonate', 'Chemical', 'MESH:D008798', (119, 129))	('SREBP', 'Gene', (95, 100))	('SREBP', 'Gene', (174, 179))	('activate', 'PosReg', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('SREBP', 'Gene', '7555', (95, 100))	('SREBP', 'Gene', '7555', (174, 179))	('mevalonate pathway', 'Pathway', (119, 137))	('p53', 'Gene', '7157', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('activate', 'PosReg', (106, 114))	('p53', 'Gene', (166, 169))	('p53', 'Gene', '7157', (37, 40))	('mutant', 'Var', (30, 36))	('SREBP2', 'Gene', (95, 101))	('p53', 'Gene', (37, 40))	('SREBP2', 'Gene', '6721', (95, 101))	('bind', 'Interaction', (59, 63))
487	29934362	In yeast, the BRE1 mutant showed higher sensitivity to ionizing radiation and was associated with RAD51, a key molecule in homologous recombination repair.	('higher', 'PosReg', (33, 39))	('associated', 'Reg', (82, 92))	('sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (40, 73))	('RAD', 'biological_process', 'GO:1990116', ('98', '101'))	('BRE1', 'Gene', (14, 18))	('mutant', 'Var', (19, 25))	('yeast', 'Species', '4932', (3, 8))	('RAD51', 'Gene', (98, 103))	('homologous recombination', 'biological_process', 'GO:0035825', ('123', '147'))	('sensitivity', 'MPA', (40, 51))
492	29934362	Mutated or defective NBS1 potentiates cell death upon ionizing radiation due to impaired homologous recombination and NHEJ repair mechanisms.	('homologous recombination', 'CPA', (89, 113))	('NBS1', 'Gene', '4683', (21, 25))	('impaired', 'NegReg', (80, 88))	('defective', 'Var', (11, 20))	('cell death', 'CPA', (38, 48))	('NBS1', 'Gene', (21, 25))	('potentiates', 'PosReg', (26, 37))	('Mutated', 'Var', (0, 7))
496	29934362	Silencing of RNF20 by si/shRNA in cells augmented ionizing radiation and DNA damaging agents such as camptothecin, neocarzinostatin, and mitomycin C, with severe impairment of DNA repair mechanisms.	('DNA', 'cellular_component', 'GO:0005574', ('176', '179'))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('ionizing radiation', 'CPA', (50, 68))	('mitomycin C', 'Chemical', 'MESH:D016685', (137, 148))	('Silencing', 'Var', (0, 9))	('DNA repair', 'biological_process', 'GO:0006281', ('176', '186'))	('neocarzinostatin', 'Chemical', 'MESH:D009353', (115, 131))	('camptothecin', 'Chemical', 'MESH:D002166', (101, 113))	('men', 'Species', '9606', (43, 46))	('si/shRNA', 'Var', (22, 30))	('RNF20', 'Gene', (13, 18))	('augmented', 'PosReg', (40, 49))	('men', 'Species', '9606', (168, 171))
497	29934362	Moreover, overexpression of mutant H2B and silencing of RNF20 did not have any additional effect on cells, indicating that RNF20 functions by ubiquitinating H2B in DSB repair.	('RNF20', 'Gene', (56, 61))	('mutant', 'Var', (28, 34))	('H2B', 'Gene', (157, 160))	('DSB', 'Disease', (164, 167))	('H2B', 'Gene', (35, 38))	('silencing', 'Var', (43, 52))	('H2B', 'Gene', '8349', (157, 160))	('ubiquitinating', 'MPA', (142, 156))	('H2B', 'Gene', '8349', (35, 38))	('RNF20', 'Gene', (123, 128))
498	29934362	(2011) showed that H2B ubiquitination obstructs chromatin compaction, resulting in an open and biochemically accessible fiber conformation.	('ubiquitination', 'Var', (23, 37))	('obstructs', 'NegReg', (38, 47))	('H2B', 'Gene', '8349', (19, 22))	('chromatin', 'MPA', (48, 57))	('H2B', 'Gene', (19, 22))
508	29934362	(2018) showed that abrogation of RNF20 is strongly associated with suppression of H2Bub1 and DNA transcription.	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('H2Bub1', 'Gene', (82, 88))	('suppression', 'NegReg', (67, 78))	('RNF20', 'Gene', (33, 38))	('abrogation', 'Var', (19, 29))	('DNA transcription', 'MPA', (93, 110))	('transcription', 'biological_process', 'GO:0006351', ('97', '110'))	('H2Bub1', 'Gene', '8349', (82, 88))
514	29934362	Deregulated epigenetic changes have been implicated in the development of several inflammation-driven diseases, including cancer.	('men', 'Species', '9606', (66, 69))	('Deregulated epigenetic changes', 'Var', (0, 30))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('implicated', 'Reg', (41, 51))	('inflammation', 'Disease', 'MESH:D007249', (82, 94))	('inflammation', 'Disease', (82, 94))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('inflammation', 'biological_process', 'GO:0006954', ('82', '94'))
519	29934362	Interestingly, RNF20 depletion has been shown to enhance NF-kappaB-dependent gene transcription, and TNF-mediated H2Bub1 down-regulation augments NF-kappaB's response in the up-regulation of proinflammatory cytokines or chemokines that may act in an autocrine or paracrine fashion to sustain the prosurvival gene expression in cancer cells.	('men', 'Species', '9606', (140, 143))	('cancer', 'Disease', (327, 333))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('NF-kappaB', 'Gene', (57, 66))	('down-regulation augments', 'NegReg', (121, 145))	('enhance', 'PosReg', (49, 56))	('TNF', 'Gene', (101, 104))	('H2Bub1', 'Gene', '8349', (114, 120))	('NF-kappaB', 'Gene', '4790', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('RNF20', 'Gene', (15, 20))	('depletion', 'Var', (21, 30))	('TNF', 'Gene', '7124', (101, 104))	('H2Bub1', 'Gene', (114, 120))	('up-regulation', 'PosReg', (174, 187))	('NF-kappaB', 'Gene', (146, 155))	('NF-kappaB', 'Gene', '4790', (57, 66))
616	26504848	An exhaustive search of PubMed was performed on March, 2014, with combinations of the following terms: "rectal cancer," "response," "prediction," "microarray," "gene expression," "mi-RNA," and "ln- RNA."	('mi', 'Chemical', 'MESH:C011506', (180, 182))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('rectal cancer', 'Disease', 'MESH:D012004', (104, 117))	('mi-RNA', 'Var', (180, 186))	('rectal cancer', 'Disease', (104, 117))	('rectal cancer', 'Phenotype', 'HP:0100743', (104, 117))	('mi', 'Chemical', 'MESH:C011506', (147, 149))
652	26504848	Tumor response was assessed in surgical specimens by pathological examination based on Mandard's tumor regression grading (TRG) system: TRG 1 and TRG 2 scores were considered responders, whereas TRG 3, TRG 4, and TRG 5 scores were classified as nonresponders.	('TRG 2', 'Gene', '7196', (146, 151))	('TRG 2', 'Gene', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mi', 'Chemical', 'MESH:C011506', (69, 71))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('TRG 1', 'Gene', '7195', (136, 141))	('TRG 4', 'Gene', (202, 207))	('TRG 1', 'Gene', (136, 141))	('TRG 3', 'Gene', (195, 200))	('tumor', 'Disease', (97, 102))	('TRG 5', 'Gene', '7198', (213, 218))	('TRG 3', 'Gene', '7197', (195, 200))	('TRG 4', 'Gene', '64717', (202, 207))	('scores', 'Var', (152, 158))	('TRG 5', 'Gene', (213, 218))
668	26504848	The top 10 downregulated genes included LOC729399, SERINC5, SCNN1B, ZC3H6, SLC4A4, DTWD2, MS4A12, BEX5, MMRN1, and CLCA4.	('DTWD2', 'Gene', (83, 88))	('BEX5', 'Gene', '340542', (98, 102))	('downregulated', 'NegReg', (11, 24))	('ZC3H6', 'Gene', '376940', (68, 73))	('ZC3H6', 'Gene', (68, 73))	('MS4A12', 'Gene', (90, 96))	('BEX5', 'Gene', (98, 102))	('SERINC5', 'Gene', '256987', (51, 58))	('MS4A12', 'Gene', '54860', (90, 96))	('SLC4A4', 'Gene', (75, 81))	('MMRN1', 'Gene', '22915', (104, 109))	('SCNN1B', 'Gene', (60, 66))	('CLCA4', 'Gene', '22802', (115, 120))	('SLC4A4', 'Gene', '8671', (75, 81))	('LOC729399', 'Var', (40, 49))	('DTWD2', 'Gene', '285605', (83, 88))	('CLCA4', 'Gene', (115, 120))	('MMRN1', 'Gene', (104, 109))	('SCNN1B', 'Gene', '6338', (60, 66))	('SERINC5', 'Gene', (51, 58))
695	26504848	The aberrant expression of miRNA is involved in numerous pathologies and some alterations in its regulation have been associated with colorectal cancer.	('miRNA', 'Gene', (27, 32))	('colorectal cancer', 'Disease', (134, 151))	('aberrant', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('regulation', 'MPA', (97, 107))	('alterations', 'Reg', (78, 89))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('rectal cancer', 'Phenotype', 'HP:0100743', (138, 151))	('associated', 'Reg', (118, 128))	('involved', 'Reg', (36, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))	('mi', 'Chemical', 'MESH:C011506', (27, 29))
696	26504848	Furthermore, it has been determined that CRT in LARC can induce alterations in the expression of miRNA in normal tissue samples and these have been associated with positive response to treatment.	('miRNA', 'Protein', (97, 102))	('mi', 'Chemical', 'MESH:C011506', (97, 99))	('mi', 'Chemical', 'MESH:C011506', (30, 32))	('alterations', 'Reg', (64, 75))	('expression', 'MPA', (83, 93))	('CRT', 'Var', (41, 44))
701	26504848	Following a pilot study of normal mucosa biopsies researchers found that microRNAs mi-R125b and mi-R137 showed significant induction and exhibited the same expression trends in most samples two weeks after starting therapy, so they were chosen for further analysis in the total sample set.	('mi', 'Chemical', 'MESH:C011506', (96, 98))	('mi', 'Chemical', 'MESH:C011506', (83, 85))	('induction', 'PosReg', (123, 132))	('mi', 'Chemical', 'MESH:C011506', (73, 75))	('mi-R137', 'Gene', (96, 103))	('mi-R137', 'Gene', '406928', (96, 103))	('mi-R125b', 'Var', (83, 91))
704	26504848	MiR125b is downregulated in several cancers and thought to act as a tumor suppressor.	('tumor', 'Disease', (68, 73))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('MiR125b', 'Chemical', '-', (0, 7))	('MiR125b', 'Var', (0, 7))	('downregulated', 'NegReg', (11, 24))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
705	26504848	In this study, tumors with the highest upregulation of mi-R125b level two weeks after starting therapy showed no downstaging and less regression (poor response).	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('mi', 'Chemical', 'MESH:C011506', (55, 57))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('upregulation', 'PosReg', (39, 51))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('mi-R125b', 'Var', (55, 63))
707	26504848	Researchers concluded that higher induced levels of mi-R125b and mi-R137 were associated with a worse response to the therapy.	('mi-R125b', 'Var', (52, 60))	('mi', 'Chemical', 'MESH:C011506', (65, 67))	('mi-R137', 'Gene', (65, 72))	('mi-R137', 'Gene', '406928', (65, 72))	('mi', 'Chemical', 'MESH:C011506', (52, 54))
709	26504848	The team took biopsies from 35 patients affected by rectal cancer T3-4/N+ prior to the initiation of radiotherapy (45 Gy) combined with capecitabine and oxaliplatin.	('capecitabine', 'Chemical', 'MESH:D000069287', (136, 148))	('T3-4/N+', 'Var', (66, 73))	('rectal cancer', 'Disease', 'MESH:D012004', (52, 65))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (153, 164))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('rectal cancer', 'Disease', (52, 65))	('patients', 'Species', '9606', (31, 39))	('rectal cancer', 'Phenotype', 'HP:0100743', (52, 65))
715	26504848	They identified three RNAs associated with complete response (miR-16, miR-153, and miR-590-5p), employing Mansard's tumor regression grade for quantification and two (miR-519c-3p and miR-561) that predicted good versus poor response, with exactness close to 100%.	('miR-590-5p', 'Var', (83, 93))	('miR-561', 'Gene', (183, 190))	('mi', 'Chemical', 'MESH:C011506', (62, 64))	('mi', 'Chemical', 'MESH:C011506', (70, 72))	('mi', 'Chemical', 'MESH:C011506', (83, 85))	('miR-16', 'Gene', (62, 68))	('mi', 'Chemical', 'MESH:C011506', (183, 185))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('miR-561', 'Gene', '693146', (183, 190))	('miR-16', 'Gene', '51573', (62, 68))	('mi', 'Chemical', 'MESH:C011506', (167, 169))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('miR-519c-3p', 'Var', (167, 178))	('tumor', 'Disease', (116, 121))	('miR-153', 'Var', (70, 77))
723	26504848	Three of them (miR-215, miR190b, and miR-29b-2) were overexpressed, while the other five (let7e, miR-196b, miR-450a, miR-450b-5p, and miR-99a) showed lower expression levels in nonresponders.	('miR-29b-2', 'Gene', '407025', (37, 46))	('mi', 'Chemical', 'MESH:C011506', (97, 99))	('mi', 'Chemical', 'MESH:C011506', (134, 136))	('miR-450b-5p', 'Var', (117, 128))	('miR-450a', 'Var', (107, 115))	('miR190b', 'Gene', (24, 31))	('miR-99a', 'Gene', '407055', (134, 141))	('mi', 'Chemical', 'MESH:C011506', (117, 119))	('mi', 'Chemical', 'MESH:C011506', (24, 26))	('miR-29b-2', 'Gene', (37, 46))	('miR-215', 'Gene', '406997', (15, 22))	('mi', 'Chemical', 'MESH:C011506', (37, 39))	('expression levels', 'MPA', (156, 173))	('miR-196b', 'Gene', '442920', (97, 105))	('mi', 'Chemical', 'MESH:C011506', (15, 17))	('miR190b', 'Gene', '100126346', (24, 31))	('let7e', 'Gene', (90, 95))	('mi', 'Chemical', 'MESH:C011506', (107, 109))	('miR-215', 'Gene', (15, 22))	('let7e', 'Gene', '406887', (90, 95))	('lower', 'NegReg', (150, 155))	('miR-99a', 'Gene', (134, 141))	('miR-196b', 'Gene', (97, 105))	('overexpressed', 'PosReg', (53, 66))
725	26504848	Five of them (miR-215, miR-99a*, miR-196b, miR-450b-5p, and let-7e) were previously correlated with radioresistance or chemoresistance to thymidylate synthase inhibitors.	('miR-99a', 'Gene', (23, 30))	('let-7e', 'Gene', '406887', (60, 66))	('mi', 'Chemical', 'MESH:C011506', (141, 143))	('mi', 'Chemical', 'MESH:C011506', (23, 25))	('miR-196b', 'Gene', '442920', (33, 41))	('thymidylate synthase', 'Gene', (138, 158))	('miR-215', 'Gene', '406997', (14, 21))	('miR-99a', 'Gene', '407055', (23, 30))	('thymidylate synthase', 'Gene', '7298', (138, 158))	('mi', 'Chemical', 'MESH:C011506', (14, 16))	('mi', 'Chemical', 'MESH:C011506', (43, 45))	('miR-215', 'Gene', (14, 21))	('radioresistance', 'CPA', (100, 115))	('correlated', 'Reg', (84, 94))	('miR-450b-5p', 'Var', (43, 54))	('mi', 'Chemical', 'MESH:C011506', (33, 35))	('miR-196b', 'Gene', (33, 41))	('chemoresistance', 'CPA', (119, 134))	('let-7e', 'Gene', (60, 66))
727	26504848	The let-7 family of miRNAs (let-7a through let-7h) regulates expression of key oncogenes, such as RAS and MYC, and is specifically downregulated in many cancer types.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('let-7h', 'Var', (43, 49))	('mi', 'Chemical', 'MESH:C011506', (12, 14))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('RAS', 'Disease', (98, 101))	('regulates', 'Reg', (51, 60))	('MYC', 'Disease', (106, 109))	('downregulated', 'NegReg', (131, 144))	('mi', 'Chemical', 'MESH:C011506', (20, 22))	('let-7a', 'Var', (28, 34))	('expression', 'MPA', (61, 71))
737	26504848	Response to CRT was evaluated by three parameters:  With regard to the histopathological examination of surgically resected specimens, two genes are differentially expressed at significant levels in responders and nonresponders (miR-223 and miR-142-3p), with responders showing higher expression in comparison to nonresponders.	('mi', 'Chemical', 'MESH:C011506', (241, 243))	('miR-223', 'Gene', '407008', (229, 236))	('expression', 'MPA', (285, 295))	('mi', 'Chemical', 'MESH:C011506', (92, 94))	('mi', 'Chemical', 'MESH:C011506', (229, 231))	('higher', 'PosReg', (278, 284))	('miR-223', 'Gene', (229, 236))	('miR-142-3p', 'Var', (241, 251))
738	26504848	Nine genes were differentially expressed at significant levels with regard to RECIST: one (miR-223) showed a higher expression, while eight showed a lower expression (miR-20b, miR-92a, let-7a*, miR-20a, miR-17*, miR-106a, miR-17, and miR-20a*) in responders compared to nonresponders.	('miR-223', 'Gene', '407008', (91, 98))	('miR-20a', 'Gene', (234, 241))	('miR-20a', 'Gene', '406982', (234, 241))	('mi', 'Chemical', 'MESH:C011506', (222, 224))	('miR-17', 'Gene', '406952', (222, 228))	('miR-20a', 'Gene', (194, 201))	('miR-20a', 'Gene', '406982', (194, 201))	('miR-106a', 'Gene', '406899', (212, 220))	('higher', 'PosReg', (109, 115))	('miR-20b', 'Gene', '574032', (167, 174))	('mi', 'Chemical', 'MESH:C011506', (203, 205))	('mi', 'Chemical', 'MESH:C011506', (212, 214))	('miR-17', 'Gene', '406952', (203, 209))	('let-7a*', 'Var', (185, 192))	('miR-17', 'Gene', (222, 228))	('mi', 'Chemical', 'MESH:C011506', (91, 93))	('miR-223', 'Gene', (91, 98))	('mi', 'Chemical', 'MESH:C011506', (234, 236))	('mi', 'Chemical', 'MESH:C011506', (176, 178))	('expression', 'MPA', (116, 126))	('miR-92a', 'Var', (176, 183))	('expression', 'MPA', (155, 165))	('mi', 'Chemical', 'MESH:C011506', (194, 196))	('miR-106a', 'Gene', (212, 220))	('mi', 'Chemical', 'MESH:C011506', (167, 169))	('miR-17', 'Gene', (203, 209))	('lower', 'NegReg', (149, 154))	('miR-20b', 'Gene', (167, 174))
776	26504848	Moreover, miRNAs are involved in different stages of colorectal cancer pathogenesis by regulating the expression of oncogenes and tumor suppressor genes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('130', '146'))	('mi', 'Chemical', 'MESH:C011506', (10, 12))	('miRNAs', 'Var', (10, 16))	('rectal cancer', 'Phenotype', 'HP:0100743', (57, 70))	('expression', 'MPA', (102, 112))	('involved', 'Reg', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('colorectal cancer', 'Disease', 'MESH:D015179', (53, 70))	('oncogenes', 'Protein', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor suppressor', 'biological_process', 'GO:0051726', ('130', '146'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (53, 70))	('pathogenesis', 'biological_process', 'GO:0009405', ('71', '83'))	('tumor', 'Disease', (130, 135))	('regulating', 'Reg', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('colorectal cancer', 'Disease', (53, 70))
793	24791633	Deregulated miRs have been shown to modulate a tumor's ability to evade apoptosis, migrate, invade, and undergo epithelial to mesenchymal transition.	('migrate', 'CPA', (83, 90))	('Deregulated', 'Var', (0, 11))	('modulate', 'Reg', (36, 44))	('miRs', 'Protein', (12, 16))	('epithelial to mesenchymal transition', 'CPA', (112, 148))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('undergo', 'Reg', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('invade', 'CPA', (92, 98))	('evade apoptosis', 'CPA', (66, 81))	('tumor', 'Disease', (47, 52))
812	24791633	After preprocessing and normalization, 3 high-interest CRC candidate miR probes (miR-320, miR-145, and miR-192) were selected for further analysis, based on a prior knowledge and investigator interest.	('miR-145', 'Gene', (90, 97))	('miR-145', 'Gene', '406937', (90, 97))	('CRC', 'Phenotype', 'HP:0003003', (55, 58))	('miR-320', 'Var', (81, 88))	('miR-192', 'Gene', (103, 110))	('miR-192', 'Gene', '406967', (103, 110))	('miR-320', 'Chemical', '-', (81, 88))
830	24791633	Loss of p53 has been thought to be a key step in colon carcinogenesis.	('p53', 'Gene', (8, 11))	('p53', 'Gene', '7157', (8, 11))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (49, 69))	('colon carcinogenesis', 'Disease', (49, 69))	('Loss', 'Var', (0, 4))
833	24791633	The authors further suggested that one of the miR-320a downstream targets, beta-catenin, is suppressed when miR-320a expression levels are restored in CRC cell lines and concluded that restoration of miR-320a leads to inhibition of cell proliferation.	('beta-catenin', 'Gene', '1499', (75, 87))	('suppressed', 'NegReg', (92, 102))	('miR-320a', 'Gene', (108, 116))	('CRC', 'Phenotype', 'HP:0003003', (151, 154))	('restoration', 'Var', (185, 196))	('inhibition', 'NegReg', (218, 228))	('miR-320a', 'Gene', (46, 54))	('miR-320a', 'Gene', '407037', (108, 116))	('expression', 'MPA', (117, 127))	('miR-320a', 'Gene', (200, 208))	('miR-320a', 'Gene', '407037', (46, 54))	('miR-320a', 'Gene', '407037', (200, 208))	('beta-catenin', 'Gene', (75, 87))	('cell proliferation', 'CPA', (232, 250))
834	24791633	In support of these findings, Shepeler et al demonstrated that in stage II colon microsatellite stable tumors, when stratifying on age, gender, and T stage, the progressive free survival was 6.6 times higher for patients with high expression of miR-320a, compared with tumors with low expression.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('miR-320a', 'Gene', (245, 253))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('patients', 'Species', '9606', (212, 220))	('high expression', 'Var', (226, 241))	('tumors', 'Disease', (103, 109))	('miR-320a', 'Gene', '407037', (245, 253))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('II colon microsatellite stable tumors', 'Disease', (72, 109))	('tumors', 'Disease', (269, 275))	('tumors', 'Disease', 'MESH:D009369', (269, 275))	('progressive free survival', 'CPA', (161, 186))	('higher', 'PosReg', (201, 207))	('II colon microsatellite stable tumors', 'Disease', 'MESH:D053842', (72, 109))
845	24791633	Based on this study, it appears that deregulation of miR-145 is an early event in the NMA-AC progression, and its loss of function may lead progression to adenocarcinoma.	('NMA-AC', 'Disease', (86, 92))	('miR-145', 'Gene', (53, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('miR-145', 'Gene', '406937', (53, 60))	('adenocarcinoma', 'Disease', (155, 169))	('loss of function', 'NegReg', (114, 130))	('deregulation', 'Var', (37, 49))	('adenocarcinoma', 'Disease', 'MESH:D000230', (155, 169))
850	24791633	Although we saw differing expressions of the miRs, 320a, 145, and 192, in sessile serrated and in tubular adenomas, future studies would have to take place to examine how these miRs may be associated with the CIN and CpG island methylator phenotype pathways of colorectal carcinogenesis.	('CIN', 'Disease', (209, 212))	('tubular adenomas', 'Disease', 'MESH:D000236', (98, 114))	('tubular adenomas', 'Disease', (98, 114))	('associated', 'Reg', (189, 199))	('320a', 'Var', (51, 55))	('CIN', 'Disease', 'MESH:D007674', (209, 212))	('145', 'Var', (57, 60))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (261, 286))	('CIN', 'Phenotype', 'HP:0040012', (209, 212))	('sessile serrated', 'Phenotype', 'HP:0032222', (74, 90))	('colorectal carcinogenesis', 'Disease', (261, 286))
851	24791633	In summary, we have found unique alterations in miRs-145, -192, and -320a expression levels during progression of normal/benign colorectal mucosa to tubular villous or high-grade dysplasia.	('miRs-145', 'Var', (48, 56))	('tubular villous', 'Phenotype', 'HP:0011473', (149, 164))	('alterations', 'Reg', (33, 44))	('expression levels', 'MPA', (74, 91))	('dysplasia', 'Disease', (179, 188))	('dysplasia', 'Disease', 'MESH:D004476', (179, 188))
857	24791633	Overall, our findings support progressive epigenetic changes at the level of the miRs in the NM-A-AC progression that might provide unique biomarkers for patient risk stratification and may, through future mechanism studies, guide prevention efforts at specific events in early carcinogenesis in the colorectum.	('NM-A', 'Gene', (93, 97))	('patient', 'Species', '9606', (154, 161))	('NM-A', 'Gene', '25805', (93, 97))	('epigenetic changes', 'Var', (42, 60))	('carcinogenesis', 'Disease', 'MESH:D063646', (278, 292))	('carcinogenesis', 'Disease', (278, 292))	('guide', 'Reg', (225, 230))
858	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))
859	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))
863	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))
864	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))
867	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))
872	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))	('serous ovarian cancer', 'Disease', (78, 99))	('tumors', 'Disease', (128, 134))	('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))
873	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.	('tumor', 'Disease', (28, 33))	('mutations', 'Var', (76, 85))	('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))
875	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'))	('mutations', 'Var', (18, 27))
877	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.,).	('breast carcinomas', 'Disease', (68, 85))	('methylated', 'Var', (47, 57))	('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))
881	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))
895	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.	('SEPT9', 'Gene', '10801', (188, 193))	('SEPT9', 'Gene', (188, 193))	('patient', 'Species', '9606', (98, 105))	('methylated', 'Var', (177, 187))
910	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))
918	25988180	Methylated CDKN2A (often designated as p16) was an early focus of the search for a plasma diagnostic biomarker for lung cancer; however, while the early studies identified CDKN2A promoter methylation in the plasma of lung cancer patients, they either had very small numbers of healthy controls (Bearzatto et al.,), or they did not include a cancer-free control group in their analysis (Kurakawa et al.,; An et al.,; Ng et al.,), extrapolating instead from the lack of CDKN2A methylation in plasma of patients whose tumors were CDKN2A methylation free.	('patients', 'Species', '9606', (229, 237))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('CDKN2A', 'Gene', (527, 533))	('cancer', 'Disease', (120, 126))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('tumors', 'Phenotype', 'HP:0002664', (515, 521))	('CDKN2A', 'Gene', (11, 17))	('cancer', 'Disease', (341, 347))	('CDKN2A', 'Gene', '1029', (172, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('methylation', 'Var', (188, 199))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('tumor', 'Phenotype', 'HP:0002664', (515, 520))	('cancer', 'Disease', (222, 228))	('tumors', 'Disease', (515, 521))	('CDKN2A', 'Gene', '1029', (527, 533))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('CDKN2A', 'Gene', '1029', (11, 17))	('lung cancer', 'Disease', (217, 228))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (515, 521))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('lung cancer', 'Disease', (115, 126))	('CDKN2A', 'Gene', (468, 474))	('p16', 'Gene', (39, 42))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('patients', 'Species', '9606', (500, 508))	('p16', 'Gene', '1029', (39, 42))	('CDKN2A', 'Gene', (172, 178))	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))	('CDKN2A', 'Gene', '1029', (468, 474))
934	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))
936	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', '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))
939	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))
943	25988180	On the other hand, lack of detectable methylation is potentially useful in distinguishing cancer from conditions which present with similar symptoms.	('methylation', 'Var', (38, 49))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))
944	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))
951	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))	('aberrent', 'Var', (33, 41))	('ovarian cancer', 'Disease', 'MESH:D010051', (141, 155))	('ovarian cancer', 'Phenotype', 'HP:0100615', (57, 71))	('ovarian cancer', 'Disease', (141, 155))
952	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))	('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))
955	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))
979	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))
1031	25574498	It is estimated that, in patients with a DBWC, the risk to develop a neoplasia can be as high as 7000 times the general population less than 25 years of age.	('neoplasia', 'Disease', (69, 78))	('DBWC', 'Var', (41, 45))	('neoplasia', 'Disease', 'MESH:D009369', (69, 78))	('neoplasia', 'Phenotype', 'HP:0002664', (69, 78))
1036	33567287	Inhibition of HSP90 activity blocks packaging of GOF, but not wild-type, p53 in small EVs.	('activity', 'MPA', (20, 28))	('GOF', 'Var', (49, 52))	('Inhibition', 'NegReg', (0, 10))	('HSP90', 'Gene', (14, 19))	('HSP90', 'Gene', '3320', (14, 19))	('packaging', 'MPA', (36, 45))	('blocks', 'NegReg', (29, 35))
1038	33567287	In vivo studies reveal that GOF p53-containing small EVs can enhance tumor growth and promote fibroblast transformation into a cancer-associated phenotype.	('enhance', 'PosReg', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', (69, 74))	('promote', 'PosReg', (86, 93))	('fibroblast transformation', 'CPA', (94, 119))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('GOF', 'Var', (28, 31))
1041	33567287	Small EVs with GOF p53 activate Nrf2-mediated pathways in fibroblasts and induce their conversion to a cancer-associated phenotype.	('activate', 'PosReg', (23, 31))	('Nrf2', 'Gene', (32, 36))	('conversion', 'MPA', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Nrf2', 'Gene', '4780', (32, 36))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('GOF p53', 'Var', (15, 22))	('induce', 'Reg', (74, 80))
1045	33567287	TP53 is the most commonly mutated gene in cancer, with more than 50% of all tumors containing TP53 mutations, resulting in loss or inactivation of its protein product.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('inactivation', 'NegReg', (131, 143))	('tumors', 'Disease', (76, 82))	('mutations', 'Var', (99, 108))	('cancer', 'Disease', (42, 48))	('loss', 'NegReg', (123, 127))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('protein product', 'MPA', (151, 166))
1046	33567287	Considering these effects of p53 signaling, packaging of mutant p53 protein into EVs or spread of p53 protein between cells via an alternate mechanism can impact a variety of stromal cell processes, producing alterations in the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('mutant', 'Var', (57, 63))	('alterations', 'Reg', (209, 220))	('tumor', 'Disease', (228, 233))	('p53', 'Gene', (64, 67))	('protein', 'Protein', (68, 75))	('impact', 'Reg', (155, 161))
1047	33567287	TP53R273H mutation has been reported in exosomal DNA from patients with pancreatic ductal adenocarcinoma or intraductal papillary mucinous neoplasm, suggesting that small EVs are potential biomarkers of cancer risk.	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (72, 104))	('patients', 'Species', '9606', (58, 66))	('papillary mucinous neoplasm', 'Disease', (120, 147))	('reported', 'Reg', (28, 36))	('papillary mucinous neoplasm', 'Disease', 'MESH:D000077779', (120, 147))	('TP53R273H mutation', 'Var', (0, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('neoplasm', 'Phenotype', 'HP:0002664', (139, 147))	('pancreatic ductal adenocarcinoma', 'Disease', (72, 104))	('mucinous neoplasm', 'Phenotype', 'HP:0031495', (130, 147))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (72, 104))	('exosomal', 'MPA', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
1048	33567287	Several studies have shown that GOF p53 protein can be detected in cancer-associated fibroblasts (CAFs).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('GOF', 'Var', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('protein', 'Protein', (40, 47))
1049	33567287	Importantly, expression of GOF p53 in fibroblasts promotes their conversion to the cancer-associated phenotype, and tumor cells co-injected with mutant p53-expressing fibroblasts exhibit increased growth and metastasis.	('p53-expressing', 'Gene', (152, 166))	('mutant', 'Var', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('increased', 'PosReg', (187, 196))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Disease', (116, 121))	('cancer', 'Disease', (83, 89))	('conversion', 'MPA', (65, 75))
1052	33567287	We also demonstrated the capacity for GOF p53 protein to be transferred from tumor cells to normal fibroblasts.	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('GOF', 'Var', (38, 41))
1053	33567287	Furthermore, the interaction of HSP90 with GOF p53, but not WT p53, was important for the packaging of p53 into small EVs.	('interaction', 'Interaction', (17, 28))	('GOF p53', 'Var', (43, 50))	('HSP90', 'Gene', (32, 37))	('HSP90', 'Gene', '3320', (32, 37))
1054	33567287	Additionally, in tumor-bearing mice, GOF p53-containing EVs resulted in increased tumor size as well as increased CAF-associated gene expression.	('tumor', 'Disease', (17, 22))	('expression', 'MPA', (134, 144))	('increased', 'PosReg', (72, 81))	('increased', 'PosReg', (104, 113))	('GOF p53-containing', 'Var', (37, 55))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('mice', 'Species', '10090', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('CAF-associated gene', 'Gene', (114, 133))
1055	33567287	These results demonstrate the relevance of small EVs containing GOF p53 in promoting a pro-tumor microenvironment through the conversion of fibroblasts to CAFs, as well as a molecular mechanism by which selective packaging of GOF p53 in small EVs occurs.	('GOF p53', 'Var', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('promoting', 'PosReg', (75, 84))	('tumor', 'Disease', (91, 96))
1056	33567287	To investigate whether fibroblasts in the tumor microenvironment contain mutant p53 protein, we examined a tissue microarray of high-grade serous ovarian cancer (HGSOC) samples based on immunohistochemistry (IHC) because HGSOC is characterized most frequently with TP53 mutation (96%).	('tumor', 'Disease', (42, 47))	('TP53', 'Gene', '7157', (265, 269))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('p53', 'Gene', (80, 83))	('serous ovarian cancer', 'Disease', (139, 160))	('mutant', 'Var', (73, 79))	('TP53', 'Gene', (265, 269))	('ovarian cancer', 'Phenotype', 'HP:0100615', (146, 160))	('protein', 'Protein', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (139, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
1057	33567287	In the patients with a missense mutation of TP53 (indicated by strong and diffuse immune-expression of p53), we found p53-positive staining in adjacent regions of fibroblasts (Figure 1A).	('patients', 'Species', '9606', (7, 15))	('TP53', 'Gene', '7157', (44, 48))	('missense mutation', 'Var', (23, 40))	('TP53', 'Gene', (44, 48))
1058	33567287	To further illustrate whether hotspot mutant p53 protein can be found in fibroblasts, we obtained patient tumor tissues and performed whole-genome sequencing on those samples (Table S1).	('mutant', 'Var', (38, 44))	('p53', 'Gene', (45, 48))	('patient', 'Species', '9606', (98, 105))	('protein', 'Protein', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('tumor', 'Disease', (106, 111))
1062	33567287	Tumors with WT TP53 (n = 2), nonsense mutation (n = 1), or a splice site mutation (X187, n = 1) did not show positive p53 staining in fibroblasts (Figure S1B).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('nonsense mutation', 'Var', (29, 46))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('TP53', 'Gene', (15, 19))	('TP53', 'Gene', '7157', (15, 19))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
1063	33567287	To determine whether the p53 protein can be secreted within small EVs, we selected 10 cell lines from six common tumor types (breast, prostate, ovarian, uterine, lung, and colorectal) with WT TP53 (A2780, MCF7, RKO, A549, and lymph node carcinoma of the prostate [LNCaP]) or mutant GOF TP53 (KLE [TP53R175H mutation], T47D [TP53L194F mutation], HT29 [TP53R273H mutation], H1975 [TP53R273H mutation], and DU145 [TP53P223L/V274F mutation]) for analysis.	('TP53', 'Gene', (411, 415))	('A549', 'CellLine', 'CVCL:0023', (216, 220))	('TP53', 'Gene', '7157', (351, 355))	('TP53L', 'Gene', (324, 329))	('TP53', 'Gene', (379, 383))	('TP53', 'Gene', (324, 328))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('ovarian', 'Disease', 'MESH:D010049', (144, 151))	('HT29', 'CellLine', 'CVCL:0320', (345, 349))	('TP53', 'Gene', '7157', (286, 290))	('lymph node carcinoma', 'Phenotype', 'HP:0002665', (226, 246))	('lymph node carcinoma of the prostate', 'Disease', (226, 262))	('TP53', 'Gene', (297, 301))	('TP53', 'Gene', (192, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('TP53', 'Gene', '7157', (411, 415))	('tumor', 'Disease', (113, 118))	('TP53', 'Gene', '7157', (379, 383))	('TP53', 'Gene', (351, 355))	('TP53', 'Gene', '7157', (324, 328))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('LNCaP', 'CellLine', 'CVCL:0395', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('RKO', 'CellLine', 'CVCL:0504', (211, 214))	('DU145', 'CellLine', 'CVCL:0105', (404, 409))	('ovarian', 'Disease', (144, 151))	('H1975', 'CellLine', 'CVCL:1511', (372, 377))	('mutant', 'Var', (275, 281))	('MCF7', 'CellLine', 'CVCL:0031', (205, 209))	('lymph node carcinoma of the prostate', 'Disease', 'MESH:D011471', (226, 262))	('TP53', 'Gene', (286, 290))	('TP53', 'Gene', '7157', (297, 301))	('TP53L', 'Gene', '8626', (324, 329))	('T47D', 'CellLine', 'CVCL:0553', (318, 322))	('TP53', 'Gene', '7157', (192, 196))	('V274F', 'Mutation', 'rs1057520005', (421, 426))
1068	33567287	We used a p53 (DO-1) antibody that can recognize both WT and mutant human p53 protein.	('human', 'Species', '9606', (68, 73))	('DO-1', 'Gene', '109375', (15, 19))	('p53', 'Gene', (74, 77))	('DO-1', 'Gene', (15, 19))	('mutant', 'Var', (61, 67))	('protein', 'Protein', (78, 85))
1069	33567287	The western blotting results revealed that the p53 protein expression level was higher in mutant GOF TP53 cell lines than WT TP53 cell lines (Figure 1D).	('GOF', 'Var', (97, 100))	('p53 protein expression level', 'MPA', (47, 75))	('TP53', 'Gene', '7157', (125, 129))	('TP53', 'Gene', '7157', (101, 105))	('TP53', 'Gene', (125, 129))	('TP53', 'Gene', (101, 105))	('mutant GOF', 'Var', (90, 100))	('higher', 'PosReg', (80, 86))	('protein', 'cellular_component', 'GO:0003675', ('51', '58'))
1070	33567287	Small EVs containing p53 protein were detectable in four of the five GOF TP53 cell lines, whereas the WT cell lines had either undetectable or extremely low levels of p53 (Figure 1D).	('TP53', 'Gene', '7157', (73, 77))	('GOF', 'Var', (69, 72))	('protein', 'Protein', (25, 32))	('TP53', 'Gene', (73, 77))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('p53', 'Gene', (21, 24))
1078	33567287	We established HT29 colorectal cancer cells expressing mCherry-tagged p53 or a control vector using lentiviral transduction.	('colorectal cancer', 'Phenotype', 'HP:0003003', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('p53', 'Gene', (70, 73))	('colorectal cancer', 'Disease', (20, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (20, 37))	('HT29 colorectal', 'CellLine', 'CVCL:0320', (15, 30))	('mCherry-tagged', 'Var', (55, 69))
1084	33567287	KPC cells express mutant GOF p53 protein in the presence of pancreatic and duodenal homeobox 1 (PDX1) (Figure 2E).	('pancreatic', 'Disease', 'MESH:D010195', (60, 70))	('mutant', 'Var', (18, 24))	('GOF p53', 'Gene', (25, 32))	('PDX1', 'Gene', (96, 100))	('pancreatic', 'Disease', (60, 70))	('protein', 'Protein', (33, 40))	('PDX1', 'Gene', '18609', (96, 100))
1085	33567287	PDX1 leads to Cre recombinase expression, which excises LSL to enable the transcription of the mutant Trp53 gene.	('PDX1', 'Gene', '18609', (0, 4))	('PDX1', 'Gene', (0, 4))	('Trp53', 'Gene', '22059', (102, 107))	('mutant', 'Var', (95, 101))	('transcription', 'MPA', (74, 87))	('Trp53', 'Gene', (102, 107))
1090	33567287	The results showed that R172H mutant p53 protein was present in fibroblasts of KPC cell xenograft mice (Figures 2J and S2B).	('protein', 'cellular_component', 'GO:0003675', ('41', '48'))	('protein', 'Protein', (41, 48))	('p53', 'Gene', (37, 40))	('R172H', 'Var', (24, 29))	('mice', 'Species', '10090', (98, 102))	('R172H', 'Mutation', 'rs767964519', (24, 29))
1092	33567287	These results demonstrated that p53 protein can be transferred to fibroblasts from mutant GOF TP53 cancer cells.	('mutant', 'Var', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
1095	33567287	A NTA assay revealed no significant differences in small EV secretion after knockdown of TP53 (Figure S3A).	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('knockdown', 'Var', (76, 85))	('NTA', 'Chemical', '-', (2, 5))	('small EV secretion', 'MPA', (51, 69))	('secretion', 'biological_process', 'GO:0046903', ('60', '69'))
1097	33567287	In addition, the total protein amount carried by small EVs was not impacted by the knockdown of TP53, as revealed in an analysis using the Qubit protein assay kit (Figure S3B).	('kit', 'Gene', (159, 162))	('TP53', 'Gene', (96, 100))	('kit', 'Gene', '3815', (159, 162))	('knockdown', 'Var', (83, 92))	('TP53', 'Gene', '7157', (96, 100))
1100	33567287	The gene expression fold-change (FC) data showed that the most frequently upregulated and downregulated genes were long noncoding RNAs (lncRNAs; e.g., lnc-MYO1F-2 and lnc-XBP-1) in shP53-sEVs relative to ntsh-sEVs (Figures 3C and S3C).	('ntsh', 'Chemical', '-', (204, 208))	('XBP-1', 'Gene', '7494', (171, 176))	('upregulated', 'PosReg', (74, 85))	('shP53-sEVs', 'Var', (181, 191))	('long noncoding', 'Protein', (115, 129))	('XBP-1', 'Gene', (171, 176))	('lnc-MYO1F-2', 'Gene', (151, 162))
1103	33567287	The mRNA array data revealed that multiple markers of the cancer-associated phenotype were upregulated in the fibroblasts treated with ntsh-sEVs relative to shP53-sEVs (Table S2).	('upregulated', 'PosReg', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ntsh-sEVs', 'Var', (135, 144))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('ntsh', 'Chemical', '-', (135, 139))
1105	33567287	The pathways most upregulated in fibroblasts treated with ntsh-sEVs were related to direct p53 effectors, platelet-derived growth factor (PDGF) signaling, and TGF-beta signaling (Figure 3E).	('ntsh-sEVs', 'Var', (58, 67))	('TGF-beta', 'Gene', (159, 167))	('PDGF', 'Gene', '18595', (138, 142))	('PDGF', 'Gene', (138, 142))	('ntsh', 'Chemical', '-', (58, 62))	('TGF-beta', 'Gene', '7039', (159, 167))	('upregulated', 'PosReg', (18, 29))
1113	33567287	The quantitative real-time RT-PCR results suggested that ML385 can significantly abrogate the effects of GOF p53-containing small EVs on the induction of CAF-related gene expression (Figure 3F).	('gene expression', 'biological_process', 'GO:0010467', ('166', '181'))	('CAF-related gene', 'Gene', (154, 170))	('ML385', 'Chemical', '-', (57, 62))	('abrogate', 'NegReg', (81, 89))	('GOF', 'Var', (105, 108))	('ML385', 'Var', (57, 62))	('induction', 'MPA', (141, 150))
1114	33567287	We further evaluated cytokine secretion in the cell culture supernatant of NoF 151 fibroblasts after treatment with ntsh-sEVs or shP53-sEVs.	('ntsh', 'Chemical', '-', (116, 120))	('evaluated', 'Reg', (11, 20))	('cytokine secretion', 'biological_process', 'GO:0050663', ('21', '39'))	('shP53-sEVs', 'Var', (129, 139))	('cytokine secretion', 'MPA', (21, 39))
1117	33567287	In particular, HSP70 and HSP90 exhibit much greater binding affinity with mutant p53 than other partners.	('binding affinity', 'Interaction', (52, 68))	('HSP70', 'Gene', '3308', (15, 20))	('HSP70', 'Gene', (15, 20))	('HSP90', 'Gene', (25, 30))	('p53', 'Gene', (81, 84))	('HSP90', 'Gene', '3320', (25, 30))	('mutant', 'Var', (74, 80))
1127	33567287	To determine whether these results were due to differences in HSP90 and p53 binding in the EV compartment, we performed co-immunoprecipitation in small EVs of mutant TP53 HT29 cells and WT TP53 RKO cells.	('TP53', 'Gene', '7157', (189, 193))	('RKO', 'CellLine', 'CVCL:0504', (194, 197))	('mutant', 'Var', (159, 165))	('TP53', 'Gene', (189, 193))	('p53 binding', 'molecular_function', 'GO:0002039', ('72', '83'))	('TP53', 'Gene', '7157', (166, 170))	('HSP90', 'Gene', (62, 67))	('TP53', 'Gene', (166, 170))	('HT29 cells', 'CellLine', 'CVCL:0320', (171, 181))	('HSP90', 'Gene', '3320', (62, 67))
1128	33567287	The data showed that HSP90 was bound to p53 in HT29-, but not RKO-derived, small EVs, demonstrating that HSP90 and GOF p53, but not WT p53, interact within the EV compartment (Figure 4D).	('HSP90', 'Gene', '3320', (105, 110))	('HSP90', 'Gene', (21, 26))	('RKO', 'CellLine', 'CVCL:0504', (62, 65))	('interact', 'Interaction', (140, 148))	('HSP90', 'Gene', '3320', (21, 26))	('HT29', 'CellLine', 'CVCL:0320', (47, 51))	('GOF p53', 'Var', (115, 122))	('HSP90', 'Gene', (105, 110))
1131	33567287	The tumors injected with ntsh-sEVs had significantly higher tumor weights than did those injected with shP53-sEVs (Figure 5A).	('tumor', 'Disease', (4, 9))	('higher', 'PosReg', (53, 59))	('ntsh-sEVs', 'Var', (25, 34))	('tumors', 'Disease', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('ntsh', 'Chemical', '-', (25, 29))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (60, 65))
1132	33567287	The tumor tissues were then harvested and embedded in paraffin and then sectioned and stained for p53 (DO-1), alphaSMA, and fibronectin.	('tumor', 'Disease', (4, 9))	('fibronectin', 'Protein', (124, 135))	('DO-1', 'Gene', '109375', (103, 107))	('DO-1', 'Gene', (103, 107))	('p53', 'Var', (98, 101))	('paraffin', 'Chemical', 'MESH:D010232', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('alphaSMA', 'Protein', (110, 118))
1133	33567287	Also, the results revealed that injection of GOF p53-containing small EVs resulted in increased expression of alphaSMA, pointing to the capacity of these EVs to induce a cancer-associated phenotype (Figure 5B).	('GOF', 'Var', (45, 48))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('increased', 'PosReg', (86, 95))	('cancer', 'Disease', (170, 176))	('induce', 'Reg', (161, 167))	('expression', 'MPA', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('alphaSMA', 'Protein', (110, 118))
1134	33567287	To further determine the endogenous effects of GOF p53 on cancer-associated phenotype conversion, we established an orthotopic colorectal cancer model by injecting HT29-ntsh or HT29-shP53 cells into the cecal wall in nude mice.	('HT29-shP53', 'Var', (177, 187))	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('colorectal cancer', 'Disease', 'MESH:D015179', (127, 144))	('HT29', 'CellLine', 'CVCL:0320', (177, 181))	('colorectal cancer', 'Disease', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('nude mice', 'Species', '10090', (217, 226))	('HT29', 'CellLine', 'CVCL:0320', (164, 168))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('ntsh', 'Chemical', '-', (169, 173))
1135	33567287	The tumor weights did not differ significantly between the two groups (Figure 5C), but the p53 expression level was considerably lower in the HT29-shP53 group than in the HT29-ntsh group (Figure 5D).	('tumor', 'Disease', (4, 9))	('HT29', 'CellLine', 'CVCL:0320', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('HT29', 'CellLine', 'CVCL:0320', (171, 175))	('p53 expression level', 'MPA', (91, 111))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('ntsh', 'Chemical', '-', (176, 180))	('HT29-shP53', 'Var', (142, 152))	('lower', 'NegReg', (129, 134))
1136	33567287	Importantly, the expression of alphaSMA and fibronectin was substantially lower in the HT29-shP53 group than in the HT29-ntsh group (Figure 5D).	('HT29', 'CellLine', 'CVCL:0320', (87, 91))	('expression', 'MPA', (17, 27))	('fibronectin', 'Protein', (44, 55))	('ntsh', 'Chemical', '-', (121, 125))	('HT29', 'CellLine', 'CVCL:0320', (116, 120))	('lower', 'NegReg', (74, 79))	('HT29-shP53', 'Var', (87, 97))
1137	33567287	We further isolated fresh fibroblasts from tumors in HT29-ntsh and HT29-shP53 orthotopic mouse models via fluorescence-activated cell sorting (FACS).	('HT29-shP53', 'Var', (67, 77))	('ntsh', 'Chemical', '-', (58, 62))	('HT29', 'CellLine', 'CVCL:0320', (67, 71))	('HT29', 'CellLine', 'CVCL:0320', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('mouse', 'Species', '10090', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
1142	33567287	We have shown that HSP90 was an important chaperone for the packaging of GOF p53 into small EVs.	('GOF', 'Var', (73, 76))	('HSP90', 'Gene', '3320', (19, 24))	('HSP90', 'Gene', (19, 24))
1144	33567287	In this model, mice given 17-AAG had smaller tumor burdens than did the control group, but the difference did not reach statistical significance (Figure S5B).	('smaller', 'NegReg', (37, 44))	('S5B', 'Gene', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('S5B', 'Gene', '66998', (153, 156))	('tumor', 'Disease', (45, 50))	('17-AAG', 'Var', (26, 32))	('17-AAG', 'Chemical', 'MESH:C112765', (26, 32))	('mice', 'Species', '10090', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
1146	33567287	These findings suggest that inhibition of HSP90 activity could influence the transfer of GOF p53 from tumor cells to stromal cells in this model.	('activity', 'MPA', (48, 56))	('HSP90', 'Gene', (42, 47))	('transfer', 'MPA', (77, 85))	('inhibition', 'Var', (28, 38))	('HSP90', 'Gene', '3320', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('influence', 'Reg', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('GOF p53', 'Gene', (89, 96))
1149	33567287	Herein, we demonstrate the capacity of cancer cells to spread GOF p53 to the stromal compartment through small EVs and create a permissive environment for tumor growth.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('GOF p53', 'Var', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('permissive environment', 'MPA', (128, 150))
1150	33567287	In particular, fibroblasts that take up these GOF p53-containing small EVs are re-educated to adopt a cancer-associated phenotype, marked by increased expression of alphaSMA, fibronectin, and FAP.	('FAP', 'Gene', '2191', (192, 195))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('GOF', 'Var', (46, 49))	('increased', 'PosReg', (141, 150))	('expression', 'MPA', (151, 161))	('FAP', 'Gene', (192, 195))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('alphaSMA', 'Protein', (165, 173))	('fibronectin', 'Protein', (175, 186))
1151	33567287	Notably, EV p53 protein upregulates the PDGF and TGF-beta signaling pathways in fibroblasts.	('TGF-beta', 'Gene', (49, 57))	('protein', 'cellular_component', 'GO:0003675', ('16', '23'))	('TGF-beta', 'Gene', '7039', (49, 57))	('PDGF', 'Gene', (40, 44))	('PDGF', 'Gene', '18595', (40, 44))	('PDGF', 'molecular_function', 'GO:0005161', ('40', '44'))	('upregulates', 'PosReg', (24, 35))	('EV p53', 'Var', (9, 15))	('signaling', 'biological_process', 'GO:0023052', ('58', '67'))
1153	33567287	Conversely, mutant p53 cooperates with Nrf2, influencing the levels of oxidative stress within the tumor cells and microenvironment.	('tumor', 'Disease', (99, 104))	('Nrf2', 'Gene', (39, 43))	('oxidative stress', 'Phenotype', 'HP:0025464', (71, 87))	('influencing', 'Reg', (45, 56))	('mutant', 'Var', (12, 18))	('p53', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('Nrf2', 'Gene', '4780', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('levels of oxidative stress', 'MPA', (61, 87))
1158	33567287	Previous studies demonstrated that p53 could facilitate the secretion of EVs by inducing expression of STEAP3 metalloreductase (TSAP6) and maspin in H460 human non-small cell lung cancer cell lines with a WT TP53 allele.	('human', 'Species', '9606', (154, 159))	('STEAP3 metalloreductase', 'Gene', (103, 126))	('facilitate', 'PosReg', (45, 55))	('lung cancer', 'Disease', (175, 186))	('TP53', 'Gene', '7157', (208, 212))	('H460', 'CellLine', 'CVCL:0459', (149, 153))	('p53', 'Var', (35, 38))	('TSAP6', 'Gene', (128, 133))	('expression', 'MPA', (89, 99))	('lung cancer', 'Disease', 'MESH:D008175', (175, 186))	('STEAP3 metalloreductase', 'Gene', '55240', (103, 126))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('inducing', 'PosReg', (80, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('TP53', 'Gene', (208, 212))	('maspin', 'Gene', '5268', (139, 145))	('secretion', 'MPA', (60, 69))	('maspin', 'Gene', (139, 145))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (164, 186))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (160, 186))	('TSAP6', 'Gene', '55240', (128, 133))
1159	33567287	However, in contrast with these reports, we observed that the knockdown of GOF p53 protein resulted in a trend of greater small EV secretion than did the HT29-ntsh cells.	('small EV secretion', 'MPA', (122, 140))	('protein', 'Protein', (83, 90))	('greater', 'PosReg', (114, 121))	('GOF p53', 'Gene', (75, 82))	('ntsh', 'Chemical', '-', (159, 163))	('HT29', 'CellLine', 'CVCL:0320', (154, 158))	('knockdown', 'Var', (62, 71))
1171	33567287	Therefore, HSP90 inhibitors and immune therapy may be a rational combination therapy regimen for cancer patients with certain p53 mutations.	('cancer', 'Disease', (97, 103))	('HSP90', 'Gene', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutations', 'Var', (130, 139))	('HSP90', 'Gene', '3320', (11, 16))	('p53', 'Gene', (126, 129))	('patients', 'Species', '9606', (104, 112))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
1172	33567287	Considering that half of cancers have some form of alteration of TP53, these findings and future discoveries hold great potential in broadening our understanding of tumor biology.	('TP53', 'Gene', '7157', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('TP53', 'Gene', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('alteration', 'Var', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancers', 'Disease', (25, 32))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('tumor', 'Disease', (165, 170))
1254	33567287	Mice from HT29-ntsh and HT29-shP53 orthotopic models were killed using cervical dislocation, and their tumors were collected using sterilized surgical tools.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('HT29', 'CellLine', 'CVCL:0320', (24, 28))	('HT29-shP53', 'Var', (24, 34))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (103, 109))	('Mice', 'Species', '10090', (0, 4))	('ntsh', 'Chemical', '-', (15, 19))	('HT29', 'CellLine', 'CVCL:0320', (10, 14))
1269	33567287	Fold change in gene expression between the fibroblasts treated with ntsh-sEVs and in those treated with shP53-sEVs was used for NetWalker analysis (https://www.netwalkersuite.org/).	('ntsh', 'Chemical', '-', (68, 72))	('ntsh-sEVs', 'Var', (68, 77))	('gene expression', 'MPA', (15, 30))
1281	33567287	Next, HT29 cells transduced with mCherry-tagged p53 in a pLVX-mCherry-C1 Lentiviral vector, or transduced with a control vector, were plated onto the insert at a concentration of 1 x 106 cells/well.	('HT29 cells', 'CellLine', 'CVCL:0320', (6, 16))	('p53', 'Gene', (48, 51))	('mCherry-tagged', 'Var', (33, 47))
1283	33567287	Cancer cells with mutant TP53 can package mutant p53 protein in small EVs Small EVs with GOF p53 can convert fibroblasts into a cancer-associated phenotype Packaging of GOF p53 into small EVs is regulated by HSP90 Small EVs with GOF p53 promote tumor growth in vivo	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('mutant', 'Var', (42, 48))	('p53', 'Gene', (49, 52))	('TP53', 'Gene', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('mutant', 'Var', (18, 24))	('promote', 'PosReg', (237, 244))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('Cancer', 'Disease', (0, 6))	('HSP90', 'Gene', '3320', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('protein', 'Protein', (53, 60))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', (245, 250))	('TP53', 'Gene', '7157', (25, 29))	('HSP90', 'Gene', (208, 213))	('cancer', 'Disease', (128, 134))
1292	32824649	The genetic and epigenetic changes cooperatively produce intratumoral heterogeneity, which may promote the development of competitive cancer cell phenotypes.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('epigenetic changes', 'Var', (16, 34))	('promote', 'PosReg', (95, 102))	('competitive cancer', 'Disease', 'MESH:D009369', (122, 140))	('competitive cancer', 'Disease', (122, 140))	('tumor', 'Disease', (62, 67))	('rat', 'Species', '10116', (40, 43))	('rat', 'Species', '10116', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('produce', 'Reg', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
1303	32824649	As a consequence, even when the tumor mass is reduced, CSCs enriched in mutations, may accumulate within the remainder of the tumor.	('mutations', 'Var', (72, 81))	('accumulate', 'PosReg', (87, 97))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', (126, 131))
1376	32824649	CAF-derived sEV miR-92a-3p caused an increased nuclear beta-catenin expression in colorectal carcinoma cells with the appearance of CSC markers and several processes associated with EMT, such as the E-cadherin to N-cadherin switch.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('beta-catenin', 'Gene', (55, 67))	('cadherin', 'molecular_function', 'GO:0008014', ('215', '223'))	('N-cadherin', 'Gene', (213, 223))	('cadherin', 'molecular_function', 'GO:0008014', ('201', '209'))	('beta-catenin', 'Gene', '1499', (55, 67))	('N-cadherin', 'Gene', '1000', (213, 223))	('E-cadherin', 'Gene', (199, 209))	('miR-92a-3p', 'Var', (16, 26))	('colorectal carcinoma', 'Disease', (82, 102))	('CAF', 'Gene', (0, 3))	('increased', 'PosReg', (37, 46))	('CAF', 'Gene', '8850', (0, 3))	('E-cadherin', 'Gene', '999', (199, 209))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (82, 102))	('EMT', 'biological_process', 'GO:0001837', ('182', '185'))
1422	32711505	In addition to environmental factors, there is proven evidence that CRC results from the accumulation of genetic and epigenetic changes, which changes colonic epithelial cells into adenocarcinoma cells.	('CRC', 'Phenotype', 'HP:0003003', (68, 71))	('colonic', 'Disease', 'MESH:D003110', (151, 158))	('colonic', 'Disease', (151, 158))	('changes', 'Reg', (143, 150))	('CRC', 'Disease', (68, 71))	('men', 'Species', '9606', (22, 25))	('epigenetic changes', 'Var', (117, 135))
1423	32711505	Epigenetic alterations such as DNA methylation has been associated with many human diseases including cancer and have also been reported to occur early in the development of colorectal tumors by playing a role in gene expression and genomic stability.	('Epigenetic alterations', 'Var', (0, 22))	('genomic stability', 'CPA', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('colorectal tumors', 'Disease', (174, 191))	('DNA', 'Gene', (31, 34))	('role', 'Reg', (205, 209))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('playing', 'Reg', (195, 202))	('gene expression', 'MPA', (213, 228))	('associated', 'Reg', (56, 66))	('cancer', 'Disease', (102, 108))	('men', 'Species', '9606', (166, 169))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('human', 'Species', '9606', (77, 82))	('colorectal tumors', 'Disease', 'MESH:D015179', (174, 191))
1452	32711505	Furthermore, using the sixteen-CpG panel we calculated a methylation risk score (MRS) for each subject on the training dataset using the formula: The methylation levels of 4 CpG (cg01419670, cg16530981, cg11240062, cg24702253) sites were hypermethylated, and 12 CpG (cg06551493, cg18022036, cg12691488, cg17292758, cg16170495, cg21585512, cg17187762, cg05983326, cg06825163, cg11885357, cg08829299, cg07044115) sites were hypomethylated.	('cg17292758', 'Var', (303, 313))	('cg01419670', 'Var', (179, 189))	('cg16530981', 'Var', (191, 201))	('cg06825163', 'Var', (363, 373))	('cg24702253', 'Var', (215, 225))	('cg21585512', 'Var', (327, 337))	('methylation', 'biological_process', 'GO:0032259', ('150', '161'))	('methylation', 'biological_process', 'GO:0032259', ('57', '68'))	('cg16170495', 'Chemical', '-', (315, 325))	('cg11240062', 'Var', (203, 213))	('cg11885357', 'Chemical', '-', (375, 385))	('cg21585512', 'Chemical', '-', (327, 337))	('cg06551493', 'Chemical', '-', (267, 277))	('hypermethylated', 'PosReg', (238, 253))	('cg17292758', 'Chemical', '-', (303, 313))	('cg17187762', 'Var', (339, 349))	('cg08829299', 'Var', (387, 397))	('cg05983326', 'Var', (351, 361))	('cg12691488', 'Chemical', '-', (291, 301))	('cg24702253', 'Chemical', '-', (215, 225))	('cg11885357', 'Var', (375, 385))	('cg16170495', 'Var', (315, 325))
1453	32711505	We identified nine CpGs (cg06551493, cg12691488, cg17292758, cg16170495, cg21585512, cg24702253, cg17187762, cg05983326, cg11885357) that were associated with CRC, and the MRS for each sample was calculated.	('cg24702253', 'Chemical', '-', (85, 95))	('cg11885357', 'Chemical', '-', (121, 131))	('associated', 'Reg', (143, 153))	('cg06551493', 'Var', (25, 35))	('cg21585512', 'Chemical', '-', (73, 83))	('CRC', 'Phenotype', 'HP:0003003', (159, 162))	('cg12691488', 'Chemical', '-', (37, 47))	('cg12691488', 'Var', (37, 47))	('cg16170495', 'Chemical', '-', (61, 71))	('cg24702253', 'Var', (85, 95))	('cg17292758', 'Chemical', '-', (49, 59))	('cg21585512', 'Var', (73, 83))	('cg05983326', 'Var', (109, 119))	('cg17292758', 'Var', (49, 59))	('cg17187762', 'Var', (97, 107))	('cg16170495', 'Var', (61, 71))	('cg06551493', 'Chemical', '-', (25, 35))	('CRC', 'Disease', (159, 162))
1454	32711505	Although the mechanisms underlying the aberrations in the methylation of peripheral blood DNA among individuals who are susceptible to CRC are not clear, our analysis used pre-diagnostic peripheral blood DNA, which indicates that methylation aberrations in peripheral blood DNA could possibly be a long-term CRC predisposition risk markers or a far early response to CRC cells before cancer could be detected by techniques used before now such as endoscopy and cytology.	('CRC', 'Phenotype', 'HP:0003003', (367, 370))	('methylation', 'biological_process', 'GO:0032259', ('230', '241'))	('DNA', 'cellular_component', 'GO:0005574', ('90', '93'))	('DNA', 'cellular_component', 'GO:0005574', ('204', '207'))	('cancer', 'Phenotype', 'HP:0002664', (384, 390))	('cancer', 'Disease', 'MESH:D009369', (384, 390))	('aberrations', 'Var', (242, 253))	('CRC', 'Disease', (308, 311))	('DNA', 'cellular_component', 'GO:0005574', ('274', '277'))	('cancer', 'Disease', (384, 390))	('CRC', 'Phenotype', 'HP:0003003', (135, 138))	('methylation', 'biological_process', 'GO:0032259', ('58', '69'))	('pre', 'molecular_function', 'GO:0003904', ('172', '175'))	('CRC', 'Phenotype', 'HP:0003003', (308, 311))	('methylation aberrations', 'Var', (230, 253))
1456	32711505	In the present study, the methylation-based markers for CRC included LGR6, PTPN12, PPFIA3, LOC399959, PCDHGA1, RNF39, ESYT3, MRGPRG and ATHL1, all of which were located in the promoter regions or first introns of nearby genes.	('PCDHGA1', 'Gene', (102, 109))	('ESYT3', 'Gene', (118, 123))	('RNF39', 'Gene', (111, 116))	('ATHL1', 'Gene', (136, 141))	('PTPN12', 'Gene', (75, 81))	('ESYT3', 'Gene', '83850', (118, 123))	('LOC399959', 'Var', (91, 100))	('PPFIA3', 'Gene', '8541', (83, 89))	('LGR6', 'Gene', '59352', (69, 73))	('PCDHGA1', 'Gene', '56114', (102, 109))	('LGR6', 'Gene', (69, 73))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('ATHL1', 'Gene', '80162', (136, 141))	('MRGPRG', 'Gene', '386746', (125, 131))	('PPFIA3', 'Gene', (83, 89))	('RNF39', 'Gene', '80352', (111, 116))	('PTPN12', 'Gene', '5782', (75, 81))	('CRC', 'Phenotype', 'HP:0003003', (56, 59))	('MRGPRG', 'Gene', (125, 131))
1459	32711505	A study on whole-exome sequencing identified that PTPN12 variant is associated with CRC susceptibility.	('PTPN12', 'Gene', '5782', (50, 56))	('associated', 'Reg', (68, 78))	('PTPN12', 'Gene', (50, 56))	('variant', 'Var', (57, 64))	('CRC', 'Phenotype', 'HP:0003003', (84, 87))	('CRC susceptibility', 'Disease', (84, 102))
1463	32711505	The pathway and biological processes put together demonstrate that multiple pathways, which were affected by aberrant methylation were involved in CRC tumorigenesis.	('CRC', 'Phenotype', 'HP:0003003', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('aberrant methylation', 'Var', (109, 129))	('tumor', 'Disease', (151, 156))	('involved', 'Reg', (135, 143))	('methylation', 'Var', (118, 129))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
1464	32711505	It is noteworthy that PTPN12, RNF39, LOC399959, PCDHGA1, and LGR6 are also significantly hypomethylated in CRC tissue compared to normal tissue in the TCGA dataset, suggesting that the changes observed in DNA methylation levels may be clinically important.	('LOC399959', 'Var', (37, 46))	('PTPN12', 'Gene', '5782', (22, 28))	('PCDHGA1', 'Gene', (48, 55))	('LGR6', 'Gene', '59352', (61, 65))	('CRC', 'Phenotype', 'HP:0003003', (107, 110))	('RNF39', 'Gene', '80352', (30, 35))	('PTPN12', 'Gene', (22, 28))	('RNF39', 'Gene', (30, 35))	('hypomethylated', 'Var', (89, 103))	('PCDHGA1', 'Gene', '56114', (48, 55))	('LGR6', 'Gene', (61, 65))
1474	32355204	Silencing Bcl-3 suppresses the self-renewal capacity of colorectal CSCs and sensitizes CRC cells to chemotherapeutic drugs through a decrease in Wnt/beta-catenin signaling.	('sensitizes', 'Reg', (76, 86))	('suppresses', 'NegReg', (16, 26))	('colorectal CSCs', 'Disease', (56, 71))	('decrease', 'NegReg', (133, 141))	('signaling', 'biological_process', 'GO:0023052', ('162', '171'))	('colorectal CSCs', 'Disease', 'MESH:D015179', (56, 71))	('CRC', 'Phenotype', 'HP:0003003', (87, 90))	('beta-catenin', 'Gene', (149, 161))	('Bcl-3', 'Gene', (10, 15))	('beta-catenin', 'Gene', '1499', (149, 161))	('Silencing', 'Var', (0, 9))
1477	32355204	Bcl-3 depletion decreases the Ac-K49-beta-catenin level by increasing the level of histone deacetylase 1 to remove acetyl groups from beta-catenin, thus interrupting Wnt/beta-catenin activity.	('beta-catenin', 'Gene', '1499', (134, 146))	('histone deacetylase 1', 'Gene', '3065', (83, 104))	('beta-catenin', 'Gene', (170, 182))	('beta-catenin', 'Gene', (37, 49))	('depletion', 'Var', (6, 15))	('increasing', 'PosReg', (59, 69))	('beta-catenin', 'Gene', '1499', (37, 49))	('beta-catenin', 'Gene', '1499', (170, 182))	('histone deacetylase 1', 'Gene', (83, 104))	('decreases', 'NegReg', (16, 25))	('beta-catenin', 'Gene', (134, 146))	('interrupting', 'NegReg', (153, 165))
1491	32355204	Under normal circumstances, GSK-3 phosphorylates beta-catenin on its N-terminal Thr41, Ser37, and Ser33 residues.	('beta-catenin', 'Gene', (49, 61))	('Ser33', 'Var', (98, 103))	('Ser37', 'Chemical', '-', (87, 92))	('Ser33', 'Chemical', '-', (98, 103))	('GSK-3', 'Gene', (28, 33))	('beta-catenin', 'Gene', '1499', (49, 61))	('Ser37', 'Var', (87, 92))	('Thr41', 'Chemical', '-', (80, 85))
1516	32355204	2a, b, Bcl-3 depletion significantly suppressed xenograft tumor growth and tumorigenic cell frequency.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('depletion', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('suppressed', 'NegReg', (37, 47))
1517	32355204	2c), suggesting that Bcl-3 KD reduced tumor-initiating capacity.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('reduced', 'NegReg', (30, 37))	('Bcl-3 KD', 'Var', (21, 29))
1522	32355204	Bcl-3 depletion markedly reduced chemoresistance and increased the percentage of apoptotic cells upon treatment with 5-FU and Oxal (Fig.	('reduced', 'NegReg', (25, 32))	('Bcl-3', 'Protein', (0, 5))	('chemoresistance', 'CPA', (33, 48))	('Oxal', 'Chemical', 'MESH:D000077150', (126, 130))	('depletion', 'Var', (6, 15))	('increased', 'PosReg', (53, 62))	('5-FU', 'Chemical', 'MESH:D005472', (117, 121))
1523	32355204	These data suggest that Bcl-3 depletion increases 5-FU- and Oxal-induced cell apoptosis, and enhances drug sensitivity in CRC cells.	('enhances', 'PosReg', (93, 101))	('5-FU-', 'MPA', (50, 55))	('CRC', 'Phenotype', 'HP:0003003', (122, 125))	('Oxal', 'Chemical', 'MESH:D000077150', (60, 64))	('depletion', 'Var', (30, 39))	('Bcl-3', 'Gene', (24, 29))	('drug sensitivity', 'Phenotype', 'HP:0020174', (102, 118))	('5-FU', 'Chemical', 'MESH:D005472', (50, 54))	('drug sensitivity', 'MPA', (102, 118))	('increases', 'PosReg', (40, 49))
1531	32355204	As GSK-3 binds to and phosphorylates Bcl-3 at Ser394/398, which causes the degradation of Bcl-3 by the ubiquitin-proteasome system, we confirmed that the GSK-3 inhibitor SB216763 significantly increased Bcl-3 expression (Supplementary Fig.	('SB216763', 'Var', (170, 178))	('SB216763', 'Chemical', 'MESH:C417521', (170, 178))	('expression', 'MPA', (209, 219))	('degradation', 'biological_process', 'GO:0009056', ('75', '86'))	('proteasome', 'cellular_component', 'GO:0000502', ('113', '123'))	('proteasome', 'molecular_function', 'GO:0004299', ('113', '123'))	('ubiquitin', 'molecular_function', 'GO:0031386', ('103', '112'))	('GSK', 'molecular_function', 'GO:0050321', ('3', '6'))	('Bcl-3', 'Gene', (203, 208))	('Ser394', 'Chemical', '-', (46, 52))	('degradation', 'MPA', (75, 86))	('increased', 'PosReg', (193, 202))	('GSK', 'molecular_function', 'GO:0050321', ('154', '157'))	('Ser', 'cellular_component', 'GO:0005790', ('46', '49'))	('expression', 'Species', '29278', (209, 219))
1544	32355204	Interestingly, Bcl-3 KD strongly inhibited TOP/Flash reporter expression in the HCT116 cell line with or without Wnt3a treatment (Fig.	('expression', 'Species', '29278', (62, 72))	('Wnt3a', 'Gene', (113, 118))	('Bcl-3 KD', 'Var', (15, 23))	('HCT116', 'CellLine', 'CVCL:0291', (80, 86))	('TOP/Flash reporter expression', 'MPA', (43, 72))	('Wnt3a', 'Gene', '89780', (113, 118))	('inhibited', 'NegReg', (33, 42))
1551	32355204	The mRNA levels of AXIN2 and ZCCHC12 were decreased in HCT116 cells with Bcl-3 KD (Fig.	('Bcl-3 KD', 'Var', (73, 81))	('decreased', 'NegReg', (42, 51))	('ZCCHC12', 'Gene', '170261', (29, 36))	('HCT116', 'CellLine', 'CVCL:0291', (55, 61))	('ZCCHC12', 'Gene', (29, 36))	('AXIN2', 'Gene', (19, 24))	('AXIN2', 'Gene', '8313', (19, 24))
1556	32355204	In addition, we cotransfected vectors encoding Flag-tagged Bcl-3, HA-tagged beta-catenin (WT), or an N-terminal deletion mutant of beta-catenin (dN89, transcriptionally active form of beta-catenin lacking the N-terminal 89 amino acids) into HEK293T cells, followed by IP of the cell lysates with an antibody against the HA tag.	('beta-catenin', 'Gene', (131, 143))	('beta-catenin', 'Gene', (76, 88))	('deletion', 'Var', (112, 120))	('beta-catenin', 'Gene', (184, 196))	('beta-catenin', 'Gene', '1499', (184, 196))	('beta-catenin', 'Gene', '1499', (131, 143))	('beta-catenin', 'Gene', '1499', (76, 88))	('HEK293T', 'CellLine', 'CVCL:0063', (241, 248))	('lacking', 'NegReg', (197, 204))
1557	32355204	Immunoblot assays revealed that both WT and dN89 beta-catenin could bind to Bcl-3 (Fig.	('beta-catenin', 'Gene', (49, 61))	('bind', 'Interaction', (68, 72))	('beta-catenin', 'Gene', '1499', (49, 61))	('dN89', 'Var', (44, 48))
1559	32355204	To ascertain whether Bcl-3 mutants affect the transcriptional activity of Wnt/beta-catenin signaling, Bcl-3 full-length and mutant constructs were cotransfected with TOP/FOP Flash luciferase reporter vectors into 293T cells.	('mutants', 'Var', (27, 34))	('affect', 'Reg', (35, 41))	('293T', 'CellLine', 'CVCL:0063', (213, 217))	('Bcl-3', 'Gene', (102, 107))	('mutant', 'Var', (124, 130))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('transcriptional activity', 'MPA', (46, 70))	('Bcl-3', 'Gene', (21, 26))	('beta-catenin', 'Gene', (78, 90))	('beta-catenin', 'Gene', '1499', (78, 90))
1560	32355204	5d), overexpression of full-length Bcl-3 and dC116 (a mutant form of Bcl-3 lacking the C-terminal 116 amino acids) mutants strongly activated TOP/Flash reporter activity, whereas dN125 and dNC did not (Fig.	('activated', 'PosReg', (132, 141))	('TOP/Flash reporter activity', 'MPA', (142, 169))	('expression', 'Species', '29278', (9, 19))	('dC116', 'Gene', (45, 50))	('dNC', 'Gene', (189, 192))	('mutants', 'Var', (115, 122))	('dN125', 'Chemical', '-', (179, 184))	('dNC', 'Gene', '31309', (189, 192))
1571	32355204	When de novo protein synthesis was inhibited by CHX, the degradation of Ac-K49 beta-catenin was remarkably faster in Bcl-3-silenced cells than in control cells (Fig.	('Ac-K49', 'Var', (72, 78))	('faster', 'PosReg', (107, 113))	('beta-catenin', 'Gene', '1499', (79, 91))	('degradation', 'MPA', (57, 68))	('CHX', 'Chemical', 'MESH:D003513', (48, 51))	('inhibited', 'NegReg', (35, 44))	('beta-catenin', 'Gene', (79, 91))
1577	32355204	The number of spheres in ICG-001-treated HCT116 cells was found to be >2-fold less than the number of spheres formed in DMSO-treated cells (Supplementary Fig.	('spheres', 'CPA', (14, 21))	('DMSO', 'Chemical', 'MESH:D004121', (120, 124))	('less', 'NegReg', (78, 82))	('HCT116', 'CellLine', 'CVCL:0291', (41, 47))	('ICG-001-treated', 'Var', (25, 40))	('ICG-001', 'Chemical', 'MESH:C492448', (25, 32))
1612	32355204	Taken together, these data indicate Bcl-3 as a potential biomarker for CRC, and the prognosis of patients with high Bcl-3 expression was worse than that of patients with low Bcl-3 expression.	('patients', 'Species', '9606', (156, 164))	('CRC', 'Disease', (71, 74))	('Bcl-3', 'Gene', (116, 121))	('expression', 'Species', '29278', (180, 190))	('CRC', 'Phenotype', 'HP:0003003', (71, 74))	('expression', 'Species', '29278', (122, 132))	('high', 'Var', (111, 115))	('patients', 'Species', '9606', (97, 105))
1623	32355204	Aside from the phosphorylation of GSK-3 at S394/398, other kinases, including Akt, Erk2, and IKK, participate in Bcl-3 phosphorylation and regulate its transcriptional activity.	('S394/398', 'Var', (43, 51))	('regulate', 'Reg', (139, 147))	('Bcl-3 phosphorylation', 'MPA', (113, 134))	('GSK-3', 'Gene', (34, 39))	('Erk2', 'Gene', '5594', (83, 87))	('Erk2', 'molecular_function', 'GO:0004707', ('83', '87'))	('Akt', 'Gene', '207', (78, 81))	('GSK', 'molecular_function', 'GO:0050321', ('34', '37'))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))	('transcriptional activity', 'MPA', (152, 176))	('IKK', 'molecular_function', 'GO:0008384', ('93', '96'))	('Erk2', 'Gene', (83, 87))	('participate', 'Reg', (98, 109))	('Akt', 'Gene', (78, 81))	('phosphorylation', 'biological_process', 'GO:0016310', ('15', '30'))
1624	32355204	The phosphorylation of Bcl-3 at Ser33 through Akt could promote Bcl-3 stabilization and nuclear localization.	('Ser33', 'Chemical', '-', (32, 37))	('nuclear', 'CPA', (88, 95))	('Akt', 'Gene', '207', (46, 49))	('Akt', 'Gene', (46, 49))	('Bcl-3', 'MPA', (64, 69))	('promote', 'PosReg', (56, 63))	('phosphorylation', 'Var', (4, 19))
1632	32355204	Because of the crucial role of Wnt signaling in CRC progression and colorectal CSC maintenance, inhibition of Wnt/beta-catenin signaling by targeting Bcl-3 may offer a therapeutic approach in CRC treatment.	('CRC', 'Disease', (48, 51))	('beta-catenin', 'Gene', (114, 126))	('CRC', 'Phenotype', 'HP:0003003', (192, 195))	('signaling', 'biological_process', 'GO:0023052', ('127', '136'))	('Bcl-3', 'Gene', (150, 155))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('signaling', 'biological_process', 'GO:0023052', ('35', '44'))	('beta-catenin', 'Gene', '1499', (114, 126))	('CRC', 'Disease', (192, 195))	('inhibition', 'Var', (96, 106))
1725	31892257	The important metabolites of the G. oblongifolia species; polyisoprenylated benzophenones and xanthones have anticancer, antioxidant, antifungal, apoptotic, and anti-pathogenic properties.	('polyisoprenylated', 'Var', (58, 75))	('oblongifolia species', 'Disease', 'MESH:C564159', (36, 56))	('G. oblongifolia', 'Species', '1009475', (33, 48))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('oblongifolia species', 'Disease', (36, 56))	('cancer', 'Disease', (113, 119))	('apoptotic', 'CPA', (146, 155))	('xanthones', 'Chemical', 'MESH:D044004', (94, 103))	('benzophenones', 'Chemical', 'MESH:D001577', (76, 89))	('antioxidant', 'CPA', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('anti-pathogenic properties', 'CPA', (161, 187))	('antifungal', 'CPA', (134, 144))
1731	31892257	The vacuole size was increased at high concentrations of 500 g/mL and 1000 g/mL.	('increased', 'PosReg', (21, 30))	('vacuole size', 'CPA', (4, 16))	('rat', 'Species', '10116', (46, 49))	('1000 g/mL', 'Var', (70, 79))
1802	31892257	reported the inhibition of cell growth by isoegomaketone when treated for over 24 h, cleaved caspase-3, 8, and 9 in a time-dependent and dose-dependent manner.	('caspase-3', 'Gene', (93, 102))	('isoegomaketone', 'Chemical', 'MESH:C568138', (42, 56))	('caspase-3', 'Gene', '836', (93, 102))	('cleaved', 'Var', (85, 92))	('inhibition', 'NegReg', (13, 23))	('cell growth', 'CPA', (27, 38))	('inhibition of cell growth', 'biological_process', 'GO:0030308', ('13', '38'))
1812	31892257	In addition, platycodin D upregulate cellular levels of protein Bax and Bcl-2 and downregulate the activation of caspase-9.	('platycodin D', 'Chemical', 'MESH:C108953', (13, 25))	('activation', 'MPA', (99, 109))	('Bcl-2', 'Gene', (72, 77))	('downregulate', 'NegReg', (82, 94))	('caspase-9', 'Gene', '842', (113, 122))	('Bcl-2', 'Gene', '596', (72, 77))	('upregulate', 'PosReg', (26, 36))	('Bax', 'Gene', (64, 67))	('caspase-9', 'Gene', (113, 122))	('platycodin', 'Var', (13, 23))	('Bax', 'Gene', '581', (64, 67))
1817	31892257	showed that suppression of telomerase activity and cytotoxic effect on leukemia cells by platycodin D was through post-translational and transcriptional inhibition of hTERT.	('leukemia', 'Disease', (71, 79))	('platycodin D', 'Chemical', 'MESH:C108953', (89, 101))	('inhibition', 'NegReg', (153, 163))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('platycodin', 'Var', (89, 99))	('cytotoxic effect', 'CPA', (51, 67))	('suppression', 'NegReg', (12, 23))	('hTERT', 'Gene', '7015', (167, 172))	('leukemia', 'Disease', 'MESH:D007938', (71, 79))	('telomerase', 'CPA', (27, 37))	('hTERT', 'Gene', (167, 172))
1892	31892257	But on the other hand, the knockdown of Tie2 decreases the inhibitory activities of triptolide on endothelial network formation.	('knockdown', 'Var', (27, 36))	('decreases', 'NegReg', (45, 54))	('Tie2', 'Gene', (40, 44))	('inhibitory activities of triptolide', 'MPA', (59, 94))	('formation', 'biological_process', 'GO:0009058', ('118', '127'))	('endothelial network', 'MPA', (98, 117))	('Tie2', 'Gene', '7010', (40, 44))	('triptolide', 'Chemical', 'MESH:C001899', (84, 94))
1913	31892257	The study of B16F-10 melanoma metastatic cell line showed that the concentrations of some important antioxidant enzymes (including catalase, superoxide dismutase, and glutathione peroxidase) increased many folds in the treatment groups.	('men', 'Species', '9606', (224, 227))	('catalase', 'Gene', (131, 139))	('B16F', 'Var', (13, 17))	('rat', 'Species', '10116', (74, 77))	('concentrations', 'MPA', (67, 81))	('increased', 'PosReg', (191, 200))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('catalase', 'Gene', '12359', (131, 139))	('melanoma', 'Disease', (21, 29))	('antioxidant enzymes', 'MPA', (100, 119))	('B16F', 'SUBSTITUTION', 'None', (13, 17))	('melanoma', 'Disease', 'MESH:D008545', (21, 29))	('superoxide dismutase', 'MPA', (141, 161))	('superoxide', 'Chemical', 'MESH:D013481', (141, 151))	('glutathione', 'Chemical', 'MESH:D005978', (167, 178))
1919	31892257	For instance, dihydroartemisinin was reported to inhibit tumor tissue, increase the level of interferon-gamma (IFN-gamma), and decrease interleukin 4 (IL-4) in tumor-bearing mice.	('mice', 'Species', '10090', (174, 178))	('IFN-gamma', 'Gene', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('increase', 'PosReg', (71, 79))	('interferon-gamma', 'Gene', '15978', (93, 109))	('interferon-gamma', 'Gene', (93, 109))	('dihydroartemisinin', 'Var', (14, 32))	('interleukin 4', 'Gene', (136, 149))	('tumor', 'Disease', (57, 62))	('dihydroartemisinin', 'Chemical', 'MESH:C039060', (14, 32))	('interleukin 4', 'Gene', '16189', (136, 149))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('IL-4', 'Gene', (151, 155))	('tumor', 'Disease', (160, 165))	('decrease', 'NegReg', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('IL-4', 'Gene', '16189', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('IFN-gamma', 'Gene', '15978', (111, 120))	('inhibit', 'NegReg', (49, 56))
1944	31892257	Manjamalai and Grace reported the apoptosis along with lowering angiogenesis and lung metastasis activities of the essential oils of W. chinensis by using B16F-10 melanoma cell line in C57BL/6 mice.	('apoptosis', 'biological_process', 'GO:0006915', ('34', '43'))	('angiogenesis', 'biological_process', 'GO:0001525', ('64', '76'))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('lung metastasis activities', 'CPA', (81, 107))	('angiogenesis', 'CPA', (64, 76))	('W. chinensis', 'Species', '318065', (133, 145))	('B16F', 'SUBSTITUTION', 'None', (155, 159))	('essential oils', 'Chemical', 'MESH:D009822', (115, 129))	('apoptosis', 'CPA', (34, 43))	('mice', 'Species', '10090', (193, 197))	('apoptosis', 'biological_process', 'GO:0097194', ('34', '43'))	('lowering', 'NegReg', (55, 63))	('B16F', 'Var', (155, 159))
1945	31892257	The mice were injected with B16F-10 melanoma cells through the tail vein and treated with different doses of essential oil.	('B16F', 'SUBSTITUTION', 'None', (28, 32))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('mice', 'Species', '10090', (4, 8))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('essential oil', 'Chemical', 'MESH:D009822', (109, 122))	('B16F', 'Var', (28, 32))
1953	31892257	Results of the study reported that dimer-Sal, dimer-OH, and DHA significantly suppressed tumors in rats compared to the control group.	('tumors', 'Disease', (89, 95))	('rats', 'Species', '10116', (99, 103))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('dimer-OH', 'Var', (46, 54))	('suppressed', 'NegReg', (78, 88))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('DHA', 'Chemical', 'MESH:C039060', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
1991	31892257	Many studies have reported inhibition of enzymes that stops tumor growth.	('enzymes', 'Enzyme', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('inhibition', 'Var', (27, 37))	('tumor', 'Disease', (60, 65))
2004	31164625	The dysregulation of oncogenes or tumor suppressor genes in tumor cells results in alterations in cell growth, apoptosis, migration, invasion, and so on.	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('34', '50'))	('invasion', 'CPA', (133, 141))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('dysregulation', 'Var', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('34', '50'))	('oncogenes', 'Gene', (21, 30))	('cell growth', 'CPA', (98, 109))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('migration', 'CPA', (122, 131))	('tumor', 'Disease', (60, 65))	('apoptosis', 'CPA', (111, 120))	('cell growth', 'biological_process', 'GO:0016049', ('98', '109'))	('alterations', 'Reg', (83, 94))
2007	31164625	Increasing evidence has shown that dysregulated mRNAs is a potential tumor markers to predict disease progression and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('dysregulated', 'Var', (35, 47))	('disease progression', 'CPA', (94, 113))	('metastasis', 'CPA', (118, 128))	('tumor', 'Disease', (69, 74))	('mRNAs', 'Protein', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
2022	31164625	The membrane was then treated with TBST containing 50 g/L skimmed milk at room temperature for 4 hours, followed by incubation with the primary antibodies: anti-CLCA4 anti-E-cadherin (1: 1000, Proteintech), anti-N-cadherin (1: 1000, Proteintech), anti-Vimentin (1: 2000, Proteintech), anti-alpha-SMA (1: 500, Proteintech), anti-Snail (1: 200, Proteintech), anti-PI3K (1: 2000, Abcam), anti-p-PI3K (1: 1000, Abcam), anti-pan AKT (1: 500, Abcam), anti-p-AKT (1: 5000, Abcam), and anti-GAPDH (1: 1000, Proteintech) respectively, at 37 C for 1 hour.	('1: 2000', 'Var', (368, 375))	('AKT', 'Gene', '207', (424, 427))	('N-cadherin', 'Gene', (212, 222))	('anti-pan', 'Var', (415, 423))	('N-cadherin', 'Gene', '1000', (212, 222))	('Vimentin', 'cellular_component', 'GO:0045099', ('252', '260'))	('E-cadherin', 'Gene', (172, 182))	('E-cadherin', 'Gene', '999', (172, 182))	('AKT', 'Gene', (452, 455))	('Snail', 'Gene', (328, 333))	('GAPDH', 'Gene', '2597', (483, 488))	('membrane', 'cellular_component', 'GO:0016020', ('4', '12'))	('PI3K', 'molecular_function', 'GO:0016303', ('362', '366'))	('Vimentin', 'Gene', '7431', (252, 260))	('Vimentin', 'cellular_component', 'GO:0045098', ('252', '260'))	('AKT', 'Gene', '207', (452, 455))	('cadherin', 'molecular_function', 'GO:0008014', ('214', '222'))	('AKT', 'Gene', (424, 427))	('Vimentin', 'Gene', (252, 260))	('GAPDH', 'Gene', (483, 488))	('anti-p-PI3K', 'Var', (385, 396))	('Snail', 'Gene', '6615', (328, 333))	('cadherin', 'molecular_function', 'GO:0008014', ('174', '182'))	('PI3K', 'molecular_function', 'GO:0016303', ('392', '396'))	('1: 1000', 'Var', (398, 405))
2042	31164625	Especially, the expression level of CLCA4 is even lower in LoVo and SW620, which have higher metastatic potential (Figure 2A).	('metastatic potential', 'CPA', (93, 113))	('lower', 'NegReg', (50, 55))	('SW620', 'CellLine', 'CVCL:0547', (68, 73))	('SW620', 'Var', (68, 73))	('expression level', 'MPA', (16, 32))	('CLCA4', 'Gene', (36, 41))	('higher', 'PosReg', (86, 92))	('LoVo', 'CellLine', 'CVCL:0399', (59, 63))
2049	31164625	It was found that CLCA4 over-expression could enhance the expression of epithelial cell marker E-cadherin but decrease the mesenchymal markers N-cadherin, Vimentin, Snail and alpha-SMA exactly (Figure 3F).	('Vimentin', 'Gene', (155, 163))	('Vimentin', 'cellular_component', 'GO:0045099', ('155', '163'))	('N-cadherin', 'Gene', (143, 153))	('E-cadherin', 'Gene', (95, 105))	('expression', 'MPA', (58, 68))	('Snail', 'Gene', (165, 170))	('cadherin', 'molecular_function', 'GO:0008014', ('97', '105'))	('N-cadherin', 'Gene', '1000', (143, 153))	('Snail', 'Gene', '6615', (165, 170))	('E-cadherin', 'Gene', '999', (95, 105))	('Vimentin', 'Gene', '7431', (155, 163))	('cadherin', 'molecular_function', 'GO:0008014', ('145', '153'))	('mesenchymal', 'CPA', (123, 134))	('decrease', 'NegReg', (110, 118))	('enhance', 'PosReg', (46, 53))	('over-expression', 'Var', (24, 39))	('Vimentin', 'cellular_component', 'GO:0045098', ('155', '163'))	('CLCA4', 'Gene', (18, 23))
2050	31164625	Meanwhile, the western blot results showed that CLCA4 over-expression could inhibit the activation of PI3K-AKT signaling to some extent (Figure 3G).	('CLCA4', 'Gene', (48, 53))	('inhibit', 'NegReg', (76, 83))	('AKT', 'Gene', (107, 110))	('over-expression', 'Var', (54, 69))	('AKT', 'Gene', '207', (107, 110))
2056	31164625	Over-expression of CLCA4 could reduce the invasive and migration abilities of SW620 and LoVo cells through EMT inhibition.	('EMT', 'CPA', (107, 110))	('CLCA4', 'Gene', (19, 24))	('LoVo', 'CellLine', 'CVCL:0399', (88, 92))	('reduce', 'NegReg', (31, 37))	('Over-expression', 'Var', (0, 15))	('SW620', 'CellLine', 'CVCL:0547', (78, 83))
2062	31164625	As for CLCA4, it has been reported that loss of CLCA4 promotes epithelial-to-mesenchymal transition in breast cancer cells which suggested the regulation of CLCA4 on EMT for the first time.	('epithelial-to-mesenchymal transition', 'CPA', (63, 99))	('CLCA4', 'Gene', (48, 53))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('loss', 'Var', (40, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('promotes', 'PosReg', (54, 62))
2114	30031768	Colonoscopy procedures were identified using Current Procedural Terminology codes (44388-44394, 44397, 44398, 44401-44403, 44405, 45355, 45378-45393), International Classification of Disease procedure codes (45.21-45.23, 45.25, 45.42, 45.43, 98.04, as well as codes 48.24 and 48.36 [rectal biopsy] when there was no corresponding sigmoidoscopy procedure on or near the procedure date), Healthcare Common Procedure Coding System codes (G0105, G0121), and internal codes for tracking colonoscopies performed prior to joining KPNC (12142332, 204456, 230847, and 235525).	('204456', 'Var', (539, 545))	('235525', 'Var', (559, 565))	('12142332', 'Var', (529, 537))	('230847', 'Var', (547, 553))	('230847, and 235525', 'Chemical', 'None', (547, 565))
2115	30031768	Sigmoidoscopy procedures were identified using Current Procedural Terminology codes (45300, 45303, 45305, 45307-45309, 45315, 45317, 45320, 45321, 45327, 45330-45335, 45337-45342, and 45345), International Classification of Disease procedure codes (45.24 and 48.21-48.23), and internal codes for tracking sigmoidoscopies performed prior to joining (224770 and 230854).	('230854', 'Var', (360, 366))	('45330-45335', 'Var', (154, 165))	('224770 and 230854', 'Chemical', 'None', (349, 366))	('45317', 'Var', (126, 131))	('45320', 'Var', (133, 138))	('45321', 'Var', (140, 145))	('45307-45309', 'Var', (106, 117))	('45300', 'Var', (85, 90))	('45315', 'Var', (119, 124))	('45305', 'Var', (99, 104))	('224770', 'Var', (349, 355))
2116	30031768	Colorectal cancer was defined as an adenocarcinoma within the colon or rectum using Surveillance Epidemiology and End Results (SEER) cancer site group codes 21040 and 21050, and International Classification of Disease oncology codes C18.0-C18.9, C19.9, and C20.9.	('adenocarcinoma within the colon', 'Phenotype', 'HP:0040276', (36, 67))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('C20.9', 'Var', (257, 262))	('C19.9', 'CellLine', 'CVCL:F711', (246, 251))	('oncology', 'Phenotype', 'HP:0002664', (218, 226))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('adenocarcinoma within the colon', 'Disease', (36, 67))	('cancer', 'Disease', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('C18.0-C18.9', 'Var', (233, 244))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('Colorectal cancer', 'Disease', (0, 17))	('cancer', 'Disease', (11, 17))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('adenocarcinoma within the colon', 'Disease', 'MESH:D015179', (36, 67))	('C19.9', 'Var', (246, 251))
2150	30031768	Changes from modified risk factors, for example, would be expected to influence both cancer incidence and mortality among all age groups, whereas reduced incidence from CRC screening, such as through polyp removal in the younger age group, would largely be anticipated, as seen in the current data, with cancer incidence until several years later, among older patients.	('CRC', 'Disease', (169, 172))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (304, 310))	('CRC', 'Phenotype', 'HP:0003003', (169, 172))	('mortality', 'CPA', (106, 115))	('cancer', 'Disease', (85, 91))	('Changes', 'Var', (0, 7))	('patients', 'Species', '9606', (360, 368))	('CRC', 'Disease', 'MESH:D015179', (169, 172))	('influence', 'Reg', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
2164	28075415	Our study results indicated that the PM153 strain exhibits the best adhesion ability and the highest survival in the gastrointestinal tract simulation experiment.	('gastrointestinal tract', 'Disease', 'MESH:D004067', (117, 139))	('adhesion ability', 'CPA', (68, 84))	('gastrointestinal tract', 'Disease', (117, 139))	('PM153', 'Var', (37, 42))	('survival', 'CPA', (101, 109))
2165	28075415	Furthermore, after an 8-h co-culture of PM153 and HT-29 cells, the PM153 strain can induce the secretion of nitric oxide from the HT-29 cells.	('induce', 'PosReg', (84, 90))	('HT-29 cells', 'CellLine', 'CVCL:0320', (50, 61))	('HT-29 cells', 'CellLine', 'CVCL:0320', (130, 141))	('secretion of nitric oxide', 'MPA', (95, 120))	('PM153', 'Var', (67, 72))	('nitric oxide', 'Chemical', 'MESH:D009569', (108, 120))
2166	28075415	In addition, after the co-culture of the BCRC17010 strain (109 cfu/mL) and HT-29 cells, the Bax/Bcl-2 ratio in the HT-29 cells was 1.19, which showed a significant difference from the other control and LAB groups (p < 0.05), which therefore led to the inference that the BCRC17010 strain exerts a pro-apoptotic effect on the HT-29 cells.	('Bcl-2', 'Gene', (96, 101))	('Bcl-2', 'Gene', '596', (96, 101))	('HT-29 cells', 'CellLine', 'CVCL:0320', (115, 126))	('Bax', 'Gene', (92, 95))	('HT-29 cells', 'CellLine', 'CVCL:0320', (325, 336))	('pro-apoptotic effect', 'CPA', (297, 317))	('HT-29 cells', 'CellLine', 'CVCL:0320', (75, 86))	('BCRC17010 strain', 'Var', (271, 287))	('BCRC17010', 'Var', (41, 50))	('Bax', 'Gene', '581', (92, 95))
2169	28075415	In summary, we demonstrated that the BCRC17010 strain, good abilities of adhesion and increased LDH release, was the best probiotic potential for inhibition of HT-29 growth amongst the seven LAB strains tested in vitro.	('increased', 'PosReg', (86, 95))	('HT-29', 'CellLine', 'CVCL:0320', (160, 165))	('inhibition', 'NegReg', (146, 156))	('BCRC17010', 'Var', (37, 46))	('adhesion', 'CPA', (73, 81))	('HT-29', 'Protein', (160, 165))	('LDH release', 'MPA', (96, 107))
2195	28075415	Table 3 shows that the IC 50 values for the HT-29 cells treated with supernatants from the seven Lactobacillus strains are 479.2 muL/mL (BCRC17010), 609.8 muL/mL (BCRC10696), 370.7 muL/mL (BCRC14625), 467.9 muL/mL (BCRC14759), 667.5 muL/mL (PM150), 299.3 muL/mL (PM153) and 134.9 muL/mL (PM177).	('Lactobacillus', 'Species', '33959', (97, 110))	('BCRC10696', 'Var', (163, 172))	('HT-29 cells', 'CellLine', 'CVCL:0320', (44, 55))	('BCRC14759', 'Var', (215, 224))
2197	28075415	The results showed that the supernatants (500 muL/mL) of BCRC17010 and BCRC14625, compared to those in other concentrations, induced a significant increase in LDH concentration, indicating that supernatants of high concentration will damage the HT-29 cell membrane causing LDH release (Figure 2A).	('HT-29', 'CellLine', 'CVCL:0320', (245, 250))	('damage', 'Reg', (234, 240))	('LDH concentration', 'MPA', (159, 176))	('BCRC17010', 'Var', (57, 66))	('release', 'MPA', (277, 284))	('LDH', 'MPA', (273, 276))	('BCRC14625', 'Var', (71, 80))	('increase', 'PosReg', (147, 155))
2198	28075415	For Lactobacillus cells, the LDH level was significantly increased (p < 0.05) upon co-culture of BCRC14625 (109 cfu/mL) with HT-29 cells for 4, 8 and 12 h. Similarly, the LDH level was also elevated (p < 0.05) upon co-culture of 108 cfu/mL of BCRC14625 and HT-29 cells for 12 h. Thus, it can be concluded that BCRC14625 damages the HT-29 cell membrane, leading to the release of LDH, and that lower numbers of bacteria would take longer to cause harm in the cell membrane (Figure 2B).	('LDH', 'MPA', (379, 382))	('BCRC14625', 'Var', (310, 319))	('HT-29 cells', 'CellLine', 'CVCL:0320', (125, 136))	('HT-29', 'CellLine', 'CVCL:0320', (332, 337))	('Lactobacillus', 'Species', '33959', (4, 17))	('HT-29', 'CellLine', 'CVCL:0320', (257, 262))	('HT-29', 'CellLine', 'CVCL:0320', (125, 130))	('HT-29 cells', 'CellLine', 'CVCL:0320', (257, 268))	('release', 'MPA', (368, 375))
2199	28075415	The ratios of Bax/Bcl-2 protein expression in the HT-29 cells incubated with BCRC14625 were less than 1 (Figure 3).	('Bcl-2', 'Gene', (18, 23))	('HT-29 cells', 'CellLine', 'CVCL:0320', (50, 61))	('Bax', 'Gene', '581', (14, 17))	('Bcl-2', 'molecular_function', 'GO:0015283', ('18', '23'))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('BCRC14625', 'Var', (77, 86))	('Bax', 'Gene', (14, 17))	('Bcl-2', 'Gene', '596', (18, 23))
2200	28075415	To assess the effect of Lactobacillus cells on HT-29 cell apoptosis, the ratio of Bax and Bcl-2 protein expression was determined after incubating the HT-29 cells with 109 cfu/mL of Lactobacillus cells for 8 h. The Bax/Bcl-2 ratio in response to BCRC17010 was 1.19, which was significantly different from that in response to other strains (p < 0.05), demonstrating that the BCRC17010 cells showed a pro-apoptotic effect in the HT-29 cells (Figure 4).	('Lactobacillus', 'Species', '33959', (182, 195))	('HT-29', 'CellLine', 'CVCL:0320', (427, 432))	('Bax', 'Gene', (215, 218))	('Bcl-2', 'Gene', (90, 95))	('HT-29', 'CellLine', 'CVCL:0320', (47, 52))	('Bcl-2', 'Gene', '596', (90, 95))	('HT-29 cells', 'CellLine', 'CVCL:0320', (427, 438))	('pro-apoptotic effect', 'CPA', (399, 419))	('BCRC17010', 'Var', (374, 383))	('Bax', 'Gene', (82, 85))	('Bax', 'Gene', '581', (215, 218))	('Lactobacillus', 'Species', '33959', (24, 37))	('HT-29 cells', 'CellLine', 'CVCL:0320', (151, 162))	('HT-29', 'CellLine', 'CVCL:0320', (151, 156))	('Bax', 'Gene', '581', (82, 85))	('Bcl-2', 'Gene', (219, 224))	('Bcl-2', 'Gene', '596', (219, 224))
2203	28075415	In terms of Lactobacillus cells, after a 4-h treatment of the HT-29 cells with the Lactobacillus strains BCRC17010, BCRC14625, PM153 and PM177, the corresponding NO concentrations were not significantly different from that in the control group (p > 0.05) (Figure 5B).	('PM177', 'Var', (137, 142))	('PM153', 'Var', (127, 132))	('HT-29 cells', 'CellLine', 'CVCL:0320', (62, 73))	('BCRC17010', 'Var', (105, 114))	('Lactobacillus', 'Species', '33959', (12, 25))	('BCRC14625', 'Var', (116, 125))	('Lactobacillus', 'Species', '33959', (83, 96))
2204	28075415	The concentration of NO was also analysed after treating the HT-29 cells with individual Lactobacillus strains, showing that the NO concentration induced by BCRC14625 (109 cfu/mL) was significantly higher than that in the control group (p < 0.05) (Figure 5C).	('NO concentration', 'MPA', (129, 145))	('HT-29 cells', 'CellLine', 'CVCL:0320', (61, 72))	('BCRC14625', 'Var', (157, 166))	('Lactobacillus', 'Species', '33959', (89, 102))	('higher', 'PosReg', (198, 204))
2230	28075415	bulgarius BCRC10696, L. salivarius BCRC14759, L. reuteri BCRC14625, L. brevis PM150, L. plantarum PM153 and L. brevis PM177, were obtained from isolated strains of Lactobacillus found in fermented plant products (PM150, PM153 and PM177) or from the Bioresource Collection and Research Center (BCRC), Hsin-Chu, Taiwan.	('PM150', 'Var', (213, 218))	('PM177', 'Var', (230, 235))	('L. reuteri', 'Species', '1598', (46, 56))	('L. brevis', 'Species', '1580', (108, 117))	('L. plantarum', 'Species', '1590', (85, 97))	('L. salivarius', 'Species', '1624', (21, 34))	('Lactobacillus', 'Species', '33959', (164, 177))	('L. brevis', 'Species', '1580', (68, 77))
2266	28075415	In conclusion, the BCRC14625 strain causes harm to the HT-29 cell membrane according to significant increase in lactate dehydrogenase (LDH) activity.	('lactate dehydrogenase', 'MPA', (112, 133))	('increase in lactate dehydrogenase', 'Phenotype', 'HP:0025435', (100, 133))	('cell membrane', 'cellular_component', 'GO:0005886', ('61', '74'))	('harm', 'MPA', (43, 47))	('BCRC14625', 'Var', (19, 28))	('activity', 'MPA', (140, 148))	('HT-29', 'CellLine', 'CVCL:0320', (55, 60))	('increase', 'PosReg', (100, 108))
2268	28075415	Our findings are that the ratio of apoptotic proteins Bax: Bcl-2 for BCRC17010 significantly differed from other strains, indicating that BCRC17010 may lead to apoptosis via the apoptotic mitochondrial pathway.	('Bcl-2', 'molecular_function', 'GO:0015283', ('59', '64'))	('apoptosis', 'CPA', (160, 169))	('apoptosis', 'biological_process', 'GO:0097194', ('160', '169'))	('apoptosis', 'biological_process', 'GO:0006915', ('160', '169'))	('Bax', 'Gene', (54, 57))	('Bcl-2', 'Gene', (59, 64))	('apoptotic mitochondrial pathway', 'Pathway', (178, 209))	('Bax', 'Gene', '581', (54, 57))	('BCRC17010', 'Var', (138, 147))	('lead to', 'Reg', (152, 159))	('Bcl-2', 'Gene', '596', (59, 64))
2273	29423086	By gain- and loss-of-function studies, we showed miR-27b remarkably suppressed cell proliferation and invasion of colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('cell proliferation', 'CPA', (79, 97))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('suppressed', 'NegReg', (68, 78))	('invasion', 'CPA', (102, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('cell proliferation', 'biological_process', 'GO:0008283', ('79', '97'))	('miR-27b', 'Var', (49, 56))	('colorectal cancer', 'Disease', (114, 131))
2274	29423086	Finally, the animal experiment showed miR-27b plays a crucial role on colorectal cancer progression by targeting Rab3D.	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('Rab3D', 'Protein', (113, 118))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('targeting', 'Reg', (103, 112))	('miR-27b', 'Var', (38, 45))	('colorectal cancer', 'Disease', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
2275	29423086	Taken together, our study implied miR-27b inhibits cell growth and invasion by targeting Rab3D, and miR-27b is a potential biomarker for prognosis and therapeutic target in colorectal cancer.	('colorectal cancer', 'Disease', (173, 190))	('inhibits', 'NegReg', (42, 50))	('colorectal cancer', 'Disease', 'MESH:D015179', (173, 190))	('Rab3D', 'Protein', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('miR-27b', 'Var', (34, 41))	('targeting', 'Reg', (79, 88))	('miR-27b', 'Var', (100, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (173, 190))
2281	29423086	Previous study has shown miR-27b could inhibit promoter methylation and target HMGB3 mRNA to modulate tamoxifen resistance and epithelial-mesenchymal transition (EMT) in breast cancer cells.	('modulate', 'Reg', (93, 101))	('HMGB3', 'Gene', '3149', (79, 84))	('inhibit', 'NegReg', (39, 46))	('tamoxifen', 'Chemical', 'MESH:D013629', (102, 111))	('miR-27b', 'Var', (25, 32))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('tamoxifen resistance', 'MPA', (102, 122))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('breast cancer', 'Disease', (170, 183))	('target', 'Reg', (72, 78))	('promoter methylation', 'MPA', (47, 67))	('HMGB3', 'Gene', (79, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))
2283	29423086	found miR-27b exerts tumor-suppressive effects in gastric cancer through the suppression of oncogene ROR1 expression.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Disease', (21, 26))	('gastric cancer', 'Disease', (50, 64))	('expression', 'MPA', (106, 116))	('ROR1', 'Gene', (101, 105))	('miR-27b', 'Var', (6, 13))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))	('ROR1', 'Gene', '4919', (101, 105))	('suppression', 'NegReg', (77, 88))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
2285	29423086	In this study, we examined miR-27b expression in a large cohort of colorectal cancer tissue specimens and found miR-27b is tightly associated with overall survival of CRC patients.	('CRC', 'Phenotype', 'HP:0003003', (167, 170))	('miR-27b', 'Var', (112, 119))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('patients', 'Species', '9606', (171, 179))	('CRC', 'Disease', (167, 170))	('associated with', 'Reg', (131, 146))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colorectal cancer', 'Disease', (67, 84))
2286	29423086	Furthermore, in vitro experiments showed that miR-27b inhibited growth and invasion of colorectal cancer cells through targeting Rab3D.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('inhibited', 'NegReg', (54, 63))	('Rab3D', 'Gene', (129, 134))	('colorectal cancer', 'Phenotype', 'HP:0003003', (87, 104))	('targeting', 'Reg', (119, 128))	('colorectal cancer', 'Disease', (87, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (87, 104))	('miR-27b', 'Var', (46, 53))
2291	29423086	As shown in Table 1, the level of miR-27b was negatively associated with tumor size (P = 0.041) and tumor node metastasis (TNM) stage (P = 0.004).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('miR-27b', 'Var', (34, 41))	('negatively', 'NegReg', (46, 56))	('tumor node metastasis', 'Disease', 'MESH:D009362', (100, 121))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor node metastasis', 'Disease', (100, 121))
2293	29423086	The results revealed high expression of miR-27b was positively associated with overall survival (OS) (n = 80, P = 0.001, Figure 1E), which indicates that OS is better in CRC patients with high miR-27b expression than in those with low miR-27b expression.	('high', 'Var', (188, 192))	('miR-27b', 'Gene', (193, 200))	('miR-27b', 'Gene', (40, 47))	('CRC', 'Disease', (170, 173))	('patients', 'Species', '9606', (174, 182))	('CRC', 'Phenotype', 'HP:0003003', (170, 173))	('overall', 'Disease', (79, 86))
2300	29423086	Our data indicated that miR-27b can inhibit cell proliferation and invasion in colorectal cancer cells in vitro.	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('cell proliferation', 'CPA', (44, 62))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('invasion', 'CPA', (67, 75))	('inhibit', 'NegReg', (36, 43))	('colorectal cancer', 'Disease', (79, 96))	('cell proliferation', 'biological_process', 'GO:0008283', ('44', '62'))	('miR-27b', 'Var', (24, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))
2302	29423086	To verify whether miR-27b can bind to the predicted site of Rab3D, a human Rab3D 3' untranslated region (3'UTR) fragment containing the wild-type or mutant miR-27b-binding site was inserted downstream of the luciferase open reading frame (Figure 4A).	('binding', 'molecular_function', 'GO:0005488', ('164', '171'))	('mutant', 'Var', (149, 155))	('human', 'Species', '9606', (69, 74))	('miR-27b-binding', 'Gene', (156, 171))
2303	29423086	The luciferase reporter assay showed the relative luciferase activity was markedly decreased after co-transfection with pmirGLO/Rab3D-WT-3'UTR and miR-27b in SW480 and SW1116 cells, compared with control (Figure 4G).	('SW480', 'CellLine', 'CVCL:0546', (158, 163))	('decreased', 'NegReg', (83, 92))	('miR-27b', 'Var', (147, 154))	('luciferase', 'Enzyme', (50, 60))	("pmirGLO/Rab3D-WT-3'UTR", 'Var', (120, 142))	('SW1116', 'CellLine', 'CVCL:0544', (168, 174))	('activity', 'MPA', (61, 69))
2307	29423086	Finally, we found overall survival is poorer in CRC patients with high Rab3D expression than in those with low Rab3D expression (P = 0.01, Figure 5D).	('CRC', 'Disease', (48, 51))	('poorer', 'NegReg', (38, 44))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('Rab3D', 'Gene', (71, 76))	('high', 'Var', (66, 70))	('patients', 'Species', '9606', (52, 60))
2309	29423086	These data collectively indicated that miR-27b inhibits cell proliferation and invasion by targeting Rab3D, and that miR-27b may act as a "tumor suppressor" in colorectal cancer.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('targeting', 'Reg', (91, 100))	('colorectal cancer', 'Disease', 'MESH:D015179', (160, 177))	('miR-27b', 'Gene', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('colorectal cancer', 'Phenotype', 'HP:0003003', (160, 177))	('miR-27b', 'Var', (117, 124))	('cell proliferation', 'CPA', (56, 74))	('invasion', 'CPA', (79, 87))	('Rab3D', 'Protein', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('colorectal cancer', 'Disease', (160, 177))	('cell proliferation', 'biological_process', 'GO:0008283', ('56', '74'))	('inhibits', 'NegReg', (47, 55))
2310	29423086	To verify the effects of miR-27b on tumorigenesis in vivo, miR-27b agomir or control agomir was directly injected into the CRC implanted tumor, and found miR-27b significantly decreased tumor growth (Figure 7A-7C), not reduced tumor metastasis (date not showed).	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('miR-27b', 'Var', (154, 161))	('decreased', 'NegReg', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor metastasis', 'Disease', 'MESH:D009362', (227, 243))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor metastasis', 'Disease', (227, 243))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Disease', (36, 41))	('CRC', 'Phenotype', 'HP:0003003', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
2311	29423086	We also found overall survival is better in mice with high miR-27b expression than in those with low miR-27b expression (P = 0.0321, Figure 7D).	('mice', 'Species', '10090', (44, 48))	('high miR-27b expression', 'Var', (54, 77))	('better', 'PosReg', (34, 40))
2312	29423086	And the expression of miR-27b was significantly increased in the miR-27b treated with mice (Figure 7E).	('increased', 'PosReg', (48, 57))	('miR-27b', 'Gene', (22, 29))	('mice', 'Species', '10090', (86, 90))	('miR-27b', 'Var', (65, 72))	('expression', 'MPA', (8, 18))
2314	29423086	Accumulating evidence indicates that Dysregulation of miRNAs is connected with initiation and progression of CRC, since they may serve as oncogenes or tumor suppressors.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('miRNAs', 'Protein', (54, 60))	('connected', 'Reg', (64, 73))	('CRC', 'Disease', (109, 112))	('tumor', 'Disease', (151, 156))	('CRC', 'Phenotype', 'HP:0003003', (109, 112))	('Dysregulation', 'Var', (37, 50))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
2317	29423086	Similarly, miR-27b has been found in a poor prognostic phenotype of human gastric cancer, which is due to the regulatory effect on invasive growth and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('invasive growth', 'biological_process', 'GO:0007125', ('131', '146'))	('human', 'Species', '9606', (68, 73))	('invasive growth', 'biological_process', 'GO:0051831', ('131', '146'))	('invasive growth', 'CPA', (131, 146))	('miR-27b', 'Var', (11, 18))	('gastric cancer', 'Disease', (74, 88))	('invasive growth', 'biological_process', 'GO:0036267', ('131', '146'))	('invasive growth', 'biological_process', 'GO:0001404', ('131', '146'))	('gastric cancer', 'Disease', 'MESH:D013274', (74, 88))	('invasive growth', 'biological_process', 'GO:0044412', ('131', '146'))	('gastric cancer', 'Phenotype', 'HP:0012126', (74, 88))	('invasive growth', 'biological_process', 'GO:0044409', ('131', '146'))
2318	29423086	Therefore, it is reasonable to hypothesize miR-27b may play a role in the pathogenesis of CRC patients.	('pathogenesis', 'biological_process', 'GO:0009405', ('74', '86'))	('patients', 'Species', '9606', (94, 102))	('CRC patients', 'Disease', (90, 102))	('miR-27b', 'Var', (43, 50))	('CRC', 'Phenotype', 'HP:0003003', (90, 93))	('play', 'Reg', (55, 59))
2320	29423086	Importantly, Univariate and multivariate analysis suggested miR-27b expression was an independent risk factor for poor outcome of CRC patients.	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('miR-27b', 'Var', (60, 67))	('patients', 'Species', '9606', (134, 142))	('CRC', 'Disease', (130, 133))
2323	29423086	Consistent with the observation in ccRCC, we also demonstrated miR-27b acts as a tumor suppressor in CRC in cell proliferation and invasive capacity.	('tumor suppressor', 'biological_process', 'GO:0051726', ('81', '97'))	('CRC', 'Disease', (101, 104))	('cell proliferation', 'CPA', (108, 126))	('miR-27b', 'Var', (63, 70))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('81', '97'))	('invasive capacity', 'CPA', (131, 148))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('CRC', 'Phenotype', 'HP:0003003', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (35, 40))	('ccRCC', 'Disease', (35, 40))	('tumor', 'Disease', (81, 86))	('cell proliferation', 'biological_process', 'GO:0008283', ('108', '126'))
2324	29423086	These findings imply miR-27b may be function as tumor suppressor in CRC.	('CRC', 'Phenotype', 'HP:0003003', (68, 71))	('tumor', 'Disease', (48, 53))	('miR-27b', 'Var', (21, 28))	('CRC', 'Disease', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
2327	29423086	Despite several studies emphasized Rab3D can promote tumor progression by targeting with signaling pathways, the precise molecular mechanism for the functional role of Rab3D in cancer remains elusive.	('targeting', 'Reg', (74, 83))	('Rab3D', 'Var', (35, 40))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('signaling pathways', 'Pathway', (89, 107))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('promote', 'PosReg', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Disease', (53, 58))
2328	29423086	In colorectal and breast cancer, Rab3D has been reported to promote metastasis through activating Akt/GSK3beta/Snail pathway and inducing epithelial mesenchymal transition (EMT) process.	('promote', 'PosReg', (60, 67))	('epithelial mesenchymal transition', 'CPA', (138, 171))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Rab3D', 'Var', (33, 38))	('Akt', 'Gene', '207', (98, 101))	('GSK3beta', 'Gene', (102, 110))	('activating', 'PosReg', (87, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('metastasis', 'CPA', (68, 78))	('Akt', 'Gene', (98, 101))	('inducing', 'Reg', (129, 137))	('colorectal and breast cancer', 'Disease', 'MESH:D015179', (3, 31))	('GSK3beta', 'Gene', '2932', (102, 110))
2329	29423086	However, whether Akt/GSK3beta/Snail signaling pathways is involved in the anti-oncogenic activities of miR-27b in CRC remain further investigation.	('GSK3beta', 'Gene', '2932', (21, 29))	('Akt', 'Gene', '207', (17, 20))	('CRC', 'Phenotype', 'HP:0003003', (114, 117))	('miR-27b', 'Var', (103, 110))	('GSK3beta', 'Gene', (21, 29))	('Akt', 'Gene', (17, 20))
2332	29423086	More importantly, miR-27b might be a novel biomarker for diagnosis and prognosis and a potential therapeutic target in colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('colorectal cancer', 'Disease', (119, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('miR-27b', 'Var', (18, 25))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))
2348	29423086	Membranes were incubated with blocking buffer for 90 min at room temperature and then incubated with an antibody against Rab3D (1:1000, Abcam, UK) or GAPDH (1:1000, Abcam, UK) overnight at 4 C. The membranes were washed and incubated with a horseradish peroxidase (HRP)-conjugated secondary antibody.	('1:1000', 'Var', (157, 163))	('horseradish', 'Species', '3704', (241, 252))	('GAPDH', 'Gene', '2597', (150, 155))	('GAPDH', 'Gene', (150, 155))	('Rab3D', 'Gene', (121, 126))
2352	29423086	When the average value of tumor sizes was up to 100 mm3, the mice were separated into 2 groups randomly, one with subcutaneous injection of miR-27b (Agomir) at different sites, and the other with Control (Agomir).	('mice', 'Species', '10090', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('miR-27b', 'Var', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
2354	28280091	Dual Inhibition of EGFR and c-Src by Cetuximab and Dasatinib Combined with FOLFOX Chemotherapy in Patients with Metastatic Colorectal Cancer Aberrant activation of the intracellular tyrosine kinase Src has been implicated as a mechanism of acquired chemotherapy resistance in metastatic colorectal cancer (mCRC).	('CRC', 'Phenotype', 'HP:0003003', (307, 310))	('Patients', 'Species', '9606', (98, 106))	('colorectal cancer', 'Disease', 'MESH:D015179', (287, 304))	('EGFR', 'Gene', (19, 23))	('FOLFOX', 'Chemical', '-', (75, 81))	('c-Src', 'Gene', '6714', (28, 33))	('tyrosine', 'Chemical', 'MESH:D014443', (182, 190))	('colorectal cancer', 'Disease', (287, 304))	('Metastatic Colorectal Cancer', 'Disease', 'MESH:D015179', (112, 140))	('Inhibition', 'NegReg', (5, 15))	('EGFR', 'molecular_function', 'GO:0005006', ('19', '23'))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('activation', 'PosReg', (150, 160))	('EGFR', 'Gene', '1956', (19, 23))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (123, 140))	('Aberrant', 'Var', (141, 149))	('intracellular', 'cellular_component', 'GO:0005622', ('168', '181'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (287, 304))	('Dasatinib', 'Chemical', 'MESH:D000069439', (51, 60))	('Metastatic Colorectal Cancer', 'Disease', (112, 140))	('Cetuximab', 'Chemical', 'MESH:D000068818', (37, 46))	('c-Src', 'Gene', (28, 33))	('intracellular tyrosine', 'MPA', (168, 190))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
2363	28280091	Response rates were 20%(6/30) in the Phase IB escalation and expansion cohort, and 13%(3/24) and 0%(0/23) in the KRAS c12/13WT and mutant cohorts of Phase II, respectively.	('mutant', 'Var', (131, 137))	('KRAS', 'Gene', (113, 117))	('KRAS', 'Gene', '3845', (113, 117))
2375	28280091	Colon cancer cell lines with defective Src kinases are particularly sensitive to oxaliplatin-induced apoptosis.	('Colon cancer', 'Phenotype', 'HP:0003003', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('sensitive', 'Reg', (68, 77))	('Colon cancer', 'Disease', (0, 12))	('Src kinases', 'Enzyme', (39, 50))	('apoptosis', 'biological_process', 'GO:0097194', ('101', '110'))	('Colon cancer', 'Disease', 'MESH:D015179', (0, 12))	('defective', 'Var', (29, 38))	('apoptosis', 'biological_process', 'GO:0006915', ('101', '110'))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (81, 92))
2381	28280091	CRC tumors treated with the combination of dasatinib and oxaliplatin demonstrate markedly decreased microvessel activity and increased oxidative stress.	('CRC tumors', 'Disease', 'MESH:D015179', (0, 10))	('dasatinib', 'Chemical', 'MESH:D000069439', (43, 52))	('CRC', 'Phenotype', 'HP:0003003', (0, 3))	('increased', 'PosReg', (125, 134))	('oxidative stress', 'MPA', (135, 151))	('microvessel activity', 'CPA', (100, 120))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('decreased', 'NegReg', (90, 99))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (57, 68))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (125, 151))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('oxaliplatin', 'Var', (57, 68))	('CRC tumors', 'Disease', (0, 10))
2387	28280091	Patients in the Phase II cohort must have progressed on fluorouracil (5-FU) or capecitabine and oxaliplatin if KRAS mutant, and either cetuximab or panitumumab if KRAS wild type.	('oxaliplatin', 'Chemical', 'MESH:D000077150', (96, 107))	('capecitabine', 'Chemical', 'MESH:D000069287', (79, 91))	('KRAS', 'Gene', (111, 115))	('KRAS', 'Gene', '3845', (111, 115))	('KRAS', 'Gene', (163, 167))	('cetuximab', 'Chemical', 'MESH:D000068818', (135, 144))	('KRAS', 'Gene', '3845', (163, 167))	('Patients', 'Species', '9606', (0, 8))	('5-FU', 'Chemical', 'MESH:D005472', (70, 74))	('mutant', 'Var', (116, 122))	('panitumumab', 'Chemical', 'MESH:D000077544', (148, 159))	('fluorouracil', 'Chemical', 'MESH:D005472', (56, 68))
2390	28280091	For the Phase II cohort, patients were categorized as KRAS G12 and G13 mutant or wild type based on mass spectroscopy genotyping for all RAS mutations in tumor tissue.	('G13', 'Var', (67, 70))	('KRAS', 'Gene', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('patients', 'Species', '9606', (25, 33))	('KRAS', 'Gene', '3845', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('RAS', 'Gene', (137, 140))	('tumor', 'Disease', (154, 159))
2392	28280091	The primary objectives of the Phase IB portion of the study were to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combination of dasatinib, cetuximab and modified FOLFOX6 in adult patients with mCRC and to determine if biological activity of the combination regimen on c-Src activity occurred at the MTD in the expansion cohort.	('toxicity', 'Disease', (129, 137))	('modified', 'Var', (191, 199))	('FOLFOX6', 'Chemical', '-', (200, 207))	('c-Src', 'Gene', (306, 311))	('c-Src', 'Gene', '6714', (306, 311))	('men', 'Species', '9606', (299, 302))	('CRC', 'Phenotype', 'HP:0003003', (232, 235))	('cetuximab', 'Chemical', 'MESH:D000068818', (177, 186))	('dasatinib', 'Chemical', 'MESH:D000069439', (166, 175))	('patients', 'Species', '9606', (217, 225))	('mCRC', 'Disease', (231, 235))	('toxicity', 'Disease', 'MESH:D064420', (129, 137))
2439	28280091	Of the 6 responding patients, 5 had a wild type KRAS oncogene, while the KRAS status was unknown for 1 patient.	('KRAS', 'Gene', (73, 77))	('KRAS', 'Gene', (48, 52))	('wild type', 'Var', (38, 47))	('KRAS', 'Gene', '3845', (73, 77))	('KRAS', 'Gene', '3845', (48, 52))	('patient', 'Species', '9606', (20, 27))	('patients', 'Species', '9606', (20, 28))	('patient', 'Species', '9606', (103, 110))
2456	28280091	The median TTF on the immediate prior regimen to the study was 3.8 months in KRAS c12/13 wild type patients (range, 0 to 14.0 months), and 2.0 months in KRAS mutant patients (range, 0 to 16.0 months).	('men', 'Species', '9606', (42, 45))	('KRAS', 'Gene', (153, 157))	('patients', 'Species', '9606', (99, 107))	('KRAS', 'Gene', '3845', (153, 157))	('KRAS', 'Gene', (77, 81))	('patients', 'Species', '9606', (165, 173))	('KRAS', 'Gene', '3845', (77, 81))	('mutant', 'Var', (158, 164))
2457	28280091	The median TTF on our study regimen was 2.3 months in the KRAS wild type cohort (range, 1.4 to 8.5 months), and 2.3 months in the KRAS mutant cohort (range, 0.9 to 5.8 months) (Figure 2B).	('KRAS', 'Gene', (58, 62))	('KRAS', 'Gene', '3845', (58, 62))	('mutant', 'Var', (135, 141))	('men', 'Species', '9606', (32, 35))	('KRAS', 'Gene', (130, 134))	('KRAS', 'Gene', '3845', (130, 134))
2458	28280091	The median ratio of TTF on study regimen to TTF on prior regimen was 0.9 for all patients (range, 0.1 to 5.5), and 0.8 (range, 0.1 to 7.6) and 1.0 (range, 0.1 to 5.5) in the KRAS wild type and mutant patients, respectively (Figure 2C).	('KRAS', 'Gene', '3845', (174, 178))	('patients', 'Species', '9606', (200, 208))	('patients', 'Species', '9606', (81, 89))	('mutant', 'Var', (193, 199))	('men', 'Species', '9606', (37, 40))	('to 7', 'Species', '1214577', (131, 135))	('men', 'Species', '9606', (61, 64))	('KRAS', 'Gene', (174, 178))
2459	28280091	The median overall survival was 6.7 months (range, 1.0 to 28.4 months) in all patients, 7.7 months in KRAS wild type patients (range, 2.0 to 22.6 months), and 5.9 months (range, 1.0 to 28.4 months) in KRAS mutant patients (Figure 2D).	('mutant', 'Var', (206, 212))	('KRAS', 'Gene', (201, 205))	('KRAS', 'Gene', '3845', (201, 205))	('patients', 'Species', '9606', (78, 86))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (213, 221))	('KRAS', 'Gene', (102, 106))	('KRAS', 'Gene', '3845', (102, 106))
2476	28280091	Aberrant activation of the intracellular tyrosine kinase Src has been implicated as a mechanism of acquired chemotherapy resistance in mCRC.	('activation', 'PosReg', (9, 19))	('CRC', 'Phenotype', 'HP:0003003', (136, 139))	('Aberrant', 'Var', (0, 8))	('mCRC', 'Disease', (135, 139))	('tyrosine', 'Chemical', 'MESH:D014443', (41, 49))
2501	28280091	There was no meaningful activity in the KRAS mutant arm.	('KRAS', 'Gene', (40, 44))	('mutant', 'Var', (45, 51))	('KRAS', 'Gene', '3845', (40, 44))
2513	28280091	Copy number gain in ephrin receptors, Abl, or SFK are factors that affect NSCLC's sensitivity to dasatinib in vitro.	('ephrin receptors', 'Protein', (20, 36))	('ephrin', 'molecular_function', 'GO:0046875', ('20', '26'))	('sensitivity to dasatinib', 'MPA', (82, 106))	('Abl', 'Gene', '25', (38, 41))	('affect', 'Reg', (67, 73))	('dasatinib', 'Chemical', 'MESH:D000069439', (97, 106))	('NSCLC', 'Disease', (74, 79))	('gain', 'PosReg', (12, 16))	('Abl', 'Gene', (38, 41))	('ephrin', 'molecular_function', 'GO:0005106', ('20', '26'))	('SFK', 'Gene', (46, 49))	('Copy number', 'Var', (0, 11))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('SFK', 'Gene', '6714;20779', (46, 49))
2528	28169291	Hotspots of aberrant enhancer activity punctuate the colorectal cancer epigenome In addition to mutations in genes, aberrant enhancer element activity at non-coding regions of the genome is a key driver of tumorigenesis.	('activity', 'MPA', (142, 150))	('colorectal cancer', 'Disease', 'MESH:D015179', (53, 70))	('enhancer', 'PosReg', (125, 133))	('colorectal cancer', 'Phenotype', 'HP:0003003', (53, 70))	('colorectal cancer', 'Disease', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('aberrant', 'Var', (116, 124))
2531	28169291	The development of cancer is closely associated with the accumulation of not only oncogene and tumour suppressor mutations, but also epigenetic changes that alter chromatin structure and lead to dysregulated gene expression.	('accumulation', 'PosReg', (57, 69))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('dysregulated gene expression', 'MPA', (195, 223))	('epigenetic changes', 'Var', (133, 151))	('alter', 'Reg', (157, 162))	('cancer', 'Disease', (19, 25))	('tumour', 'Disease', (95, 101))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('chromatin structure', 'MPA', (163, 182))	('lead to', 'Reg', (187, 194))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
2536	28169291	Collectively, these studies suggest that aberrant enhancer activity is a fundamental driver of tumour formation and maintenance.	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('aberrant', 'Var', (41, 49))	('tumour', 'Disease', (95, 101))
2544	28169291	Lastly, whether aberrant enhancers in cancer represent drivers of tumorigenesis or are simply bystanders accrued during malignant transformation remains to be investigated.	('aberrant', 'Var', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('enhancers', 'PosReg', (25, 34))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))
2547	28169291	We conclude that the formation of CRC is accompanied by a signature pattern of epigenetic changes at enhancer elements that contributes to tumour risk, progression, growth and survival.	('tumour', 'Disease', (139, 145))	('growth', 'CPA', (165, 171))	('contributes', 'Reg', (124, 135))	('epigenetic changes', 'Var', (79, 97))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('survival', 'CPA', (176, 184))	('CRC', 'Disease', (34, 37))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('progression', 'CPA', (152, 163))
2552	28169291	Gained VELs were defined as sites in which the H3K27ac mark was more enriched in CRC than in the normal crypts.	('H3K27ac', 'Var', (47, 54))	('VEL', 'Gene', (7, 10))	('CRC', 'Disease', (81, 84))	('VEL', 'Gene', '388588', (7, 10))
2554	28169291	In all cases, the percentage of gained and lost VELs within 2 kb of TSSs was far fewer than those more distal to TSSs (67-84% at distal loci, Mann-Whitney-Wilcoxon (MWW) P<1 x 10-10).	('VEL', 'Gene', '388588', (48, 51))	('TSSs', 'Var', (68, 72))	('fewer', 'NegReg', (81, 86))	('VEL', 'Gene', (48, 51))	('lost', 'NegReg', (43, 47))
2563	28169291	The clusters failed to correlate with microsatellite instability status, tumour side, patient ethnicity, or age at diagnosis.	('tumour', 'Disease', (73, 79))	('patient', 'Species', '9606', (86, 93))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('microsatellite instability', 'Var', (38, 64))
2571	28169291	Moreover, dysregulated genes associated with recurrent VELs were more likely to validate as dysregulated in patient tumours than misexpressed genes not associated with VELs (chi2, P<1 x 10-10).	('VEL', 'Gene', '388588', (55, 58))	('dysregulated', 'Var', (10, 22))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('VEL', 'Gene', (168, 171))	('tumours', 'Disease', 'MESH:D009369', (116, 123))	('VEL', 'Gene', (55, 58))	('tumours', 'Disease', (116, 123))	('patient', 'Species', '9606', (108, 115))	('VEL', 'Gene', '388588', (168, 171))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
2573	28169291	To directly characterize the regulatory effects of VELs, we performed CRISPR/Cas9-mediated disruption of three recurrently gained enhancers predicted to upregulate PHLDA1 in HCT116 cells (Fig.	('upregulate', 'PosReg', (153, 163))	('disruption', 'Var', (91, 101))	('HCT116', 'CellLine', 'CVCL:0291', (174, 180))	('VEL', 'Gene', '388588', (51, 54))	('PHLDA1', 'Gene', (164, 170))	('VEL', 'Gene', (51, 54))	('PHLDA1', 'Gene', '22822', (164, 170))
2574	28169291	Compared with the unedited parental cell line, PHLDA1 levels were reduced by more than 60% in each of the three the cell lines containing the edited enhancers (Fig.	('reduced', 'NegReg', (66, 73))	('PHLDA1', 'Gene', '22822', (47, 53))	('PHLDA1', 'Gene', (47, 53))	('edited', 'Var', (142, 148))	('enhancers', 'PosReg', (149, 158))
2581	28169291	Several of the recurrent VEL genes have been shown through functional studies to enhance tumorgenicity in CRC.	('genes', 'Var', (29, 34))	('VEL', 'Gene', (25, 28))	('VEL', 'Gene', '388588', (25, 28))	('CRC', 'Disease', (106, 109))	('enhance', 'PosReg', (81, 88))	('tumorgenicity', 'MPA', (89, 102))
2582	28169291	For example, overexpression of FOXQ1 has been shown to increase CRC tumour growth in mice.	('FOXQ1', 'Gene', (31, 36))	('mice', 'Species', '10090', (85, 89))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('CRC tumour growth', 'Disease', (64, 81))	('increase', 'PosReg', (55, 63))	('CRC tumour growth', 'Disease', 'MESH:D015179', (64, 81))	('overexpression', 'Var', (13, 27))
2600	28169291	Through variant set enrichment (VSE) analyses we confirmed that CRC risk locus variants were most enriched in highly recurrent gained VELs, and that this enrichment was specific for recurrent gained VELs and not recurrent lost VELs or other genomic features such as 5'UTRs, exons or introns (Fig.	('recurrent gained VELs', 'Phenotype', 'HP:0004406', (117, 138))	('gained', 'PosReg', (127, 133))	('gained', 'PosReg', (192, 198))	('VEL', 'Gene', '388588', (227, 230))	('recurrent gained VELs', 'Phenotype', 'HP:0004406', (182, 203))	('variants', 'Var', (79, 87))	('VEL', 'Gene', (134, 137))	('VEL', 'Gene', (199, 202))	('CRC', 'Gene', (64, 67))	('VEL', 'Gene', (227, 230))	('VEL', 'Gene', '388588', (134, 137))	('VEL', 'Gene', '388588', (199, 202))
2613	28169291	We next compared the H3K27ac ChIP-seq signal strength of the most highly recurrent gained VELs (G30+) in the CRC cell lines versus the adenoma samples.	('adenoma', 'Disease', (135, 142))	('H3K27ac', 'Var', (21, 28))	('VEL', 'Gene', '388588', (90, 93))	('recurrent gained VELs', 'Phenotype', 'HP:0004406', (73, 94))	('VEL', 'Gene', (90, 93))	('G30+', 'Var', (96, 100))	('adenoma', 'Disease', 'MESH:D000236', (135, 142))
2619	28169291	Based on the notion that malignant transformation fundamentally represents a major transition in cell state, and that tumour expression programs are often responsive to microenvironmental cues, we investigated the chromatin status of gained VELs before malignant transformation, through analysis of H3K4me1 and H3K27me3 ChIP-seq data from the normal colon crypts.	('VEL', 'Gene', '388588', (241, 244))	('tumour', 'Disease', (118, 124))	('H3K4me1', 'Var', (299, 306))	('VEL', 'Gene', (241, 244))	('H3K27me3', 'Var', (311, 319))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (118, 124))
2631	28169291	Flow cytometry analyses indicated that CRC cells treated with JQ1 underwent both cell cycle arrest and apoptosis (Supplementary Fig.	('apoptosis', 'biological_process', 'GO:0097194', ('103', '112'))	('JQ1', 'Var', (62, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('103', '112'))	('arrest', 'Disease', 'MESH:D006323', (92, 98))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('81', '98'))	('apoptosis', 'CPA', (103, 112))	('arrest', 'Disease', (92, 98))
2634	28169291	JQ1 had similar effects in all three xenograft models, significantly slowing tumour growth (Fig.	('slowing tumour growth', 'Disease', (69, 90))	('slowing tumour growth', 'Disease', 'MESH:D006130', (69, 90))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('JQ1', 'Var', (0, 3))
2641	28169291	Thus, recurrent gained VELs mark a set of genes that are specifically downregulated following JQ1 treatment.	('JQ1', 'Var', (94, 97))	('VEL', 'Gene', (23, 26))	('recurrent gained VELs', 'Phenotype', 'HP:0004406', (6, 27))	('VEL', 'Gene', '388588', (23, 26))	('downregulated', 'NegReg', (70, 83))
2651	28169291	The classic genetic model of CRC tumorigenesis, or the 'Vogelgram', states that mutation of APC initiates the conversion of normal colon epithelium to the early adenoma stage.	('APC', 'Gene', (92, 95))	('adenoma', 'Disease', 'MESH:D000236', (161, 168))	('APC', 'Gene', '324', (92, 95))	('CRC', 'Disease', (29, 32))	('adenoma', 'Disease', (161, 168))	('mutation', 'Var', (80, 88))
2652	28169291	The progression from adenoma to frank carcinoma is accompanied by additional mutations in other genes including KRAS, SMAD4, PIK3CA and TP53 (ref.).	('SMAD4', 'Gene', (118, 123))	('adenoma to frank carcinoma', 'Disease', 'MESH:D000236', (21, 47))	('adenoma to frank carcinoma', 'Disease', (21, 47))	('TP53', 'Gene', '7157', (136, 140))	('PIK3CA', 'Gene', (125, 131))	('SMAD4', 'Gene', '4089', (118, 123))	('mutations', 'Var', (77, 86))	('KRAS', 'Gene', (112, 116))	('PIK3CA', 'Gene', '5290', (125, 131))	('KRAS', 'Gene', '3845', (112, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('TP53', 'Gene', (136, 140))
2656	28169291	Collectively, these findings indicate that epigenomic enhancer dysregulation occurs in parallel to the well described DNA mutations that occur at canonical proto-oncogenes and tumour suppressors during malignant transformation of colon crypt cells into CRC.	('malignant transformation of colon', 'Phenotype', 'HP:0100273', (202, 235))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('enhancer', 'PosReg', (54, 62))	('mutations', 'Var', (122, 131))	('tumour', 'Disease', 'MESH:D009369', (176, 182))	('tumour', 'Disease', (176, 182))
2661	28169291	Third, we demonstrate that the growth of CRC cells can be mitigated by targeted knockout of individual genes activated by the recurrent VELs, or with a BET inhibitor that selectively and potently suppresses genes associated with the recurrently acquired VELs.	('knockout', 'Var', (80, 88))	('BET', 'Gene', '92737', (152, 155))	('VEL', 'Gene', '388588', (254, 257))	('BET', 'Gene', (152, 155))	('VEL', 'Gene', (136, 139))	('suppresses', 'NegReg', (196, 206))	('VEL', 'Gene', (254, 257))	('VEL', 'Gene', '388588', (136, 139))
2663	28169291	One possibility is that VELs are formed through somatic mutations that introduce transcription factor binding sites, similar to somatic mutations that result in recruitment of MYB to the TAL1 enhancer previously described in T-cell acute lymphoblastic leukaemia.	('VEL', 'Gene', '388588', (24, 27))	('mutations', 'Var', (56, 65))	('binding', 'Interaction', (102, 109))	('MYB', 'Gene', '4602', (176, 179))	('recruitment', 'PosReg', (161, 172))	('T-cell acute lymphoblastic leukaemia', 'Disease', 'MESH:D054218', (225, 261))	('TAL1', 'Gene', (187, 191))	('MYB', 'Gene', (176, 179))	('VEL', 'Gene', (24, 27))	('T-cell acute lymphoblastic leukaemia', 'Disease', (225, 261))	('TAL1', 'Gene', '6886', (187, 191))
2664	28169291	Moreover, given that the frequency of recurrent VELs exceeds that of all but the most common mutations in CRC, DNA variation alone cannot fully account for all recurrent VELs.	('VEL', 'Gene', (170, 173))	('VEL', 'Gene', '388588', (48, 51))	('mutations', 'Var', (93, 102))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('VEL', 'Gene', '388588', (170, 173))	('VEL', 'Gene', (48, 51))	('CRC', 'Gene', (106, 109))
2667	28169291	An alternative hypothesis is that recurrent VELs form downstream of primary mutational events which deregulate a common signalling mechanism, such as Wnt/beta-catenin.	('mutational', 'Var', (76, 86))	('VEL', 'Gene', (44, 47))	('beta-catenin', 'Gene', '1499', (154, 166))	('deregulate', 'Reg', (100, 110))	('VEL', 'Gene', '388588', (44, 47))	('beta-catenin', 'Gene', (154, 166))
2671	28169291	The gained and lost VELs presented here were identified by an unbiased survey of the CRC enhancer epigenome and evaluated using metrics that were, by design, analogous to accepted methods for identifying likely driver DNA mutations, such as recurrence, association with known cancer genes and oncogenic pathways, and impact on gene expression.	('recurrence', 'Disease', (241, 251))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('VEL', 'Gene', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('mutations', 'Var', (222, 231))	('gene expression', 'MPA', (327, 342))	('oncogenic pathways', 'Pathway', (293, 311))	('VEL', 'Gene', '388588', (20, 23))	('association', 'Interaction', (253, 264))	('impact', 'Reg', (317, 323))
2694	28169291	ChIPs were performed using 8 mug of the following antibodies: rabbit anti-H3K4me1 (Abcam #8895), rabbit anti-H3K27ac (Abcam #4729) and H3K27me3 (Abcam #6002).	('anti-H3K4me1', 'Var', (69, 81))	('rabbit', 'Species', '9986', (62, 68))	('H3K27me3', 'Var', (135, 143))	('rabbit', 'Species', '9986', (97, 103))
2708	28169291	PreSTIGE predicted target genes of recurrent gained (G10+) and lost (L14+) VELs are listed in Supplementary Data 7 and 8.	('VEL', 'Gene', (75, 78))	('gained', 'PosReg', (45, 51))	('lost', 'NegReg', (63, 67))	('VEL', 'Gene', '388588', (75, 78))	('G10+', 'Var', (53, 57))
2714	28169291	Next, dysregulated genes were classified based on VEL status into four groups: overexpressed genes not associated with any VELs (n=1106 genes), overexpressed genes associated with recurrent gained VELs (G10+, n=352), underexpressed genes not associated with any VELs (n=418) and underexpressed genes associated with recurrent lost VELs genes (L14+, n=589).	('VEL', 'Gene', (197, 200))	('VEL', 'Gene', (50, 53))	('VEL', 'Gene', (331, 334))	('G10+', 'Var', (203, 207))	('VEL', 'Gene', '388588', (262, 265))	('VEL', 'Gene', (123, 126))	('recurrent gained VELs', 'Phenotype', 'HP:0004406', (180, 201))	('VEL', 'Gene', '388588', (197, 200))	('VEL', 'Gene', '388588', (50, 53))	('VEL', 'Gene', '388588', (331, 334))	('gained', 'PosReg', (190, 196))	('VEL', 'Gene', (262, 265))	('VEL', 'Gene', '388588', (123, 126))
2716	28169291	Guide RNA (gRNA) sequences were designed and then used to target disruption of putative enhancers at the PHLDA1 and MYC loci (Supplementary Data 9).	('MYC', 'Gene', '4609', (116, 119))	('PHLDA1', 'Gene', (105, 111))	('PHLDA1', 'Gene', '22822', (105, 111))	('disruption', 'Var', (65, 75))	('enhancers', 'PosReg', (88, 97))	('MYC', 'Gene', (116, 119))
2719	28169291	All seven enhancers targeted for disruption using this strategy were verified by PCR to contain both targeted blasticidin and puromycin resistance cassettes within the pool of cells.	('disruption', 'Var', (33, 43))	('puromycin resistance', 'MPA', (126, 146))	('blasticidin', 'Chemical', 'MESH:C004500', (110, 121))	('blasticidin', 'Gene', (110, 121))	('puromycin', 'Chemical', 'MESH:D011691', (126, 135))
2723	28169291	GO analyses were performed on genes associated with recurrent gained and lost VELs (G10+ and L14+) using g:Profiler and the Enrichment Map plug-in to Cytoscape.	('gained', 'PosReg', (62, 68))	('VEL', 'Gene', (78, 81))	('G10+', 'Var', (84, 88))	('lost', 'NegReg', (73, 77))	('VEL', 'Gene', '388588', (78, 81))	('L14+', 'Var', (93, 97))
2739	28169291	Genes that were both associated with recurrent gained VELs (G10+) present in HCT116 and 1.5-fold overexpressed in HCT116 compared with normal colon were identified.	('HCT116', 'CellLine', 'CVCL:0291', (77, 83))	('VEL', 'Gene', (54, 57))	('HCT116', 'Var', (114, 120))	('overexpressed', 'PosReg', (97, 110))	('recurrent gained VELs', 'Phenotype', 'HP:0004406', (37, 58))	('VEL', 'Gene', '388588', (54, 57))	('HCT116', 'CellLine', 'CVCL:0291', (114, 120))	('gained', 'PosReg', (47, 53))	('HCT116', 'Gene', (77, 83))
2746	28169291	Hotspots of aberrant enhancer activity punctuate the colorectal cancer epigenome.	('colorectal cancer', 'Disease', 'MESH:D015179', (53, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (53, 70))	('colorectal cancer', 'Disease', (53, 70))	('aberrant', 'Var', (12, 20))	('enhancer activity', 'PosReg', (21, 38))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
2749	27119506	MicroRNA-320 suppresses colorectal cancer by targeting SOX4, FOXM1, and FOXQ1 Colorectal cancer (CRC) is the third most common cancer causing high mortality rates world-wide.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('FOXM1', 'Gene', (61, 66))	('cancer', 'Disease', (89, 95))	('colorectal cancer', 'Disease', 'MESH:D015179', (24, 41))	('SOX4', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('colorectal cancer', 'Disease', (24, 41))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('SOX4', 'Gene', '6659', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('CRC', 'Phenotype', 'HP:0003003', (97, 100))	('Colorectal cancer', 'Disease', (78, 95))	('FOXM1', 'Gene', '2305', (61, 66))	('colorectal cancer', 'Phenotype', 'HP:0003003', (24, 41))	('suppresses', 'NegReg', (13, 23))	('MicroRNA-320', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (35, 41))	('FOXQ1', 'Gene', (72, 77))
2763	27119506	Over the past decade, aberrant expression of different miRNAs (oncomiRs and tumor suppressor miRNAs) have been implicated in driving colorectal cancer progression.	('aberrant expression', 'Var', (22, 41))	('colorectal cancer', 'Disease', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('colorectal cancer', 'Disease', 'MESH:D015179', (133, 150))	('miR', 'Gene', '220972', (55, 58))	('miR', 'Gene', (55, 58))	('miR', 'Gene', '220972', (93, 96))	('miR', 'Gene', (93, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (133, 150))	('miR', 'Gene', '220972', (67, 70))	('miR', 'Gene', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('implicated', 'Reg', (111, 121))
2778	27119506	Similar inhibitory effects were observed on cell migration toward media containing 10% FBS in the miR-320c HCT116 compared to LV control cells employing two independent assays: microelectroic sensor plate assay (Figure 1f) and transwell assay (Figure 1g), implicating a role for this miRNA in migration as well as in proliferation.	('miR', 'Gene', '220972', (284, 287))	('miR', 'Gene', (284, 287))	('HCT116', 'Gene', (107, 113))	('miR', 'Gene', '220972', (98, 101))	('miR', 'Gene', (98, 101))	('miR-320', 'Gene', '723838', (98, 105))	('migration', 'CPA', (293, 302))	('cell migration', 'biological_process', 'GO:0016477', ('44', '58'))	('FBS', 'Var', (87, 90))	('HCT116', 'CellLine', 'CVCL:0291', (107, 113))	('transwell assay', 'CPA', (227, 242))	('cell migration', 'CPA', (44, 58))	('miR-320', 'Gene', (98, 105))
2787	27119506	Alignment of miR-320c and gene targets 3` UTR using TargetScan algorithm indicated two potential binding sites for SOX4 (position 1236-1242 and 2070-2076), two binding sites for FOXM1 (position 862-868 and 619-625), and one binding site for FOXQ1 (position 614-621) (Figure 4a).	('miR-320', 'Gene', (13, 20))	('position 1236-1242', 'Var', (121, 139))	('SOX4', 'Gene', (115, 119))	('FOXQ1', 'Gene', '94234', (241, 246))	('SOX4', 'Gene', '6659', (115, 119))	('miR-320', 'Gene', '723838', (13, 20))	('binding', 'Interaction', (97, 104))	('FOXM1', 'Gene', (178, 183))	('FOXM1', 'Gene', '2305', (178, 183))	('FOXQ1', 'Gene', (241, 246))
2788	27119506	Correspondingly, SOX4, FOXM1 and FOXQ1 protein levels were decreased in miR-320c HCT116 compare to the LV control cells, indicating suppression of those genes at the protein level (Figure 4b).	('miR-320', 'Gene', (72, 79))	('HCT116', 'CellLine', 'CVCL:0291', (81, 87))	('FOXQ1', 'Gene', (33, 38))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('decreased', 'NegReg', (59, 68))	('FOXM1', 'Gene', '2305', (23, 28))	('suppression', 'NegReg', (132, 143))	('FOXM1', 'Gene', (23, 28))	('protein levels', 'MPA', (39, 53))	('SOX4', 'Gene', (17, 21))	('miR-320', 'Gene', '723838', (72, 79))	('HCT116', 'Var', (81, 87))	('SOX4', 'Gene', '6659', (17, 21))	('FOXQ1', 'Gene', '94234', (33, 38))
2816	27119506	In addition to CRC, aberrant expression of miR-320 has been reported in several other types of human cancers.	('human', 'Species', '9606', (95, 100))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('CRC', 'Disease', (15, 18))	('cancers', 'Disease', (101, 108))	('miR-320', 'Gene', '723838', (43, 50))	('aberrant expression', 'Var', (20, 39))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('miR-320', 'Gene', (43, 50))	('CRC', 'Phenotype', 'HP:0003003', (15, 18))	('reported', 'Reg', (60, 68))
2821	27119506	In conclusion, based on our newly-generated data, we propose a model (see schema in Figure 6f), whereby loss of miR-320 family leads to increased levels of several miR-320 target genes, resulting in CRC progression, and drug resistance.	('schema', 'Disease', 'None', (74, 80))	('drug resistance', 'biological_process', 'GO:0042493', ('220', '235'))	('drug resistance', 'CPA', (220, 235))	('loss', 'Var', (104, 108))	('miR-320', 'Gene', '723838', (112, 119))	('CRC', 'Phenotype', 'HP:0003003', (199, 202))	('drug resistance', 'Phenotype', 'HP:0020174', (220, 235))	('miR-320', 'Gene', '723838', (164, 171))	('schema', 'Disease', (74, 80))	('levels', 'MPA', (146, 152))	('CRC progression', 'CPA', (199, 214))	('drug resistance', 'biological_process', 'GO:0009315', ('220', '235'))	('increased', 'PosReg', (136, 145))	('miR-320', 'Gene', (164, 171))	('miR-320', 'Gene', (112, 119))
2847	27119506	Immunoblotting was conducted using anti-SOX4 rabbit polyclonal antibody (H-90, dilution 1:1000, Santa Cruz Biotechnology, Santa Cruz, CA), anti-FOXM1 antibody 263C2a (ab58675, dilution 1:400), and anti-FOXQ1 antibody (ab51340, dilution 1:400), both from Abcam (Abcam, Cambridge, MA).	('FOXM1', 'Gene', '2305', (144, 149))	('ab58675', 'Var', (167, 174))	('FOXQ1', 'Gene', '94234', (202, 207))	('SOX4', 'Gene', (40, 44))	('SOX4', 'Gene', '6659', (40, 44))	('FOXM1', 'Gene', (144, 149))	('ab51340', 'Var', (218, 225))	('rabbit', 'Species', '9986', (45, 51))	('FOXQ1', 'Gene', (202, 207))
2870	26074400	Association between Int7G24A rs334354 polymorphism and cancer risk: a meta-analysis of case-control studies Accumulating evidences have suggested the potential association between Int7G24A (rs334354) polymorphism and cancer risk.	('polymorphism', 'Var', (38, 50))	('Int7G24A', 'Gene', (180, 188))	('rs334354', 'Mutation', 'rs334354', (190, 198))	('rs334354', 'Mutation', 'rs334354', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('rs334354 polymorphism', 'Var', (29, 50))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('polymorphism', 'Var', (200, 212))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('Int7G24A', 'Gene', (20, 28))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('Association', 'Interaction', (0, 11))	('rs334354) polymorphism', 'Var', (190, 212))	('cancer', 'Disease', (55, 61))
2871	26074400	The results of the overall population had suggested that Int7G24A polymorphism had an increased risk for cancer, reaching significant levels in the 2 genetic models (allele model, OR = 1.25, 95% CI 1.09-1.42, P = 0.001; dominant model, OR = 1.24, 95% CI 1.06-1.46, P < 0.008).	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('Int7G24A', 'Gene', (57, 65))	('polymorphism', 'Var', (66, 78))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
2872	26074400	The present meta-analysis had suggested that Int7G24A polymorphism of gene TGFBR1 involved in the transforming growth factor beta (TGF-beta) signaling pathway had a significantly increased risk for cancer development.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('Int7G24A polymorphism', 'Var', (45, 66))	('cancer', 'Disease', (198, 204))	('TGF-beta', 'Gene', '7040', (131, 139))	('TGF-beta', 'Gene', (131, 139))	('TGFBR1', 'Gene', '7046', (75, 81))	('transforming growth factor beta', 'Gene', (98, 129))	('TGFBR1', 'Gene', (75, 81))	('polymorphism', 'Var', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('98', '129'))	('signaling pathway', 'biological_process', 'GO:0007165', ('141', '158'))	('transforming growth factor beta', 'Gene', '7040', (98, 129))
2879	26074400	Alterations of TGF-beta superfamily signaling have been implicated in various human pathologies, including cancer, developmental disorders, cardiovascular and autoimmune diseases.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cardiovascular and autoimmune diseases', 'Disease', 'MESH:D002318', (140, 178))	('Alterations', 'Var', (0, 11))	('TGF-beta', 'Gene', '7040', (15, 23))	('TGF-beta', 'Gene', (15, 23))	('developmental disorders', 'Disease', (115, 138))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (159, 178))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('developmental disorders', 'Disease', 'MESH:D002658', (115, 138))	('implicated', 'Reg', (56, 66))	('human', 'Species', '9606', (78, 83))	('cancer', 'Disease', (107, 113))
2881	26074400	Among the polymorphism variations of gene TGFBR1, Int7G24A (rs334354), representing a G to A transversion in the +24 position of the donor splice site in intron 7, had been firstly found to be possibly related with cancer risk by Chen in 1999.	('Int7G24A (rs334354', 'Var', (50, 68))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('rs334354', 'Mutation', 'rs334354', (60, 68))	('donor', 'Species', '9606', (133, 138))	('rs334354', 'Var', (60, 68))	('related', 'Reg', (202, 209))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('TGFBR1', 'Gene', '7046', (42, 48))	('TGFBR1', 'Gene', (42, 48))
2882	26074400	After that, several studies had reported the potential associations between Int7G24A rs334354 genotype and the risk for kidney, breast and lung cancer.	('Int7G24A', 'Gene', (76, 84))	('kidney', 'Disease', (120, 126))	('breast and lung cancer', 'Disease', 'MESH:D001943', (128, 150))	('rs334354', 'Mutation', 'rs334354', (85, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('rs334354', 'Var', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
2883	26074400	A meta-analysis of 3 studies conducted 9 years ago indicated that Int7G24A might be a tumor susceptibility allele for non-small cell lung cancer (NSCLC), kidney and bladder cancer.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (118, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('tumor', 'Disease', (86, 91))	('non-small cell lung cancer', 'Disease', (118, 144))	('NSCLC', 'Disease', (146, 151))	('kidney and bladder cancer', 'Phenotype', 'HP:0009726', (154, 179))	('bladder cancer', 'Phenotype', 'HP:0009725', (165, 179))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('kidney and bladder cancer', 'Disease', 'MESH:D001749', (154, 179))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (118, 144))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (122, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (146, 151))	('Int7G24A', 'Var', (66, 74))
2884	26074400	Another meta-analysis performed by Zhang found non-significant association between Int7G24A rs334354 polymorphism with colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('colorectal cancer', 'Disease', (119, 136))	('rs334354', 'Mutation', 'rs334354', (92, 100))	('polymorphism', 'Var', (101, 113))	('rs334354 polymorphism', 'Var', (92, 113))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))	('Int7G24A', 'Gene', (83, 91))
2887	26074400	To our knowledge, this is the most comprehensive meta-analysis with the most included studies regarding the Int7G24A rs334354 polymorphisms and cancer risk.	('rs334354', 'Mutation', 'rs334354', (117, 125))	('Int7G24A', 'Gene', (108, 116))	('rs334354', 'Var', (117, 125))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
2891	26074400	Forest plots of meta-analysis on the association between Int7G24A rs334354 polymorphism and cancer risk applying the 2 models were displayed in Figs 3 and 4.	('rs334354', 'Mutation', 'rs334354', (66, 74))	('cancer', 'Disease', (92, 98))	('rs334354 polymorphism', 'Var', (66, 87))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('Int7G24A', 'Gene', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('polymorphism', 'Var', (75, 87))
2892	26074400	The overall effects of Int7G24A rs334354 mutation on the risk for cancer were investigated in 13 studies with 4092 cases and 5909 controls.	('rs334354', 'Var', (32, 40))	('rs334354', 'Mutation', 'rs334354', (32, 40))	('Int7G24A', 'Gene', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
2893	26074400	To assess the potential effects of specific study characteristics on the association between Int7G24A polymorphism and cancer risk, we pooled the ORs and 95% CIs from the subgroups of ethnicity, control source, genotyping method, type of sample, type of cancer and sample size.	('polymorphism', 'Var', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('association', 'Interaction', (73, 84))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('Int7G24A', 'Gene', (93, 101))
2894	26074400	When stratified by ethnicity, significant association between Int7G24A rs334354 polymorphism and cancer risk was detected among the Asian population and the mixed population in both of the allele model (Asian population, OR = 1.27, 95% CI 1.11-1.45, P < 0.001; mixed population, OR = 2.02, 95% CI 1.52-2.68, P < 0.001) and dominant model (Asian population, OR = 1.28, 95% CI 1.11-1.49, P < 0.001; mixed population, OR = 2.27, 95% CI 1.64-3.15, P < 0.001), while non-significant relationship was detected for the Caucasian population (allele model, OR = 1.08, 95% CI 0.92-1.26, P = 0.352; dominant model, OR = 1.05, 95% CI 0.87-1.26, P = 0.639).	('cancer', 'Disease', (97, 103))	('rs334354', 'Mutation', 'rs334354', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('rs334354', 'Var', (71, 79))	('Int7G24A', 'Gene', (62, 70))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
2895	26074400	When stratified by control source, Int7G24A rs334354 had been found to have an increased risk for cancer risk for population-based (PB) group (OR = 1.19, 95% CI 1.04-1.35, P = 0.01) and hospital-based (HB) group (OR = 1.32, 95% CI = 1.06-1.63, P = 0.012) in allele model.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('rs334354', 'Mutation', 'rs334354', (44, 52))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('rs334354', 'Var', (44, 52))	('PB', 'Chemical', '-', (132, 134))	('cancer', 'Disease', (98, 104))	('Int7G24A', 'Gene', (35, 43))
2898	26074400	In the PCR-RFLP group and PCR- SSCP group, significantly increased associations between Int7G24A rs334354 polymorphism and cancer risk were found in allele model (PCR-RFLP group, OR = 1.19.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('rs334354 polymorphism', 'Var', (97, 118))	('Int7G24A', 'Gene', (88, 96))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('associations', 'Interaction', (67, 79))	('increased', 'PosReg', (57, 66))	('polymorphism', 'Var', (106, 118))	('rs334354', 'Mutation', 'rs334354', (97, 105))
2900	26074400	However, no significant association was found between Int7G24A rs334354 and colorectal cancer in the two models (allele model, OR = 1.08, 95% CI 0.88-1.33, P = 0.469; dominant model OR = 1.03, 95% CI 0.78-1.36, P = 0.834).	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('Int7G24A', 'Gene', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('colorectal cancer', 'Disease', (76, 93))	('rs334354', 'Var', (63, 71))	('rs334354', 'Mutation', 'rs334354', (63, 71))
2902	26074400	Among the group of other type cancer, Int7G24A polymorphism was confirmed to increase the risk for cancer (allele model, OR = 1.25, 95% CI 1.09-1.42, P < 0.001; dominant model, OR = 1.34, 95% CI 1.14-1.57, P < 0.001).	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Disease', (99, 105))	('type cancer', 'Disease', 'MESH:D009369', (25, 36))	('Int7G24A', 'Gene', (38, 46))	('polymorphism', 'Var', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('type cancer', 'Disease', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
2903	26074400	Based on the data in HapMap database (http://www.hapmap.org), G allele distributions of Int7G24A variant were 78% for Utah residents with ancestry from Northern and Western Europe (CEU) and 51% for Han Chinese in Beijing (CHB) and A allele distributions were 22% for CEU and 49% for CHB.	('variant', 'Var', (97, 104))	('CEU', 'Chemical', '-', (181, 184))	('CHB', 'Disease', 'None', (283, 286))	('CHB', 'Disease', 'None', (222, 225))	('Int7G24A', 'Gene', (88, 96))	('CEU', 'Chemical', '-', (267, 270))	('CHB', 'Disease', (283, 286))	('CHB', 'Disease', (222, 225))
2904	26074400	When the allele frequency of A allele was set to be 0.49, our meta-analysis had a power of 98.6% to detect an OR of 1.24 for the association between Int7G24A polymorphism and cancer risk.	('polymorphism', 'Var', (158, 170))	('association', 'Interaction', (129, 140))	('Int7G24A', 'Gene', (149, 157))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
2905	26074400	When the allele frequency of A was set to be 0.22, our meta-analysis had a power of 99.7% to detect an OR of 1.24 for the association between Int7G24A polymorphism and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('Int7G24A', 'Gene', (142, 150))	('association', 'Interaction', (122, 133))	('polymorphism', 'Var', (151, 163))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))
2906	26074400	Evidence of epidemiology studies, mechanism researches and animal experiments had confirmed the important role for genetic polymorphism in the development and progression of cancer, especially for the genes involved in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (219, 224))	('genetic polymorphism', 'Var', (115, 135))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
2908	26074400	The transforming growth factor beta (TGF-beta) signaling pathway is a key player in metazoan biology, and its misregulation can result in tumor development.	('result in', 'Reg', (128, 137))	('transforming growth factor beta', 'Gene', '7040', (4, 35))	('tumor', 'Disease', (138, 143))	('TGF-beta', 'Gene', '7040', (37, 45))	('misregulation', 'Var', (110, 123))	('TGF-beta', 'Gene', (37, 45))	('transforming growth factor beta', 'Gene', (4, 35))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
2911	26074400	As an indispensable member of the TGF-beta family, several mutations in the gene had been found to be related with cancer risk, including polymorphism of Int7G24A rs334354.	('TGF-beta', 'Gene', (34, 42))	('cancer', 'Disease', (115, 121))	('rs334354', 'Mutation', 'rs334354', (163, 171))	('polymorphism', 'Var', (138, 150))	('rs334354', 'Var', (163, 171))	('related', 'Reg', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('TGF-beta', 'Gene', '7040', (34, 42))	('mutations', 'Var', (59, 68))	('Int7G24A', 'Gene', (154, 162))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
2912	26074400	Since the identification of the potential association between Int7G24A (rs334354) polymorphism and cancer risk, an increasing number of relevant studies had been conducted with results suggesting the important role of Int7G24A rs334354 mutation in cancer development.	('cancer', 'Disease', (248, 254))	('rs334354', 'Var', (72, 80))	('rs334354', 'Mutation', 'rs334354', (72, 80))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('rs334354', 'Mutation', 'rs334354', (227, 235))	('Int7G24A', 'Gene', (62, 70))	('rs334354 mutation', 'Var', (227, 244))
2913	26074400	Power analysis indicated that we had a power of 98.6% under the allele frequency of 0.49 and 99.7% under the allele frequency of 0.22 to detect an OR of 1.24 for the association between Int7G24A polymorphism and cancer risk, based on the sample size of our analysis.	('polymorphism', 'Var', (195, 207))	('Int7G24A', 'Gene', (186, 194))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
2914	26074400	The results of the overall population had indicated that Int7G24A rs334354 polymorphism had an increased risk for cancer development, reaching significant levels at both of the 2 genetic models.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('rs334354', 'Var', (66, 74))	('rs334354', 'Mutation', 'rs334354', (66, 74))	('Int7G24A', 'Gene', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
2915	26074400	In our analysis, dominant model was indicated to be the best genetic model for clarifying the association between Int7G24A polymorphism and cancer risk.	('Int7G24A', 'Gene', (114, 122))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('polymorphism', 'Var', (123, 135))
2917	26074400	With respect to Int7G24A rs334354, the genotype frequencies also differ between ethnicities (G allele: 78% for CEU, 51% for CHB; A allele: 22% for CEU, 49% for CHB).	('CHB', 'Disease', 'None', (124, 127))	('CHB', 'Disease', (124, 127))	('CEU', 'Chemical', '-', (111, 114))	('CHB', 'Disease', (160, 163))	('CEU', 'Disease', (111, 114))	('rs334354', 'Var', (25, 33))	('CEU', 'Chemical', '-', (147, 150))	('rs334354', 'Mutation', 'rs334354', (25, 33))	('CHB', 'Disease', 'None', (160, 163))
2924	26074400	As for colorectal cancer, no significant association with Int7G24A rs334354 polymorphism was found in both allele model and dominant model (allele model, OR = 1.08, 95% CI = 0.88-1.33; dominant model, OR = 1.03, 95% CI = 0.78-1.36), compared with the previous meta-analysis including 3 studies by Zhang in 2012 (heterozygote model, OR = 0.97, 95% CI = 0.67-1.42; homozygote model, OR = 1.68, 95% CI = 1.14-2.47; recessive model, pooled OR = 1.71, 95% CI = 1.17-2.51).	('colorectal cancer', 'Phenotype', 'HP:0003003', (7, 24))	('rs334354', 'Mutation', 'rs334354', (67, 75))	('colorectal cancer', 'Disease', (7, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('rs334354', 'Var', (67, 75))	('Int7G24A', 'Gene', (58, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (7, 24))
2930	26074400	Secondly, the number of included studies for Int7G24A rs334354 polymorphism was limited for further analysis due to shortage of original studies.	('Int7G24A', 'Gene', (45, 53))	('rs334354', 'Var', (54, 62))	('rs334354', 'Mutation', 'rs334354', (54, 62))
2931	26074400	In conclusion, the present meta-analysis of 13 studies including 4092 cases and 5909 controls suggested that Int7G24A rs334354 polymorphism of gene TGFBR1 involved in the TGF-beta signaling pathway had a significantly increased risk on the risk for cancer in both of the two genetic models.	('polymorphism', 'Var', (127, 139))	('rs334354', 'Mutation', 'rs334354', (118, 126))	('TGFBR1', 'Gene', (148, 154))	('risk', 'Reg', (228, 232))	('signaling pathway', 'biological_process', 'GO:0007165', ('180', '197'))	('TGFBR1', 'Gene', '7046', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('cancer', 'Disease', (249, 255))	('TGF-beta', 'Gene', '7040', (171, 179))	('rs334354 polymorphism', 'Var', (118, 139))	('TGF-beta', 'Gene', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
2932	26074400	Additionally, compared with Caucasian population, Asian population with Int7G24A polymorphism had been found to have a greater risk for the development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('polymorphism', 'Var', (81, 93))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
2933	26074400	In this paper, we conducted a literature search on PubMed (Medline), Embase, Web of Science and Chinese National Knowledge Infrastructure (CNKI) from January 1966 through August 2014 for case-control studies examining the association between Int7G24A (rs334354) polymorphism of TGFBR1 and the risk for cancer, applying the search terms "TGFBR1 or transforming growth factor receptor 1 or type 1 TGF-beta receptor", "polymorphism or mutation or variation or genotype or SNP" and "cancer or tumor or neoplasm or carcinoma".	('"cancer', 'Disease', (478, 485))	('tumor', 'Disease', 'MESH:D009369', (489, 494))	('cancer', 'Disease', (479, 485))	('neoplasm', 'Phenotype', 'HP:0002664', (498, 506))	('cancer', 'Phenotype', 'HP:0002664', (479, 485))	('cancer', 'Disease', (302, 308))	('neoplasm or carcinoma', 'Disease', 'MESH:D009369', (498, 519))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('tumor', 'Phenotype', 'HP:0002664', (489, 494))	('rs334354) polymorphism', 'Var', (252, 274))	('TGFBR1', 'Gene', (337, 343))	('TGFBR1', 'Gene', '7046', (337, 343))	('"cancer', 'Disease', 'MESH:D009369', (478, 485))	('cancer', 'Disease', 'MESH:D009369', (479, 485))	('rs334354', 'Mutation', 'rs334354', (252, 260))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('TGF-beta', 'Gene', '7040', (395, 403))	('carcinoma', 'Phenotype', 'HP:0030731', (510, 519))	('neoplasm or carcinoma', 'Disease', (498, 519))	('polymorphism', 'Var', (262, 274))	('tumor', 'Disease', (489, 494))	('TGFBR1', 'Gene', '7046', (278, 284))	('variation', 'Var', (444, 453))	('TGFBR1', 'Gene', (278, 284))	('TGF-beta', 'Gene', (395, 403))
2934	26074400	Studies meeting the following criteria were included in the meta-analysis: (1) the study design was case-control (2) the outcome of interest was cancer, (3) the study evaluated the association between Int7G24A rs334354 polymorphism and the risk for cancer, (4) the study reported sufficient data to calculate odds ratios (ORs) and their 95% confidence intervals (CI), (5) the study should be human research.	('cancer', 'Disease', (145, 151))	('Int7G24A', 'Gene', (201, 209))	('association', 'Interaction', (181, 192))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('human', 'Species', '9606', (392, 397))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', (249, 255))	('rs334354', 'Mutation', 'rs334354', (210, 218))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('rs334354', 'Var', (210, 218))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
2940	26074400	Forest plots were applied to assess the association between Int7G24A rs334354 polymorphism and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('Int7G24A', 'Gene', (60, 68))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('rs334354', 'Var', (69, 77))	('rs334354', 'Mutation', 'rs334354', (69, 77))
2941	26074400	Power analysis was performed to calculate the power for our meta-analysis to detect the estimated risk of the association between Int7G24A polymorphism and cancer risk.	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('association', 'Interaction', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Int7G24A', 'Gene', (130, 138))	('polymorphism', 'Var', (139, 151))
2942	26074400	Association between Int7G24A rs334354 polymorphism and cancer risk: a meta-analysis of case-control studies.	('rs334354', 'Mutation', 'rs334354', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('rs334354', 'Var', (29, 37))	('Int7G24A', 'Gene', (20, 28))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
2943	25019063	We show here that blockade of VEGF by bevacizumab induces stabilization of angiogenic tumor blood vessels in human tumor specimen by recruiting Nestin-positive cells, whereas mature vessels down-regulated Nestin-expression.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('human', 'Species', '9606', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('recruiting', 'PosReg', (133, 143))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', (115, 120))	('blood vessel', 'Disease', (92, 104))	('blood vessel', 'Disease', 'MESH:D009383', (92, 104))	('blockade', 'Var', (18, 26))	('bevacizumab', 'Chemical', 'MESH:D000068258', (38, 49))	('stabilization', 'MPA', (58, 71))	('down-regulated', 'NegReg', (190, 204))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
3042	25019063	This may at least be partially due to the fact that anti-angiogenic drugs trigger vascular stabilization involving pericyte-coverage and that pericyte-coverage impairs further tumor vessel regression in response to anti-angiogenic treatment.	('impairs', 'NegReg', (160, 167))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('vascular stabilization', 'CPA', (82, 104))	('pericyte-coverage', 'Var', (142, 159))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
3046	25019063	However, the exact role of these cells in post-natal vasculogenesis and their contribution to vascularization of primary tumors is not yet clear; the respective values range from 50% incorporated BM-EPCs to undetectable numbers.	('primary tumors', 'Disease', 'MESH:D009369', (113, 127))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('EPCs', 'cellular_component', 'GO:0140268', ('199', '203'))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('vasculogenesis', 'biological_process', 'GO:0001570', ('53', '67'))	('BM-EPCs', 'Var', (196, 203))	('primary tumors', 'Disease', (113, 127))
3086	23858319	CDX2 immunoexpression has recently been shown to be useful in establishing gastrointestinal origin in metastatic tumors and has become a useful addition to the standard immunohistochemistry panel for carcinomas of unknown primary sites.	('gastrointestinal', 'Disease', 'MESH:D005767', (75, 91))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (200, 210))	('carcinomas', 'Disease', (200, 210))	('carcinomas', 'Disease', 'MESH:D002277', (200, 210))	('gastrointestinal', 'Disease', (75, 91))	('CDX2', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('immunoexpression', 'Var', (5, 21))	('CDX2', 'Gene', '1045', (0, 4))
3121	23454027	Genome-wide association studies in PSC have shown strong associations with HLA haplotypes, particularly HLA-DR3 (DRB1*0301) and HLA-B8 (B*0801).	('B*0801', 'Var', (136, 142))	('PSC', 'Gene', '100653366', (35, 38))	('DRB1*0301', 'Var', (113, 122))	('PSC', 'Gene', (35, 38))	('associations', 'Interaction', (57, 69))
3122	23454027	Polymorphisms of several non-HLA genes have also been shown to influence susceptibility to PSC such as those encoding intracellular adhesion molecule 1 (ICAM-1), tumor-necrosis factor, and matrix metalloproteinase 3 (MMP-3).	('tumor-necrosis', 'Disease', 'MESH:D009336', (162, 176))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('ICAM-1', 'Gene', '3383', (153, 159))	('tumor-necrosis', 'Disease', (162, 176))	('MMP-3', 'Gene', (217, 222))	('Polymorphisms', 'Var', (0, 13))	('intracellular adhesion molecule 1', 'Gene', (118, 151))	('MMP-3', 'Gene', '4314', (217, 222))	('influence', 'Reg', (63, 72))	('ICAM-1', 'Gene', (153, 159))	('PSC', 'Gene', '100653366', (91, 94))	('intracellular adhesion molecule 1', 'Gene', '3383', (118, 151))	('matrix metalloproteinase 3', 'Gene', (189, 215))	('matrix metalloproteinase 3', 'Gene', '4314', (189, 215))	('PSC', 'Gene', (91, 94))
3135	23454027	A wide variety of non-organ specific auto-antibodies can be detected in the serum of patients with PSC, including anti-nuclear antibodies, anti-cardiolipin antibodies, thyroperoxidase, rheumatoid factor, and smooth muscle antibodies in keeping with underlying alterations in immune regulation.	('PSC', 'Gene', (99, 102))	('smooth muscle antibodies', 'Phenotype', 'HP:0003262', (208, 232))	('anti-nuclear', 'Var', (114, 126))	('detected', 'Reg', (60, 68))	('rheumatoid', 'Disease', 'MESH:D001172', (185, 195))	('anti-cardiolipin', 'Var', (139, 155))	('patients', 'Species', '9606', (85, 93))	('regulation', 'biological_process', 'GO:0065007', ('282', '292'))	('rheumatoid', 'Disease', (185, 195))	('PSC', 'Gene', '100653366', (99, 102))
3177	23454027	Several risk factors for CCA in PSC have been recognized including older age at PSC diagnosis, smoking, alcohol use, elevated bilirubin, a longer duration of associated IBD, presence of colorectal neoplasia in patients with IBD, proctocolectomy, variceal bleeding, and polymorphism of the NKG2D gene.	('CCA', 'Phenotype', 'HP:0030153', (25, 28))	('NKG2D', 'Gene', '22914', (289, 294))	('alcohol use', 'Phenotype', 'HP:0030955', (104, 115))	('PSC', 'Gene', '100653366', (32, 35))	('CCA', 'Disease', (25, 28))	('bilirubin', 'Chemical', 'MESH:D001663', (126, 135))	('IBD', 'Phenotype', 'HP:0002037', (169, 172))	('patients', 'Species', '9606', (210, 218))	('PSC', 'Gene', '100653366', (80, 83))	('PSC', 'Gene', (32, 35))	('IBD', 'Phenotype', 'HP:0002037', (224, 227))	('colorectal neoplasia', 'Disease', (186, 206))	('variceal bleeding', 'Disease', 'MESH:D014648', (246, 263))	('elevated bilirubin', 'Phenotype', 'HP:0003573', (117, 135))	('alcohol use', 'Disease', (104, 115))	('proctocolectomy', 'Disease', (229, 244))	('PSC', 'Gene', (80, 83))	('variceal bleeding', 'Disease', (246, 263))	('polymorphism', 'Var', (269, 281))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (186, 206))	('NKG2D', 'Gene', (289, 294))	('alcohol', 'Chemical', 'MESH:D000438', (104, 111))	('neoplasia', 'Phenotype', 'HP:0002664', (197, 206))	('bilirubin', 'MPA', (126, 135))	('elevated', 'PosReg', (117, 125))	('smoking', 'Disease', (95, 102))
3184	23454027	The demonstration of polysomy by FISH analysis of cytologic specimens has demonstrated a sensitivity of 41% and a specificity of 98% for the diagnosis of CCA in PSC patients.	('PSC', 'Gene', '100653366', (161, 164))	('men', 'Species', '9606', (65, 68))	('CCA', 'Disease', (154, 157))	('PSC', 'Gene', (161, 164))	('patients', 'Species', '9606', (165, 173))	('CCA', 'Phenotype', 'HP:0030153', (154, 157))	('polysomy', 'Var', (21, 29))
3257	23454027	Active IBD at the time of LT, discontinuation of 5-aminosalicylate at the time of LT, use of tacrolimus-based immunosuppression and infrequent use of azathioprine may be associated with an unfavorable course of IBD after LT.	('tacrolimus', 'Chemical', 'MESH:D016559', (93, 103))	('IBD', 'Phenotype', 'HP:0002037', (211, 214))	('discontinuation', 'Var', (30, 45))	('Active IBD', 'Disease', (0, 10))	('azathioprine', 'Chemical', 'MESH:D001379', (150, 162))	('IBD', 'Phenotype', 'HP:0002037', (7, 10))	('associated with', 'Reg', (170, 185))	('5-aminosalicylate', 'Chemical', 'MESH:D019804', (49, 66))
3300	33383776	In a randomized crossover study enrolling twenty young subjects (10 females and 10 males; Body Mass Index (BMI) = 21.7 +- 2.2 kg/m2), Kristensen and co-workers reported that, with respect to refined counterparts, WG wheat bread ingestion led to increased satiety and reduced hunger, without modifying energy intake at the subsequent meals.	('WG wheat', 'Var', (213, 221))	('red', 'Gene', (267, 270))	('satiety', 'MPA', (255, 262))	('increased', 'PosReg', (245, 254))	('reduced hunger', 'Phenotype', 'HP:0004396', (267, 281))	('hunger', 'MPA', (275, 281))	('red', 'Gene', '15357', (267, 270))	('increased satiety', 'Phenotype', 'HP:0002591', (245, 262))
3314	33383776	As it will be discussed, high dietary fiber intake improves intestinal health, increases satiety, and reduces risk of some chronic diseases, including cancer.	('red', 'Gene', '15357', (102, 105))	('red', 'Gene', (102, 105))	('increases', 'PosReg', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('increases satiety', 'Phenotype', 'HP:0002591', (79, 96))	('intestinal health', 'MPA', (60, 77))	('improves', 'PosReg', (51, 59))	('chronic diseases', 'Disease', (123, 139))	('cancer', 'Disease', (151, 157))	('chronic diseases', 'Disease', 'MESH:D002908', (123, 139))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('satiety', 'MPA', (89, 96))	('fiber', 'Chemical', 'MESH:D004043', (38, 43))	('high dietary fiber', 'Var', (25, 43))
3351	33383776	In this context, WGs represent protective factors, as high intakes have been associated with significant decrease of cancer risk (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('decrease of cancer', 'Disease', 'MESH:D009369', (105, 123))	('decrease of cancer', 'Disease', (105, 123))	('high intakes', 'Var', (54, 66))
3368	33383776	High fiber and WG intake after diagnosis also leads to lower death rate, and this positive association again depends on fiber sources, with cereal fiber (especially from WG) showing the strongest link.	('fiber', 'Chemical', 'MESH:D004043', (5, 10))	('High fiber', 'Var', (0, 10))	('death', 'Disease', 'MESH:D003643', (61, 66))	('death', 'Disease', (61, 66))	('fiber', 'Chemical', 'MESH:D004043', (120, 125))	('lower', 'NegReg', (55, 60))	('fiber', 'Chemical', 'MESH:D004043', (147, 152))
3374	33383776	Likewise, in human colon cancer cells, secoisolariciresinol diglycoside and its metabolites (enterolactone and enterodiol) induce S-phase cell cycle arrest, by modulating key regulatory proteins (cyclin A and cyclin-dependent kinase 4).	('cyclin', 'molecular_function', 'GO:0016538', ('209', '215'))	('colon cancer', 'Phenotype', 'HP:0003003', (19, 31))	('cyclin A', 'Gene', (196, 204))	('cyclin', 'molecular_function', 'GO:0016538', ('196', '202'))	('arrest', 'Disease', (149, 155))	('diglycoside', 'Chemical', '-', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('colon cancer', 'Disease', 'MESH:D015179', (19, 31))	('enterolactone', 'Chemical', 'MESH:C029497', (93, 106))	('secoisolariciresinol', 'Var', (39, 59))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('138', '155'))	('modulating', 'Reg', (160, 170))	('arrest', 'Disease', 'MESH:D006323', (149, 155))	('colon cancer', 'Disease', (19, 31))	('enterodiol', 'Chemical', 'MESH:C029498', (111, 121))	('human', 'Species', '9606', (13, 18))	('cyclin-dependent kinase 4', 'Gene', (209, 234))	('S-phase', 'biological_process', 'GO:0051320', ('130', '137'))	('cyclin A', 'Gene', '890', (196, 204))	('secoisolariciresinol', 'Chemical', 'MESH:C060283', (39, 59))	('cyclin-dependent kinase 4', 'Gene', '1019', (209, 234))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (138, 155))
3376	33383776	Finally, some miRNAs involved in colorectal cancer are sensitive to phenolic compounds: for example, miRNA384 is up-regulated by luteolin, thus resulting in decreased expression levels of pleiotrophin, a cytokine upregulated in colorectal tumors.	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('rectal cancer', 'Phenotype', 'HP:0100743', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('pleiotrophin', 'Gene', '5764', (188, 200))	('colorectal cancer', 'Disease', 'MESH:D015179', (33, 50))	('colorectal tumors', 'Disease', 'MESH:D015179', (228, 245))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('luteolin', 'Chemical', 'MESH:D047311', (129, 137))	('up-regulated', 'PosReg', (113, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (33, 50))	('colorectal tumors', 'Disease', (228, 245))	('miRNA384', 'Var', (101, 109))	('pleiotrophin', 'Gene', (188, 200))	('decreased', 'NegReg', (157, 166))	('expression levels', 'MPA', (167, 184))	('colorectal cancer', 'Disease', (33, 50))
3404	33383776	Potential mechanisms of protective action include modification of gastroesophageal reflux and/or weight control, neutralization of carcinogens contained in food, amelioration of cancer-associated esophageal dysbiosis, and direct action on cancer cells.	('gastroesophageal reflux', 'MPA', (66, 89))	('modification', 'Var', (50, 62))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('amelioration', 'PosReg', (162, 174))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('esophageal reflux', 'Phenotype', 'HP:0002020', (72, 89))	('esophageal dysbiosis', 'Disease', (196, 216))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', (239, 245))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('esophageal dysbiosis', 'Disease', 'MESH:D064806', (196, 216))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (66, 89))	('neutralization', 'MPA', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
3408	33383776	Additionally, polyphenols could be beneficial in esophageal cancer, thanks to their antioxidant activity, ability to improve esophageal reflux-related inflammation, and modulation of cell proliferation and survival.	('esophageal reflux', 'Phenotype', 'HP:0002020', (125, 142))	('modulation', 'Reg', (169, 179))	('inflammation', 'biological_process', 'GO:0006954', ('151', '163'))	('esophageal cancer', 'Disease', (49, 66))	('survival', 'CPA', (206, 214))	('antioxidant activity', 'MPA', (84, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (49, 66))	('antioxidant activity', 'molecular_function', 'GO:0016209', ('84', '104'))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('polyphenols', 'Chemical', 'MESH:D059808', (14, 25))	('inflammation', 'Disease', 'MESH:D007249', (151, 163))	('improve', 'PosReg', (117, 124))	('cell proliferation', 'biological_process', 'GO:0008283', ('183', '201'))	('cell proliferation', 'CPA', (183, 201))	('polyphenols', 'Var', (14, 25))	('inflammation', 'Disease', (151, 163))	('esophageal reflux-related', 'Disease', (125, 150))
3414	33383776	It has been estimated, in fact, that low WG intake resulted in almost 270,000 avoidable deaths and almost 4 million disability-adjusted life years in the European Union in 2015.	('deaths', 'Disease', (88, 94))	('low', 'Var', (37, 40))	('deaths', 'Disease', 'MESH:D003643', (88, 94))
3437	31792281	Furthermore, miRNA deregulation is also correlated to angiogenesis, proliferation and migration of cancer cells in CRC, thus contributing to cancerogenesis and invasion.	('proliferation', 'CPA', (68, 81))	('migration', 'CPA', (86, 95))	('invasion', 'CPA', (160, 168))	('CRC', 'Disease', (115, 118))	('angiogenesis', 'CPA', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('contributing to', 'Reg', (125, 140))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('correlated', 'Reg', (40, 50))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('deregulation', 'Var', (19, 31))	('miRNA', 'Protein', (13, 18))	('CRC', 'Disease', 'MESH:D015179', (115, 118))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
3442	31792281	It consists of the following steps: data collection, statistics and data visualization, in silico screening for miRNA-mRNA interactions in CRC, and experimental validation.	('CRC', 'Disease', (139, 142))	('miRNA-mRNA', 'Var', (112, 122))	('CRC', 'Disease', 'MESH:D015179', (139, 142))
3487	31792281	Moreover, hsa-miR-429 expression was upregulated in human CRC tissues, and high hsa-miR-429 expression was significantly associated with tumor size, lymph node metastasis and poor prognosis.	('CRC', 'Disease', 'MESH:D015179', (58, 61))	('upregulated', 'PosReg', (37, 48))	('hsa-miR-429', 'Gene', (10, 21))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('lymph node metastasis', 'CPA', (149, 170))	('high', 'Var', (75, 79))	('associated', 'Reg', (121, 131))	('hsa-miR-429', 'Gene', (80, 91))	('human', 'Species', '9606', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('hsa-miR-429', 'Gene', '554210', (10, 21))	('CRC', 'Disease', (58, 61))	('poor prognosis', 'CPA', (175, 189))	('hsa-miR-429', 'Gene', '554210', (80, 91))	('expression', 'MPA', (22, 32))	('expression', 'MPA', (92, 102))
3492	31792281	Many of these miRNAs target genes in Jak/Stat NF-kappaB and Akt pathways, which are immune response pathways.	('Akt', 'Gene', '207', (60, 63))	('Akt', 'Gene', (60, 63))	('NF-kappaB', 'Pathway', (46, 55))	('Jak/Stat', 'Var', (37, 45))
3523	29954404	Our data suggests that a consequent CME during an open operation leads to significantly more removed lymph nodes than in laparoscopically resected patients and in several so far published data of open control groups from Europe.	('more', 'PosReg', (88, 92))	('removed lymph nodes', 'CPA', (93, 112))	('lap', 'Gene', (121, 124))	('lap', 'Gene', '7939', (121, 124))	('patients', 'Species', '9606', (147, 155))	('CME', 'Var', (36, 39))	('CME', 'biological_process', 'GO:0072583', ('36', '39'))
3530	29954404	A population-based study from Denmark showed a significantly increased disease-free survival after 4 years in the group of patients operated with CME.	('CME', 'Var', (146, 149))	('disease-free survival', 'CPA', (71, 92))	('increased', 'PosReg', (61, 70))	('patients', 'Species', '9606', (123, 131))
3577	29954404	A population-based study in Denmark showed that the disease-free survival is significantly increased when patients are operated with CME and that significantly more lymph nodes are resected (median 19 vs. 34).	('CME', 'biological_process', 'GO:0072583', ('133', '136'))	('disease-free survival', 'CPA', (52, 73))	('patients', 'Species', '9606', (106, 114))	('increased', 'PosReg', (91, 100))	('CME', 'Var', (133, 136))
3615	29872716	In 1998, the first SELEX screening protocol was constructed for isolating high specificity aptamers, this study illustrated that aptamers have a great potential for combining with multiple targets and aid in dissecting complex biological systems.	('aid', 'Gene', (201, 204))	('aptamers', 'Var', (129, 137))	('combining', 'Interaction', (165, 174))	('aid', 'Gene', '57379', (201, 204))
3617	29872716	Binding with cell surface receptors via signaling transduction pathway, aptamers can regulate cell signaling and aid in the discovery of new function.	('aid', 'Gene', (113, 116))	('regulate', 'Reg', (85, 93))	('aid', 'Gene', '57379', (113, 116))	('cell signaling', 'MPA', (94, 108))	('aptamers', 'Var', (72, 80))
3619	29872716	Using B-cell Burkitt's lymphoma cell line (Ramors cells), aptamer TD50 with strong affinity and excellent specificity was selected and identified.	('Ramors cells', 'CellLine', 'CVCL:0320', (43, 55))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (13, 31))	('lymphoma', 'Phenotype', 'HP:0002665', (23, 31))	('TD50', 'Var', (66, 70))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (13, 31))	("Burkitt's lymphoma", 'Disease', (13, 31))
3627	29872716	Aptamer AS1411, HCHO7, and Apt-32 have been confirmed to specifically bind to the biomarkers on the surface of cancer cells.	('Apt-32', 'Gene', (27, 33))	('bind', 'Interaction', (70, 74))	('AS1411', 'Chemical', 'MESH:C513936', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('Aptamer', 'Protein', (0, 7))	('AS1411', 'Var', (8, 14))	('cancer', 'Disease', (111, 117))	('HCHO7', 'CellLine', 'CVCL:J486', (16, 21))	('HCHO7', 'Gene', (16, 21))
3631	29872716	Aptamer 32 was identified to bind to the epidermal growth factor receptor variant III (EGFRvIII) on the glioblastoma multiforme (GBM) U87Delta cell line.	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (104, 127))	('U87Delta', 'CellLine', 'CVCL:0022', (134, 142))	('bind', 'Interaction', (29, 33))	('variant', 'Var', (74, 81))	('glioblastoma multiforme', 'Disease', (104, 127))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))
3659	29872716	Moreover, the Epi-Apt-SPION bioconjugate can reduce the viability of cancer cell.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('reduce', 'NegReg', (45, 51))	('Epi-Apt-SPION', 'Var', (14, 27))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('Epi-Apt-SPION', 'Chemical', '-', (14, 27))	('cancer', 'Disease', (69, 75))
3692	28653677	Subsequently, the anti-PD-1 antibodies nivolumab and pembrolizumab, and the anti-PD-L1 antibody atezolizumab, have shown marked therapeutic activity in various solid tumours and lymphomas, resulting in a number of regulatory approvals of these agents for the treatment of different malignancies.	('solid tumours', 'Disease', 'MESH:D009369', (160, 173))	('nivolumab', 'Chemical', 'MESH:D000077594', (39, 48))	('atezolizumab', 'Chemical', 'MESH:C000594389', (96, 108))	('lymphomas', 'Disease', 'MESH:D008223', (178, 187))	('anti-PD-1', 'Var', (18, 27))	('lymphomas', 'Phenotype', 'HP:0002665', (178, 187))	('solid tumours', 'Disease', (160, 173))	('lymphomas', 'Disease', (178, 187))	('malignancies', 'Disease', 'MESH:D009369', (282, 294))	('therapeutic', 'MPA', (128, 139))	('pembrolizumab', 'Chemical', 'MESH:C582435', (53, 66))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('tumours', 'Phenotype', 'HP:0002664', (166, 173))	('malignancies', 'Disease', (282, 294))
3772	28653677	In their study, IHC assessment of pretreatment tissue samples from patients with advanced-stage cancer treated with atezolizumab revealed PD-L1 positivity on both tumour cells and TILs, with a higher percentage of PD-L1-positive TILs than PD-L1-positive tumour cells.	('atezolizumab', 'Chemical', 'MESH:C000594389', (116, 128))	('patients', 'Species', '9606', (67, 75))	('positivity', 'Var', (144, 154))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (254, 260))	('advanced-stage cancer', 'Disease', (81, 102))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('tumour', 'Disease', (254, 260))	('advanced-stage cancer', 'Disease', 'MESH:D006223', (81, 102))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('PD-L1', 'Gene', (138, 143))	('tumour', 'Disease', (163, 169))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))
3777	28653677	In both the discovery and validation cohorts, patients with >20% PD-1hi/CTLA-4hi cytotoxic T lymphocytes (CTLs) had higher response rates and longer PFS durations than those with <=20% PD-1hi/CTLA-4hi CTLs (ORR: 85.7% versus 0%, PFS: 31.6 months versus 9.6 months in the discovery cohort; ORR: 78.6% versus 0%, PFS: 15.9 months versus 9.9 months in the validation cohort).	('higher', 'PosReg', (116, 122))	('patients', 'Species', '9606', (46, 54))	('response', 'CPA', (123, 131))	('PD-1hi/CTLA-4hi', 'Var', (65, 80))
3783	28653677	The immunoscore reflects the density of two lymphocyte populations (cytotoxic (CD8+) and memory (CD45RO+) T cells) in the core and in the invasive margin regions of tumours, resulting in a four-point scale score ranging from immunoscore 0 (I0; low densities of both cell types in both regions), to immunoscore 4 (I4; high densities of both cell types in both regions).	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('CD45RO+', 'Var', (97, 104))	('CD8', 'Gene', (79, 82))	('tumours', 'Phenotype', 'HP:0002664', (165, 172))	('CD8', 'Gene', '925', (79, 82))	('tumours', 'Disease', 'MESH:D009369', (165, 172))	('tumours', 'Disease', (165, 172))
3806	28653677	Additionally, in a study of mutations associated with acquired resistance to pembrolizumab therapy, loss-of-function mutations in the genes encoding the IFN-receptor-associated tyrosine kinases JAK1 and JAK2 were identified as relevant.	('mutations', 'Var', (117, 126))	('JAK1', 'Gene', (194, 198))	('JAK1', 'Gene', '3716', (194, 198))	('loss-of-function', 'NegReg', (100, 116))	('JAK', 'molecular_function', 'GO:0004713', ('203', '206'))	('JAK2', 'Gene', '3717', (203, 207))	('JAK', 'molecular_function', 'GO:0004713', ('194', '197'))	('pembrolizumab', 'Chemical', 'MESH:C582435', (77, 90))	('JAK2', 'Gene', (203, 207))
3807	28653677	Truncating mutations in JAK1 and JAK2 resulted in a lack of response to IFNgamma in cell lines derived from tumours that were progressing.	('tumours', 'Disease', (108, 115))	('Truncating mutations', 'Var', (0, 20))	('IFNgamma', 'Gene', '3458', (72, 80))	('JAK2', 'Gene', (33, 37))	('lack', 'NegReg', (52, 56))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('JAK1', 'Gene', (24, 28))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('tumours', 'Disease', 'MESH:D009369', (108, 115))	('JAK1', 'Gene', '3716', (24, 28))	('JAK2', 'Gene', '3717', (33, 37))	('IFNgamma', 'Gene', (72, 80))
3810	28653677	These mutations in tumour cells can result in the generation of novel antigens, termed neoantigens, which can be recognized as non-self-epitopes by the immune system, thereby enhancing T-cell reactivity against the tumour, thus facilitating the efficacy of ICB.	('tumour', 'Disease', 'MESH:D009369', (19, 25))	('tumour', 'Disease', 'MESH:D009369', (215, 221))	('enhancing', 'PosReg', (175, 184))	('antigens', 'MPA', (70, 78))	('tumour', 'Disease', (215, 221))	('T-cell reactivity against', 'CPA', (185, 210))	('facilitating', 'PosReg', (228, 240))	('result in', 'Reg', (36, 45))	('tumour', 'Disease', (19, 25))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('ICB', 'CPA', (257, 260))	('efficacy', 'CPA', (245, 253))	('ICB', 'Chemical', '-', (257, 260))	('tumour', 'Phenotype', 'HP:0002664', (215, 221))	('mutations', 'Var', (6, 15))
3814	28653677	In a study by Rizvi et al., a higher burden of somatic nonsynonymous mutations was associated with clinical efficacy in response to pembrolizumab in patients with NSCLC.	('patients', 'Species', '9606', (149, 157))	('nonsynonymous mutations', 'Var', (55, 78))	('pembrolizumab', 'Chemical', 'MESH:C582435', (132, 145))	('NSCLC', 'Disease', (163, 168))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('response', 'MPA', (120, 128))
3817	28653677	In a validation cohort of 18 samples from patients with NSCLC treated with pembrolizumab, a higher rate of durable clinical benefit and longer PFS durations were noted in patients with a nonsynonymous mutational burden above 200 (median mutational burden of this cohort) compared with other patients (durable clinical benefit rate: 83% versus 22%, P = 0.04; median PFS: not reached versus 3.4 months, P = 0.006).	('NSCLC', 'Disease', (56, 61))	('patients', 'Species', '9606', (171, 179))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('patients', 'Species', '9606', (291, 299))	('pembrolizumab', 'Chemical', 'MESH:C582435', (75, 88))	('patients', 'Species', '9606', (42, 50))	('nonsynonymous mutational burden', 'Var', (187, 218))
3819	28653677	Mutations in MMR genes in tumour cells therefore result in a large number of mutations that affect, among others, DNA microsatellite motifs.	('result in', 'Reg', (49, 58))	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('tumour', 'Disease', (26, 32))	('DNA microsatellite motifs', 'MPA', (114, 139))	('Mutations', 'Var', (0, 9))	('affect', 'Reg', (92, 98))	('mutations', 'Var', (77, 86))	('MMR', 'Gene', (13, 16))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))
3830	28653677	In addition, the association between mutational burden and response to treatment was found only when samples obtained before treatment were analysed, whereas no association between mutation burden and treatment response was noted in patients whose tumour samples had been collected after initiating anti-CTLA-4 therapy.	('tumour', 'Disease', (248, 254))	('mutational', 'Var', (37, 47))	('tumour', 'Phenotype', 'HP:0002664', (248, 254))	('tumour', 'Disease', 'MESH:D009369', (248, 254))	('patients', 'Species', '9606', (233, 241))
3858	28487883	Peutz-Jeghers is an autosomal dominant disorder caused by pathogenic variants of the serine threonine kinase STK11.	('STK11', 'molecular_function', 'GO:0033868', ('109', '114'))	('STK11', 'Gene', (109, 114))	('variants', 'Var', (69, 77))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (20, 47))	('STK11', 'Gene', '6794', (109, 114))	('Peutz-Jeghers', 'Disease', (0, 13))	('autosomal dominant disorder', 'Disease', (20, 47))	('caused by', 'Reg', (48, 57))
3862	28487883	In addition, methylome analysis revealed global hypomethylation and CpG island hypermethylation, two features that have been described as hallmarks of the colorectal cancer epigenome.	('colorectal cancer', 'Disease', 'MESH:D015179', (155, 172))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('CpG island hypermethylation', 'Var', (68, 95))	('global', 'MPA', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('colorectal cancer', 'Disease', (155, 172))
3867	28487883	Peutz-Jeghers is an autosomal dominant disorder caused by pathogenic variants of the STK11 gene located on human Chromosome 19p13.	('Chromosome', 'cellular_component', 'GO:0005694', ('113', '123'))	('variants', 'Var', (69, 77))	('STK11', 'Gene', (85, 90))	('human', 'Species', '9606', (107, 112))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (20, 47))	('Peutz-Jeghers', 'Disease', (0, 13))	('STK11', 'Gene', '6794', (85, 90))	('STK11', 'molecular_function', 'GO:0033868', ('85', '90'))	('autosomal dominant disorder', 'Disease', (20, 47))	('caused by', 'Reg', (48, 57))
3883	28487883	Data analysis identified 2079 high-confidence somatic single-nucleotide variants (SNVs), most of which correspond to C > T substitutions in an ACG trinucleotide context.	('ACG', 'Chemical', 'MESH:C023716', (143, 146))	('single-nucleotide variants', 'Var', (54, 80))	('trinucleotide', 'Chemical', '-', (147, 160))	('C > T', 'Var', (117, 122))
3884	28487883	Notably, the ERBB3 p.P306H mutation has been described in the COSMIC (Catalogue of Somatic Mutations in Cancer) database and was also identified in a non-small-cell lung adenocarcinoma in our in-house tumor cohorts.	('ERBB3', 'Gene', '2065', (13, 18))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (165, 184))	('ERBB3', 'Gene', (13, 18))	('Cancer', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', (201, 206))	('p.P306H', 'Mutation', 'rs556251328', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('Cancer', 'Disease', (104, 110))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (165, 184))	('p.P306H', 'Var', (19, 26))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lung adenocarcinoma', 'Disease', (165, 184))
3888	28487883	The FLT3 frameshift insertion is located in the protein kinase domain, just 30 amino acids from the hotspot position at D835.	('FLT3', 'Gene', '2322', (4, 8))	('frameshift', 'Var', (9, 19))	('FLT3', 'Gene', (4, 8))
3891	28487883	We could also not identify any rare or private coding germline SNV or indel in known cancer-predisposing genes.	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('indel', 'Var', (70, 75))
3892	28487883	These results are consistent with the findings from the only other published study investigating the STK11 mutation status of a solitary PJ polyp.	('STK11', 'molecular_function', 'GO:0033868', ('101', '106'))	('STK11', 'Gene', (101, 106))	('mutation', 'Var', (107, 115))	('STK11', 'Gene', '6794', (101, 106))
3896	28487883	2A), thus indicating an aberrant methylome in the adenoma sample.	('indicating', 'Reg', (10, 20))	('adenoma', 'Disease', (50, 57))	('aberrant', 'Var', (24, 32))	('methylome', 'MPA', (33, 42))	('adenoma', 'Disease', 'MESH:D000236', (50, 57))
3899	28487883	This identified several CpG islands that showed tumor-associated hypermethylation in the solitary PJ polyp (Fig.	('hypermethylation', 'Var', (65, 81))	('tumor', 'Disease', (48, 53))	('solitary PJ polyp', 'Disease', (89, 106))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
3903	28487883	Our report provides the first genome sequence of a solitary PJ polyp and reveals a number of genetic variants with relatively low allele frequencies (~10%) and in genes that are not commonly associated with colorectal carcinogenesis.	('variants', 'Var', (101, 109))	('colorectal carcinogenesis', 'Disease', (207, 232))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (207, 232))
3909	28487883	The acquisition of a tumor-driving mutation in a specific subclone could then represent the initiating event for tumor growth.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mutation', 'Var', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
3911	28487883	More specifically, we identified "tumor-prone CpG islands" that showed a similar degree of hypermethylation in the polyp and in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (128, 145))	('tumor', 'Disease', (34, 39))	('colorectal cancer', 'Phenotype', 'HP:0003003', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('colorectal cancer', 'Disease', (128, 145))	('polyp', 'Disease', (115, 120))	('hypermethylation', 'Var', (91, 107))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
3912	28487883	These findings are consistent with the notion that epigenetic changes represent early events during colorectal carcinogenesis.	('colorectal carcinogenesis', 'Disease', (100, 125))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (100, 125))	('epigenetic changes', 'Var', (51, 69))
3918	28487883	Our finding of tumor-like CpG island hypermethylation and genomic hypomethylation in a solitary PJ polyp supports the notion that such polyps do carry a cancer risk and should be removed.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('polyps', 'Disease', 'MESH:D011127', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('cancer', 'Disease', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', (15, 20))	('polyps', 'Disease', (135, 141))	('genomic hypomethylation', 'Var', (58, 81))
3939	26311743	Functionally, we validated this finding in vitro and found that inhibition of DDX3 with siRNA resulted in reduced TCF4-reporter activity and lowered the mRNA expression levels of downstream TCF4-regulated genes.	('mRNA expression levels', 'MPA', (153, 175))	('siRNA', 'Gene', (88, 93))	('inhibition', 'Var', (64, 74))	('lowered', 'NegReg', (141, 148))	('TCF4', 'Gene', (114, 118))	('TCF4', 'Gene', (190, 194))	('TCF4', 'Gene', '6925', (190, 194))	('TCF4', 'Gene', '6925', (114, 118))	('DDX3', 'Gene', (78, 82))	('reduced', 'NegReg', (106, 113))
3940	26311743	In addition, DDX3 knockdown in colorectal cancer cell lines reduced proliferation and caused a G1 arrest, supporting a potential oncogenic role of DDX3 in colorectal cancer.	('knockdown', 'Var', (18, 27))	('colorectal cancer', 'Disease', 'MESH:D015179', (31, 48))	('proliferation', 'CPA', (68, 81))	('colorectal cancer', 'Disease', 'MESH:D015179', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('caused', 'Reg', (86, 92))	('G1 arrest', 'CPA', (95, 104))	('rat', 'Species', '10116', (75, 78))	('colorectal cancer', 'Phenotype', 'HP:0003003', (31, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('colorectal cancer', 'Disease', (31, 48))	('reduced', 'NegReg', (60, 67))	('colorectal cancer', 'Disease', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('DDX3', 'Gene', (13, 17))
3943	26311743	The highest RK-33 sensitivity was observed in tumors with wild-type APC-status and a mutation in CTNNB1.	('APC', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('APC', 'Gene', '324', (68, 71))	('CTNNB1', 'Gene', '1499', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('mutation', 'Var', (85, 93))	('tumors', 'Disease', (46, 52))	('CTNNB1', 'Gene', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
3945	26311743	Inhibition of DDX3 with the small molecule inhibitor RK-33 causes inhibition of Wnt signaling and may therefore be a promising future treatment strategy for a subset of colorectal cancers.	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('rat', 'Species', '10116', (146, 149))	('DDX3', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('RK-33', 'Gene', (53, 58))	('colorectal cancer', 'Phenotype', 'HP:0003003', (169, 186))	('colorectal cancers', 'Disease', 'MESH:D015179', (169, 187))	('Inhibition', 'Var', (0, 10))	('Wnt signaling', 'Pathway', (80, 93))	('colorectal cancers', 'Disease', (169, 187))	('inhibition', 'NegReg', (66, 76))
3949	26311743	The most common alteration is inactivation of the APC gene (>70%).	('APC', 'cellular_component', 'GO:0005680', ('50', '53'))	('APC', 'Gene', '324', (50, 53))	('inactivation', 'Var', (30, 42))	('rat', 'Species', '10116', (20, 23))	('APC', 'Gene', (50, 53))
3958	26311743	Notably, DDX3 activity has also been linked to Wnt-signaling activity by the identification of coinciding CTNNB1 and DDX3X activating mutations in Wnt-type medulloblastomas.	('activating', 'PosReg', (123, 133))	('CTNNB1', 'Gene', (106, 112))	('DDX3X', 'Gene', '1654', (117, 122))	('medulloblastomas', 'Disease', 'MESH:D008527', (156, 172))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('mutations', 'Var', (134, 143))	('DDX3X', 'Gene', (117, 122))	('CTNNB1', 'Gene', '1499', (106, 112))	('medulloblastomas', 'Disease', (156, 172))
3959	26311743	It remains to be determined whether colorectal cancer cells, which usually harbor activating mutations in the Wnt-signaling pathway, are dependent on DDX3 as well.	('mutations', 'Var', (93, 102))	('colorectal cancer', 'Disease', (36, 53))	('activating', 'PosReg', (82, 92))	('Wnt-signaling pathway', 'Pathway', (110, 131))	('colorectal cancer', 'Disease', 'MESH:D015179', (36, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (36, 53))	('Wnt-signaling pathway', 'biological_process', 'GO:0016055', ('110', '131'))
3962	26311743	DDX3 knockdown resulted in a reduction of cell proliferation in both cell lines (Figure 1B).	('DDX3', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('reduction', 'NegReg', (29, 38))	('rat', 'Species', '10116', (54, 57))	('cell proliferation', 'CPA', (42, 60))	('cell proliferation', 'biological_process', 'GO:0008283', ('42', '60'))
3965	26311743	In addition, a slight decrease in S-phase was observed in HT29 (3.4%; p = 0.05).	('HT29', 'Var', (58, 62))	('S-phase', 'CPA', (34, 41))	('HT29', 'CellLine', 'CVCL:0320', (58, 62))	('decrease', 'NegReg', (22, 30))
3968	26311743	Given the activating role of DDX3 in Wnt signaling in other settings, we wanted to determine whether high DDX3 expression is associated with activated Wnt signaling in colorectal cancer patient samples as reflected by an increased cytoplasmic and nuclear beta-catenin pool (Figure 3).	('beta-catenin', 'Gene', (255, 267))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('beta-catenin', 'Gene', '1499', (255, 267))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('increased', 'PosReg', (221, 230))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('colorectal cancer', 'Disease', (168, 185))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('expression', 'MPA', (111, 121))	('activated', 'MPA', (141, 150))	('high', 'Var', (101, 105))	('DDX3', 'Gene', (106, 110))	('patient', 'Species', '9606', (186, 193))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))
3969	26311743	We separately scored the membranous, cytoplasmic and nuclear localization of beta-catenin in tumors with low and high DDX3 expression, which is shown in Table 2.	('high', 'Var', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('rat', 'Species', '10116', (7, 10))	('DDX3', 'Gene', (118, 122))	('tumors', 'Disease', (93, 99))	('beta-catenin', 'Gene', (77, 89))	('beta-catenin', 'Gene', '1499', (77, 89))
3973	26311743	Five colorectal cancer cell lines (HCT116, HT29, DLD-1, SW480 and Colo205) were treated with RK-33 and cell viability was assessed by an MTS assay (Figure 4A-4B).	('RK-33', 'Var', (93, 98))	('colorectal cancer', 'Disease', 'MESH:D015179', (5, 22))	('HT29', 'CellLine', 'CVCL:0320', (43, 47))	('SW480', 'CellLine', 'CVCL:0546', (56, 61))	('HCT116', 'CellLine', 'CVCL:0291', (35, 41))	('colorectal cancer', 'Phenotype', 'HP:0003003', (5, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('colorectal cancer', 'Disease', (5, 22))
3975	26311743	To assess whether RK-33 also showed cytotoxicity in 3D cultures, we expanded our panel with four patient-derived colorectal cancer spheroid cell lines.	('colorectal cancer', 'Disease', (113, 130))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('cytotoxicity', 'Disease', 'MESH:D064420', (36, 48))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('patient', 'Species', '9606', (97, 104))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('RK-33', 'Var', (18, 23))	('cytotoxicity', 'Disease', (36, 48))
3980	26311743	Unlike the RK-33 sensitive cell lines HCT116 and HT29, proliferation in DLD-1 and SW480 was not affected by DDX3 knockdown (Figure 4H) and only a moderate drop in S-phase was observed in SW480 (3.7%; p = 0.02).	('SW480', 'CellLine', 'CVCL:0546', (82, 87))	('DDX3', 'Gene', (108, 112))	('HCT116', 'CellLine', 'CVCL:0291', (38, 44))	('drop', 'NegReg', (155, 159))	('rat', 'Species', '10116', (150, 153))	('S-phase', 'MPA', (163, 170))	('knockdown', 'Var', (113, 122))	('rat', 'Species', '10116', (62, 65))	('SW480', 'CellLine', 'CVCL:0546', (187, 192))	('HT29', 'CellLine', 'CVCL:0320', (49, 53))
3981	26311743	Centered on our finding of differential sensitivity to RK-33, we hypothesized that sensitivity to RK-33 in colorectal cancer cells may also be associated with other genomic drivers of cellular transformation.	('associated', 'Reg', (143, 153))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('sensitivity', 'Var', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('colorectal cancer', 'Disease', (107, 124))	('colorectal cancer', 'Disease', 'MESH:D015179', (107, 124))
3983	26311743	Interestingly, we found that two of the three RK-33 sensitive cell lines had wild-type APC and TP53, whereas the less sensitive group had mutations in these genes.	('APC', 'Gene', (87, 90))	('APC', 'Gene', '324', (87, 90))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))	('mutations', 'Var', (138, 147))
3984	26311743	To further determine if TP53 mutations in cell lines alters sensitivity to RK-33, we compared RK-33 sensitivity in isogenic cell lines with wild-type TP53 (HCT116-p53+/+) and without TP53 (HCT116-p53-/-; Figure 5A).	('alters', 'Reg', (53, 59))	('TP53', 'Gene', (150, 154))	('TP53', 'Gene', '7157', (183, 187))	('TP53', 'Gene', (24, 28))	('HCT116', 'CellLine', 'CVCL:0291', (156, 162))	('p53', 'Gene', (163, 166))	('mutations', 'Var', (29, 38))	('p53', 'Gene', '7157', (163, 166))	('TP53', 'Gene', (183, 187))	('HCT116', 'CellLine', 'CVCL:0291', (189, 195))	('TP53', 'Gene', '7157', (150, 154))	('p53', 'Gene', '7157', (196, 199))	('p53', 'Gene', (196, 199))	('sensitivity', 'MPA', (60, 71))	('TP53', 'Gene', '7157', (24, 28))
3986	26311743	In addition, similar to the parental cell line that expresses p53 (Figure 1C), knockdown of DDX3 resulted in a G1 arrest (13.9% increase; p = 0.04) and a decrease of cells in S-phase (4.8%; p = 0.11; Figure 5C-5D).	('knockdown', 'Var', (79, 88))	('S-phase', 'biological_process', 'GO:0051320', ('175', '182'))	('increase', 'PosReg', (128, 136))	('decrease', 'NegReg', (154, 162))	('DDX3', 'Gene', (92, 96))	('cells in S-phase', 'CPA', (166, 182))	('G1 arrest', 'CPA', (111, 120))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))
3988	26311743	Although DDX3 is thought to play a role in Wnt signaling, cells that harbor an APC mutation were less sensitive to RK-33 than cells with wild-type APC.	('APC', 'cellular_component', 'GO:0005680', ('147', '150'))	('APC', 'Gene', (147, 150))	('APC', 'Gene', (79, 82))	('sensitive', 'MPA', (102, 111))	('APC', 'cellular_component', 'GO:0005680', ('79', '82'))	('mutation', 'Var', (83, 91))	('APC', 'Gene', '324', (147, 150))	('APC', 'Gene', '324', (79, 82))	('signaling', 'biological_process', 'GO:0023052', ('47', '56'))	('less', 'NegReg', (97, 101))
3989	26311743	Since CTNNB1 and DDX3X mutations co-occur in Wnt-type medulloblastomas, we hypothesized that DDX3 dependency may be higher in cells with other genetic aberrations in the Wnt-signaling pathway, like mutations in the gene encoding beta-catenin.	('medulloblastomas', 'Disease', (54, 70))	('rat', 'Species', '10116', (155, 158))	('CTNNB1', 'Gene', '1499', (6, 12))	('DDX3X', 'Gene', '1654', (17, 22))	('higher', 'PosReg', (116, 122))	('CTNNB1', 'Gene', (6, 12))	('beta-catenin', 'Gene', (229, 241))	('mutations', 'Var', (23, 32))	('medulloblastomas', 'Disease', 'MESH:D008527', (54, 70))	('DDX3X', 'Gene', (17, 22))	('beta-catenin', 'Gene', '1499', (229, 241))
3991	26311743	Interestingly, we found that cells with mutant beta-catenin were slightly more sensitive (IC50 2.68 muM) than those with only a wild-type allele (IC50 3.71 muM) and that DDX3 expression is slightly higher in HCT116 beta-cateninDelta45/- cells (Figure 5D-5E).	('beta-catenin', 'Gene', '1499', (47, 59))	('expression', 'MPA', (175, 185))	('muM', 'Gene', '56925', (100, 103))	('cateninDelta45', 'Chemical', '-', (220, 234))	('DDX3', 'Gene', (170, 174))	('muM', 'Gene', (100, 103))	('beta-catenin', 'Gene', (215, 227))	('muM', 'Gene', '56925', (156, 159))	('beta-catenin', 'Gene', (47, 59))	('sensitive', 'MPA', (79, 88))	('muM', 'Gene', (156, 159))	('mutant', 'Var', (40, 46))	('HCT116', 'CellLine', 'CVCL:0291', (208, 214))	('beta-catenin', 'Gene', '1499', (215, 227))	('higher', 'PosReg', (198, 204))
3992	26311743	These results indicate that APC wild-type colorectal cancers harboring an activating CTNNB1 mutation may be more sensitive to RK-33 treatment.	('activating', 'PosReg', (74, 84))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (42, 59))	('mutation', 'Var', (92, 100))	('CTNNB1', 'Gene', (85, 91))	('APC', 'cellular_component', 'GO:0005680', ('28', '31'))	('sensitive', 'MPA', (113, 122))	('colorectal cancers', 'Disease', 'MESH:D015179', (42, 60))	('APC', 'Gene', (28, 31))	('colorectal cancers', 'Disease', (42, 60))	('CTNNB1', 'Gene', '1499', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('APC', 'Gene', '324', (28, 31))
3994	26311743	Knockdown of DDX3 resulted in a significant decrease in Wnt signaling in HCT116 (42%, p = 0.001) and a small decrease in HT29 (17%, p = 0.23; Figure 6A).	('decrease', 'NegReg', (109, 117))	('HT29', 'CellLine', 'CVCL:0320', (121, 125))	('decrease', 'NegReg', (44, 52))	('Knockdown', 'Var', (0, 9))	('Wnt signaling', 'MPA', (56, 69))	('HCT116', 'CellLine', 'CVCL:0291', (73, 79))	('HCT116', 'Protein', (73, 79))	('DDX3', 'Gene', (13, 17))
3997	26311743	As seen in Figure 6C and Supplementary Table 1, DDX3 knockdown resulted in reduced expression of AXIN2, CCND1 and BIRC5A in HCT116.	('CCND1', 'Gene', (104, 109))	('DDX3', 'Gene', (48, 52))	('knockdown', 'Var', (53, 62))	('BIRC5A', 'Gene', (114, 120))	('CCND1', 'Gene', '595', (104, 109))	('reduced', 'NegReg', (75, 82))	('AXIN2', 'Gene', (97, 102))	('AXIN2', 'Gene', '8313', (97, 102))	('expression', 'MPA', (83, 93))	('HCT116', 'CellLine', 'CVCL:0291', (124, 130))
4000	26311743	Again this result was slightly less profound in HT29, where RK-33 caused a reduction in AXIN2, CCND1 and BIRC5A.	('HT29', 'CellLine', 'CVCL:0320', (48, 52))	('AXIN2', 'Gene', '8313', (88, 93))	('BIRC5A', 'MPA', (105, 111))	('reduction', 'NegReg', (75, 84))	('CCND1', 'Gene', (95, 100))	('RK-33', 'Var', (60, 65))	('AXIN2', 'Gene', (88, 93))	('CCND1', 'Gene', '595', (95, 100))
4003	26311743	Although we found earlier that RK-33 does not bind directly to DDX5, exposure to RK-33 resulted in decreased DDX5 protein levels, but did not affect DDX17 expression (Figure 7).	('decreased', 'NegReg', (99, 108))	('DDX17', 'Gene', '10521', (149, 154))	('DDX5', 'Gene', '1655', (63, 67))	('DDX5', 'Gene', (109, 113))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('DDX5', 'Gene', '1655', (109, 113))	('RK-33', 'Var', (81, 86))	('DDX5', 'Gene', (63, 67))	('DDX17', 'Gene', (149, 154))
4006	26311743	As the majority of colorectal cancers is driven by mutations in the Wnt-signaling pathway, we explored the possible contribution of DDX3 to Wnt-associated colorectal cancer oncogenesis.	('mutations', 'Var', (51, 60))	('colorectal cancer', 'Disease', 'MESH:D015179', (155, 172))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('driven by', 'Reg', (41, 50))	('colorectal cancer', 'Disease', 'MESH:D015179', (19, 36))	('oncogenesis', 'biological_process', 'GO:0007048', ('173', '184'))	('Wnt-signaling pathway', 'biological_process', 'GO:0016055', ('68', '89'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (19, 36))	('colorectal cancers', 'Disease', 'MESH:D015179', (19, 37))	('colorectal cancer', 'Disease', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('Wnt-signaling pathway', 'Pathway', (68, 89))	('colorectal cancers', 'Disease', (19, 37))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
4007	26311743	In the present study, we showed that DDX3 is overexpressed in 39% of colorectal cancers and that inhibition of DDX3 results in reduced Wnt signaling and a G1 arrest, making DDX3 an attractive therapeutic target in these cancers.	('inhibition', 'Var', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('DDX3', 'Gene', (111, 115))	('colorectal cancers', 'Disease', 'MESH:D015179', (69, 87))	('colorectal cancers', 'Disease', (69, 87))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('Wnt signaling', 'MPA', (135, 148))	('G1 arrest', 'CPA', (155, 164))	('cancers', 'Disease', (220, 227))	('reduced', 'NegReg', (127, 134))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
4008	26311743	The clinical relevance of the development of Wnt signaling inhibitors which work in a constitutively activated setting is tremendous, since mutations in the Wnt-signaling pathway are not only the first genetic alterations in the adenoma-carcinoma sequence, but advanced colorectal cancers with mutations in APC or CTNNB1 remain dependent on upstream Wnt signaling activity.	('adenoma-carcinoma', 'Disease', (229, 246))	('CTNNB1', 'Gene', '1499', (314, 320))	('colorectal cancers', 'Disease', (270, 288))	('APC', 'Gene', (307, 310))	('rat', 'Species', '10116', (214, 217))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (229, 246))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('APC', 'Gene', '324', (307, 310))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('mutations', 'Var', (294, 303))	('CTNNB1', 'Gene', (314, 320))	('colorectal cancer', 'Phenotype', 'HP:0003003', (270, 287))	('colorectal cancers', 'Disease', 'MESH:D015179', (270, 288))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
4015	26311743	For example, we found high DDX3 expression to be associated with worse prognosis in smoking patients with head and neck squamous cell carcinomas, whereas the opposite was observed in non-smoking patients.	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('high', 'Var', (22, 26))	('patients', 'Species', '9606', (92, 100))	('neck squamous cell carcinomas', 'Disease', (115, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (120, 144))	('patients', 'Species', '9606', (195, 203))	('neck', 'cellular_component', 'GO:0044326', ('115', '119'))	('expression', 'MPA', (32, 42))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (115, 144))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (106, 144))	('DDX3', 'Gene', (27, 31))
4016	26311743	DDX3 inhibition resulted in a reduction of proliferation in several colorectal cell lines and all of the colorectal cancer cell lines used in this study were susceptible to RK-33, pleading for reliance of colorectal cancer cells on DDX3 for their survival and arguing against a tumor suppressive role in this particular setting.	('DDX3', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('colorectal cancer', 'Disease', 'MESH:D015179', (105, 122))	('colorectal cancer', 'Disease', 'MESH:D015179', (205, 222))	('tumor', 'Disease', (278, 283))	('rat', 'Species', '10116', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('colorectal cancer', 'Phenotype', 'HP:0003003', (205, 222))	('RK-33', 'Var', (173, 178))	('inhibition', 'NegReg', (5, 15))	('reduction', 'NegReg', (30, 39))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('colorectal cancer', 'Disease', (205, 222))	('proliferation', 'CPA', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('colorectal cancer', 'Disease', (105, 122))
4019	26311743	The sensitivity to DDX3 inhibition with both RK-33 and siDDX3 was greatest in HCT116, closely followed by HT29.	('RK-33', 'Gene', (45, 50))	('HCT116', 'CellLine', 'CVCL:0291', (78, 84))	('DDX3', 'Enzyme', (19, 23))	('siDDX3', 'Gene', (55, 61))	('HCT116', 'Var', (78, 84))	('HT29', 'CellLine', 'CVCL:0320', (106, 110))	('inhibition', 'NegReg', (24, 34))
4022	26311743	Another possibility is that in conjunction with DDX3, there could be an association with other specific genetic alterations that promotes RK-33 sensitivity.	('promotes', 'PosReg', (129, 137))	('RK-33 sensitivity', 'MPA', (138, 155))	('association', 'Interaction', (72, 83))	('rat', 'Species', '10116', (116, 119))	('alterations', 'Var', (112, 123))
4023	26311743	DDX3 dependency seemed to be greater in the presence of wild-type APC-status and activating mutations in CTNNB1.	('APC', 'Gene', (66, 69))	('APC', 'cellular_component', 'GO:0005680', ('66', '69'))	('DDX3 dependency', 'MPA', (0, 15))	('mutations', 'Var', (92, 101))	('APC', 'Gene', '324', (66, 69))	('CTNNB1', 'Gene', '1499', (105, 111))	('activating', 'PosReg', (81, 91))	('CTNNB1', 'Gene', (105, 111))
4024	26311743	This finding is in line with the co-occurrence of DDX3X and CTNNB1 mutations in medulloblastomas and provides a potential explanation for the fact that HT29, which harbors a mutation in APC, does not show a clear G1 arrest upon DDX3 knockdown.	('APC', 'Gene', '324', (186, 189))	('CTNNB1', 'Gene', (60, 66))	('mutation', 'Var', (174, 182))	('HT29', 'CellLine', 'CVCL:0320', (152, 156))	('DDX3X', 'Gene', (50, 55))	('mutations', 'Var', (67, 76))	('medulloblastomas', 'Disease', 'MESH:D008527', (80, 96))	('DDX3X', 'Gene', '1654', (50, 55))	('CTNNB1', 'Gene', '1499', (60, 66))	('APC', 'Gene', (186, 189))	('APC', 'cellular_component', 'GO:0005680', ('186', '189'))	('medulloblastomas', 'Disease', (80, 96))
4028	26311743	However, mutations in CTNNB1 are highly prevalent in hepatocellular carcinoma (24%), sarcoma (44%) and testicular cancer(24%), suggesting that these cancers may potentially have increased sensitivity to RK-33.	('CTNNB1', 'Gene', (22, 28))	('mutations', 'Var', (9, 18))	('sarcoma', 'Disease', 'MESH:D012509', (85, 92))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (53, 77))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('sarcoma', 'Disease', (85, 92))	('testicular cancer', 'Disease', 'MESH:D013736', (103, 120))	('prevalent', 'Reg', (40, 49))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (53, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('cancers', 'Disease', (149, 156))	('testicular cancer', 'Disease', (103, 120))	('CTNNB1', 'Gene', '1499', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('hepatocellular carcinoma', 'Disease', (53, 77))	('testicular cancer', 'Phenotype', 'HP:0010788', (103, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
4031	26311743	In these more often APC-wild-type cancers, inhibition of DDX3 causes a potent reduction of Wnt signaling and a G1 arrest.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('inhibition', 'Var', (43, 53))	('APC', 'Gene', (20, 23))	('APC', 'cellular_component', 'GO:0005680', ('20', '23'))	('reduction', 'NegReg', (78, 87))	('APC', 'Gene', '324', (20, 23))	('signaling', 'biological_process', 'GO:0023052', ('95', '104'))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('DDX3', 'Gene', (57, 61))	('G1 arrest', 'CPA', (111, 120))	('cancers', 'Disease', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('Wnt signaling', 'MPA', (91, 104))
4045	26311743	After gel-electrophoresis proteins were transferred onto PVDF membranes, blocked with 5% milk and probed overnight with primary antibodies against DDX3 (1:1000, mAb AO196), Actin (1:10000, A5441, Sigma-Aldrich, St Louis, MO, USA), DDX5 (1:1000, pab204, EMD Millipore, Billarica, MA, USA), DDX17 (1:1000, Bethyl, Montgomery, TX, USA) and p53 (1:1000, DO-1, Santa-Cruz Biotechnology, Dallas, TX, USA) and followed by appropriate secondary antibodies.	('DDX3', 'Gene', (147, 151))	('DDX17', 'Gene', (289, 294))	('DDX17', 'Gene', '10521', (289, 294))	('1:10000', 'Var', (180, 187))	('p53', 'Gene', (337, 340))	('p53', 'Gene', '7157', (337, 340))	('DDX5', 'Gene', (231, 235))	('DDX5', 'Gene', '1655', (231, 235))	('1:1000', 'Var', (153, 159))	('1:1000', 'Var', (342, 348))
4056	26311743	For the DDX3 knockdown experiments 12.5-15 x 103 HCT116 and HT29 cells were plated in a 24-well plate.	('HCT116', 'CellLine', 'CVCL:0291', (49, 55))	('knockdown', 'Var', (13, 22))	('DDX3', 'Gene', (8, 12))	('HT29 cells', 'CellLine', 'CVCL:0320', (60, 70))
4081	26109431	The MUTYH base excision repair gene protects against inflammation-associated colorectal carcinogenesis MUTYH DNA glycosylase removes mismatched adenine opposite 7, 8-dihydro-8-oxoguanine (8-oxoG), which is the major mutagenic lesion induced by oxidative stress.	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (77, 102))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('mismatched', 'Var', (133, 143))	('MUTYH', 'Gene', '70603', (103, 108))	('inflammation', 'Disease', 'MESH:D007249', (53, 65))	('MUTYH', 'Gene', (4, 9))	('7, 8-dihydro-8-oxoguanine', 'Chemical', 'MESH:C453560', (161, 186))	('glycosylase', 'molecular_function', 'GO:0016798', ('113', '124'))	('MUTYH', 'Gene', (103, 108))	('colorectal carcinogenesis', 'Disease', (77, 102))	('8-oxoG', 'Chemical', '-', (188, 194))	('inflammation', 'Disease', (53, 65))	('oxidative stress', 'Phenotype', 'HP:0025464', (244, 260))	('base excision repair', 'biological_process', 'GO:0006284', ('10', '30'))	('inflammation', 'biological_process', 'GO:0006954', ('53', '65'))	('MUTYH', 'Gene', '70603', (4, 9))	('adenine', 'Chemical', 'MESH:D000225', (144, 151))
4082	26109431	Biallelic mutations in MUTYH are associated with MUTYH-Associated polyposis (MAP) and increased risk in colorectal cancer (CRC).	('Biallelic mutations', 'Var', (0, 19))	('MUTYH-Associated polyposis', 'Disease', 'MESH:D011125', (49, 75))	('colorectal cancer', 'Disease', 'MESH:D015179', (104, 121))	('MUTYH-Associated polyposis', 'Disease', (49, 75))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('MAP', 'molecular_function', 'GO:0004239', ('77', '80'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (104, 121))	('associated', 'Reg', (33, 43))	('colorectal cancer', 'Disease', (104, 121))	('CRC', 'Phenotype', 'HP:0003003', (123, 126))	('MUTYH', 'Gene', (23, 28))
4083	26109431	We investigated cancer susceptibility associated with MUTYH inactivation in a mouse model of inflammation-dependent carcinogenesis induced by azoxymethane (AOM) and dextran sulphate (DSS).	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('inflammation-dependent carcinogenesis', 'Disease', (93, 130))	('MUTYH inactivation', 'Var', (54, 72))	('dextran sulphate', 'Chemical', 'MESH:D016264', (165, 181))	('DSS', 'Chemical', 'MESH:D016264', (183, 186))	('AOM', 'Disease', (156, 159))	('inflammation-dependent carcinogenesis', 'Disease', 'MESH:D007249', (93, 130))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('mouse', 'Species', '10090', (78, 83))	('azoxymethane', 'Chemical', 'MESH:D001397', (142, 154))	('AOM', 'Disease', 'MESH:C537492', (156, 159))	('inflammation', 'biological_process', 'GO:0006954', ('93', '105'))
4091	26109431	8-OxoG can mispair with adenine during DNA replication to generate G:C to T:A transversion mutations.	('G:C to T:A', 'Var', (67, 77))	('adenine', 'Chemical', 'MESH:D000225', (24, 31))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('mispair', 'Var', (11, 18))	('rat', 'Species', '10116', (62, 65))	('DNA replication', 'biological_process', 'GO:0006260', ('39', '54'))
4094	26109431	MUTYH mutations are associated with colorectal cancer (CRC).	('associated', 'Reg', (20, 30))	('colorectal cancer', 'Disease', (36, 53))	('CRC', 'Phenotype', 'HP:0003003', (55, 58))	('colorectal cancer', 'Disease', 'MESH:D015179', (36, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (36, 53))	('MUTYH mutations', 'Var', (0, 15))
4096	26109431	Since biallelic MUTYH mutations confer a spontaneous mutator phenotype in human cell lines and in mice, it is generally regarded that MUTYH inactivation in MAP patients drives genomic instability in colorectal epithelial cells thereby increasing CRC risk.	('human', 'Species', '9606', (74, 79))	('patients', 'Species', '9606', (160, 168))	('drives', 'Reg', (169, 175))	('increasing', 'PosReg', (235, 245))	('CRC', 'Disease', (246, 249))	('mice', 'Species', '10090', (98, 102))	('CRC', 'Phenotype', 'HP:0003003', (246, 249))	('mutations', 'Var', (22, 31))	('genomic instability', 'MPA', (176, 195))	('MAP', 'molecular_function', 'GO:0004239', ('156', '159'))	('MUTYH', 'Var', (134, 139))
4097	26109431	Consistent with this view, CRC in MAP patients displays a distinctive molecular fingerprint of somatic G:C to T:A transversions in tumor suppressors and/or oncogenes including the adenomatous polyposis coli (APC) and KRAS genes.	('KRAS', 'Gene', (217, 221))	('CRC', 'Phenotype', 'HP:0003003', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('APC', 'Disease', (208, 211))	('KRAS', 'Gene', '3845', (217, 221))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (180, 206))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (180, 206))	('tumor', 'Disease', (131, 136))	('APC', 'Phenotype', 'HP:0005227', (208, 211))	('adenomatous polyposis coli', 'Disease', (180, 206))	('patients', 'Species', '9606', (38, 46))	('APC', 'Disease', 'MESH:D011125', (208, 211))	('transversions', 'Var', (114, 127))
4105	26109431	In a previous study we reported that MUTYH influences the inflammatory response in a mouse model of UC.	('mouse', 'Species', '10090', (85, 90))	('inflammatory response', 'CPA', (58, 79))	('UC', 'Phenotype', 'HP:0100279', (100, 102))	('MUTYH', 'Var', (37, 42))	('influences', 'Reg', (43, 53))	('inflammatory response', 'biological_process', 'GO:0006954', ('58', '79'))
4110	26109431	To examine further the CRC risk associated with MUTYH abrogation, we have used a two-stage, initiation-promotion carcinogenesis model.	('carcinogenesis', 'Disease', 'MESH:D063646', (113, 127))	('CRC', 'Disease', (23, 26))	('MUTYH abrogation', 'Var', (48, 64))	('carcinogenesis', 'Disease', (113, 127))	('CRC', 'Phenotype', 'HP:0003003', (23, 26))
4112	26109431	Our findings demonstrate that MUTYH loss is indeed associated with an increased CRC risk.	('CRC', 'Phenotype', 'HP:0003003', (80, 83))	('CRC', 'Disease', (80, 83))	('MUTYH loss', 'Var', (30, 40))	('rat', 'Species', '10116', (20, 23))
4139	26109431	The increased basal levels of pro-inflammatory cytokines in the colon of Mutyh-/- mice indicate that MUTYH inactivation is associated with an inflammation-prone phenotype.	('mice', 'Species', '10090', (82, 86))	('associated', 'Reg', (123, 133))	('inflammation', 'Disease', (142, 154))	('MUTYH inactivation', 'Var', (101, 119))	('Mutyh', 'Gene', (73, 78))	('Mutyh', 'Gene', '70603', (73, 78))	('increased', 'PosReg', (4, 13))	('inflammation', 'biological_process', 'GO:0006954', ('142', '154'))	('inflammation', 'Disease', 'MESH:D007249', (142, 154))
4140	26109431	In contrast, MUTYH inactivation does not appear to impair the early response to AOM/DSS treatment.	('MUTYH inactivation', 'Var', (13, 31))	('AOM', 'Disease', (80, 83))	('DSS', 'Chemical', 'MESH:D016264', (84, 87))	('AOM', 'Disease', 'MESH:C537492', (80, 83))
4157	26109431	MUTYH inactivation in mice is associated with small intestinal tumour and/or lymphomas, either spontaneous or induced by KBrO3 exposure.	('associated', 'Reg', (30, 40))	('mice', 'Species', '10090', (22, 26))	('small intestinal tumour', 'Disease', (46, 69))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('lymphomas', 'Disease', 'MESH:D008223', (77, 86))	('lymphomas', 'Disease', (77, 86))	('small intestinal tumour', 'Phenotype', 'HP:0100833', (46, 69))	('small intestinal tumour', 'Disease', 'MESH:D007414', (46, 69))	('KBrO3', 'Chemical', '-', (121, 126))	('lymphomas', 'Phenotype', 'HP:0002665', (77, 86))	('MUTYH inactivation', 'Var', (0, 18))
4169	26109431	Modulation of MUTYH expression has been shown to be among the genomic predictors of cellular sensitivity to alkylation damage induced by N-methyl-N'-nitro-N-nitrosoguanidine.	('Modulation', 'Var', (0, 10))	("N-methyl-N'-nitro-N-nitrosoguanidine", 'Chemical', 'MESH:D008769', (137, 173))	('alkylation damage', 'Disease', 'MESH:D004194', (108, 125))	('alkylation damage', 'Disease', (108, 125))	('MUTYH', 'Gene', (14, 19))
4172	26109431	Thus, a cancer-prone phenotype is always associated with MUTYH loss, independently from the contrasting toxicities induced by AOM/DSS or AZA/UVA exposures.	('AOM', 'Disease', (126, 129))	('cancer', 'Disease', (8, 14))	('toxicities', 'Disease', (104, 114))	('DSS', 'Chemical', 'MESH:D016264', (130, 133))	('AOM', 'Disease', 'MESH:C537492', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('toxicities', 'Disease', 'MESH:D064420', (104, 114))	('AZA', 'Chemical', 'MESH:D001379', (137, 140))	('MUTYH loss', 'Var', (57, 67))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
4226	26109431	The following procedure was applied to both spleen single cell suspensions and blood samples: after erythrocyte depletion with ACK lysis buffer, 106 cells were suspended in 100 mul RPMI, 10 mM Hepes, 1 mM EDTA, 2% FBS and labeled for 30' at RT with 1 mug of the following antibodies: CD4-APC (eBioscience, SanDiego, CA, USA), CD8-PeCy7 (eBioscience), CD11b-FITC (eBioscience), B220-PacificBlue (BioLegend, San Diego, CA, USA), Ly-6G-PE (BioLegend), Ly-6C-APCeFluor780 (eBioscience).	('APC', 'Disease', 'MESH:D011125', (288, 291))	('APC', 'Disease', (455, 458))	('FBS', 'Disease', 'MESH:D005198', (214, 217))	('CD11b', 'Gene', (351, 356))	('APC', 'Disease', (288, 291))	('Ly-6G-PE', 'Var', (427, 435))	('CD8-PeCy7', 'Var', (326, 335))	('EDTA', 'Chemical', 'MESH:D004492', (205, 209))	('CD11b', 'Gene', '16409', (351, 356))	('CD4', 'Gene', (284, 287))	('APC', 'Phenotype', 'HP:0005227', (288, 291))	('APC', 'Phenotype', 'HP:0005227', (455, 458))	('FBS', 'Disease', (214, 217))	('APC', 'Disease', 'MESH:D011125', (455, 458))	('CD4', 'Gene', '12504', (284, 287))
4258	26334895	The site codes used included the following: right colon (C18.0, C18.2-C18.4), left colon (C18.5-C18.7), large intestine NOS (C18.8-C18.9, C26.0), and rectum (C19.9 and C20.9).	('C26', 'CellLine', 'CVCL:0240', (138, 141))	('C18.0', 'Var', (57, 62))	('C20.9', 'Var', (168, 173))	('C18.2-C18.4', 'Var', (64, 75))	('C18.8-C18.9', 'Var', (125, 136))	('C19.9', 'Var', (158, 163))	('C18.5-C18.7', 'Var', (90, 101))	('C20.9', 'CellLine', 'CVCL:W178', (168, 173))	('C26.0', 'Var', (138, 143))
4260	26334895	The histology type was divided into 3 classes according to SEER histology codes: adenocarcinoma (8010, 8140-8141, 8144-8145, 8210-8211, 8220-8221, 8230-8231, and 8260-8263), mucinous carcinoma (8480 and 8481), and signet ring-cell carcinoma (8490).	('8230-8231', 'Var', (147, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('8010', 'Var', (97, 101))	('8260-8263', 'Var', (162, 171))	('adenocarcinoma', 'Disease', (81, 95))	('8480', 'Var', (194, 198))	('8144-8145', 'Var', (114, 123))	('ring-cell carcinoma', 'Disease', (221, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('adenocarcinoma', 'Disease', 'MESH:D000230', (81, 95))	('8210-8211', 'Var', (125, 134))	('mucinous carcinoma', 'Disease', 'MESH:D002288', (174, 192))	('8220-8221', 'Var', (136, 145))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (174, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('mucinous carcinoma', 'Disease', (174, 192))	('ring-cell carcinoma', 'Disease', 'MESH:D018279', (221, 240))
4345	26234583	The pooled data of studies showed that high OPN expression was significantly associated with high tumor grades (OR = 2.24, 95% CI 1.55-3.23), lymph node metastasis (OR = 2.36, 95% CI 1.71-3.26) and tumor distant metastasis (OR = 2.38, 95% CI 1.01-5.60).	('lymph node metastasis', 'CPA', (142, 163))	('high', 'Var', (39, 43))	('OPN', 'Gene', (44, 47))	('high tumor', 'Disease', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('high tumor', 'Disease', 'MESH:D009369', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('OPN', 'Gene', '6696', (44, 47))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', (198, 203))
4346	26234583	Moreover, high OPN expression was significantly associated with the 2-year (HR 1.97, 95% CI 1.30-3.00), 3-year (HR 1.82, 95% CI 1.24-2.68), 5 year (HR 1.53, 95% CI 1.28-1.82) survival rates and overall survival (OS, HR 1.70, 95% CI 1.12-2.60), respectively.	('associated', 'Reg', (48, 58))	('overall survival', 'CPA', (194, 210))	('OPN', 'Gene', '6696', (15, 18))	('high', 'Var', (10, 14))	('OPN', 'Gene', (15, 18))	('survival rates', 'CPA', (175, 189))
4353	26234583	It is suggested that OPN levels in blood or tumor samples may be valuable for predicting the prognosis of carcinomas, and the inhibition of OPN might be helpful for the treatment of patients with carcinoma.	('carcinoma', 'Disease', (106, 115))	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('carcinomas', 'Disease', (106, 116))	('OPN', 'Gene', (21, 24))	('carcinomas', 'Disease', 'MESH:D002277', (106, 116))	('carcinoma', 'Disease', (196, 205))	('inhibition', 'Var', (126, 136))	('OPN', 'Gene', (140, 143))	('OPN', 'Gene', '6696', (140, 143))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('carcinoma', 'Disease', 'MESH:D002277', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patients', 'Species', '9606', (182, 190))	('carcinoma', 'Disease', 'MESH:D002277', (196, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('tumor', 'Disease', (44, 49))	('OPN', 'Gene', '6696', (21, 24))
4364	26234583	2a, the pooled data of eight studies showed that high OPN expression was significantly associated with tumor grades (OR = 2.24, 95% CI = 1.55-3.23), and no significant heterogeneity between studies were observed (I2 = 10.6%, P = 0.348).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('expression', 'MPA', (58, 68))	('tumor', 'Disease', (103, 108))	('associated', 'Reg', (87, 97))	('OPN', 'Gene', '6696', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('high', 'Var', (49, 53))	('OPN', 'Gene', (54, 57))
4370	26234583	3c, there was correlation between high OPN expression and tumor distant metastasis (OR = 2.38, 95% CI = 1.01-5.60), but there was significant heterogeneity among these studies (I2 = 73.8%, P = 0.000).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('high', 'Var', (34, 38))	('OPN', 'Gene', '6696', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('OPN', 'Gene', (39, 42))
4371	26234583	4 exhibited that high OPN expression was significantly associated with the 2-year (HR 1.97, 95% CI 1.30-3.00), 3-year (HR 1.82, 95% CI 1.24-2.68), and 5 year (HR 1.53, 95% CI 1.28-1.82) survival rates in colorectal cancer patients, respectively.	('colorectal cancer', 'Disease', 'MESH:D015179', (204, 221))	('patients', 'Species', '9606', (222, 230))	('high', 'Var', (17, 21))	('associated', 'Reg', (55, 65))	('OPN', 'Gene', '6696', (22, 25))	('colorectal cancer', 'Phenotype', 'HP:0003003', (204, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('OPN', 'Gene', (22, 25))	('colorectal cancer', 'Disease', (204, 221))
4385	26234583	Firstly, the results of pooled analysis on the relationship of OPN expression with CRC tumor grade suggested the significant association between high OPN expressions and the high tumor grade.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('OPN', 'Gene', '6696', (63, 66))	('high tumor', 'Disease', 'MESH:D009369', (174, 184))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('OPN', 'Gene', (63, 66))	('tumor', 'Disease', (87, 92))	('CRC', 'Phenotype', 'HP:0003003', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('OPN', 'Gene', '6696', (150, 153))	('high tumor', 'Disease', (174, 184))	('OPN', 'Gene', (150, 153))	('high', 'Var', (145, 149))	('tumor', 'Disease', (179, 184))
4388	26234583	Also the results of present meta-analysis showed that high OPN expression was closely related to tumor metastasis, including lymph node metastasis and distant metastasis.	('OPN', 'Gene', '6696', (59, 62))	('OPN', 'Gene', (59, 62))	('high', 'Var', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor metastasis', 'Disease', 'MESH:D009362', (97, 113))	('related', 'Reg', (86, 93))	('tumor metastasis', 'Disease', (97, 113))	('distant metastasis', 'CPA', (151, 169))	('lymph node metastasis', 'CPA', (125, 146))
4389	26234583	Taken together, the pooled data of present meta-analysis supported the hypothesis that high OPN expression might promote CRC invasion and metastasis, leading to the poor prognosis of patients with CRC.	('OPN', 'Gene', (92, 95))	('promote', 'PosReg', (113, 120))	('CRC', 'Disease', (197, 200))	('CRC', 'Phenotype', 'HP:0003003', (121, 124))	('expression', 'MPA', (96, 106))	('high', 'Var', (87, 91))	('OPN', 'Gene', '6696', (92, 95))	('CRC', 'Phenotype', 'HP:0003003', (197, 200))	('CRC invasion', 'CPA', (121, 133))	('patients', 'Species', '9606', (183, 191))
4402	26234583	In conclusion, the results of present meta-analysis demonstrated that OPN expression might be significantly associated with tumor grade, invasion, metastasis, and survival of CRC patients, although the cut-off value of high OPN should be further studied.	('CRC', 'Phenotype', 'HP:0003003', (175, 178))	('OPN', 'Gene', '6696', (224, 227))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('OPN', 'Gene', '6696', (70, 73))	('OPN', 'Gene', (224, 227))	('expression', 'Var', (74, 84))	('invasion', 'CPA', (137, 145))	('tumor', 'Disease', (124, 129))	('associated', 'Reg', (108, 118))	('OPN', 'Gene', (70, 73))	('patients', 'Species', '9606', (179, 187))	('survival', 'CPA', (163, 171))	('metastasis', 'CPA', (147, 157))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
4411	25660948	Not surprisingly, the deregulation of homeostatic control of miRNA biogenesis is associated with multiple pathological diseases, including cancers.	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('miRNA biogenesis', 'MPA', (61, 77))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('miRNA biogenesis', 'biological_process', 'GO:0035196', ('61', '77'))	('homeostatic control', 'MPA', (38, 57))	('associated', 'Reg', (81, 91))	('deregulation', 'Var', (22, 34))
4414	25660948	Indeed, miRNA maturation is subjected to complex regulations, and defects along this process may significantly contribute to tumorigenesis and cancer progression.	('defects', 'Var', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('contribute', 'Reg', (111, 121))
4443	25660948	Transcriptionally inactive p53 mutants, frequently identified in human tumors, interfere with the functional assembly between Drosha complex and DDX5, which in turn hinder the nuclear processing of these miRNAs.	('human', 'Species', '9606', (65, 70))	('mutants', 'Var', (31, 38))	('p53', 'Gene', '7157', (27, 30))	('DDX5', 'Gene', (145, 149))	('hinder', 'NegReg', (165, 171))	('Drosha', 'Gene', (126, 132))	('nuclear processing', 'MPA', (176, 194))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('interfere', 'NegReg', (79, 88))	('functional assembly', 'MPA', (98, 117))	('tumors', 'Disease', (71, 77))	('Drosha', 'Gene', '29102', (126, 132))	('p53', 'Gene', (27, 30))
4450	25660948	More specifically, DDX5 interacts directly with transcription factors p53, AR, RunX2, and NF-kB (p50 subunit), and DDX17 upregulates MDM2 transcription in both p53-dependent and -independent manners.	('RunX2', 'Gene', '860', (79, 84))	('RunX2', 'Gene', (79, 84))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('transcription', 'biological_process', 'GO:0006351', ('48', '61'))	('MDM2', 'Gene', '4193', (133, 137))	('MDM2', 'Gene', (133, 137))	('transcription', 'MPA', (138, 151))	('p53', 'Gene', (160, 163))	('p53', 'Gene', '7157', (160, 163))	('transcription', 'biological_process', 'GO:0006351', ('138', '151'))	('upregulates', 'PosReg', (121, 132))	('DDX17', 'Var', (115, 120))
4452	25660948	Consistently, silencing both DDX5 and DDX17 inhibits cell proliferation whereas overexpression of DDX5 facilitates cell growth and promotes epithelial-to-mesenchymal (EMT) transition upon growth factor stimulation.	('silencing', 'Var', (14, 23))	('EMT', 'Gene', '3702', (167, 170))	('DDX5', 'Gene', (29, 33))	('cell growth', 'CPA', (115, 126))	('facilitates', 'PosReg', (103, 114))	('DDX17', 'Gene', (38, 43))	('DDX5', 'Gene', (98, 102))	('inhibits', 'NegReg', (44, 52))	('cell proliferation', 'CPA', (53, 71))	('promotes', 'PosReg', (131, 139))	('EMT', 'Gene', (167, 170))
4453	25660948	In human invasive breast carcinomas, overexpression and gene amplification, but rarely mutations, are frequently observed in DDX5 (8.6% amplification vs. 0.3% mutation).	('human', 'Species', '9606', (3, 8))	('gene amplification', 'Var', (56, 74))	('breast carcinomas', 'Disease', 'MESH:D001943', (18, 35))	('breast carcinomas', 'Disease', (18, 35))	('breast carcinomas', 'Phenotype', 'HP:0003002', (18, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (25, 35))
4461	25660948	As a protein-binding switch, phosphorylation of MeCP2 at Ser80 maintains it in an open conformation to allow interaction with DGCR8, leading to inhibition of miRNA maturation by dissembling the microprocessor complex.	('Ser80', 'Var', (57, 62))	('MeCP2', 'Gene', (48, 53))	('phosphorylation', 'Var', (29, 44))	('DGCR8', 'Gene', (126, 131))	('MeCP2', 'Gene', '4204', (48, 53))	('miRNA maturation', 'MPA', (158, 174))	('inhibition', 'NegReg', (144, 154))	('Ser80', 'Chemical', '-', (57, 62))	('DGCR8', 'Gene', '54487', (126, 131))	('interaction', 'Interaction', (109, 120))
4464	25660948	Different from other miRNA regulators, knockdown of SNIP1 downregulates pri- (transcription unaffected), pre- and mature miRNAs, suggesting that SNIP1 regulates the turnover/stability of pri-miRNAs rather than the processing efficacy in the nucleus.	('SNIP1', 'Gene', '79753', (145, 150))	('transcription', 'biological_process', 'GO:0006351', ('78', '91'))	('turnover/stability', 'MPA', (165, 183))	('knockdown', 'Var', (39, 48))	('pre', 'molecular_function', 'GO:0003904', ('105', '108'))	('SNIP1', 'Gene', (52, 57))	('pri-', 'CPA', (72, 76))	('SNIP1', 'Gene', (145, 150))	('downregulates', 'NegReg', (58, 71))	('regulates', 'Reg', (151, 160))	('SNIP1', 'Gene', '79753', (52, 57))	('nucleus', 'cellular_component', 'GO:0005634', ('241', '248'))
4481	25660948	A frameshift mutation was identified in pre-miRNA nuclear export receptor, XPO5, which creates a premature termination codon, results in a truncated protein that lacks a small region in the C-terminus.	('frameshift mutation', 'Var', (2, 21))	('truncated protein', 'MPA', (139, 156))	('results in', 'Reg', (126, 136))	('XPO5', 'Gene', (75, 79))	('lacks', 'NegReg', (162, 167))	('XPO5', 'Gene', '57510', (75, 79))
4482	25660948	Interestingly, mutant XPO5 fails to form a proper XPO5/Ran-GTP/pre-miRNA ternary complex due to its reduced binding and/or recognition capability with the pre-miRNA cargo.	('XPO5', 'Gene', (50, 54))	('XPO5', 'Gene', '57510', (50, 54))	('reduced', 'NegReg', (100, 107))	('binding', 'Interaction', (108, 115))	('XPO5', 'Gene', (22, 26))	('GTP', 'Chemical', 'MESH:D006160', (59, 62))	('Ran', 'Gene', (55, 58))	('XPO5', 'Gene', '57510', (22, 26))	('recognition', 'MPA', (123, 134))	('mutant', 'Var', (15, 21))	('Ran', 'Gene', '5901', (55, 58))
4483	25660948	Genetic alterations of XPO5 are heterogeneous in human cancers that generally occur at a low frequency.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('Genetic alterations', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('human', 'Species', '9606', (49, 54))	('XPO5', 'Gene', '57510', (23, 27))	('XPO5', 'Gene', (23, 27))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancers', 'Disease', (55, 62))
4487	25660948	As a haploinsufficient tumor suppressor, mutations and heterozygous deletion of DICER1 are frequently observed in human tumors.	('mutations', 'Var', (41, 50))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (5, 28))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('23', '39'))	('DICER1', 'Gene', (80, 86))	('DICER1', 'Gene', '23405', (80, 86))	('haploinsufficient tumor', 'Disease', (5, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('human', 'Species', '9606', (114, 119))	('tumor suppressor', 'biological_process', 'GO:0051726', ('23', '39'))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
4489	25660948	Both let-7 and miR-103/107 reduce the protein level of Dicer through direct interaction with multiple binding sequences found in the 3' UTR or the coding region of DICER1 mRNA.	('protein level', 'MPA', (38, 51))	('DICER1', 'Gene', '23405', (164, 170))	('Dicer', 'Gene', '23405', (55, 60))	('miR-103/107', 'Var', (15, 26))	('Dicer', 'Gene', (55, 60))	('interaction', 'Interaction', (76, 87))	('reduce', 'NegReg', (27, 33))	('DICER1', 'Gene', (164, 170))
4490	25660948	High expression of miR-103/107 attenuates Dicer-mediated miRNA processing, resulting in downregulation of mature miRNAs.	('downregulation', 'NegReg', (88, 102))	('miR-103/107', 'Var', (19, 30))	('attenuates', 'NegReg', (31, 41))	('mature miRNAs', 'MPA', (106, 119))	('Dicer', 'Gene', '23405', (42, 47))	('Dicer', 'Gene', (42, 47))
4491	25660948	Subsequently, blocked biogenesis, particularly of the miR-200 family, promotes EMT in breast cancer cells.	('EMT', 'biological_process', 'GO:0001837', ('79', '82'))	('blocked', 'Var', (14, 21))	('EMT', 'Gene', (79, 82))	('EMT', 'Gene', '3702', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('biogenesis', 'CPA', (22, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))	('promotes', 'PosReg', (70, 78))
4494	25660948	Frameshift TRBP mutants with reduced binding affinity with Dicer have been identified in human colorectal tumors with microsatellite instability.	('binding', 'molecular_function', 'GO:0005488', ('37', '44'))	('human', 'Species', '9606', (89, 94))	('binding', 'Interaction', (37, 44))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('TRBP', 'Gene', (11, 15))	('TRBP', 'Gene', '6895', (11, 15))	('microsatellite instability', 'MPA', (118, 144))	('Dicer', 'Gene', (59, 64))	('Frameshift', 'Var', (0, 10))	('colorectal tumors', 'Disease', 'MESH:D015179', (95, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('identified', 'Reg', (75, 85))	('Dicer', 'Gene', '23405', (59, 64))	('colorectal tumors', 'Disease', (95, 112))
4497	25660948	The underlying mechanisms of genetic deletion as well as the corresponding functional consequences of TRBP deletion in these tumors remain to be investigated.	('TRBP', 'Gene', '6895', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('genetic deletion', 'Var', (29, 45))	('deletion', 'Var', (107, 115))	('TRBP', 'Gene', (102, 106))
4498	25660948	Interestingly, TRBP is rapidly phosphorylated by mitogen-activated protein kinase 1 (Erk) at S142, S152, S283 and S286 in response to growth factor stimulation.	('mitogen-activated protein kinase 1', 'Gene', (49, 83))	('S286', 'Var', (114, 118))	('Erk', 'Gene', (85, 88))	('TRBP', 'Gene', (15, 19))	('S283', 'Var', (105, 109))	('S152', 'Var', (99, 103))	('TRBP', 'Gene', '6895', (15, 19))	('S142', 'Var', (93, 97))	('mitogen-activated protein kinase 1', 'Gene', '5594', (49, 83))	('Erk', 'Gene', '5594', (85, 88))
4513	25660948	In the context of cellular stress, Ago2 is modified by poly-ADP-ribosylation which consequently relieves miRNA-mediated gene silencing.	('poly-ADP', 'Chemical', '-', (55, 63))	('miRNA-mediated gene silencing', 'MPA', (105, 134))	('relieves', 'NegReg', (96, 104))	('poly-ADP-ribosylation', 'Var', (55, 76))
4515	25660948	Human Ago2 is phosphorylated at Ser387 by both p38 MAP kinase and the proto-oncogene Akt3.	('Human', 'Species', '9606', (0, 5))	('p38', 'Gene', '5594', (47, 50))	('Akt3', 'Gene', '10000', (85, 89))	('Ser387', 'Var', (32, 38))	('Ser387', 'Chemical', '-', (32, 38))	('p38', 'Gene', (47, 50))	('Akt3', 'Gene', (85, 89))
4516	25660948	S387 phosphorylation of Ago2 facilitates its localization to the cytoplasmic processing bodies (P bodies, which are intracellular sites for mRNA turnover and translational repression) and enhances its binding with GW182, a key component of RISC.	('phosphorylation', 'MPA', (5, 20))	('localization', 'MPA', (45, 57))	('GW182', 'Protein', (214, 219))	('Ago2', 'Gene', (24, 28))	('enhances', 'PosReg', (188, 196))	('S387', 'Var', (0, 4))	('binding', 'Interaction', (201, 208))	('GW182', 'Chemical', '-', (214, 219))	('facilitates', 'PosReg', (29, 40))
4517	25660948	Substitution of Y529 with a negatively charged glutamate reduces the binding ability of Ago2 to small RNAs.	('Substitution', 'Var', (0, 12))	('binding', 'Interaction', (69, 76))	('small RNAs', 'Protein', (96, 106))	('glutamate', 'Chemical', 'MESH:D018698', (47, 56))	('glutamate', 'Protein', (47, 56))	('Y529', 'Var', (16, 20))	('reduces', 'NegReg', (57, 64))	('Ago2', 'Protein', (88, 92))
4519	25660948	More recently, our laboratory reported another phosphorylation of Ago2 at a highly conserved residue Y393, which is located in the linker region between the PAZ and MID domain.	('Y393', 'Var', (101, 105))	('phosphorylation', 'MPA', (47, 62))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('MID', 'Disease', 'None', (165, 168))	('MID', 'Disease', (165, 168))
4520	25660948	In response to hypoxia, Ago2-Y393 is phosphorylated by internalized EGFR due to enhanced EGFR-Ago2 association in multivesicular bodies (MVBs).	('hypoxia', 'Disease', (15, 22))	('Ago2-Y393', 'Var', (24, 33))	('EGFR', 'Gene', (89, 93))	('EGFR', 'Gene', '1956', (89, 93))	('hypoxia', 'Disease', 'MESH:D000860', (15, 22))	('EGFR', 'Gene', '1956', (68, 72))	('enhanced', 'PosReg', (80, 88))	('EGFR', 'Gene', (68, 72))	('association', 'Interaction', (99, 110))
4521	25660948	Phosphorylation of Ago2 at Y393 decreases its binding with Dicer, which consequently suppresses the maturation of a subset of miRNAs with long-loop structures in their precursors, leading to a reduced RISC activity under hypoxia (Figure 1H).	('hypoxia', 'Disease', (221, 228))	('hypoxia', 'Disease', 'MESH:D000860', (221, 228))	('binding', 'molecular_function', 'GO:0005488', ('46', '53'))	('suppresses', 'NegReg', (85, 95))	('reduced', 'NegReg', (193, 200))	('Dicer', 'Gene', (59, 64))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('binding', 'Interaction', (46, 53))	('decreases', 'NegReg', (32, 41))	('Dicer', 'Gene', '23405', (59, 64))	('maturation', 'MPA', (100, 110))	('Y393', 'Var', (27, 31))
4522	25660948	Interestingly, a majority of the miRNAs regulated by Ago2-Y393 phosphorylation in response to hypoxic stress possesses tumor-suppressive properties, at least in the cell lines examined such as HeLa and MDA-MB-231.	('HeLa', 'CellLine', 'CVCL:0030', (193, 197))	('tumor', 'Disease', (119, 124))	('phosphorylation', 'biological_process', 'GO:0016310', ('63', '78'))	('hypoxic stress', 'Disease', 'MESH:D004194', (94, 108))	('hypoxic stress', 'Disease', (94, 108))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (202, 212))	('miRNAs', 'MPA', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('Ago2-Y393', 'Var', (53, 62))	('response to hypoxic stress', 'biological_process', 'GO:0001666', ('82', '108'))
4523	25660948	Consistently, phospho-Y393-Ago2 enhances cell survival and invasiveness under hypoxia, and is significantly correlated with poorer overall survival in breast cancer patients.	('enhances', 'PosReg', (32, 40))	('hypoxia', 'Disease', (78, 85))	('hypoxia', 'Disease', 'MESH:D000860', (78, 85))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('phospho-Y393-Ago2', 'Var', (14, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('breast cancer', 'Disease', (151, 164))	('poorer', 'NegReg', (124, 130))	('patients', 'Species', '9606', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cell survival', 'CPA', (41, 54))
4524	25660948	Moreover, Ago2-Y393 phosphorylation is also regulated by tyrosine phosphatase 1B (PTP1B) and plays a pivotal role in H-RASV12-induced senescence in primary non-transformed cells.	('PTP1B', 'Gene', '5770', (82, 87))	('PTP1B', 'Gene', (82, 87))	('Ago2-Y393', 'Var', (10, 19))	('phosphorylation', 'biological_process', 'GO:0016310', ('20', '35'))	('phosphatase', 'molecular_function', 'GO:0016791', ('66', '77'))	('phosphorylation', 'MPA', (20, 35))	('regulated', 'Reg', (44, 53))	('senescence', 'biological_process', 'GO:0010149', ('134', '144'))
4527	25660948	A possible explanation is that p53 and RB, two key master regulators in oncogene-induced senescence, are frequently mutated in human breast cancer cells, and thus bypassing Ago2 phosphorylation-induced checkpoint in senescence.	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('breast cancer', 'Disease', (133, 146))	('senescence', 'biological_process', 'GO:0010149', ('89', '99'))	('human', 'Species', '9606', (127, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('senescence', 'biological_process', 'GO:0010149', ('216', '226'))	('phosphorylation', 'biological_process', 'GO:0016310', ('178', '193'))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mutated', 'Var', (116, 123))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
4529	25660948	Amplification of AGO2, but not other AGO family members, is frequently observed in human cancers, including ovarian serous cystadenocarcinoma (23.4%), breast invasive carcinoma (15.7%), and metastatic prostate adenocarcinoma (14.8%).	('breast invasive carcinoma', 'Disease', (151, 176))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('cancers', 'Disease', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('AGO2', 'Gene', (17, 21))	('observed', 'Reg', (71, 79))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (108, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (151, 176))	('metastatic prostate adenocarcinoma', 'Disease', (190, 224))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('ovarian serous cystadenocarcinoma', 'Disease', (108, 141))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (151, 176))	('Amplification', 'Var', (0, 13))	('metastatic prostate adenocarcinoma', 'Disease', 'MESH:D011471', (190, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (108, 141))	('human', 'Species', '9606', (83, 88))	('AGO2', 'Gene', '27161', (17, 21))
4530	25660948	Intriguingly, amplification and/or upregulation of EGFR and AGO2 as well as TP53 mutation have a strong tendency toward co-occurrence in breast invasive tumors (EGFR and AGO2, P < 0.000001, odds ratio = 11.096; AGO2 and TP53, P < 0.000001, odds ratio = 5.946; EGFR and TP53, P < 0.000001, odds ratio = 19.063; Fisher's Exact Test, from cBioPortal for Cancer Genomics), suggesting a common regulatory event upstream of EGFR, AGO2, and TP53, or a cross-regulation among them.	('EGFR', 'Gene', (260, 264))	('AGO2', 'Gene', (60, 64))	('TP53', 'Gene', (220, 224))	('EGFR', 'Gene', (51, 55))	('TP53', 'Gene', (269, 273))	('TP53', 'Gene', (434, 438))	('EGFR', 'Gene', '1956', (418, 422))	('Cancer', 'Phenotype', 'HP:0002664', (351, 357))	('AGO2', 'Gene', (170, 174))	('AGO2', 'Gene', (424, 428))	('EGFR', 'Gene', (161, 165))	('TP53', 'Gene', (76, 80))	('EGFR', 'Gene', '1956', (260, 264))	('EGFR', 'Gene', '1956', (51, 55))	('TP53', 'Gene', '7157', (220, 224))	('mutation', 'Var', (81, 89))	('TP53', 'Gene', '7157', (269, 273))	('TP53', 'Gene', '7157', (434, 438))	('AGO2', 'Gene', '27161', (211, 215))	('AGO2', 'Gene', '27161', (60, 64))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('upregulation', 'PosReg', (35, 47))	('EGFR', 'Gene', '1956', (161, 165))	('EGFR', 'Gene', (418, 422))	('cross-regulation', 'Reg', (445, 461))	('AGO2', 'Gene', '27161', (170, 174))	('TP53', 'Gene', '7157', (76, 80))	('breast invasive tumors', 'Disease', (137, 159))	('breast invasive tumors', 'Disease', 'MESH:D001943', (137, 159))	('AGO2', 'Gene', '27161', (424, 428))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('AGO2', 'Gene', (211, 215))
4531	25660948	It remains unclear whether Ago2 itself, via miRNA-dependent and/or -independent functions, is a potential driver in cancer development or whether Ago2 is frequently phosphorylated due to concomitant hyper-activation of kinases (EGFR and possibly other tyrosine kinases), thereby conferring advantages for tumor progression with certain genetic background, such as TP53 mutation.	('TP53', 'Gene', '7157', (364, 368))	('mutation', 'Var', (369, 377))	('hyper-activation', 'PosReg', (199, 215))	('TP53', 'Gene', (364, 368))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('advantages', 'PosReg', (290, 300))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('EGFR', 'Gene', '1956', (228, 232))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('EGFR', 'Gene', (228, 232))	('tumor', 'Disease', (305, 310))	('EGFR', 'molecular_function', 'GO:0005006', ('228', '232'))
4535	23887658	Long Non-Coding RNAs in Haematological Malignancies Long non-coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides in length.	('Long non-coding RNAs', 'Var', (52, 72))	('Haematological Malignancies', 'Disease', (24, 51))	('Haematological Malignancies', 'Disease', 'MESH:D019337', (24, 51))
4541	23887658	These include microRNAs (miRNAs), small interfering RNAs (siRNAs) and piwi interacting RNAs (piRNAs).	('miR', 'Gene', (25, 28))	('small interfering', 'Var', (34, 51))	('miR', 'Gene', '220972', (25, 28))
4553	23887658	Long intergenic non coding RNAs (lincRNAs) are a special class of intergenic lncRNAs whose genes have histone mark signatures of active transcription (trimethylation in lysine 4 and lysine 36 of histone 3: H3K4m3, H3K36m3).	('lysine', 'Chemical', 'MESH:D008239', (169, 175))	('H3K36m3', 'Var', (214, 221))	('lysine', 'Chemical', 'MESH:D008239', (182, 188))	('H3K4m3', 'Var', (206, 212))
4563	23887658	For instance, pseudogenes may act as miRNA decoys that lead to increased stability and translation of their parental gene.	('translation', 'MPA', (87, 98))	('miR', 'Gene', '220972', (37, 40))	('increased', 'PosReg', (63, 72))	('miR', 'Gene', (37, 40))	('stability', 'MPA', (73, 82))	('pseudogenes', 'Var', (14, 25))	('translation', 'biological_process', 'GO:0006412', ('87', '98'))
4585	23887658	Expression of antisense UCHL1 lncRNA leads to an increase in Uchl1 protein level without any change at the Uchl1 mRNA level.	('increase', 'PosReg', (49, 57))	('Uchl1', 'Gene', '7345', (107, 112))	('Uchl1', 'Gene', (107, 112))	('UCHL1', 'Gene', '7345', (24, 29))	('antisense', 'Var', (14, 23))	('Uchl1', 'Gene', '7345', (61, 66))	('UCHL1', 'Gene', (24, 29))	('Uchl1', 'Gene', (61, 66))
4593	23887658	Linc-MD1 binds two miRNAs, which downregulate transcription factors involved in muscle differentiation and therefore muscle differentiation is induced upon Linc-MD1 expression.	('miR', 'Gene', '220972', (19, 22))	('miR', 'Gene', (19, 22))	('downregulate', 'NegReg', (33, 45))	('muscle differentiation', 'CPA', (80, 102))	('Linc-MD1', 'Gene', '101154644', (156, 164))	('transcription factors', 'MPA', (46, 67))	('transcription', 'biological_process', 'GO:0006351', ('46', '59'))	('Linc-MD1', 'Gene', (156, 164))	('induced', 'Reg', (143, 150))	('Linc-MD1', 'Gene', (0, 8))	('Linc-MD1', 'Gene', '101154644', (0, 8))	('muscle differentiation', 'CPA', (117, 139))	('expression', 'Var', (165, 175))
4610	23887658	The impact of non-coding RNAs on haematological malignancies has been well described for microRNAs.	('haematological malignancies', 'Disease', (33, 60))	('haematological malignancies', 'Disease', 'MESH:D019337', (33, 60))	('non-coding', 'Var', (14, 24))
4622	23887658	vtRNA2-1 is transcribed from the long arm of chromosome 5 region whose deletion is associated with poor outcome in AML.	('AML', 'Disease', 'MESH:D015470', (115, 118))	('AML', 'Phenotype', 'HP:0004808', (115, 118))	('vtRNA2-1', 'Gene', '100126299', (0, 8))	('AML', 'Disease', (115, 118))	('deletion', 'Var', (71, 79))	('vtRNA2-1', 'Gene', (0, 8))
4623	23887658	Furthermore, decreased expression by monoallelic or biallelic DNA methylation correlates with a worse outcome in AML patients.	('decreased', 'NegReg', (13, 22))	('monoallelic', 'Var', (37, 48))	('AML', 'Disease', 'MESH:D015470', (113, 116))	('biallelic DNA methylation', 'Var', (52, 77))	('AML', 'Phenotype', 'HP:0004808', (113, 116))	('AML', 'Disease', (113, 116))	('patients', 'Species', '9606', (117, 125))	('expression', 'MPA', (23, 33))
4632	23887658	Translocations within c-Myc or PVT1, which cause the overexpression of these two oncogenes compared to healthy cells, are characteristics associated with B cell malignancies including Burkitt Lymphoma (BL), AIDs, Non-Hodgkin lymphoma, mouse plasmacytoma (Pct) and multiple myeloma (MM).	('lymphoma', 'Phenotype', 'HP:0002665', (225, 233))	('overexpression', 'PosReg', (53, 67))	('AIDs', 'Disease', 'None', (207, 211))	('malignancies', 'Disease', (161, 173))	('multiple myeloma', 'Disease', (264, 280))	('BL', 'Phenotype', 'HP:0030080', (202, 204))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (217, 233))	('Lymphoma', 'Phenotype', 'HP:0002665', (192, 200))	('plasmacytoma', 'Phenotype', 'HP:0011857', (241, 253))	('Translocations', 'Var', (0, 14))	('Pct', 'Phenotype', 'HP:0011857', (255, 258))	('mouse', 'Species', '10090', (235, 240))	('PVT1', 'Gene', (31, 35))	('Non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (213, 233))	('multiple myeloma', 'Phenotype', 'HP:0006775', (264, 280))	('Burkitt Lymphoma', 'Disease', 'MESH:D002051', (184, 200))	('Burkitt Lymphoma', 'Phenotype', 'HP:0030080', (184, 200))	('c-Myc', 'Gene', (22, 27))	('Non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (213, 233))	('multiple myeloma', 'Disease', 'MESH:D009101', (264, 280))	('Burkitt Lymphoma', 'Disease', (184, 200))	('mouse plasmacytoma', 'Disease', (235, 253))	('associated', 'Reg', (138, 148))	('c-Myc', 'Gene', '4609', (22, 27))	('AIDs', 'Disease', (207, 211))	('Non-Hodgkin lymphoma', 'Disease', (213, 233))	('malignancies', 'Disease', 'MESH:D009369', (161, 173))
4641	23887658	Therefore, expression of the INK4b-ARF-INK4a locus is tightly controlled and the Polycomb group (PcG) complexes are required to initiate and maintain silencing of this locus.	('INK4', 'Gene', (39, 43))	('ARF', 'Disease', (35, 38))	('INK4b', 'Gene', (29, 34))	('silencing', 'Var', (150, 159))	('INK4b', 'Gene', '1030', (29, 34))	('ARF', 'Disease', 'MESH:D058186', (35, 38))	('INK4', 'Gene', '1029', (29, 33))	('INK4', 'Gene', (29, 33))	('INK4', 'Gene', '1029', (39, 43))
4646	23887658	Several single nucleotide polymorphisms (SNP) in this locus alter ANRIL structure and ANRIL gene expression, mediating susceptibility to disease.	('ANRIL', 'Gene', (86, 91))	('alter', 'Reg', (60, 65))	('mediating', 'Reg', (109, 118))	('gene expression', 'biological_process', 'GO:0010467', ('92', '107'))	('ANRIL', 'Gene', '100048912', (66, 71))	('ANRIL', 'Gene', '100048912', (86, 91))	('single nucleotide polymorphisms', 'Var', (8, 39))	('expression', 'MPA', (97, 107))	('ANRIL', 'Gene', (66, 71))
4647	23887658	There is a statistically significant association between an ANRIL polymorphism and Philadelphia positive Acute Lymphoblastic Leukemia (Ph+ ALL).	('ANRIL', 'Gene', '100048912', (60, 65))	('Leukemia', 'Phenotype', 'HP:0001909', (125, 133))	('Philadelphia positive Acute Lymphoblastic Leukemia', 'Disease', (83, 133))	('polymorphism', 'Var', (66, 78))	('Lymphoblastic Leukemia', 'Phenotype', 'HP:0005526', (111, 133))	('ANRIL', 'Gene', (60, 65))	('significant association', 'Reg', (25, 48))	('Philadelphia positive Acute Lymphoblastic Leukemia', 'Disease', 'MESH:D054198', (83, 133))	('Acute Lymphoblastic Leukemia', 'Phenotype', 'HP:0006721', (105, 133))
4650	23887658	In fact, the INK4b-ARF-INK4a locus is subject to frequent deletion or hypermethylation in cancers, including leukemia, melanoma, lung and bladder cancers.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('bladder cancers', 'Phenotype', 'HP:0009725', (138, 153))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('bladder cancer', 'Phenotype', 'HP:0009725', (138, 152))	('melanoma', 'Disease', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('leukemia', 'Phenotype', 'HP:0001909', (109, 117))	('INK4', 'Gene', '1029', (23, 27))	('INK4b', 'Gene', '1030', (13, 18))	('INK4', 'Gene', '1029', (13, 17))	('ARF', 'Disease', 'MESH:D058186', (19, 22))	('bladder cancers', 'Disease', 'MESH:D001749', (138, 153))	('leukemia', 'Disease', (109, 117))	('leukemia', 'Disease', 'MESH:D007938', (109, 117))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('INK4', 'Gene', (23, 27))	('bladder cancers', 'Disease', (138, 153))	('INK4', 'Gene', (13, 17))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('hypermethylation', 'Var', (70, 86))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('ARF', 'Disease', (19, 22))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('deletion', 'Var', (58, 66))	('lung', 'Disease', (129, 133))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('INK4b', 'Gene', (13, 18))
4665	23887658	Inactivation of MEG3 in the brain increases the expression of genes involved in angiogenesis, suggesting that the tumour suppressor function of MEG3 works, in part, by inhibiting angiogenesis.	('tumour', 'Disease', (114, 120))	('MEG3', 'Gene', '55384', (144, 148))	('expression of genes', 'MPA', (48, 67))	('MEG3', 'Gene', (16, 20))	('inhibiting', 'NegReg', (168, 178))	('angiogenesis', 'CPA', (179, 191))	('MEG3', 'Gene', (144, 148))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('MEG3', 'Gene', '55384', (16, 20))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('Inactivation', 'Var', (0, 12))	('increases', 'PosReg', (34, 43))
4673	23887658	Knocking out hsa-miR-16-1 and hsa-miR-15a in mice leads to a lymphoproliferative disease.	('lymphoproliferative disease', 'Disease', (61, 88))	('mice', 'Species', '10090', (45, 49))	('lymphoproliferative disease', 'Phenotype', 'HP:0005523', (61, 88))	('hsa-miR-15a', 'Gene', '406948', (30, 41))	('lymphoproliferative disease', 'Disease', 'MESH:D008232', (61, 88))	('hsa-miR-15a', 'Gene', (30, 41))	('leads to', 'Reg', (50, 58))	('Knocking out', 'Var', (0, 12))	('hsa-miR-16-1', 'Gene', (13, 25))
4674	23887658	However the knockout model of DLEU2, which includes deletion of hsa-miR-16-1 and hsa-miR-15a as well, shows a more aggressive phenotype than the hsa-miR-16-1/hsa-miR-15a 6 knockout model alone, suggesting that DLEU2 can participate in CLL development on its own.	('deletion', 'Var', (52, 60))	('DLEU2', 'Gene', (30, 35))	('CLL development', 'CPA', (235, 250))	('DLEU2', 'Gene', '8847', (210, 215))	('hsa-miR-15a', 'Gene', '406948', (81, 92))	('hsa-miR-15a', 'Gene', '406948', (158, 169))	('aggressive phenotype', 'CPA', (115, 135))	('DLEU2', 'Gene', (210, 215))	('DLEU2', 'Gene', '8847', (30, 35))	('CLL', 'Phenotype', 'HP:0005550', (235, 238))	('hsa-miR-15a', 'Gene', (81, 92))	('hsa-miR-16-1', 'Gene', (64, 76))	('participate', 'Reg', (220, 231))	('hsa-miR-15a', 'Gene', (158, 169))
4693	23887658	However, depletion of H19 caused increased polyp count in a mouse model for colorectal cancer, larger tumor growth in a mouse teratocarcinoma model and an earlier development of tumours in a mouse hepatocarcinoma model.	('hepatocarcinoma', 'Disease', 'None', (197, 212))	('tumours', 'Phenotype', 'HP:0002664', (178, 185))	('tumours', 'Disease', 'MESH:D009369', (178, 185))	('larger', 'PosReg', (95, 101))	('mouse', 'Species', '10090', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('polyp count', 'MPA', (43, 54))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('hepatocarcinoma', 'Disease', (197, 212))	('H19', 'Gene', (22, 25))	('depletion', 'Var', (9, 18))	('teratocarcinoma', 'Disease', 'MESH:D018243', (126, 141))	('teratocarcinoma', 'Disease', (126, 141))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('increased', 'PosReg', (33, 42))	('tumor', 'Disease', (102, 107))	('mouse', 'Species', '10090', (60, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('colorectal cancer', 'Disease', (76, 93))	('tumours', 'Disease', (178, 185))	('mouse', 'Species', '10090', (120, 125))
4696	23887658	Certain SNPs in T-UCR genes were associated with increased familial breast cancer risk.	('SNPs', 'Var', (8, 12))	('familial breast cancer', 'Disease', (59, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('associated', 'Reg', (33, 43))	('T-UCR genes', 'Gene', (16, 27))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('familial breast cancer', 'Disease', 'MESH:D001943', (59, 81))
4700	23887658	This is the case of UC.349A and UC.352, differentially expressed between normal and leukemic CD5-positive cells and located within a chromosomal region linked to susceptibility to familial CLL.	('CLL', 'Phenotype', 'HP:0005550', (189, 192))	('leukemic', 'Disease', (84, 92))	('UC.352', 'Var', (32, 38))	('leukemic', 'Disease', 'MESH:D007938', (84, 92))	('CD5', 'Gene', (93, 96))	('CD5', 'Gene', '921', (93, 96))
4708	23887658	These rearrangements in TCR commonly lead to activation of TCL6 lncRNA and other oncogenes related to T cell leukemogenesis.	('lead', 'Reg', (37, 41))	('rearrangements', 'Var', (6, 20))	('T cell leukemogenesis', 'Disease', (102, 123))	('TCL6', 'Gene', '27004', (59, 63))	('TCL6', 'Gene', (59, 63))	('activation', 'PosReg', (45, 55))	('TCR', 'Gene', (24, 27))
4709	23887658	WT1-AS: is an antisense lncRNA to WT-1, a well-characterized developmental gene that is mutated in Wilms' tumor (WT) and AML.	('AML', 'Phenotype', 'HP:0004808', (121, 124))	("Wilms' tumor", 'Disease', 'MESH:D009396', (99, 111))	('AML', 'Disease', (121, 124))	("Wilms' tumor", 'Disease', (99, 111))	('WT-1', 'Gene', (34, 38))	('WT1-AS', 'Gene', '51352', (0, 6))	('mutated', 'Var', (88, 95))	('WT1-AS', 'Gene', (0, 6))	('WT-1', 'Gene', '7490', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('AML', 'Disease', 'MESH:D015470', (121, 124))
4712	23887658	It has been suggested that the abnormal splicing of WT1-AS in AML could play a role in the development of this malignancy.	('role', 'Reg', (79, 83))	('abnormal splicing', 'Var', (31, 48))	('play', 'Reg', (72, 76))	('malignancy', 'Disease', 'MESH:D009369', (111, 121))	('malignancy', 'Disease', (111, 121))	('AML', 'Disease', 'MESH:D015470', (62, 65))	('WT1-AS', 'Gene', (52, 58))	('WT1-AS', 'Gene', '51352', (52, 58))	('AML', 'Disease', (62, 65))	('AML', 'Phenotype', 'HP:0004808', (62, 65))
4723	23887658	HOXA genes are important transcriptional regulators in normal and malignant hematopoiesis and are known to be important for many cancers including leukemias harbouring MLL rearrangements.	('leukemias', 'Disease', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('malignant hematopoiesis', 'Disease', (66, 89))	('MLL', 'Gene', '4297', (168, 171))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('MLL', 'Gene', (168, 171))	('important', 'Reg', (110, 119))	('rearrangements', 'Var', (172, 186))	('cancers', 'Disease', (129, 136))	('HOXA', 'Gene', (0, 4))	('leukemias', 'Disease', 'MESH:D007938', (147, 156))	('malignant hematopoiesis', 'Disease', 'MESH:C536227', (66, 89))	('HOXA', 'Gene', '3197', (0, 4))
4735	23887658	Altered expression of lncRNAs, similar to that of coding genes, can be the result of genomic alterations, epigenetic regulation or a change in response to transcription factors or stability effectors such as miRNAs.	('miR', 'Gene', (208, 211))	('rat', 'Species', '10116', (97, 100))	('result', 'Reg', (75, 81))	('change', 'Reg', (133, 139))	('alterations', 'Var', (93, 104))	('lncRNAs', 'Gene', (22, 29))	('transcription', 'biological_process', 'GO:0006351', ('155', '168'))	('expression', 'MPA', (8, 18))	('epigenetic regulation', 'Var', (106, 127))	('response to transcription factors', 'MPA', (143, 176))	('regulation', 'biological_process', 'GO:0065007', ('117', '127'))	('miR', 'Gene', '220972', (208, 211))
4736	23887658	The presence of mutations in the lncRNA primary sequence correlates highly with human diseases.	('lncRNA', 'Gene', (33, 39))	('human', 'Species', '9606', (80, 85))	('human diseases', 'Disease', (80, 94))	('mutations', 'Var', (16, 25))
4741	23887658	Germline and somatic mutations in lncRNA genes have been identified in haematological malignancies and colorectal cancers.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('colorectal cancers', 'Disease', 'MESH:D015179', (103, 121))	('lncRNA genes', 'Gene', (34, 46))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('colorectal cancers', 'Disease', (103, 121))	('haematological malignancies', 'Disease', (71, 98))	('identified', 'Reg', (57, 67))	('haematological malignancies', 'Disease', 'MESH:D019337', (71, 98))	('mutations', 'Var', (21, 30))
4742	23887658	SNPs that may affect ANRIL have been associated with increased risk of type 2 diabetes and increased susceptibility to coronary artery disease and atherosclerosis.	('ANRIL', 'Gene', '100048912', (21, 26))	('coronary artery disease', 'Disease', 'MESH:D003324', (119, 142))	('type 2 diabetes', 'Disease', 'MESH:D003924', (71, 86))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (71, 86))	('atherosclerosis', 'Disease', 'MESH:D050197', (147, 162))	('atherosclerosis', 'Phenotype', 'HP:0002621', (147, 162))	('SNPs', 'Var', (0, 4))	('coronary artery disease', 'Disease', (119, 142))	('ANRIL', 'Gene', (21, 26))	('atherosclerosis', 'Disease', (147, 162))	('type 2 diabetes', 'Disease', (71, 86))
4743	23887658	Some of these mutations did not affect ANRIL transcription or stability.	('stability', 'MPA', (62, 71))	('ANRIL', 'Gene', (39, 44))	('transcription', 'biological_process', 'GO:0006351', ('45', '58'))	('ANRIL', 'Gene', '100048912', (39, 44))	('mutations', 'Var', (14, 23))
4745	23887658	Moreover, genetic aberrations of the GAS5 locus have been found in melanoma, breast and prostate cancers.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('prostate cancers', 'Phenotype', 'HP:0012125', (88, 104))	('genetic aberrations', 'Var', (10, 29))	('GAS5', 'Gene', (37, 41))	('breast and prostate cancers', 'Disease', 'MESH:D011471', (77, 104))	('rat', 'Species', '10116', (22, 25))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('GAS5', 'Gene', '60674', (37, 41))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))	('found', 'Reg', (58, 63))
4750	23887658	AML patients with aberrant hypermethylation of the MEG3 promoter showed decreased overall survival.	('MEG3', 'Gene', '55384', (51, 55))	('decreased', 'NegReg', (72, 81))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('MEG3', 'Gene', (51, 55))	('overall', 'MPA', (82, 89))	('patients', 'Species', '9606', (4, 12))	('aberrant hypermethylation', 'Var', (18, 43))	('AML', 'Phenotype', 'HP:0004808', (0, 3))	('AML', 'Disease', (0, 3))
4751	23887658	Thus, MEG3 methylation status may serve as a useful biomarker in this leukemia.	('methylation status', 'Var', (11, 29))	('methylation', 'biological_process', 'GO:0032259', ('11', '22'))	('leukemia', 'Disease', (70, 78))	('MEG3', 'Gene', (6, 10))	('leukemia', 'Disease', 'MESH:D007938', (70, 78))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('MEG3', 'Gene', '55384', (6, 10))
4754	23887658	Demethylation correlated with transcriptional deregulation of the neighbouring candidate tumour suppressor genes.	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('Demethylation', 'Var', (0, 13))	('transcriptional deregulation', 'MPA', (30, 58))	('Demethylation', 'biological_process', 'GO:0070988', ('0', '13'))
4764	23887658	This could be used for silencing of oncogenes or reactivation of tumour suppressor genes.	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('silencing', 'Var', (23, 32))	('oncogenes', 'Protein', (36, 45))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('reactivation', 'Var', (49, 61))	('tumour', 'Disease', (65, 71))
4783	23887658	When the downregulation of tumour suppressor lncRNAs results from aberrant epigenetic mechanisms such as DNA hypermethylation or loss of histone acetylation, demethylating agents or histone deacetylase inhibitors could help to reestablish expression.	('downregulation', 'NegReg', (9, 23))	('DNA hypermethylation', 'Var', (105, 125))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('loss', 'NegReg', (129, 133))	('histone', 'Protein', (137, 144))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('tumour', 'Disease', (27, 33))
4797	33066157	The development of cancer is a multistage process that begins with genetic alteration and is followed by abnormal cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('114', '132'))	('genetic alteration', 'Var', (67, 85))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (105, 132))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cell proliferation', 'CPA', (114, 132))	('men', 'Species', '9606', (11, 14))
4798	33066157	Carcinogenesis is strictly related to the activation of oncogenes (induction of cell growth) and the inactivation of tumor suppressor genes (repression of cell growth), resulting in a loss of control of cell cycle progression.	('Carcinogenesis', 'Disease', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('control', 'MPA', (192, 199))	('tumor', 'Disease', (117, 122))	('loss', 'NegReg', (184, 188))	('cell growth', 'biological_process', 'GO:0016049', ('80', '91'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('117', '133'))	('cell growth', 'biological_process', 'GO:0016049', ('155', '166'))	('activation', 'PosReg', (42, 52))	('control of cell cycle progression', 'biological_process', 'GO:0051726', ('192', '225'))	('inactivation', 'Var', (101, 113))	('oncogenes', 'Gene', (56, 65))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('117', '133'))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('cell cycle progression', 'CPA', (203, 225))
4799	33066157	This initiation stage is followed by progression related to additive mutation within cells, some of which are implicated in even more rapid growth, and the suppression of cancer cell death.	('death', 'Disease', (183, 188))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('additive mutation', 'Var', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('death', 'Disease', 'MESH:D003643', (183, 188))
4800	33066157	As a result of these changes, mature epithelial cancer cells may undergo epithelial-mesenchymal transition (EMT), which is characterized by the reduction of adhesion among cells and increased cell motility.	('cell motility', 'biological_process', 'GO:0048870', ('192', '205'))	('increased', 'PosReg', (182, 191))	('EMT', 'biological_process', 'GO:0001837', ('108', '111'))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('epithelial cancer', 'Phenotype', 'HP:0031492', (37, 54))	('cell motility', 'CPA', (192, 205))	('epithelial-mesenchymal transition', 'CPA', (73, 106))	('adhesion among', 'CPA', (157, 171))	('undergo', 'Reg', (65, 72))	('changes', 'Var', (21, 28))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('reduction', 'NegReg', (144, 153))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('73', '106'))
4819	33066157	Cancer occurs by a series of successive mutations in the relevant genes, leading to changes in cell function.	('cell function', 'MPA', (95, 108))	('changes', 'Reg', (84, 91))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (40, 49))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
4820	33066157	Various physical and chemical factors play an obvious role in the formation of gene mutations and the appearance of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('gene mutations', 'Var', (79, 93))
4834	33066157	Among others, important common driver gene mutations in patients with NSCLC are as follows: tumor suppressor genes TP53 and PTEN; EGFR, which encodes protein, is involved in cell growth and survival.	('patients', 'Species', '9606', (56, 64))	('PTEN', 'Gene', (124, 128))	('PTEN', 'Gene', '5728', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('NSCLC', 'Disease', (70, 75))	('TP53', 'Gene', '7157', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('mutations', 'Var', (43, 52))	('TP53', 'Gene', (115, 119))	('tumor', 'Disease', (92, 97))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))
4840	33066157	In turn, mutations in the BRCA1 and BRCA2 genes cause as much as 80% of genetic breast cancer.	('BRCA1', 'Gene', (26, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('mutations', 'Var', (9, 18))	('genetic breast cancer', 'Disease', 'MESH:D001943', (72, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('BRCA2', 'Gene', (36, 41))	('cause', 'Reg', (48, 53))	('genetic breast cancer', 'Disease', (72, 93))	('BRCA1', 'Gene', '672', (26, 31))	('BRCA2', 'Gene', '675', (36, 41))
4848	33066157	Inherited mutations in specific genes, such as BRCA1, BRCA2, and HOXB13, are the cause of some hereditary prostate cancer cases.	('cause', 'Reg', (81, 86))	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('BRCA1', 'Gene', (47, 52))	('HOXB13', 'Gene', (65, 71))	('BRCA1', 'Gene', '672', (47, 52))	('hereditary prostate cancer', 'Disease', (95, 121))	('hereditary prostate cancer', 'Disease', 'MESH:C537243', (95, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('BRCA2', 'Gene', (54, 59))	('HOXB13', 'Gene', '10481', (65, 71))	('mutations', 'Var', (10, 19))	('BRCA2', 'Gene', '675', (54, 59))
4850	33066157	Men with mutations in these genes are at high risk of developing prostate cancer and, in some cases, other cancers during their lifetime.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('prostate cancer', 'Disease', 'MESH:D011471', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('mutations', 'Var', (9, 18))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('prostate cancer', 'Disease', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('Men', 'Species', '9606', (0, 3))
4851	33066157	Additionally, other different genes have been implicated in prostate cancer by genetic alteration, depending on types (familial, sporadic, hereditary): TP53, PTEN, and protooncogenes MYC, which also constitute molecular targets for compounds from the Lamiaceae family.	('MYC', 'Gene', '4609', (183, 186))	('prostate cancer', 'Disease', (60, 75))	('implicated', 'Reg', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('MYC', 'Gene', (183, 186))	('TP53', 'Gene', '7157', (152, 156))	('prostate cancer', 'Disease', 'MESH:D011471', (60, 75))	('TP53', 'Gene', (152, 156))	('PTEN', 'Gene', (158, 162))	('PTEN', 'Gene', '5728', (158, 162))	('alteration', 'Var', (87, 97))	('prostate cancer', 'Phenotype', 'HP:0012125', (60, 75))
4854	33066157	Colorectal cancer has been attributed to a number of mutations: mutational inactivation of tumor suppressor genes such as TP53, and activation of the oncogene pathway PI3K.	('activation', 'PosReg', (132, 142))	('TP53', 'Gene', (122, 126))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('91', '107'))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('oncogene pathway PI3K', 'Pathway', (150, 171))	('mutational inactivation', 'Var', (64, 87))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Colorectal cancer', 'Disease', (0, 17))	('PI3K', 'molecular_function', 'GO:0016303', ('167', '171'))	('TP53', 'Gene', '7157', (122, 126))	('tumor', 'Disease', (91, 96))	('tumor suppressor', 'biological_process', 'GO:0051726', ('91', '107'))
4855	33066157	Genetically, colorectal cancer is divided into three categories: sporadic (about 60%) for patients with no family history, family (about 30%) for patients with at least one relative with colorectal cancer or adenoma, and hereditary forms (about 10%) due to the germline inheritance of mutations.	('colorectal cancer', 'Disease', (187, 204))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mutations', 'Var', (285, 294))	('adenoma', 'Disease', (208, 215))	('colorectal cancer', 'Disease', 'MESH:D015179', (187, 204))	('colorectal cancer', 'Disease', (13, 30))	('colorectal cancer', 'Phenotype', 'HP:0003003', (13, 30))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (187, 204))	('colorectal cancer', 'Disease', 'MESH:D015179', (13, 30))	('patients', 'Species', '9606', (90, 98))	('patients', 'Species', '9606', (146, 154))	('adenoma', 'Disease', 'MESH:D000236', (208, 215))
4877	33066157	Polyphenols are believed to cause cancer cell death by apoptosis through several mechanisms, such as DNA fragmentation, alteration of the level of apoptotic proteins, and mitochondrial membrane potential and cell cycle arrest.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('level of apoptotic proteins', 'MPA', (138, 165))	('DNA fragmentation', 'biological_process', 'GO:0006309', ('101', '118'))	('DNA', 'cellular_component', 'GO:0005574', ('101', '104'))	('death', 'Disease', (46, 51))	('arrest', 'Disease', (219, 225))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (208, 225))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('171', '193'))	('mitochondrial membrane potential', 'CPA', (171, 203))	('Polyphenols', 'Chemical', 'MESH:D059808', (0, 11))	('alteration', 'Reg', (120, 130))	('death', 'Disease', 'MESH:D003643', (46, 51))	('men', 'Species', '9606', (109, 112))	('arrest', 'Disease', 'MESH:D006323', (219, 225))	('Polyphenols', 'Var', (0, 11))	('DNA fragmentation', 'CPA', (101, 118))	('cell death', 'biological_process', 'GO:0008219', ('41', '51'))	('cancer', 'Disease', (34, 40))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('208', '225'))
4900	33066157	Satureja khuzistanica extract enriched with rosmarinic acid was found to increase the size of the apoptotic sub-G0/G1 population in MCF-7 cells.	('increase', 'PosReg', (73, 81))	('rosmarinic acid', 'Var', (44, 59))	('rosmarinic acid', 'Chemical', 'MESH:C041376', (44, 59))	('Satureja khuzistanica', 'Species', '1114304', (0, 21))	('MCF-7', 'CellLine', 'CVCL:0031', (132, 137))	('apoptotic sub-G0/G1 population', 'CPA', (98, 128))
4921	33066157	The insertion of Bax/Bak into the mitochondrial membrane results in the formation of a pore complex and release of cytochrome c into the cytosol from the intermembrane space.	('cytochrome c', 'molecular_function', 'GO:0045155', ('115', '127'))	('cytochrome c', 'Gene', (115, 127))	('cytosol', 'cellular_component', 'GO:0005829', ('137', '144'))	('results in', 'Reg', (57, 67))	('insertion', 'Var', (4, 13))	('formation of a pore complex', 'MPA', (72, 99))	('cytochrome c', 'Gene', '54205', (115, 127))	('cytochrome c', 'molecular_function', 'GO:0009461', ('115', '127'))	('Bax', 'Gene', (17, 20))	('formation', 'biological_process', 'GO:0009058', ('72', '81'))	('pore complex', 'cellular_component', 'GO:0046930', ('87', '99'))	('Bak', 'Gene', (21, 24))	('Bak', 'Gene', '578', (21, 24))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('34', '56'))	('Bax', 'Gene', '581', (17, 20))
4937	33066157	Caspase-8 induction was found to induce apoptosis in MCF-7 and HCT-116 cells following Micromeria fruticose aerial part extract administration, as well as treatment with Vitex rotundifolia leaf extract in T-47D cells, Stachys pilifera leaf extract in the HT-29 cell line, and for Teucrium chamaedrys aerial flowering part extract in SW480 cells.	('Stachys pilifera', 'Species', '1541664', (218, 234))	('induction', 'Var', (10, 19))	('apoptosis', 'CPA', (40, 49))	('Vitex rotundifolia', 'Species', '413484', (170, 188))	('flowering', 'Species', '3398', (307, 316))	('SW480', 'CellLine', 'CVCL:0546', (333, 338))	('MCF-7', 'CellLine', 'CVCL:0031', (53, 58))	('HCT-116', 'CellLine', 'CVCL:0291', (63, 70))	('Teucrium chamaedrys', 'Species', '53176', (280, 299))	('fruticose', 'Chemical', '-', (98, 107))	('Caspase-8', 'Gene', '841', (0, 9))	('T-47D', 'CellLine', 'CVCL:0553', (205, 210))	('men', 'Species', '9606', (160, 163))	('Micromeria', 'Species', '306389', (87, 97))	('HT-29', 'CellLine', 'CVCL:0320', (255, 260))	('Caspase-8', 'Gene', (0, 9))
4949	33066157	DNA damage occurs due to metabolic processes and environmental factors including ROS and results in an increase in the levels of tumor suppressor protein p53.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('129', '145'))	('increase', 'PosReg', (103, 111))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('men', 'Species', '9606', (56, 59))	('tumor suppressor', 'biological_process', 'GO:0051726', ('129', '145'))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('p53', 'Gene', (154, 157))	('ROS', 'Var', (81, 84))	('p53', 'Gene', '7157', (154, 157))	('tumor', 'Disease', (129, 134))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))
4959	33066157	That PI3K signaling cascade induces protein kinase B, which is also known as PKB or Akt.	('signaling cascade', 'biological_process', 'GO:0007165', ('10', '27'))	('Akt', 'Gene', '207', (84, 87))	('PI3K signaling', 'biological_process', 'GO:0014065', ('5', '19'))	('protein', 'cellular_component', 'GO:0003675', ('36', '43'))	('protein kinase B', 'Gene', (36, 52))	('Akt', 'Gene', (84, 87))	('induces', 'Reg', (28, 35))	('PI3K', 'Var', (5, 9))	('PI3K', 'molecular_function', 'GO:0016303', ('5', '9'))	('PKB', 'Gene', '207', (77, 80))	('protein kinase B', 'Gene', '2185', (36, 52))	('PKB', 'Gene', (77, 80))
4963	33066157	Akt may inactivate mammalian target of rapamycin complex 1 (mTORC1), p70S6 kinase, and p21, which are known to stimulate cell growth and proliferation.	('mTORC1', 'Gene', '382056', (60, 66))	('p21', 'Gene', (87, 90))	('mammalian', 'MPA', (19, 28))	('p70S6', 'Var', (69, 74))	('mTORC1', 'Gene', (60, 66))	('p21', 'Gene', '644914', (87, 90))	('Akt', 'Gene', '207', (0, 3))	('cell growth', 'biological_process', 'GO:0016049', ('121', '132'))	('mTORC1', 'cellular_component', 'GO:0031931', ('60', '66'))	('stimulate', 'PosReg', (111, 120))	('target of rapamycin complex', 'cellular_component', 'GO:0038201', ('29', '56'))	('Akt', 'Gene', (0, 3))	('cell growth', 'CPA', (121, 132))	('inactivate', 'NegReg', (8, 18))
4991	33066157	The first elongation step involves the enrollment of numerous autophagy-related (Atg) proteins by PI3P.	('men', 'Species', '9606', (45, 48))	('PI3P', 'Var', (98, 102))	('enrollment', 'MPA', (39, 49))	('PI3P', 'Chemical', '-', (98, 102))
5049	33066157	Acetyl-macrocalin B induces apoptosis in an ROS-dependent manner in A549 cells and then upregulates the p38 MAPK signaling pathway that mediates caspase-9 release.	('p38', 'Gene', (104, 107))	('caspase-9', 'Gene', (145, 154))	('p38 MAPK signaling', 'biological_process', 'GO:0051403', ('104', '122'))	('apoptosis', 'biological_process', 'GO:0097194', ('28', '37'))	('Acetyl-macrocalin B', 'Var', (0, 19))	('upregulates', 'PosReg', (88, 99))	('apoptosis', 'CPA', (28, 37))	('apoptosis', 'biological_process', 'GO:0006915', ('28', '37'))	('signaling pathway', 'biological_process', 'GO:0007165', ('113', '130'))	('caspase-9', 'Gene', '842', (145, 154))	('p38', 'Gene', '5594', (104, 107))	('ROS', 'Chemical', 'MESH:D017382', (44, 47))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))
5070	33066157	Nepeta rtanjensis essential oils rich in trans,cis-nepetalactone induced programmed cell death against A549 and MDA-MB-231 cells, as did Origanum onites essential oil, which is rich in carvacrol, against Ht-29 cells.	('oil', 'Chemical', 'MESH:D009821', (163, 166))	('death', 'Disease', 'MESH:D003643', (89, 94))	('Origanum onites', 'Species', '452416', (137, 152))	('essential oils', 'Chemical', 'MESH:D009822', (18, 32))	('Ht-29', 'CellLine', 'CVCL:C834', (204, 209))	('cis-nepetalactone', 'Var', (47, 64))	('trans,cis-nepetalactone', 'Chemical', '-', (41, 64))	('carvacrol', 'Chemical', 'MESH:C073316', (185, 194))	('death', 'Disease', (89, 94))	('oil', 'Chemical', 'MESH:D009821', (28, 31))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (112, 122))	('Nepeta rtanjensis', 'Species', '2721193', (0, 17))
5072	33066157	Salvia aurea, S. judaica, and S. viscosa essential oils containing caryophyllene oxide as a main constituent induced apoptosis triggered by excessive ROS formation in DU-145 cells, as did Zataria multiflora essential oils in HCT-116 and SW48 cell lines.	('S. judaica', 'Var', (14, 24))	('apoptosis', 'CPA', (117, 126))	('caryophyllene oxide', 'Chemical', 'MESH:C515179', (67, 86))	('ROS', 'Chemical', 'MESH:D017382', (150, 153))	('ROS formation', 'MPA', (150, 163))	('Zataria multiflora essential oils', 'Disease', (188, 221))	('ROS formation', 'biological_process', 'GO:1903409', ('150', '163'))	('DU-145', 'CellLine', 'CVCL:0105', (167, 173))	('SW48', 'CellLine', 'CVCL:1724', (237, 241))	('induced', 'Reg', (109, 116))	('Salvia aurea', 'Disease', 'None', (0, 12))	('HCT-116', 'CellLine', 'CVCL:0291', (225, 232))	('S. viscosa', 'Species', '718', (30, 40))	('Zataria multiflora essential oils', 'Disease', 'MESH:D020329', (188, 221))	('Salvia aurea', 'Disease', (0, 12))	('essential oils', 'Chemical', 'MESH:D009822', (41, 55))	('essential oils', 'Chemical', 'MESH:D009822', (207, 221))	('apoptosis', 'biological_process', 'GO:0097194', ('117', '126'))	('apoptosis', 'biological_process', 'GO:0006915', ('117', '126'))
5077	33066157	Stachys viticina essential oils, with their main components being endo-borneol, eucalyptol, and epizonarene, inhibit mediators of apoptosis suppression COX-2 in COLO 205 cells.	('apoptosis', 'biological_process', 'GO:0097194', ('130', '139'))	('COX-2', 'Gene', (152, 157))	('Stachys viticina', 'Species', '1007651', (0, 16))	('eucalyptol', 'Chemical', 'MESH:D000077591', (80, 90))	('COX-2', 'Gene', '5743', (152, 157))	('inhibit', 'NegReg', (109, 116))	('epizonarene', 'Chemical', '-', (96, 107))	('COLO', 'Species', '307630', (161, 165))	('epizonarene', 'Var', (96, 107))	('endo-borneol', 'Chemical', 'MESH:C022871', (66, 78))	('apoptosis', 'biological_process', 'GO:0006915', ('130', '139'))	('essential oils', 'Chemical', 'MESH:D009822', (17, 31))
5150	32651686	Cancer treatment for patients who are COVID-19 positive should be as conservative as possible, using stent placement for stenosing cancer and performing surgery after the resolution of infection.	('cancer', 'Disease', (131, 137))	('positive', 'Var', (47, 55))	('infection', 'Disease', (185, 194))	('infection', 'Disease', 'MESH:D007239', (185, 194))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('patients', 'Species', '9606', (21, 29))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('COVID-19', 'Disease', 'MESH:C000657245', (38, 46))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('COVID-19', 'Disease', (38, 46))
5152	32651686	This can be achieved by minimizing the creation of a plume (reduce power setting) through the use of electrocautery or ultrasonic scalpels, limiting CO2 release into the operating room by lowering the pneumoperitoneum pressure, reducing the Trendelenburg position, or deflating the abdomen before retrieving a specimen or before removing the trocars.	('reducing', 'NegReg', (228, 236))	('limiting', 'NegReg', (140, 148))	('lowering', 'NegReg', (188, 196))	('pneumoperitoneum pressure', 'MPA', (201, 226))	('deflating', 'Var', (268, 277))	('minimizing', 'NegReg', (24, 34))	('CO2', 'Chemical', 'MESH:D002245', (149, 152))	('CO2', 'Protein', (149, 152))	('release', 'MPA', (153, 160))
5241	32651686	Cases have been reported of patients undergoing lung cancer surgery, who tested PCR-positive for COVID-19 when their symptoms worsened postoperatively.	('COVID-19', 'Disease', (97, 105))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('PCR-positive', 'Var', (80, 92))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('COVID-19', 'Disease', 'MESH:C000657245', (97, 105))	('patients', 'Species', '9606', (28, 36))
5333	32627006	However, dysregulation in the mechanisms underlying proliferation and differentiation initiates the malignant transformation of adult stem cells leading to tumorigenesis.	('malignant transformation', 'CPA', (100, 124))	('initiates', 'Reg', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('dysregulation', 'Var', (9, 22))
5360	32627006	8480), phospho-beta-catenin (Ser33/37/Thr41; cat.	('Ser33/37/Thr41', 'Var', (29, 43))	('cat', 'molecular_function', 'GO:0004096', ('45', '48'))	('beta-catenin', 'Gene', (15, 27))	('beta-catenin', 'Gene', '1499', (15, 27))	('Ser', 'cellular_component', 'GO:0005790', ('29', '32'))
5379	32627006	Cells were seeded into a 96-well plate at 5x103 cells/well with 100 microl culture medium which contained the various TNF-alpha concentrations (0, 0.01, 0.1, 1, 10, 50 and 100 ng/ml).	('0.1', 'Var', (153, 156))	('TNF-alpha', 'Gene', (118, 127))	('TNF-alpha', 'Gene', '7124', (118, 127))
5403	32627006	Results indicated that NCM460s cells exhibited higher mRNA and protein expression of stem cell genes such as Oct4, Nanog and Sox2 and Lgr5, a marker gene of intestinal stem cells, compared with those in NCM460 adherent cells (Fig.	('Nanog', 'Gene', '79923', (115, 120))	('Oct4', 'Gene', '5460', (109, 113))	('Nanog', 'Gene', (115, 120))	('higher', 'PosReg', (47, 53))	('stem cell genes', 'Gene', (85, 100))	('Sox2', 'Gene', (125, 129))	('NCM460s', 'Var', (23, 30))	('Oct4', 'Gene', (109, 113))	('Lgr5', 'Gene', (134, 138))	('Sox2', 'Gene', '6657', (125, 129))
5434	32627006	To elucidate the potential molecular mechanisms of TNF-alpha-induced malignant transformation in NCM460s cells, p65 shRNA was used to knockdown the activity of NF-kappaB signaling.	('NF-kappaB', 'Gene', (160, 169))	('TNF-alpha', 'Gene', '7124', (51, 60))	('malignant transformation', 'CPA', (69, 93))	('p65', 'Gene', (112, 115))	('signaling', 'biological_process', 'GO:0023052', ('170', '179'))	('activity', 'MPA', (148, 156))	('TNF-alpha', 'Gene', (51, 60))	('knockdown', 'Var', (134, 143))	('p65', 'Gene', '5970', (112, 115))	('NF-kappaB', 'Gene', '4790', (160, 169))
5440	32627006	These results indicated that p65 knockdown blocked the protein expression of total p65 and suppressed the nuclear translocation of p65, both of which were promoted by TNF-alpha treatment.	('suppressed', 'NegReg', (91, 101))	('nuclear translocation', 'MPA', (106, 127))	('p65', 'Gene', (131, 134))	('p65', 'Gene', (29, 32))	('p65', 'Gene', '5970', (83, 86))	('knockdown', 'Var', (33, 42))	('blocked', 'NegReg', (43, 50))	('p65', 'Gene', '5970', (131, 134))	('p65', 'Gene', '5970', (29, 32))	('protein expression', 'MPA', (55, 73))	('TNF-alpha', 'Gene', '7124', (167, 176))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('p65', 'Gene', (83, 86))	('TNF-alpha', 'Gene', (167, 176))
5447	32627006	Notably, PDTC counteracted TNF-alpha-induced activation of the Wnt/beta-catenin pathway in NCM460s cells, including the increased phosphorylation of GSK3beta and beta-catenin, as well as the increased protein levels of c-Myc and nuclear translocation of beta-catenin (Fig.	('beta-catenin', 'Gene', (254, 266))	('beta-catenin', 'Gene', '1499', (254, 266))	('GSK3beta', 'Gene', '2931', (149, 157))	('TNF-alpha', 'Gene', '7124', (27, 36))	('TNF-alpha', 'Gene', (27, 36))	('increased', 'PosReg', (120, 129))	('PDTC', 'Chemical', 'MESH:C020972', (9, 13))	('phosphorylation', 'MPA', (130, 145))	('GSK3beta', 'Gene', (149, 157))	('beta-catenin', 'Gene', (162, 174))	('c-Myc', 'Gene', (219, 224))	('protein levels', 'MPA', (201, 215))	('beta-catenin', 'Gene', '1499', (162, 174))	('increased', 'PosReg', (191, 200))	('PDTC', 'Var', (9, 13))	('activation', 'PosReg', (45, 55))	('nuclear translocation', 'MPA', (229, 250))	('beta-catenin', 'Gene', (67, 79))	('beta-catenin', 'Gene', '1499', (67, 79))	('c-Myc', 'Gene', '4609', (219, 224))
5448	32627006	Furthermore, as an inhibitor of Wnt processing and secretion, IWP-2 prevented TNF-alpha-induced nuclear translocation of beta-catenin in a dose-dependent manner.	('IWP-2', 'Var', (62, 67))	('nuclear translocation', 'MPA', (96, 117))	('prevented', 'NegReg', (68, 77))	('beta-catenin', 'Gene', (121, 133))	('TNF-alpha', 'Gene', '7124', (78, 87))	('secretion', 'biological_process', 'GO:0046903', ('51', '60'))	('beta-catenin', 'Gene', '1499', (121, 133))	('TNF-alpha', 'Gene', (78, 87))
5452	32627006	Unfortunately, genetic alterations of tumor-initiating cells drive the acquisition of oncogenic mutations through the interactions with abnormal environmental elements.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('oncogenic', 'Disease', (86, 95))	('genetic alterations', 'Var', (15, 34))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('interactions', 'Interaction', (118, 130))	('mutations', 'Var', (96, 105))
5454	32627006	Notably, dysregulation in the mechanisms underlying proliferation and differentiation initiates the malignant transformation of normal stem cells, leading to tumorigenesis.	('malignant transformation', 'CPA', (100, 124))	('tumor', 'Disease', (158, 163))	('initiates', 'Reg', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('leading to', 'Reg', (147, 157))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('dysregulation', 'Var', (9, 22))
5463	32627006	Furthermore, the proportion of CD133+ cells, a colorectal CSC-specific surface marker, was significantly increased in NCM460s cells compared with NCM460 adherent cells.	('NCM460s', 'Var', (118, 125))	('CD133', 'Gene', '8842', (31, 36))	('CD133', 'Gene', (31, 36))	('increased', 'PosReg', (105, 114))
5483	32627006	Schwitalla et al, revealed that NF-kappaB signaling played a crucial role in the expression of Wnt/beta-catenin and the intestinal epithelial cell-specific ablation of p65 suppressed the expansion of crypt stem cells.	('ablation', 'Var', (156, 164))	('NF-kappaB', 'Gene', (32, 41))	('p65', 'Gene', (168, 171))	('suppressed', 'NegReg', (172, 182))	('beta-catenin', 'Gene', (99, 111))	('expansion of crypt stem cells', 'CPA', (187, 216))	('p65', 'Gene', '5970', (168, 171))	('NF-kappaB', 'Gene', '4790', (32, 41))	('beta-catenin', 'Gene', '1499', (99, 111))
5495	32627006	Subsequently, TCF/LEF promoter activity and expression of Wnt target genes c-Myc and cyclin D1 were also suppressed by p65 knockdown.	('suppressed', 'NegReg', (105, 115))	('expression', 'MPA', (44, 54))	('p65', 'Gene', (119, 122))	('cyclin D1', 'Gene', '595', (85, 94))	('c-Myc', 'Gene', '4609', (75, 80))	('p65', 'Gene', '5970', (119, 122))	('cyclin D1', 'Gene', (85, 94))	('TCF/LEF', 'Gene', '3172', (14, 21))	('c-Myc', 'Gene', (75, 80))	('TCF/LEF', 'Gene', (14, 21))	('knockdown', 'Var', (123, 132))
5504	31953485	Our findings confirm the persistence of known clinically-relevant mutations (e.g., those of RAS family of oncogenes) in CRC primary and metastases, yet reveal that latency and interval systemic therapy affect the course of evolutionary events within metastatic lesions.	('mutations', 'Var', (66, 75))	('CRC', 'Phenotype', 'HP:0003003', (120, 123))	('evolutionary', 'CPA', (223, 235))	('CRC', 'Disease', 'MESH:D015179', (120, 123))	('metastases', 'Disease', (136, 146))	('CRC', 'Disease', (120, 123))	('metastases', 'Disease', 'MESH:D009362', (136, 146))	('affect', 'Reg', (202, 208))	('RAS', 'Gene', (92, 95))
5514	31953485	Current analyses of primary and metastatic CRC indicate low rates of variation between tumor sites for the clinically-relevant mutations that may impact upon treatment decisions.	('CRC', 'Disease', 'MESH:D015179', (43, 46))	('impact', 'Reg', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('CRC', 'Disease', (43, 46))	('CRC', 'Phenotype', 'HP:0003003', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mutations', 'Var', (127, 136))
5529	31953485	Loci harboring clinically-relevant mutations of TP53 (codons 175, 213, 245, 248, 273 and 306), APC (codons 1378 and 1450), KRAS (codons 12, 13, 22, 61, 117 and 146), NRAS (codons 12, 13 and 61), PIK3CA (codons 539, 542, 545 and 1047), and BRAF (codon 600) were captured by multiplex amplification on Fluidigm access arrays (South San Francisco, CA) using 50 ng of DNA.	('PIK3CA', 'Gene', (195, 201))	('TP53', 'Gene', '7157', (48, 52))	('NRAS', 'Gene', (166, 170))	('APC', 'Disease', (95, 98))	('BRAF', 'Gene', (239, 243))	('BRAF', 'Gene', '673', (239, 243))	('TP53', 'Gene', (48, 52))	('NRAS', 'Gene', '4893', (166, 170))	('PIK3CA', 'Gene', '5290', (195, 201))	('APC', 'cellular_component', 'GO:0005680', ('95', '98'))	('KRAS', 'Gene', (123, 127))	('KRAS', 'Gene', '3845', (123, 127))	('DNA', 'cellular_component', 'GO:0005574', ('364', '367'))	('APC', 'Disease', 'MESH:D011125', (95, 98))	('mutations', 'Var', (35, 44))
5536	31953485	In cases of copy neutral loss of heterozygosity, we add half of alternate reads to the number of reference reads and use it as the new value for reference read counts (Copy Neutral LOH: Ref' = Ref + Alt/2; Alt' = Alt/2).	('copy neutral', 'Var', (12, 24))	('Alt/2', 'Gene', '84706', (199, 204))	('Alt/2', 'Gene', '84706', (213, 218))	('loss', 'NegReg', (25, 29))	('Alt/2', 'Gene', (199, 204))	('Alt/2', 'Gene', (213, 218))
5542	31953485	As reported recently, mutational signatures can shed light on mutagenic processes that affect cancer genomes.	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutational', 'Var', (22, 32))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
5543	31953485	We observed that the primary tumor in patient-009 (REACT-009-A) and metastatic samples REACT-010-B and E are enriched for signature 6 (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('patient', 'Species', '9606', (38, 45))	('tumor', 'Disease', (29, 34))	('REACT-010-B', 'Var', (87, 98))
5546	31953485	Our WES results from patient-009's primary tumor confirmed a hypermutated genome in this tumor, with mutations in the MMR genes MSH2 and MSH5 (Supplementary Tables 1 and 4).	('mutations', 'Var', (101, 110))	('hypermutated', 'Var', (61, 73))	('patient', 'Species', '9606', (21, 28))	('MMR', 'Gene', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('MSH5', 'Gene', '4439', (137, 141))	('MSH5', 'Gene', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('MSH2', 'Gene', (128, 132))	('MMR', 'biological_process', 'GO:0006298', ('118', '121'))	('MSH2', 'Gene', '4436', (128, 132))	('tumor', 'Disease', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
5547	31953485	Next, we focused on non-silent somatic mutations in primary tumors, and identified 1116 such mutations affecting 1019 genes following manual in silico verification of mutations using Integrative Genomics Viewer (IGV) (Supplementary Table 4).	('mutations', 'Var', (93, 102))	('primary tumors', 'Disease', (52, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('primary tumors', 'Disease', 'MESH:D001932', (52, 66))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
5549	31953485	Among these 9 patients, APC and TP53 were the most frequently mutated genes affected by somatic mutations in 78% followed by KRAS which was mutated in 44% of primary tumors (Fig.	('primary tumors', 'Disease', (158, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('KRAS', 'Gene', (125, 129))	('KRAS', 'Gene', '3845', (125, 129))	('TP53', 'Gene', '7157', (32, 36))	('APC', 'Disease', 'MESH:D011125', (24, 27))	('primary tumors', 'Disease', 'MESH:D001932', (158, 172))	('TP53', 'Gene', (32, 36))	('APC', 'Disease', (24, 27))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (96, 105))
5554	31953485	Notably, these genes were not mutated concurrently in tumors highlighting a mutually-exclusive pattern for RAS pathway mutations (Fig.	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('RAS pathway', 'Pathway', (107, 118))	('tumors', 'Disease', (54, 60))	('mutations', 'Var', (119, 128))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (54, 60))
5555	31953485	Three patients were affected with PIK3CA mutations, two of which (E545G and Q546K) have been previously reported in CRC.	('Q546K', 'Mutation', 'rs121913286', (76, 81))	('E545G', 'Var', (66, 71))	('CRC', 'Phenotype', 'HP:0003003', (116, 119))	('PIK3CA', 'Gene', (34, 40))	('E545G', 'Mutation', 'rs121913274', (66, 71))	('Q546K', 'Var', (76, 81))	('CRC', 'Disease', 'MESH:D015179', (116, 119))	('affected', 'Reg', (20, 28))	('PIK3CA', 'Gene', '5290', (34, 40))	('patients', 'Species', '9606', (6, 14))	('CRC', 'Disease', (116, 119))
5556	31953485	A third PIK3CA mutation (H665D) with uncertain clinical significance has no previous record in COSMIC database, but was predicted as likely functional based on CADD and fitCons scores.	('H665D', 'Mutation', 'p.H665D', (25, 30))	('H665D', 'Var', (25, 30))	('fitCons', 'Disease', 'None', (169, 176))	('fitCons', 'Disease', (169, 176))	('PIK3CA', 'Gene', (8, 14))	('PIK3CA', 'Gene', '5290', (8, 14))
5557	31953485	Three additional tumors were affected with mutations in PIK3C2G, resulting in a frequency of 55.5% of primary samples affected with PI3K pathway mutations (Fig.	('PI3K', 'molecular_function', 'GO:0016303', ('132', '136'))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('PI3K pathway', 'Pathway', (132, 144))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('mutations', 'Var', (43, 52))	('PIK3C2G', 'Gene', (56, 63))	('PIK3C2G', 'Gene', '5288', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
5560	31953485	Analysis of the chromosomal copy number alterations (CNAs) revealed highly recurrent amplifications of 13q in 75% (6/8) of primary tumors.	('amplifications', 'Var', (85, 99))	('primary tumors', 'Disease', (123, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('primary tumors', 'Disease', 'MESH:D001932', (123, 137))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))
5561	31953485	This was followed by gains of 11q and 6q in 50% (4/8) and 37.5% (3/8) of primary tumors, respectively.	('primary tumors', 'Disease', (73, 87))	('11q', 'Var', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('primary tumors', 'Disease', 'MESH:D001932', (73, 87))	('gains', 'PosReg', (21, 26))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
5568	31953485	Our results show that patients who had received an interval treatment seem to show a greater decrease in the total number of complete arm aberrations, that is loss or gain of a complete chromosome arm, between their samples (REACT-007, REACT-008 and REACT-014) compared to patients who did not receive any treatment (REACT-011 and REACT-015) (Supplementary Table 5).	('patients', 'Species', '9606', (273, 281))	('loss', 'NegReg', (159, 163))	('patients', 'Species', '9606', (22, 30))	('chromosome', 'cellular_component', 'GO:0005694', ('186', '196'))	('REACT-014', 'Var', (250, 259))	('decrease', 'NegReg', (93, 101))	('REACT-007', 'Var', (225, 234))	('gain', 'PosReg', (167, 171))
5572	31953485	Analysis of primary tumor and metastases in patients who had received no interval therapy revealed consistency for presence and relative frequency of identified driver mutations.	('patients', 'Species', '9606', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('metastases', 'Disease', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mutations', 'Var', (168, 177))	('metastases', 'Disease', 'MESH:D009362', (30, 40))	('tumor', 'Disease', (20, 25))
5573	31953485	For example, in patient REACT-001, where no interval chemotherapy was administered, the relative frequency of main driver mutations (APC E1288*, TP53 L125LH, and KRAS G12A) did not change between the primary and metastatic tumors, suggesting that the cluster of cells disseminated from the primary tumor to form the metastatic tumor harbored the entire set of main driver mutations (i.e.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', (223, 229))	('KRAS', 'Gene', '3845', (162, 166))	('TP53', 'Gene', '7157', (145, 149))	('patient', 'Species', '9606', (16, 23))	('G12A', 'Mutation', 'rs876658274', (167, 171))	('KRAS', 'Gene', (162, 166))	('APC', 'Disease', 'MESH:D011125', (133, 136))	('tumor', 'Disease', (298, 303))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('APC', 'Disease', (133, 136))	('E1288*', 'SUBSTITUTION', 'None', (137, 143))	('tumor', 'Disease', (327, 332))	('E1288*', 'Var', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('APC', 'cellular_component', 'GO:0005680', ('133', '136'))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('tumor', 'Disease', (223, 228))	('TP53', 'Gene', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))
5578	31953485	TP53 (R114H) and APC (E1379*) mutations exist in a sub-clone present in relatively high frequency in both primary and metastasis.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('E1379*', 'Var', (22, 28))	('APC', 'Disease', 'MESH:D011125', (17, 20))	('APC', 'Disease', (17, 20))	('R114H', 'Mutation', 'rs28934576', (6, 11))	('E1379*', 'SUBSTITUTION', 'None', (22, 28))
5579	31953485	However, relative abundance of a fraction of cells harboring PIK3CA (H665D) and mTOR (V1795M) mutations, which are predicted as likely functional mutations, declined substantially in the lung metastasis compared to the primary tumor (Fig.	('lung metastasis', 'CPA', (187, 202))	('PIK3CA', 'Gene', (61, 67))	('PIK3CA', 'Gene', '5290', (61, 67))	('mutations', 'Var', (94, 103))	('H665D', 'Var', (69, 74))	('mTOR', 'Gene', (80, 84))	('tumor', 'Disease', (227, 232))	('mTOR', 'Gene', '2475', (80, 84))	('declined', 'NegReg', (157, 165))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('V1795M', 'Mutation', 'p.V1795M', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('H665D', 'Mutation', 'p.H665D', (69, 74))
5580	31953485	This could be due to either cytotoxicity on the metastatic tumor or the absence of these mutations in the cluster of cells that disseminated from the primary tumor to form the lung metastasis.	('cytotoxicity', 'Disease', 'MESH:D064420', (28, 40))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', (59, 64))	('absence', 'NegReg', (72, 79))	('cytotoxicity', 'Disease', (28, 40))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('mutations', 'Var', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
5581	31953485	Interestingly, the most frequent cell population shows a relatively stable frequency in the metastatic lesion, which may be explained by the presence of the TP53 mutation, possibly conferring resistance to chemotherapy in these cells.	('TP53', 'Gene', (157, 161))	('presence', 'Var', (141, 149))	('metastatic lesion', 'CPA', (92, 109))	('mutation', 'Var', (162, 170))	('TP53', 'Gene', '7157', (157, 161))
5582	31953485	The possible elimination of the sub-clone harboring mutations in mTOR, PIK3CA and a FAT4 due to adjuvant chemotherapy could have happened either in the primary tumor or in the metastasis.	('mutations', 'Var', (52, 61))	('mTOR', 'Gene', (65, 69))	('mTOR', 'Gene', '2475', (65, 69))	('PIK3CA', 'Gene', '5290', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('FAT4', 'Gene', '79633', (84, 88))	('FAT4', 'Gene', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))	('PIK3CA', 'Gene', (71, 77))
5589	31953485	Metastases in the liver share the same mutational profile for the driver mutations along with some private mutations in each (Fig.	('Metastases', 'Disease', (0, 10))	('mutations', 'Var', (73, 82))	('Metastases', 'Disease', 'MESH:D009362', (0, 10))
5591	31953485	In contrast, for two lung metastatic tumors, which are only one-month apart, each harbor an exclusive driver mutation which is absent in the other.	('lung metastatic tumors', 'Disease', (21, 43))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('harbor', 'Reg', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('lung metastatic tumors', 'Disease', 'MESH:D008175', (21, 43))	('mutation', 'Var', (109, 117))
5592	31953485	These are APC Q1349* (depicted by orange color in Fig.	('APC', 'Disease', (10, 13))	('Q1349*', 'SUBSTITUTION', 'None', (14, 20))	('Q1349*', 'Var', (14, 20))	('APC', 'Disease', 'MESH:D011125', (10, 13))
5593	31953485	4), which is present only in REACT-010-C, and a start loss mutation in TP53 (depicted by dark blue in Fig.	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('mutation', 'Var', (59, 67))
5596	31953485	The similar profiles of driver mutations in the liver lesions (B and E) suggest that although these metastases manifested at different times, their founding cell-clusters disseminated around the same time.	('metastases', 'Disease', (100, 110))	('mutations', 'Var', (31, 40))	('metastases', 'Disease', 'MESH:D009362', (100, 110))	('liver lesions', 'Disease', 'MESH:D017093', (48, 61))	('liver lesions', 'Disease', (48, 61))
5603	31953485	The tumors did not have mutations in any RAS pathway gene, but they share a missense mutation in the epigenetic modifier gene KMT2C, which shows high allele frequency in both lesions.	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('missense mutation', 'Var', (76, 93))	('KMT2C', 'Gene', '58508', (126, 131))	('KMT2C', 'Gene', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
5605	31953485	The shift in the allele frequencies of all the mutations towards higher values in the lung metastasis REACT-011-C suggests that relatively higher allele frequency of the main driver mutations in this tumor could be due to differences in tumor content between the two metastatic samples (40% vs 60%) (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('higher', 'PosReg', (139, 145))	('mutations', 'Var', (182, 191))
5607	31953485	While our findings support previous studies highlighting the persistence of known clinically-relevant mutations between primary and metastatic CRC lesions, we showed that, when present in the primary tumor, clinically-relevant KRAS and NRAS mutations are transmitted to the metastatic lesions of different organs and likely represent ubiquitous driver mutations.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('transmitted', 'Reg', (255, 266))	('KRAS', 'Gene', (227, 231))	('CRC', 'Disease', 'MESH:D015179', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('KRAS', 'Gene', '3845', (227, 231))	('NRAS', 'Gene', (236, 240))	('tumor', 'Disease', (200, 205))	('CRC', 'Disease', (143, 146))	('NRAS', 'Gene', '4893', (236, 240))	('CRC', 'Phenotype', 'HP:0003003', (143, 146))	('mutations', 'Var', (241, 250))
5611	31953485	In CRC, analysis of cell lines and biopsy tissue from patients with tumors previously wild-type for KRAS mutations has shown that cetuximab treatment results in the emergence of KRAS-mutated sub-clones, as detected by analyzing circulating tumor DNA (ctDNA).	('KRAS', 'Gene', (100, 104))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('patients', 'Species', '9606', (54, 62))	('mutations', 'Var', (105, 114))	('CRC', 'Disease', (3, 6))	('tumor', 'Disease', (68, 73))	('CRC', 'Phenotype', 'HP:0003003', (3, 6))	('tumor', 'Disease', (240, 245))	('KRAS', 'Gene', '3845', (178, 182))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('KRAS', 'Gene', (178, 182))	('CRC', 'Disease', 'MESH:D015179', (3, 6))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('DNA', 'cellular_component', 'GO:0005574', ('246', '249'))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumors', 'Disease', (68, 74))	('KRAS', 'Gene', '3845', (100, 104))
5614	31953485	Notably, however, in the lung metastasis of patient REACT-008 we observed that cells affected by mTOR or PIK3CA mutations were eliminated following chemotherapy.	('PIK3CA', 'Gene', (105, 111))	('patient', 'Species', '9606', (44, 51))	('mTOR', 'Gene', '2475', (97, 101))	('mTOR', 'Gene', (97, 101))	('PIK3CA', 'Gene', '5290', (105, 111))	('mutations', 'Var', (112, 121))
5618	31953485	Interestingly, these tumors exhibited different mutational landscapes as WES revealed a hypermutated genome only in the primary and not in the recurrent tumor.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('hypermutated', 'Var', (88, 100))	('tumor', 'Disease', (21, 26))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
5620	31953485	By examining mutations of candidate genes, it has been suggested that anastomotic recurrences are clonally related to primary tumors.	('primary tumors', 'Disease', 'MESH:D001932', (118, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('primary tumors', 'Disease', (118, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (13, 22))
5621	31953485	However, this study included only microsatellite stable tumors, whereas tumor 9A in our study is a hypermutated tumor with mutations in MSH2 and MSH5 genes, suggesting that this tumor is affected by microsatellite instability.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('MSH2', 'Gene', (136, 140))	('tumors', 'Disease', (56, 62))	('tumor', 'Disease', (178, 183))	('MSH2', 'Gene', '4436', (136, 140))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', (56, 61))	('MSH5', 'Gene', '4439', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('MSH5', 'Gene', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (123, 132))
5622	31953485	Development of malignancy through clonal expansion may occur due to somatic mutations in key genes, for example in KRAS and NRAS in CRC, leading to dysregulation of the normal homeostatic mechanisms.	('CRC', 'Disease', (132, 135))	('mutations', 'Var', (76, 85))	('NRAS', 'Gene', '4893', (124, 128))	('KRAS', 'Gene', (115, 119))	('malignancy', 'Disease', 'MESH:D009369', (15, 25))	('KRAS', 'Gene', '3845', (115, 119))	('malignancy', 'Disease', (15, 25))	('CRC', 'Phenotype', 'HP:0003003', (132, 135))	('CRC', 'Disease', 'MESH:D015179', (132, 135))	('leading to', 'Reg', (137, 147))	('dysregulation', 'MPA', (148, 161))	('NRAS', 'Gene', (124, 128))
5623	31953485	Mutations conferring growth advantage are drivers of the carcinogenic and metastatic process and provide clinically-relevant targets for treatment.	('carcinogenic', 'Disease', (57, 69))	('Mutations', 'Var', (0, 9))	('growth advantage', 'CPA', (21, 37))	('carcinogenic', 'Disease', 'MESH:D063646', (57, 69))
5627	31953485	Furthermore, driver gene mutations were constantly present with high frequency in both liver lesions, a pattern which was not the same in lung metastatic tumors.	('lung metastatic tumors', 'Disease', (138, 160))	('mutations', 'Var', (25, 34))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('liver lesions', 'Disease', 'MESH:D017093', (87, 100))	('liver lesions', 'Disease', (87, 100))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('lung metastatic tumors', 'Disease', 'MESH:D008175', (138, 160))
5633	31953485	Although presence of KRAS mutations using standardized clinical techniques may predict for resistance to anti-EGFR therapy, responses in KRAS wild-type tumors are not universal (single-agent response rates of 10-41%).	('KRAS', 'Gene', '3845', (21, 25))	('predict', 'Reg', (79, 86))	('EGFR', 'Gene', '1956', (110, 114))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('EGFR', 'Gene', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('resistance', 'MPA', (91, 101))	('mutations', 'Var', (26, 35))	('KRAS', 'Gene', (137, 141))	('KRAS', 'Gene', (21, 25))	('tumors', 'Disease', (152, 158))	('KRAS', 'Gene', '3845', (137, 141))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
5634	31953485	Use of alternative technologies may detect low-level, or less frequent, KRAS mutations of uncertain clinical significance, undetectable by standard direct-sequencing and may also detect regional intratumor heterogeneity possibly directing treatment resistance.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('detect', 'Reg', (179, 185))	('KRAS', 'Gene', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('KRAS', 'Gene', '3845', (72, 76))	('tumor', 'Disease', (200, 205))	('mutations', 'Var', (77, 86))
5637	31953485	Data from our patient cohort highlights tumors lacking known clinically-relevant KRAS mutations with a complex, heterogeneous mutational landscape characterized by the presence of non-RAS mutations, as well as other KRAS mutations of uncertain clinical significance.	('KRAS', 'Gene', '3845', (81, 85))	('mutations', 'Var', (86, 95))	('mutations', 'Var', (188, 197))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('non-RAS', 'Protein', (180, 187))	('patient', 'Species', '9606', (14, 21))	('KRAS', 'Gene', (81, 85))	('KRAS', 'Gene', (216, 220))	('KRAS', 'Gene', '3845', (216, 220))	('tumors', 'Disease', (40, 46))
5641	31953485	As there is greater understanding of the molecular landscape of CRC and as non-invasive methods of molecular testing become more frequently ultilised targeted ultra-deep sequencing of driver mutations provides a powerful tool to monitor tumor behavior in clinic, and to identify recurrent lesions, molecularly distinct from primary tumors.	('tumors', 'Phenotype', 'HP:0002664', (332, 338))	('tumor', 'Disease', (237, 242))	('CRC', 'Disease', 'MESH:D015179', (64, 67))	('mutations', 'Var', (191, 200))	('primary tumors', 'Disease', (324, 338))	('tumor', 'Disease', 'MESH:D009369', (332, 337))	('CRC', 'Disease', (64, 67))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('primary tumors', 'Disease', 'MESH:D001932', (324, 338))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('CRC', 'Phenotype', 'HP:0003003', (64, 67))	('tumor', 'Disease', (332, 337))
5642	31953485	This technique demonstrates high sensitivity for mutation detection and its use in this study has confirmed the persistence of clinically-relevant mutations between primary tumor and metastatic lesions.	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('mutations', 'Var', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', (173, 178))
5644	31953485	By enhancing our knowledge about the behavior of driver mutations, these findings may have translational value for future clinical management of patients.	('patients', 'Species', '9606', (145, 153))	('mutations', 'Var', (56, 65))	('enhancing', 'PosReg', (3, 12))
5649	31164794	This study aimed to develop a competing endogenous RNA (ceRNA) network to elucidate the role of long non-coding RNA H19 in colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (123, 140))	('colorectal cancer', 'Disease', (123, 140))	('long non-coding RNA', 'Var', (96, 115))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('colorectal cancer', 'Disease', 'MESH:D015179', (123, 140))
5654	31164794	In the ceRNA network of CRC, H19 up-regulates various cancer-related mRNA by competitively sponging various miRNA, and participates in PI3K-Akt signaling pathway in this manner.	('CRC', 'Phenotype', 'HP:0003003', (24, 27))	('sponging various miRNA', 'MPA', (91, 113))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('signaling pathway', 'biological_process', 'GO:0007165', ('144', '161'))	('Akt', 'Gene', '207', (140, 143))	('cancer', 'Disease', (54, 60))	('participates', 'Reg', (119, 131))	('Akt signaling', 'biological_process', 'GO:0043491', ('140', '153'))	('up-regulates', 'PosReg', (33, 45))	('PI3K', 'molecular_function', 'GO:0016303', ('135', '139'))	('H19', 'Var', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Akt', 'Gene', (140, 143))
5655	31164794	Cox regression and correlation analysis showed that H19 and some other competing endogenous RNAs in the network are associated with poor prognosis and clinical parameters such as tumor grade and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('H19', 'Var', (52, 55))	('tumor', 'Disease', (179, 184))
5656	31164794	H19 regulates PI3K-Akt signal pathway through a competing endogenous RNA network and predicts poor prognosis in colorectal cancer.	('colorectal cancer', 'Disease', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('H19', 'Var', (0, 3))	('Akt', 'Gene', '207', (19, 22))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('regulates', 'Reg', (4, 13))	('Akt', 'Gene', (19, 22))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))
5662	31164794	Aberrant transcriptomes are common in cancer.	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (38, 44))
5673	31164794	Silencing H19 expression has been shown to cause a noticeable reduction in cancer cell proliferation and migration.	('H19', 'Gene', (10, 13))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cell proliferation', 'biological_process', 'GO:0008283', ('82', '100'))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Silencing', 'Var', (0, 9))	('reduction', 'NegReg', (62, 71))
5691	31164794	LncRNA Smart Silencer (RiboBio, Guangzhou, China) was used to knock down the expression of lncRNA H19.	('expression', 'MPA', (77, 87))	('ncRNA', 'Gene', (92, 97))	('ncRNA', 'Gene', '220202', (1, 6))	('ncRNA', 'Gene', '220202', (92, 97))	('knock', 'Var', (62, 67))	('ncRNA', 'Gene', (1, 6))
5714	31164794	There were 10 lncRNAs, 5 pseudogenes, 122 mRNAs, and 39 miRNAs in the ceRNA network.	('ncRNA', 'Gene', '220202', (15, 20))	('ncRNA', 'Gene', (15, 20))	('pseudogenes', 'Var', (25, 36))
5717	31164794	Mediated by miR-454-3p, miR-130a-3p, and miR-130b-3p, H19 interacted with ZEB1, CSF1, MET, and other 15 mRNAs.	('interacted', 'Interaction', (58, 68))	('CSF1', 'Gene', (80, 84))	('miR-130', 'Chemical', '-', (24, 31))	('miR-130', 'Chemical', '-', (41, 48))	('miR-130a-3p', 'Var', (24, 35))	('CSF1', 'molecular_function', 'GO:0005011', ('80', '84'))	('H19', 'Gene', (54, 57))	('miR-130b', 'Gene', '406920', (41, 49))	('miR-454', 'Gene', '768216', (12, 19))	('CSF1', 'Gene', '1435', (80, 84))	('miR-130b', 'Gene', (41, 49))	('miR-454', 'Gene', (12, 19))
5718	31164794	Mediated by miR-29b-3p, miR-29c-3p, and miR-370-3p, H19 interacted with TRAF5, ABCB6, AKT3, and other 17 mRNAs (Fig.	('ABCB6', 'Gene', (79, 84))	('interacted', 'Interaction', (56, 66))	('TRAF5', 'Gene', '7188', (72, 77))	('ABCB6', 'Gene', '10058', (79, 84))	('AKT3', 'Gene', (86, 90))	('H19', 'Gene', (52, 55))	('miR-370-3p', 'Var', (40, 50))	('AKT3', 'Gene', '10000', (86, 90))	('miR-29b-3p', 'Var', (12, 22))	('TRAF5', 'Gene', (72, 77))	('miR-29c-3p', 'Var', (24, 34))
5719	31164794	A total of 11 KEGG pathways related to biological pathways were enriched among the mRNAs in the ceRNA network, including the PI3K-Akt signaling pathway (hsa04151), the Ras signaling pathway (hsa04014), regulation of actin cytoskeleton (hsa04810), and the central carbon metabolism in cancer pathway (hsa05230) (Fig.	('hsa04151', 'Var', (153, 161))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('cancer', 'Disease', (284, 290))	('Akt', 'Gene', '207', (130, 133))	('hsa04014', 'Var', (191, 199))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('carbon', 'Chemical', 'MESH:D002244', (263, 269))	('Ras signaling pathway', 'Pathway', (168, 189))	('Akt', 'Gene', (130, 133))
5730	31164794	To verify the conclusions derived from bioinformatics analysis, we investigated how knockdown of the lncRNA H19 in CRC cell lines HT-29 and HCT116 affected protein expression.	('HCT116', 'Gene', (140, 146))	('HCT116', 'CellLine', 'CVCL:0291', (140, 146))	('affected', 'Reg', (147, 155))	('knockdown', 'Var', (84, 93))	('ncRNA', 'Gene', (102, 107))	('HT-29', 'CellLine', 'CVCL:0320', (130, 135))	('CRC', 'Phenotype', 'HP:0003003', (115, 118))	('ncRNA', 'Gene', '220202', (102, 107))	('protein expression', 'MPA', (156, 174))
5732	31164794	Our data demonstrated that knockdown of H19 could downregulate the expression of MET, ZEB1, and COL1A1 in both HT-29 and HCT116 cells (Fig.	('COL1A1', 'Gene', (96, 102))	('ZEB1', 'Gene', (86, 90))	('knockdown', 'Var', (27, 36))	('downregulate', 'NegReg', (50, 62))	('MET', 'Gene', (81, 84))	('H19', 'Gene', (40, 43))	('HCT116', 'CellLine', 'CVCL:0291', (121, 127))	('expression', 'MPA', (67, 77))	('HT-29', 'CellLine', 'CVCL:0320', (111, 116))
5743	31164794	The GO enrichment results suggested that dysregulation of mRNAs results in significant alteration in cell migration, regulation of developmental growth, and molecular functions closely related to the PI3K-Akt signaling pathway (Fig.	('Akt', 'Gene', '207', (205, 208))	('alteration', 'Reg', (87, 97))	('molecular functions', 'CPA', (157, 176))	('Akt', 'Gene', (205, 208))	('dysregulation', 'Var', (41, 54))	('cell migration', 'CPA', (101, 115))	('mRNAs', 'Gene', (58, 63))
5748	31164794	Beta-catenin signaling, induced by PI3K and mediated by Akt, appears to be essential for activation of progenitor cells during progression from ulcerative colitis to CRC.	('CRC', 'Disease', (166, 169))	('Akt', 'Gene', (56, 59))	('Beta-catenin', 'Gene', (0, 12))	('signaling', 'biological_process', 'GO:0023052', ('13', '22'))	('ulcerative colitis', 'Disease', (144, 162))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (144, 162))	('colitis', 'Phenotype', 'HP:0002583', (155, 162))	('PI3K', 'Var', (35, 39))	('CRC', 'Phenotype', 'HP:0003003', (166, 169))	('Akt', 'Gene', '207', (56, 59))	('Beta-catenin', 'Gene', '1499', (0, 12))	('ulcerative colitis', 'Disease', 'MESH:D003093', (144, 162))	('PI3K', 'molecular_function', 'GO:0016303', ('35', '39'))
5751	31164794	Taken together the evidence suggests that H19 up-regulates various cancer-related mRNA expression levels via serving as a ceRNA, and participates in the PI3K-Akt signaling pathway in this manner, playing a key role in promoting cancer progression.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (228, 234))	('cancer', 'Disease', (67, 73))	('H19', 'Var', (42, 45))	('Akt', 'Gene', '207', (158, 161))	('participates', 'Reg', (133, 145))	('mRNA expression levels', 'MPA', (82, 104))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('up-regulates', 'PosReg', (46, 58))	('promoting', 'PosReg', (218, 227))	('Akt', 'Gene', (158, 161))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
5754	31164794	Mutant p53 gain-of-function induces EMT through modulation of the miR-130b-ZEB1 axis, and this axis was regulated by H19 in the present ceRNA network.	('miR-130b', 'Gene', '406920', (66, 74))	('modulation', 'MPA', (48, 58))	('miR-130b', 'Gene', (66, 74))	('EMT', 'CPA', (36, 39))	('p53', 'Gene', '7157', (7, 10))	('gain-of-function induces', 'PosReg', (11, 35))	('EMT', 'biological_process', 'GO:0001837', ('36', '39'))	('Mutant', 'Var', (0, 6))	('p53', 'Gene', (7, 10))
5755	31164794	It has been reported that miR-29b-3p was regulated by H19 and promoted EMT in both CRC and bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('bladder cancer', 'Disease', (91, 105))	('EMT', 'CPA', (71, 74))	('CRC', 'Phenotype', 'HP:0003003', (83, 86))	('miR-29b-3p', 'Var', (26, 36))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('promoted', 'PosReg', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('CRC', 'Disease', (83, 86))
5756	31164794	Two previous studies have shown that phosphorylation of key kinases in the PI3K/AKT/mTOR pathways was regulated by H19 through a ceRNA manner.	('phosphorylation', 'MPA', (37, 52))	('AKT', 'Gene', '207', (80, 83))	('mTOR', 'Gene', '2475', (84, 88))	('regulated', 'Reg', (102, 111))	('H19', 'Var', (115, 118))	('AKT', 'Gene', (80, 83))	('mTOR', 'Gene', (84, 88))
5757	31164794	Furthermore, H19 regulated many other cancer-related genes in this network, such as AKT3, CSF1, MET, COL1A1, COL5A1, WWTR1, EPHB4, and TMPRSS3.	('TMPRSS3', 'Gene', '64699', (135, 142))	('MET', 'Gene', (96, 99))	('AKT3', 'Gene', '10000', (84, 88))	('COL5A1', 'Gene', (109, 115))	('WWTR1', 'Gene', '25937', (117, 122))	('AKT3', 'Gene', (84, 88))	('cancer', 'Disease', (38, 44))	('regulated', 'Reg', (17, 26))	('H19', 'Var', (13, 16))	('TMPRSS3', 'Gene', (135, 142))	('EPHB4', 'Gene', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('COL1A1', 'Gene', (101, 107))	('WWTR1', 'Gene', (117, 122))	('CSF1', 'Gene', (90, 94))	('COL5A1', 'Gene', '1289', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('CSF1', 'Gene', '1435', (90, 94))	('EPHB4', 'Gene', '2050', (124, 129))
5759	31164794	We found that, in addition to H19, some other lncRNAs or pseudogenes in the present ceRNA network were also associated with OS or other important prognostic parameters.	('OS', 'Chemical', '-', (124, 126))	('ncRNA', 'Gene', (47, 52))	('ncRNA', 'Gene', '220202', (47, 52))	('associated', 'Reg', (108, 118))	('pseudogenes', 'Var', (57, 68))
5762	31164794	Aberration of KCNQ1OT1 transcription was common in CRC.	('transcription', 'biological_process', 'GO:0006351', ('23', '36'))	('CRC', 'Phenotype', 'HP:0003003', (51, 54))	('KCNQ1OT1', 'Gene', '10984', (14, 22))	('KCNQ1OT1', 'Gene', (14, 22))	('transcription', 'MPA', (23, 36))	('CRC', 'Disease', (51, 54))	('Aberration', 'Var', (0, 10))	('common', 'Reg', (41, 47))
5770	31164794	Since RPLP0P2, H19, and KCNQ1OT1 are associated with survival, they may serve as potential prognostic biomarkers for CRC.	('KCNQ1OT1', 'Gene', '10984', (24, 32))	('survival', 'MPA', (53, 61))	('CRC', 'Phenotype', 'HP:0003003', (117, 120))	('KCNQ1OT1', 'Gene', (24, 32))	('associated', 'Reg', (37, 47))	('H19', 'Var', (15, 18))	('RPLP0P2', 'Gene', '113157', (6, 13))	('RPLP0P2', 'Gene', (6, 13))	('CRC', 'Disease', (117, 120))
5774	31164794	In conclusion, the present study successfully applied bioinformatics analysis of large-scale samples in the TCGA database to identify cancer-specific lncRNAs and pseudogenes in CRC.	('ncRNA', 'Gene', '220202', (151, 156))	('cancer', 'Disease', (134, 140))	('CRC', 'Gene', (177, 180))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('pseudogenes', 'Var', (162, 173))	('ncRNA', 'Gene', (151, 156))	('CRC', 'Phenotype', 'HP:0003003', (177, 180))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
5800	25007286	Multiple experimental animal models have demonstrated that JCV can cause brain tumors in rodents and nonhuman primates.	('JCV', 'Var', (59, 62))	('cause', 'Reg', (67, 72))	('brain tumors', 'Disease', (73, 85))	('brain tumors', 'Phenotype', 'HP:0030692', (73, 85))	('human', 'Species', '9606', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('JCV', 'Species', '10632', (59, 62))	('brain tumors', 'Disease', 'MESH:D001932', (73, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
5801	25007286	When T-Ag induces tumorigenesis, all of the tumors are aneuploid.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Disease', (18, 23))	('T-Ag', 'Var', (5, 9))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('induces', 'Reg', (10, 17))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
5808	25007286	A recent study evaluating the presence of JCV in anal cancer also evaluated the concomitant presence of human papillomavirus (HPV), since it is assumed that HPV causes anal cancer, as well as cervical cancer.	('HPV', 'Species', '10566', (157, 160))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('anal cancer', 'Phenotype', 'HP:0032186', (49, 60))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('causes', 'Reg', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('HPV', 'Var', (157, 160))	('JCV', 'Species', '10632', (42, 45))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (54, 60))	('human papillomavirus', 'Species', '10566', (104, 124))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cervical cancer', 'Disease', (192, 207))	('cervical cancer', 'Disease', 'MESH:D002583', (192, 207))	('anal cancer', 'Phenotype', 'HP:0032186', (168, 179))	('HPV', 'Species', '10566', (126, 129))
5892	28440295	Here we report that the KDM3 family of histone demethylases plays an important role in tumorigenic potential and survival of human colorectal CSCs by epigenetically activating Wnt target gene transcription.	('KDM3', 'Chemical', '-', (24, 28))	('transcription', 'biological_process', 'GO:0006351', ('192', '205'))	('transcription', 'MPA', (192, 205))	('human', 'Species', '9606', (125, 130))	('epigenetically activating', 'Var', (150, 175))	('colorectal CSCs', 'Disease', 'MESH:D015179', (131, 146))	('colorectal CSCs', 'Disease', (131, 146))	('tumorigenic potential', 'CPA', (87, 108))	('Wnt', 'Gene', (176, 179))
5894	28440295	Mechanistically, KDM3 not only directly erases repressive H3K9me2 marks, but also helps to recruit histone methyltransferase MLL1 to promote H3K4 methylation, thereby promoting Wnt target gene transcription.	('KDM3', 'Var', (17, 21))	('repressive', 'MPA', (47, 57))	('erases', 'NegReg', (40, 46))	('MLL1', 'Gene', (125, 129))	('promote', 'PosReg', (133, 140))	('methylation', 'MPA', (146, 157))	('promoting', 'PosReg', (167, 176))	('MLL1', 'Gene', '4297', (125, 129))	('H3K9me2 marks', 'Protein', (58, 71))	('H3K4', 'Protein', (141, 145))	('transcription', 'MPA', (193, 206))	('KDM3', 'Chemical', '-', (17, 21))	('Wnt target gene', 'Gene', (177, 192))
5896	28440295	Epigenetic factors can regulate functional properties of human colorectal cancer stem cells.	('Epigenetic factors', 'Var', (0, 18))	('regulate', 'Reg', (23, 31))	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('colorectal cancer', 'Disease', (63, 80))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('functional', 'MPA', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('human', 'Species', '9606', (57, 62))
5899	28440295	The hyperactivated Wnt/beta-catenin signalling pathway has been found to be associated with various types of human cancers, most notably colorectal cancers (CRCs) due to APC and CTNNB1 (beta-catenin) mutations.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('mutations', 'Var', (200, 209))	('cancers', 'Disease', (115, 122))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('colorectal cancers', 'Disease', 'MESH:D015179', (137, 155))	('CTNNB1', 'Gene', (178, 184))	('beta-catenin', 'Gene', (23, 35))	('beta-catenin', 'Gene', '1499', (23, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (137, 154))	('APC', 'cellular_component', 'GO:0005680', ('170', '173'))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('associated', 'Reg', (76, 86))	('APC', 'Disease', 'MESH:D011125', (170, 173))	('APC', 'Disease', (170, 173))	('human', 'Species', '9606', (109, 114))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('signalling pathway', 'biological_process', 'GO:0007165', ('36', '54'))	('hyperactivated', 'PosReg', (4, 18))	('cancers', 'Disease', (148, 155))	('colorectal cancers', 'Disease', (137, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('beta-catenin', 'Gene', (186, 198))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('beta-catenin', 'Gene', '1499', (186, 198))	('CTNNB1', 'Gene', '1499', (178, 184))
5909	28440295	APC and CTNNB1 (beta-catenin) mutations are the major cause of the abnormal activation of Wnt/beta-catenin signalling in human CRCs.	('APC', 'cellular_component', 'GO:0005680', ('0', '3'))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('CTNNB1', 'Gene', '1499', (8, 14))	('beta-catenin', 'Gene', (94, 106))	('beta-catenin', 'Gene', (16, 28))	('human', 'Species', '9606', (121, 126))	('APC', 'Disease', (0, 3))	('mutations', 'Var', (30, 39))	('beta-catenin', 'Gene', '1499', (16, 28))	('beta-catenin', 'Gene', '1499', (94, 106))	('signalling', 'biological_process', 'GO:0023052', ('107', '117'))	('CTNNB1', 'Gene', (8, 14))	('activation', 'PosReg', (76, 86))
5912	28440295	Emerging evidence suggests that epigenetic factors might help to govern colon tumour initiation.	('epigenetic factors', 'Var', (32, 50))	('colon tumour initiation', 'Disease', 'MESH:D015179', (72, 95))	('colon tumour initiation', 'Disease', (72, 95))	('colon tumour', 'Phenotype', 'HP:0100273', (72, 84))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
5913	28440295	Although APC and CTNNB1 mutations play a critical role in human CRC development, epigenetic and genetic alternations are likely to act synergistically in human CRC development.	('APC', 'Disease', (9, 12))	('human', 'Species', '9606', (154, 159))	('human', 'Species', '9606', (58, 63))	('CTNNB1', 'Gene', (17, 23))	('act', 'Reg', (131, 134))	('APC', 'Disease', 'MESH:D011125', (9, 12))	('mutations', 'Var', (24, 33))	('CTNNB1', 'Gene', '1499', (17, 23))
5914	28440295	Bivalent chromatin domains, characterized by co-existence of both active H3K4me3 and repressive H3K27me3 marks, have been found to play an important role in regulation of gene expression in both embryonic stem cells and adult stem cells.	('H3K4me3', 'Protein', (73, 80))	('expression', 'Species', '29278', (176, 186))	('gene expression', 'MPA', (171, 186))	('chromatin', 'cellular_component', 'GO:0000785', ('9', '18'))	('H3K27me3', 'Var', (96, 104))	('regulation of gene expression', 'biological_process', 'GO:0010468', ('157', '186'))
5915	28440295	H3K4me3 is important for the expression of Wnt target genes by facilitating chromatin association with the co-activators PYGO2 and BCL9 (refs).	('chromatin', 'cellular_component', 'GO:0000785', ('76', '85'))	('PYGO2', 'Gene', (121, 126))	('PYGO2', 'Gene', '90780', (121, 126))	('H3K4me3', 'Var', (0, 7))	('BCL9', 'Gene', (131, 135))	('chromatin association', 'MPA', (76, 97))	('expression', 'Species', '29278', (29, 39))	('BCL9', 'Gene', '607', (131, 135))	('facilitating', 'PosReg', (63, 75))
5917	28440295	However, whether modifying H3K9 methylation regulates human colorectal CSCs is still unclear.	('colorectal CSCs', 'Disease', 'MESH:D015179', (60, 75))	('H3K9', 'Protein', (27, 31))	('colorectal CSCs', 'Disease', (60, 75))	('modifying', 'Var', (17, 26))	('regulates', 'Reg', (44, 53))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('human', 'Species', '9606', (54, 59))
5927	28440295	The KDM3 family demethylases contain three subfamily members, namely KDM3A, KDM3B and JMJD1C, which are responsible for removing the methyl groups from H3K9 with a preference for H3K9me2.	('KDM3A', 'Gene', '55818', (69, 74))	('JMJD1C', 'Gene', '221037', (86, 92))	('KDM3', 'Chemical', '-', (69, 73))	('KDM3A', 'Gene', (69, 74))	('KDM3', 'Chemical', '-', (76, 80))	('JMJD1C', 'Gene', (86, 92))	('H3K9me2', 'Var', (179, 186))	('H3K9', 'Protein', (152, 156))	('removing', 'NegReg', (120, 128))	('KDM3', 'Chemical', '-', (4, 8))	('KDM3B', 'Gene', '51780', (76, 81))	('methyl groups', 'MPA', (133, 146))	('KDM3B', 'Gene', (76, 81))
5929	28440295	To further determine whether KDM3 family members were required for beta-catenin/Tcf-mediated transcription, we also examined whether their knockdown impaired the expression of the well-known Wnt target genes AXIN2 and DKK1.	('transcription', 'biological_process', 'GO:0006351', ('93', '106'))	('DKK1', 'Gene', '22943', (218, 222))	('DKK1', 'Gene', (218, 222))	('AXIN2', 'Gene', '8313', (208, 213))	('impaired', 'NegReg', (149, 157))	('knockdown', 'Var', (139, 148))	('expression', 'Species', '29278', (162, 172))	('expression', 'MPA', (162, 172))	('KDM3', 'Chemical', '-', (29, 33))	('beta-catenin', 'Gene', (67, 79))	('AXIN2', 'Gene', (208, 213))	('beta-catenin', 'Gene', '1499', (67, 79))
5935	28440295	The depletion of KDM3A/B also inhibited the expression of AXIN2 and DKK1 induced by Wnt3a, a canonical Wnt ligand (Fig.	('KDM3A/B', 'Var', (17, 24))	('expression', 'MPA', (44, 54))	('DKK1', 'Gene', (68, 72))	('DKK1', 'Gene', '22943', (68, 72))	('inhibited', 'NegReg', (30, 39))	('AXIN2', 'Gene', (58, 63))	('AXIN2', 'Gene', '8313', (58, 63))	('Wnt3a', 'Gene', '89780', (84, 89))	('depletion', 'MPA', (4, 13))	('Wnt3a', 'Gene', (84, 89))	('expression', 'Species', '29278', (44, 54))
5936	28440295	Overexpression of KDM3A or KDM3B significantly enhanced the Topflash reporter activation induced by a mutant form of beta-catenin in a dose-dependent manner (Fig.	('mutant', 'Var', (102, 108))	('beta-catenin', 'Gene', (117, 129))	('enhanced', 'PosReg', (47, 55))	('expression', 'Species', '29278', (4, 14))	('KDM3A', 'Gene', (18, 23))	('KDM3B', 'Gene', '51780', (27, 32))	('beta-catenin', 'Gene', '1499', (117, 129))	('KDM3B', 'Gene', (27, 32))	('activation', 'PosReg', (78, 88))	('Topflash', 'Gene', (60, 68))	('KDM3A', 'Gene', '55818', (18, 23))
5938	28440295	The ectopic expression of KDM3A fully restored Topflash reporter activities (Fig.	('KDM3A', 'Gene', (26, 31))	('restored', 'PosReg', (38, 46))	('KDM3A', 'Gene', '55818', (26, 31))	('expression', 'Species', '29278', (12, 22))	('ectopic expression', 'Var', (4, 22))	('Topflash reporter activities', 'MPA', (47, 75))
5943	28440295	Because Wnt/beta-catenin signalling plays an important role in human CRC development, we examined whether KDM3 epigenetically regulated Wnt target genes in human colorectal cancer cells.	('colorectal cancer', 'Disease', 'MESH:D015179', (162, 179))	('human', 'Species', '9606', (63, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (162, 179))	('beta-catenin', 'Gene', (12, 24))	('colorectal cancer', 'Disease', (162, 179))	('epigenetically', 'Var', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('beta-catenin', 'Gene', '1499', (12, 24))	('human', 'Species', '9606', (156, 161))	('KDM3', 'Chemical', '-', (106, 110))	('KDM3', 'Gene', (106, 110))
5945	28440295	HCT116 cells have constitutively active beta-catenin/Tcf-mediated transcription due to Ser45 mutation in beta-catenin.	('Ser45', 'Chemical', '-', (87, 92))	('Ser45 mutation', 'Var', (87, 101))	('beta-catenin', 'Gene', (105, 117))	('HCT116', 'CellLine', 'CVCL:0291', (0, 6))	('beta-catenin', 'Gene', (40, 52))	('beta-catenin', 'Gene', '1499', (40, 52))	('beta-catenin', 'Gene', '1499', (105, 117))
5946	28440295	Real-time RT-PCR showed that both ABsh-1 and ABsh-2 significantly inhibited the expression of well-known Wnt target genes, including AXIN2, DKK1, CCND1 and MYC (Fig.	('ABsh-2', 'Gene', (45, 51))	('MYC', 'Gene', '4609', (156, 159))	('DKK1', 'Gene', (140, 144))	('MYC', 'Gene', (156, 159))	('CCND1', 'Gene', '595', (146, 151))	('expression', 'Species', '29278', (80, 90))	('AXIN2', 'Gene', '8313', (133, 138))	('DKK1', 'Gene', '22943', (140, 144))	('expression', 'MPA', (80, 90))	('inhibited', 'NegReg', (66, 75))	('ABsh-1', 'Var', (34, 40))	('CCND1', 'Gene', (146, 151))	('AXIN2', 'Gene', (133, 138))
5948	28440295	Compared with published gene expression profiles from CRC cell lines, gene set enrichment analysis (GSEA) revealed that, there existed a significant negative correlation between Wnt/beta-catenin upregulated genes and downregulated genes following KDM3A/B depletion, highlighting the critical role of KDM3 in beta-catenin/Tcf-mediated transcription (Fig.	('GSEA', 'Chemical', '-', (100, 104))	('gene expression', 'biological_process', 'GO:0010467', ('24', '39'))	('beta-catenin', 'Gene', '1499', (182, 194))	('transcription', 'biological_process', 'GO:0006351', ('334', '347'))	('KDM3', 'Chemical', '-', (300, 304))	('beta-catenin', 'Gene', '1499', (308, 320))	('downregulated', 'NegReg', (217, 230))	('beta-catenin', 'Gene', (308, 320))	('depletion', 'Var', (255, 264))	('expression', 'Species', '29278', (29, 39))	('upregulated genes', 'PosReg', (195, 212))	('negative', 'NegReg', (149, 157))	('KDM3', 'Chemical', '-', (247, 251))	('beta-catenin', 'Gene', (182, 194))
5962	28440295	Therefore, we were interested in whether KDM3A/B might epigenetically affect CSC functions by controlling Wnt/beta-catenin signalling.	('affect', 'Reg', (70, 76))	('beta-catenin', 'Gene', (110, 122))	('KDM3A/B', 'Gene', (41, 48))	('beta-catenin', 'Gene', '1499', (110, 122))	('CSC', 'Disease', (77, 80))	('controlling', 'Reg', (94, 105))	('epigenetically', 'Var', (55, 69))
5967	28440295	To further confirm our results, we isolated ALDH+ cells from HCT116 cells and then knocked down KDM3A/B with siRNA immediately after isolation.	('ALDH', 'Gene', '11670', (44, 48))	('HCT116', 'CellLine', 'CVCL:0291', (61, 67))	('ALDH', 'Gene', (44, 48))	('KDM3A/B', 'Gene', (96, 103))	('knocked', 'Var', (83, 90))
5970	28440295	Notably, while ALDH+HCT116 cells effectively formed sphere-like colonies as opposed to ALDH- cells, knockdown of KDM3A/B dramatically abolished the tumorsphere formation ability of ALDH+HCT116 cells (Fig.	('knockdown', 'Var', (100, 109))	('KDM3A/B', 'Gene', (113, 120))	('ALDH', 'Gene', (15, 19))	('ALDH', 'molecular_function', 'GO:0004030', ('15', '19'))	('ALDH', 'Gene', '11670', (181, 185))	('formation', 'biological_process', 'GO:0009058', ('160', '169'))	('HCT116', 'CellLine', 'CVCL:0291', (20, 26))	('ALDH', 'Gene', (181, 185))	('tumorsphere formation ability', 'CPA', (148, 177))	('ALDH', 'Gene', '11670', (87, 91))	('ALDH', 'Gene', '11670', (15, 19))	('HCT116', 'CellLine', 'CVCL:0291', (186, 192))	('ALDH', 'molecular_function', 'GO:0004030', ('181', '185'))	('ALDH', 'Gene', (87, 91))	('ALDH', 'molecular_function', 'GO:0004030', ('87', '91'))	('abolished', 'NegReg', (134, 143))
5971	28440295	Similarly, knockdown of KDM3A/B also significantly reduced the ALDH+ subpopulation in SW480 cells (Supplementary Fig.	('reduced', 'NegReg', (51, 58))	('ALDH', 'molecular_function', 'GO:0004030', ('63', '67'))	('ALDH', 'Gene', '11670', (63, 67))	('KDM3A/B', 'Gene', (24, 31))	('SW480', 'CellLine', 'CVCL:0546', (86, 91))	('ALDH', 'Gene', (63, 67))	('knockdown', 'Var', (11, 20))
5974	28440295	To determine whether KDM3A/B played an important role in the tumorigenesis of ALDH+HCT116 cells in vivo, we knocked them down in ALDH+HCT116 cells using shRNA.	('HCT116', 'CellLine', 'CVCL:0291', (134, 140))	('ALDH', 'Gene', (129, 133))	('ALDH', 'Gene', (78, 82))	('ALDH', 'molecular_function', 'GO:0004030', ('78', '82'))	('tumorigenesis', 'CPA', (61, 74))	('ALDH', 'Gene', '11670', (78, 82))	('HCT116', 'CellLine', 'CVCL:0291', (83, 89))	('ALDH', 'molecular_function', 'GO:0004030', ('129', '133'))	('knocked', 'Var', (108, 115))	('ALDH', 'Gene', '11670', (129, 133))
5982	28440295	ALDH+/EpCAM+ cells, CD133+/EpCAM+ and CD44v6+/EpCAM+ effectively formed sphere-like colonies in vitro (Fig.	('CD44v6+/EpCAM+', 'Var', (38, 52))	('ALDH', 'molecular_function', 'GO:0004030', ('0', '4'))	('sphere-like colonies', 'CPA', (72, 92))	('ALDH', 'Gene', '11670', (0, 4))	('ALDH', 'Gene', (0, 4))	('CD133', 'Gene', (20, 25))	('CD133', 'Gene', '8842', (20, 25))
5987	28440295	Moreover, knockdown of KDM3A/B also significantly inhibited the expression of Wnt target genes, including AXIN2, DKK1, CCND1 and MYC (Fig.	('AXIN2', 'Gene', (106, 111))	('KDM3A/B', 'Gene', (23, 30))	('AXIN2', 'Gene', '8313', (106, 111))	('expression', 'MPA', (64, 74))	('DKK1', 'Gene', '22943', (113, 117))	('inhibited', 'NegReg', (50, 59))	('MYC', 'Gene', '4609', (129, 132))	('CCND1', 'Gene', (119, 124))	('expression', 'Species', '29278', (64, 74))	('MYC', 'Gene', (129, 132))	('knockdown', 'Var', (10, 19))	('CCND1', 'Gene', '595', (119, 124))	('DKK1', 'Gene', (113, 117))
5988	28440295	Similarly, knockdown of KDMA/B in CD133+/EpCAM+ and CD44v6+/EpCAM+ also inhibited tumorsphere formation (Supplementary Fig.	('formation', 'biological_process', 'GO:0009058', ('94', '103'))	('CD133', 'Gene', '8842', (34, 39))	('KDMA/B', 'Gene', (24, 30))	('CD44v6+/EpCAM+', 'Var', (52, 66))	('tumorsphere formation', 'CPA', (82, 103))	('inhibited', 'NegReg', (72, 81))	('CD133', 'Gene', (34, 39))
5990	28440295	While ALDH+/EpCAM+ cells expressing scramble shRNA (PS1-ALDH+/Scrsh) rapidly formed large tumours in vivo, ALDH+/EpCAM+ cells expressing ABshRNA-1 (PS1-ALDH+ /ABsh-1 cells) only formed small tumours or could not form tumour at all (Fig.	('ALDH', 'Gene', '11670', (6, 10))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('ALDH', 'Gene', (152, 156))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('tumours', 'Disease', (191, 198))	('small tumours', 'Disease', (185, 198))	('tumour', 'Disease', 'MESH:D009369', (217, 223))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('ALDH', 'Gene', '11670', (107, 111))	('tumour', 'Disease', (217, 223))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('tumours', 'Phenotype', 'HP:0002664', (191, 198))	('tumour', 'Disease', (90, 96))	('ALDH', 'Gene', (56, 60))	('tumours', 'Disease', 'MESH:D009369', (191, 198))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('ALDH', 'Gene', (6, 10))	('ABshRNA-1', 'Var', (137, 146))	('ALDH', 'Gene', '11670', (152, 156))	('small tumours', 'Disease', 'MESH:D055752', (185, 198))	('tumour', 'Disease', 'MESH:D009369', (191, 197))	('tumour', 'Disease', (191, 197))	('ALDH', 'Gene', '11670', (56, 60))	('tumours', 'Disease', (90, 97))	('ALDH', 'Gene', (107, 111))
5997	28440295	Moreover, knockdown of KDM3A/B also inhibited tumorigenic potentials of ALDH+ cells from HCP1 cells in Nude Mice (Fig.	('KDM3A/B', 'Gene', (23, 30))	('inhibited', 'NegReg', (36, 45))	('ALDH', 'Gene', (72, 76))	('Nude Mice', 'Species', '10090', (103, 112))	('ALDH', 'Gene', '11670', (72, 76))	('ALDH', 'molecular_function', 'GO:0004030', ('72', '76'))	('knockdown', 'Var', (10, 19))
5999	28440295	To determine the potential role of KDM3 in chemoresistance of ALDH+ cells, we examined whether the depletion of KDM3A/B promoted apoptosis in ALDH+HCT116 cells following treatment with two commonly used chemotherapeutic agents cisplatin and irinotecan.	('KDM3A/B', 'Gene', (112, 119))	('cisplatin', 'Chemical', 'MESH:D002945', (227, 236))	('apoptosis', 'CPA', (129, 138))	('KDM3', 'Chemical', '-', (112, 116))	('promoted', 'PosReg', (120, 128))	('KDM3', 'Chemical', '-', (35, 39))	('depletion', 'Var', (99, 108))	('ALDH', 'Gene', '11670', (142, 146))	('ALDH', 'Gene', '11670', (62, 66))	('HCT116', 'CellLine', 'CVCL:0291', (147, 153))	('irinotecan', 'Chemical', 'MESH:D000077146', (241, 251))	('ALDH', 'Gene', (62, 66))	('ALDH', 'Gene', (142, 146))
6001	28440295	We observed that the transfection of KDM3A/B siRNA alone increased the basal level of cell death in ALDH+HCT116 cells.	('HCT116', 'CellLine', 'CVCL:0291', (105, 111))	('cell death', 'biological_process', 'GO:0008219', ('86', '96'))	('ALDH', 'molecular_function', 'GO:0004030', ('100', '104'))	('ALDH', 'Gene', '11670', (100, 104))	('basal level of cell death', 'MPA', (71, 96))	('ALDH', 'Gene', (100, 104))	('increased', 'PosReg', (57, 66))	('KDM3A/B', 'Var', (37, 44))
6002	28440295	While cisplatin or irinotecan modestly induced cell death in ALDH+HCT116 cells transfected with scramble siRNA, KDM3A/B siRNA significantly enhanced ALDH+HCT116 cell death induced by cisplatin and irinotecan (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (6, 15))	('irinotecan', 'Chemical', 'MESH:D000077146', (197, 207))	('ALDH', 'Gene', '11670', (61, 65))	('HCT116', 'CellLine', 'CVCL:0291', (154, 160))	('enhanced', 'PosReg', (140, 148))	('irinotecan', 'Chemical', 'MESH:D000077146', (19, 29))	('cisplatin', 'Chemical', 'MESH:D002945', (183, 192))	('ALDH', 'Gene', (61, 65))	('HCT116', 'CellLine', 'CVCL:0291', (66, 72))	('ALDH', 'Gene', '11670', (149, 153))	('KDM3A/B', 'Var', (112, 119))	('ALDH', 'Gene', (149, 153))
6003	28440295	Western blot analysis revealed that the knockdown of KDM3A/B increased caspase-3 activities induced by cisplatin and irinotecan in ALDH+HCT116 cells (Fig.	('irinotecan', 'MPA', (117, 127))	('ALDH', 'Gene', (131, 135))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('HCT116', 'CellLine', 'CVCL:0291', (136, 142))	('knockdown', 'Var', (40, 49))	('caspase-3', 'Gene', (71, 80))	('irinotecan', 'Chemical', 'MESH:D000077146', (117, 127))	('increased', 'PosReg', (61, 70))	('ALDH', 'Gene', '11670', (131, 135))	('caspase-3', 'Gene', '836', (71, 80))	('cisplatin', 'MPA', (103, 112))	('KDM3A/B', 'Gene', (53, 60))	('activities', 'MPA', (81, 91))
6004	28440295	Consistently, knockdown of KDM3A/B also enhanced the cleavage of poly (ADP-ribose) polymerase 1 (PARP1) induced by these two drugs (Fig.	('cleavage', 'MPA', (53, 61))	('PARP1', 'Gene', '142', (97, 102))	('PARP1', 'Gene', (97, 102))	('poly (ADP-ribose) polymerase 1', 'Gene', '142', (65, 95))	('KDM3A/B', 'Gene', (27, 34))	('knockdown', 'Var', (14, 23))	('enhanced', 'PosReg', (40, 48))	('poly (ADP-ribose) polymerase 1', 'Gene', (65, 95))
6011	28440295	Western blot also found that the knockdown of KDM3A/B increased caspase-3 activities and cleavage of PARP-1 induced by cisplatin or irinotecan in ALDH+CSCs from patient case #1 (Fig.	('irinotecan', 'Chemical', 'MESH:D000077146', (132, 142))	('caspase-3', 'Gene', '836', (64, 73))	('ALDH', 'molecular_function', 'GO:0004030', ('146', '150'))	('knockdown', 'Var', (33, 42))	('patient', 'Species', '9606', (161, 168))	('PARP-1', 'Gene', (101, 107))	('cleavage', 'MPA', (89, 97))	('increased', 'PosReg', (54, 63))	('PARP-1', 'Gene', '142', (101, 107))	('ALDH', 'Gene', '11670', (146, 150))	('caspase-3', 'Gene', (64, 73))	('ALDH', 'Gene', (146, 150))	('activities', 'MPA', (74, 84))	('KDM3A/B', 'Gene', (46, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))
6014	28440295	Since knockdown of KDM3A/B impaired CSC growth, we first performed ChIP-seq in HCT116 cells because we needed a large amount of cells for ChIP-seq.	('HCT116', 'CellLine', 'CVCL:0291', (79, 85))	('CSC growth', 'CPA', (36, 46))	('impaired', 'NegReg', (27, 35))	('knockdown', 'Var', (6, 15))	('KDM3A/B', 'Gene', (19, 26))
6025	28440295	6d, the average profile of KDM3B enrichment decreased corresponding to a dramatic increase in H3K9me2 enrichment following KDM3A/B depletion as compared to control cells.	('H3K9me2', 'Protein', (94, 101))	('KDM3A/B depletion', 'Var', (123, 140))	('KDM3B', 'Gene', '51780', (27, 32))	('increase', 'PosReg', (82, 90))	('KDM3B', 'Gene', (27, 32))	('decreased', 'NegReg', (44, 53))
6028	28440295	KDM3A/B depletion resulted in enhanced H3K9me2 enrichment in both intron and coding exon regions of AXIN2, which was validated by qPCR targeted at the Wnt-responsive-element (WRE), introns and coding exons (A1-A5).	('depletion', 'Var', (8, 17))	('enhanced', 'PosReg', (30, 38))	('enrichment', 'MPA', (47, 57))	('AXIN2', 'Gene', (100, 105))	('KDM3A/B depletion', 'Var', (0, 17))	('AXIN2', 'Gene', '8313', (100, 105))	('H3K9me2', 'Protein', (39, 46))
6029	28440295	Furthermore, the recruitment of beta-catenin to these regions, especially at the WRE, was not affected following KDM3A/B depletion (Supplementary Fig.	('KDM3A/B', 'Gene', (113, 120))	('beta-catenin', 'Gene', (32, 44))	('beta-catenin', 'Gene', '1499', (32, 44))	('recruitment', 'MPA', (17, 28))	('depletion', 'Var', (121, 130))
6041	28440295	KDM3A/B depletion resulted in increased H3K9me2 enrichments on the AXIN2 promoter while they did not affect beta-catenin binding to their promoters (Fig.	('beta-catenin', 'Gene', (108, 120))	('AXIN2', 'Gene', '8313', (67, 72))	('depletion', 'Var', (8, 17))	('KDM3A/B depletion', 'Var', (0, 17))	('beta-catenin', 'Gene', '1499', (108, 120))	('enrichments', 'MPA', (48, 59))	('H3K9me2', 'Protein', (40, 47))	('increased', 'PosReg', (30, 39))	('AXIN2', 'Gene', (67, 72))
6042	28440295	Similarly, KDM3A/B were detected on the DKK1 promoter, and the depletion of KDM3A/B elevated H3K9me2 marks on the DKK1 promoter without interfering with beta-catenin occupancy on the chromatin (Fig.	('DKK1', 'Gene', '22943', (114, 118))	('elevated', 'PosReg', (84, 92))	('KDM3A/B', 'Var', (76, 83))	('H3K9me2', 'Protein', (93, 100))	('beta-catenin', 'Gene', (153, 165))	('DKK1', 'Gene', (114, 118))	('beta-catenin', 'Gene', '1499', (153, 165))	('DKK1', 'Gene', '22943', (40, 44))	('DKK1', 'Gene', (40, 44))	('depletion', 'MPA', (63, 72))
6045	28440295	KDM3A/B depletion also increased H3K9me2 marks on the promoters of AXIN2 and DKK1, but did not affect beta-catenin levels on chromatin (Supplementary Fig.	('H3K9me2', 'Var', (33, 40))	('AXIN2', 'Gene', '8313', (67, 72))	('depletion', 'Var', (8, 17))	('DKK1', 'Gene', '22943', (77, 81))	('DKK1', 'Gene', (77, 81))	('beta-catenin', 'Gene', '1499', (102, 114))	('beta-catenin', 'Gene', (102, 114))	('KDM3A/B depletion', 'Var', (0, 17))	('increased', 'PosReg', (23, 32))	('AXIN2', 'Gene', (67, 72))
6046	28440295	H3K4me3 is a hallmark for gene activation and it is critical for recruiting the transcriptional co-activator BCL9/PYGO2 to activate Wnt target gene transcription.	('PYGO2', 'Gene', '90780', (114, 119))	('H3K4me3', 'Var', (0, 7))	('PYGO2', 'Gene', (114, 119))	('transcription', 'MPA', (148, 161))	('BCL9', 'Gene', '607', (109, 113))	('BCL9', 'Gene', (109, 113))	('activate', 'PosReg', (123, 131))
6047	28440295	Unexpectedly, following KDM3A/B depletion, the enrichment of H3K4me3 at the WRE of AXIN2 was significantly reduced in ALDH+ cells isolated from HCP1 cells (Fig.	('ALDH', 'molecular_function', 'GO:0004030', ('118', '122'))	('ALDH', 'Gene', (118, 122))	('AXIN2', 'Gene', (83, 88))	('reduced', 'NegReg', (107, 114))	('AXIN2', 'Gene', '8313', (83, 88))	('enrichment of', 'MPA', (47, 60))	('KDM3A/B depletion', 'Var', (24, 41))	('ALDH', 'Gene', '11670', (118, 122))	('H3K4me3', 'Protein', (61, 68))
6050	28440295	KDM3A/B knockdown significantly decreased recruitment of MLL1 to the AXIN2 promoter (Fig.	('recruitment', 'MPA', (42, 53))	('MLL1', 'Gene', '4297', (57, 61))	('knockdown', 'Var', (8, 17))	('AXIN2', 'Gene', (69, 74))	('AXIN2', 'Gene', '8313', (69, 74))	('MLL1', 'Gene', (57, 61))	('decreased', 'NegReg', (32, 41))
6051	28440295	Similarly, ChIP-qPCR also revealed that KDM3A/B knockdown impaired MLL1 binding to the DKK1 promoter and reduced H3K4me3 enrichment in ALDH+ cells (Fig.	('binding', 'Interaction', (72, 79))	('DKK1', 'Gene', (87, 91))	('MLL1', 'Gene', (67, 71))	('MLL1', 'Gene', '4297', (67, 71))	('H3K4me3', 'Protein', (113, 120))	('reduced', 'NegReg', (105, 112))	('knockdown', 'Var', (48, 57))	('DKK1', 'Gene', '22943', (87, 91))	('ALDH', 'Gene', '11670', (135, 139))	('KDM3A/B', 'Gene', (40, 47))	('impaired', 'NegReg', (58, 66))	('ALDH', 'Gene', (135, 139))
6055	28440295	PYGO2 binds to H3K4me3 and H3K4me2 on Wnt target gene promoters to promote transcription in colorectal cancer cells.	('PYGO2', 'Gene', '90780', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('promote', 'PosReg', (67, 74))	('colorectal cancer', 'Disease', 'MESH:D015179', (92, 109))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('H3K4me2', 'Var', (27, 34))	('PYGO2', 'Gene', (0, 5))	('transcription', 'MPA', (75, 88))	('colorectal cancer', 'Disease', (92, 109))
6058	28440295	Similarly, the knockdown of KDM3A/B also impaired the recruitment of BCL9/BCL9L and PYGO2 to the DKK1 promoter in ALDH+ cells (Fig.	('ALDH', 'Gene', (114, 118))	('BCL9L', 'Gene', (74, 79))	('DKK1', 'Gene', (97, 101))	('knockdown', 'Var', (15, 24))	('BCL9', 'Gene', '607', (69, 73))	('BCL9', 'Gene', (69, 73))	('ALDH', 'molecular_function', 'GO:0004030', ('114', '118'))	('BCL9', 'Gene', '607', (74, 78))	('PYGO2', 'Gene', (84, 89))	('recruitment', 'MPA', (54, 65))	('BCL9L', 'Gene', '283149', (74, 79))	('KDM3A/B', 'Gene', (28, 35))	('PYGO2', 'Gene', '90780', (84, 89))	('impaired', 'NegReg', (41, 49))	('DKK1', 'Gene', '22943', (97, 101))	('BCL9', 'Gene', (74, 78))	('ALDH', 'Gene', '11670', (114, 118))
6059	28440295	In this study, we identified that KDM3 family histone demethylases play a critical role in beta-catenin/Tcf-mediated transcription by demethylating H3K9me2.	('demethylating', 'Var', (134, 147))	('beta-catenin', 'Gene', (91, 103))	('H3K9me2', 'Protein', (148, 155))	('beta-catenin', 'Gene', '1499', (91, 103))	('KDM3', 'Chemical', '-', (34, 38))
6060	28440295	Mechanistically, we showed that KDM3A/B not only demethylated H3K9me2 but also indirectly promoted H3K4 methylation by recruiting MLL1.	('MLL1', 'Gene', '4297', (130, 134))	('H3K9me2', 'Protein', (62, 69))	('H3K4', 'Protein', (99, 103))	('demethylated', 'MPA', (49, 61))	('methylation', 'MPA', (104, 115))	('KDM3A/B', 'Var', (32, 39))	('MLL1', 'Gene', (130, 134))	('promoted', 'PosReg', (90, 98))	('methylation', 'biological_process', 'GO:0032259', ('104', '115'))
6061	28440295	In consequence, methylated H3K4 promoted the recruitment of BCL9/PYGO to the chromatin, promoting Wnt target gene transcription.	('promoted', 'PosReg', (32, 40))	('Wnt target gene transcription', 'MPA', (98, 127))	('H3K4', 'Protein', (27, 31))	('BCL9', 'Gene', '607', (60, 64))	('promoting', 'PosReg', (88, 97))	('methylated', 'Var', (16, 26))	('BCL9', 'Gene', (60, 64))	('recruitment', 'MPA', (45, 56))
6062	28440295	Our results provide novel insights into how repressive and active epigenetic histone marks are epigenetically modified and subsequently how they regulate beta-catenin/Tcf-mediated transcription.	('beta-catenin', 'Gene', '1499', (154, 166))	('epigenetic', 'Var', (66, 76))	('regulate', 'Reg', (145, 153))	('beta-catenin', 'Gene', (154, 166))
6073	28440295	Importantly, we found that KDM3A/B also interacted with MLL1 and promoted MLL1 binding to the Wnt target gene promoter.	('KDM3A/B', 'Var', (27, 34))	('MLL1', 'Gene', (56, 60))	('MLL1', 'Gene', (74, 78))	('binding', 'Interaction', (79, 86))	('promoted', 'PosReg', (65, 73))	('MLL1', 'Gene', '4297', (56, 60))	('interacted', 'Interaction', (40, 50))	('MLL1', 'Gene', '4297', (74, 78))
6080	28440295	KDM3A/B have been found to be upregulated in human CRC tissues.	('KDM3A/B', 'Var', (0, 7))	('upregulated', 'PosReg', (30, 41))	('human', 'Species', '9606', (45, 50))
6081	28440295	It is possible that they might help non-stem tumour cells to epigenetically reacquire CSC-like properties by promoting Wnt/beta-catenin signalling in human CRCs.	('epigenetically', 'Var', (61, 75))	('human', 'Species', '9606', (150, 155))	('beta-catenin', 'Gene', '1499', (123, 135))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('beta-catenin', 'Gene', (123, 135))	('promoting', 'PosReg', (109, 118))	('tumour', 'Disease', (45, 51))
6090	28440295	The shRNA sequences for the knockdown of KDM3A and KDM3B simultaneously are 5'-GATCTGGGCCCCAAGATGTA-3' (KDM3AB-1) and 5'-AACAAATCTTCACTTAGATGT-3' (KDM3AB-2).	('KDM3A', 'Gene', '55818', (104, 109))	('KDM3A', 'Gene', (147, 152))	('KDM3A', 'Gene', (41, 46))	('KDM3B', 'Gene', '51780', (51, 56))	('KDM3A', 'Gene', (104, 109))	('KDM3A', 'Gene', '55818', (41, 46))	('knockdown', 'Var', (28, 37))	('KDM3A', 'Gene', '55818', (147, 152))	('KDM3B', 'Gene', (51, 56))
6091	28440295	The shRNA sequences for the knockdown of JMJD1C is 5'-GCGGAATCAATTAGTCTTGAT-3'.	('JMJD1C', 'Gene', (41, 47))	('JMJD1C', 'Gene', '221037', (41, 47))	('knockdown', 'Var', (28, 37))
6104	28440295	To knock down KDM3A and KDM3B by shRNA, AB-1, AB-2 shRNA or control shRNA were cloned into with pLKO.1-puro vector (Addgene).	('knock down', 'Var', (3, 13))	('KDM3A', 'Gene', (14, 19))	('AB-1', 'Gene', (40, 44))	('KDM3B', 'Gene', '51780', (24, 29))	('KDM3B', 'Gene', (24, 29))	('KDM3A', 'Gene', '55818', (14, 19))
6131	28440295	KDM3 epigenetically controls tumorigenic potentials of human colorectal cancer stem cells through Wnt/beta-catenin signalling.	('controls', 'Reg', (20, 28))	('KDM3', 'Chemical', '-', (0, 4))	('colorectal cancer', 'Disease', (61, 78))	('KDM3', 'Gene', (0, 4))	('epigenetically', 'Var', (5, 19))	('beta-catenin', 'Gene', '1499', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (55, 60))	('signalling', 'biological_process', 'GO:0023052', ('115', '125'))	('colorectal cancer', 'Disease', 'MESH:D015179', (61, 78))	('beta-catenin', 'Gene', (102, 114))	('colorectal cancer', 'Phenotype', 'HP:0003003', (61, 78))	('tumorigenic potentials of human', 'CPA', (29, 60))
6139	26114883	Among the tumor types, PD-L1 was associated with worse 3 year-OS of esophageal cancer, gastric cancer, hepatocellular carcinoma, and urothelial cancer, and 5 year-OS of esophageal cancer, gastric cancer and colorectal cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (188, 202))	('colorectal cancer', 'Disease', 'MESH:D015179', (207, 224))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (103, 127))	('OS of esophageal cancer', 'Disease', (62, 85))	('OS of esophageal cancer', 'Disease', 'MESH:C567932', (62, 85))	('colorectal cancer', 'Disease', (207, 224))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('PD-L1', 'Var', (23, 28))	('tumor', 'Disease', (10, 15))	('hepatocellular carcinoma', 'Disease', (103, 127))	('gastric cancer', 'Disease', (188, 202))	('OS of esophageal cancer', 'Disease', (163, 186))	('OS of esophageal cancer', 'Disease', 'MESH:C567932', (163, 186))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (207, 224))	('gastric cancer', 'Disease', 'MESH:D013274', (188, 202))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (103, 127))	('urothelial cancer', 'Disease', 'MESH:D014523', (133, 150))	('gastric cancer', 'Disease', (87, 101))	('urothelial cancer', 'Disease', (133, 150))
6140	26114883	These results suggest that expression of PD-L1 is associated with worse survival in solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('worse', 'NegReg', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('expression', 'Var', (27, 37))	('associated', 'Reg', (50, 60))	('PD-L1', 'Gene', (41, 46))	('solid tumors', 'Disease', (84, 96))
6145	26114883	The abnormal expression of these ligands has been linked with prognosis and treatment response of multiple malignancies.	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('multiple malignancies', 'Disease', 'MESH:D009369', (98, 119))	('linked', 'Reg', (50, 56))	('multiple malignancies', 'Disease', (98, 119))
6150	26114883	Another two studies showed that across multiple cancer types, responses were observed in patients with tumors expressing high levels of PD-L1, especially when PD-L1 expressed on tumor-infiltrating immune cells.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (178, 183))	('multiple cancer', 'Disease', (39, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('tumors', 'Disease', (103, 109))	('PD-L1', 'Var', (136, 141))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('multiple cancer', 'Disease', 'MESH:D009369', (39, 54))	('patients', 'Species', '9606', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
6177	26114883	A decade ago some studies reported that blockade of PD-L1 could improve antitumor immunity.	('blockade', 'Var', (40, 48))	('improve', 'PosReg', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('PD-L1', 'Gene', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
6183	26114883	Among the tumor types evaluated, esophageal cancer was the tumor type most linked with worse 3-year and 5-year outcome for patients with high levels of PD-L1.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Disease', (10, 15))	('patients', 'Species', '9606', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('esophageal cancer', 'Disease', (33, 50))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('PD-L1', 'Gene', (152, 157))	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('high levels', 'Var', (137, 148))
6187	26114883	A recent study reported that epithelial-originated cancer patients with positive expression of PD-L1 on tumor tissues were associated with significantly poorer OS when compared to those with negative expression of PD-L1.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('PD-L1', 'Gene', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('poorer', 'NegReg', (153, 159))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Disease', (51, 57))	('positive expression', 'Var', (72, 91))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
6198	25172549	Aberrant signaling in these pathways has been implicated in the development and progression of multiple cancers by allowing increased proliferation, angiogenesis, survival and metastasis.	('metastasis', 'CPA', (176, 186))	('Aberrant', 'Var', (0, 8))	('angiogenesis', 'CPA', (149, 161))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('implicated', 'Reg', (46, 56))	('increased', 'PosReg', (124, 133))	('multiple cancers', 'Disease', (95, 111))	('multiple cancers', 'Disease', 'MESH:D009369', (95, 111))	('angiogenesis', 'biological_process', 'GO:0001525', ('149', '161'))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('survival', 'CPA', (163, 171))	('signaling', 'biological_process', 'GO:0023052', ('9', '18'))
6206	25172549	The vital role of Wnt signaling in development was largely elucidated in Drosophila, where loss of Wg led to segment polarity defects in mutant embryos.	('signaling', 'biological_process', 'GO:0023052', ('22', '31'))	('loss', 'Var', (91, 95))	('mutant', 'Var', (137, 143))	('segment polarity defects', 'CPA', (109, 133))	('Drosophila', 'Species', '7227', (73, 83))
6222	25172549	Aberrant Wnt signaling was first implicated in cancer in mouse studies, where mouse mammary tumor virus (MMTV) was found to be virally inserted into the promoter region of Int-1, promoting mammary tumors.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('MMTV', 'Species', '11757', (105, 109))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('inserted', 'Var', (135, 143))	('ser', 'Chemical', 'MESH:D012694', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('promoting', 'PosReg', (179, 188))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mouse', 'Species', '10090', (78, 83))	('tumors', 'Disease', (197, 203))	('mouse', 'Species', '10090', (57, 62))	('mouse mammary tumor virus', 'Species', '11757', (78, 103))
6224	25172549	Abnormal beta-catenin activation has been well characterized in colon cancer, where mutations in APC, or less frequently in beta-catenin, results in constitutively active beta-catenin and consequently active downstream effectors.	('beta-catenin', 'Protein', (9, 21))	('colon cancer', 'Phenotype', 'HP:0003003', (64, 76))	('colon cancer', 'Disease', 'MESH:D015179', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('activation', 'PosReg', (22, 32))	('active', 'PosReg', (201, 207))	('mutations', 'Var', (84, 93))	('beta-catenin', 'Protein', (171, 183))	('constitutively', 'MPA', (149, 163))	('colon cancer', 'Disease', (64, 76))	('APC', 'Phenotype', 'HP:0005227', (97, 100))	('APC', 'Disease', 'MESH:D011125', (97, 100))	('APC', 'Disease', (97, 100))
6231	25172549	Inhibition of Wnt signaling by RNAi targeting LEF1 and HOXB9 reduced brain and bone metastasis using a mouse model of lung adenocarcinoma.	('LEF1', 'Var', (46, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('mouse', 'Species', '10090', (103, 108))	('lung adenocarcinoma', 'Disease', (118, 137))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (118, 137))	('RNAi', 'Gene', (31, 35))	('reduced', 'NegReg', (61, 68))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))
6237	25172549	Furthermore, WIF-1 has been shown to be epigenetically silenced in lung and bladder cancer.	('bladder cancer', 'Disease', (76, 90))	('WIF-1', 'Gene', (13, 18))	('WIF-1', 'Gene', '11197', (13, 18))	('epigenetically silenced', 'Var', (40, 63))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('lung', 'Disease', (67, 71))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))
6238	25172549	Epigenetic silencing of DKK-1 has been shown in colorectal cancer and SFRP in NSCLC, hepatocellular carcinoma and colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('NSCLC', 'Disease', (78, 83))	('colorectal cancer', 'Disease', (114, 131))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (85, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (48, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('colorectal cancer', 'Disease', (48, 65))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (85, 109))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('DKK-1', 'Gene', '22943', (24, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('DKK-1', 'Gene', (24, 29))	('Epigenetic silencing', 'Var', (0, 20))	('hepatocellular carcinoma', 'Disease', (85, 109))	('colorectal cancer', 'Phenotype', 'HP:0003003', (48, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('shown', 'Reg', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
6251	25172549	Thus, Wnt16B may not only confer therapy resistance, but also alter the tumor microenvironment and as the authors suggest, possibly promote immune evasion.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('immune evasion', 'biological_process', 'GO:0042783', ('140', '154'))	('Wnt16B', 'Var', (6, 12))	('therapy resistance', 'MPA', (33, 51))	('immune evasion', 'MPA', (140, 154))	('immune evasion', 'biological_process', 'GO:0051842', ('140', '154'))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('alter', 'Reg', (62, 67))	('promote', 'PosReg', (132, 139))
6253	25172549	Aberrant Wnt signaling in the stem cell compartment has been shown to contribute to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('contribute', 'Reg', (70, 80))	('Wnt signaling', 'Pathway', (9, 22))
6276	25172549	COX-2 inhibitors may target the Wnt pathway by inhibiting prostaglandin E2 (PGE2), the product of COX-2, which acts to phosphorylate GSK-3 (Figure 1 [Fujino et al., 2002]).	('inhibiting', 'NegReg', (47, 57))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (58, 74))	('COX-2', 'Gene', '4513', (98, 103))	('COX-2', 'Gene', '4513', (0, 5))	('COX-2', 'Gene', (98, 103))	('inhibitors', 'Var', (6, 16))	('PGE2', 'Chemical', 'MESH:D015232', (76, 80))	('GSK', 'molecular_function', 'GO:0050321', ('133', '136'))	('COX-2', 'Gene', (0, 5))	('PGE2', 'Gene', (76, 80))	('Wnt pathway', 'Pathway', (32, 43))
6285	25172549	Similarly, natural compounds that disrupt the beta-catenin/TCF interaction have been identified using high-throughput ELISAs, including PKF115-584, PKF222-815 and CPG049090.	('TCF', 'Gene', (59, 62))	('TCF', 'Gene', '3172', (59, 62))	('thr', 'Chemical', 'MESH:D013912', (107, 110))	('PKF115-584', 'Var', (136, 146))	('interaction', 'Interaction', (63, 74))	('CPG049090', 'Var', (163, 172))	('PKF222-815', 'Var', (148, 158))
6287	25172549	One group showed synergistic effects in growth inhibition when combining PKF115-584 or pyrivium, a Wnt small molecule inhibitor mentioned below, with a KRAS inhibitor in colorectal cancer cells that were Wnt driven and/or carrying an activating KRAS mutation, making an argument for Wnt inhibitors in combination therapy.	('pyrivium', 'Chemical', '-', (87, 95))	('PKF115-584', 'Var', (73, 83))	('mutation', 'Var', (250, 258))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('growth inhibition', 'MPA', (40, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (170, 187))	('activating', 'PosReg', (234, 244))	('KRAS', 'Gene', (152, 156))	('KRAS', 'Gene', (245, 249))	('colorectal cancer', 'Phenotype', 'HP:0003003', (170, 187))	('KRAS', 'Gene', '3845', (152, 156))	('KRAS', 'Gene', '3845', (245, 249))	('combining', 'Interaction', (63, 72))	('colorectal cancer', 'Disease', (170, 187))
6289	25172549	PNU74654 was discovered by high-throughput screening, and was shown to inhibit the interaction of beta-catenin and TCF (Figure 1).	('PNU74654', 'Var', (0, 8))	('inhibit', 'NegReg', (71, 78))	('interaction', 'Interaction', (83, 94))	('TCF', 'Gene', (115, 118))	('beta-catenin', 'Protein', (98, 110))	('thr', 'Chemical', 'MESH:D013912', (32, 35))	('TCF', 'Gene', '3172', (115, 118))
6293	25172549	ICG-001, at higher doses, was found to induce apoptosis in colon cancer cells with minimal effects on normal colon cells in vitro.	('colon cancer', 'Disease', (59, 71))	('apoptosis', 'CPA', (46, 55))	('ICG', 'Chemical', 'MESH:D007208', (0, 3))	('colon cancer', 'Phenotype', 'HP:0003003', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('ICG-001', 'Var', (0, 7))	('colon cancer', 'Disease', 'MESH:D015179', (59, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('46', '55'))	('apoptosis', 'biological_process', 'GO:0006915', ('46', '55'))	('ICG', 'cellular_component', 'GO:0035061', ('0', '3'))	('induce', 'PosReg', (39, 45))
6296	25172549	These salivary gland tumors were originally grown in mice that were double-mutants, wherein mice had a gain of function mutation in beta-catenin and a loss of function mutation in BMPR1A, a receptor in bone morphogenetic proteins (BMP) signaling which has been shown to inhibit CSCs proliferation in glioblastomas.	('salivary gland tumors', 'Disease', (6, 27))	('CSCs proliferation', 'CPA', (278, 296))	('signaling', 'biological_process', 'GO:0023052', ('236', '245'))	('inhibit', 'NegReg', (270, 277))	('salivary gland tumors', 'Disease', 'MESH:D012468', (6, 27))	('BMPR1A', 'Gene', '12166', (180, 186))	('mice', 'Species', '10090', (92, 96))	('mice', 'Species', '10090', (53, 57))	('glioblastomas', 'Disease', (300, 313))	('beta-catenin', 'Protein', (132, 144))	('BMPR1A', 'Gene', (180, 186))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('glioblastomas', 'Disease', 'MESH:D005909', (300, 313))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('loss of function', 'NegReg', (151, 167))	('mutation', 'Var', (120, 128))	('mutation', 'Var', (168, 176))	('salivary gland tumors', 'Phenotype', 'HP:0100684', (6, 27))	('gain of function', 'PosReg', (103, 119))	('glioblastomas', 'Phenotype', 'HP:0012174', (300, 313))
6301	25172549	JW55 inhibited in vivo tumor growth in APC mutant mice using colorectal carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('inhibited', 'NegReg', (5, 14))	('APC', 'Disease', 'MESH:D011125', (39, 42))	('APC', 'Disease', (39, 42))	('APC', 'cellular_component', 'GO:0005680', ('39', '42'))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('colorectal carcinoma', 'Disease', (61, 81))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutant', 'Var', (43, 49))	('APC', 'Phenotype', 'HP:0005227', (39, 42))	('JW55', 'Var', (0, 4))	('mice', 'Species', '10090', (50, 54))	('tumor', 'Disease', (23, 28))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (61, 81))
6305	25172549	Interestingly exome sequencing a panel of 40 HNSCC cell lines showed a strong correlation between LGK974 sensitivity and Notch1 mutations although the significance of this has yet to be elucidated.	('correlation', 'Interaction', (78, 89))	('mutations', 'Var', (128, 137))	('HNSCC', 'Phenotype', 'HP:0012288', (45, 50))	('Notch1', 'Gene', (121, 127))	('Notch1', 'Gene', '4851', (121, 127))	('LGK974', 'Gene', (98, 104))
6307	25172549	NSC668036, FJ9 and 3289-8625 were shown to inhibit Wnt signaling by directly binding the PDZ domain of Dvl.	('NSC668036', 'Var', (0, 9))	('Dvl', 'Gene', (103, 106))	('inhibit', 'NegReg', (43, 50))	('Dvl', 'Gene', '8215', (103, 106))	('Wnt signaling', 'Pathway', (51, 64))	('FJ9', 'Var', (11, 14))	('binding', 'Interaction', (77, 84))	('3289-8625', 'Var', (19, 28))
6308	25172549	3289-8625 was shown to inhibit PC3 prostate cancer cells growth, and FJ9 was shown to induce apoptosis in both melanoma and NSCLC cell lines.	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('3289-8625', 'Var', (0, 9))	('prostate cancer', 'Disease', 'MESH:D011471', (35, 50))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('NSCLC', 'Disease', (124, 129))	('inhibit', 'NegReg', (23, 30))	('prostate cancer', 'Phenotype', 'HP:0012125', (35, 50))	('induce', 'PosReg', (86, 92))	('PC3', 'CellLine', 'CVCL:0035', (31, 34))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('apoptosis', 'CPA', (93, 102))	('FJ9', 'Var', (69, 72))	('prostate cancer', 'Disease', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))
6311	25172549	Pyrivinium, classically used in the treatment for pinworm infection, inhibits Wnt signaling at multiple points in the pathway (Figure 1).	('Pyrivinium', 'Var', (0, 10))	('signaling', 'biological_process', 'GO:0023052', ('82', '91'))	('Wnt signaling at multiple points in the pathway', 'Pathway', (78, 125))	('infection', 'Disease', (58, 67))	('inhibits', 'NegReg', (69, 77))	('infection', 'Disease', 'MESH:D007239', (58, 67))	('Pyrivinium', 'Chemical', '-', (0, 10))
6313	25172549	Pyrivinium has recently been shown to target Wnt signaling in colon cancer cells, resulting in increased cell death, inhibition of cell migration and delaying liver metastasis growth in vivo.	('Pyrivinium', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cell death', 'CPA', (105, 115))	('signaling', 'biological_process', 'GO:0023052', ('49', '58'))	('colon cancer', 'Disease', (62, 74))	('delaying', 'NegReg', (150, 158))	('cell migration', 'CPA', (131, 145))	('Pyrivinium', 'Chemical', '-', (0, 10))	('colon cancer', 'Phenotype', 'HP:0003003', (62, 74))	('liver metastasis growth', 'CPA', (159, 182))	('inhibition', 'NegReg', (117, 127))	('cell death', 'biological_process', 'GO:0008219', ('105', '115'))	('increased', 'PosReg', (95, 104))	('colon cancer', 'Disease', 'MESH:D015179', (62, 74))	('inhibition of cell migration', 'biological_process', 'GO:0030336', ('117', '145'))
6348	25172549	The fusion of the CRD domain of Fzd8 with Fc (F8CRDhFc) exhibited an extended half-life in vivo in comparison to Fzd8(1-173)hFc and successfully inhibited growth in human teratoma tumor xenografts with very limited toxicity to regenerating tissues.	('Fzd8', 'Gene', (32, 36))	('Fzd8', 'Gene', '8325', (32, 36))	('Fzd8', 'Gene', '8325', (113, 117))	('human', 'Species', '9606', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('Fzd8', 'Gene', (113, 117))	('fusion', 'Var', (4, 10))	('half-life', 'MPA', (78, 87))	('toxicity', 'Disease', 'MESH:D064420', (215, 223))	('teratoma tumor', 'Disease', (171, 185))	('toxicity', 'Disease', (215, 223))	('teratoma', 'Phenotype', 'HP:0009792', (171, 179))	('teratoma tumor', 'Disease', 'MESH:D013724', (171, 185))	('inhibited', 'NegReg', (145, 154))
6371	25172549	Modulation of the WNT pathway has been shown to have effects in the bone including bone remodeling.	('Modulation', 'Var', (0, 10))	('WNT', 'Gene', (18, 21))	('effects', 'Reg', (53, 60))	('bone remodeling', 'CPA', (83, 98))	('WNT', 'Gene', '114487', (18, 21))	('bone', 'CPA', (68, 72))
6481	25038797	Levels of ANXA1 expression was increased in AGS and N87 cells induced ANXA1/pcDNA3.1 transfection (Figure 5A, B).	('ANXA1', 'Gene', (10, 15))	('ANXA1/pcDNA3.1', 'Gene', (70, 84))	('AGS', 'Gene', '182', (44, 47))	('transfection', 'Var', (85, 97))	('N87', 'CellLine', 'CVCL:1603', (52, 55))	('expression', 'Species', '29278', (16, 26))	('AGS', 'Gene', (44, 47))	('expression', 'MPA', (16, 26))
6484	25038797	However, silencing of ANXA1 by ANXA1-shRNA promoted cell viability in N87 cells (Figure 6A).	('promoted', 'PosReg', (43, 51))	('silencing', 'Var', (9, 18))	('cell viability', 'CPA', (52, 66))	('N87', 'CellLine', 'CVCL:1603', (70, 73))	('ANXA1', 'Gene', (22, 27))
6486	25038797	Western blotting analysis revealed that silencing of ANXA1 leaded to up-regulation of COX-2 (Figure 6B), while forced expression of ANXA1 decreased COX-2 production (Figure 6C).	('up-regulation', 'PosReg', (69, 82))	('decreased', 'NegReg', (138, 147))	('COX-2 production', 'MPA', (148, 164))	('COX-2', 'Enzyme', (86, 91))	('ANXA1', 'Gene', (53, 58))	('expression', 'Species', '29278', (118, 128))	('silencing', 'Var', (40, 49))
6518	25038797	In line with our previous study, loss of ANXA1 is a frequent event in gastric carcinogenesis.	('ANXA1', 'Gene', (41, 46))	('gastric carcinogenesis', 'Disease', (70, 92))	('loss', 'Var', (33, 37))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (70, 92))
6527	25038797	Notably, knockdown ANXA1 expression with ANXA1-specific shRNA leads to an increase of COX-2 expression, suggesting ANXA1 mediating many diverse cellular functions, such as inflammation and proliferation.	('inflammation', 'Disease', 'MESH:D007249', (172, 184))	('expression', 'Species', '29278', (25, 35))	('knockdown', 'Var', (9, 18))	('proliferation', 'CPA', (189, 202))	('inflammation', 'Disease', (172, 184))	('expression', 'MPA', (92, 102))	('increase', 'PosReg', (74, 82))	('ANXA1', 'Gene', (19, 24))	('expression', 'Species', '29278', (92, 102))	('COX-2', 'Protein', (86, 91))
6529	25038797	This notion is supported by a previous study showing that IL-1beta increased the expression of COX-2 and concomittantly decreased the expression of lipocortin 1 (ANXA1) on the surface of A549 cells.	('decreased', 'NegReg', (120, 129))	('expression', 'MPA', (134, 144))	('IL-1beta', 'Var', (58, 66))	('A549', 'CellLine', 'CVCL:0023', (187, 191))	('IL-1', 'molecular_function', 'GO:0005149', ('58', '62'))	('lipocortin 1', 'Gene', (148, 160))	('COX-2', 'Gene', (95, 100))	('increased', 'PosReg', (67, 76))	('expression', 'Species', '29278', (81, 91))	('expression', 'MPA', (81, 91))	('expression', 'Species', '29278', (134, 144))
6538	23594372	IRS2 is a candidate driver oncogene on 13q34 in colorectal cancer Copy number alterations are frequently found in colorectal cancer (CRC), and recurrent gains or losses are likely to correspond to regions harbouring genes that promote or impede carcinogenesis respectively.	('colorectal cancer', 'Phenotype', 'HP:0003003', (48, 65))	('IRS2', 'Gene', (0, 4))	('impede', 'NegReg', (238, 244))	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('losses', 'NegReg', (162, 168))	('gains', 'PosReg', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colorectal cancer', 'Disease', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('Copy number alterations', 'Var', (66, 89))	('promote', 'PosReg', (227, 234))	('IRS2', 'Gene', '8660', (0, 4))	('colorectal cancer', 'Disease', (114, 131))	('CRC', 'Phenotype', 'HP:0003003', (133, 136))	('colorectal cancer', 'Disease', 'MESH:D015179', (48, 65))
6539	23594372	Analysis of available colorectal neoplasia data sets confirmed IRS2 gene gain as a common event.	('gain', 'PosReg', (73, 77))	('IRS2', 'Gene', (63, 67))	('colorectal neoplasia', 'Disease', (22, 42))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (22, 42))	('neoplasia', 'Phenotype', 'HP:0002664', (33, 42))	('gene', 'Var', (68, 72))
6541	23594372	Genomic instability is a common feature of the cancer genome and facilitates tumour progression (Lengauer et al.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('tumour', 'Disease', (77, 83))	('cancer', 'Disease', (47, 53))	('facilitates', 'PosReg', (65, 76))	('Genomic instability', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
6543	23594372	Microsatellite instability is characterized by the expansion or contraction of microsatellite repeats and CIN by loss of heterozygosity and by aneuploidy.	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('CIN', 'Disease', (106, 109))	('aneuploidy', 'Disease', 'MESH:D000782', (143, 153))	('loss', 'NegReg', (113, 117))	('CIN', 'Disease', 'MESH:D007674', (106, 109))	('Microsatellite instability', 'Disease', (0, 26))	('contraction', 'NegReg', (64, 75))	('microsatellite repeats', 'Var', (79, 101))	('CIN', 'Phenotype', 'HP:0040012', (106, 109))	('aneuploidy', 'Disease', (143, 153))	('expansion', 'Var', (51, 60))
6547	23594372	The pattern of recurrent copy number changes within a given cancer type is therefore likely to reflect the balance between advantageous and disadvantageous alterations (Stratton et al.).	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('changes', 'Var', (37, 44))	('cancer', 'Disease', (60, 66))	('copy number changes', 'Var', (25, 44))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
6550	23594372	A minority of cancers, however, show small, focal copy number changes which fall within the larger, more commonly affected region of interest (Martin et al.	('cancers', 'Disease', (14, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('copy number changes', 'Var', (50, 69))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('fall', 'Phenotype', 'HP:0002527', (76, 80))	('cancers', 'Disease', 'MESH:D009369', (14, 21))
6556	23594372	The significance of copy number alteration across 161 colon cancer samples, including 33 CRC cell lines, was determined using the GISTIC algorithm with methods described previously (Beroukhim et al.	('colon cancer', 'Phenotype', 'HP:0003003', (54, 66))	('colon cancer', 'Disease', 'MESH:D015179', (54, 66))	('colon cancer', 'Disease', (54, 66))	('copy', 'Var', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('CRC', 'Phenotype', 'HP:0003003', (89, 92))
6565	23594372	These focal gains fell within a larger region that showed DNA copy number gains in 35% (44/124) of tumours in these two series combined; a higher prevalence of 13q34 gains has been described in the literature (Lips et al.	('13q34', 'Var', (160, 165))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('tumours', 'Disease', (99, 106))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
6582	23594372	Consistent with prior data in breast cancer, the assays demonstrated that IRS2 over-expression does not modify cell proliferation but does increase cell adhesion, whereas IGF-1 stimulation of mock-transfected cells increased both proliferation and adhesion (Figure 4c,d).	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('111', '129'))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('breast cancer', 'Disease', (30, 43))	('cell adhesion', 'CPA', (148, 161))	('increase', 'PosReg', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('IRS2', 'Gene', (74, 78))	('over-expression', 'Var', (79, 94))	('cell adhesion', 'biological_process', 'GO:0007155', ('148', '161'))
6585	23594372	showing that IRS2 inactivation suppressed tumour progression in Pten+/- mice.	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('Pten', 'Gene', (64, 68))	('inactivation', 'Var', (18, 30))	('Pten', 'Gene', '19211', (64, 68))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('tumour', 'Disease', (42, 48))	('mice', 'Species', '10090', (72, 76))	('suppressed', 'NegReg', (31, 41))	('IRS2', 'Gene', (13, 17))
6591	23594372	Therefore, in the light of data presented here and by others showing IGF-1-independent phosphorylation of AKT by IRS2 over-expression, mTOR inhibition has the potential to activate components of the oncogenic PI3 pathway (Dearth et al.).	('oncogenic PI3 pathway', 'Pathway', (199, 220))	('inhibition', 'Var', (140, 150))	('activate', 'PosReg', (172, 180))	('mTOR', 'Gene', '2475', (135, 139))	('mTOR', 'Gene', (135, 139))	('IRS2', 'Gene', (113, 117))	('phosphorylation', 'MPA', (87, 102))
6598	23594372	Changes to adhesion, both increases and decreases, are important properties of metastasizing cancer cells and are involved in invasion, migration, arrest within the circulation and distant 'seeding' of a tumour (Hewitt et al.	('cancer', 'Disease', (93, 99))	('tumour', 'Disease', (204, 210))	('arrest within the circulation', 'Disease', (147, 176))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('adhesion', 'MPA', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('arrest within the circulation', 'Disease', 'MESH:D001929', (147, 176))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('Changes', 'Var', (0, 7))	('involved', 'Reg', (114, 122))	('decreases', 'NegReg', (40, 49))	('tumour', 'Disease', 'MESH:D009369', (204, 210))
6601	23594372	The PI3K pathway is frequently dysregulated in CRC, and this can be a consequence of alterations at any level of the pathway - from receptor mutations to the deletion of negative regulators such as PTEN and mutations and subsequent over-expression of effectors such as AKT (Parsons et al.).	('CRC', 'Phenotype', 'HP:0003003', (47, 50))	('deletion', 'Var', (158, 166))	('mutations', 'Var', (141, 150))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('PTEN', 'Gene', (198, 202))	('CRC', 'Disease', (47, 50))	('mutations', 'Var', (207, 216))	('dysregulated', 'Reg', (31, 43))	('alterations', 'Reg', (85, 96))	('AKT', 'Pathway', (269, 272))	('PTEN', 'Gene', '5728', (198, 202))	('over-expression', 'PosReg', (232, 247))	('PI3K pathway', 'Pathway', (4, 16))
6639	23626930	This, in turn, results in proteasome-dependent processing of p100 to p52, triggering activation of RelB/p52 heterodimers that target distinct kappaB elements.	('RelB', 'Gene', '5971', (99, 103))	('results in', 'Reg', (15, 25))	('proteasome-dependent processing', 'MPA', (26, 57))	('p52', 'Gene', (69, 72))	('p52', 'Gene', '4791', (69, 72))	('proteasome', 'cellular_component', 'GO:0000502', ('26', '36'))	('p52', 'Gene', (104, 107))	('heterodimers', 'Protein', (108, 120))	('activation', 'PosReg', (85, 95))	('p52', 'Gene', '4791', (104, 107))	('proteasome', 'molecular_function', 'GO:0004299', ('26', '36'))	('RelB', 'Gene', (99, 103))	('p100', 'Var', (61, 65))
6650	23626930	It has also been shown that infection with Helicobacter pylori induces active inflammation with infiltration of lymphocytes and macrophages/monocytes into the lamina propria of the mucosa of the human gastric antrum.	('Helicobacter pylori', 'Species', '210', (43, 62))	('human', 'Species', '9606', (195, 200))	('inflammation', 'Disease', 'MESH:D007249', (78, 90))	('induces', 'Reg', (63, 70))	('infection', 'Var', (28, 37))	('inflammation', 'Disease', (78, 90))	('Helicobacter', 'Gene', (43, 55))
6653	23626930	Mutations in this protein are usually observed in both tumor cells and inflamed tissues.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('Mutations', 'Var', (0, 9))	('observed', 'Reg', (38, 46))
6660	23626930	Indeed, suppression of NF-kappaB by ablation of RelA or IKKb causes persistent JNK induction by TNFalpha, resulting in cell death.	('TNFalpha', 'Gene', (96, 104))	('ablation', 'Var', (36, 44))	('IKKb', 'Gene', (56, 60))	('IKKb', 'Gene', '3551', (56, 60))	('JNK', 'Gene', '5599', (79, 82))	('cell death', 'CPA', (119, 129))	('suppression', 'NegReg', (8, 19))	('TNFalpha', 'Gene', '7124', (96, 104))	('JNK', 'molecular_function', 'GO:0004705', ('79', '82'))	('NF-kappaB', 'Protein', (23, 32))	('RelA', 'Gene', (48, 52))	('cell death', 'biological_process', 'GO:0008219', ('119', '129'))	('RelA', 'Gene', '5970', (48, 52))	('JNK', 'Gene', (79, 82))
6666	23626930	Deregulation of NF-kappaB expression can cause chronic inflammation.	('Deregulation', 'Var', (0, 12))	('chronic inflammation', 'Disease', 'MESH:D007249', (47, 67))	('chronic inflammation', 'Disease', (47, 67))	('cause', 'Reg', (41, 46))	('NF-kappaB', 'Protein', (16, 25))
6671	23626930	Blockage of such signaling has been shown to suppress experimental colitis.	('colitis', 'Phenotype', 'HP:0002583', (67, 74))	('suppress', 'NegReg', (45, 53))	('Blockage', 'Var', (0, 8))	('colitis', 'Disease', 'MESH:D003092', (67, 74))	('colitis', 'Disease', (67, 74))	('signaling', 'biological_process', 'GO:0023052', ('17', '26'))
6672	23626930	On the other hand, translocation of activated NF-kappaB into the nucleus induces the expression of cytokines such as TNF-alpha and IL-6, and chemokines, all of which contribute to development of inflammation-related tissue damage.	('expression', 'MPA', (85, 95))	('contribute', 'Reg', (166, 176))	('IL-6', 'Gene', (131, 135))	('induces', 'PosReg', (73, 80))	('TNF-alpha', 'Gene', '7124', (117, 126))	('IL-6', 'Gene', '3569', (131, 135))	('NF-kappaB', 'Protein', (46, 55))	('TNF-alpha', 'Gene', (117, 126))	('cytokines', 'MPA', (99, 108))	('inflammation', 'Disease', 'MESH:D007249', (195, 207))	('translocation', 'Var', (19, 32))	('inflammation', 'Disease', (195, 207))
6675	23626930	Inactivation of the IkappaB kinase/NF-kappaB pathway at the site of inflammation, using mice that lack IKK only in intestinal epithelial cells, has been shown to attenuate formation of inflammation-associated tumors in the model AOM-DSS induced CAC.	('inflammation', 'biological_process', 'GO:0006954', ('68', '80'))	('CAC', 'Phenotype', 'HP:0002664', (245, 248))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('inflammation', 'Disease', 'MESH:D007249', (68, 80))	('AOM', 'Chemical', 'MESH:D001397', (229, 232))	('attenuate', 'NegReg', (162, 171))	('inflammation', 'Disease', 'MESH:D007249', (185, 197))	('inflammation', 'Disease', (68, 80))	('Inactivation', 'Var', (0, 12))	('formation', 'biological_process', 'GO:0009058', ('172', '181'))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('DSS', 'Chemical', '-', (233, 236))	('inflammation', 'biological_process', 'GO:0006954', ('185', '197'))	('mice', 'Species', '10090', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('inflammation', 'Disease', (185, 197))	('IkappaB', 'Chemical', '-', (20, 27))	('tumors', 'Disease', (209, 215))	('IKK', 'molecular_function', 'GO:0008384', ('103', '106'))	('formation', 'MPA', (172, 181))	('IkappaB kinase/NF-kappaB pathway', 'Pathway', (20, 52))
6708	23626930	A considerable body of evidence from experiments with cells and whole animals indicates that NF-kappaB inhibitors may be potent if used as drugs to treat colon cancer.	('NF-kappaB', 'Protein', (93, 102))	('colon cancer', 'Phenotype', 'HP:0003003', (154, 166))	('inhibitors', 'Var', (103, 113))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('colon cancer', 'Disease', 'MESH:D015179', (154, 166))	('colon cancer', 'Disease', (154, 166))
6724	23420493	In the subgroup analysis, left-sided tumors with high PLA2GX expression showed an inverse correlation with lymph node metastasis (P=0.018) and hematogenous metastasis (P=0.017).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('lymph node metastasis', 'CPA', (107, 128))	('inverse', 'NegReg', (82, 89))	('PLA2', 'Gene', (54, 58))	('PLA2', 'Gene', '5319', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('high', 'Var', (49, 53))	('tumors', 'Disease', (37, 43))	('hematogenous metastasis', 'CPA', (143, 166))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
6801	23420493	In fact, Ganesan et al have demonstrated that the silencing of the PLA2GIIA gene enhances the invasive activity of tumor cells, whereas enforced expression inhibited invasion.	('invasion', 'CPA', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('silencing', 'Var', (50, 59))	('PLA2', 'Gene', (67, 71))	('enhances', 'PosReg', (81, 89))	('PLA2', 'Gene', '5319', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('inhibited', 'NegReg', (156, 165))
6813	23420493	It is known that right- and left-sided colonic tumors have different molecular profiles, with microsatellite instability and methylator phenotypes being prevalent in right-sided tumors and chromosomal instability being predominant in left-sided tumors, resulting in different biological features.	('prevalent', 'Reg', (153, 162))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('tumors', 'Disease', (47, 53))	('chromosomal', 'Var', (189, 200))	('tumors', 'Disease', (245, 251))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('microsatellite instability', 'MPA', (94, 120))	('chromosomal instability', 'Phenotype', 'HP:0040012', (189, 212))	('colonic tumors', 'Disease', 'MESH:D015179', (39, 53))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumors', 'Disease', (178, 184))	('methylator', 'MPA', (125, 135))	('colonic tumors', 'Disease', (39, 53))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
6827	33379141	At the plasma membrane level, HPF prevents cytosol alkalization and extracellular acidification by allowing protons to re-enter the cells.	('HPF', 'Chemical', 'MESH:C001654', (30, 33))	('cytosol alkalization', 'MPA', (43, 63))	('HPF', 'Var', (30, 33))	('protons', 'MPA', (108, 115))	('prevents', 'NegReg', (34, 42))	('extracellular acidification', 'MPA', (68, 95))	('allowing', 'Reg', (99, 107))
6836	33379141	Oncogenesis involves dysregulation of proto-oncogenes or tumor suppressor genes, which upon mutation can modify key cellular processes linked to cell proliferation and its control.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('57', '73'))	('mutation', 'Var', (92, 100))	('cell proliferation', 'biological_process', 'GO:0008283', ('145', '163'))	('modify', 'Reg', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('Oncogenesis', 'biological_process', 'GO:0007048', ('0', '11'))	('proto-oncogenes', 'Gene', (38, 53))	('dysregulation', 'Var', (21, 34))	('rat', 'Species', '10116', (157, 160))	('cell proliferation', 'CPA', (145, 163))	('tumor', 'Disease', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Oncogenesis', 'Disease', (0, 11))	('tumor suppressor', 'biological_process', 'GO:0051726', ('57', '73'))
6867	33379141	However, if ROS amount exceeds a certain threshold, serious damages occur in cells, like DNA deletions, insertions, single- and double-strand breaks that, if not repaired, might lead to either tumor transformation or cell death.	('DNA', 'Gene', (89, 92))	('lead to', 'Reg', (178, 185))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('cell death', 'CPA', (217, 227))	('insertions', 'Var', (104, 114))	('deletions', 'Var', (93, 102))	('ROS', 'Chemical', 'MESH:D017382', (12, 15))	('tumor', 'Disease', (193, 198))
6869	33379141	When the Deltapsim is high, like in cancer cells, the electron transfer is slowed down, as protons have to be pumped against an enhanced electrochemical force, so that an electron leakage and, consequently, high ROS production are favored (Figure 1).	('slowed down', 'NegReg', (75, 86))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('ROS', 'Chemical', 'MESH:D017382', (212, 215))	('Deltapsim', 'Var', (9, 18))	('ROS production', 'MPA', (212, 226))	('electron leakage', 'MPA', (171, 187))	('cancer', 'Disease', (36, 42))	('electron transfer', 'MPA', (54, 71))	('favored', 'PosReg', (231, 238))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('protons', 'MPA', (91, 98))
6871	33379141	In this regard, tumor cells have a more negative mitochondrial membrane potential inside the matrix (Deltapsim ~ -210 mV), than normal cells (Deltapsim ~ -140 mV) (Figure 1).	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('mitochondrial membrane potential', 'MPA', (49, 81))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('Deltapsim ~ -210 mV', 'Var', (101, 120))	('tumor', 'Disease', (16, 21))	('negative', 'NegReg', (40, 48))
6876	33379141	Thus, H2O2 can operate as a bona fide second messenger for the intracellular transduction signaling of hormones, growth factors, cytokines and other inflammatory mediators, by oxidizing the thiol groups of cysteine residues of target proteins, including tyrosine phosphatases (PTPs).	('rat', 'Species', '10116', (18, 21))	('thiol', 'Chemical', 'MESH:D013438', (190, 195))	('H2O2', 'Var', (6, 10))	('P', 'Chemical', 'MESH:D010758', (277, 278))	('tyrosine', 'Chemical', 'MESH:D014443', (254, 262))	('transduction', 'biological_process', 'GO:0009293', ('77', '89'))	('thiol groups', 'MPA', (190, 202))	('P', 'Chemical', 'MESH:D010758', (279, 280))	('signaling', 'biological_process', 'GO:0023052', ('90', '99'))	('oxidizing', 'MPA', (176, 185))	('H2O2', 'Chemical', 'MESH:D006861', (6, 10))	('cysteine', 'Chemical', 'MESH:D003545', (206, 214))	('intracellular', 'cellular_component', 'GO:0005622', ('63', '76'))
6882	33379141	At the same time, cancer cells can utilize ROS signaling to enhance growth by promoting the activity of pro-survival kinases (i.e., PI3K, Akt, ERK1/2, mTOR).	('ERK1/2', 'Gene', (143, 149))	('ERK1/2', 'Gene', '5595;5594', (143, 149))	('Akt', 'Gene', (138, 141))	('P', 'Chemical', 'MESH:D010758', (132, 133))	('PI3K', 'Var', (132, 136))	('ROS', 'Chemical', 'MESH:D017382', (43, 46))	('growth', 'MPA', (68, 74))	('mTOR', 'Gene', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('promoting', 'PosReg', (78, 87))	('ROS signaling', 'MPA', (43, 56))	('Akt', 'Gene', '207', (138, 141))	('enhance', 'PosReg', (60, 67))	('activity', 'MPA', (92, 100))	('mTOR', 'Gene', '2475', (151, 155))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
6892	33379141	Indeed, although it has been well documented that polyphenols and other natural compounds are able to inhibit tumorigenesis and tumor growth in several animal models, a putative ROS-dependent pro-oxidant mechanism in such in vivo inhibition has not been elucidated yet.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('polyphenols', 'Var', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('ROS', 'Chemical', 'MESH:D017382', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('inhibit', 'NegReg', (102, 109))	('tumor', 'Disease', (128, 133))	('polyphenols', 'Chemical', 'MESH:D059808', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
6900	33379141	Importantly, both pharmacological and phytochemical inhibitors of these channels were found to revert or at least attenuate the malignant phenotype of cancer cells, suggesting that a crucial role is played by pH and ion concentration changes in tumor development, as reviewed in.	('rat', 'Species', '10116', (227, 230))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cancer', 'Disease', (151, 157))	('attenuate', 'NegReg', (114, 123))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Disease', (245, 250))	('inhibitors', 'Var', (52, 62))
6902	33379141	In this way, pH dysregulation can simultaneously modify charge and function of many protein targets, facilitating gain- or loss-of-function of mutated proteins as it occurs in the R337H substitution of the tumor suppressor p53 in cancer.	('loss-of-function', 'NegReg', (123, 139))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('R337H', 'Mutation', 'p.R337H', (180, 185))	('p53', 'Gene', (223, 226))	('p53', 'Gene', '7157', (223, 226))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('R337H', 'Var', (180, 185))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('charge', 'MPA', (56, 62))	('gain-', 'PosReg', (114, 119))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('tumor suppressor', 'biological_process', 'GO:0051726', ('206', '222'))	('modify', 'Reg', (49, 55))	('function', 'MPA', (67, 75))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('206', '222'))
6931	33379141	Moreover, it should be stressed that HPF is able to induce long-lasting changes in the cell signaling and transcriptional pathways even after being withdrawn from the cell culture medium following a pre-incubation period.	('transcriptional pathways', 'Pathway', (106, 130))	('HPF', 'Chemical', 'MESH:C001654', (37, 40))	('HPF', 'Var', (37, 40))	('cell signaling', 'Pathway', (87, 101))	('changes', 'Reg', (72, 79))
6937	33379141	In our laboratory, we observed that, in pancreatic beta cells as well as in rat and human pancreatic islets, SJW and HPF are able to markedly inhibit both IFN-gamma-elicited STAT-1 and TNF-alpha/IL-1beta-triggered NF-kappaB activities, leading to prevention of iNOS gene expression and protection against beta-cell damage.	('gene expression', 'biological_process', 'GO:0010467', ('266', '281'))	('SJW', 'Chemical', '-', (109, 112))	('iNOS gene', 'Gene', (261, 270))	('inhibit', 'NegReg', (142, 149))	('rat', 'Species', '10116', (76, 79))	('IFN-gamma', 'Gene', (155, 164))	('IFN-gamma', 'Gene', '3458', (155, 164))	('STAT-1', 'Gene', '6772', (174, 180))	('activities', 'MPA', (224, 234))	('human', 'Species', '9606', (84, 89))	('HPF', 'Chemical', 'MESH:C001654', (117, 120))	('rat', 'Species', '10116', (11, 14))	('SJW', 'Var', (109, 112))	('STAT-1', 'Gene', (174, 180))	('prevention', 'NegReg', (247, 257))	('IL-1', 'molecular_function', 'GO:0005149', ('195', '199'))
6941	33379141	Additionally, 1 microM HPF triggers differentiation in primary cultures of human keratinocytes and in derived HaCaT cell lines and inhibits their proliferation.	('rat', 'Species', '10116', (83, 86))	('HPF', 'Chemical', 'MESH:C001654', (23, 26))	('proliferation', 'CPA', (146, 159))	('rat', 'Species', '10116', (153, 156))	('HPF', 'Var', (23, 26))	('triggers', 'Reg', (27, 35))	('inhibits', 'NegReg', (131, 139))	('differentiation', 'CPA', (36, 51))	('human', 'Species', '9606', (75, 80))	('HaCaT', 'CellLine', 'CVCL:0038', (110, 115))
6962	33379141	Indeed, the ability of HPF to increase proton conductance of plasmatic and organelle membranes was firstly disclosed by Roz and Rehavi to explain its inhibitory action on neurotransmitter reuptake by a non-competitive mechanism.	('HPF', 'Chemical', 'MESH:C001654', (23, 26))	('HPF', 'Var', (23, 26))	('neurotransmitter reuptake', 'biological_process', 'GO:0098810', ('171', '196'))	('organelle', 'cellular_component', 'GO:0043226', ('75', '84'))	('increase', 'PosReg', (30, 38))	('neurotransmitter reuptake', 'MPA', (171, 196))
6967	33379141	observed that HPF, likewise the protonophore and uncoupler FCCP, cause a concentration-dependent drop in the mitochondrial membrane potential.	('rat', 'Species', '10116', (80, 83))	('drop', 'NegReg', (97, 101))	('mitochondrial membrane potential', 'MPA', (109, 141))	('FCCP', 'Chemical', 'MESH:D002259', (59, 63))	('HPF', 'Chemical', 'MESH:C001654', (14, 17))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('109', '131'))	('HPF', 'Var', (14, 17))
6968	33379141	Thus, HPF is also able to affect mitochondrial function, as well as mitochondrial (mt)ROS production.	('ROS', 'Chemical', 'MESH:D017382', (86, 89))	('affect', 'Reg', (26, 32))	('HPF', 'Chemical', 'MESH:C001654', (6, 9))	('HPF', 'Var', (6, 9))	('mitochondrial function', 'MPA', (33, 55))
6970	33379141	As already mentioned, HPF suppresses 5-LO and COX-1 activity and PGE2 production both in human whole blood at low concentrations range (0.03-2 microM) and in a number of in vivo models.	('human', 'Species', '9606', (89, 94))	('5-LO and', 'MPA', (37, 45))	('HPF', 'Var', (22, 25))	('suppresses', 'NegReg', (26, 36))	('PGE2', 'Chemical', 'MESH:D015232', (65, 69))	('COX-1', 'Gene', (46, 51))	('COX-1', 'Gene', '4512', (46, 51))	('PGE2 production', 'MPA', (65, 80))	('HPF', 'Chemical', 'MESH:C001654', (22, 25))	('rat', 'Species', '10116', (121, 124))
6975	33379141	Actually, the anti-genotoxic ability of HPF has been verified by measuring the amount of bacterial gene mutations (Ames' test), the occurrence of DNA strand breaks in human lymphocytes (comet assay) and the induction of chromosome aberrations in a mammalian cell line.	('chromosome aberrations', 'CPA', (220, 242))	('mutations', 'Var', (104, 113))	('bacterial gene', 'Gene', (89, 103))	('rat', 'Species', '10116', (235, 238))	('human', 'Species', '9606', (167, 172))	('HPF', 'Chemical', 'MESH:C001654', (40, 43))	('mammalian', 'Species', '9606', (248, 257))
6981	33379141	In fact, intracellular alkalization was detected in rat hepatic epithelial F258 cells quickly upon exposure to B[a]P, resulting in alteration of pH dynamics in different cell compartments including mitochondria and affecting mitochondrial function.	('rat', 'Species', '10116', (52, 55))	('alteration', 'Reg', (131, 141))	('affecting', 'Reg', (215, 224))	('mitochondria', 'MPA', (198, 210))	('rat', 'Species', '10116', (135, 138))	('B[a]P', 'Var', (111, 116))	('B[a]P', 'Chemical', 'MESH:D001564', (111, 116))	('pH dynamics in different cell compartments', 'MPA', (145, 187))	('F258', 'CellLine', 'CVCL:L976', (75, 79))	('mitochondrial function', 'MPA', (225, 247))
6987	33379141	In this model, at molecular level, it has been observed that NF-kappaB and ERK1/2 pathways are hampered by SJW, with a reduction in the mRNA expression level of NF-kappaB-elicited genes, such as TNF-alpha, IL-1beta, MMP-7 and -9 and iNOS.	('mRNA expression level', 'MPA', (136, 157))	('TNF-alpha', 'Gene', (195, 204))	('SJW', 'Var', (107, 110))	('ERK1/2', 'Gene', (75, 81))	('ERK1/2', 'Gene', '5595;5594', (75, 81))	('hampered', 'NegReg', (95, 103))	('SJW', 'Chemical', '-', (107, 110))	('reduction', 'NegReg', (119, 128))	('NF-kappaB', 'Pathway', (61, 70))	('MMP-7 and -9', 'Gene', '4316;4318', (216, 228))
6990	33379141	Mechanistically, DPI decreases ROS production in the colon, resulting in inhibition of TNF-alpha, IL-6 and monocyte chemoattractant protein-1 (MCP-1) production, as well as ERK1/2, STAT-3 and NF-kappaB signaling, finally exerting a strong anti-inflammatory effect.	('inhibition', 'NegReg', (73, 83))	('monocyte chemoattractant protein-1', 'Gene', '6347', (107, 141))	('ROS production', 'MPA', (31, 45))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('decreases', 'NegReg', (21, 30))	('decreases ROS production', 'Phenotype', 'HP:0025464', (21, 45))	('ROS', 'Chemical', 'MESH:D017382', (31, 34))	('MCP-1) production', 'biological_process', 'GO:0071605', ('143', '160'))	('IL-6', 'Gene', '3569', (98, 102))	('signaling', 'biological_process', 'GO:0023052', ('202', '211'))	('MCP', 'molecular_function', 'GO:0004298', ('143', '146'))	('DPI', 'Chemical', 'MESH:C007517', (17, 20))	('ERK1/2', 'Gene', (173, 179))	('IL-6', 'Gene', (98, 102))	('TNF-alpha', 'MPA', (87, 96))	('ERK1/2', 'Gene', '5595;5594', (173, 179))	('ERK1', 'molecular_function', 'GO:0004707', ('173', '177'))	('NF-kappaB', 'MPA', (192, 201))	('monocyte chemoattractant protein-1', 'Gene', (107, 141))	('IL-6', 'molecular_function', 'GO:0005138', ('98', '102'))	('DPI', 'Var', (17, 20))
6992	33379141	It is meaningful to remark that the presence of HPF in SJW extract can affect the pharmacokinetics of many co-administered drugs by inducing a number of liver cytochrome P450 (CYP) isozymes, such as CYP3A4, CYP2C19, CYP2D2.	('CYP3A4', 'Gene', '1576', (199, 205))	('CYP', 'Gene', '4051', (216, 219))	('CYP2C19', 'Gene', (207, 214))	('CYP', 'Gene', '4051', (176, 179))	('CYP3A4', 'Gene', (199, 205))	('CYP', 'Gene', '4051', (207, 210))	('CYP2C19', 'Gene', '1557', (207, 214))	('HPF', 'Chemical', 'MESH:C001654', (48, 51))	('CYP', 'Gene', '4051', (199, 202))	('pharmacokinetics', 'MPA', (82, 98))	('cytochrome P450', 'Gene', (159, 174))	('presence', 'Var', (36, 44))	('CYP', 'Gene', (216, 219))	('inducing', 'Reg', (132, 140))	('CYP', 'Gene', (176, 179))	('CYP', 'Gene', (207, 210))	('affect', 'Reg', (71, 77))	('SJW extract', 'Chemical', '-', (55, 66))	('cytochrome P450', 'Gene', '4051', (159, 174))	('CYP', 'Gene', (199, 202))
6995	33379141	Nevertheless, at variance of most in vitro studies showing carcinogen activation by CYPs, in vivo experiments performed after gene deletion of P450 isozymes have often revealed that these metabolizing enzymes have a major role in detoxification rather than activation of carcinogens.	('gene deletion', 'Var', (126, 139))	('CYP', 'Gene', (84, 87))	('rat', 'Species', '10116', (245, 248))	('P450 isozymes', 'Enzyme', (143, 156))	('CYP', 'Gene', '4051', (84, 87))	('P', 'Chemical', 'MESH:D010758', (143, 144))	('P', 'Chemical', 'MESH:D010758', (86, 87))	('detoxification', 'MPA', (230, 244))	('detoxification', 'biological_process', 'GO:0098754', ('230', '244'))
7006	33379141	When tumor has already grown, SJW and HPF can still exert therapeutic effects by down-modulating survival signaling and/or inducing apoptosis.	('apoptosis', 'CPA', (132, 141))	('SJW', 'Chemical', '-', (30, 33))	('apoptosis', 'biological_process', 'GO:0097194', ('132', '141'))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('down-modulating', 'NegReg', (81, 96))	('survival signaling', 'Pathway', (97, 115))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('apoptosis', 'biological_process', 'GO:0006915', ('132', '141'))	('HPF', 'Chemical', 'MESH:C001654', (38, 41))	('tumor', 'Disease', (5, 10))	('SJW', 'Var', (30, 33))	('inducing', 'Reg', (123, 131))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))
7007	33379141	Remarkably, in rats injected subcutaneously with MT-450 breast cancer cells and administered HPF daily at the site of the cell transfer, in vivo tumor growth was inhibited in the absence of any side effect.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('MT-450', 'Chemical', '-', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('breast cancer', 'Disease', (56, 69))	('tumor', 'Disease', (145, 150))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('MT-450', 'Var', (49, 55))	('HPF', 'Chemical', 'MESH:C001654', (93, 96))	('inhibited', 'NegReg', (162, 171))	('rats', 'Species', '10116', (15, 19))
7011	33379141	reported that in two glioblastoma cell lines, HPF prompts apoptosis, increase of cytosolic [Ca2+], loss of Deltapsim, suppression of EGFR/ERK/NF-kappaB signaling, and decrease of anti-apoptotic proteins expression.	('ERK', 'Gene', '5594', (138, 141))	('Deltapsim', 'MPA', (107, 116))	('ERK', 'Gene', (138, 141))	('increase', 'PosReg', (69, 77))	('glioblastoma', 'Disease', (21, 33))	('HPF', 'Var', (46, 49))	('suppression', 'NegReg', (118, 129))	('decrease', 'NegReg', (167, 175))	('glioblastoma', 'Disease', 'MESH:D005909', (21, 33))	('EGFR', 'Gene', '1956', (133, 137))	('loss', 'NegReg', (99, 103))	('apoptosis', 'CPA', (58, 67))	('glioblastoma', 'Phenotype', 'HP:0012174', (21, 33))	('cytosolic [Ca2+]', 'MPA', (81, 97))	('anti-apoptotic', 'MPA', (179, 193))	('EGFR', 'Gene', (133, 137))	('Ca2+', 'Chemical', 'MESH:D000069285', (92, 96))	('HPF', 'Chemical', 'MESH:C001654', (46, 49))
7012	33379141	also showed that HPF can directly impair viability of mitochondria isolated from HL-60 cells by affecting mitochondrial proton-motive force.	('impair', 'NegReg', (34, 40))	('HPF', 'Chemical', 'MESH:C001654', (17, 20))	('HL-60', 'CellLine', 'CVCL:0002', (81, 86))	('viability', 'CPA', (41, 50))	('affecting', 'Reg', (96, 105))	('HPF', 'Var', (17, 20))	('mitochondrial proton-motive force', 'MPA', (106, 139))
7013	33379141	Again, in hepatocellular carcinoma cell line, HPF significantly inhibits cell viability and cyclin D1 expression and induces loss of Deltapsim and downregulation of the anti-apoptotic proteins fetal liver LKB1 interacting protein c (c-FLIP), X linked inhibitor of apoptosis protein (XIAP) and myeloid leukemia cell differentiation protein (Mcl-1), finally triggering apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('367', '376'))	('apoptosis', 'biological_process', 'GO:0006915', ('367', '376'))	('loss', 'NegReg', (125, 129))	('hepatocellular carcinoma', 'Disease', (10, 34))	('XIAP', 'Gene', (283, 287))	('c-FLIP', 'Gene', '8837', (233, 239))	('myeloid leukemia', 'Disease', 'MESH:D007951', (293, 309))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (293, 309))	('leukemia', 'Phenotype', 'HP:0001909', (301, 309))	('apoptosis', 'biological_process', 'GO:0097194', ('264', '273'))	('Mcl-1', 'Gene', (340, 345))	('cell viability', 'CPA', (73, 87))	('apoptosis', 'biological_process', 'GO:0006915', ('264', '273'))	('protein', 'cellular_component', 'GO:0003675', ('331', '338'))	('protein', 'cellular_component', 'GO:0003675', ('222', '229'))	('HPF', 'Chemical', 'MESH:C001654', (46, 49))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (10, 34))	('Deltapsim', 'Protein', (133, 142))	('HPF', 'Var', (46, 49))	('cyclin', 'molecular_function', 'GO:0016538', ('92', '98'))	('downregulation', 'NegReg', (147, 161))	('cyclin D1', 'Gene', (92, 101))	('XIAP', 'Gene', '331', (283, 287))	('c-FLIP', 'Gene', (233, 239))	('protein', 'cellular_component', 'GO:0003675', ('274', '281'))	('cyclin D1', 'Gene', '595', (92, 101))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (10, 34))	('expression', 'MPA', (102, 112))	('myeloid leukemia', 'Disease', (293, 309))	('inhibits', 'NegReg', (64, 72))	('cell differentiation', 'biological_process', 'GO:0030154', ('310', '330'))	('Mcl-1', 'Gene', '4170', (340, 345))	('X linked inhibitor of apoptosis protein', 'Gene', '331', (242, 281))	('X linked inhibitor of apoptosis protein', 'Gene', (242, 281))
7016	33379141	In fact, HPF-induced severe dissipation of Deltapsim provokes pore formation and Cyt c release, sensitizing cancer cells to death.	('Deltapsim', 'Protein', (43, 52))	('pore formation', 'MPA', (62, 76))	('pore formation', 'biological_process', 'GO:0046931', ('62', '76'))	('cancer', 'Disease', (108, 114))	('Cyt c release', 'MPA', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('pore', 'cellular_component', 'GO:0046930', ('62', '66'))	('sensitizing', 'Reg', (96, 107))	('HPF', 'Chemical', 'MESH:C001654', (9, 12))	('provokes', 'Reg', (53, 61))	('severe dissipation', 'Var', (21, 39))
7018	33379141	As reported above, mitochondrial membranes incorporate lipophilic HPF, so that, while in normal condition the inner membrane is impervious to protons, in the presence of HPF, protons can shuttle into the matrix following their concentration and electric gradients (as described in Figure 2), with consequent breakdown of Deltapsim.	('breakdown', 'biological_process', 'GO:0009056', ('308', '317'))	('shuttle into the', 'MPA', (187, 203))	('HPF', 'Var', (170, 173))	('protons', 'MPA', (175, 182))	('rat', 'Species', '10116', (50, 53))	('HPF', 'Chemical', 'MESH:C001654', (66, 69))	('Deltapsim', 'MPA', (321, 330))	('rat', 'Species', '10116', (234, 237))	('membrane', 'cellular_component', 'GO:0016020', ('116', '124'))	('breakdown', 'NegReg', (308, 317))	('HPF', 'Chemical', 'MESH:C001654', (170, 173))
7030	33379141	show that HPF inhibits Akt kinase activity, determining dephosphorylation of Bad, an Akt substrate, and activation of its pro-apoptotic function.	('rat', 'Species', '10116', (94, 97))	('activation', 'PosReg', (104, 114))	('inhibits', 'NegReg', (14, 22))	('pro-apoptotic function', 'MPA', (122, 144))	('Akt', 'Gene', '207', (85, 88))	('Akt', 'Gene', '207', (23, 26))	('kinase activity', 'molecular_function', 'GO:0016301', ('27', '42'))	('HPF', 'Chemical', 'MESH:C001654', (10, 13))	('dephosphorylation', 'MPA', (56, 73))	('Akt', 'Gene', (23, 26))	('Akt', 'Gene', (85, 88))	('HPF', 'Var', (10, 13))	('dephosphorylation', 'biological_process', 'GO:0016311', ('56', '73'))
7035	33379141	HPF induces apoptosis in the B-CLL cells by eliciting a drop in mitochondrial transmembrane potential and activation of caspase 3.	('mitochondrial transmembrane potential', 'MPA', (64, 101))	('drop', 'NegReg', (56, 60))	('HPF', 'Chemical', 'MESH:C001654', (0, 3))	('caspase 3', 'Gene', (120, 129))	('activation', 'PosReg', (106, 116))	('HPF', 'Var', (0, 3))	('caspase 3', 'Gene', '836', (120, 129))
7036	33379141	In this study, the anti-apoptotic factors Bcl-2 and Mcl-1 as well as the protein expressions of iNOS and p27kip1b are downregulated.	('Bcl-2', 'Gene', (42, 47))	('Bcl-2', 'Gene', '596', (42, 47))	('Mcl-1', 'Gene', '4170', (52, 57))	('iNOS', 'Gene', (96, 100))	('anti-apoptotic factors', 'CPA', (19, 41))	('Mcl-1', 'Gene', (52, 57))	('protein expressions', 'MPA', (73, 92))	('downregulated', 'NegReg', (118, 131))	('p27kip1b', 'Var', (105, 113))
7048	33379141	Alike other protonophore, HPF elicits proton influx in tumor cells restoring cytosolic acidity and allowing apoptosis.	('proton influx', 'MPA', (38, 51))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('HPF', 'Chemical', 'MESH:C001654', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('HPF', 'Var', (26, 29))	('cytosolic acidity', 'MPA', (77, 94))	('restoring', 'PosReg', (67, 76))	('tumor', 'Disease', (55, 60))	('elicits', 'Reg', (30, 37))	('apoptosis', 'CPA', (108, 117))
7053	33379141	At the present state of our knowledge, the hypothesis that HPF can change the proton flux in function of the proton gradient could explain why HPF is not cytotoxic for normal cells, whereas it can induce apoptosis in cancer cells.	('induce', 'Reg', (197, 203))	('proton flux in function of the proton gradient', 'MPA', (78, 124))	('HPF', 'Chemical', 'MESH:C001654', (143, 146))	('HPF', 'Chemical', 'MESH:C001654', (59, 62))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('HPF', 'Var', (143, 146))	('change', 'Reg', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('apoptosis', 'CPA', (204, 213))
7054	33379141	In cancer cells, both at the plasma membrane level, in which DeltapH favors high proton influx, and at the hyperpolarized inner mitochondria membrane, the presence of HPF could counteract malignant phenotype, or at higher concentration, promote cell death by collapsing inner mitochondrial membrane.	('mitochondria', 'cellular_component', 'GO:0005739', ('128', '140'))	('presence', 'Var', (155, 163))	('membrane', 'cellular_component', 'GO:0016020', ('141', '149'))	('inner mitochondrial membrane', 'cellular_component', 'GO:0005743', ('270', '298'))	('high proton influx', 'MPA', (76, 94))	('HPF', 'Chemical', 'MESH:C001654', (167, 170))	('inner mitochondrial membrane', 'MPA', (270, 298))	('rat', 'Species', '10116', (229, 232))	('promote', 'PosReg', (237, 244))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('plasma membrane', 'cellular_component', 'GO:0005886', ('29', '44'))	('DeltapH', 'Var', (61, 68))	('cancer', 'Disease', (3, 9))	('collapsing', 'NegReg', (259, 269))	('cell death', 'CPA', (245, 255))	('cell death', 'biological_process', 'GO:0008219', ('245', '255'))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
7057	33379141	On the other hand, activated AMPK stabilizes the tumor suppressor p53 favoring cellular sensitization to mitochondrial apoptosis.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('sensitization', 'biological_process', 'GO:0046960', ('88', '101'))	('p53', 'Gene', '7157', (66, 69))	('AMPK', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cellular sensitization to mitochondrial apoptosis', 'MPA', (79, 128))	('stabilizes', 'Var', (34, 44))	('AMPK', 'Gene', '5564', (29, 33))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('49', '65'))	('apoptosis', 'biological_process', 'GO:0097194', ('119', '128'))	('tumor', 'Disease', (49, 54))	('AMPK', 'molecular_function', 'GO:0050405', ('29', '33'))	('apoptosis', 'biological_process', 'GO:0006915', ('119', '128'))	('AMPK', 'molecular_function', 'GO:0004691', ('29', '33'))	('AMPK', 'molecular_function', 'GO:0047322', ('29', '33'))	('p53', 'Gene', (66, 69))	('tumor suppressor', 'biological_process', 'GO:0051726', ('49', '65'))
7063	33379141	showed that HPF can inhibit angiogenesis both in bovine aortic endothelial (BAE) cells in vitro and in chorioallantoid membrane in vivo.	('HPF', 'Var', (12, 15))	('bovine', 'Species', '9913', (49, 55))	('angiogenesis', 'CPA', (28, 40))	('inhibit', 'NegReg', (20, 27))	('HPF', 'Chemical', 'MESH:C001654', (12, 15))
7064	33379141	HPF also inhibits MMP-2 and urokinase secretion from BAE cells and restrains their invasive capability in a Matrigel layer.	('invasive capability in a Matrigel layer', 'CPA', (83, 122))	('restrains', 'NegReg', (67, 76))	('HPF', 'Chemical', 'MESH:C001654', (0, 3))	('inhibits', 'NegReg', (9, 17))	('MMP-2', 'Protein', (18, 23))	('HPF', 'Var', (0, 3))
7067	33379141	Lorusso et al., using hyperforin-DCHA in human umbilical vascular endothelial cells (HUVEC), showed that HPF induces cytostatic but not cytotoxic effects, significantly reducing HUVEC cell migration triggered by chemoattractant stimuli.	('HPF', 'Chemical', 'MESH:C001654', (105, 108))	('hyperforin-DCHA', 'Chemical', '-', (22, 37))	('human', 'Species', '9606', (41, 46))	('HPF', 'Var', (105, 108))	('cell migration', 'biological_process', 'GO:0016477', ('184', '198'))	('rat', 'Species', '10116', (192, 195))	('HUVEC cell migration', 'CPA', (178, 198))	('reducing', 'NegReg', (169, 177))	('HUVEC', 'CellLine', 'CVCL:2959', (85, 90))	('HUVEC', 'CellLine', 'CVCL:2959', (178, 183))
7068	33379141	Again, the authors showed that in the presence of 1-3 microM HPF, the chemokine-elicited migration of neutrophils and monocytes as well as the TNF-alpha-stimulated nuclear translocation of NF-kappaB were markedly inhibited in HUVEC cells.	('HUVEC', 'CellLine', 'CVCL:2959', (226, 231))	('nuclear translocation', 'MPA', (164, 185))	('HPF', 'Chemical', 'MESH:C001654', (61, 64))	('inhibited', 'NegReg', (213, 222))	('rat', 'Species', '10116', (92, 95))	('chemokine-elicited migration of neutrophils', 'CPA', (70, 113))	('HPF', 'Var', (61, 64))	('NF-kappaB', 'Protein', (189, 198))
7088	33379141	Furthermore, non-cytotoxic HPF concentrations can hinder cell invasiveness by downregulating the activities of MMP-2 and -9, elastase and cathepsin G, highly expressed in inflammatory and tumor cells.	('tumor', 'Disease', (188, 193))	('elastase', 'Enzyme', (125, 133))	('cell invasiveness', 'CPA', (57, 74))	('MMP-2', 'molecular_function', 'GO:0004228', ('111', '116'))	('cathepsin G', 'Gene', (138, 149))	('HPF', 'Chemical', 'MESH:C001654', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('activities', 'MPA', (97, 107))	('MMP-2 and -9', 'Gene', '4313;4318', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('concentrations', 'Var', (31, 45))	('rat', 'Species', '10116', (38, 41))	('downregulating', 'NegReg', (78, 92))	('hinder', 'NegReg', (50, 56))	('cathepsin G', 'Gene', '1511', (138, 149))
7103	33379141	The HPF ability to drop off mitochondrial membrane hyperpolarization and consequently mtROS generation inhibits cell proliferation and favors apoptosis induction.	('mitochondrial membrane hyperpolarization', 'MPA', (28, 68))	('mtROS', 'Var', (86, 91))	('cell proliferation', 'CPA', (112, 130))	('rat', 'Species', '10116', (124, 127))	('favors', 'PosReg', (135, 141))	('drop off', 'NegReg', (19, 27))	('HPF', 'Chemical', 'MESH:C001654', (4, 7))	('inhibits', 'NegReg', (103, 111))	('apoptosis induction', 'CPA', (142, 161))	('rat', 'Species', '10116', (96, 99))	('ROS', 'Chemical', 'MESH:D017382', (88, 91))
7106	33379141	Thus, low doses of SJW/HPF, likely insufficient to induce cancer cell death, can nevertheless block ROS-elicited tumor growth and spread by hindering activity of pro-survival protein kinases and angiogenesis.	('SJW', 'Chemical', '-', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('angiogenesis', 'biological_process', 'GO:0001525', ('195', '207'))	('block', 'NegReg', (94, 99))	('pro-survival', 'biological_process', 'GO:0043066', ('162', '174'))	('spread', 'CPA', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('protein', 'cellular_component', 'GO:0003675', ('175', '182'))	('activity', 'MPA', (150, 158))	('tumor', 'Disease', (113, 118))	('HPF', 'Chemical', 'MESH:C001654', (23, 26))	('ROS', 'Chemical', 'MESH:D017382', (100, 103))	('cell death', 'biological_process', 'GO:0008219', ('65', '75'))	('protein kinases', 'Enzyme', (175, 190))	('SJW/HPF', 'Var', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('hindering', 'NegReg', (140, 149))	('angiogenesis', 'CPA', (195, 207))	('cancer', 'Disease', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
7109	33379141	Additionally, SJW/HPF, acting against different types of tumor cells, can be a broad-spectrum anti-tumor compound and should be tested in association with current chemotherapy drugs to achieve additive effects.	('SJW/HPF', 'Var', (14, 21))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('HPF', 'Chemical', 'MESH:C001654', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('SJW', 'Chemical', '-', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (57, 62))
7214	32761850	17  recently documented that apoptotic epithelial cells negatively regulate the gut commensal bacteria-stimulated proliferation of regulatory T-cells, playing a central role in the maintenance of gut tissue homeostasis: namely, apoptotic epithelial cells suppress the proliferation of regulatory T-cells to regulate mucosal homeostasis.	('homeostasis', 'biological_process', 'GO:0042592', ('324', '335'))	('proliferation', 'CPA', (268, 281))	('tissue homeostasis', 'biological_process', 'GO:0001894', ('200', '218'))	('apoptotic', 'Var', (228, 237))	('suppress', 'NegReg', (255, 263))	('rat', 'Species', '10116', (275, 278))	('regulate mucosal homeostasis', 'MPA', (307, 335))	('rat', 'Species', '10116', (121, 124))
7217	32761850	18  On the other hand, some microbiotas, especially Clostridium IV or XIV, may induce regulatory T-cells and inhibit the development of IBD.	('Clostridium IV', 'Var', (52, 66))	('IBD', 'Disease', 'MESH:D015212', (136, 139))	('inhibit', 'NegReg', (109, 116))	('induce', 'PosReg', (79, 85))	('IBD', 'Phenotype', 'HP:0002037', (136, 139))	('regulatory T-cells', 'CPA', (86, 104))	('IBD', 'Disease', (136, 139))
7230	32761850	Abnormality of enterocytic apoptosis has so far been linked to a variety of intestinal disorders.	('intestinal disorders', 'Disease', (76, 96))	('Abnormality', 'Var', (0, 11))	('intestinal disorders', 'Phenotype', 'HP:0011024', (76, 96))	('intestinal disorders', 'Disease', 'MESH:D007410', (76, 96))	('linked', 'Reg', (53, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('27', '36'))	('apoptosis', 'biological_process', 'GO:0006915', ('27', '36'))	('enterocytic apoptosis', 'Disease', (15, 36))
7239	32761850	29  recently showed in the UC rat model that microRNA-21-5p inhibited interleukin-6 receptor/signal transducer and activator of transcription signal-mediated pathway to decrease the level of inflammatory cytokines and apoptosis.	('interleukin-6 receptor', 'Gene', (70, 92))	('interleukin-6 receptor', 'Gene', '24499', (70, 92))	('apoptosis', 'biological_process', 'GO:0097194', ('218', '227'))	('decrease', 'NegReg', (169, 177))	('apoptosis', 'biological_process', 'GO:0006915', ('218', '227'))	('activator of transcription signal-mediated pathway', 'Pathway', (115, 165))	('apoptosis', 'CPA', (218, 227))	('transcription', 'biological_process', 'GO:0006351', ('128', '141'))	('level of inflammatory cytokines', 'MPA', (182, 213))	('UC', 'Phenotype', 'HP:0100279', (27, 29))	('inhibited', 'NegReg', (60, 69))	('rat', 'Species', '10116', (30, 33))	('microRNA-21-5p', 'Var', (45, 59))
7248	33029093	Results: We observed higher inflammation scores (p <0.001) and a higher number of tumors (p <0.05) in the MNNG group than the control group, both at weeks 4 and 8.	('inflammation', 'Disease', (28, 40))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('MNNG', 'Var', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('higher', 'PosReg', (21, 27))	('higher', 'PosReg', (65, 71))	('inflammation', 'Disease', 'MESH:D007249', (28, 40))	('MNNG', 'Chemical', 'MESH:D008769', (106, 110))
7292	33029093	We observed higher inflammation scores (p <0.001) and a higher number of tumors (p <0.05) in the MNNG group compared to the control group, both at weeks 4 and 8 (figures 2 and 3).	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('higher', 'PosReg', (12, 18))	('MNNG', 'Chemical', 'MESH:D008769', (97, 101))	('inflammation', 'Disease', 'MESH:D007249', (19, 31))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('inflammation', 'Disease', (19, 31))	('tumors', 'Disease', (73, 79))	('higher', 'PosReg', (56, 62))	('inflammation', 'biological_process', 'GO:0006954', ('19', '31'))	('MNNG', 'Var', (97, 101))
7314	33029093	In the present study, after applying the MNNG, there was a worsening of the inflammatory score and a progressive increase in the number of tumors over 8 weeks.	('MNNG', 'Chemical', 'MESH:D008769', (41, 45))	('worsening', 'NegReg', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('MNNG', 'Var', (41, 45))	('inflammatory score', 'MPA', (76, 94))	('tumors', 'Disease', (139, 145))	('increase', 'PosReg', (113, 121))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
7359	31427689	Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) are structurally similar oxylipid substrates, and accumulation of one PUFA family can lead to enzymatic competition and alter downstream lipid metabolism.	('omega-6 (n-6) polyunsaturated fatty acids', 'Chemical', '-', (18, 59))	('PUFA', 'Gene', '9933', (61, 65))	('Omega-3', 'Chemical', '-', (0, 7))	('PUFA', 'Gene', (61, 65))	('PUFAs', 'Chemical', 'MESH:D005231', (61, 66))	('alter', 'Reg', (188, 193))	('lead to', 'Reg', (154, 161))	('PUFA', 'Gene', '9933', (138, 142))	('lipid', 'Chemical', 'MESH:D008055', (96, 101))	('accumulation', 'Var', (118, 130))	('oxylipid', 'Chemical', '-', (93, 101))	('PUFA', 'Gene', (138, 142))	('enzymatic competition', 'MPA', (162, 183))	('lipid', 'Chemical', 'MESH:D008055', (205, 210))
7423	31427689	Individuals with >1.86 nM 5-HETE were five to six times more likely to have polyps than individuals with <= 1.86 nM 5-HETE.	('5-HETE', 'Chemical', '-', (26, 32))	('5-HETE', 'Chemical', '-', (116, 122))	('>1.86 nM 5-HETE', 'Var', (17, 32))	('polyps', 'Disease', (76, 82))	('polyps', 'Disease', 'MESH:D011127', (76, 82))
7424	31427689	Results for 11-HETE were similar to 5-HETE, participants with 11-HETE concentrations >0.39 nM were three to five times more likely to have polyps than individuals with <= 0.39 nM 11-HETE.	('11-HETE', 'Chemical', '-', (62, 69))	('polyps', 'Disease', 'MESH:D011127', (139, 145))	('11-HETE', 'Chemical', '-', (179, 186))	('>0.39 nM', 'Var', (85, 93))	('11-HETE', 'Chemical', '-', (12, 19))	('polyps', 'Disease', (139, 145))	('5-HETE', 'Chemical', '-', (36, 42))	('participants', 'Species', '9606', (44, 56))
7459	31427689	Previous epidemiologic studies suggest that high-fat diets are associated with increased incidence of tumors at different organ sites including colon.	('high-fat diets', 'Var', (44, 58))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('colon', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
7471	31352904	In this study, we assessed the long-term survival characteristics and prognostic associations and potential time-varying effects of clinico-demographic variables and two molecular markers (microsatellite instability (MSI) and BRAF Val600Glu mutation) in a population-based patient cohort followed up to ~ 19 years.	('patient', 'Species', '9606', (273, 280))	('microsatellite', 'MPA', (189, 203))	('BRAF', 'Gene', '673', (226, 230))	('BRAF', 'Gene', (226, 230))	('Val600Glu', 'Mutation', 'rs113488022', (231, 240))	('Val600Glu mutation', 'Var', (231, 249))
7490	31352904	BRAF Val600Glu mutation occurs in ~ 10% of the colorectal tumors, causes oncogenic BRAF activity, and promotes cellular transformation.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('cellular transformation', 'CPA', (111, 134))	('promotes', 'PosReg', (102, 110))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('causes', 'Reg', (66, 72))	('BRAF', 'Gene', '673', (0, 4))	('Val600Glu', 'Mutation', 'rs113488022', (5, 14))	('BRAF', 'Gene', (0, 4))	('colorectal tumors', 'Disease', 'MESH:D015179', (47, 64))	('BRAF', 'Gene', '673', (83, 87))	('Val600Glu', 'Var', (5, 14))	('rectal tumors', 'Phenotype', 'HP:0100743', (51, 64))	('colorectal tumors', 'Disease', (47, 64))	('BRAF', 'Gene', (83, 87))
7491	31352904	Literature reports also suggest a prognostic role for this BRAF mutation in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('mutation', 'Var', (64, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('BRAF', 'Gene', '673', (59, 63))	('BRAF', 'Gene', (59, 63))	('colorectal cancer', 'Disease', (76, 93))	('rectal cancer', 'Phenotype', 'HP:0100743', (80, 93))
7497	31352904	For example, disease location; age, disease stage, time period of diagnosis, or tumor site; regional cancer, age, and tumor location (pelvic/sigmoid colon); age (in two of our previous studies using subsets of the patients included in this study); tumor site (left or right), grade, sex, and stage; a set of genetic variations; and a somatic tumor alteration were reported to have or tend to have time-varying effects on patient outcomes.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('patients', 'Species', '9606', (214, 222))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('patient', 'Species', '9606', (421, 428))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Disease', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Disease', (342, 347))	('patient', 'Species', '9606', (214, 221))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('variations', 'Var', (316, 326))	('tumor', 'Disease', (80, 85))	('effects', 'Reg', (410, 417))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Disease', (101, 107))	('tumor', 'Disease', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))
7544	31352904	Tumor location and BRAF Val600Glu mutation status were associated with all outcomes.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('BRAF', 'Gene', '673', (19, 23))	('Val600Glu', 'Mutation', 'rs113488022', (24, 33))	('BRAF', 'Gene', (19, 23))	('Val600Glu', 'Var', (24, 33))	('associated', 'Reg', (55, 65))
7549	31352904	The presence of BRAF Val600Glu mutation was associated with shorter overall and disease-specific survival times within the first 2.5 years post-diagnosis (HR 2.18 for OS and 3.05 for DSS), but not after that (Additional file 1: Tables S2-S3).	('DSS', 'Gene', '5376', (183, 186))	('Val600Glu', 'Mutation', 'rs113488022', (21, 30))	('Val600Glu', 'Var', (21, 30))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('disease-specific survival times', 'CPA', (80, 111))	('overall', 'CPA', (68, 75))	('OS', 'Chemical', '-', (167, 169))	('shorter', 'NegReg', (60, 67))	('DSS', 'Gene', (183, 186))
7550	31352904	Last, patients with this tumor mutation had shorter MFS, RMFS, and EFS times without any time-varying effects (Additional file 1: Tables S5-S7).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('EFS times', 'MPA', (67, 76))	('MFS', 'MPA', (52, 55))	('tumor', 'Disease', (25, 30))	('mutation', 'Var', (31, 39))	('patients', 'Species', '9606', (6, 14))	('RMFS', 'MPA', (57, 61))	('shorter', 'NegReg', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
7558	31352904	Specifically, within the first year following diagnosis, adjuvant chemotherapy had strong and significant protective effects on OS, DSS, and EFS, after which this effect was not detectable in the EFS analysis but was still significant in the OS and DSS analyses, albeit with a decreased effect size (HR 0.05 for OS, 0.15 for DSS, and 0.40 for EFS within the first year post-diagnosis and 0.56 for OS and 0.50 for DSS after this time point) (Additional file 1: Tables S2-S3 and S7).	('DSS', 'Gene', (325, 328))	('DSS', 'Gene', '5376', (413, 416))	('DSS', 'Gene', '5376', (132, 135))	('DSS', 'Gene', '5376', (325, 328))	('DSS', 'Gene', (249, 252))	('OS', 'Chemical', '-', (128, 130))	('OS', 'Chemical', '-', (397, 399))	('DSS', 'Gene', '5376', (249, 252))	('OS', 'Chemical', '-', (242, 244))	('adjuvant', 'Var', (57, 65))	('DSS', 'Gene', (413, 416))	('DSS', 'Gene', (132, 135))	('OS', 'Chemical', '-', (312, 314))
7581	31352904	Additionally, consistent with other studies, familial risk status, while it is a risk factor for the development of colorectal cancer, had no significant relation to any survival outcomes investigated.	('colorectal cancer', 'Phenotype', 'HP:0003003', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('familial risk status', 'Var', (45, 65))	('colorectal cancer', 'Disease', (116, 133))	('rectal cancer', 'Phenotype', 'HP:0100743', (120, 133))	('colorectal cancer', 'Disease', 'MESH:D015179', (116, 133))
7604	31352904	Such a relationship between mutant BRAF and metastasis was previously reported in other cohorts.	('metastasis', 'CPA', (44, 54))	('BRAF', 'Gene', (35, 39))	('mutant', 'Var', (28, 34))	('BRAF', 'Gene', '673', (35, 39))
7605	31352904	It is not immediately clear how this mutation may influence the recurrence risk in colorectal cancer, but the association of this mutation with tumor recurrence has been reported in papillary thyroid cancer as well.	('colorectal cancer', 'Disease', 'MESH:D015179', (83, 100))	('tumor', 'Disease', (144, 149))	('mutation', 'Var', (37, 45))	('colorectal cancer', 'Phenotype', 'HP:0003003', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('papillary thyroid cancer', 'Disease', (182, 206))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (182, 206))	('colorectal cancer', 'Disease', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('rectal cancer', 'Phenotype', 'HP:0100743', (87, 100))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('thyroid cancer', 'Phenotype', 'HP:0002890', (192, 206))
7606	31352904	In addition to these, previously, BRAF Val600Glu mutation has been associated with the increased risk of mortality in colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('rectal cancer', 'Phenotype', 'HP:0100743', (122, 135))	('colorectal cancer', 'Disease', 'MESH:D015179', (118, 135))	('Val600Glu', 'Mutation', 'rs113488022', (39, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (118, 135))	('BRAF', 'Gene', '673', (34, 38))	('Val600Glu', 'Var', (39, 48))	('BRAF', 'Gene', (34, 38))	('colorectal cancer', 'Disease', (118, 135))
7607	31352904	In our study, in two death-related outcomes (OS and DSS), this mutation emerged as a predictor of death early after diagnosis (within the first 2.5 years).	('death', 'Disease', 'MESH:D003643', (98, 103))	('DSS', 'Gene', '5376', (52, 55))	('death', 'Disease', (98, 103))	('OS', 'Chemical', '-', (45, 47))	('mutation', 'Var', (63, 71))	('death', 'Disease', 'MESH:D003643', (21, 26))	('death', 'Disease', (21, 26))	('DSS', 'Gene', (52, 55))
7609	31352904	BRAF Val600Glu mutation status is the only variable identified in this study that was both an early-event (OS and DSS) and late-event (RFS) marker.	('DSS', 'Gene', '5376', (114, 117))	('OS', 'Chemical', '-', (107, 109))	('Val600Glu', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('Val600Glu', 'Mutation', 'rs113488022', (5, 14))	('BRAF', 'Gene', (0, 4))	('DSS', 'Gene', (114, 117))
7616	31352904	However, after 5.5 years following diagnosis, those patients who received radiotherapy had increased risk of developing their first metastases compared to patients who did not receive this treatment.	('radiotherapy', 'Var', (74, 86))	('metastases', 'Disease', (132, 142))	('metastases', 'Disease', 'MESH:D009362', (132, 142))	('patients', 'Species', '9606', (155, 163))	('patients', 'Species', '9606', (52, 60))
7645	31324877	Structural rearrangements as well as gains and losses of chromosome fragments are characteristic features of CIN tumors, possibly associated with higher mutation rates; the majority of sporadic cases are in this group.	('CIN tumors', 'Disease', 'MESH:D009369', (109, 119))	('losses', 'NegReg', (47, 53))	('Structural rearrangements', 'Var', (0, 25))	('CIN tumors', 'Disease', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('CIN', 'Phenotype', 'HP:0040012', (109, 112))	('gains', 'Var', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
7646	31324877	MSI is associated with changes in short microsatellite repeats, caused by deficient mismatch repair (MMR) genes, and is related to hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch Syndrome (LS), and some sporadic cases in the elderly population.	('deficient', 'NegReg', (74, 83))	('MMR', 'biological_process', 'GO:0006298', ('101', '104'))	('Lynch Syndrome', 'Disease', (195, 209))	('hereditary non-polyposis colorectal cancer', 'Disease', 'MESH:D015179', (131, 173))	('MMR) genes', 'Gene', (101, 111))	('changes', 'Var', (23, 30))	('mismatch repair', 'biological_process', 'GO:0006298', ('84', '99'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (156, 173))	('MSI', 'Disease', (0, 3))	('related', 'Reg', (120, 127))	('hereditary non-polyposis colorectal cancer', 'Phenotype', 'HP:0006716', (131, 173))	('short microsatellite repeats', 'Var', (34, 62))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('HNPCC', 'Phenotype', 'HP:0006716', (175, 180))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (195, 209))	('hereditary non-polyposis colorectal cancer', 'Disease', (131, 173))
7648	31324877	Furthermore, several studies have shown that CIMP positivity is associated with proximal colon location, presence of mucinous features, poor tumor differentiation, MSI, female gender and high BRAF mutation rates.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('associated', 'Reg', (64, 74))	('mucin', 'Gene', '100508689', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('MSI', 'Disease', (164, 167))	('BRAF', 'Gene', '673', (192, 196))	('colon location', 'Disease', (89, 103))	('tumor', 'Disease', (141, 146))	('BRAF', 'Gene', (192, 196))	('mucin', 'Gene', (117, 122))	('colon location', 'Disease', 'MESH:D015179', (89, 103))	('CIMP', 'Chemical', '-', (45, 49))	('mutation', 'Var', (197, 205))
7668	31324877	Mutations in KRAS (codons 12, 13 and 61) were determined previously in patients younger than 45 and older than 70 years.	('KRAS', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', '3845', (13, 17))	('patients', 'Species', '9606', (71, 79))
7673	31324877	Clinical characteristics were compared between different groups according to CIMP status, including age, sex, stage, tumor location, presence of mucinous features, BRAF and KRAS mutations, and MSI status.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('mucin', 'Gene', '100508689', (145, 150))	('CIMP', 'Chemical', '-', (77, 81))	('KRAS', 'Gene', (173, 177))	('BRAF', 'Gene', '673', (164, 168))	('KRAS', 'Gene', '3845', (173, 177))	('BRAF', 'Gene', (164, 168))	('mucin', 'Gene', (145, 150))	('mutations', 'Var', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
7678	31324877	Among the 59 patients with EOCRC, 8 (13.6%) patients showed MSI status, of which 3 (37.5%) were sporadic cases: 1 (12.5%) presented a BRAF mutation and 2 (25.0%) showed hypermethylation of the MLH1 gene promoter; the remaining 5 (62.5%) individuals were diagnosed with LS.	('mutation', 'Var', (139, 147))	('patients', 'Species', '9606', (44, 52))	('hypermethylation', 'Var', (169, 185))	('patients', 'Species', '9606', (13, 21))	('BRAF', 'Gene', '673', (134, 138))	('BRAF', 'Gene', (134, 138))	('CRC', 'Phenotype', 'HP:0003003', (29, 32))	('MLH1', 'Gene', '4292', (193, 197))	('MLH1', 'Gene', (193, 197))
7680	31324877	In the LOCRC group, 6 (8.5%) patients showed MSI status, all of them sporadic cases, 6 (8.5%) patients had a BRAF mutation and 1 (16.7%) case presented a KRAS mutation (Tables 1 and 2).	('LOCRC', 'Chemical', '-', (7, 12))	('KRAS', 'Gene', '3845', (154, 158))	('patients', 'Species', '9606', (29, 37))	('BRAF', 'Gene', '673', (109, 113))	('BRAF', 'Gene', (109, 113))	('MSI', 'MPA', (45, 48))	('patients', 'Species', '9606', (94, 102))	('CRC', 'Phenotype', 'HP:0003003', (9, 12))	('mutation', 'Var', (114, 122))	('KRAS', 'Gene', (154, 158))
7684	31324877	Five (10.4%) and 31 (64.6%) patients presented BRAF mutations and KRAS mutations in at least one tumor, respectively.	('mutations', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('KRAS', 'Gene', '3845', (66, 70))	('tumor', 'Disease', (97, 102))	('patients', 'Species', '9606', (28, 36))	('KRAS', 'Gene', (66, 70))
7686	31324877	Regarding a BRAF mutation, MCRC patients showed concordance between both tumors, of which 1 (2.2%) patient presented a BRAF mutation.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('patient', 'Species', '9606', (99, 106))	('patients', 'Species', '9606', (32, 40))	('BRAF', 'Gene', '673', (12, 16))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (119, 123))	('MCRC', 'Chemical', '-', (27, 31))	('CRC', 'Phenotype', 'HP:0003003', (28, 31))	('mutation', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('BRAF', 'Gene', (119, 123))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('patient', 'Species', '9606', (32, 39))
7731	30626010	Lower incidence of colorectal cancer is associated with increased fibre intake.	('fibre', 'Var', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('colorectal cancer', 'Disease', 'MESH:D015179', (19, 36))	('colorectal cancer', 'Phenotype', 'HP:0003003', (19, 36))	('colorectal cancer', 'Disease', (19, 36))
7741	30626010	In addition, butyrate worsened adipose tissue inflammation.	('inflammation', 'Disease', 'MESH:D007249', (46, 58))	('adipose', 'Gene', '230796', (31, 38))	('inflammation', 'Disease', (46, 58))	('worsened', 'NegReg', (22, 30))	('adipose tissue inflammation', 'Phenotype', 'HP:0012490', (31, 58))	('adipose', 'Gene', (31, 38))	('inflammation', 'biological_process', 'GO:0006954', ('46', '58'))	('butyrate', 'Var', (13, 21))	('butyrate', 'Chemical', 'MESH:D002087', (13, 21))
7744	30626010	Epidemiological data has shown an inverse association between total dietary fibre content and colon cancer risk, demonstrating that high fibre intake was associated with a lower risk of colon cancer; however, the type of fibre that is ingested is also important.	('colon cancer', 'Disease', (94, 106))	('colon cancer', 'Disease', (186, 198))	('colon cancer', 'Disease', 'MESH:D015179', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lower', 'NegReg', (172, 177))	('high fibre', 'Var', (132, 142))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('colon cancer', 'Phenotype', 'HP:0003003', (186, 198))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))	('colon cancer', 'Disease', 'MESH:D015179', (186, 198))
7753	30626010	In vitro, tributyrin induces apoptosis by activating caspase-3.	('apoptosis', 'CPA', (29, 38))	('caspase-3', 'Gene', '12367', (53, 62))	('tributyrin', 'Chemical', 'MESH:C005830', (10, 20))	('caspase-3', 'Gene', (53, 62))	('activating', 'PosReg', (42, 52))	('tributyrin', 'Var', (10, 20))
7762	30626010	In the context of obesity, low-grade inflammation and secretion of hypertrophic adipocytes produces dysfunction in mitochondrial colonocytes, directly affecting epithelial cell metabolism and cancer progression.	('obesity', 'Disease', (18, 25))	('hypertrophic', 'Disease', (67, 79))	('hypertrophic adipocytes', 'Phenotype', 'HP:0030759', (67, 90))	('inflammation', 'Disease', 'MESH:D007249', (37, 49))	('dysfunction', 'Var', (100, 111))	('metabolism', 'biological_process', 'GO:0008152', ('177', '187'))	('inflammation', 'biological_process', 'GO:0006954', ('37', '49'))	('epithelial cell metabolism', 'MPA', (161, 187))	('obesity', 'Phenotype', 'HP:0001513', (18, 25))	('inflammation', 'Disease', (37, 49))	('hypertrophic', 'Disease', 'MESH:D006984', (67, 79))	('cancer', 'Disease', (192, 198))	('affecting', 'Reg', (151, 160))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('secretion', 'biological_process', 'GO:0046903', ('54', '63'))	('obesity', 'Disease', 'MESH:D009765', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
7802	30626010	Histologically, the cancer groups showed that abnormal colon epithelial phenotypes, polypoid tumours on the mucosal surface, elevated lymphoid aggregates, and loss of polarity and butyrate led to colonic crypt hypertrophy.	('elevated', 'PosReg', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('colonic crypt hypertrophy', 'Disease', (196, 221))	('polypoid tumours', 'Disease', (84, 100))	('polarity', 'MPA', (167, 175))	('butyrate', 'Chemical', 'MESH:D002087', (180, 188))	('lymphoid aggregates', 'CPA', (134, 153))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('colonic crypt hypertrophy', 'Disease', 'MESH:D006984', (196, 221))	('loss', 'Var', (159, 163))	('cancer', 'Disease', (20, 26))	('polypoid tumours', 'Disease', 'MESH:D009369', (84, 100))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))
7803	30626010	Analysis of the plasma cell infiltrate in the intestinal lamina propria showed a lower percentage of plasma cells in the colon of the animals in both the CA and FOS groups (Figure 8C), compared with the control mice.	('mice', 'Species', '10090', (211, 215))	('lower', 'NegReg', (81, 86))	('FOS', 'Var', (161, 164))
7804	30626010	Interestingly, butyrate supplementation increased plasma cell distribution in the animals' colons, like that observed in the control group.	('butyrate', 'Chemical', 'MESH:D002087', (15, 23))	('plasma cell distribution', 'MPA', (50, 74))	('increased', 'PosReg', (40, 49))	('supplementation', 'Var', (24, 39))	('increased plasma cell', 'Phenotype', 'HP:0025619', (40, 61))	('increased plasma cell distribution', 'Phenotype', 'HP:0032128', (40, 74))
7812	30626010	Tributyrin supplementation induced elevation of VEGF in retroperitoneal adipose tissue and reduced VEGF in mesenteric depot (Figure 11A-D).	('adipose', 'Gene', '230796', (72, 79))	('VEGF', 'Gene', (48, 52))	('Tributyrin', 'Chemical', 'MESH:C005830', (0, 10))	('VEGF', 'Gene', '22339', (99, 103))	('adipose', 'Gene', (72, 79))	('VEGF', 'Gene', '22339', (48, 52))	('reduced', 'NegReg', (91, 98))	('supplementation', 'Var', (11, 26))	('VEGF', 'Gene', (99, 103))	('elevation', 'PosReg', (35, 44))
7815	30626010	Diet treatments did not exert a protective effect, and tributyrin diet supplementation was associated with reduced survival and inflammation within WAT.	('inflammation within WAT', 'Disease', (128, 151))	('tributyrin', 'Chemical', 'MESH:C005830', (55, 65))	('reduced', 'NegReg', (107, 114))	('inflammation', 'biological_process', 'GO:0006954', ('128', '140'))	('inflammation within WAT', 'Disease', 'MESH:D001929', (128, 151))	('survival', 'CPA', (115, 123))	('tributyrin', 'Var', (55, 65))
7838	30626010	Colorectal carcinogenesis is a multistep process with histological features and gene mutations that resemble human sporadic colon carcinogenesis.	('human', 'Species', '9606', (109, 114))	('Colorectal carcinogenesis', 'Disease', 'MESH:D063646', (0, 25))	('mutations', 'Var', (85, 94))	('colon carcinogenesis', 'Disease', (124, 144))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (124, 144))	('Colorectal carcinogenesis', 'Disease', (0, 25))
7868	30626010	Tributyrin supplementation additionally elevated VEGF in retroperitoneal tissues and reduced it in mesenteric adipose tissue.	('VEGF', 'Gene', (49, 53))	('Tributyrin', 'Chemical', 'MESH:C005830', (0, 10))	('adipose', 'Gene', '230796', (110, 117))	('elevated', 'PosReg', (40, 48))	('VEGF', 'Gene', '22339', (49, 53))	('adipose', 'Gene', (110, 117))	('supplementation', 'Var', (11, 26))	('reduced', 'NegReg', (85, 92))
7949	30484985	Eight articles (Moghimi et al., 2008; Asghari-Jafarabadi et al., 2009; Akhoond et al., 2010; NASIRI et al., 2010; Mehrabani et al., 2012; Omidvari et al., 2013; Roshanaei et al., 2014; Abbasi Asl, 2015) reported a relationship between tumor metastasis and survival rate of the patients in a way that the mortality risk of individuals with metastasis who have referred to other centers was 3.26 times more that those without it (Abbasi Asl, 2015).	('metastasis', 'Var', (339, 349))	('tumor metastasis', 'Disease', (235, 251))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('patients', 'Species', '9606', (277, 285))	('tumor metastasis', 'Disease', 'MESH:D009362', (235, 251))
7951	30484985	The relationship between metastasis to nearby lymph nodes and survival rate of the patients is mentioned in 3 articles (Moghimi et al., 2008; Tabatabaie et al., 2011; Saki Malehi et al., 2012) in a way that there was a significant relationship between presence of various metastases and a reduction in survival rate of patients (Tabatabaie et al., 2011).	('metastases', 'Disease', 'MESH:D009362', (272, 282))	('reduction', 'NegReg', (289, 298))	('patients', 'Species', '9606', (319, 327))	('survival rate', 'CPA', (302, 315))	('presence', 'Var', (252, 260))	('men', 'Species', '9606', (95, 98))	('patients', 'Species', '9606', (83, 91))	('metastases', 'Disease', (272, 282))
8017	28594897	Studies have shown dysregulation of lncRNAs contribute to cancer progression through abnormal regulation of cancer-related cellular processes, such as proliferation, invasion, metastasis, apoptosis and multi-drug resistance, and lncRNAs have been implicated as promising markers for predicting the prognosis of cancers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (311, 317))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('cancers', 'Disease', (311, 318))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('dysregulation', 'Var', (19, 32))	('proliferation', 'CPA', (151, 164))	('lncRNAs', 'Gene', (36, 43))	('contribute', 'Reg', (44, 54))	('apoptosis', 'CPA', (188, 197))	('drug resistance', 'Phenotype', 'HP:0020174', (208, 223))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('abnormal', 'Reg', (85, 93))	('cancer', 'Disease', (108, 114))	('metastasis', 'CPA', (176, 186))	('invasion', 'CPA', (166, 174))	('regulation', 'MPA', (94, 104))	('multi-drug resistance', 'CPA', (202, 223))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (58, 64))
8019	28594897	Many studies have shown that high levels of CCAT1 expression may be associated with prognosis of human cancers.	('high', 'Var', (29, 33))	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('associated', 'Reg', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('human', 'Species', '9606', (97, 102))	('CCAT1', 'Gene', '100507056', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('CCAT1', 'Gene', (44, 49))	('expression', 'MPA', (50, 60))	('cancers', 'Disease', (103, 110))
8040	28594897	An HR>1 indicates that the patients with high CCAT1 expression have a poor prognosis and the patients with low CCAT1 expression have a good prognosis.	('CCAT1', 'Gene', '100507056', (46, 51))	('CCAT1', 'Gene', '100507056', (111, 116))	('CCAT1', 'Gene', (111, 116))	('CCAT1', 'Gene', (46, 51))	('high', 'Var', (41, 45))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (93, 101))
8079	28594897	In recent years, mounting evidence has demonstrated that lncRNAs are important regulatory molecules in diverse biological and pathological processes, such as lncRNA UCA1 increases the cisplatin resistance of bladder cancer cells, lncRNA MALAT1 enhances the metastasis of osteosarcoma cells, LncRNA-ROR induces epithelial-to-mesenchymal transition of breast cancer cells and lncRNA CCAT1 promotes the proliferation and migration of hepatocellular carcinoma cells.	('breast cancer', 'Disease', 'MESH:D001943', (350, 363))	('osteosarcoma', 'Phenotype', 'HP:0002669', (271, 283))	('bladder cancer', 'Disease', 'MESH:D001749', (208, 222))	('promotes', 'PosReg', (387, 395))	('bladder cancer', 'Disease', (208, 222))	('breast cancer', 'Disease', (350, 363))	('increases', 'PosReg', (170, 179))	('bladder cancer', 'Phenotype', 'HP:0009725', (208, 222))	('UCA1', 'Gene', '652995', (165, 169))	('cisplatin resistance', 'MPA', (184, 204))	('UCA1', 'Gene', (165, 169))	('MALAT1', 'Gene', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (431, 455))	('sarcoma', 'Phenotype', 'HP:0100242', (276, 283))	('migration', 'CPA', (418, 427))	('MALAT1', 'Gene', '378938', (237, 243))	('CCAT1', 'Gene', '100507056', (381, 386))	('cancer', 'Phenotype', 'HP:0002664', (357, 363))	('epithelial-to-mesenchymal transition', 'CPA', (310, 346))	('CCAT1', 'Gene', (381, 386))	('osteosarcoma', 'Disease', (271, 283))	('proliferation', 'CPA', (400, 413))	('osteosarcoma', 'Disease', 'MESH:D012516', (271, 283))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (431, 455))	('lncRNA', 'Var', (158, 164))	('enhances', 'PosReg', (244, 252))	('metastasis', 'CPA', (257, 267))	('breast cancer', 'Phenotype', 'HP:0003002', (350, 363))	('induces', 'Reg', (302, 309))	('hepatocellular carcinoma', 'Disease', (431, 455))	('carcinoma', 'Phenotype', 'HP:0030731', (446, 455))
8088	28594897	In colon cancer and pancreatic cancer, abnormally expressed CCAT1 promotes cell proliferation and migration.	('pancreatic cancer', 'Disease', 'MESH:D010190', (20, 37))	('abnormally expressed', 'Var', (39, 59))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('colon cancer', 'Disease', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('CCAT1', 'Gene', '100507056', (60, 65))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('migration', 'CPA', (98, 107))	('promotes', 'PosReg', (66, 74))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (20, 37))	('CCAT1', 'Gene', (60, 65))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('pancreatic cancer', 'Disease', (20, 37))	('cell proliferation', 'CPA', (75, 93))
8091	28594897	In non-small cell lung cancer cell line, inhibition of CARLo-5 by siRNA suppressed the proliferation, migration, and invasion of cells and reversed the epithelial-mesenchymal transition.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('152', '185'))	('reversed', 'PosReg', (139, 147))	('inhibition', 'Var', (41, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('suppressed', 'NegReg', (72, 82))	('epithelial-mesenchymal transition', 'CPA', (152, 185))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('CARLo-5', 'Gene', (55, 62))	('non-small cell lung cancer', 'Disease', (3, 29))	('CARLo-5', 'Gene', '100507056', (55, 62))	('invasion of cells', 'CPA', (117, 134))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))
8092	28594897	Based on these studies and owing to its functions, targeting CCAT1 may be beneficial to the outcome of cancer patients and CCAT1 may serve as a prognostic biomarker.	('CCAT1', 'Gene', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('CCAT1', 'Gene', '100507056', (123, 128))	('CCAT1', 'Gene', '100507056', (61, 66))	('beneficial', 'PosReg', (74, 84))	('CCAT1', 'Gene', (61, 66))	('targeting', 'Var', (51, 60))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('patients', 'Species', '9606', (110, 118))
8095	28594897	By combining the HRs, we found that high CCAT1 expression was a poor prognostic marker for OS in tumor patients (pooled HR 2.335, 95%CI: 1.551-3.517).	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('CCAT1', 'Gene', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('expression', 'MPA', (47, 57))	('tumor', 'Disease', (97, 102))	('OS', 'Chemical', '-', (91, 93))	('CCAT1', 'Gene', '100507056', (41, 46))	('patients', 'Species', '9606', (103, 111))	('high', 'Var', (36, 40))
8105	28594897	Meta-analysis showed that patients with high CCAT1 expression were more possible to have significantly poorer RFS (pooled HR 2.659, 95%CI: 1.755-4.029) with no significant heterogeneity.	('high', 'Var', (40, 44))	('CCAT1', 'Gene', '100507056', (45, 50))	('RFS', 'CPA', (110, 113))	('CCAT1', 'Gene', (45, 50))	('poorer', 'NegReg', (103, 109))	('patients', 'Species', '9606', (26, 34))	('expression', 'Var', (51, 61))
8138	28594897	This meta-analysis is the first to demonstrate that high expression of the lncRNA CCAT1 is related to poor prognosis for cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('CCAT1', 'Gene', '100507056', (82, 87))	('high', 'Var', (52, 56))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('CCAT1', 'Gene', (82, 87))	('patients', 'Species', '9606', (128, 136))	('cancer', 'Disease', (121, 127))
8165	26321889	Other common molecular aberrations in MC are the higher rates of KRAS, BRAF and PI3K mutations, when compared with AC.	('BRAF', 'Gene', '673', (71, 75))	('KRAS', 'Gene', '3845', (65, 69))	('BRAF', 'Gene', (71, 75))	('PI3K mutations', 'Var', (80, 94))	('KRAS', 'Gene', (65, 69))
8183	26321889	SRCCs are frequently of the CpG island methylator phenotype (48 %), and BRAF mutations are found in 30-33 % of SRCCs.	('SRCCs', 'Disease', (0, 5))	('mutations', 'Var', (77, 86))	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (72, 76))
8184	26321889	KRAS is mutated in 53 % of SRCCs.	('mutated', 'Var', (8, 15))	('KRAS', 'Gene', (0, 4))	('SRCCs', 'Disease', (27, 32))	('KRAS', 'Gene', '3845', (0, 4))
8199	26321889	When applying a definition of less than 30 % of neuroendocrine differentiation in tumour, a recent meta-analysis including 1587 patients from 11 studies shows that neuroendocrine differentiation in adenocarcinomas is associated with a decreased 5-year survival rate (pooled OR 0.60, 95 % CI 0.37-0.97).	('adenocarcinomas', 'Disease', (198, 213))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('5-year survival rate', 'CPA', (245, 265))	('neuroendocrine differentiation', 'Var', (164, 194))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('tumour', 'Disease', (82, 88))	('decreased', 'NegReg', (235, 244))	('patients', 'Species', '9606', (128, 136))	('adenocarcinomas', 'Disease', 'MESH:D000230', (198, 213))	('carcinomas', 'Phenotype', 'HP:0030731', (203, 213))
8222	26321889	This subtype is invariably associated with MSI and a very high rate of BRAF mutations: 86 versus 69 % in other MSI tumours and 19 % or less in the general population.	('mutations', 'Var', (76, 85))	('MSI', 'Disease', (43, 46))	('BRAF', 'Gene', '673', (71, 75))	('MSI tumours', 'Disease', 'MESH:D009369', (111, 122))	('associated', 'Reg', (27, 37))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('BRAF', 'Gene', (71, 75))	('MSI tumours', 'Disease', (111, 122))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))
8226	26321889	Microsatellite instability rates are not different from AC, but BRAF mutations are very frequent (33.3 versus 0 %).	('Microsatellite instability', 'MPA', (0, 26))	('mutations', 'Var', (69, 78))	('BRAF', 'Gene', (64, 68))	('BRAF', 'Gene', '673', (64, 68))
8227	26321889	In addition, KRAS mutations are frequently observed (45.2 versus 27.1 %).	('KRAS', 'Gene', (13, 17))	('observed', 'Reg', (43, 51))	('KRAS', 'Gene', '3845', (13, 17))	('mutations', 'Var', (18, 27))
8262	24967040	The primary concern with metastasis is pathologic fracture and/or spinal cord compression, which may lead to intractable pain, sensory alterations, weakness, and/or paralysis.	('pain', 'Phenotype', 'HP:0012531', (121, 125))	('pain', 'Disease', 'MESH:D010146', (121, 125))	('pain', 'Disease', (121, 125))	('weakness', 'Disease', (148, 156))	('spinal cord compression', 'CPA', (66, 89))	('paralysis', 'Disease', (165, 174))	('weakness', 'Disease', 'MESH:D018908', (148, 156))	('spinal cord compression', 'Phenotype', 'HP:0002176', (66, 89))	('fracture', 'Disease', 'MESH:D050723', (50, 58))	('pathologic fracture', 'Phenotype', 'HP:0002756', (39, 58))	('paralysis', 'Phenotype', 'HP:0003470', (165, 174))	('fracture', 'Disease', (50, 58))	('pathologic', 'Var', (39, 49))	('paralysis', 'Disease', 'MESH:D010243', (165, 174))	('sensory alterations', 'Disease', (127, 146))	('lead', 'Reg', (101, 105))
8323	23497023	Patients with a lower mtDNA copy number tended to have lower 3-year survival than patients with a higher mtDNA copy number assessed by Kaplan-Meier curves, but the correlation was not significant (overall survival, 63.0 vs 83%).	('mtDNA', 'cellular_component', 'GO:0000262', ('105', '110'))	('mtDNA', 'cellular_component', 'GO:0000262', ('22', '27'))	('patients', 'Species', '9606', (82, 90))	('Patients', 'Species', '9606', (0, 8))	('lower', 'NegReg', (55, 60))	('copy number', 'Var', (28, 39))	('3-year survival', 'MPA', (61, 76))
8326	23497023	Impairment of mitochondrial respiratory function not only reduces the supply of energy (which may prevent energy-dependent apoptosis) but also enhances ROS production, which may induce mutation and oxidative damage to mtDNA.	('reduces', 'NegReg', (58, 65))	('supply of energy', 'MPA', (70, 86))	('induce', 'Reg', (178, 184))	('enhances', 'PosReg', (143, 151))	('oxidative damage', 'MPA', (198, 214))	('mitochondrial respiratory', 'Enzyme', (14, 39))	('mutation', 'MPA', (185, 193))	('ROS', 'Chemical', 'MESH:D017382', (152, 155))	('Impairment', 'Var', (0, 10))	('ROS production', 'MPA', (152, 166))
8327	23497023	It has been reported that accumulation of mtDNA mutations as well as alteration in the execution of apoptosis contribute to the onset and progression of various myopathies.	('mtDNA', 'Gene', (42, 47))	('accumulation', 'PosReg', (26, 38))	('alteration', 'Reg', (69, 79))	('myopathies', 'Disease', 'MESH:D009135', (161, 171))	('myopathies', 'Phenotype', 'HP:0003198', (161, 171))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('mtDNA', 'cellular_component', 'GO:0000262', ('42', '47'))	('myopathies', 'Disease', (161, 171))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('contribute', 'Reg', (110, 120))	('mutations', 'Var', (48, 57))
8348	23497023	The chi-square test and non-parametric test were used to examine the association between mtDNA copy number and the age and sex of the patient, pathological type of CRC sample, clinical stage, and metastases to lymph nodes.	('metastases', 'Disease', 'MESH:D009362', (196, 206))	('CRC', 'Phenotype', 'HP:0003003', (164, 167))	('copy number', 'Var', (95, 106))	('clinical', 'Species', '191496', (176, 184))	('association', 'Interaction', (69, 80))	('patient', 'Species', '9606', (134, 141))	('mtDNA', 'Gene', (89, 94))	('CRC', 'Phenotype', 'HP:0030731', (164, 167))	('metastases', 'Disease', (196, 206))
8358	23497023	Patients with lymph-node metastasis were more likely to have a lower T/N ratio compared with patients without lymph-node metastasis, (p < 0.05).	('lymph-node metastasis', 'Var', (14, 35))	('lower', 'NegReg', (63, 68))	('Patients', 'Species', '9606', (0, 8))	('T/N ratio', 'MPA', (69, 78))	('patients', 'Species', '9606', (93, 101))
8373	23497023	The mtDNA- depleted cells showed a decreased sensitivity and accumulation of anti-cancer drugs, suggesting that mtDNA depletion could develop multidrug resistance (MDR) phenotype in HCT-8 cells.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('mtDNA', 'cellular_component', 'GO:0000262', ('112', '117'))	('HCT-8', 'CellLine', 'CVCL:2478', (182, 187))	('sensitivity', 'MPA', (45, 56))	('multidrug', 'MPA', (142, 151))	('decreased', 'NegReg', (35, 44))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('mtDNA', 'cellular_component', 'GO:0000262', ('4', '9'))	('MDR', 'molecular_function', 'GO:0004745', ('164', '167'))	('mtDNA', 'Var', (112, 117))	('develop', 'PosReg', (134, 141))
8383	23497023	These studies suggest that the loss of mtDNA can promote the development and metastasis of tumors .	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('metastasis of tumors', 'Disease', 'MESH:D009362', (77, 97))	('loss', 'Var', (31, 35))	('mtDNA', 'Gene', (39, 44))	('metastasis of tumors', 'Disease', (77, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('promote', 'PosReg', (49, 56))
8384	23497023	The loss of mtDNA may affect the development of cancer and cancer metastasis by preventing apoptosis and promoting the generation of cancer-related proteins.	('apoptosis', 'biological_process', 'GO:0097194', ('91', '100'))	('preventing', 'NegReg', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('apoptosis', 'CPA', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('apoptosis', 'biological_process', 'GO:0006915', ('91', '100'))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mtDNA', 'Gene', (12, 17))	('mtDNA', 'cellular_component', 'GO:0000262', ('12', '17'))	('cancer', 'Disease', (133, 139))	('affect', 'Reg', (22, 28))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('promoting', 'PosReg', (105, 114))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('loss', 'Var', (4, 8))
8385	23497023	suggest that somatic mtDNA mutations and mtDNA depletion occur in gastric cancer and that mtDNA depletion is involved in carcinogenesis and/or cancer progression of gastric carcinoma .	('mutations', 'Var', (27, 36))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('occur', 'Reg', (57, 62))	('gastric carcinoma', 'Disease', 'MESH:D013274', (165, 182))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('gastric carcinoma', 'Disease', (165, 182))	('cancer', 'Disease', (143, 149))	('involved', 'Reg', (109, 117))	('mtDNA', 'Gene', (21, 26))	('carcinogenesis', 'Disease', (121, 135))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (165, 182))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinogenesis', 'Disease', 'MESH:D063646', (121, 135))	('gastric cancer', 'Disease', (66, 80))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
8397	23497023	Patients with a relatively high copy number of mtDNA had a higher three-year tumor-free survival than patients with a lower copy number of mtDNA.	('patients', 'Species', '9606', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('Patients', 'Species', '9606', (0, 8))	('mtDNA', 'Var', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('higher', 'PosReg', (59, 65))	('tumor', 'Disease', (77, 82))
8403	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))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
8406	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))
8408	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))
8421	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))	('cancers', 'Disease', (168, 175))	('metastasis', 'CPA', (126, 136))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('contributes', 'Reg', (91, 102))	('tight junction', 'cellular_component', 'GO:0070160', ('67', '81'))
8438	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))
8458	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))	('Mouse', 'Species', '10090', (242, 247))	('P/N 926', 'Var', (248, 255))
8472	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))	('SW620', 'Var', (86, 91))	('HCT116', 'CellLine', 'CVCL:0291', (74, 80))	('HT29', 'CellLine', 'CVCL:0320', (68, 72))	('level', 'MPA', (25, 30))	('SW620', 'CellLine', 'CVCL:0547', (86, 91))	('cancerous', 'Disease', (116, 125))	('HCT116', 'Var', (74, 80))	('higher', 'PosReg', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('HT29', 'Var', (68, 72))	('tricellulin', 'Gene', '153562', (34, 45))	('tricellulin', 'Gene', (34, 45))
8474	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))
8490	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))
8495	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))
8497	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))	('functions', 'MPA', (24, 33))	('tight junction-related proteins', 'Protein', (41, 72))
8502	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))
8509	33000262	For example, knockdown of tricellulin expression using RNAi compromised the epithelial barrier and tricellular contacts and disorganized the bicellular tight-junction.	('tricellular contacts', 'CPA', (99, 119))	('tricellulin', 'Gene', (26, 37))	('epithelial barrier', 'CPA', (76, 94))	('bicellular tight-junction', 'MPA', (141, 166))	('disorganized', 'NegReg', (124, 136))	('tricellulin', 'Gene', '153562', (26, 37))	('knockdown', 'Var', (13, 22))	('compromised', 'NegReg', (60, 71))
8522	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))	('TNF-alpha', 'Gene', '7124', (171, 180))	('Snail', 'Gene', '6615', (72, 77))	('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))	('Snail', 'Gene', (72, 77))	('tricellulin', 'Gene', (26, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (239, 256))	('NF-kappaB', 'Gene', '4790', (285, 294))	('tricellulin', 'Gene', '153562', (203, 214))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('tricellulin', 'Gene', '153562', (26, 37))	('vimentin', 'Gene', '7431', (59, 67))
8532	32810173	3D imaging of colorectal cancer organoids identifies responses to Tankyrase inhibitors Aberrant activation of the Wnt signalling pathway is required for tumour initiation and survival in the majority of colorectal cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (14, 31))	('signalling pathway', 'biological_process', 'GO:0007165', ('118', '136'))	('tumour initiation', 'Disease', (153, 170))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('colorectal cancer', 'Phenotype', 'HP:0003003', (203, 220))	('colorectal cancers', 'Disease', (203, 221))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('Tankyrase', 'Gene', '8658', (66, 75))	('colorectal cancer', 'Disease', 'MESH:D015179', (14, 31))	('activation', 'PosReg', (96, 106))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('Tankyrase', 'Gene', (66, 75))	('colorectal cancer', 'Disease', (14, 31))	('inhibitors', 'Var', (76, 86))	('colorectal cancer', 'Disease', 'MESH:D015179', (203, 220))	('colorectal cancers', 'Disease', 'MESH:D015179', (203, 221))	('tumour initiation', 'Disease', 'MESH:D009369', (153, 170))	('Wnt signalling pathway', 'Pathway', (114, 136))
8538	32810173	Here, we generated tumour organoids from colorectal cancer patients and tested their responses to inhibitors of Tankyrase (TNKSi) which are known to modulate Wnt signalling.	('colorectal cancer', 'Phenotype', 'HP:0003003', (41, 58))	('tumour', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('modulate', 'Reg', (149, 157))	('Tankyrase', 'Gene', '8658', (112, 121))	('inhibitors', 'Var', (98, 108))	('colorectal cancer', 'Disease', (41, 58))	('tumour', 'Disease', (19, 25))	('TNKS', 'Gene', (123, 127))	('patients', 'Species', '9606', (59, 67))	('Tankyrase', 'Gene', (112, 121))	('colorectal cancer', 'Disease', 'MESH:D015179', (41, 58))	('tested', 'Reg', (72, 78))	('TNKS', 'Gene', '8658', (123, 127))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('responses', 'MPA', (85, 94))
8540	32810173	Aberrant canonical Wnt/beta-catenin signalling, as a result of activating mutations within the pathway, has a prominent role in the initiation and progression of colorectal cancer (CRC).	('colorectal cancer', 'Disease', 'MESH:D015179', (162, 179))	('CRC', 'Phenotype', 'HP:0003003', (181, 184))	('Aberrant', 'Var', (0, 8))	('colorectal cancer', 'Phenotype', 'HP:0003003', (162, 179))	('mutations', 'Var', (74, 83))	('activating', 'PosReg', (63, 73))	('beta-catenin', 'Gene', (23, 35))	('colorectal cancer', 'Disease', (162, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('beta-catenin', 'Gene', '1499', (23, 35))
8547	32810173	Small molecule inhibitors of TNKS1 and TNKS2 have been shown to reduce Wnt signalling in intestinal cancer cell lines and have been suggested to prevent tumour growth due to their ability to stabilise AXIN1 and AXIN2 levels and as a result, to inhibit beta-catenin mediated transcription.	('reduce', 'NegReg', (64, 70))	('TNKS2', 'Gene', (39, 44))	('inhibitors', 'Var', (15, 25))	('AXIN2', 'Gene', '8313', (211, 216))	('AXIN1', 'Gene', '8312', (201, 206))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('TNKS1', 'Gene', (29, 34))	('Wnt signalling', 'MPA', (71, 85))	('inhibit', 'NegReg', (244, 251))	('intestinal cancer', 'Disease', (89, 106))	('tumour growth', 'Disease', 'MESH:D006130', (153, 166))	('prevent', 'NegReg', (145, 152))	('beta-catenin', 'Gene', (252, 264))	('beta-catenin', 'Gene', '1499', (252, 264))	('AXIN2', 'Gene', (211, 216))	('TNKS1', 'Gene', '8658', (29, 34))	('TNKS2', 'Gene', '80351', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('intestinal cancer', 'Disease', 'MESH:D007414', (89, 106))	('tumour growth', 'Disease', (153, 166))	('AXIN1', 'Gene', (201, 206))
8550	32810173	Similar partial-efficacy cell line responses were observed during the development of inhibitors of the CDK8 and CDK19 kinases, suggesting that growth in 2D cell culture may not be an optimal readout for compounds that are anticipated to target cancer stem cells.	('CDK8', 'Gene', (103, 107))	('CDK19', 'Gene', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('inhibitors', 'Var', (85, 95))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
8551	32810173	Whilst cancer cell lines can be usefully used to study pathway deregulation, they frequently fail to be predictive when used as readouts of anti-tumour efficacy.	('tumour', 'Disease', (145, 151))	('deregulation', 'Var', (63, 75))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', (7, 13))
8556	32810173	Organoids derived from genetically-engineered mice in which the Wnt pathway had been oncogenically-activated accurately predicted subsequent in vivo responses to inhibitors of the CDK8 and CDK19 kinases, while 2D cell culture only showed partial-efficacy.	('mice', 'Species', '10090', (46, 50))	('CDK19', 'Enzyme', (189, 194))	('CDK8', 'Enzyme', (180, 184))	('inhibitors', 'Var', (162, 172))
8579	32810173	The following additional niche factors were added to generate "Full" media: 50 ng/ml mouse recombinant EGF (Life Technologies), 100 ng/ml mouse recombinant Noggin (Peprotech), 10% RSpo-1 conditioned medium, 40% Wnt-3A conditioned medium, 500 nM A83-01 (Tocris) and 10 muM SB202190 (Sigma).	('mouse', 'Species', '10090', (85, 90))	('EGF', 'molecular_function', 'GO:0005154', ('101', '104'))	('SB202190', 'Chemical', 'MESH:C090942', (272, 280))	('mouse', 'Species', '10090', (138, 143))	('Wnt-3A', 'Gene', (211, 217))	('SB202190', 'Var', (272, 280))	('RSpo-1', 'Gene', (180, 186))	('Wnt-3A', 'Gene', '22416', (211, 217))	('muM', 'Gene', '56925', (268, 271))	('muM', 'Gene', (268, 271))	('RSpo-1', 'Gene', '192199', (180, 186))
8624	32810173	8/10 organoid lines showed good growth in 7+ basal medium whilst 2/10 were dependent on the additional inclusion of EGF (50 ng/ml), Noggin (100 ng/ml), Nicotinamide (10 mM), A-83-01 (500 nM), SB202190 (10 muM), as well as Wnt3a- (40%) and R-spondin 1- (10%) conditioned media.	('R-spondin 1', 'Gene', '284654', (239, 250))	('R-spondin 1', 'Gene', (239, 250))	('growth', 'MPA', (32, 38))	('100 ng/ml', 'Var', (140, 149))	('SB202190', 'Var', (192, 200))	('good growth', 'Phenotype', 'HP:0001510', (27, 38))	('muM', 'Gene', '56925', (205, 208))	('Wnt3a', 'Gene', '89780', (222, 227))	('Nicotinamide', 'Chemical', 'MESH:D009536', (152, 164))	('SB202190', 'Chemical', 'MESH:C090942', (192, 200))	('muM', 'Gene', (205, 208))	('Wnt3a', 'Gene', (222, 227))
8626	32810173	In particular, 80% of organoid lines harboured mutations in components of the Wnt signalling pathway, such as APC and beta -catenin (CTNNB1).	('CTNNB1', 'Gene', (133, 139))	('beta -catenin', 'Gene', (118, 131))	('beta -catenin', 'Gene', '1499', (118, 131))	('mutations', 'Var', (47, 56))	('APC', 'Phenotype', 'HP:0005227', (110, 113))	('APC', 'Disease', 'MESH:D011125', (110, 113))	('CTNNB1', 'Gene', '1499', (133, 139))	('APC', 'Disease', (110, 113))
8627	32810173	Iso 75 was found to harbour a mutation in RNF43, which is associated with an increased Frizzled (Fz) receptor expression and Wnt ligand dependence.	('Fz', 'Gene', (97, 99))	('ligand', 'molecular_function', 'GO:0005488', ('129', '135'))	('mutation', 'Var', (30, 38))	('expression', 'MPA', (110, 120))	('RNF43', 'Gene', (42, 47))	('increased', 'PosReg', (77, 86))	('RNF43', 'Gene', '54894', (42, 47))	('Iso', 'Chemical', '-', (0, 3))
8636	32810173	To assess the functional impact of Tankyrase inhibition on organoid growth, cell viability assays were performed for 3 organoid lines; Iso 50, Iso 72 and Iso 75.	('Iso 72', 'Chemical', '-', (143, 149))	('Tankyrase', 'Gene', (35, 44))	('Iso 75', 'Var', (154, 160))	('Iso', 'Chemical', '-', (135, 138))	('Iso', 'Chemical', '-', (154, 157))	('Tankyrase', 'Gene', '8658', (35, 44))	('Iso', 'Chemical', '-', (143, 146))	('Iso 72', 'Var', (143, 149))	('Iso', 'Var', (135, 138))
8643	32810173	Immunofluorescent staining showed reduced levels of the proliferation marker Ki67 in Iso 72 but not Iso 50 organoids suggesting that reduced proliferation contributed to the lower ATP levels observed (Fig 2H and 2I).	('levels', 'MPA', (42, 48))	('reduced', 'NegReg', (34, 41))	('Iso', 'Var', (85, 88))	('lower', 'NegReg', (174, 179))	('proliferation', 'MPA', (141, 154))	('ATP levels', 'MPA', (180, 190))	('Iso', 'Chemical', '-', (85, 88))	('ATP', 'Chemical', 'MESH:D000255', (180, 183))	('Iso 72', 'Chemical', '-', (85, 91))	('reduced', 'NegReg', (133, 140))	('Iso', 'Chemical', '-', (100, 103))
8645	32810173	Three Tankyrase 1/2 (TNKS1/2) small molecule inhibitors were used that differed over 3 orders of magnitude in their potency (C1; 2nM, C2; 36nM, C3; 319nM Fig 2A).	('C3; 319nM', 'Var', (144, 153))	('C1; 2nM', 'Var', (125, 132))	('C1', 'Chemical', 'MESH:C400149', (125, 127))	('C2; 36nM', 'Var', (134, 142))	('Tankyrase 1/2', 'Gene', (6, 19))	('Tankyrase 1/2', 'Gene', '8658;80351', (6, 19))
8656	32810173	Whole exome sequencing revealed that Iso 75 harboured an RNF43 mutation (Fig 1A), which would likely yield organoids that require Wnt signalling at the receptor level-upstream of the Axin-containing beta-catenin turnover complex.	('beta-catenin', 'Gene', '1499', (199, 211))	('Axin', 'Gene', '8312', (183, 187))	('RNF43', 'Gene', (57, 62))	('Axin', 'Gene', (183, 187))	('RNF43', 'Gene', '54894', (57, 62))	('mutation', 'Var', (63, 71))	('Iso', 'Chemical', '-', (37, 40))	('yield', 'Reg', (101, 106))	('beta-catenin', 'Gene', (199, 211))
8663	32810173	Expression of DKK1 and ASCL2, two direct beta-catenin target genes, were reduced in all three lines although the effect size was greater in ASCL2 levels of the TNKSi-sensitive lines Iso 72 and Iso 75 than in the TNKSi-insensitive line Iso 50 (p<0.001, Fig 4B).	('Iso 75', 'Var', (193, 199))	('beta-catenin', 'Gene', (41, 53))	('beta-catenin', 'Gene', '1499', (41, 53))	('DKK1', 'Gene', '22943', (14, 18))	('DKK1', 'Gene', (14, 18))	('TNKS', 'Gene', (212, 216))	('Iso', 'Chemical', '-', (182, 185))	('ASCL2', 'Gene', (140, 145))	('TNKS', 'Gene', '8658', (212, 216))	('Iso 72', 'Chemical', '-', (182, 188))	('reduced', 'NegReg', (73, 80))	('ASCL2', 'Gene', '430', (140, 145))	('Expression', 'MPA', (0, 10))	('Iso', 'Var', (182, 185))	('Iso', 'Chemical', '-', (235, 238))	('Iso', 'Chemical', '-', (193, 196))	('TNKS', 'Gene', (160, 164))	('ASCL2', 'Gene', (23, 28))	('TNKS', 'Gene', '8658', (160, 164))	('ASCL2', 'Gene', '430', (23, 28))
8665	32810173	Changes in gene expression which did correlate with functional TNKSi sensitivity included reductions in the expression of the intestinal stem cell marker LGR5 and the upregulation of cytokeratin 20 (KRT20) (Fig 4B; S6 Fig), suggesting that tankyrase inhibition may induce differentiation as has previously been shown with CRC cell lines.	('reductions', 'NegReg', (90, 100))	('TNKS', 'Gene', '8658', (63, 67))	('inhibition', 'Var', (250, 260))	('cytokeratin 20', 'Gene', (183, 197))	('cytokeratin 20', 'Gene', '54474', (183, 197))	('tankyrase', 'Gene', '8658', (240, 249))	('LGR5', 'Gene', (154, 158))	('induce', 'Reg', (265, 271))	('KRT20', 'Gene', (199, 204))	('gene expression', 'MPA', (11, 26))	('tankyrase', 'Gene', (240, 249))	('LGR5', 'Gene', '8549', (154, 158))	('expression', 'MPA', (108, 118))	('upregulation', 'PosReg', (167, 179))	('CRC', 'Phenotype', 'HP:0003003', (322, 325))	('TNKS', 'Gene', (63, 67))	('KRT20', 'Gene', '54474', (199, 204))	('differentiation', 'CPA', (272, 287))
8679	32810173	Alterations in the expression of stem cell marker genes including ASCL2 and LGR5 correlated with cellular responses, but larger-scale studies will be required to determine whether panels of gene expression markers reliably predict organoid (and ultimately patient) responses.	('expression', 'MPA', (19, 29))	('cellular responses', 'CPA', (97, 115))	('ASCL2', 'Gene', (66, 71))	('Alterations', 'Var', (0, 11))	('gene expression', 'biological_process', 'GO:0010467', ('190', '205'))	('correlated', 'Reg', (81, 91))	('ASCL2', 'Gene', '430', (66, 71))	('LGR5', 'Gene', '8549', (76, 80))	('LGR5', 'Gene', (76, 80))	('patient', 'Species', '9606', (256, 263))
8682	32810173	Morphometric assays showed that Iso75, a line that required Wnt3a and R-spondin for growth (mutant for RNF43 mutant and APC wild type), was sensitive to TNKSi as expected.	('Wnt3a', 'Gene', (60, 65))	('APC', 'Phenotype', 'HP:0005227', (120, 123))	('APC', 'Disease', 'MESH:D011125', (120, 123))	('TNKS', 'Gene', (153, 157))	('APC', 'Disease', (120, 123))	('Iso', 'Chemical', '-', (32, 35))	('TNKS', 'Gene', '8658', (153, 157))	('RNF43', 'Gene', '54894', (103, 108))	('mutant', 'Var', (109, 115))	('mutant', 'Var', (92, 98))	('Wnt3a', 'Gene', '89780', (60, 65))	('RNF43', 'Gene', (103, 108))
8686	32810173	Taken together with the reductions in Wnt target gene expression and beta-catenin levels, this would suggest that modulation of Wnt signalling in a sensitive line was sufficient to limit the stem-like signature of organoid cell populations.	('beta-catenin', 'Gene', (69, 81))	('modulation', 'Var', (114, 124))	('limit', 'NegReg', (181, 186))	('beta-catenin', 'Gene', '1499', (69, 81))	('stem-like signature of organoid cell populations', 'CPA', (191, 239))
8693	32117908	Here, as a case study of colorectal cancer (CRC), functional and dynamic characterizations of five types of engineered organoids with different mutation combinations of five driver genes (APC, SMAD4, KRAS, TP53, and PIK3CA) showed that sequential introductions of all five driver mutations could induce enhanced activation of more hallmark signatures, tending to cancer.	('CRC', 'Disease', (44, 47))	('cancer', 'Disease', 'MESH:D009369', (363, 369))	('enhanced activation', 'PosReg', (303, 322))	('PIK3CA', 'Gene', '5290', (216, 222))	('SMAD4', 'Gene', '4089', (193, 198))	('colorectal cancer', 'Disease', 'MESH:D015179', (25, 42))	('CRC', 'Phenotype', 'HP:0003003', (44, 47))	('TP53', 'Gene', '7157', (206, 210))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('KRAS', 'Gene', '3845', (200, 204))	('colorectal cancer', 'Disease', (25, 42))	('CRC', 'Disease', 'MESH:D015179', (44, 47))	('KRAS', 'Gene', (200, 204))	('PIK3CA', 'Gene', (216, 222))	('cancer', 'Disease', (363, 369))	('more hallmark signatures', 'MPA', (326, 350))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('TP53', 'Gene', (206, 210))	('colorectal cancer', 'Phenotype', 'HP:0003003', (25, 42))	('SMAD4', 'Gene', (193, 198))	('mutations', 'Var', (280, 289))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
8694	32117908	Comparative analysis of engineered organoids and corresponding CRC tissues revealed sequential introduction of key mutations could continually shorten the biological distance from engineered organoids to CRC tissues.	('mutations', 'Var', (115, 124))	('CRC', 'Disease', (204, 207))	('CRC', 'Phenotype', 'HP:0003003', (63, 66))	('shorten', 'NegReg', (143, 150))	('CRC', 'Disease', 'MESH:D015179', (63, 66))	('CRC', 'Phenotype', 'HP:0003003', (204, 207))	('CRC', 'Disease', 'MESH:D015179', (204, 207))	('CRC', 'Disease', (63, 66))
8697	32117908	Our results not only recapitulated the well-known adenoma-carcinoma sequence model (e.g., AKST-organoid with driver mutations in APC, KRAS, SMAD4, and TP53), but also provided potential paths for delineating alternative pathogenesis underlying CRC populations (e.g., A-organoid with APC mutation).	('KRAS', 'Gene', '3845', (134, 138))	('adenoma-carcinoma', 'Disease', (50, 67))	('CRC', 'Disease', (244, 247))	('TP53', 'Gene', (151, 155))	('CRC', 'Phenotype', 'HP:0003003', (244, 247))	('APC', 'cellular_component', 'GO:0005680', ('129', '132'))	('SMAD4', 'Gene', (140, 145))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (50, 67))	('CRC', 'Disease', 'MESH:D015179', (244, 247))	('pathogenesis', 'biological_process', 'GO:0009405', ('220', '232'))	('mutations', 'Var', (116, 125))	('KRAS', 'Gene', (134, 138))	('APC', 'cellular_component', 'GO:0005680', ('283', '286'))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('APC', 'Gene', (129, 132))	('TP53', 'Gene', '7157', (151, 155))	('SMAD4', 'Gene', '4089', (140, 145))
8698	32117908	Our strategy also can be applied to both organoids with more mutations and other cancers, which can improve and innovate mechanism across cancer patients for drug design and cancer therapy.	('patients', 'Species', '9606', (145, 153))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Disease', (81, 87))	('cancers', 'Disease', (81, 88))	('mutations', 'Var', (61, 70))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
8700	32117908	The sequential genetic alterations of APC, KRAS, SMAD4, and TP53 could recapitulate the key features in transition from normal to adenoma and to initiation and progression of CRC, which promoted the understanding of pathogenesis in CRCs (Powell et al.,; Drost et al.,; Chen et al.,).	('CRC', 'Phenotype', 'HP:0003003', (175, 178))	('CRC', 'Disease', 'MESH:D015179', (175, 178))	('adenoma', 'Disease', (130, 137))	('CRC', 'Disease', (232, 235))	('SMAD4', 'Gene', '4089', (49, 54))	('KRAS', 'Gene', (43, 47))	('TP53', 'Gene', '7157', (60, 64))	('CRC', 'Phenotype', 'HP:0003003', (232, 235))	('pathogenesis', 'biological_process', 'GO:0009405', ('216', '228'))	('alterations', 'Var', (23, 34))	('APC', 'cellular_component', 'GO:0005680', ('38', '41'))	('CRC', 'Disease', (175, 178))	('adenoma', 'Disease', 'MESH:D000236', (130, 137))	('CRC', 'Disease', 'MESH:D015179', (232, 235))	('TP53', 'Gene', (60, 64))	('KRAS', 'Gene', '3845', (43, 47))	('SMAD4', 'Gene', (49, 54))
8701	32117908	Mutations on these genes could deregulate driver pathways to confer selective growth advantages and further to drive colorectal carcinogenesis.	('colorectal carcinogenesis', 'Disease', (117, 142))	('driver pathways', 'Pathway', (42, 57))	('growth advantages', 'CPA', (78, 95))	('Mutations', 'Var', (0, 9))	('deregulate', 'Reg', (31, 41))	('drive', 'Reg', (111, 116))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (117, 142))
8702	32117908	The inactivating mutations of APC could initiate a benign adenoma by activating the WNT pathway (Powell et al.,; Roper et al.,; Takeda et al.,), which was proved by the upregulation of beta-catenin driven by APC mutations (Matano et al.,).	('inactivating mutations', 'Var', (4, 26))	('APC', 'Gene', (30, 33))	('adenoma', 'Disease', 'MESH:D000236', (58, 65))	('upregulation', 'PosReg', (169, 181))	('adenoma', 'Disease', (58, 65))	('activating', 'Reg', (69, 79))	('beta-catenin', 'Gene', '1499', (185, 197))	('initiate', 'Reg', (40, 48))	('mutations', 'Var', (212, 221))	('APC', 'Gene', (208, 211))	('WNT pathway', 'Pathway', (84, 95))	('beta-catenin', 'Gene', (185, 197))
8703	32117908	The follow genetic alterations in KRAS, SMAD4, and TP53 further promoted the transition of adenoma to CRC by activating EGFR, P53 and TGF-beta pathways (Drost et al.,; Chen et al.,).	('P53', 'Gene', '7157', (52, 55))	('CRC', 'Phenotype', 'HP:0003003', (102, 105))	('promoted', 'PosReg', (64, 72))	('SMAD4', 'Gene', (40, 45))	('KRAS', 'Gene', '3845', (34, 38))	('CRC', 'Disease', 'MESH:D015179', (102, 105))	('TGF-beta pathways', 'Pathway', (134, 151))	('TP53', 'Gene', (51, 55))	('P53', 'Gene', (126, 129))	('KRAS', 'Gene', (34, 38))	('activating', 'PosReg', (109, 119))	('SMAD4', 'Gene', '4089', (40, 45))	('EGFR', 'Gene', (120, 124))	('P53', 'Gene', (52, 55))	('P53', 'Gene', '7157', (126, 129))	('TP53', 'Gene', '7157', (51, 55))	('adenoma', 'Disease', (91, 98))	('transition', 'Disease', (77, 87))	('CRC', 'Disease', (102, 105))	('EGFR', 'Gene', '1956', (120, 124))	('adenoma', 'Disease', 'MESH:D000236', (91, 98))	('genetic alterations', 'Var', (11, 30))
8705	32117908	The activating mutations in KRAS could activate EGF signaling.	('KRAS', 'Gene', (28, 32))	('KRAS', 'Gene', '3845', (28, 32))	('EGF signaling', 'Pathway', (48, 61))	('mutations', 'Var', (15, 24))	('activating', 'PosReg', (4, 14))	('activate', 'PosReg', (39, 47))
8706	32117908	The SMAD4 and TP53 mutations promoted the transition from adenoma to adenocarcinoma stages (Fearon and Vogelstein,).	('promoted', 'PosReg', (29, 37))	('transition', 'CPA', (42, 52))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('adenoma to adenocarcinoma', 'Disease', 'MESH:D000236', (58, 83))	('mutations', 'Var', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('SMAD4', 'Gene', (4, 9))	('adenoma to adenocarcinoma', 'Disease', (58, 83))	('SMAD4', 'Gene', '4089', (4, 9))
8707	32117908	The mutation in TP53 could overexpressed a truncated TP53 protein which made TP53 lose tumor suppressor roles (Tang et al.,).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('overexpressed', 'PosReg', (27, 40))	('tumor', 'Disease', (87, 92))	('lose', 'NegReg', (82, 86))	('mutation', 'Var', (4, 12))	('tumor suppressor', 'biological_process', 'GO:0051726', ('87', '103'))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('TP53', 'Gene', '7157', (16, 20))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('87', '103'))	('TP53', 'Gene', '7157', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('TP53', 'Gene', (16, 20))	('TP53', 'Gene', (53, 57))
8710	32117908	Introducing key mutations into organoids other than cells could provide better manners to examine the influence of driver genes during cancer carcinogenesis.	('cancer carcinogenesis', 'Disease', (135, 156))	('cancer carcinogenesis', 'Disease', 'MESH:D009369', (135, 156))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))
8711	32117908	Directly targeting modification of cancer genes could produce cancer cells from the mouse primary cells or in vivo tissue (Ran et al.,; Heckl et al.,; Platt et al.,; Sanchez-Rivera et al.,; Xue et al.,).	('modification', 'Var', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('mouse', 'Species', '10090', (84, 89))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
8712	32117908	We summarized the recent studies modeling CRC using intestinal organoids with introducing driver mutations in APC, SMAD4, KRAS, TP53, and PIK3CA (Table S1) (Cooks et al.,; Onuma et al.,; Drost et al.,; Matano et al.,; Chen et al.,; Nakayama et al.,; O'Rourke et al.,; Riemer et al.,; van Lidth de Jeude et al.,).	('mutations', 'Var', (97, 106))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('CRC', 'Disease', 'MESH:D015179', (42, 45))	('CRC', 'Phenotype', 'HP:0003003', (42, 45))	('PIK3CA', 'Gene', (138, 144))	('SMAD4', 'Gene', '4089', (115, 120))	('KRAS', 'Gene', (122, 126))	('SMAD4', 'Gene', (115, 120))	('PIK3CA', 'Gene', '5290', (138, 144))	('KRAS', 'Gene', '3845', (122, 126))	('CRC', 'Disease', (42, 45))
8713	32117908	Intestinal organoids with APC mutations developed into benign tumors after transplantation (O'Rourke et al.,).	('developed', 'Reg', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('benign tumors', 'Disease', (55, 68))	('mutations', 'Var', (30, 39))	('APC', 'Gene', (26, 29))	('benign tumors', 'Disease', 'MESH:D009369', (55, 68))
8715	32117908	Engineered organoids expressing KRAS mutations could expand in the condition withdrawing EGFR signaling (Matano et al.,).	('EGFR', 'Gene', (89, 93))	('KRAS', 'Gene', (32, 36))	('KRAS', 'Gene', '3845', (32, 36))	('mutations', 'Var', (37, 46))	('EGFR', 'Gene', '1956', (89, 93))
8716	32117908	TP53 mutations induced prolongation of activation of NF-kappaB signaling, and promoted inflammation-associated colorectal cancer (Cooks et al.,).	('TP53', 'Gene', '7157', (0, 4))	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('TP53', 'Gene', (0, 4))	('activation', 'PosReg', (39, 49))	('promoted', 'PosReg', (78, 86))	('inflammation-associated colorectal cancer', 'Disease', (87, 128))	('mutations', 'Var', (5, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('inflammation', 'biological_process', 'GO:0006954', ('87', '99'))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('39', '62'))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('inflammation-associated colorectal cancer', 'Disease', 'MESH:D015179', (87, 128))	('NF-kappaB', 'MPA', (53, 62))
8717	32117908	TP53 mutation-targeted organoids could recover in the condition of activation of TP53 signaling pathway which can induce cell cycle arrest and apoptosis (Matano et al.,).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('activation', 'PosReg', (67, 77))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (121, 138))	('cell cycle arrest', 'CPA', (121, 138))	('apoptosis', 'CPA', (143, 152))	('induce', 'PosReg', (114, 120))	('mutation-targeted', 'Var', (5, 22))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
8718	32117908	Oncogenic PIK3CA could regulate cell motility though AKT, and PIK3CA mutations played key roles in reprograming glutamine metabolism in colorectal cancers (Hao et al.,).	('cell motility', 'CPA', (32, 45))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('regulate', 'Reg', (23, 31))	('Hao', 'molecular_function', 'GO:0047991', ('156', '159'))	('PIK3CA', 'Gene', '5290', (10, 16))	('colorectal cancers', 'Disease', 'MESH:D015179', (136, 154))	('glutamine', 'Chemical', 'MESH:D005973', (112, 121))	('PIK3CA', 'Gene', '5290', (62, 68))	('AKT', 'Gene', (53, 56))	('mutations', 'Var', (69, 78))	('cell motility', 'biological_process', 'GO:0048870', ('32', '45'))	('PIK3CA', 'Gene', (10, 16))	('colorectal cancer', 'Phenotype', 'HP:0003003', (136, 153))	('colorectal cancers', 'Disease', (136, 154))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('112', '132'))	('PIK3CA', 'Gene', (62, 68))	('AKT', 'Gene', '207', (53, 56))	('reprograming glutamine metabolism', 'MPA', (99, 132))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))
8719	32117908	PIK3CA mutations could induce cell attachment and motility under cooperation of CTNNB1 (Riemer et al.,).	('induce', 'PosReg', (23, 29))	('CTNNB1', 'Gene', '1499', (80, 86))	('PIK3CA', 'Gene', (0, 6))	('cell attachment', 'CPA', (30, 45))	('motility', 'CPA', (50, 58))	('CTNNB1', 'Gene', (80, 86))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutations', 'Var', (7, 16))
8721	32117908	Engineered organoids with APC and KRAS mutations grew into lager dysplasia without invasive features (Takeda et al.,), and further formed invasive submucosal tumor under condition of inhibited TGF-beta signaling pathway (Chen et al.,; Takeda et al.,).	('dysplasia', 'Disease', (65, 74))	('KRAS', 'Gene', '3845', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mutations', 'Var', (39, 48))	('dysplasia', 'Disease', 'MESH:D015792', (65, 74))	('TGF-beta signaling pathway', 'Pathway', (193, 219))	('invasive submucosal tumor', 'Disease', 'MESH:D009361', (138, 163))	('inhibited', 'NegReg', (183, 192))	('KRAS', 'Gene', (34, 38))	('invasive submucosal tumor', 'Disease', (138, 163))
8722	32117908	These studies implied that engineered organoids with sequential introducing driver mutations could provide new clues to exploring developmental mechanisms of cancers.	('mutations', 'Var', (83, 92))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
8729	32117908	We downloaded the gene expression profiles (GSE57965) of adenoma and engineered organoids (Table S3), which contained five adenoma samples with APC mutation (A-organoid), 1 adenoma sample with genetic modification of SMAD4 deletion (AS-organoid), 1 adenoma sample of genetic modification of knocking in KRASG12V (AK-organoid), 2 engineered human colon organoids carrying four gene mutations (APC, KRASG12V, SMAD4, and TP53, AKST-organoids) and 1 engineered human colon organoids carrying five gene mutations (APC, KRASG12V, SMAD4, TP53, and PIK3CAE545K, AKSTP-organoid) (Matano et al.,).	('adenoma', 'Disease', (249, 256))	('adenoma', 'Disease', 'MESH:D000236', (123, 130))	('PIK3CA', 'Gene', '5290', (541, 547))	('SMAD4', 'Gene', '4089', (217, 222))	('APC', 'Var', (509, 512))	('SMAD4', 'Gene', (524, 529))	('SMAD4', 'Gene', '4089', (407, 412))	('gene expression', 'biological_process', 'GO:0010467', ('18', '33'))	('APC', 'cellular_component', 'GO:0005680', ('144', '147'))	('adenoma', 'Disease', 'MESH:D000236', (249, 256))	('KRAS', 'Gene', '3845', (303, 307))	('adenoma', 'Disease', (57, 64))	('TP53', 'Gene', '7157', (531, 535))	('TP53', 'Gene', '7157', (418, 422))	('adenoma', 'Disease', (173, 180))	('adenoma', 'Disease', 'MESH:D000236', (57, 64))	('KRAS', 'Gene', (303, 307))	('human', 'Species', '9606', (340, 345))	('PIK3CA', 'Gene', (541, 547))	('SMAD4', 'Gene', '4089', (524, 529))	('SMAD4', 'Gene', (217, 222))	('APC', 'cellular_component', 'GO:0005680', ('509', '512'))	('adenoma', 'Disease', 'MESH:D000236', (173, 180))	('KRAS', 'Gene', '3845', (397, 401))	('KRAS', 'Gene', '3845', (514, 518))	('SMAD4', 'Gene', (407, 412))	('human', 'Species', '9606', (457, 462))	('KRAS', 'Gene', (397, 401))	('adenoma', 'Disease', (123, 130))	('KRAS', 'Gene', (514, 518))	('TP53', 'Gene', (531, 535))	('APC', 'cellular_component', 'GO:0005680', ('392', '395'))	('TP53', 'Gene', (418, 422))
8731	32117908	We extracted a mutation profiles which contained the samples with mutations in at least one of five genes (including APC, SMAD4, TP53, KRAS, and PIK3CA) and removed mutation types of silent, intron and 5'UTR.	('mutations', 'Var', (66, 75))	('SMAD4', 'Gene', '4089', (122, 127))	('silent', 'Var', (183, 189))	('KRAS', 'Gene', (135, 139))	('SMAD4', 'Gene', (122, 127))	('TP53', 'Gene', (129, 133))	('KRAS', 'Gene', '3845', (135, 139))	('TP53', 'Gene', '7157', (129, 133))	('PIK3CA', 'Gene', (145, 151))	('APC', 'Disease', (117, 120))	('PIK3CA', 'Gene', '5290', (145, 151))	('intron', 'Var', (191, 197))	('APC', 'cellular_component', 'GO:0005680', ('117', '120'))
8732	32117908	Finally, we obtained 103 samples with both gene expression profile and mutation profile (Table S3), in which 54 samples only with APC mutation, 40 samples only with mutations in both APC and KRAS, 3 samples with mutations only in both APC and SMAD4, 1 sample with mutations only in four genes (APC, KRAS, SMAD4, and TP53), and five samples with mutations of all of five genes.	('KRAS', 'Gene', (299, 303))	('APC', 'Gene', (130, 133))	('SMAD4', 'Gene', '4089', (243, 248))	('APC', 'cellular_component', 'GO:0005680', ('130', '133'))	('TP53', 'Gene', (316, 320))	('APC', 'Gene', (183, 186))	('APC', 'cellular_component', 'GO:0005680', ('183', '186'))	('APC', 'cellular_component', 'GO:0005680', ('235', '238'))	('KRAS', 'Gene', '3845', (191, 195))	('mutations', 'Var', (165, 174))	('gene expression', 'biological_process', 'GO:0010467', ('43', '58'))	('KRAS', 'Gene', (191, 195))	('SMAD4', 'Gene', (305, 310))	('TP53', 'Gene', '7157', (316, 320))	('SMAD4', 'Gene', (243, 248))	('APC', 'cellular_component', 'GO:0005680', ('294', '297'))	('KRAS', 'Gene', '3845', (299, 303))	('mutation', 'Var', (134, 142))	('SMAD4', 'Gene', '4089', (305, 310))
8739	32117908	To measure the biological distance from engineered organoids (S) and corresponding CRC samples (T), we compared the activities of 186 functions between S and T. For each type of mutation combination, we calculated the average functional activities of each function,  and , for S and T. The  measure the activity difference.	('activity', 'MPA', (303, 311))	('mutation', 'Var', (178, 186))	('CRC', 'Phenotype', 'HP:0003003', (83, 86))	('CRC', 'Disease', 'MESH:D015179', (83, 86))	('CRC', 'Disease', (83, 86))
8742	32117908	The known driver mutations were inefficient to capture cancer behaviors and to broadly explain cancer mechanisms.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', (55, 61))
8746	32117908	High tumor heterogeneity of genetic alterations in CRC made the well-known adenoma-carcinoma sequence explain a part of CRC patients, additional alternative gene paths were needed to interpret the development progression of more extensive CRC patients.	('High tumor', 'Disease', 'MESH:D009369', (0, 10))	('genetic alterations', 'Var', (28, 47))	('CRC', 'Disease', 'MESH:D015179', (120, 123))	('patients', 'Species', '9606', (124, 132))	('CRC', 'Phenotype', 'HP:0003003', (120, 123))	('adenoma-carcinoma', 'Disease', (75, 92))	('patients', 'Species', '9606', (243, 251))	('CRC', 'Phenotype', 'HP:0003003', (51, 54))	('CRC', 'Disease', 'MESH:D015179', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('CRC', 'Disease', (239, 242))	('High tumor', 'Disease', (0, 10))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (75, 92))	('CRC', 'Disease', (120, 123))	('CRC', 'Disease', (51, 54))	('CRC', 'Phenotype', 'HP:0003003', (239, 242))	('CRC', 'Disease', 'MESH:D015179', (239, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
8747	32117908	Different patients with similar phenotype had different combinations of genetic alterations that tended to participate in same or similar functions.	('genetic alterations', 'Var', (72, 91))	('participate', 'Reg', (107, 118))	('patients', 'Species', '9606', (10, 18))
8748	32117908	Finally, using the well-known adenoma-carcinoma sequence model as the template, each gene cascading path was identified by starting from the mutant genes in the organoids and ending at the potential key gene showing the maximum shortest distance with mutant genes.	('mutant genes', 'Var', (141, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (30, 47))	('adenoma-carcinoma', 'Disease', (30, 47))
8749	32117908	The mutations of five genes (including APC, KRAS, SMAD4, TP53, and PIK3CA) were reported to play driver roles in CRC progression.	('PIK3CA', 'Gene', '5290', (67, 73))	('APC', 'Gene', (39, 42))	('CRC', 'Disease', 'MESH:D015179', (113, 116))	('KRAS', 'Gene', '3845', (44, 48))	('TP53', 'Gene', '7157', (57, 61))	('APC', 'cellular_component', 'GO:0005680', ('39', '42'))	('play', 'Reg', (92, 96))	('CRC', 'Phenotype', 'HP:0003003', (113, 116))	('PIK3CA', 'Gene', (67, 73))	('SMAD4', 'Gene', (50, 55))	('CRC', 'Disease', (113, 116))	('KRAS', 'Gene', (44, 48))	('mutations', 'Var', (4, 13))	('TP53', 'Gene', (57, 61))	('roles', 'Reg', (104, 109))	('SMAD4', 'Gene', '4089', (50, 55))
8754	32117908	Interestingly, only 0.72, 0.94, 0.45, 0% (0/72), 0% samples harbored the mutations of all five genes across the five CRC populations (Figure 2B).	('harbored', 'Reg', (60, 68))	('CRC', 'Phenotype', 'HP:0003003', (117, 120))	('CRC', 'Disease', 'MESH:D015179', (117, 120))	('mutations', 'Var', (73, 82))	('CRC', 'Disease', (117, 120))
8755	32117908	CRC samples harboring mutations in four genes only occupied 16.7, 5.7, 5.5, 8.3, and 3.9%, respectively.	('CRC', 'Disease', (0, 3))	('CRC', 'Disease', 'MESH:D015179', (0, 3))	('mutations', 'Var', (22, 31))	('CRC', 'Phenotype', 'HP:0003003', (0, 3))
8756	32117908	Most CRC samples (74.6, 65.1, 63.6, 58.3, and 54.1%) carried mutations of two or three genes.	('mutations', 'Var', (61, 70))	('carried', 'Reg', (53, 60))	('CRC', 'Disease', (5, 8))	('CRC', 'Phenotype', 'HP:0003003', (5, 8))	('CRC', 'Disease', 'MESH:D015179', (5, 8))
8760	32117908	These phenomenon implied that although the mutations of the five driver genes could explain the CRC pathogenesis well, which could only explain the progressive mechanism for a fraction of CRC patients, but the molecular pathogenesis of major patients remains unclear.	('CRC', 'Phenotype', 'HP:0003003', (188, 191))	('CRC', 'Disease', 'MESH:D015179', (188, 191))	('CRC', 'Phenotype', 'HP:0003003', (96, 99))	('patients', 'Species', '9606', (192, 200))	('CRC', 'Disease', 'MESH:D015179', (96, 99))	('pathogenesis', 'biological_process', 'GO:0009405', ('220', '232'))	('mutations', 'Var', (43, 52))	('CRC', 'Disease', (188, 191))	('CRC', 'Disease', (96, 99))	('pathogenesis', 'biological_process', 'GO:0009405', ('100', '112'))	('patients', 'Species', '9606', (242, 250))
8768	32117908	The mutations of the driver genes could influence gene expression levels of driver genes (P = 0.021 for APC, P = 0.0174 for SMAD4, P = 2.7e-5 for TP53, P = 0.0013 for KRAS, and P = 0.0183 for PIK3CA, Figure S3).	('TP53', 'Gene', '7157', (146, 150))	('influence', 'Reg', (40, 49))	('PIK3CA', 'Gene', (192, 198))	('gene expression levels', 'MPA', (50, 72))	('TP53', 'Gene', (146, 150))	('KRAS', 'Gene', '3845', (167, 171))	('SMAD4', 'Gene', '4089', (124, 129))	('KRAS', 'Gene', (167, 171))	('APC', 'Disease', (104, 107))	('PIK3CA', 'Gene', '5290', (192, 198))	('mutations', 'Var', (4, 13))	('SMAD4', 'Gene', (124, 129))
8769	32117908	According to the mutation status of the five driver genes, the 103 CRC samples were grouped into five groups (Table S3).	('CRC', 'Disease', 'MESH:D015179', (67, 70))	('mutation', 'Var', (17, 25))	('CRC', 'Disease', (67, 70))	('CRC', 'Phenotype', 'HP:0003003', (67, 70))
8770	32117908	To evaluate whether CRC samples with different combinations of driver mutations showed differential activities of hallmark signatures, we calculated the activities of hallmark signatures using single-sample GSEA for each CRC sample (Hanzelmann et al.,).	('mutations', 'Var', (70, 79))	('CRC', 'Phenotype', 'HP:0003003', (20, 23))	('activities', 'MPA', (100, 110))	('CRC', 'Disease', (221, 224))	('GSEA', 'Chemical', '-', (207, 211))	('CRC', 'Disease', 'MESH:D015179', (20, 23))	('CRC', 'Phenotype', 'HP:0003003', (221, 224))	('CRC', 'Disease', (20, 23))	('CRC', 'Disease', 'MESH:D015179', (221, 224))
8778	32117908	In the A-organoids, the WNT pathway showed similar functional activity with the CRC samples with APC mutation (P = 0.015, Figure S5A).	('WNT pathway', 'Pathway', (24, 35))	('CRC', 'Disease', (80, 83))	('CRC', 'Phenotype', 'HP:0003003', (80, 83))	('CRC', 'Disease', 'MESH:D015179', (80, 83))	('mutation', 'Var', (101, 109))
8782	32117908	The RAS and MAPK signaling pathway showed similar activity between AK-organoids and CRC samples (P = 0.11 and P = 0.33, Figures S5C,D), suggesting the combination of APC and KRAS mutations enabled the activity of RAS and MAPK signaling pathway to reach the physiological state of CRCs.	('enabled', 'PosReg', (189, 196))	('CRC', 'Disease', (84, 87))	('CRC', 'Phenotype', 'HP:0003003', (84, 87))	('APC', 'cellular_component', 'GO:0005680', ('166', '169'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('12', '26'))	('CRC', 'Disease', (280, 283))	('MAPK signaling pathway', 'Pathway', (12, 34))	('APC', 'Gene', (166, 169))	('CRC', 'Phenotype', 'HP:0003003', (280, 283))	('CRC', 'Disease', 'MESH:D015179', (84, 87))	('MAPK signaling', 'biological_process', 'GO:0000165', ('221', '235'))	('AK-organoids', 'Chemical', '-', (67, 79))	('mutations', 'Var', (179, 188))	('CRC', 'Disease', 'MESH:D015179', (280, 283))	('signaling pathway', 'biological_process', 'GO:0007165', ('17', '34'))	('KRAS', 'Gene', '3845', (174, 178))	('activity', 'MPA', (201, 209))	('MAPK', 'molecular_function', 'GO:0004707', ('12', '16'))	('MAPK signaling pathway', 'Pathway', (221, 243))	('MAPK', 'molecular_function', 'GO:0004707', ('221', '225'))	('KRAS', 'Gene', (174, 178))	('signaling pathway', 'biological_process', 'GO:0007165', ('226', '243'))
8784	32117908	These results gave a clue that combinations of multiple drive mutations approximated the organoids to CRC by activating or inactivating the activities of functions.	('CRC', 'Phenotype', 'HP:0003003', (102, 105))	('CRC', 'Disease', 'MESH:D015179', (102, 105))	('CRC', 'Disease', (102, 105))	('inactivating', 'NegReg', (123, 135))	('activities of functions', 'MPA', (140, 163))	('mutations', 'Var', (62, 71))	('activating', 'PosReg', (109, 119))
8785	32117908	To characterize the step-by-step progression of CRCs from organoids engineered by introducing mutations, we compared the activity difference of 186 functions from five types of organoids.	('CRC', 'Disease', (48, 51))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('CRC', 'Disease', 'MESH:D015179', (48, 51))	('mutations', 'Var', (94, 103))
8788	32117908	With the increasing number of mutated genes, the activity difference of these functions between organoids and CRCs tended to random state, suggesting the driver progression of key genes during carcinogenesis.	('CRC', 'Disease', (110, 113))	('carcinogenesis', 'Disease', (193, 207))	('CRC', 'Phenotype', 'HP:0003003', (110, 113))	('CRC', 'Disease', 'MESH:D015179', (110, 113))	('mutated genes', 'Var', (30, 43))	('carcinogenesis', 'Disease', 'MESH:D063646', (193, 207))
8789	32117908	APC mutation was a key gene for forming an adenoma.	('adenoma', 'Disease', (43, 50))	('adenoma', 'Disease', 'MESH:D000236', (43, 50))	('mutation', 'Var', (4, 12))	('APC', 'Gene', (0, 3))
8790	32117908	The adenoma still maintained the benign state after introducing SMAD4 mutation.	('SMAD4', 'Gene', '4089', (64, 69))	('adenoma', 'Disease', 'MESH:D000236', (4, 11))	('SMAD4', 'Gene', (64, 69))	('adenoma', 'Disease', (4, 11))	('mutation', 'Var', (70, 78))
8791	32117908	KRAS mutation made the adenoma canceration by dysregulating the activities of many functions, implying KRAS mutation played a key role during transformation from adenoma to CRC.	('KRAS', 'Gene', (103, 107))	('activities', 'MPA', (64, 74))	('adenoma canceration', 'Disease', (23, 42))	('KRAS', 'Gene', '3845', (103, 107))	('CRC', 'Disease', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('adenoma', 'Disease', (23, 30))	('adenoma canceration', 'Disease', 'MESH:D009369', (23, 42))	('CRC', 'Phenotype', 'HP:0003003', (173, 176))	('CRC', 'Disease', 'MESH:D015179', (173, 176))	('adenoma', 'Disease', 'MESH:D000236', (162, 169))	('adenoma', 'Disease', (162, 169))	('KRAS', 'Gene', (0, 4))	('adenoma', 'Disease', 'MESH:D000236', (23, 30))	('mutation', 'Var', (5, 13))	('KRAS', 'Gene', '3845', (0, 4))
8795	32117908	Meanwhile, we found that 27 functions showed significant activity difference between all of five types of organoids and CRCs, such as the PI3K signaling pathway, suggesting that additional key driver mutations were needed to transform the organoids to CRCs.	('CRC', 'Phenotype', 'HP:0003003', (120, 123))	('CRC', 'Disease', 'MESH:D015179', (120, 123))	('mutations', 'Var', (200, 209))	('CRC', 'Disease', (252, 255))	('CRC', 'Phenotype', 'HP:0003003', (252, 255))	('activity', 'MPA', (57, 65))	('signaling pathway', 'biological_process', 'GO:0007165', ('143', '160'))	('CRC', 'Disease', (120, 123))	('CRC', 'Disease', 'MESH:D015179', (252, 255))	('PI3K', 'molecular_function', 'GO:0016303', ('138', '142'))	('PI3K signaling', 'biological_process', 'GO:0014065', ('138', '152'))
8797	32117908	Meanwhile, due to tumor heterogeneity of CRCs, the mutations of five driver genes could explain development mechanisms of a part of CRC patients.	('CRC', 'Disease', (132, 135))	('CRC', 'Phenotype', 'HP:0003003', (41, 44))	('mutations', 'Var', (51, 60))	('tumor', 'Disease', (18, 23))	('CRC', 'Disease', 'MESH:D015179', (41, 44))	('patients', 'Species', '9606', (136, 144))	('CRC', 'Phenotype', 'HP:0003003', (132, 135))	('CRC', 'Disease', 'MESH:D015179', (132, 135))	('CRC', 'Disease', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('explain', 'Reg', (88, 95))
8805	32117908	ERBB4, one of the ErbB receptor tyrosine kinases, showed the functional coherence of 0.56, 0.59, 0.63, and 0.57 with APC, KRAS, PIK3CA, and TP53, respectively, which also participated in cancer associated functions such as MAPK cascade, cell migration and cell proliferation.	('0.59', 'Var', (91, 95))	('participated', 'Reg', (171, 183))	('ERBB4', 'Gene', (0, 5))	('ErbB', 'Gene', (18, 22))	('KRAS', 'Gene', '3845', (122, 126))	('cell proliferation', 'CPA', (256, 274))	('PIK3CA', 'Gene', '5290', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('TP53', 'Gene', (140, 144))	('0.57', 'Var', (107, 111))	('KRAS', 'Gene', (122, 126))	('0.63', 'Var', (97, 101))	('PIK3CA', 'Gene', (128, 134))	('MAPK cascade', 'Pathway', (223, 235))	('TP53', 'Gene', '7157', (140, 144))	('cell migration', 'CPA', (237, 251))	('cancer', 'Disease', (187, 193))	('ErbB', 'Gene', '1956;2065;2066;13869', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
8807	32117908	ERBB4 itself could not induce tumor transformation of mouse colonocytes, while under the condition of colonocytes with mutant Apc and Ras, ERBB4 enhanced the transformed phenotype both in vitro and in vivo (Williams et al.,).	('ERBB4', 'Gene', (139, 144))	('Apc', 'cellular_component', 'GO:0005680', ('126', '129'))	('Apc', 'Gene', '11789', (126, 129))	('transformed phenotype', 'CPA', (158, 179))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('mouse', 'Species', '10090', (54, 59))	('Apc', 'Gene', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('enhanced', 'PosReg', (145, 153))	('mutant', 'Var', (119, 125))	('tumor', 'Disease', (30, 35))	('Ras', 'Gene', (134, 137))
8808	32117908	The increased co-expression of ErbB4-CYT-2 with KITENIN promoted the transition of colon adenoma to adenocarcinoma in tumor microenvironment of APC loss (Bae et al.,).	('KITENIN', 'Gene', '81839', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('KITENIN', 'Gene', (48, 55))	('APC loss', 'Disease', 'MESH:D011125', (144, 152))	('transition', 'MPA', (69, 79))	('APC loss', 'Disease', (144, 152))	('co-expression', 'Var', (14, 27))	('ErbB4-CYT-2', 'Gene', (31, 42))	('colon adenoma to adenocarcinoma in tumor', 'Disease', 'MESH:D015179', (83, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('promoted', 'PosReg', (56, 64))	('increased', 'PosReg', (4, 13))	('colon adenoma to adenocarcinoma in tumor', 'Disease', (83, 123))
8809	32117908	NRG1, neuregulin 1, showed the functional coherence of 0.54, 0.58, 0.55, 0.58, and 0.51 with APC, KRAS, PIK3CA, SMAD4, and TP53, respectively.	('APC', 'cellular_component', 'GO:0005680', ('93', '96'))	('0.51', 'Var', (83, 87))	('SMAD4', 'Gene', (112, 117))	('0.55', 'Var', (67, 71))	('neuregulin 1', 'Gene', (6, 18))	('NRG1', 'Gene', (0, 4))	('PIK3CA', 'Gene', (104, 110))	('neuregulin 1', 'Gene', '3084', (6, 18))	('KRAS', 'Gene', (98, 102))	('SMAD4', 'Gene', '4089', (112, 117))	('TP53', 'Gene', '7157', (123, 127))	('KRAS', 'Gene', '3845', (98, 102))	('0.58', 'Var', (73, 77))	('PIK3CA', 'Gene', '5290', (104, 110))	('NRG1', 'Gene', '3084', (0, 4))	('TP53', 'Gene', (123, 127))
8811	32117908	NRG1 was methylated in tumors and the knockdown of NRG1 could increase net cell proliferation (Chua et al.,).	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('NRG1', 'Gene', (0, 4))	('NRG1', 'Gene', '3084', (51, 55))	('NRG1', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('net cell proliferation', 'CPA', (71, 93))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('knockdown', 'Var', (38, 47))	('NRG1', 'Gene', '3084', (0, 4))	('increase', 'PosReg', (62, 70))
8814	32117908	The silencing of PIK3CG contributed to inhibit the PI3K-Akt/PKB signaling system which was responsible for the tumorigenesis and progression of colorectal cancers (Semba et al.,).	('colorectal cancer', 'Phenotype', 'HP:0003003', (144, 161))	('colorectal cancers', 'Disease', 'MESH:D015179', (144, 162))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('PIK3CG', 'Gene', (17, 23))	('PI3K', 'molecular_function', 'GO:0016303', ('51', '55'))	('PIK3CG', 'Gene', '5294', (17, 23))	('PKB signaling', 'biological_process', 'GO:0043491', ('60', '73'))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Akt', 'Gene', (56, 59))	('inhibit', 'NegReg', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('colorectal cancers', 'Disease', (144, 162))	('tumor', 'Disease', (111, 116))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('Akt', 'Gene', '207', (56, 59))	('silencing', 'Var', (4, 13))
8819	32117908	PKHD1 were the second potential key genes which showed function coherence of 0.47, 0.49, 0.48, 0.45, and 0.45 with APC, SMAD4, KRAS, TP53, and PIC3CA, respectively.	('PKHD1', 'Gene', '5314', (0, 5))	('PKHD1', 'Gene', (0, 5))	('0.45', 'Var', (105, 109))	('SMAD4', 'Gene', (120, 125))	('KRAS', 'Gene', (127, 131))	('SMAD4', 'Gene', '4089', (120, 125))	('TP53', 'Gene', '7157', (133, 137))	('TP53', 'Gene', (133, 137))	('KRAS', 'Gene', '3845', (127, 131))
8821	32117908	Inhibition of PKHD1 may control cell cycle via mTOR signaling pathway (Zheng et al.,), and induced cell apoptosis through PI3K and NF-kappaB pathways (Sun et al.,).	('NF-kappaB pathways', 'Pathway', (131, 149))	('PKHD1', 'Gene', '5314', (14, 19))	('cell apoptosis', 'CPA', (99, 113))	('PKHD1', 'Gene', (14, 19))	('mTOR', 'Gene', '2475', (47, 51))	('Inhibition', 'Var', (0, 10))	('cell cycle', 'CPA', (32, 42))	('mTOR', 'Gene', (47, 51))	('induced', 'PosReg', (91, 98))	('control', 'Reg', (24, 31))
8822	32117908	We found that PKHD1 showed high frequency of mutations in the CRC populations (from 8.9 to 11.8%, Figure S12).	('mutations', 'Var', (45, 54))	('PKHD1', 'Gene', '5314', (14, 19))	('CRC', 'Phenotype', 'HP:0003003', (62, 65))	('CRC', 'Disease', 'MESH:D015179', (62, 65))	('PKHD1', 'Gene', (14, 19))	('CRC', 'Disease', (62, 65))
8823	32117908	Previous studies showed that PKHD1 was a candidate CRC gene by screening mutations in the consensus coding sequences profile, and was assigned to the function of cell adhesion with the first rank (Sjoblom et al.,).	('cell adhesion', 'biological_process', 'GO:0007155', ('162', '175'))	('CRC', 'Disease', (51, 54))	('CRC', 'Phenotype', 'HP:0003003', (51, 54))	('CRC', 'Disease', 'MESH:D015179', (51, 54))	('PKHD1', 'Gene', '5314', (29, 34))	('PKHD1', 'Gene', (29, 34))	('mutations', 'Var', (73, 82))
8824	32117908	The germline mutations of PKHD1 played a protective role in colorectal cancer (Ward et al.,).	('PKHD1', 'Gene', (26, 31))	('PKHD1', 'Gene', '5314', (26, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (60, 77))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('germline mutations', 'Var', (4, 22))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('colorectal cancer', 'Disease', (60, 77))
8825	32117908	Thus, introduction of PKHD1 mutations following the five driver genes may contribute to CRC invasion and metastasis.	('contribute', 'Reg', (74, 84))	('CRC', 'Disease', (88, 91))	('metastasis', 'CPA', (105, 115))	('PKHD1', 'Gene', '5314', (22, 27))	('CRC', 'Phenotype', 'HP:0003003', (88, 91))	('CRC', 'Disease', 'MESH:D015179', (88, 91))	('mutations', 'Var', (28, 37))	('PKHD1', 'Gene', (22, 27))
8826	32117908	The adenoma-carcinoma sequence was recognized as the mechanism model of CRC, in which mutations of APC, KRAS, SMAD4, TP53, and PIK3CA could sequentially drive CRC transformation.	('TP53', 'Gene', (117, 121))	('CRC', 'Disease', 'MESH:D015179', (72, 75))	('drive', 'Reg', (153, 158))	('SMAD4', 'Gene', (110, 115))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (4, 21))	('KRAS', 'Gene', '3845', (104, 108))	('adenoma-carcinoma', 'Disease', (4, 21))	('PIK3CA', 'Gene', '5290', (127, 133))	('KRAS', 'Gene', (104, 108))	('CRC', 'Disease', (159, 162))	('mutations', 'Var', (86, 95))	('TP53', 'Gene', '7157', (117, 121))	('CRC', 'Phenotype', 'HP:0003003', (159, 162))	('SMAD4', 'Gene', '4089', (110, 115))	('APC', 'Gene', (99, 102))	('CRC', 'Disease', (72, 75))	('CRC', 'Disease', 'MESH:D015179', (159, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('PIK3CA', 'Gene', (127, 133))	('CRC', 'Phenotype', 'HP:0003003', (72, 75))
8832	32117908	The AKST- and AKSTP- organoids approximated the true CRC with corresponding mutations.	('CRC', 'Disease', (53, 56))	('mutations', 'Var', (76, 85))	('CRC', 'Phenotype', 'HP:0003003', (53, 56))	('CRC', 'Disease', 'MESH:D015179', (53, 56))
8837	32117908	Although the adenoma-carcinoma sequence of CRC was recognized, it only explained molecular mechanism in a fraction of CRC populations with mutations of all five genes.	('CRC', 'Disease', 'MESH:D015179', (43, 46))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (13, 30))	('mutations', 'Var', (139, 148))	('CRC', 'Disease', (118, 121))	('adenoma-carcinoma', 'Disease', (13, 30))	('CRC', 'Disease', (43, 46))	('CRC', 'Phenotype', 'HP:0003003', (118, 121))	('CRC', 'Disease', 'MESH:D015179', (118, 121))	('CRC', 'Phenotype', 'HP:0003003', (43, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))
8843	32117908	Sequential introduction of the mutations in gene paths may provide a new avenue for understanding the dynamic progression of CRC.	('CRC', 'Phenotype', 'HP:0003003', (125, 128))	('mutations', 'Var', (31, 40))	('CRC', 'Disease', (125, 128))	('CRC', 'Disease', 'MESH:D015179', (125, 128))
8892	31950049	Moreover, the BBR and galangin combination not only suppressed Wnt3a and beta-catenin expression but also induced apoptosis in esophageal cancer cells.	('Wnt3a', 'Gene', '89780', (63, 68))	('beta-catenin', 'Gene', (73, 85))	('esophageal cancer', 'Disease', (127, 144))	('combination', 'Var', (31, 42))	('Wnt3a', 'Gene', (63, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('induced', 'Reg', (106, 113))	('beta-catenin', 'Gene', '1499', (73, 85))	('suppressed', 'NegReg', (52, 62))	('galangin', 'Chemical', 'MESH:C037032', (22, 30))	('BBR', 'Chemical', 'MESH:D001599', (14, 17))	('apoptosis', 'biological_process', 'GO:0097194', ('114', '123'))	('apoptosis', 'biological_process', 'GO:0006915', ('114', '123'))	('apoptosis', 'CPA', (114, 123))
8894	31950049	found that the radiosensitivity of xenografts in nude mice and ESCC cells was significantly enhanced by BBR via the suppression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1alpha) expression.	('nude mice', 'Species', '10090', (49, 58))	('hypoxia inducible factor-1 alpha', 'Gene', (177, 209))	('ESCC', 'Disease', 'MESH:C562729', (63, 67))	('expression', 'MPA', (223, 233))	('nt', 'Chemical', 'MESH:D009711', (87, 89))	('HIF-1alpha', 'Gene', (211, 221))	('BBR', 'Var', (104, 107))	('vascular endothelial growth factor', 'Gene', '22339', (131, 165))	('radiosensitivity', 'CPA', (15, 31))	('ESCC', 'Disease', (63, 67))	('vascular endothelial growth factor', 'Gene', (131, 165))	('hypoxia inducible factor-1 alpha', 'Gene', '15251', (177, 209))	('BBR', 'Chemical', 'MESH:D001599', (104, 107))	('suppression', 'NegReg', (116, 127))	('enhanced', 'PosReg', (92, 100))
8920	31950049	Liu found that BBR represses the proliferation and migration of CRC cells in vitro and in vivo by inhibiting JAK2 and STAT3 phosphorylation, which prevents the increase in COX-2/PGE2 levels and consequently decreases MMP-2/-9 expression.	('CRC', 'Disease', 'MESH:D015179', (64, 67))	('phosphorylation', 'biological_process', 'GO:0016310', ('124', '139'))	('JAK2', 'Gene', '3717', (109, 113))	('inhibiting', 'NegReg', (98, 108))	('PGE2', 'Chemical', 'MESH:D015232', (178, 182))	('nt', 'Chemical', 'MESH:D009711', (202, 204))	('STAT3', 'Gene', (118, 123))	('prevents', 'NegReg', (147, 155))	('JAK', 'molecular_function', 'GO:0004713', ('109', '112'))	('represses', 'NegReg', (19, 28))	('COX-2', 'Gene', (172, 177))	('MMP-2', 'molecular_function', 'GO:0004228', ('217', '222'))	('JAK2', 'Gene', (109, 113))	('STAT3', 'Gene', '6774', (118, 123))	('MMP-2/-9', 'Gene', (217, 225))	('CRC', 'Disease', (64, 67))	('nt', 'Chemical', 'MESH:D009711', (152, 154))	('MMP-2/-9', 'Gene', '4313;4318', (217, 225))	('BBR', 'Chemical', 'MESH:D001599', (15, 18))	('COX-2', 'Gene', '5743', (172, 177))	('increase', 'PosReg', (160, 168))	('proliferation', 'CPA', (33, 46))	('decreases', 'NegReg', (207, 216))	('BBR', 'Var', (15, 18))
8924	31950049	Their in vitro experiment showed that BBR exerts antiproliferative and proapoptotic effects on CRC cells via AMPK-dependent inhibition of the mTOR signaling pathway and prevents NF-kappaB activation, decreases cyclin D1 and survivin levels, induces p53 phosphorylation, and enhances caspase-3 cleavage in an AMPK-independent manner.	('nt', 'Chemical', 'MESH:D009711', (23, 25))	('AMP', 'Chemical', 'MESH:D000249', (109, 112))	('BBR', 'Var', (38, 41))	('AMP', 'Chemical', 'MESH:D000249', (308, 311))	('p53', 'Gene', (249, 252))	('activation', 'MPA', (188, 198))	('nt', 'Chemical', 'MESH:D009711', (322, 324))	('caspase-3 cleavage', 'MPA', (283, 301))	('nt', 'Chemical', 'MESH:D009711', (121, 123))	('NF-kappaB', 'Protein', (178, 187))	('nt', 'Chemical', 'MESH:D009711', (50, 52))	('inhibition', 'NegReg', (124, 134))	('phosphorylation', 'MPA', (253, 268))	('survivin levels', 'MPA', (224, 239))	('CRC', 'Disease', (95, 98))	('decreases', 'NegReg', (200, 209))	('cyclin D1', 'MPA', (210, 219))	('prevents', 'NegReg', (169, 177))	('induces', 'PosReg', (241, 248))	('nt', 'Chemical', 'MESH:D009711', (174, 176))	('enhances', 'PosReg', (274, 282))	('mTOR signaling pathway', 'Pathway', (142, 164))	('BBR', 'Chemical', 'MESH:D001599', (38, 41))	('p53', 'Gene', '7157', (249, 252))	('CRC', 'Disease', 'MESH:D015179', (95, 98))
8933	31950049	In a study by Zhang, BBR was found to reduce the number and size of intestinal polyps in ApcMin/+ mice, in addition to reducing the Wnt activity and downregulating the expression of its target genes, cyclin D1 and c-Myc.	('intestinal polyps', 'Disease', (68, 85))	('expression', 'MPA', (168, 178))	('nt', 'Chemical', 'MESH:D009711', (133, 135))	('intestinal polyps', 'Phenotype', 'HP:0005266', (68, 85))	('cyclin D1', 'Gene', (200, 209))	('downregulating', 'NegReg', (149, 163))	('BBR', 'Var', (21, 24))	('Wnt activity', 'CPA', (132, 144))	('BBR', 'Chemical', 'MESH:D001599', (21, 24))	('intestinal polyp', 'Phenotype', 'HP:0005266', (68, 84))	('reduce', 'NegReg', (38, 44))	('Apc', 'Gene', (89, 92))	('nt', 'Chemical', 'MESH:D009711', (69, 71))	('Apc', 'Gene', '11789', (89, 92))	('intestinal polyps', 'Disease', 'MESH:D007417', (68, 85))	('c-Myc', 'Gene', (214, 219))	('mice', 'Species', '10090', (98, 102))	('reducing', 'NegReg', (119, 127))
8937	31950049	They found that BBR directly bound to the nuclear receptor retinoid X receptor alpha (RXRalpha) at the region containing Gln275, Arg316, and Arg371 residues and promoted its interaction with nuclear beta-catenin, leading to c-Cbl-mediated degradation of beta-catenin and consequent prevention of colon cancer cell proliferation.	('c-Cbl', 'Gene', (224, 229))	('cell proliferation', 'biological_process', 'GO:0008283', ('309', '327'))	('colon cancer', 'Phenotype', 'HP:0003003', (296, 308))	('beta-catenin', 'Gene', (199, 211))	('beta-catenin', 'Gene', (254, 266))	('beta-catenin', 'Gene', '1499', (199, 211))	('Arg316', 'Var', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('beta-catenin', 'Gene', '1499', (254, 266))	('degradation', 'biological_process', 'GO:0009056', ('239', '250'))	('bound', 'Interaction', (29, 34))	('nt', 'Chemical', 'MESH:D009711', (287, 289))	('nt', 'Chemical', 'MESH:D009711', (112, 114))	('colon cancer', 'Disease', 'MESH:D015179', (296, 308))	('BBR', 'Chemical', 'MESH:D001599', (16, 19))	('BBR', 'Gene', (16, 19))	('nt', 'Chemical', 'MESH:D009711', (279, 281))	('Gln275', 'Var', (121, 127))	('prevention', 'NegReg', (282, 292))	('colon cancer', 'Disease', (296, 308))	('Arg371', 'Chemical', 'MESH:C116795', (141, 147))	('nt', 'Chemical', 'MESH:D009711', (175, 177))	('promoted', 'PosReg', (161, 169))	('degradation', 'MPA', (239, 250))	('c-Cbl', 'Gene', '867', (224, 229))	('Arg371 residues', 'Var', (141, 156))	('Arg316', 'Chemical', 'MESH:C002934', (129, 135))	('interaction', 'Interaction', (174, 185))
8958	31950049	MiRNAs are short 20-22-nt-long ncRNAs that repress the translation of their target mRNAs by binding to their 3'-untranslated region (UTR) by imperfect complementary matches.	('binding', 'Interaction', (92, 99))	('nt', 'Chemical', 'MESH:D009711', (23, 25))	('imperfect complementary matches', 'Var', (141, 172))	('binding', 'molecular_function', 'GO:0005488', ('92', '99'))	('nt', 'Chemical', 'MESH:D009711', (159, 161))	('nt', 'Chemical', 'MESH:D009711', (113, 115))	('repress', 'NegReg', (43, 50))	('translation', 'MPA', (55, 66))	('translation', 'biological_process', 'GO:0006412', ('55', '66'))
8975	31950049	In their study, overexpressed miRNA-429 inhibited cell apoptosis by directly targeting SOX2 in CRC cells, suggesting that miRNA-429 plays an oncogenic role in CRC and can thus be used as a new prognostic biomarker for CRC.	('CRC', 'Disease', 'MESH:D015179', (218, 221))	('targeting', 'Reg', (77, 86))	('SOX2', 'Gene', '6657', (87, 91))	('cell apoptosis', 'CPA', (50, 64))	('SOX2', 'Gene', (87, 91))	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('inhibited', 'NegReg', (40, 49))	('CRC', 'Disease', 'MESH:D015179', (159, 162))	('CRC', 'Disease', (95, 98))	('CRC', 'Disease', (218, 221))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('CRC', 'Disease', 'MESH:D015179', (95, 98))	('miRNA-429', 'Var', (122, 131))	('miRNA-429', 'Var', (30, 39))	('CRC', 'Disease', (159, 162))
8976	31950049	investigated the effect of BBR and evodiamine on CRC and miRNA-429 expression using an in vitro culture of colorectal tissue and found that BBR and evodiamine exert therapeutic effects on CRC by downregulating miRNA-429 expression.	('colorectal tissue', 'Disease', (107, 124))	('CRC', 'Disease', 'MESH:D015179', (188, 191))	('evodiamine', 'Chemical', 'MESH:C049639', (148, 158))	('colorectal tissue', 'Disease', 'MESH:D015179', (107, 124))	('BBR', 'Var', (140, 143))	('expression', 'MPA', (220, 230))	('miRNA-429', 'Gene', (210, 219))	('evodiamine', 'Chemical', 'MESH:C049639', (35, 45))	('BBR', 'Chemical', 'MESH:D001599', (27, 30))	('CRC', 'Disease', 'MESH:D015179', (49, 52))	('BBR', 'Chemical', 'MESH:D001599', (140, 143))	('CRC', 'Disease', (188, 191))	('downregulating', 'NegReg', (195, 209))	('CRC', 'Disease', (49, 52))
8980	31950049	revealed that the combination of NVP-AUY922 (a Hsp90 inhibitor) and BBR retards human colon adenocarcinoma cell proliferation by inhibiting cyclin dependent kinase 4 (CDK4) expression and inducing miRNA-296-mediated suppression of the Pin1-beta-catenin-cyclin D1 signaling pathway.	('cyclin dependent kinase 4', 'Gene', '1019', (140, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('beta-catenin', 'Gene', (240, 252))	('beta-catenin', 'Gene', '1499', (240, 252))	('BBR', 'Chemical', 'MESH:D001599', (68, 71))	('cyclin dependent kinase 4', 'Gene', (140, 165))	('miRNA-296', 'Gene', '407022', (197, 206))	('Hsp90', 'Gene', '3320', (47, 52))	('retards human colon adenocarcinoma', 'Disease', (72, 106))	('NVP-AUY922', 'Var', (33, 43))	('Hsp90', 'Gene', (47, 52))	('Pin1', 'Gene', (235, 239))	('inducing', 'Reg', (188, 196))	('inhibiting', 'NegReg', (129, 139))	('retards human colon adenocarcinoma', 'Disease', 'MESH:D015179', (72, 106))	('CDK4', 'Gene', (167, 171))	('miRNA-296', 'Gene', (197, 206))	('expression', 'MPA', (173, 183))	('Pin1', 'Gene', '5300', (235, 239))	('CDK4', 'Gene', '1019', (167, 171))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (33, 43))	('suppression', 'NegReg', (216, 227))
8981	31950049	These findings suggest that the therapeutic effects of the combination of NVP-AUY922 and BBR occur via the inhibition of multiple oncogenic signaling pathways.	('NVP-AUY922', 'Var', (74, 84))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (74, 84))	('BBR', 'Chemical', 'MESH:D001599', (89, 92))	('oncogenic signaling pathways', 'Pathway', (130, 158))	('BBR', 'Gene', (89, 92))	('inhibition', 'NegReg', (107, 117))
8987	31950049	Accumulating evidence has indicated that the aberrant expression of lncRNAs may induce the onset and progression of various cancers.	('cancer', 'Disease', (124, 130))	('aberrant expression', 'Var', (45, 64))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('nt', 'Chemical', 'MESH:D009711', (51, 53))	('lncRNAs', 'Gene', (68, 75))	('induce', 'PosReg', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('progression', 'CPA', (101, 112))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
8991	31950049	In their functional experiment, BBR exerted its effects by inducing the overexpression of lncRNA cancer susceptibility candidate 2 (CASC2), the downstream target of which was found to be the antiapoptotic gene BCL2.	('inducing', 'PosReg', (59, 67))	('BBR', 'Chemical', 'MESH:D001599', (32, 35))	('BCL2', 'Gene', '596', (210, 214))	('cancer', 'Disease', (97, 103))	('CASC2', 'Gene', (132, 137))	('nt', 'Chemical', 'MESH:D009711', (192, 194))	('BCL2', 'molecular_function', 'GO:0015283', ('210', '214'))	('CASC2', 'Gene', '255082', (132, 137))	('nt', 'Chemical', 'MESH:D009711', (28, 30))	('BCL2', 'Gene', (210, 214))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('BBR', 'Var', (32, 35))	('overexpression', 'MPA', (72, 86))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
9003	31950049	At the genus level, BBR decreased the abundance of Akkermansia, blocked mucin degradation, and increased that of some short chain fatty acid-producing bacteria.	('decreased', 'NegReg', (24, 33))	('Akkermansia', 'MPA', (51, 62))	('BBR', 'Var', (20, 23))	('blocked', 'NegReg', (64, 71))	('mucin degradation', 'MPA', (72, 89))	('BBR', 'Chemical', 'MESH:D001599', (20, 23))	('fatty acid', 'Chemical', 'MESH:D005227', (130, 140))	('degradation', 'biological_process', 'GO:0009056', ('78', '89'))	('increased', 'PosReg', (95, 104))	('short chain fatty acid-producing bacteria', 'MPA', (118, 159))	('abundance', 'MPA', (38, 47))
9007	31950049	BBR treatment alleviated the F. nucleatum-mediated increase in opportunistic pathogens and decreased the secretion of IL-21/22/31 and CD40L and the expression of p-STAT3, p-STAT5, and p-ERK1/2 in vivo.	('p-STAT5', 'Var', (171, 178))	('increase', 'PosReg', (51, 59))	('F. nucleatum', 'Species', '851', (29, 41))	('alleviated', 'NegReg', (14, 24))	('CD40L', 'MPA', (134, 139))	('opportunistic pathogens', 'MPA', (63, 86))	('secretion of IL-21/22/31', 'MPA', (105, 129))	('p-ERK1/2', 'Gene', (184, 192))	('nt', 'Chemical', 'MESH:D009711', (11, 13))	('BBR', 'Chemical', 'MESH:D001599', (0, 3))	('STAT3', 'Gene', '6774', (164, 169))	('expression', 'MPA', (148, 158))	('decreased', 'NegReg', (91, 100))	('STAT3', 'Gene', (164, 169))
9019	31300350	BMAL1 single nucleotide gene polymorphisms (SNPs) were analysed by DNA-microarray in clinical samples.	('single nucleotide gene polymorphisms', 'Var', (6, 42))	('BMAL1', 'Gene', (0, 5))	('clinical samples', 'Species', '191496', (85, 101))
9021	31300350	In murine CRCs, high BMAL1 expression correlated with poor preclinical response to Beva treatment.	('clinical', 'Species', '191496', (62, 70))	('men', 'Species', '9606', (93, 96))	('high', 'Var', (16, 20))	('expression', 'Species', '29278', (27, 37))	('Beva', 'Chemical', 'MESH:D000068258', (83, 87))	('expression', 'MPA', (27, 37))	('BMAL1', 'Gene', (21, 26))	('murine', 'Species', '10090', (3, 9))
9022	31300350	In CRC patients' tumours (n = 74), high BMAL1 expression was associated with clinical non-response to combination chemotherapy with Beva (*p = .0061) and reduced progression-free survival (PFS) [*p = .0223, Hazard Ratio (HR) = 1.69].	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('BMAL1', 'Gene', (40, 45))	('clinical', 'Species', '191496', (77, 85))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('progression-free survival', 'CPA', (162, 187))	('Beva', 'Chemical', 'MESH:D000068258', (132, 136))	('expression', 'Species', '29278', (46, 56))	('tumours', 'Disease', 'MESH:D009369', (17, 24))	('tumours', 'Disease', (17, 24))	('reduced', 'NegReg', (154, 161))	('high', 'Var', (35, 39))	('patients', 'Species', '9606', (7, 15))
9023	31300350	BMAL1 SNPs also correlated with shorter PFS (rs7396943, rs7938307, rs2279287) and overall survival (OS) [rs11022780, *p = .014, HR = 1.61].	('rs2279287', 'Var', (67, 76))	('rs7938307', 'Var', (56, 65))	('rs7938307', 'Mutation', 'rs7938307', (56, 65))	('rs11022780', 'Mutation', 'rs11022780', (105, 115))	('rs2279287', 'Mutation', 'rs2279287', (67, 76))	('BMAL1', 'Gene', (0, 5))	('rs7396943', 'Mutation', 'rs7396943', (45, 54))	('shorter', 'NegReg', (32, 39))	('rs7396943', 'Var', (45, 54))	('overall survival', 'CPA', (82, 98))	('PFS', 'MPA', (40, 43))
9026	31300350	Inhibition of REVERBA-BMAL1 signalling may prevent resistance to anti-angiogenic therapy.	('prevent', 'NegReg', (43, 50))	('REVERBA-BMAL1', 'Gene', '406', (14, 27))	('Inhibition', 'Var', (0, 10))	('REVERBA-BMAL1', 'Gene', (14, 27))	('resistance to anti-angiogenic therapy', 'CPA', (51, 88))
9047	31300350	Conversely, Bmal1 silencing lowered Vegfa mRNA in genetically engineered mouse models (GEMMs) and impaired vessel growth in zebrafish.	('Vegfa', 'Protein', (36, 41))	('silencing', 'Var', (18, 27))	('impaired vessel growth', 'Disease', 'MESH:D006130', (98, 120))	('Bmal1', 'Gene', (12, 17))	('zebrafish', 'Species', '7955', (124, 133))	('impaired vessel growth', 'Disease', (98, 120))	('mouse', 'Species', '10090', (73, 78))	('lowered', 'NegReg', (28, 35))
9048	31300350	In contrast to the normal body physiology, aberrant expression or arrhythmic activities endow BMAL1 (and other circadian transcription factors) with more specialised functions in disease conditions.	('expression', 'Species', '29278', (52, 62))	('endow', 'Reg', (88, 93))	('BMAL1', 'Gene', (94, 99))	('arrhythmic', 'Disease', (66, 76))	('arrhythmic', 'Disease', 'MESH:D001145', (66, 76))	('aberrant', 'Var', (43, 51))
9050	31300350	jet lag, shift work, neuro-psychiatric disorders) or gene mutations, are associated with metabolic or inflammatory disturbances and presumably with an enhanced risk for cardiovascular diseases and cancer.	('neuro-psychiatric disorders', 'Disease', 'MESH:D001523', (21, 48))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('neuro-psychiatric disorders', 'Disease', (21, 48))	('associated', 'Reg', (73, 83))	('cardiovascular diseases', 'Disease', (169, 192))	('gene mutations', 'Var', (53, 67))	('psychiatric disorders', 'Phenotype', 'HP:0000708', (27, 48))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (169, 192))	('jet lag', 'Disease', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (169, 192))	('metabolic', 'MPA', (89, 98))
9053	31300350	For example, mutant KRAS abrogates oscillation cycles of BMAL1, and MYC out-competes BMAL1 at shared E-boxes on target genes.	('mutant', 'Var', (13, 19))	('abrogates', 'NegReg', (25, 34))	('BMAL1', 'Gene', (57, 62))	('MYC', 'Gene', '4609', (68, 71))	('oscillation cycles', 'MPA', (35, 53))	('KRAS', 'Gene', (20, 24))	('MYC', 'Gene', (68, 71))
9055	31300350	Thus, a deregulated clock is implicated as a hallmark of cancer.	('hallmark of cancer', 'Disease', 'MESH:D009369', (45, 63))	('hallmark of cancer', 'Disease', (45, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('deregulated', 'Var', (8, 19))
9058	31300350	In patients, high BMAL1 expression has been associated with advanced CRC as well as other cancers.	('associated', 'Reg', (44, 54))	('cancers', 'Disease', (90, 97))	('expression', 'Species', '29278', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('BMAL1', 'Gene', (18, 23))	('patients', 'Species', '9606', (3, 11))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('advanced CRC', 'Disease', (60, 72))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
9062	31300350	Abs for Western blots were REVERBA (#PA-29865, Thermo Fisher Scientific (FS), Darmstadt, Germany), BMAL1 (sc-48790) and HSP90 (sc-7947) (all from Santa Cruz Biotech., CA).	('sc-7947', 'Var', (127, 134))	('REVERBA', 'Chemical', '-', (27, 34))	('HSP90', 'Gene', (120, 125))	('HSP90', 'Gene', '3320', (120, 125))	('sc-48790', 'Var', (106, 114))
9063	31300350	Abs for immunohistochemistry (IHC) were Ki67 (#550609, BD Bioscience, Heidelberg, Germany), CD31 (#Clone SZ31, Dianova, Hamburg, Germany), BMAL1 (#NBP2-02544, for human, Novus Biologicals, Littleton, CO), BMAL1 (#NB100-2288, for mouse, Novus).	('Ki67', 'Gene', (40, 44))	('#550609', 'Var', (46, 53))	('human', 'Species', '9606', (163, 168))	('mouse', 'Species', '10090', (229, 234))	('Ki67', 'Gene', '17345', (40, 44))
9065	31300350	Human REVERBA (67 kDa, NM_021724, MHS1010-9205700) and BMAL1 (69 kDa, NM_001178.5, MHS6278-202757260) were obtained as full-length cDNA clones in pCMV SPORT6 (Thermo FS).	('REVERBA', 'Chemical', '-', (6, 13))	('MHS6278-202757260', 'Var', (83, 100))	('MHS1010-9205700', 'Var', (34, 49))	('Human', 'Species', '9606', (0, 5))
9085	31300350	Four SNPs in BMAL1 were analysed: rs11022780, rs7396943, rs7938307 and rs2279287 (Supplementary Table 2).	('rs2279287', 'Var', (71, 80))	('BMAL1', 'Gene', (13, 18))	('rs11022780', 'Mutation', 'rs11022780', (34, 44))	('rs7396943', 'Mutation', 'rs7396943', (46, 55))	('men', 'Species', '9606', (88, 91))	('rs7938307', 'Var', (57, 66))	('rs7938307', 'Mutation', 'rs7938307', (57, 66))	('rs11022780', 'Var', (34, 44))	('rs2279287', 'Mutation', 'rs2279287', (71, 80))	('rs7396943', 'Var', (46, 55))
9097	31300350	Simian Virus 40 (SV40) large T-antigen transformed human embryonic kidney (HEK293T) and human colon adenocarcinoma (SW480, HCT116) cell lines (all purchased from the American Type Culture Collection, Rockville, MD) were cultivated in Dulbecco's Modified Eagle's Medium (DMEM) (#41965) supplemented with 10% (v/v) fetal calf serum (#SV30160), 20 mM glutamine and penicillin / streptomycin (1000 U/ml; all from Thermo FS), herewith termed "complete" medium, as recommended by the distributors.	('#SV30160', 'Var', (331, 339))	('colon adenocarcinoma', 'Disease', (94, 114))	('men', 'Species', '9606', (464, 467))	('SW480', 'CellLine', 'CVCL:0546', (116, 121))	('HEK293T', 'CellLine', 'CVCL:0063', (75, 82))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (94, 114))	('embryonic kidney', 'Disease', 'MESH:D007674', (57, 73))	('HCT116', 'CellLine', 'CVCL:0291', (123, 129))	('calf', 'Species', '9913', (319, 323))	('human', 'Species', '9606', (51, 56))	('human', 'Species', '9606', (88, 93))	('SV40', 'Species', '1891767', (17, 21))	('DMEM', 'Chemical', '-', (270, 274))	('embryonic kidney', 'Disease', (57, 73))	('Simian Virus 40', 'Species', '1891767', (0, 15))	('men', 'Species', '9606', (291, 294))
9138	31300350	Thus, neutralization of VEGFA in vivo prevented CRC growth in mice without a major impact on neoangiogenesis.	('CRC growth', 'CPA', (48, 58))	('prevented', 'NegReg', (38, 47))	('mice', 'Species', '10090', (62, 66))	('neutralization', 'Var', (6, 20))	('VEGFA', 'Protein', (24, 29))
9145	31300350	These findings indicated that VEGFA neutralization despite attenuation of tumour growth fails to reduce vessel formation in vivo, presumably by up-regulation of alternate pathways, such as BMAL1.	('neutralization', 'Var', (36, 50))	('vessel formation', 'CPA', (104, 120))	('VEGFA', 'Protein', (30, 35))	('growth fails', 'Phenotype', 'HP:0001510', (81, 93))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('tumour growth', 'Disease', (74, 87))	('up-regulation', 'PosReg', (144, 157))	('tumour growth', 'Disease', 'MESH:D006130', (74, 87))	('reduce', 'NegReg', (97, 103))
9148	31300350	Notably, high BMAL1 staining was associated with preclinical non-response of individual mice to mBeva.	('clinical', 'Species', '191496', (52, 60))	('mBeva', 'Chemical', '-', (96, 101))	('BMAL1', 'Protein', (14, 19))	('mice', 'Species', '10090', (88, 92))	('high', 'Var', (9, 13))
9150	31300350	Collectively, these data proposed that failure of mice to respond to mBeva correlates with high BMAL1 expression.	('expression', 'Species', '29278', (102, 112))	('high', 'Var', (91, 95))	('expression', 'MPA', (102, 112))	('mBeva', 'Chemical', '-', (69, 74))	('BMAL1', 'Gene', (96, 101))	('mice', 'Species', '10090', (50, 54))
9165	31300350	There was a significant association between low BMAL1 staining (scores 0/1) in tumour cells and stable disease (SD) in patients undergoing Beva therapy (Cochrane Armitage trend test *p = .0061; Fisher Exact test *p = .0130; n = 44) (Fig.	('patients', 'Species', '9606', (119, 127))	('low', 'Var', (44, 47))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('Beva', 'Chemical', 'MESH:D000068258', (139, 143))	('SD', 'Disease', 'MESH:D029461', (112, 114))	('stable disease', 'Disease', (96, 110))	('BMAL1', 'Protein', (48, 53))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (79, 85))
9167	31300350	Consistently, patients who had high BMAL1 staining in their tumour tissue were less likely to belong to the disease control rate group (DCR: PR/SD) responding to Beva (R vs. NR, Cochrane Armitage trend test p = .0921; n = 63) (Fig.	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('BMAL1', 'Gene', (36, 41))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('tumour', 'Disease', (60, 66))	('Beva', 'Chemical', 'MESH:D000068258', (162, 166))	('high', 'Var', (31, 35))	('patients', 'Species', '9606', (14, 22))	('less', 'NegReg', (79, 83))	('SD', 'Disease', 'MESH:D029461', (144, 146))	('staining', 'Var', (42, 50))
9170	31300350	High BMAL1 positivity in tumour tissue was also associated with the likelihood to show a progress (PD) in the first restaging according to RECIST (Supplementary Fig.	('PD', 'Disease', 'MESH:D010300', (99, 101))	('High', 'Var', (0, 4))	('positivity', 'Var', (11, 21))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('men', 'Species', '9606', (153, 156))	('tumour', 'Disease', (25, 31))	('BMAL1', 'Gene', (5, 10))
9171	31300350	Overall, high BMAL1 protein expression in tumours was associated with reduced PFS (Fig.	('reduced', 'NegReg', (70, 77))	('expression', 'Species', '29278', (28, 38))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('protein', 'Protein', (20, 27))	('expression', 'MPA', (28, 38))	('tumours', 'Phenotype', 'HP:0002664', (42, 49))	('protein', 'cellular_component', 'GO:0003675', ('20', '27'))	('BMAL1', 'Gene', (14, 19))	('PFS', 'Disease', (78, 81))	('tumours', 'Disease', 'MESH:D009369', (42, 49))	('tumours', 'Disease', (42, 49))	('high', 'Var', (9, 13))
9176	31300350	Finally, the impact on the clinical outcome of four single nucleotide polymorphisms (SNPs) in the BMAL1 (ARNTL) gene was evaluated in mCRC patients (TU, n = 215) treated with first-line FOLFIRI plus Beva in the randomised phase III TRIBE trial.	('single nucleotide polymorphisms', 'Var', (52, 83))	('patients', 'Species', '9606', (139, 147))	('Beva', 'Chemical', 'MESH:D000068258', (199, 203))	('FOLFIRI', 'Chemical', '-', (186, 193))	('ARNTL', 'Gene', '406', (105, 110))	('ARNTL', 'Gene', (105, 110))	('clinical', 'Species', '191496', (27, 35))
9179	31300350	Among the evaluated SNPs, rs11022780 showed a significant association with overall survival (OS) (Fig.	('rs11022780', 'Var', (26, 36))	('overall', 'MPA', (75, 82))	('association', 'Reg', (58, 69))	('rs11022780', 'Mutation', 'rs11022780', (26, 36))
9182	31300350	4a) and RAS mutational status (Supplementary Fig.	('mutational status', 'Var', (12, 29))	('men', 'Species', '9606', (37, 40))	('RAS', 'Protein', (8, 11))
9183	31300350	Notably, rs2279287, rs7938307 and rs7396943 SNPs revealed significant associations with a shorter PFS in subgroups by gender, tumour location or RAS mutational status (Fig.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('rs2279287', 'Var', (9, 18))	('rs7938307', 'Var', (20, 29))	('rs7938307', 'Mutation', 'rs7938307', (20, 29))	('PFS', 'MPA', (98, 101))	('tumour location', 'Disease', 'MESH:D009369', (126, 141))	('tumour location', 'Disease', (126, 141))	('shorter', 'NegReg', (90, 97))	('rs7396943', 'Mutation', 'rs7396943', (34, 43))	('rs7396943 SNPs', 'Var', (34, 48))	('rs2279287', 'Mutation', 'rs2279287', (9, 18))
9187	31300350	In summary, BMAL1 (ARNTL) gene alteration(s) and high protein expression correlated with unfavourable clinical outcomes in CRC patients treated with Beva.	('correlated', 'Reg', (73, 83))	('expression', 'Species', '29278', (62, 72))	('ARNTL', 'Gene', '406', (19, 24))	('ARNTL', 'Gene', (19, 24))	('patients', 'Species', '9606', (127, 135))	('CRC', 'Disease', (123, 126))	('Beva', 'Chemical', 'MESH:D000068258', (149, 153))	('alteration', 'Var', (31, 41))	('clinical', 'Species', '191496', (102, 110))
9189	31300350	To decipher the molecular mechanism, underlying the observed in vivo resistance to Beva in presence of BMAL1, two human CRC cell lines (SW480, HCT116) with activating mutations in Wnt/Ras-signalling pathway components (such as in APC and KRAS) were chosen as in vitro models for the Apc min/+ GEMM and the majority of human CRCs (CMS2/3).	('SW480', 'CellLine', 'CVCL:0546', (136, 141))	('APC', 'cellular_component', 'GO:0005680', ('230', '233'))	('Apc', 'cellular_component', 'GO:0005680', ('283', '286'))	('Beva', 'Chemical', 'MESH:D000068258', (83, 87))	('signalling pathway', 'biological_process', 'GO:0007165', ('188', '206'))	('HCT116', 'CellLine', 'CVCL:0291', (143, 149))	('mutations', 'Var', (167, 176))	('APC', 'Disease', 'MESH:D011125', (230, 233))	('APC', 'Disease', (230, 233))	('human', 'Species', '9606', (114, 119))	('activating', 'PosReg', (156, 166))	('CMS2', 'Gene', (330, 334))	('human', 'Species', '9606', (318, 323))	('CMS2', 'Gene', '109466', (330, 334))
9193	31300350	Two putative RORE sites (-1464 bp; -672 bp) were identified in proximity to a cognate BMAL1 binding site (E-box) (-1688 bp) and estrogen receptor-responsive element (ERE) (-1542 bp) (Fig.	('-1688', 'Var', (114, 119))	('ROR', 'Gene', '100885779', (13, 16))	('-1464', 'Var', (25, 30))	('binding', 'molecular_function', 'GO:0005488', ('92', '99'))	('men', 'Species', '9606', (160, 163))	('ROR', 'Gene', (13, 16))
9208	31300350	The positive effect of REVERBA on endogenous VEGFA expression was most prominent in SW480 cells, possibly due to already high basal VEGFA levels in HCT116 (555 +- 47 vs. 519 +- 13 pg/ml) and HEK293T (305 +- 23 vs. 165 +- 10 pg/ml) cells (Supplementary Fig.	('305 +-', 'Var', (200, 206))	('men', 'Species', '9606', (244, 247))	('HEK293T', 'CellLine', 'CVCL:0063', (191, 198))	('expression', 'Species', '29278', (51, 61))	('endogenous VEGFA expression', 'MPA', (34, 61))	('REVERBA', 'Chemical', '-', (23, 30))	('HCT116', 'CellLine', 'CVCL:0291', (148, 154))	('SW480', 'CellLine', 'CVCL:0546', (84, 89))
9226	31300350	7a), whereas REVERBA knock-down by siRNA reduced proliferation (Fig.	('reduced', 'NegReg', (41, 48))	('knock-down', 'Var', (21, 31))	('proliferation', 'CPA', (49, 62))	('REVERBA', 'Chemical', '-', (13, 20))
9243	31300350	Instead, Ki67 data indicates that reduced proliferation of cancer (stem) cells is one mechanism whereby neutralization of VEGFA inhibits tumour growth in mice, and this process may be counteracted by a gain of function in BMAL1.	('neutralization', 'Var', (104, 118))	('tumour growth', 'Disease', 'MESH:D006130', (137, 150))	('reduced', 'NegReg', (34, 41))	('mice', 'Species', '10090', (154, 158))	('Ki67', 'Gene', (9, 13))	('proliferation', 'CPA', (42, 55))	('inhibits', 'NegReg', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Ki67', 'Gene', '17345', (9, 13))	('VEGFA', 'Protein', (122, 127))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('tumour growth', 'Disease', (137, 150))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
9245	31300350	Thus, high BMAL1 expression in murine CRCs may be a drug-mediated passenger effect, but not necessarily the causative driver of resistance to Beva.	('expression', 'Species', '29278', (17, 27))	('expression', 'MPA', (17, 27))	('Beva', 'Chemical', 'MESH:D000068258', (142, 146))	('high', 'Var', (6, 10))	('BMAL1', 'Gene', (11, 16))	('murine', 'Species', '10090', (31, 37))
9247	31300350	Our preclinical studies were confirmed by molecular and genomic analyses which revealed that SNPs in the BMAL1 (ARNTL) gene and high BMAL1 expression in tumour cells correlated with unfavourable clinical outcome in CRC patients that underwent combination chemotherapy with Beva.	('SNPs', 'Var', (93, 97))	('tumour', 'Disease', (153, 159))	('patients', 'Species', '9606', (219, 227))	('BMAL1', 'Gene', (133, 138))	('CRC', 'Disease', (215, 218))	('clinical', 'Species', '191496', (7, 15))	('tumour', 'Disease', 'MESH:D009369', (153, 159))	('ARNTL', 'Gene', (112, 117))	('expression', 'Species', '29278', (139, 149))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('ARNTL', 'Gene', '406', (112, 117))	('expression', 'MPA', (139, 149))	('correlated with', 'Reg', (166, 181))	('clinical', 'Species', '191496', (195, 203))	('Beva', 'Chemical', 'MESH:D000068258', (273, 277))
9250	31300350	Likewise, Notch signalling via delta-like ligand-4 evokes resistance by increasing VEGFR1 expression in the tumour-adjacent stroma.	('VEGF', 'Gene', (83, 87))	('Notch', 'Var', (10, 15))	('tumour-adjacent stroma', 'Disease', 'MESH:D009369', (108, 130))	('expression', 'Species', '29278', (90, 100))	('VEGF', 'Gene', '7422', (83, 87))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('expression', 'MPA', (90, 100))	('increasing', 'PosReg', (72, 82))	('resistance', 'MPA', (58, 68))	('tumour-adjacent stroma', 'Disease', (108, 130))
9254	31300350	In this context, the biological significances of the SNPs in the BMAL1 (ARNTL) gene in CRC remain to be defined as well.	('CRC', 'Disease', (87, 90))	('ARNTL', 'Gene', (72, 77))	('SNPs', 'Var', (53, 57))	('ARNTL', 'Gene', '406', (72, 77))
9274	31300350	Pharmacological re-entrainment of the circadian clock in cancer cells improves tumour control, e.g.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('tumour', 'Disease', (79, 85))	('cancer', 'Disease', (57, 63))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('men', 'Species', '9606', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('improves', 'PosReg', (70, 78))	('Pharmacological', 'Var', (0, 15))
9279	31300350	REVERBA-agonists (SR9009/SR9011) exert strong cytotoxicity and facilitate oncogene-induced senescence in cell and mouse cancer models.	('REVERBA', 'Chemical', '-', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('SR9011', 'Chemical', 'MESH:C572450', (25, 31))	('facilitate', 'PosReg', (63, 73))	('cytotoxicity', 'Disease', 'MESH:D064420', (46, 58))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('mouse', 'Species', '10090', (114, 119))	('SR9009', 'Chemical', 'MESH:C572451', (18, 24))	('SR9009/SR9011', 'Var', (18, 31))	('senescence', 'biological_process', 'GO:0010149', ('91', '101'))	('cytotoxicity', 'Disease', (46, 58))	('oncogene-induced senescence', 'CPA', (74, 101))
9293	31031748	Polyphenols: Immunomodulatory and Therapeutic Implication in Colorectal Cancer Polyphenolic compounds, widely present in fruits, vegetables, and cereals, have potential benefits for human health and are protective agents against the development of chronic/degenerative diseases including cancer.	('Polyphenolic', 'Var', (79, 91))	('Colorectal Cancer', 'Disease', (61, 78))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('human', 'Species', '9606', (182, 187))	('benefits', 'PosReg', (169, 177))	('Polyphenols', 'Chemical', 'MESH:D059808', (0, 11))	('degenerative diseases', 'Disease', (256, 277))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (61, 78))	('cancer', 'Disease', (288, 294))	('Polyphenolic compounds', 'Chemical', '-', (79, 101))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('degenerative diseases', 'Disease', 'MESH:D019636', (256, 277))
9297	31031748	Many experimental studies and clinical evidence suggest that polyphenols have a relevant role in CRC chemoprevention, exhibit cytotoxic capability vs. CRC cells and induce increased sensitization to chemo/radiotherapies.	('CRC chemoprevention', 'Disease', (97, 116))	('polyphenols', 'Chemical', 'MESH:D059808', (61, 72))	('CRC', 'Phenotype', 'HP:0003003', (151, 154))	('polyphenols', 'Var', (61, 72))	('cytotoxic capability', 'CPA', (126, 146))	('CRC', 'Phenotype', 'HP:0003003', (97, 100))	('sensitization', 'CPA', (182, 195))
9306	31031748	In sporadic (no-colitis-associated) CRC genetic alterations, such as adenomatous polyposis coli (Apc) mutations, DNA mismatch repair (MMR) deficiency, and microsatellite instability (MSI) are reported.	('colitis', 'Disease', (16, 23))	('CRC', 'Phenotype', 'HP:0003003', (36, 39))	('colitis', 'Disease', 'MESH:D003092', (16, 23))	('mismatch repair', 'biological_process', 'GO:0006298', ('117', '132'))	('MMR', 'biological_process', 'GO:0006298', ('134', '137'))	('mutations', 'Var', (102, 111))	('deficiency', 'Var', (139, 149))	('DNA', 'cellular_component', 'GO:0005574', ('113', '116'))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (69, 95))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (69, 95))	('MSI', 'Disease', 'None', (183, 186))	('Apc', 'cellular_component', 'GO:0005680', ('97', '100'))	('Apc', 'Phenotype', 'HP:0005227', (97, 100))	('adenomatous polyposis coli', 'Disease', (69, 95))	('MSI', 'Disease', (183, 186))	('colitis', 'Phenotype', 'HP:0002583', (16, 23))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (69, 90))	('rat', 'Species', '10116', (52, 55))	('microsatellite', 'MPA', (155, 169))
9312	31031748	Among bioactive compounds, polyphenols are known as potential anti-inflammatory and anti-tumor agents (Figure 1) and could be good candidates for cancer prevention and treatment targeting key molecular pathways involved in colorectal cancer.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('anti-inflammatory', 'CPA', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('colorectal cancer', 'Phenotype', 'HP:0003003', (223, 240))	('polyphenols', 'Var', (27, 38))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('polyphenols', 'Chemical', 'MESH:D059808', (27, 38))	('colorectal cancer', 'Disease', (223, 240))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', (234, 240))	('colorectal cancer', 'Disease', 'MESH:D015179', (223, 240))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
9329	31031748	Epidemiological data are concordant in suggesting that the adherence to MD decreases the risk of a variety of cancers.	('cancers', 'Disease', (110, 117))	('adherence', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('decreases', 'NegReg', (75, 84))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
9332	31031748	Furthermore, great attention has been addressed to the effect that MD has on maintenance of "good" GM and on control of carcinogenesis through specific epigenetic alterations.	('rat', 'Species', '10116', (167, 170))	('epigenetic alterations', 'Var', (152, 174))	('carcinogenesis', 'Disease', (120, 134))	('carcinogenesis', 'Disease', 'MESH:D063646', (120, 134))
9342	31031748	In mouse C57BL/6J-Min/+, bearing a germline Apc mutation, a classical model of familial adenomatous polyposis (FAP) and sporadic colorectal cancer, administration of curcumin increases mucosal CD4+ T and B cells and contributes to prevent adenoma formation.	('colorectal cancer', 'Disease', (129, 146))	('Apc', 'Phenotype', 'HP:0005227', (44, 47))	('adenoma', 'Disease', (239, 246))	('familial adenomatous polyposis', 'Disease', (79, 109))	('adenoma', 'Disease', (88, 95))	('FAP', 'Disease', (111, 114))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (79, 109))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (88, 109))	('formation', 'biological_process', 'GO:0009058', ('247', '256'))	('CD4', 'Gene', '920', (193, 196))	('colorectal cancer', 'Phenotype', 'HP:0003003', (129, 146))	('adenoma', 'Disease', 'MESH:D000236', (239, 246))	('FAP', 'Disease', 'MESH:C567782', (111, 114))	('increases', 'PosReg', (175, 184))	('adenoma', 'Disease', 'MESH:D000236', (88, 95))	('rat', 'Species', '10116', (156, 159))	('CD4', 'Gene', (193, 196))	('mutation', 'Var', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('curcumin', 'Chemical', 'MESH:D003474', (166, 174))	('mouse', 'Species', '10090', (3, 8))	('Apc', 'cellular_component', 'GO:0005680', ('44', '47'))	('colorectal cancer', 'Disease', 'MESH:D015179', (129, 146))
9408	30931980	Increased synthesis of PGE2 in CRC has been shown to occur through COX-2-dependent mechanisms; however, loss of the PGE2-catabolizing enzyme, 15-hydroxyprostaglandin dehydrogenase (15-PGDH, HPGD), in colonic tumors contributes to increased prostaglandin levels and poor patient survival.	('PGE2', 'Chemical', 'MESH:D015232', (116, 120))	('15-hydroxyprostaglandin dehydrogenase', 'Gene', (142, 179))	('patient', 'Species', '9606', (270, 277))	('synthesis', 'biological_process', 'GO:0009058', ('10', '19'))	('colonic tumors', 'Disease', 'MESH:D015179', (200, 214))	('prostaglandin', 'Chemical', 'MESH:D011453', (240, 253))	('HPGD', 'Gene', '3248', (190, 194))	('prostaglandin', 'Chemical', 'MESH:D011453', (152, 165))	('colonic tumors', 'Disease', (200, 214))	('increased prostaglandin levels', 'Phenotype', 'HP:0003566', (230, 260))	('COX-2', 'Gene', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('increased', 'PosReg', (230, 239))	('PGE2', 'Chemical', 'MESH:D015232', (23, 27))	('loss', 'Var', (104, 108))	('CRC', 'Phenotype', 'HP:0003003', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('prostaglandin levels', 'MPA', (240, 260))	('COX-2', 'Gene', '5743', (67, 72))	('HPGD', 'Gene', (190, 194))	('15-hydroxyprostaglandin dehydrogenase', 'Gene', '873', (142, 179))
9413	30931980	miR-21 inhibition represses CRC cell proliferation, which is enhanced with EGF receptor (EGFR) inhibition.	('cell proliferation', 'biological_process', 'GO:0008283', ('32', '50'))	('EGFR', 'Gene', (89, 93))	('enhanced', 'PosReg', (61, 69))	('CRC cell proliferation', 'CPA', (28, 50))	('represses', 'NegReg', (18, 27))	('inhibition', 'Var', (95, 105))	('EGF receptor', 'Gene', '1956', (75, 87))	('EGF receptor', 'Gene', (75, 87))	('miR-21', 'Gene', (0, 6))	('CRC', 'Phenotype', 'HP:0003003', (28, 31))	('inhibition', 'Var', (7, 17))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('miR-21', 'Gene', '406991', (0, 6))	('EGFR', 'Gene', '1956', (89, 93))	('EGF', 'molecular_function', 'GO:0005154', ('75', '78'))
9414	30931980	These findings present a novel regulatory mechanism of 15-PGDH by miR-21, and how dysregulated expression of miR-21 may contribute to loss of 15-PGDH expression and promote CRC progression via increased accumulation of PGE2.	('expression', 'MPA', (150, 160))	('CRC', 'Disease', (173, 176))	('PGE2', 'Chemical', 'MESH:D015232', (219, 223))	('miR-21', 'Gene', (66, 72))	('miR-21', 'Gene', '406991', (109, 115))	('increased accumulation', 'PosReg', (193, 215))	('CRC', 'Phenotype', 'HP:0003003', (173, 176))	('promote', 'PosReg', (165, 172))	('loss', 'NegReg', (134, 138))	('dysregulated', 'Var', (82, 94))	('15-PGDH', 'Protein', (142, 149))	('miR-21', 'Gene', (109, 115))	('PGE2', 'Protein', (219, 223))	('miR-21', 'Gene', '406991', (66, 72))
9420	30931980	15-PGDH catalyzes the rate-limiting step of prostaglandin catabolism, and its inactivation has been shown to contribute to elevated levels of PGE2 in the colon.	('inactivation', 'Var', (78, 90))	('prostaglandin', 'Chemical', 'MESH:D011453', (44, 57))	('levels of PGE2', 'MPA', (132, 146))	('elevated', 'PosReg', (123, 131))	('PGE2', 'Chemical', 'MESH:D015232', (142, 146))	('prostaglandin catabolism', 'biological_process', 'GO:1905344', ('44', '68'))
9424	30931980	It has been reported that 15-PGDH expression is primarily lost through mechanisms involving epigenetic silencing and TGF-beta signaling.	('15-PGDH', 'Protein', (26, 33))	('TGF-beta', 'Gene', '7040', (117, 125))	('TGF-beta', 'Gene', (117, 125))	('expression', 'MPA', (34, 44))	('lost', 'NegReg', (58, 62))	('signaling', 'biological_process', 'GO:0023052', ('126', '135'))	('epigenetic silencing', 'Var', (92, 112))
9433	30931980	Intriguingly, miR-21 has been shown to be upregulated in resistant cells, and inhibition of miR-21 resensitized cells to chemotherapeutics.	('miR-21', 'Gene', '406991', (14, 20))	('miR-21', 'Gene', (14, 20))	('miR-21', 'Gene', '406991', (92, 98))	('inhibition', 'Var', (78, 88))	('upregulated', 'PosReg', (42, 53))	('miR-21', 'Gene', (92, 98))
9460	30931980	Consistent with these results, miR-21 inhibited luciferase protein levels > 2-fold in cells containing the Luc + 15-PGDH 3'UTR reporter, along with inhibiting endogenous 15-PGDH protein levels (Fig.	('endogenous 15-PGDH protein levels', 'MPA', (159, 192))	('Luc + 15-PGDH', 'Var', (107, 120))	('miR-21', 'Gene', (31, 37))	('inhibited', 'NegReg', (38, 47))	('luciferase', 'Enzyme', (48, 58))	('miR-21', 'Gene', '406991', (31, 37))	('inhibiting', 'NegReg', (148, 158))
9489	30931980	While overexpression of COX-2 is considered a primary means for increased PG synthesis in CRC, loss of 15-PGDH expression in colonic tumors is now recognized as a contributing factor to increased PGE2 levels.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('PGE2', 'Chemical', 'MESH:D015232', (196, 200))	('PG', 'Chemical', 'MESH:D011453', (74, 76))	('colonic tumors', 'Disease', (125, 139))	('PG', 'Chemical', 'MESH:D011453', (106, 108))	('PG', 'Chemical', 'MESH:D011453', (196, 198))	('synthesis', 'biological_process', 'GO:0009058', ('77', '86'))	('increased', 'PosReg', (186, 195))	('CRC', 'Phenotype', 'HP:0003003', (90, 93))	('colonic tumors', 'Disease', 'MESH:D015179', (125, 139))	('PG synthesis', 'MPA', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('COX-2', 'Gene', '5743', (24, 29))	('PGE2 levels', 'MPA', (196, 207))	('15-PGDH', 'Protein', (103, 110))	('increased', 'PosReg', (64, 73))	('COX-2', 'Gene', (24, 29))	('loss', 'Var', (95, 99))
9500	30931980	Inhibition of COX-2 activity has been associated with adverse cardiovascular side effects, highlighting the importance of developing alternative therapeutic strategies to regulate prostaglandin levels.	('activity', 'MPA', (20, 28))	('COX-2', 'Gene', '5743', (14, 19))	('prostaglandin', 'Chemical', 'MESH:D011453', (180, 193))	('Inhibition', 'Var', (0, 10))	('COX-2', 'Gene', (14, 19))
9502	30931980	We show that inhibition of miR-21 using a deliverable miRNA sponge increased 15-PGDH levels and significantly reduced CRC cell proliferation rates (Fig.	('miR', 'Gene', '220972', (54, 57))	('reduced', 'NegReg', (110, 117))	('miR', 'Gene', (54, 57))	('miR-21', 'Gene', (27, 33))	('inhibition', 'Var', (13, 23))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('increased', 'PosReg', (67, 76))	('CRC', 'Phenotype', 'HP:0003003', (118, 121))	('miR-21', 'Gene', '406991', (27, 33))	('CRC cell proliferation rates', 'CPA', (118, 146))	('15-PGDH', 'Protein', (77, 84))
9517	30931980	Thus, it will be important to study how miR-21 functions within the tumor microenvironment, and how modulation of miR-21 could potentially reprogram the tumor microenvironment to influence tumor growth.	('tumor', 'Disease', (68, 73))	('miR-21', 'Gene', '406991', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('modulation', 'Var', (100, 110))	('influence', 'Reg', (179, 188))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('miR-21', 'Gene', '406991', (40, 46))	('miR-21', 'Gene', (114, 120))	('reprogram', 'Reg', (139, 148))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('miR-21', 'Gene', (40, 46))
9521	30931980	PGE2 has also been shown to transactivate EGFR allowing for increased prostaglandin signaling and tumor cell growth, which could potentiate the effect of dysregulated 15-PGDH and miR-21 expression.	('transactivate', 'Var', (28, 41))	('prostaglandin signaling', 'MPA', (70, 93))	('tumor', 'Disease', (98, 103))	('miR-21', 'Gene', '406991', (179, 185))	('potentiate', 'PosReg', (129, 139))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('EGFR', 'Gene', (42, 46))	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('increased', 'PosReg', (60, 69))	('PGE2', 'Chemical', 'MESH:D015232', (0, 4))	('miR-21', 'Gene', (179, 185))	('PGE2', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('cell growth', 'biological_process', 'GO:0016049', ('104', '115'))	('dysregulated 15-PGDH', 'Disease', (154, 174))	('dysregulated 15-PGDH', 'Disease', 'MESH:D021081', (154, 174))	('EGFR', 'Gene', '1956', (42, 46))	('prostaglandin', 'Chemical', 'MESH:D011453', (70, 83))	('expression', 'MPA', (186, 196))	('increased prostaglandin signaling', 'Phenotype', 'HP:0003566', (60, 93))
9530	30931980	The 15-PGDH 3'UTR was amplified from HeLa cDNA using the following Apa1-tagged primers, sense 5'-GGGCCCACAGCTTATGTGTTAGCCATAGCTG-3' and antisense 5'-GGGCCCCCCCTCCCCTAACTTCAGTTTA-3'.	('Apa1', 'Gene', (67, 71))	("antisense 5'-GGGCCCCCCCTCCCCTAACTTCAGTTTA-3", 'Var', (136, 179))	('Apa1', 'Gene', '57862', (67, 71))	('HeLa', 'CellLine', 'CVCL:0030', (37, 41))
9543	30931980	Western blots were performed using antibodies against 15-PGDH (HPGD; HPA005679; Sigma-Aldrich, St. Louis, MO), anti-Luciferase (Promega, Madison, WI), COX-2 (160112, Cayman Chemical, Ann Arbor, MI), and PTEN (9559, Cell Signaling Technology, Danvers, MA).	('PTEN', 'Gene', (203, 207))	('15-PGDH', 'Protein', (54, 61))	('COX-2', 'Gene', (151, 156))	('PTEN', 'Gene', '5728', (203, 207))	('HPGD', 'Gene', (63, 67))	('COX-2', 'Gene', '5743', (151, 156))	('HPGD', 'Gene', '3248', (63, 67))	('Signaling', 'biological_process', 'GO:0023052', ('220', '229'))	('160112', 'Var', (158, 164))
9544	30931980	Membranes were stripped and re-probed using beta-actin (Clone C4; MP Biomedicals, Solon, OH), tubulin (HRP-66031, Proteintech, Rosemont, IL) or GAPDH (HRP-60004, Proteintech, Rosemont, IL).	('GAPDH', 'Gene', '2597', (144, 149))	('GAPDH', 'Gene', (144, 149))	('beta-actin', 'Protein', (44, 54))	('HRP-66031', 'Var', (103, 112))	('HRP-60004', 'Var', (151, 160))
9562	29511483	The studies indicate that gene expression changes for many of well-known genes are accompanied with onset of disease.	('onset of disease', 'Disease', 'MESH:D000544', (100, 116))	('onset of disease', 'Disease', (100, 116))	('gene expression', 'MPA', (26, 41))	('gene expression', 'biological_process', 'GO:0010467', ('26', '41'))	('changes', 'Var', (42, 49))
9612	28828520	The following variables were assessed: age (<60 years versus > 60 years), sex, tumour location (right versus left colon where the former includes all tumours proximal to the splenic flexure), T stage, N stage, mucinous content (any tumour containing mucinous content versus those without) and presence of SA.	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('tumour', 'Disease', (232, 238))	('tumours', 'Disease', 'MESH:D009369', (150, 157))	('tumour', 'Disease', (150, 156))	('tumours', 'Disease', (150, 157))	('SA', 'Chemical', '-', (305, 307))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('mucinous content', 'Var', (250, 266))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('tumour', 'Disease', (79, 85))	('tumour', 'Disease', 'MESH:D009369', (232, 238))
9659	28828520	The observed association between proximal tumours and adenomas was previously believed to arise from cases with undiagnosed HNPCC and microsatellite instability (MSI) who are more likely to present with multiple lesions.	('adenomas', 'Disease', 'MESH:D000236', (54, 62))	('proximal tumours', 'Disease', 'MESH:D009369', (33, 49))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('HNPCC', 'Disease', 'None', (124, 129))	('HNPCC', 'Disease', (124, 129))	('MSI', 'Disease', 'None', (162, 165))	('tumours', 'Phenotype', 'HP:0002664', (42, 49))	('adenomas', 'Disease', (54, 62))	('microsatellite instability', 'Var', (134, 160))	('MSI', 'Disease', (162, 165))	('proximal tumours', 'Disease', (33, 49))
9660	28828520	Yet, there have recently been reports to suggest that the risk of MAs is not linked to microsatellite instability nor is the incidence of MA in patients with various degrees of MSI any different.	('microsatellite', 'Var', (87, 101))	('MAs', 'Disease', (66, 69))	('patients', 'Species', '9606', (144, 152))	('MSI', 'Disease', 'None', (177, 180))	('MAs', 'cellular_component', 'GO:0034992', ('66', '69'))	('MSI', 'Disease', (177, 180))
9670	28828520	There may be little survival benefit in removing metachronous lesions in the elderly population who undergo cancer resection, and these patients are more likely to develop disease recurrence rather than de novo cancer.	('metachronous', 'Var', (49, 61))	('develop', 'PosReg', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('patients', 'Species', '9606', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('disease', 'Disease', (172, 179))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
9685	28435250	In sum, DOX@TD-2F2S exhibited a synergic anticancer biological effect with chemotherapy and can be a promising strategy for treating colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (133, 150))	('colorectal cancer', 'Disease', (133, 150))	('DOX@TD-2F2S', 'Var', (8, 19))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('colorectal cancer', 'Disease', 'MESH:D015179', (133, 150))	('DOX', 'Chemical', 'MESH:D004317', (8, 11))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
9689	28435250	At present, several aptamers have been used in clinical studies for diseases, including mNOX-E36-3'PEG aptamer for glomerulosclerosis, AS1411 aptamer for acute myeloid leukemia, and ARC 1779 for von Willebrand factor-mediated platelet activation and thrombosis.	('glomerulosclerosis', 'Disease', 'MESH:D005921', (115, 133))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (154, 176))	('AS1411', 'Chemical', 'MESH:C513936', (135, 141))	('von Willebrand', 'Disease', (195, 209))	('leukemia', 'Phenotype', 'HP:0001909', (168, 176))	('acute myeloid leukemia', 'Disease', (154, 176))	('glomerulosclerosis', 'Disease', (115, 133))	('thrombosis', 'Disease', (250, 260))	('AS1411', 'Var', (135, 141))	('von Willebrand', 'Disease', 'MESH:D014842', (195, 209))	('glomerulosclerosis', 'Phenotype', 'HP:0000096', (115, 133))	('platelet activation', 'biological_process', 'GO:0030168', ('226', '245'))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (154, 176))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (160, 176))	('thrombosis', 'Disease', 'MESH:D013927', (250, 260))
9699	28435250	Nanoparticles comprising AS1411 aptamer (glioma targeting) and trans-Golgi network peptide (blood-brain barrier [BBB] targeting) showed more penetration across BBB and brain-glioma barrier to improve the survival of glioma-bearing mice.	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('improve', 'PosReg', (192, 199))	('glioma', 'Disease', 'MESH:D005910', (216, 222))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('glioma', 'Disease', (41, 47))	('glioma', 'Disease', (174, 180))	('brain-glioma', 'Disease', 'MESH:C564230', (168, 180))	('trans-Golgi network', 'cellular_component', 'GO:0005802', ('63', '82'))	('mice', 'Species', '10090', (231, 235))	('brain-glioma', 'Disease', (168, 180))	('AS1411 aptamer', 'Var', (25, 39))	('AS1411', 'Chemical', 'MESH:C513936', (25, 31))	('survival', 'CPA', (204, 212))	('glioma', 'Disease', (216, 222))
9702	28435250	Parekh et al had demonstrated that multimeric C2NP aptamer was able to trimerize CD30 receptor, activate downstream signaling, and enhance cell apoptosis compared with a single aptamer.	('apoptosis', 'biological_process', 'GO:0006915', ('144', '153'))	('activate', 'PosReg', (96, 104))	('C2NP', 'Var', (46, 50))	('cell apoptosis', 'CPA', (139, 153))	('enhance', 'PosReg', (131, 138))	('CD30', 'Gene', '943', (81, 85))	('CD30', 'Gene', (81, 85))	('apoptosis', 'biological_process', 'GO:0097194', ('144', '153'))	('downstream signaling', 'MPA', (105, 125))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))	('trimerize', 'MPA', (71, 80))
9788	28435250	Cell inhibition was further enhanced with F and/or SL2B modification.	('enhanced', 'PosReg', (28, 36))	('SL2B', 'Gene', '6187', (51, 55))	('Cell inhibition', 'CPA', (0, 15))	('SL2B', 'Gene', (51, 55))	('modification', 'Var', (56, 68))
9789	28435250	Different numbers of F and/or SL2B modification also resulted in varied cell inhibition, especially when DOX concentrations were 0.5 and 1 muM.	('SL2B', 'Gene', (30, 34))	('SL2B', 'Gene', '6187', (30, 34))	('muM', 'Gene', '56925', (139, 142))	('modification', 'Var', (35, 47))	('DOX', 'Chemical', 'MESH:D004317', (105, 108))	('cell', 'CPA', (72, 76))	('muM', 'Gene', (139, 142))
9791	28435250	Among all the treatments, DOX@TD-2F2S showed the highest anti-HT-29 cell efficacy (Figure 3).	('DOX@TD-2F2S', 'Var', (26, 37))	('anti-HT-29 cell efficacy', 'CPA', (57, 81))	('HT-29', 'CellLine', 'CVCL:0320', (62, 67))	('DOX', 'Chemical', 'MESH:D004317', (26, 29))
9793	28435250	DOX@TD-FS and DOX@TD-2F2S significantly increased late apoptosis of HT-29 cells to 52% and 69.5%, respectively (Figure 4A).	('DOX', 'Chemical', 'MESH:D004317', (0, 3))	('TD-FS', 'Chemical', '-', (4, 9))	('DOX', 'Chemical', 'MESH:D004317', (14, 17))	('DOX@TD-FS', 'Var', (0, 9))	('HT-29 cells', 'CellLine', 'CVCL:0320', (68, 79))	('increased', 'PosReg', (40, 49))	('DOX@TD-2F2S', 'Var', (14, 25))	('late apoptosis', 'CPA', (50, 64))
9799	28435250	In this work, functionalization of SL2B to TD significantly increased the capacity of cell inhibition by SL2B.	('functionalization', 'Var', (14, 31))	('SL2B', 'Gene', '6187', (35, 39))	('SL2B', 'Gene', (35, 39))	('cell inhibition', 'CPA', (86, 101))	('SL2B', 'Gene', '6187', (105, 109))	('increased', 'PosReg', (60, 69))	('SL2B', 'Gene', (105, 109))
9823	28435250	Figure 3 confirmed that DOX@TD-2F2S had higher cell inhibition than DOX@TD-FS.	('DOX', 'Chemical', 'MESH:D004317', (68, 71))	('higher', 'PosReg', (40, 46))	('DOX', 'Chemical', 'MESH:D004317', (24, 27))	('TD-FS', 'Chemical', '-', (72, 77))	('cell inhibition', 'CPA', (47, 62))	('DOX@TD-2F2S', 'Var', (24, 35))
9825	28435250	In other words, at the same TD concentration, DOX@TD-2F2S possessed more F and SL2B than DOX@TD-FS.	('more', 'PosReg', (68, 72))	('TD-FS', 'Chemical', '-', (93, 98))	('DOX@TD-2F2S', 'Var', (46, 57))	('SL2B', 'Gene', '6187', (79, 83))	('SL2B', 'Gene', (79, 83))	('DOX', 'Chemical', 'MESH:D004317', (46, 49))	('DOX', 'Chemical', 'MESH:D004317', (89, 92))
9826	28435250	Hence, DOX@TD-2F2S showed better anticancer efficacy than DOX@TD-FS as shown in Figure 3.	('DOX', 'Chemical', 'MESH:D004317', (7, 10))	('DOX', 'Chemical', 'MESH:D004317', (58, 61))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('TD-FS', 'Chemical', '-', (62, 67))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('DOX@TD-2F2S', 'Var', (7, 18))
9832	28435250	With the dual-targeting strategy, DOX@TD-2F2S is expected to possess higher specificity to HT-29 tumor in vivo and demonstrate better tumor targeting than single-ligand targeted treatment schemes.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('DOX', 'Chemical', 'MESH:D004317', (34, 37))	('better', 'PosReg', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('HT-29 tumor', 'Disease', (91, 102))	('HT-29 tumor', 'Disease', 'OMIM:614890', (91, 102))	('tumor', 'Disease', (97, 102))	('specificity', 'MPA', (76, 87))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('DOX@TD-2F2S', 'Var', (34, 45))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('higher', 'PosReg', (69, 75))	('tumor', 'Disease', (134, 139))
9851	28435250	Functionalization of F and/or SL2B to TD further increased intracellular DOX (Figures 6B and S3).	('S3', 'Gene', '6188', (93, 95))	('SL2B', 'Gene', (30, 34))	('increased', 'PosReg', (49, 58))	('DOX', 'Chemical', 'MESH:D004317', (73, 76))	('SL2B', 'Gene', '6187', (30, 34))	('intracellular', 'cellular_component', 'GO:0005622', ('59', '72'))	('intracellular DOX', 'MPA', (59, 76))	('Functionalization', 'Var', (0, 17))
9852	28435250	Flow cytometry data confirmed significantly more intracellular DOX uptake by DOX@TD (~81 fold more than the free DOX group) after 1 h incubation.	('DOX', 'Chemical', 'MESH:D004317', (113, 116))	('more', 'PosReg', (44, 48))	('DOX', 'Chemical', 'MESH:D004317', (63, 66))	('intracellular', 'cellular_component', 'GO:0005622', ('49', '62'))	('DOX@TD', 'Var', (77, 83))	('uptake', 'biological_process', 'GO:0098657', ('67', '73'))	('uptake', 'biological_process', 'GO:0098739', ('67', '73'))	('DOX', 'Chemical', 'MESH:D004317', (77, 80))	('intracellular DOX uptake', 'MPA', (49, 73))
9853	28435250	With F and SL2B functionalization, intracellular DOX was further increased (~1,308 fold more than the free DOX group) (Figure 6C).	('increased', 'PosReg', (65, 74))	('DOX', 'Chemical', 'MESH:D004317', (49, 52))	('DOX', 'Chemical', 'MESH:D004317', (107, 110))	('SL2B', 'Gene', '6187', (11, 15))	('SL2B', 'Gene', (11, 15))	('functionalization', 'Var', (16, 33))	('intracellular DOX', 'MPA', (35, 52))
9859	28435250	These results suggested superior anticancer efficacy of DOX@TD-2F2S and a synergic anticancer effect of SL2B and DOX.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('DOX', 'Var', (56, 59))	('cancer', 'Disease', (37, 43))	('SL2B', 'Gene', '6187', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('SL2B', 'Gene', (104, 108))	('DOX', 'Chemical', 'MESH:D004317', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('DOX', 'Chemical', 'MESH:D004317', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('superior', 'PosReg', (24, 32))
9863	27027436	Association of genetic variants in lncRNA H19 with risk of colorectal cancer in a Chinese population The long non-coding RNA (lncRNA) gene, H19, has been involving in multiple biological functions, which also plays a vital role in colorectal cancer carcinogenesis.	('H19', 'Gene', (140, 143))	('H19', 'Gene', '283120', (42, 45))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('colorectal cancer', 'Disease', 'MESH:D015179', (231, 248))	('H19', 'Gene', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('colorectal cancer', 'Disease', (59, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (231, 248))	('colorectal cancer carcinogenesis', 'Disease', (231, 263))	('RNA', 'cellular_component', 'GO:0005562', ('121', '124'))	('variants', 'Var', (23, 31))	('Association', 'Interaction', (0, 11))	('colorectal cancer carcinogenesis', 'Disease', 'MESH:D015179', (231, 263))	('colorectal cancer', 'Disease', 'MESH:D015179', (59, 76))	('H19', 'Gene', '283120', (140, 143))
9864	27027436	However, the association between genetic variants in H19 and colorectal cancer susceptibility has not been reported.	('colorectal cancer', 'Disease', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('colorectal cancer', 'Phenotype', 'HP:0003003', (61, 78))	('colorectal cancer', 'Disease', 'MESH:D015179', (61, 78))	('H19', 'Gene', '283120', (53, 56))	('H19', 'Gene', (53, 56))	('genetic variants', 'Var', (33, 49))
9865	27027436	In this study, we aim to explore whether H19 polymorphisms are related to the susceptibility of colorectal cancer.	('H19', 'Gene', '283120', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('polymorphisms', 'Var', (45, 58))	('colorectal cancer', 'Disease', (96, 113))	('related', 'Reg', (63, 70))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))	('H19', 'Gene', (41, 44))
9866	27027436	We conducted a case-control study to evaluate the association between four selected single nucleotide polymorphisms (SNPs) (rs2839698, rs3024270, rs217727, and rs2735971) in H19 and the risk of colorectal cancer in a Chinese population.	('rs217727', 'Var', (146, 154))	('rs3024270', 'Mutation', 'rs3024270', (135, 144))	('rs2839698', 'Mutation', 'rs2839698', (124, 133))	('rs2735971', 'Var', (160, 169))	('colorectal cancer', 'Disease', 'MESH:D015179', (194, 211))	('rs3024270', 'Var', (135, 144))	('colorectal cancer', 'Phenotype', 'HP:0003003', (194, 211))	('rs217727', 'Mutation', 'rs217727', (146, 154))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('H19', 'Gene', '283120', (174, 177))	('rs2735971', 'Mutation', 'rs2735971', (160, 169))	('rs2839698', 'Var', (124, 133))	('colorectal cancer', 'Disease', (194, 211))	('H19', 'Gene', (174, 177))
9867	27027436	We found that individuals with rs2839698 A allele had a significantly increased risk of colorectal cancer, compared to those carrying G allele [odds ratio (OR) = 1.20, 95% confidence interval (CI) = 1.05-1.36 in additive model].	('rs2839698', 'Mutation', 'rs2839698', (31, 40))	('colorectal cancer', 'Disease', (88, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('rs2839698 A', 'Var', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
9869	27027436	Additionally, bioinformatic analysis showed that rs2839698 may change the crucial folding structures and alter the target microRNAs of H19.	('rs2839698', 'Mutation', 'rs2839698', (49, 58))	('alter', 'Reg', (105, 110))	('crucial folding structures', 'MPA', (74, 100))	('target microRNAs', 'MPA', (115, 131))	('H19', 'Gene', '283120', (135, 138))	('H19', 'Gene', (135, 138))	('change', 'Reg', (63, 69))	('rs2839698', 'Var', (49, 58))
9870	27027436	Our results provided the evidence that rs2839698 in H19 was associated with elevated risk of colorectal cancer, which may be a potential biomarker for predicting colorectal cancer susceptibility.	('colorectal cancer', 'Disease', 'MESH:D015179', (162, 179))	('rs2839698', 'Var', (39, 48))	('H19', 'Gene', '283120', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (162, 179))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('H19', 'Gene', (52, 55))	('rs2839698', 'Mutation', 'rs2839698', (39, 48))	('colorectal cancer', 'Disease', (162, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('colorectal cancer', 'Disease', (93, 110))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))
9874	27027436	In recent years, considerable genome-wide association studies (GWAS) have identified numerous genetic variants impacting the risk of colorectal cancer.	('variants', 'Var', (102, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (133, 150))	('colorectal cancer', 'Disease', (133, 150))	('colorectal cancer', 'Disease', 'MESH:D015179', (133, 150))	('impacting', 'Reg', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
9884	27027436	Induction of epithelial-mesenchymal transition (EMT) in cancer cells due to aberrant H19 expression can promote pancreatic ductal adenocarcinoma cell invasion and migration.	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('13', '46'))	('migration', 'CPA', (163, 172))	('pancreatic ductal adenocarcinoma', 'Disease', (112, 144))	('H19', 'Gene', '283120', (85, 88))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (112, 144))	('aberrant', 'Var', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('EMT', 'biological_process', 'GO:0001837', ('48', '51'))	('promote', 'PosReg', (104, 111))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (112, 144))	('H19', 'Gene', (85, 88))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
9885	27027436	Recently several single nucleotide polymorphisms (SNPs) within lncRNA genes have been extensively confirmed to modulate the expression and function of lncRNA and further cause tumor susceptibility and prognosis changing.	('single nucleotide polymorphisms', 'Var', (17, 48))	('modulate', 'Reg', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('lncRNA', 'Gene', (151, 157))	('lncRNA', 'Gene', (63, 69))	('tumor', 'Disease', (176, 181))	('expression', 'MPA', (124, 134))	('cause', 'Reg', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('function', 'MPA', (139, 147))
9887	27027436	In this study, we conducted a case-control study to genotype the candidate SNPs in H19 (rs2839698, rs3024270, rs217727, and rs2735971) and investigate the association with the risk of colorectal cancer.	('rs2839698', 'Var', (88, 97))	('rs2735971', 'Mutation', 'rs2735971', (124, 133))	('colorectal cancer', 'Disease', 'MESH:D015179', (184, 201))	('rs2839698', 'Mutation', 'rs2839698', (88, 97))	('H19', 'Gene', '283120', (83, 86))	('H19', 'Gene', (83, 86))	('rs3024270', 'Var', (99, 108))	('rs3024270', 'Mutation', 'rs3024270', (99, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (184, 201))	('rs217727', 'Mutation', 'rs217727', (110, 118))	('colorectal cancer', 'Disease', (184, 201))	('rs217727', 'Var', (110, 118))	('rs2735971', 'Var', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
9895	27027436	Primary information and the distributions of genotypes were consistent with those expected from Hardy-Weinberg equilibrium (HWE) in the control group (P = 0.666 for rs2839698, P = 0.979 for rs3024270, P = 0.959 for rs217727 and P = 0.175 for rs2735971, respectively.	('rs3024270', 'Mutation', 'rs3024270', (190, 199))	('rs217727', 'Mutation', 'rs217727', (215, 223))	('rs2735971', 'Mutation', 'rs2735971', (242, 251))	('rs217727', 'Var', (215, 223))	('rs2735971', 'Var', (242, 251))	('rs2839698', 'Var', (165, 174))	('rs3024270', 'Var', (190, 199))	('rs2839698', 'Mutation', 'rs2839698', (165, 174))
9897	27027436	As a result, we observed that rs2839698 was significantly associated with the risk of colorectal cancer after the adjustment for age, gender, smoking and drinking status by performing multivariate logistic regression analysis in additive model [odds ratios (ORs) = 1.20, 95% confidence intervals (CIs) = 1.05-1.36, P = 0.007 and P = 0.028 after Bonferroni correction].	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('associated', 'Reg', (58, 68))	('rs2839698', 'Var', (30, 39))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('colorectal cancer', 'Disease', (86, 103))	('rs2839698', 'Mutation', 'rs2839698', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))
9898	27027436	No significant association between rs3024270, rs217727 and rs2735971 and colorectal cancer risk were found in the additive model.	('rs217727', 'Var', (46, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('rs3024270', 'Var', (35, 44))	('rs2735971', 'Mutation', 'rs2735971', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', (73, 90))	('rs2735971', 'Var', (59, 68))	('rs217727', 'Mutation', 'rs217727', (46, 54))	('rs3024270', 'Mutation', 'rs3024270', (35, 44))
9899	27027436	To exclude whether the possible confounders play roles in the colorectal cancer risk, we conducted the stratified analysis upon the associations between rs2839698 and colorectal cancer by age, sex, smokers, drinkers and family history of cancers.	('cancers', 'Disease', (238, 245))	('colorectal cancer', 'Disease', 'MESH:D015179', (62, 79))	('cancers', 'Disease', 'MESH:D009369', (238, 245))	('colorectal cancer', 'Disease', (167, 184))	('rs2839698', 'Mutation', 'rs2839698', (153, 162))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('associations', 'Interaction', (132, 144))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('colorectal cancer', 'Disease', (62, 79))	('colorectal cancer', 'Disease', 'MESH:D015179', (167, 184))	('colorectal cancer', 'Phenotype', 'HP:0003003', (167, 184))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))	('rs2839698', 'Var', (153, 162))
9901	27027436	Next, we performed the subgroup analysis in different clinicopathologic variables to evaluate the relationship between rs2839698 and colorectal cancer risk.	('colorectal cancer', 'Disease', (133, 150))	('colorectal cancer', 'Disease', 'MESH:D015179', (133, 150))	('rs2839698', 'Var', (119, 128))	('rs2839698', 'Mutation', 'rs2839698', (119, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
9902	27027436	As shown in Supplementary Table S2, rs2839698 GA/AA genotypes were associated with an increased risk of colorectal cancer in individuals with colon tumor site (OR = 1.25, 95% CI = 1.02-1.52, P = 0.033), well differentiated grade (OR = 1.54, 95% CI = 1.13-2.11, P = 0.007) and Duke's C/D stage (OR = 1.37 95% CI = 1.12-1.68, P = 0.002).	('colon tumor', 'Disease', 'MESH:D015179', (142, 153))	('colorectal cancer', 'Disease', 'MESH:D015179', (104, 121))	('rs2839698', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('colon tumor', 'Phenotype', 'HP:0100273', (142, 153))	('rs2839698', 'Mutation', 'rs2839698', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('colon tumor', 'Disease', (142, 153))	('colorectal cancer', 'Phenotype', 'HP:0003003', (104, 121))	('colorectal cancer', 'Disease', (104, 121))	("Duke's C/D stage", 'CPA', (276, 292))
9905	27027436	As a result, the secondary structure was dramatically changed with rs2839698 G/A alleles (Figure 2), rs3024270 C/G alleles and rs217727 G/A alleles (Supplementary Figure S1).	('secondary structure', 'MPA', (17, 36))	('rs217727 G/A', 'Var', (127, 139))	('rs217727', 'Mutation', 'rs217727', (127, 135))	('rs2839698', 'Mutation', 'rs2839698', (67, 76))	('changed', 'Reg', (54, 61))	('rs3024270', 'Mutation', 'rs3024270', (101, 110))	('rs2839698 G/A', 'Var', (67, 80))	('rs3024270 C/G', 'Var', (101, 114))
9907	27027436	According to the fact that rs2839698 (G/A) is located in the exon (3'untranslated region) of H19 gene, we speculate that genetic variant in rs2839698 may change the promoter activity and function of H19 to a certain extent through alteration of target miRNAs and subsequently lead to colorectal cancer.	('H19', 'Gene', '283120', (199, 202))	('change', 'Reg', (154, 160))	('H19', 'Gene', (199, 202))	('lead to', 'Reg', (276, 283))	('colorectal cancer', 'Disease', 'MESH:D015179', (284, 301))	('H19', 'Gene', (93, 96))	('H19', 'Gene', '283120', (93, 96))	('rs2839698', 'Var', (140, 149))	('alteration', 'Reg', (231, 241))	('function', 'MPA', (187, 195))	('rs2839698', 'Mutation', 'rs2839698', (140, 149))	('colorectal cancer', 'Phenotype', 'HP:0003003', (284, 301))	('promoter activity', 'MPA', (165, 182))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('rs2839698', 'Mutation', 'rs2839698', (27, 36))	('colorectal cancer', 'Disease', (284, 301))
9909	27027436	We found that hsa-miR-24-1-5p, hsa-miR-4486, hsa-miR-566 and hsa-miR-24-2-5p may lose the target H19 gene, following with the creating binding site of hsa-miR-612, hsa-miR-5189, hsa-miR-1285-3p and hsa-miR-3187-5p (Supplementary Table S3).	('miR-5189', 'Gene', '100847057', (168, 176))	('miR-4486', 'Gene', '100616118', (35, 43))	('hsa-miR-612', 'Gene', '693197', (151, 162))	('H19', 'Gene', '283120', (97, 100))	('miR-5189', 'Gene', (168, 176))	('H19', 'Gene', (97, 100))	('binding', 'molecular_function', 'GO:0005488', ('135', '142'))	('lose', 'NegReg', (81, 85))	('hsa-miR-24-2-5p', 'Var', (61, 76))	('hsa-miR-566', 'Gene', (45, 56))	('hsa-miR-566', 'Gene', '693151', (45, 56))	('miR-4486', 'Gene', (35, 43))	('hsa-miR-612', 'Gene', (151, 162))
9916	27027436	Emerging evidences have implied that genetic variants in lncRNAs may modify the risk of multiply tumors.	('genetic variants', 'Var', (37, 53))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('multiply tumors', 'Disease', (88, 103))	('lncRNAs', 'Gene', (57, 64))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('multiply tumors', 'Disease', 'MESH:D009369', (88, 103))	('modify', 'Reg', (69, 75))
9917	27027436	have found that H19 gene polymorphisms were concerned in susceptibility of bladder cancer in European Caucasians.	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('bladder cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('H19', 'Gene', '283120', (16, 19))	('polymorphisms', 'Var', (25, 38))	('H19', 'Gene', (16, 19))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))
9918	27027436	However, to our knowledge, no data previously has explored the correlation between H19 genetic variants and colorectal cancer susceptibility in a Chinese population.	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('H19', 'Gene', '283120', (83, 86))	('H19', 'Gene', (83, 86))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('genetic variants', 'Var', (87, 103))	('colorectal cancer', 'Disease', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
9919	27027436	In this study, we selected four tagSNPs (rs2839698, rs3024270, rs217727, and rs2735971) in H19 gene and DMR to estimate the association between these variants and colorectal cancer susceptibility.	('rs2735971', 'Mutation', 'rs2735971', (77, 86))	('colorectal cancer', 'Disease', 'MESH:D015179', (163, 180))	('rs2735971', 'Var', (77, 86))	('rs3024270', 'Var', (52, 61))	('H19', 'Gene', (91, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('rs217727', 'Var', (63, 71))	('H19', 'Gene', '283120', (91, 94))	('rs2839698', 'Var', (41, 50))	('rs217727', 'Mutation', 'rs217727', (63, 71))	('rs3024270', 'Mutation', 'rs3024270', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('colorectal cancer', 'Disease', (163, 180))	('rs2839698', 'Mutation', 'rs2839698', (41, 50))
9920	27027436	We observed that rs2839698 GA/AA genotype has an increased risk of colorectal cancer in the Chinese populations compared with the GG genotype.	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('rs2839698', 'Var', (17, 26))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('rs2839698', 'Mutation', 'rs2839698', (17, 26))	('colorectal cancer', 'Disease', (67, 84))
9921	27027436	also demonstrated that rs2839698 contributed to the risk of gastric cancer in a Chinese population.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('rs2839698', 'Var', (23, 32))	('gastric cancer', 'Disease', (60, 74))	('rs2839698', 'Mutation', 'rs2839698', (23, 32))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('risk', 'Reg', (52, 56))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))
9922	27027436	All of the above suggested that H19 genetic variants play an important role in cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('H19', 'Gene', '283120', (32, 35))	('H19', 'Gene', (32, 35))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('genetic variants', 'Var', (36, 52))
9924	27027436	Our stratified analyses demonstrated that individuals, including smokers and drinkers, carrying rs2839698 GA/AA genotype had a significantly increased susceptibility of colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('colorectal cancer', 'Disease', 'MESH:D015179', (169, 186))	('rs2839698 GA/AA', 'Var', (96, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (169, 186))	('rs2839698', 'Mutation', 'rs2839698', (96, 105))	('colorectal cancer', 'Disease', (169, 186))
9925	27027436	Therefore, the markedly induced risk of colorectal cancer associated with variant rs2839698 genotypes could partly attribute to the accumulated exposure/exposure history to alcohol consumption or tobacco carcinogens.	('variant rs2839698', 'Var', (74, 91))	('colorectal cancer', 'Disease', (40, 57))	('rs2839698', 'Var', (82, 91))	('tobacco', 'Species', '4097', (196, 203))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('rs2839698', 'Mutation', 'rs2839698', (82, 91))	('colorectal cancer', 'Disease', 'MESH:D015179', (40, 57))	('alcohol consumption', 'Disease', 'MESH:D000437', (173, 192))	('alcohol consumption', 'Disease', (173, 192))	('colorectal cancer', 'Phenotype', 'HP:0003003', (40, 57))
9926	27027436	Moreover, we found that increased colorectal cancer risk correlated with rs2839698 was more remarkable in subgroups of younger individuals and male, suggested that promoting effects of H19 variants on colorectal cancer may be modulated by specific epidemiological features.	('rs2839698', 'Mutation', 'rs2839698', (73, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (201, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('H19', 'Gene', (185, 188))	('colorectal cancer', 'Phenotype', 'HP:0003003', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('variants', 'Var', (189, 197))	('colorectal cancer', 'Disease', (34, 51))	('colorectal cancer', 'Phenotype', 'HP:0003003', (201, 218))	('rs2839698', 'Var', (73, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (34, 51))	('colorectal cancer', 'Disease', (201, 218))	('promoting', 'PosReg', (164, 173))	('H19', 'Gene', '283120', (185, 188))
9930	27027436	We further found that rs2839698 GA/AA genotype had an increased risk of colorectal cancer among patients with Duke's stage of C or D. It is rational that the genetic variants may play a vital role in the advanced stage of colorectal cancer and lead to our present result.	('colorectal cancer', 'Disease', 'MESH:D015179', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('colorectal cancer', 'Disease', (222, 239))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('rs2839698', 'Mutation', 'rs2839698', (22, 31))	('rs2839698', 'Var', (22, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (222, 239))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('patients', 'Species', '9606', (96, 104))	('colorectal cancer', 'Disease', (72, 89))	('colorectal cancer', 'Phenotype', 'HP:0003003', (222, 239))
9931	27027436	However, the results showed that subjects with the gene loci variation were involved in the obviously increased risk of colorectal cancer among colon site and well differentiated grade subgroups, indicating that different colorectal cancer site and grade regulated by different molecular biological mechanisms may bring about different level of risk in carcinogenesis of colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('colorectal cancer', 'Disease', (222, 239))	('colorectal cancer', 'Disease', (120, 137))	('colorectal cancer', 'Disease', 'MESH:D015179', (222, 239))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('colorectal cancer', 'Phenotype', 'HP:0003003', (371, 388))	('carcinogenesis of colorectal cancer', 'Disease', 'MESH:D015179', (353, 388))	('carcinogenesis of colorectal cancer', 'Disease', (353, 388))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('colorectal cancer', 'Disease', 'MESH:D015179', (120, 137))	('colorectal cancer', 'Disease', 'MESH:D015179', (371, 388))	('colorectal cancer', 'Phenotype', 'HP:0003003', (222, 239))	('gene loci variation', 'Var', (51, 70))	('variation', 'Var', (61, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))
9933	27027436	We found that the folding architectures markedly changed along with the genetic variant of rs2839689, rs3024270, rs217727, and rs2735971, suggested that SNPs may be involved in occurrence and development of colorectal cancer by altering the specific structural motifs of H19 and exerting various effects on H19 expression and function.	('H19', 'Gene', (271, 274))	('colorectal cancer', 'Disease', 'MESH:D015179', (207, 224))	('rs217727', 'Var', (113, 121))	('rs2735971', 'Var', (127, 136))	('rs2839689', 'Var', (91, 100))	('colorectal cancer', 'Disease', (207, 224))	('altering', 'Reg', (228, 236))	('function', 'MPA', (326, 334))	('rs3024270', 'Var', (102, 111))	('folding architectures', 'MPA', (18, 39))	('H19', 'Gene', '283120', (271, 274))	('expression', 'MPA', (311, 321))	('specific structural motifs', 'MPA', (241, 267))	('changed', 'Reg', (49, 56))	('rs2839689', 'Mutation', 'rs2839689', (91, 100))	('H19', 'Gene', (307, 310))	('involved', 'Reg', (165, 173))	('rs2735971', 'Mutation', 'rs2735971', (127, 136))	('colorectal cancer', 'Phenotype', 'HP:0003003', (207, 224))	('effects', 'Reg', (296, 303))	('rs217727', 'Mutation', 'rs217727', (113, 121))	('rs3024270', 'Mutation', 'rs3024270', (102, 111))	('H19', 'Gene', '283120', (307, 310))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))
9935	27027436	The changes of target miRNAs may potentially affect the expression and function of H19 due to rs2839689 variant, which ultimately modulate the risk of colorectal cancer.	('affect', 'Reg', (45, 51))	('function', 'MPA', (71, 79))	('colorectal cancer', 'Phenotype', 'HP:0003003', (151, 168))	('H19', 'Gene', '283120', (83, 86))	('rs2839689', 'Var', (94, 103))	('H19', 'Gene', (83, 86))	('colorectal cancer', 'Disease', (151, 168))	('modulate', 'Reg', (130, 138))	('expression', 'MPA', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (151, 168))	('rs2839689', 'Mutation', 'rs2839689', (94, 103))
9936	27027436	In summary, we have provided the evidence that H19 rs2839689 contributes to the susceptible to colorectal cancer in the Chinese population.	('H19', 'Gene', (47, 50))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('colorectal cancer', 'Disease', (95, 112))	('rs2839689', 'Var', (51, 60))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('rs2839689', 'Mutation', 'rs2839689', (51, 60))	('H19', 'Gene', '283120', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
9944	27027436	We used RNAfold (http://rna.tbi.univie.ac.at/) and SNPfold (http://ribosnitch.bio.unc.edu/snpfold/SNPfold.html) algorithms to predict the folding structure variants of H19 on account of tagSNPs genotypes.	('variants', 'Var', (156, 164))	('folding structure', 'MPA', (138, 155))	('H19', 'Gene', (168, 171))	('H19', 'Gene', '283120', (168, 171))
9956	27688749	We identified hypermethylated CpG sites in the following genes: L3MBTL1, NKX6-2, PREX1, TRAF7, PRDM14, and NEFM with the number of CpG sites being 14, 17, 10, 16, 6, and 6, respectively, after pairwise analysis of normal versus adenoma, adenoma versus cancer, and normal versus cancer.	('NEFM', 'Gene', '4741', (107, 111))	('NEFM', 'Gene', (107, 111))	('PREX1', 'Gene', (81, 86))	('PRDM14', 'Gene', (95, 101))	('adenoma versus cancer', 'Disease', 'MESH:D000236', (237, 258))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('TRAF7', 'Gene', (88, 93))	('PRDM14', 'Gene', '63978', (95, 101))	('NKX6-2', 'Gene', (73, 79))	('PREX1', 'Gene', '57580', (81, 86))	('TRAF7', 'Gene', '84231', (88, 93))	('adenoma versus cancer', 'Disease', (237, 258))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('L3MBTL1', 'Gene', (64, 71))	('hypermethylated', 'Var', (14, 29))	('L3MBTL1', 'Gene', '26013', (64, 71))	('NKX6-2', 'Gene', '84504', (73, 79))
9958	27688749	This work provides insight into novel differential CpGs hypermethylation sites in colorectal carcinogenesis.	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (82, 107))	('colorectal carcinogenesis', 'Disease', (82, 107))	('hypermethylation', 'Var', (56, 72))	('CpGs hypermethylation', 'Var', (51, 72))
9962	27688749	Many genes are silenced by aberrant methylation in CRC (APC, p16INK4a, and TIMP3); such genes have the potential to become useful biomarkers for early detection of colorectal neoplasia.	('colorectal neoplasia', 'Disease', 'MESH:D009369', (164, 184))	('TIMP3', 'Gene', (75, 80))	('p16', 'Gene', (61, 64))	('p16INK4a', 'Gene', (61, 69))	('CRC', 'Phenotype', 'HP:0003003', (51, 54))	('TIMP3', 'Gene', '7078', (75, 80))	('APC', 'cellular_component', 'GO:0005680', ('56', '59'))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('aberrant methylation', 'Var', (27, 47))	('p16INK4a', 'Gene', '1029', (61, 69))	('APC', 'Disease', 'MESH:D011125', (56, 59))	('p16', 'Gene', '1029', (61, 64))	('APC', 'Disease', (56, 59))	('colorectal neoplasia', 'Disease', (164, 184))	('neoplasia', 'Phenotype', 'HP:0002664', (175, 184))
9982	27688749	found that high levels of L3MBTL1 methylation were related to slightly elevated risk of breast cancer death, and hypermethylation of L3MBTL1 in breast cancer patients can be reduced through physical exercise which positively associated with overall survival.	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('methylation', 'Var', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer death', 'Disease', (88, 107))	('breast cancer', 'Disease', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('L3MBTL1', 'Gene', (26, 33))	('breast cancer death', 'Disease', 'MESH:D001943', (88, 107))	('hypermethylation', 'Var', (113, 129))	('L3MBTL1', 'Gene', (133, 140))	('associated', 'Reg', (225, 235))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
9983	27688749	If found in any preneoplastic lesions, this gene's methylation should point to highly carcinogenic lesions that need to be addressed and monitored aggressively due to its implication with major cancer pathways, including VEGF that points to metastasis implications as well as NKX6-2 gene located on chromosome 10, known as a prognostic marker.	('carcinogenic lesions', 'Disease', (86, 106))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('NKX6-2', 'Gene', (276, 282))	('chromosome', 'cellular_component', 'GO:0005694', ('299', '309'))	('methylation', 'Var', (51, 62))	('point', 'Reg', (70, 75))	('carcinogenic lesions', 'Disease', 'MESH:D051437', (86, 106))
9984	27688749	Previous studies showed that NKX6-2 is hypermethylated in bladder tumors and hypomethylated in normal leukocytes.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('NKX6-2', 'Gene', (29, 35))	('hypermethylated', 'Var', (39, 54))	('bladder tumors', 'Disease', 'MESH:D001749', (58, 72))	('bladder tumors', 'Phenotype', 'HP:0009725', (58, 72))	('bladder tumors', 'Disease', (58, 72))
9985	27688749	Another study demonstrated that DNA hypermethylation of NKX6-2 is a hallmark of CIMP at very early stages of renal carcinogenesis.	('CIMP', 'Chemical', '-', (80, 84))	('renal carcinogenesis', 'Disease', 'MESH:D007674', (109, 129))	('NKX6-2', 'Gene', (56, 62))	('DNA', 'Var', (32, 35))	('renal carcinogenesis', 'Disease', (109, 129))
9986	27688749	NKX6-2 was also identified as a biomarker in stages II and III lung adenocarcinoma, where it was hypomethylated in stage II and hypermethylated in stage III.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (63, 82))	('NKX6-2', 'Gene', (0, 6))	('III lung adenocarcinoma', 'Disease', 'MESH:D000077192', (59, 82))	('hypomethylated', 'Var', (97, 111))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (63, 82))	('hypermethylated', 'Var', (128, 143))	('III lung adenocarcinoma', 'Disease', (59, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
9988	27688749	The impact of the hypermethylated NKX6-2 gene has been reported in bladder cancer, renal cancer, and lung adenocarcinoma, and this is consistent with our results in colorectal cancer specimens.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (101, 120))	('colorectal cancer', 'Phenotype', 'HP:0003003', (165, 182))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('renal cancer', 'Disease', (83, 95))	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('lung adenocarcinoma', 'Disease', (101, 120))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('renal cancer', 'Disease', 'MESH:D007680', (83, 95))	('renal cancer', 'Phenotype', 'HP:0009726', (83, 95))	('NKX6-2', 'Gene', (34, 40))	('hypermethylated', 'Var', (18, 33))
9989	27688749	A retrospective study showed that PRDM14 is frequently overexpressed in breast cancers and that its overexpression is often associated with gene amplification.	('breast cancers', 'Phenotype', 'HP:0003002', (72, 86))	('PRDM14', 'Gene', (34, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('breast cancers', 'Disease', 'MESH:D001943', (72, 86))	('overexpressed', 'PosReg', (55, 68))	('breast cancers', 'Disease', (72, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('overexpression', 'PosReg', (100, 114))	('gene amplification', 'Var', (140, 158))
9990	27688749	The present in silica study also suggests that DNA methylation of a CpG site located -620 to -627 bp upstream from the transcription start site in the promoter of PRDM14 may affect the expression of this gene.	('expression', 'MPA', (185, 195))	('silica', 'Chemical', 'MESH:D012822', (15, 21))	('PRDM14', 'Gene', (163, 169))	('affect', 'Reg', (174, 180))	('DNA', 'Var', (47, 50))
10015	27342639	Furthermore, low-dose TCP-1/TNFalpha (1 ng/mouse) potentiated the antitumor effect of 5-fluorouracil (5-FU) by normalizing the tumor vasculature, facilitating the infiltration of immune cells to the tumor as well as improving 5-FU penetration into the tumor mass.	('5-FU', 'MPA', (226, 230))	('5-FU', 'Chemical', 'MESH:D005472', (226, 230))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumor', 'Disease', (252, 257))	('TCP-1/TNFalpha', 'Var', (22, 36))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('facilitating', 'PosReg', (146, 158))	('potentiated', 'PosReg', (50, 61))	('improving', 'PosReg', (216, 225))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('mouse', 'Species', '10090', (43, 48))	('infiltration', 'CPA', (163, 175))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (86, 100))	('5-FU', 'Chemical', 'MESH:D005472', (102, 106))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (70, 75))	('normalizing', 'MPA', (111, 122))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
10035	27342639	Anti-mouse CD31 (553274), anti-mouse CD4 (553043) and anti-mouse CD8 (550281) monoclonal antibodies were purchased from BD Pharmingen.	('553274', 'Var', (17, 23))	('CD4', 'Gene', '12504', (37, 40))	('mouse', 'Species', '10090', (59, 64))	('553043', 'Var', (42, 48))	('mouse', 'Species', '10090', (31, 36))	('CD4', 'Gene', (37, 40))	('550281', 'Var', (70, 76))	('mouse', 'Species', '10090', (5, 10))	('CD31', 'Gene', '18613', (11, 15))	('CD31', 'Gene', (11, 15))
10037	27342639	PE-Cy  7 anti-mouse CD3 (100320), PE anti-mouse CD4 (103405) and FITC anti-mouse CD8a (100706), APC anti-mouse CD34 (128612), PE-Cy  7 anti-mouse CD45 (103222) antibodies, and isotype IgG were purchased from Biolegend.	('CD3', 'Gene', '12501', (111, 114))	('CD45', 'Gene', (146, 150))	('128612', 'Var', (117, 123))	('CD4', 'Gene', (48, 51))	('CD8a', 'Gene', (81, 85))	('CD3', 'Gene', (20, 23))	('mouse', 'Species', '10090', (14, 19))	('CD3', 'Gene', '12501', (20, 23))	('CD4', 'Gene', '12504', (48, 51))	('PE-Cy', 'Chemical', '-', (0, 5))	('100320', 'Var', (25, 31))	('mouse', 'Species', '10090', (140, 145))	('CD34', 'Gene', (111, 115))	('PE-Cy', 'Chemical', '-', (126, 131))	('CD4', 'Gene', (146, 149))	('100706', 'Var', (87, 93))	('CD3', 'Gene', (111, 114))	('mouse', 'Species', '10090', (75, 80))	('103405', 'Var', (53, 59))	('CD45', 'Gene', '19264', (146, 150))	('mouse', 'Species', '10090', (42, 47))	('CD34', 'Gene', '12490', (111, 115))	('APC', 'Disease', 'MESH:D011125', (96, 99))	('CD4', 'Gene', '12504', (146, 149))	('APC', 'Disease', (96, 99))	('mouse', 'Species', '10090', (105, 110))	('CD8a', 'Gene', '12525', (81, 85))	('FITC', 'Chemical', 'MESH:D016650', (65, 69))
10060	27342639	Intact blue nuclei, condensed/fragmented blue nuclei, condensed/fragmented pink nuclei, and intact pink nuclei were considered viable, early apoptotic, late apoptotic and necrotic cells, respectively.	('condensed/fragmented', 'Var', (54, 74))	('necrotic', 'Disease', (171, 179))	('necrotic', 'Disease', 'MESH:D009336', (171, 179))
10072	27342639	After 24 h treatment, TCP-1/IFNgamma induced more MHC-I expression inside the tumor than control or IFNgamma (Fig.	('TCP-1/IFNgamma', 'Var', (22, 36))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('MHC-I', 'Gene', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('expression', 'MPA', (56, 66))	('tumor', 'Disease', (78, 83))
10075	27342639	We used the dose of 1 mug/mouse for TNFalpha and TCP-1/TNFalpha and 5 mug/mouse for IFNgamma and TCP-1/IFNgamma according to previous experiment which indicated that 5 mug TCP-1/IFNgamma can induce maximal anti-tumor effect (Additional file 3: Fig.	('mug', 'molecular_function', 'GO:0043739', ('70', '73'))	('TNFalpha and 5', 'Gene', '21926', (55, 69))	('mug', 'molecular_function', 'GO:0043739', ('168', '171'))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('mug', 'molecular_function', 'GO:0043739', ('22', '25'))	('TCP-1/IFNgamma', 'Var', (172, 186))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('mouse', 'Species', '10090', (74, 79))	('tumor', 'Disease', (211, 216))	('mouse', 'Species', '10090', (26, 31))
10076	27342639	Compared with the control group, TNFalpha or IFNgamma slightly but not significantly suppressed tumor growth, while TCP-1/TNFalpha or TCP-1/IFNgamma significantly decreased tumor size compared with their unconjugated counterparts (Fig.	('TCP-1/TNFalpha', 'Var', (116, 130))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('TCP-1/IFNgamma', 'Var', (134, 148))	('suppressed', 'NegReg', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('decreased', 'NegReg', (163, 172))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
10083	27342639	Due to systemic toxicity, mice given TNFalpha combined with IFNgamma all died within 2 days while the group given the same dose but conjugated with TCP-1 all survived (Fig.	('toxicity', 'Disease', 'MESH:D064420', (16, 24))	('mice', 'Species', '10090', (26, 30))	('toxicity', 'Disease', (16, 24))	('TNFalpha', 'Var', (37, 45))
10085	27342639	S4A, B) and at the same time alleviated systematic toxicity induced by non-targeted TNFalpha and IFNgamma.	('toxicity', 'Disease', 'MESH:D064420', (51, 59))	('non-targeted', 'Var', (71, 83))	('alleviated', 'NegReg', (29, 39))	('toxicity', 'Disease', (51, 59))	('TNFalpha', 'Gene', (84, 92))	('IFNgamma', 'Gene', (97, 105))
10096	27342639	Both TCP-1/TNFalpha and TCP-1/IFNgamma increased CD3+ cells in the spleen meaning more T lymphocytes were generated by the spleen.	('TCP-1/TNFalpha', 'Var', (5, 19))	('T lymphocytes', 'CPA', (87, 100))	('more', 'PosReg', (82, 86))	('CD3', 'Gene', (49, 52))	('TCP-1/IFNgamma', 'Var', (24, 38))	('CD3', 'Gene', '12501', (49, 52))	('increased', 'PosReg', (39, 48))
10100	27342639	Taken together, the data suggest that TCP-1/TNFalpha and TCP-1/IFNgamma could increase the generation of T lymphocyte in the spleen and enhance the penetration of T lymphocytes into the tumor.	('TCP-1/IFNgamma', 'Var', (57, 71))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('TCP-1/TNFalpha', 'Var', (38, 52))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('generation of T lymphocyte in the spleen', 'MPA', (91, 131))	('tumor', 'Disease', (186, 191))	('increase', 'PosReg', (78, 86))	('enhance', 'PosReg', (136, 143))
10102	27342639	To elucidate the mechanism by which TCP-1/TNFalpha combined with TCP-1/IFNgamma induced massive cell death inside the tumor, Hochest and PI double stain was first performed in frozen tissue sections.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('cell death', 'biological_process', 'GO:0008219', ('96', '106'))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('TCP-1/TNFalpha', 'Var', (36, 50))
10108	27342639	TNFalpha (100 ng/mL) and IFNgamma (500 ng/mL) synergistically inhibited cell growth as shown by MTT assay (Fig.	('cell growth', 'CPA', (72, 83))	('100 ng/mL', 'Var', (10, 19))	('TNFalpha', 'Gene', (0, 8))	('MTT', 'Chemical', 'MESH:C070243', (96, 99))	('IFNgamma', 'Gene', (25, 33))	('inhibited', 'NegReg', (62, 71))
10125	27342639	Our previous study has demonstrated that low dose TCP-1/TNFalpha could normalize tumor blood vessel, enhance the intratumoral accumulation of anticancer drug 5-FU, thus potentiating its antitumor activity.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('5-FU', 'Chemical', 'MESH:D005472', (158, 162))	('potentiating', 'PosReg', (169, 181))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('enhance', 'PosReg', (101, 108))	('TCP-1/TNFalpha', 'Var', (50, 64))	('tumor', 'Disease', (81, 86))
10126	27342639	Our previous result demonstrated that TNFalpha or TCP-1/TNFalpha at 5 mug/mouse could lead to acute vessel destruction.	('mug', 'molecular_function', 'GO:0043739', ('70', '73'))	('acute vessel destruction', 'CPA', (94, 118))	('mouse', 'Species', '10090', (74, 79))	('lead to', 'Reg', (86, 93))	('TCP-1/TNFalpha', 'Var', (50, 64))
10128	27342639	For IFNgamma, consistent with previous findings that a dose-response curve of IFNgamma-NGR is bell-shaped, our result also showed that TCP-1/IFNgamma achieved optimal antitumor effect at the dose of 5 mug/mouse.	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('NGR', 'Gene', (87, 90))	('mouse', 'Species', '10090', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('TCP-1/IFNgamma', 'Var', (135, 149))	('NGR', 'Gene', '65079', (87, 90))
10129	27342639	In addition to inducing tumor apoptosis, TCP-1/TNFalpha or TCP-1/IFNgamma also increased the infiltration of CD8+ and CD4+ T cell in the tumor leading to enhanced antitumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('increased', 'PosReg', (79, 88))	('tumor', 'Disease', (137, 142))	('enhanced', 'PosReg', (154, 162))	('tumor', 'Disease', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('TCP-1/TNFalpha', 'Var', (41, 55))	('CD4', 'Gene', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('inducing', 'Reg', (15, 23))	('TCP-1/IFNgamma', 'Var', (59, 73))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('CD4', 'Gene', '12504', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('infiltration', 'CPA', (93, 105))	('tumor', 'Disease', (167, 172))
10130	27342639	Previous study has shown that the antitumor effect of targeted IFNgamma in animal study mainly involves inhibition of angiogenesis and induction of apoptosis but not infiltration of immune cells, which is different from our result.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('inhibition', 'NegReg', (104, 114))	('tumor', 'Disease', (38, 43))	('inhibition of angiogenesis', 'biological_process', 'GO:0016525', ('104', '130'))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('IFNgamma', 'Gene', (63, 71))	('apoptosis', 'CPA', (148, 157))	('targeted', 'Var', (54, 62))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('135', '157'))	('angiogenesis', 'CPA', (118, 130))
10207	26904353	She eventually recovered following a cardiac diet (low fat, low cholesterol, and high protein) with peritoneal drainage and octreotide.	('low', 'NegReg', (60, 63))	('cholesterol', 'Chemical', 'MESH:D002784', (64, 75))	('low', 'Var', (51, 54))	('low cholesterol', 'Phenotype', 'HP:0003146', (60, 75))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('octreotide', 'Chemical', 'MESH:D015282', (124, 134))
10232	26904353	suggest microsatellite instability testing could be applied to all patients with colorectal and urological cancers to assist in detecting a common genetic aberration between malignancies.	('colorectal and urological cancers', 'Disease', 'MESH:D015179', (81, 114))	('patients', 'Species', '9606', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('malignancies', 'Disease', (174, 186))	('microsatellite', 'Var', (8, 22))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('malignancies', 'Disease', 'MESH:D009369', (174, 186))
10248	26509158	Aberrant protein glycosylation is well known hallmark of cancer and represents a promising source of potential biomarkers.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (57, 63))	('protein', 'Protein', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
10263	26509158	Aberrant glycosylation of proteins is a well-known hallmark of cancer and represents a valuable source of information.	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('proteins', 'Protein', (26, 34))	('glycosylation', 'MPA', (9, 22))	('cancer', 'Disease', (63, 69))
10297	26509158	It is a 28.4 kDa glycoprotein with one N-linked glycosylation site and is further subcategorized into glycosylated (gp28, gp22, gp18, and gp12) or nonglycosylated (p26-full length nonglycosylated PSA, p20, p16, p10, and p6) peptides.	('p16', 'Gene', '1029', (206, 209))	('PSA', 'Gene', '354', (196, 199))	('PSA', 'Gene', (196, 199))	('gp12', 'Var', (138, 142))	('p20', 'Gene', (201, 204))	('N', 'Chemical', 'MESH:D009584', (39, 40))	('p10', 'Gene', (211, 214))	('gp28', 'Var', (116, 120))	('p26', 'Gene', '23423', (164, 167))	('glycosylation', 'biological_process', 'GO:0070085', ('48', '61'))	('gp18', 'Var', (128, 132))	('p16', 'Gene', (206, 209))	('p10', 'Gene', '6281', (211, 214))	('p20', 'Gene', '51673', (201, 204))	('gp22', 'Var', (122, 126))	('p26', 'Gene', (164, 167))
10299	26509158	Disruption of the prostatic epithelium in inflammation and prostate disorders, including benign prostatic hyperplasia (BPH) and prostate cancer, causes diffusion of PSA into the tissue around the epithelium and leads to elevated concentrations of circulating PSA in these conditions.	('elevated concentrations of circulating PSA', 'Phenotype', 'HP:0031956', (220, 262))	('benign prostatic hyperplasia', 'Phenotype', 'HP:0008711', (89, 117))	('Disruption', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('PSA', 'Gene', (165, 168))	('prostate cancer', 'Disease', 'MESH:D011471', (128, 143))	('prostate cancer', 'Phenotype', 'HP:0012125', (128, 143))	('prostate disorders', 'Disease', (59, 77))	('PSA', 'Gene', (259, 262))	('diffusion', 'MPA', (152, 161))	('inflammation', 'Disease', 'MESH:D007249', (42, 54))	('prostate cancer', 'Disease', (128, 143))	('benign prostatic hyperplasia', 'Disease', (89, 117))	('prostate disorders', 'Disease', 'MESH:D011469', (59, 77))	('BPH', 'Phenotype', 'HP:0008711', (119, 122))	('inflammation', 'Disease', (42, 54))	('benign prostatic hyperplasia', 'Disease', 'MESH:D011470', (89, 117))	('PSA', 'Gene', '354', (165, 168))	('elevated', 'PosReg', (220, 228))	('PSA', 'Gene', '354', (259, 262))	('causes', 'Reg', (145, 151))
10311	26509158	showed that fucosylated PSA had better predictive power to differentiate between aggressive and nonaggressive forms of prostate cancer compared to total PSA.	('prostate cancer', 'Phenotype', 'HP:0012125', (119, 134))	('PSA', 'Gene', (24, 27))	('fucosylated', 'Var', (12, 23))	('PSA', 'Gene', '354', (24, 27))	('prostate cancer', 'Disease', (119, 134))	('PSA', 'Gene', (153, 156))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('PSA', 'Gene', '354', (153, 156))	('prostate cancer', 'Disease', 'MESH:D011471', (119, 134))
10359	26509158	The ECD portion can be released by cleavage from the HER2 receptor and shed into serum.	('ECD', 'Disease', 'MESH:C574275', (4, 7))	('cleavage', 'Var', (35, 43))	('ECD', 'Disease', (4, 7))	('HER2', 'Gene', (53, 57))	('HER2', 'Gene', '2064', (53, 57))
10373	26509158	CEA expressed by CD44-double knockdown LS174T colon carcinoma cells is more densely substituted with sialylated and fucosylated epitopes than CEA on wild-type LS174T cells.	('CEA', 'Gene', (142, 145))	('CEA', 'Gene', '1048', (142, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('CD44', 'Gene', '960', (17, 21))	('LS174T', 'CellLine', 'CVCL:1384', (39, 45))	('CD44', 'Gene', (17, 21))	('LS174T', 'Var', (39, 45))	('CEA', 'Gene', '1048', (0, 3))	('LS174T', 'CellLine', 'CVCL:1384', (159, 165))	('colon carcinoma', 'Disease', 'MESH:D015179', (46, 61))	('sialylated', 'MPA', (101, 111))	('colon carcinoma', 'Disease', (46, 61))	('CEA', 'Gene', (0, 3))
10374	26509158	The avidity of the altered glycoforms of CEA for selectins was increased when compared to glycoforms from the wild-type cells, which may contribute to metastatic dissemination.	('increased', 'PosReg', (63, 72))	('metastatic dissemination', 'CPA', (151, 175))	('avidity', 'MPA', (4, 11))	('selectins', 'Protein', (49, 58))	('glycoform', 'Chemical', '-', (27, 36))	('CEA', 'Gene', '1048', (41, 44))	('contribute', 'Reg', (137, 147))	('glycoform', 'Chemical', '-', (90, 99))	('altered', 'Var', (19, 26))	('CEA', 'Gene', (41, 44))
10378	26509158	CA19-9 is also currently recognised as one of the most common tumour markers for colorectal, gastric, and hepatocellular cancer.	('colorectal', 'Disease', 'MESH:D015179', (81, 91))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (106, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('hepatocellular cancer', 'Disease', (106, 127))	('gastric', 'Disease', (93, 100))	('colorectal', 'Disease', (81, 91))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('tumour', 'Disease', (62, 68))	('CA19-9', 'Var', (0, 6))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (106, 127))
10402	26509158	High concentrations of hCG are usually indicative of adverse prognosis for cancer progression.	('hCG', 'Gene', '93659', (23, 26))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('High concentrations', 'Var', (0, 19))	('cancer', 'Disease', (75, 81))	('hCG', 'Gene', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
10409	26509158	Fucosylated A1AT can also efficiently distinguish adenocarcinoma (n = 28) from BPD (AUC 0.919).	('A1AT', 'Gene', '5265', (12, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('A1AT', 'Gene', (12, 16))	('adenocarcinoma', 'Disease', 'MESH:D000230', (50, 64))	('Fucosylated', 'Var', (0, 11))	('adenocarcinoma', 'Disease', (50, 64))
10471	26509158	Patients with lymph-node positive breast cancer showed increased proportions of biantennary (FA2) and terminally sialylated N-linked oligosaccharides (A3F1G1S1 and A2F1G1S1) containing the sLex structure in their serum when compared to lymph node-negative patients with early breast cancer.	('A3F1G1S1', 'Var', (151, 159))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('A2F1G1S1', 'Var', (164, 172))	('increased', 'PosReg', (55, 64))	('breast cancer', 'Disease', (34, 47))	('patients', 'Species', '9606', (256, 264))	('FA2', 'Gene', (93, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('Patients', 'Species', '9606', (0, 8))	('breast cancer', 'Disease', 'MESH:D001943', (276, 289))	('biantennary', 'Protein', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('breast cancer', 'Disease', (276, 289))	('breast cancer', 'Phenotype', 'HP:0003002', (276, 289))	('FA2', 'Gene', '2187', (93, 96))	('N-linked oligosaccharides', 'Chemical', '-', (124, 149))
10476	26509158	Triantennary trigalactosylated (A3G3) and tetra-antennary tetrasialylated N-linked oligosaccharides with outer arm fucose (A4FS4) (Figure 2) were significantly decreased on serum PSA from patients with a Gleason score of 7 (more aggressive cancer and a higher chance of relapse) compared to a Gleason score of 5.	('tetra', 'Species', '42554', (58, 63))	('PSA', 'Gene', (179, 182))	('PSA', 'Gene', '354', (179, 182))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('N-linked oligosaccharides', 'Chemical', '-', (74, 99))	('aggressive cancer', 'Disease', 'MESH:D009369', (229, 246))	('patients', 'Species', '9606', (188, 196))	('Gleason score of 7', 'Var', (204, 222))	('aggressive cancer', 'Disease', (229, 246))	('decreased', 'NegReg', (160, 169))	('fucose', 'Chemical', 'MESH:D005643', (115, 121))	('tetra', 'Species', '42554', (42, 47))
10489	24759962	Currently, only mutant KRAS, mutant BRAF, MSI and the Oncotype DX  Colon Cancer Assay are used in clinical practice.	('BRAF', 'Gene', (36, 40))	('KRAS', 'Gene', '3845', (23, 27))	('KRAS', 'Gene', (23, 27))	('Colon Cancer', 'Phenotype', 'HP:0003003', (67, 79))	('mutant', 'Var', (16, 22))	('clinical', 'Species', '191496', (98, 106))	('Colon Cancer', 'Disease', 'MESH:D015179', (67, 79))	('BRAF', 'Gene', '673', (36, 40))	('Colon Cancer', 'Disease', (67, 79))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))
10517	24759962	One form, called microsatellite instability (MSI), refers to a clonal change in the number of repeated DNA nucleotide units in microsatellites caused by deletions or insertions, and appears in tumors with deficient mismatch repair (MMR).	('caused', 'Reg', (143, 149))	('mismatch repair', 'biological_process', 'GO:0006298', ('215', '230'))	('microsatellites', 'Gene', (127, 142))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('insertions', 'Var', (166, 176))	('deletions', 'Var', (153, 162))	('MMR', 'biological_process', 'GO:0006298', ('232', '235'))
10519	24759962	The biochemical basis of this phenotype can be explained by strand-specific mismatch repair defects and was initially linked to germline mutations of the mismatch repair (MMR) gene hMSH2, followed by the identification of mutations in another MMR gene, hMLH1.	('mismatch repair', 'biological_process', 'GO:0006298', ('154', '169'))	('hMSH', 'molecular_function', 'GO:0018775', ('181', '185'))	('mismatch repair', 'biological_process', 'GO:0006298', ('76', '91'))	('MMR', 'biological_process', 'GO:0006298', ('171', '174'))	('MMR', 'biological_process', 'GO:0006298', ('243', '246'))	('linked', 'Reg', (118, 124))	('hMSH2', 'Gene', '4436', (181, 186))	('mutations', 'Var', (137, 146))	('defects', 'NegReg', (92, 99))	('hMSH2', 'Gene', (181, 186))	('hMLH1', 'Gene', (253, 258))	('hMLH1', 'Gene', '4292', (253, 258))
10520	24759962	Only a short period thereafter, mutations in PMS2 and hMSH6 were found in Lynch Syndrome, completing the biological background of this MSI phenotype.	('Lynch Syndrome', 'Disease', (74, 88))	('PMS2', 'Gene', (45, 49))	('PMS2', 'Gene', '5395', (45, 49))	('hMSH6', 'Gene', (54, 59))	('mutations', 'Var', (32, 41))	('hMSH6', 'Gene', '2956', (54, 59))	('found', 'Reg', (65, 70))	('Lynch Syndrome', 'Disease', 'MESH:D003123', (74, 88))
10526	24759962	This sporadic type of MSI could be investigated through testing for a BRAF V600E mutation that is strongly associated with a sporadic origin or by analysis of hMLH1 promoter hypermethylation.	('V600E', 'Mutation', 'rs113488022', (75, 80))	('hMLH1', 'Gene', (159, 164))	('V600E', 'Var', (75, 80))	('BRAF', 'Gene', '673', (70, 74))	('hMLH1', 'Gene', '4292', (159, 164))	('BRAF', 'Gene', (70, 74))
10540	24759962	Active KRAS mutations are found in 35-42% of CRCs and are thought to occur early in CRC carcinogenesis.	('KRAS', 'Gene', '3845', (7, 11))	('CRC carcinogenesis', 'Disease', (84, 102))	('CRCs', 'Disease', (45, 49))	('mutations', 'Var', (12, 21))	('CRC', 'Phenotype', 'HP:0003003', (45, 48))	('CRC carcinogenesis', 'Disease', 'MESH:D015179', (84, 102))	('CRC', 'Phenotype', 'HP:0003003', (84, 87))	('KRAS', 'Gene', (7, 11))
10541	24759962	Almost 97% of all observed genetic events within KRAS are caused by seven different DNA base-pair substitutions within codon 12 and 13 of exon 2, resulting in an amino acid substitution in the protein.	('KRAS', 'Gene', '3845', (49, 53))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('substitutions', 'Var', (98, 111))	('caused by', 'Reg', (58, 67))	('KRAS', 'Gene', (49, 53))
10542	24759962	KRAS mutation was associated with a significantly higher risk of recurrence in the QUASAR study compared with wild-type KRAS, but not in the PETACC-3 study.	('recurrence', 'MPA', (65, 75))	('KRAS', 'Gene', (120, 124))	('KRAS', 'Gene', '3845', (120, 124))	('KRAS', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('KRAS', 'Gene', '3845', (0, 4))
10543	24759962	Other studies performed were also conflicting, with some finding a prognostic value of mutated KRAS alone, others finding this value concomitantly with mutated TP53 or PIK3CA and some reporting no prognostic value of mutated KRAS at all.	('KRAS', 'Gene', '3845', (95, 99))	('mutated', 'Var', (87, 94))	('PIK3CA', 'Gene', (168, 174))	('TP53', 'Gene', '7157', (160, 164))	('KRAS', 'Gene', (225, 229))	('PIK3CA', 'Gene', '5290', (168, 174))	('KRAS', 'Gene', '3845', (225, 229))	('TP53', 'Gene', (160, 164))	('KRAS', 'Gene', (95, 99))
10545	24759962	Initially, KRAS was found to be a strong prognostic factor in CRC, but this finding was later restricted to a codon 12 mutation, leading to a glycine to valine substitution (G12V).	('KRAS', 'Gene', (11, 15))	('CRC', 'Phenotype', 'HP:0003003', (62, 65))	('valine', 'Chemical', 'MESH:D014633', (153, 159))	('KRAS', 'Gene', '3845', (11, 15))	('G12V', 'Var', (174, 178))	('glycine', 'Chemical', 'MESH:D005998', (142, 149))	('CRC', 'Disease', (62, 65))	('G12V', 'SUBSTITUTION', 'None', (174, 178))
10550	24759962	However, in a predictive setting, mutated KRAS has shown differentiation resistance to anti-EGFR monoclonal antibodies and since then has been used in clinic for this purpose.	('KRAS', 'Gene', (42, 46))	('KRAS', 'Gene', '3845', (42, 46))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('mutated', 'Var', (34, 41))
10552	24759962	Nearly all oncogenic transformations of BRAF are the V600E mutations.	('BRAF', 'Gene', '673', (40, 44))	('V600E', 'Mutation', 'rs113488022', (53, 58))	('BRAF', 'Gene', (40, 44))	('V600E', 'Var', (53, 58))	('oncogenic transformations', 'CPA', (11, 36))
10553	24759962	A lot of studies investigated and confirmed the potential adverse prognostic impact of BRAF mutations.	('BRAF', 'Gene', (87, 91))	('BRAF', 'Gene', '673', (87, 91))	('mutations', 'Var', (92, 101))
10555	24759962	Presence of this mutation was associated with a significantly higher risk of cancer-related death, independent of other confounding factors.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('Presence', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
10560	24759962	Patients with mutated BRAF may not have benefited from the survival advantage offered by this agent.	('BRAF', 'Gene', (22, 26))	('BRAF', 'Gene', '673', (22, 26))	('mutated', 'Var', (14, 21))	('Patients', 'Species', '9606', (0, 8))
10561	24759962	Therefore, the prognostic relevance of mutated BRAF on OS may have been overestimated.	('mutated', 'Var', (39, 46))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))
10562	24759962	However, the outcome of patients with CRC having BRAF mutations is worse than that of patients with wild-type BRAF CRC, independent of treatment with cetuximab, which further strengthens BRAF as a marker for a worse chance of survival.	('CRC', 'Phenotype', 'HP:0003003', (38, 41))	('patients', 'Species', '9606', (86, 94))	('BRAF', 'Gene', '673', (187, 191))	('mutations', 'Var', (54, 63))	('CRC', 'Phenotype', 'HP:0003003', (115, 118))	('BRAF', 'Gene', '673', (110, 114))	('cetuximab', 'Chemical', 'MESH:D000068818', (150, 159))	('BRAF', 'Gene', '673', (49, 53))	('patients', 'Species', '9606', (24, 32))	('BRAF', 'Gene', (110, 114))	('BRAF', 'Gene', (49, 53))	('BRAF', 'Gene', (187, 191))
10566	24759962	Mutations of the TP53 gene are detected in up to 85% of CRCs, usually occurring during the adenoma to adenocarcinoma transition.	('detected', 'Reg', (31, 39))	('CRCs', 'Disease', (56, 60))	('adenoma to adenocarcinoma', 'Disease', (91, 116))	('CRC', 'Phenotype', 'HP:0003003', (56, 59))	('Mutations', 'Var', (0, 9))	('adenoma to adenocarcinoma', 'Disease', 'MESH:D000236', (91, 116))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
10569	24759962	Higher expression has been shown in tumors with lymph nodal involvement and 5-year survival is lower for patients with positive p53 staining.	('lower', 'NegReg', (95, 100))	('positive', 'Var', (119, 127))	('patients', 'Species', '9606', (105, 113))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (128, 131))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('expression', 'MPA', (7, 17))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
10572	24759962	Mutations in TP53 lead to disruption of normal TP53 function and accumulation of mutant p53 levels that are high enough to be detected by immunohistochemistry.	('TP53', 'Gene', (13, 17))	('accumulation', 'PosReg', (65, 77))	('disruption', 'NegReg', (26, 36))	('p53', 'Gene', (88, 91))	('p53', 'Gene', '7157', (88, 91))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (47, 51))	('function', 'MPA', (52, 60))	('mutant', 'Var', (81, 87))	('TP53', 'Gene', '7157', (13, 17))	('TP53', 'Gene', (47, 51))
10574	24759962	High expression of p53 staining was associated with mutated TP53.	('mutated', 'Var', (52, 59))	('p53', 'Gene', '7157', (19, 22))	('p53', 'Gene', (19, 22))	('TP53', 'Gene', '7157', (60, 64))	('associated', 'Reg', (36, 46))	('TP53', 'Gene', (60, 64))
10576	24759962	Studies have shown that immunohistochemistry does not always match with mutation studies and that expression of mutant forms of p53 are not simply correlated to loss of TP53 function.	('function', 'MPA', (174, 182))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (128, 131))	('TP53', 'Gene', '7157', (169, 173))	('TP53', 'Gene', (169, 173))	('mutant', 'Var', (112, 118))	('expression', 'MPA', (98, 108))
10577	24759962	reported that approximately 33% of the CRCs that do not show positive immunohistochemical staining of p53 do not have a detectable TP53 mutation.	('mutation', 'Var', (136, 144))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('p53', 'Gene', (102, 105))	('p53', 'Gene', '7157', (102, 105))	('CRCs', 'Disease', (39, 43))	('CRC', 'Phenotype', 'HP:0003003', (39, 42))
10580	24759962	In this study immunohistochemistry revealed three distinct staining patterns of p53 expression; complete negative staining associated with truncating TP53 mutations, diffuse overexpression associated with TP53 missense mutations and restricted overexpression associated with wild-type TP53.	('TP53', 'Gene', (150, 154))	('TP53', 'Gene', '7157', (285, 289))	('mutations', 'Var', (155, 164))	('truncating', 'MPA', (139, 149))	('p53', 'Gene', (80, 83))	('TP53', 'Gene', '7157', (205, 209))	('TP53', 'Gene', (285, 289))	('TP53', 'Gene', (205, 209))	('overexpression', 'PosReg', (174, 188))	('p53', 'Gene', '7157', (80, 83))	('missense mutations', 'Var', (210, 228))	('negative', 'NegReg', (105, 113))	('TP53', 'Gene', '7157', (150, 154))
10582	24759962	In 30.8% of the tumors with negative p53 staining, TP53 mutations were found as well, indicating no complete correlation between immunohistochemistry and mutation analysis based on RNA expression.	('mutations', 'Var', (56, 65))	('TP53', 'Gene', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('RNA', 'cellular_component', 'GO:0005562', ('181', '184'))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('tumors', 'Disease', (16, 22))	('TP53', 'Gene', '7157', (51, 55))
10592	24759962	There are also reasons to believe that differences exist as a result of microsatellite status of the tumor, location of the tumor in the bowel or biological differences between rectal and colon cancer.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('microsatellite', 'Var', (72, 86))	('bowel', 'Disease', 'MESH:D015212', (137, 142))	('colon cancer', 'Phenotype', 'HP:0003003', (188, 200))	('bowel', 'Disease', (137, 142))	('colon cancer', 'Disease', 'MESH:D015179', (188, 200))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('colon cancer', 'Disease', (188, 200))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
10598	24759962	Recently, the Cancer Genome Atlas Network attempted to find biological differences between colonic and rectal cancer, but they only found differences in the anatomical tumor site with more hypermethylation in right-sided tumors, which might be explained by the different embryonic origins of the right-and left-sided tumors.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumors', 'Phenotype', 'HP:0002664', (317, 323))	('rectal cancer', 'Disease', (103, 116))	('rectal cancer', 'Phenotype', 'HP:0100743', (103, 116))	('Cancer', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('colonic', 'Disease', 'MESH:D015179', (91, 98))	('tumors', 'Disease', (317, 323))	('tumors', 'Disease', (221, 227))	('colonic', 'Disease', (91, 98))	('Cancer', 'Disease', 'MESH:D009369', (14, 20))	('hypermethylation', 'Var', (189, 205))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', (317, 322))	('tumor', 'Disease', (221, 226))	('rectal cancer', 'Disease', 'MESH:D012004', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (317, 323))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
10600	24759962	Two important hallmarks of tumorigenesis can cause disturbance of this balance; deregulation of the proliferative signaling pathway and deregulation of the apoptotic pathway.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('apoptotic pathway', 'Pathway', (156, 173))	('deregulation', 'Reg', (136, 148))	('disturbance', 'Var', (51, 62))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('proliferative signaling pathway', 'Pathway', (100, 131))
10609	24759962	Most studies in CRC have reported an inverse relationship between ki67 expression and patient outcome; thus patients with high expression of ki67 in their tumor sections showed a better chance of survival.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('survival', 'CPA', (196, 204))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('better', 'PosReg', (179, 185))	('ki67', 'Var', (141, 145))	('high expression', 'Var', (122, 137))	('tumor', 'Disease', (155, 160))	('ki67', 'Chemical', '-', (66, 70))	('patient', 'Species', '9606', (86, 93))	('ki67', 'Chemical', '-', (141, 145))	('CRC', 'Phenotype', 'HP:0003003', (16, 19))	('patient', 'Species', '9606', (108, 115))	('patients', 'Species', '9606', (108, 116))
10611	24759962	However, a high ki-67 index was associated with improved survival in MSI tumors only and therefore microsatellite status might influence ki67 expression as well.	('MSI tumors', 'Disease', 'MESH:D009369', (69, 79))	('improved', 'PosReg', (48, 56))	('expression', 'MPA', (142, 152))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('MSI tumors', 'Disease', (69, 79))	('survival', 'MPA', (57, 65))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('influence', 'Reg', (127, 136))	('ki-67', 'Gene', (16, 21))	('high', 'Var', (11, 15))	('ki67', 'Chemical', '-', (137, 141))
10616	24759962	Furthermore, analyses should be stratified for microsatellite status and location of the tumor, in order to truly understand the prognostic value of ki67.	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('ki67', 'Chemical', '-', (149, 153))	('microsatellite', 'Var', (47, 61))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
10629	24759962	Accumulation of frameshift-derived-peptides (FSP) may contribute to immune recognition and dense lymphocyte infiltration observed in MSI tumors.	('MSI tumors', 'Disease', (133, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('contribute', 'Reg', (54, 64))	('dense lymphocyte infiltration', 'CPA', (91, 120))	('MSI tumors', 'Disease', 'MESH:D009369', (133, 143))	('frameshift-derived-peptides', 'Var', (16, 43))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
10632	24759962	T cell responses in patients with MSI CRCs are frequently directed against selected microsatellite instability-induced FSP, possibly creating more immune-mediated tumor rejection.	('T cell responses', 'CPA', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('CRC', 'Phenotype', 'HP:0003003', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('microsatellite instability-induced', 'Var', (84, 118))	('tumor', 'Disease', (163, 168))	('MSI CRC', 'Disease', (34, 41))	('MSI CRC', 'Disease', 'MESH:D015179', (34, 41))	('patients', 'Species', '9606', (20, 28))	('more', 'PosReg', (142, 146))
10633	24759962	Therefore, immune escape mechanisms may play a role in tumors characterized by microsatellite instability, and thus both features should be considered when analysing clinical prognosis in this tumor type.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('play', 'Reg', (40, 44))	('clinical', 'Species', '191496', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('immune escape', 'MPA', (11, 24))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Disease', (193, 198))	('microsatellite instability', 'Var', (79, 105))
10654	24759962	Mutations have been shown to activate the AKT-pathway, driving cell proliferation, and are present in 10-30% of all CRCs.	('CRC', 'Phenotype', 'HP:0003003', (116, 119))	('AKT', 'Gene', (42, 45))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))	('cell proliferation', 'CPA', (63, 81))	('Mutations', 'Var', (0, 9))	('driving', 'PosReg', (55, 62))	('activate', 'PosReg', (29, 37))	('AKT', 'Gene', '207', (42, 45))	('CRCs', 'Disease', (116, 120))
10655	24759962	PIK3CA mutations were related to a worse chance of survival in CRC patients.	('patients', 'Species', '9606', (67, 75))	('CRC', 'Phenotype', 'HP:0003003', (63, 66))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('CRC', 'Disease', (63, 66))	('mutations', 'Var', (7, 16))
10656	24759962	Also, when stratified by KRAS status, a worse colon cancer-specific mortality associated with a PIK3CA mutation was only found in KRAS wild-type tumors.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('colon cancer', 'Disease', (46, 58))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('colon cancer', 'Disease', 'MESH:D015179', (46, 58))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('KRAS', 'Gene', (130, 134))	('PIK3CA', 'Gene', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('PIK3CA', 'Gene', '5290', (96, 102))	('mutation', 'Var', (103, 111))	('KRAS', 'Gene', (25, 29))	('colon cancer', 'Phenotype', 'HP:0003003', (46, 58))	('KRAS', 'Gene', '3845', (130, 134))	('worse', 'NegReg', (40, 45))	('KRAS', 'Gene', '3845', (25, 29))
10657	24759962	Allelic loss of 18q has been thought to occur late in the process of carcinogenesis and occurred in approximately 70% of CRCs.	('18q', 'Gene', (16, 19))	('occurred', 'Reg', (88, 96))	('Allelic loss', 'Var', (0, 12))	('CRC', 'Phenotype', 'HP:0003003', (121, 124))	('CRCs', 'Disease', (121, 125))	('carcinogenesis', 'Disease', 'MESH:D063646', (69, 83))	('carcinogenesis', 'Disease', (69, 83))
10659	24759962	Patients who harbored an 18q loss of heterozygosity (LOH) showed a worse OS, but other studies showed contradictory results.	('Patients', 'Species', '9606', (0, 8))	('loss', 'NegReg', (29, 33))	('18q', 'Var', (25, 28))
10661	24759962	A meta-analysis also showed that patients with 18q allelic imbalance and DCC loss of expression were associated with a worse survival, compared with patients with an intact 18q and expression of DCC.	('DCC', 'Gene', (73, 76))	('patients', 'Species', '9606', (149, 157))	('DCC', 'Gene', '1630', (73, 76))	('patients', 'Species', '9606', (33, 41))	('18q', 'Var', (47, 50))	('imbalance', 'Phenotype', 'HP:0002172', (59, 68))	('DCC', 'cellular_component', 'GO:0120206', ('73', '76'))	('DCC', 'cellular_component', 'GO:0120206', ('195', '198'))	('loss of expression', 'NegReg', (77, 95))	('DCC', 'Gene', (195, 198))	('DCC', 'Gene', '1630', (195, 198))
10662	24759962	In the last few years, the existence of a new pathway for CRC pathogenesis has gained attention, which involves the transcriptional silencing of tumor suppressor genes by hypermethylation of CpG islands of the promoter region of various genes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('145', '161'))	('CRC', 'Phenotype', 'HP:0003003', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('silencing', 'NegReg', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('pathogenesis', 'biological_process', 'GO:0009405', ('62', '74'))	('tumor', 'Disease', (145, 150))	('CRC', 'Disease', (58, 61))	('tumor suppressor', 'biological_process', 'GO:0051726', ('145', '161'))	('hypermethylation', 'Var', (171, 187))
10664	24759962	CIMP tumors with methylation-induced silencing of MLH1 constitute the majority of sporadic MSI CRCs.	('MLH1', 'Gene', '4292', (50, 54))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('MLH1', 'Gene', (50, 54))	('MSI CRC', 'Disease', 'MESH:D015179', (91, 98))	('methylation-induced', 'Var', (17, 36))	('sporadic', 'Disease', (82, 90))	('silencing', 'NegReg', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('CIMP', 'Chemical', '-', (0, 4))	('CRC', 'Phenotype', 'HP:0003003', (95, 98))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('MSI CRC', 'Disease', (91, 98))
10668	24759962	On the contrary, CIMP positive CRCs showed a worse overall survival after surgery alone.	('CIMP', 'Chemical', '-', (17, 21))	('CIMP positive', 'Var', (17, 30))	('CRC', 'Phenotype', 'HP:0003003', (31, 34))	('CRCs', 'Disease', (31, 35))
10671	24759962	In addition to microsatellite instability and CIMP, the chromosomal instability (CIN) pathway is also involved in colorectal cancer pathogenesis.	('rectal cancer', 'Phenotype', 'HP:0100743', (118, 131))	('involved', 'Reg', (102, 110))	('CIMP', 'Chemical', '-', (46, 50))	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('CIN', 'Disease', 'MESH:D007674', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('chromosomal instability', 'Phenotype', 'HP:0040012', (56, 79))	('CIN', 'Phenotype', 'HP:0040012', (81, 84))	('microsatellite', 'Var', (15, 29))	('pathogenesis', 'biological_process', 'GO:0009405', ('132', '144'))	('colorectal cancer', 'Disease', (114, 131))	('CIN', 'Disease', (81, 84))
10672	24759962	Most CRCs arise through this pathway, which is characterized by widespread imbalances in chromosome number (aneuploidy) and loss of heterozygosity.	('aneuploidy', 'Disease', (108, 118))	('arise through', 'Reg', (10, 23))	('imbalances', 'Var', (75, 85))	('chromosome', 'cellular_component', 'GO:0005694', ('89', '99'))	('imbalance', 'Phenotype', 'HP:0002172', (75, 84))	('aneuploidy', 'Disease', 'MESH:D000782', (108, 118))	('CRCs', 'Disease', (5, 9))	('CRC', 'Phenotype', 'HP:0003003', (5, 8))	('imbalances', 'Phenotype', 'HP:0002172', (75, 85))
10684	24759962	reported a positive reduction in disease progression rate in MSI CRC patients treated with 5-FU, but this was only due to the HNPCC cases.	('5-FU', 'Chemical', 'MESH:D005472', (91, 95))	('HNPCC', 'Gene', (126, 131))	('MSI CRC', 'Disease', (61, 68))	('disease progression rate', 'CPA', (33, 57))	('HNPCC', 'Gene', '4292', (126, 131))	('MSI CRC', 'Disease', 'MESH:D015179', (61, 68))	('CRC', 'Phenotype', 'HP:0003003', (65, 68))	('reduction', 'NegReg', (20, 29))	('patients', 'Species', '9606', (69, 77))	('5-FU', 'Var', (91, 95))
10696	24759962	KRAS can acquire activating mutations in exon 20 resulting in isolation of this pathway from the EGFR effect and thus rendering EGFR inhibitors, like cetuximab, ineffective.	('EGFR', 'Gene', '1956', (97, 101))	('EGFR', 'Gene', '1956', (128, 132))	('activating', 'PosReg', (17, 27))	('EGFR', 'Gene', (128, 132))	('EGFR', 'Gene', (97, 101))	('isolation', 'MPA', (62, 71))	('cetuximab', 'Chemical', 'MESH:D000068818', (150, 159))	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (28, 37))	('KRAS', 'Gene', '3845', (0, 4))
10697	24759962	Indeed, previous studies showed the ineffectiveness of cetuximab or other EGFR inhibitors for CRC patients bearing mutated KRAS.	('cetuximab', 'Chemical', 'MESH:D000068818', (55, 64))	('mutated', 'Var', (115, 122))	('patients', 'Species', '9606', (98, 106))	('CRC', 'Phenotype', 'HP:0003003', (94, 97))	('EGFR', 'Gene', '1956', (74, 78))	('KRAS', 'Gene', (123, 127))	('KRAS', 'Gene', '3845', (123, 127))	('EGFR', 'Gene', (74, 78))	('CRC', 'Disease', (94, 97))
10699	24759962	Furthermore, the addition of EGFR-antibodies to chemotherapy for patients with KRAS mutations appeared to be detrimental.	('KRAS', 'Gene', '3845', (79, 83))	('mutations', 'Var', (84, 93))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('patients', 'Species', '9606', (65, 73))	('KRAS', 'Gene', (79, 83))
10700	24759962	KRAS mutation has thus emerged as the major negative predictor for EGFR therapy efficacy, resulting in clinical recommendation for use by patients with wild-type KRAS tumors only.	('KRAS', 'Gene', (162, 166))	('patients', 'Species', '9606', (138, 146))	('clinical', 'Species', '191496', (103, 111))	('KRAS tumors', 'Disease', 'MESH:D009369', (162, 173))	('KRAS', 'Gene', '3845', (162, 166))	('KRAS tumors', 'Disease', (162, 173))	('EGFR', 'molecular_function', 'GO:0005006', ('67', '71'))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('KRAS', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('KRAS', 'Gene', '3845', (0, 4))
10701	24759962	KRAS mutational testing of metastatic CRC has become routine and is nowadays incorporated in many centers.	('metastatic CRC', 'Disease', (27, 41))	('CRC', 'Phenotype', 'HP:0003003', (38, 41))	('mutational', 'Var', (5, 15))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
10704	24759962	Less-frequently observed KRAS mutations beyond the well-studied codons 12 and 13, mutations in NRAS, BRAF and PIK3CA also showed that they are associated with resistance to anti-EGFR therapy.	('BRAF', 'Gene', (101, 105))	('resistance', 'MPA', (159, 169))	('associated', 'Reg', (143, 153))	('EGFR', 'Gene', '1956', (178, 182))	('EGFR', 'Gene', (178, 182))	('NRAS', 'Gene', (95, 99))	('BRAF', 'Gene', '673', (101, 105))	('mutations', 'Var', (82, 91))	('PIK3CA', 'Gene', (110, 116))	('NRAS', 'Gene', '4893', (95, 99))	('KRAS', 'Gene', (25, 29))	('PIK3CA', 'Gene', '5290', (110, 116))	('KRAS', 'Gene', '3845', (25, 29))
10709	24759962	Only a few studies have been performed on the relationship between BRAF and the effect of cetuximab, both showing that BRAF mutations were related to resistance for EGFR-targeted therapies.	('EGFR', 'Gene', (165, 169))	('BRAF', 'Gene', '673', (67, 71))	('mutations', 'Var', (124, 133))	('cetuximab', 'Chemical', 'MESH:D000068818', (90, 99))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', (67, 71))	('resistance', 'MPA', (150, 160))	('BRAF', 'Gene', (119, 123))	('related to', 'Reg', (139, 149))	('EGFR', 'Gene', '1956', (165, 169))
10710	24759962	Although evidence is still insufficient to demonstrate a real association of BRAF mutations with non-responsiveness to anti-EGFR therapy, it has been recommended by the National Comprehensive Cancer Network (NCCN) for this purpose.	('EGFR', 'Gene', '1956', (124, 128))	('BRAF', 'Gene', '673', (77, 81))	('Cancer', 'Disease', (192, 198))	('insufficient', 'Disease', (27, 39))	('insufficient', 'Disease', 'MESH:D000309', (27, 39))	('EGFR', 'Gene', (124, 128))	('BRAF', 'Gene', (77, 81))	('Cancer', 'Disease', 'MESH:D009369', (192, 198))	('mutations', 'Var', (82, 91))	('Cancer', 'Phenotype', 'HP:0002664', (192, 198))	('EGFR', 'molecular_function', 'GO:0005006', ('124', '128'))	('non-responsiveness', 'MPA', (97, 115))
10714	24759962	In addition to sorafenib, other compounds targeting either BRAF (PLX4032 and PLX4720) or its downstream effectors (ARRY-162, AZD6244 and PD0325901) are in clinical development and could be exploited in combination with EGFR-targeted therapy.	('EGFR', 'Gene', '1956', (219, 223))	('clinical', 'Species', '191496', (155, 163))	('PLX4720', 'Var', (77, 84))	('PD0325901', 'Var', (137, 146))	('EGFR', 'Gene', (219, 223))	('AZD6244', 'Chemical', 'MESH:C517975', (125, 132))	('sorafenib', 'Chemical', 'MESH:D000077157', (15, 24))	('PD0325901', 'Chemical', 'MESH:C506614', (137, 146))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('PLX4032', 'Chemical', 'MESH:D000077484', (65, 72))	('PLX4032', 'Var', (65, 72))
10717	24759962	On the other hand, PLX4720 caused substantial delays in tumor growth, including tumor regression, without toxicities.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (56, 61))	('PLX4720', 'Var', (19, 26))	('toxicities', 'Disease', 'MESH:D064420', (106, 116))	('tumor', 'Disease', (80, 85))	('delays', 'NegReg', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('toxicities', 'Disease', (106, 116))
10735	24759962	In addition to the influence of tumor COX-2 expression on aspirin treatment benefit in CRC as detailed above, a recent study showed that only CRC patients bearing a mutation in PIK3CA (exon 9 or exon 20) benefitted from aspirin treatment, and not patients with wild-type PIK3CA tumors.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('PIK3CA', 'Gene', '5290', (177, 183))	('tumors', 'Disease', (278, 284))	('aspirin', 'Chemical', 'MESH:D001241', (220, 227))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('PIK3CA', 'Gene', '5290', (271, 277))	('benefitted', 'PosReg', (204, 214))	('COX-2', 'Gene', (38, 43))	('aspirin', 'Chemical', 'MESH:D001241', (58, 65))	('tumors', 'Disease', 'MESH:D009369', (278, 284))	('PIK3CA', 'Gene', (177, 183))	('patients', 'Species', '9606', (146, 154))	('COX-2', 'Gene', '5743', (38, 43))	('tumor', 'Disease', (278, 283))	('PIK3CA', 'Gene', (271, 277))	('patients', 'Species', '9606', (247, 255))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('CRC', 'Phenotype', 'HP:0003003', (142, 145))	('CRC', 'Phenotype', 'HP:0003003', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mutation', 'Var', (165, 173))
10737	24759962	Mutations in PIK3CA are present in 15-20% of colorectal cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (45, 62))	('PIK3CA', 'Gene', (13, 19))	('colorectal cancers', 'Disease', 'MESH:D015179', (45, 63))	('present', 'Reg', (24, 31))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('PIK3CA', 'Gene', '5290', (13, 19))	('Mutations', 'Var', (0, 9))	('colorectal cancers', 'Disease', (45, 63))	('rectal cancer', 'Phenotype', 'HP:0100743', (49, 62))
10740	24759962	Unfortunately, only one study on the role of PIK3CA mutations with aspirin treatment in CRC has so far been performed, which also had limited statistical power.	('mutations', 'Var', (52, 61))	('CRC', 'Phenotype', 'HP:0003003', (88, 91))	('CRC', 'Disease', (88, 91))	('PIK3CA', 'Gene', (45, 51))	('PIK3CA', 'Gene', '5290', (45, 51))	('aspirin', 'Chemical', 'MESH:D001241', (67, 74))
10749	24759962	Titration of the dose in DPD-deficient patients could significantly reduce the frequency of severe, potentially deadly toxicity caused by fluoropyrimidines.	('DPD-deficient', 'Disease', (25, 38))	('Titration', 'Var', (0, 9))	('patients', 'Species', '9606', (39, 47))	('deadly toxicity', 'Disease', (112, 127))	('DPD-deficient', 'Disease', 'MESH:D054067', (25, 38))	('deadly toxicity', 'Disease', 'MESH:D064420', (112, 127))	('fluoropyrimidines', 'MPA', (138, 155))	('reduce', 'NegReg', (68, 74))	('fluoropyrimidines', 'Chemical', '-', (138, 155))
10752	24759962	New mutations have been identified, which are related to fluoropyrimidine toxicity, such as DPYD 2846A > T and 1236G > A, and could be implemented in genotyping DPD deficiency.	('toxicity', 'Disease', (74, 82))	('related', 'Reg', (46, 53))	('2846A > T', 'Var', (97, 106))	('DPYD', 'Gene', (92, 96))	('DPD deficiency', 'Disease', (161, 175))	('fluoropyrimidine', 'Chemical', '-', (57, 73))	('toxicity', 'Disease', 'MESH:D064420', (74, 82))	('1236G > A', 'Mutation', 'rs56038477', (111, 120))	('2846A > T', 'Mutation', 'rs67376798', (97, 106))	('DPYD', 'Gene', '1806', (92, 96))	('DPD', 'molecular_function', 'GO:0017113', ('161', '164'))	('DPD deficiency', 'Disease', 'MESH:D054067', (161, 175))	('1236G > A', 'Var', (111, 120))
10762	24759962	At least 63 UGT1A1 variants have been described, including single base pair changes, frame shift mutations, insertions and deletions in the promoter region, five exons and two introns of the gene.	('single base pair changes', 'Var', (59, 83))	('deletions', 'Var', (123, 132))	('insertions', 'Var', (108, 118))	('UGT1A1', 'Gene', '54658', (12, 18))	('frame', 'Var', (85, 90))	('variants', 'Var', (19, 27))	('UGT1A1', 'Gene', (12, 18))
10770	24759962	Also, the data on the clinical validity of tests for UGT1A1 variants other than *28 are limited and the analytic validity of UGT1A1 testing in clinical practice is unknown.	('UGT1A1', 'Gene', '54658', (125, 131))	('UGT1A1', 'Gene', (125, 131))	('clinical', 'Species', '191496', (22, 30))	('UGT1A1', 'Gene', '54658', (53, 59))	('clinical', 'Species', '191496', (143, 151))	('variants', 'Var', (60, 68))	('UGT1A1', 'Gene', (53, 59))
10771	24759962	Furthermore, there are limited data on UGT1A1 variants in Hispanic and African-American populations.	('variants', 'Var', (46, 54))	('UGT1A1', 'Gene', (39, 45))	('UGT1A1', 'Gene', '54658', (39, 45))
10778	24759962	Only mutant KRAS, mutant BRAF, MSI and the Oncotype DX  Colon Cancer Assay are currently used in clinical practice for determining whether to treat metastatic CRC patients with cetuximab or panitumumab, for the evaluation of Lynch syndrome and to inform treatment planning in stage II and -III colon cancer patients.	('metastatic CRC', 'Disease', (148, 162))	('clinical', 'Species', '191496', (97, 105))	('KRAS', 'Gene', '3845', (12, 16))	('patients', 'Species', '9606', (307, 315))	('colon cancer', 'Phenotype', 'HP:0003003', (294, 306))	('mutant', 'Var', (18, 24))	('KRAS', 'Gene', (12, 16))	('II colon cancer', 'Disease', (291, 306))	('II colon cancer', 'Disease', 'MESH:D015179', (291, 306))	('patients', 'Species', '9606', (163, 171))	('Colon Cancer', 'Phenotype', 'HP:0003003', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('CRC', 'Phenotype', 'HP:0003003', (159, 162))	('Lynch syndrome', 'Disease', (225, 239))	('Colon Cancer', 'Disease', (56, 68))	('Cancer', 'Phenotype', 'HP:0002664', (62, 68))	('panitumumab', 'Chemical', 'MESH:D000077544', (190, 201))	('Colon Cancer', 'Disease', 'MESH:D015179', (56, 68))	('BRAF', 'Gene', '673', (25, 29))	('Lynch syndrome', 'Disease', 'MESH:D003123', (225, 239))	('mutant', 'Var', (5, 11))	('cetuximab', 'Chemical', 'MESH:D000068818', (177, 186))	('BRAF', 'Gene', (25, 29))
10786	24759962	Our group has recently demonstrated that patients with both presence of HLA class I expression and Treg tumor infiltration had fewer relapses when treated with chemotherapy.	('HLA class I expression', 'Protein', (72, 94))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('presence', 'Var', (60, 68))	('patients', 'Species', '9606', (41, 49))	('relapses', 'CPA', (133, 141))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
10793	33883026	Epigenetic deregulations are also important risk factors during tumor progression which are reversible transcriptional alterations without any genomic changes.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('Epigenetic deregulations', 'Var', (0, 24))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
10796	33883026	Promoter hyper methylation is frequently observed as an inhibitory molecular mechanism in various genes associated with DNA repair, cell cycle regulation, and apoptosis during tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('apoptosis', 'biological_process', 'GO:0097194', ('159', '168'))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('Promoter hyper methylation', 'Var', (0, 26))	('tumor', 'Disease', (176, 181))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('132', '153'))	('apoptosis', 'biological_process', 'GO:0006915', ('159', '168'))	('DNA', 'cellular_component', 'GO:0005574', ('120', '123'))	('DNA repair', 'biological_process', 'GO:0006281', ('120', '130'))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
10797	33883026	Since aberrant promoter methylations have critical roles in early stages of neoplastic transformations, in present review we have summarized all of the aberrant methylations which have been reported during tumor progression among Iranian cancer patients.	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('patients', 'Species', '9606', (245, 253))	('tumor', 'Disease', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('aberrant', 'Var', (152, 160))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
10798	33883026	Aberrant promoter methylations are targetable and prepare novel therapeutic options for the personalized medicine in cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('patients', 'Species', '9606', (124, 132))
10812	33883026	DNA hypo methylation leads to aberrant activation of oncogenes while the hyper methylation is associated with inhibition of tumor suppressor genes.	('inhibition', 'NegReg', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('activation', 'PosReg', (39, 49))	('tumor', 'Disease', (124, 129))	('oncogenes', 'Protein', (53, 62))	('hypo methylation', 'Var', (4, 20))
10813	33883026	Various tumor suppressor genes such as p16, MutL homolog 1 (MLH1), and breast cancer type 1 susceptibility protein (BRCA1) which are involved in DNA repair, cell cycle, cell adhesion, and apoptosis have been shown to undergo tumor-specific silencing by hyper methylation.	('BRCA1', 'Gene', (116, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('breast cancer type 1 susceptibility protein', 'Gene', '672', (71, 114))	('MutL homolog 1', 'Gene', (44, 58))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('MLH1', 'Gene', (60, 64))	('silencing', 'NegReg', (240, 249))	('MLH1', 'Gene', '4292', (60, 64))	('breast cancer type 1 susceptibility protein', 'Gene', (71, 114))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('MutL homolog 1', 'Gene', '4292', (44, 58))	('hyper methylation', 'Var', (253, 270))	('tumor', 'Disease', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('p16', 'Gene', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('p16', 'Gene', '1029', (39, 42))	('BRCA1', 'Gene', '672', (116, 121))
10814	33883026	Histone modifications through histone acetyl-transferase (HATs), histone methyltransferase (HMTs), kinases, ubiquitin ligases, and sumoligases are important regulatory processes in chromatin remodeling, gene expression, and carcinogenesis.	('histone methyltransferase', 'Gene', (65, 90))	('HMTs', 'Gene', '56979', (92, 96))	('gene expression', 'biological_process', 'GO:0010467', ('203', '218'))	('HATs', 'Disease', (58, 62))	('HATs', 'Disease', 'None', (58, 62))	('HMTs', 'Gene', (92, 96))	('histone methyltransferase', 'Gene', '56979', (65, 90))	('modifications', 'Var', (8, 21))	('ubiquitin', 'molecular_function', 'GO:0031386', ('108', '117'))	('Histone modifications', 'Var', (0, 21))	('carcinogenesis', 'Disease', 'MESH:D063646', (224, 238))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('181', '201'))	('carcinogenesis', 'Disease', (224, 238))	('chromatin', 'cellular_component', 'GO:0000785', ('181', '190'))
10816	33883026	Epigenetic markers are considered as emerging diagnostic and prognostic biomarkers in cancer.	('Epigenetic markers', 'Var', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (86, 92))
10817	33883026	Since, aberrant DNA methylation can be tracked in body fluids; they can be suggested as efficient diagnostic and prognostic markers in primary stages of tumor progression.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('DNA methylation', 'biological_process', 'GO:0006306', ('16', '31'))	('DNA', 'cellular_component', 'GO:0005574', ('16', '19'))	('aberrant', 'Var', (7, 15))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))
10820	33883026	In present review we have summarized all of the significant epigenetic deregulations associated with tumor progression which have been reported until now among Iranian cancer patients (Fig.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('epigenetic deregulations', 'Var', (60, 84))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('patients', 'Species', '9606', (175, 183))	('cancer', 'Disease', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
10833	33883026	There was a significant correlation between BRCA1 hyper methylation and poor survival.	('poor survival', 'CPA', (72, 85))	('BRCA1', 'Gene', '672', (44, 49))	('BRCA1', 'Gene', (44, 49))	('hyper methylation', 'Var', (50, 67))
10834	33883026	Moreover, MBT cases had hypo methylation of histone H4 lysine 20 (H4K20) and hypo acetylation of histone H3 on lysine 18 (H3K18).	('lysine', 'Chemical', 'MESH:D008239', (55, 61))	('H4K', 'Gene', (66, 69))	('hypo', 'Var', (24, 28))	('H4K', 'Gene', '8368', (66, 69))	('lysine', 'Chemical', 'MESH:D008239', (111, 117))
10841	33883026	P53 is stabilized by posttranslational modification in the primary stages of glioblastoma progression.	('glioblastoma', 'Disease', (77, 89))	('glioblastoma', 'Disease', 'MESH:D005909', (77, 89))	('glioblastoma', 'Phenotype', 'HP:0012174', (77, 89))	('P53', 'Gene', (0, 3))	('posttranslational modification', 'Var', (21, 51))	('P53', 'Gene', '7157', (0, 3))
10842	33883026	The MGMT suppression induces p53 mutation which can further deregulate the methylation pattern of MGMT.	('MGMT', 'Gene', '4255', (4, 8))	('methylation', 'biological_process', 'GO:0032259', ('75', '86'))	('deregulate', 'Reg', (60, 70))	('MGMT', 'molecular_function', 'GO:0003908', ('98', '102'))	('mutation', 'Var', (33, 41))	('induces', 'Reg', (21, 28))	('methylation pattern', 'MPA', (75, 94))	('p53', 'Gene', (29, 32))	('MGMT', 'Gene', (98, 102))	('p53', 'Gene', '7157', (29, 32))	('MGMT', 'Gene', '4255', (98, 102))	('MGMT', 'Gene', (4, 8))	('MGMT', 'molecular_function', 'GO:0003908', ('4', '8'))
10850	33883026	The expression profile of the genes located within cancer/placenta hypomethylated blocks were assessed for CRC that showed the epigenetic regulation of NF-kB signaling during tumorigenesis and placentogenesis.	('CRC', 'Disease', (107, 110))	('tumor', 'Disease', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('CRC', 'Phenotype', 'HP:0003003', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('CRC', 'Disease', 'MESH:D015179', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('cancer', 'Disease', (51, 57))	('epigenetic', 'Var', (127, 137))
10852	33883026	Therefore, the MMR aberrations can be associated with tumor progression.	('associated', 'Reg', (38, 48))	('MMR aberrations', 'Var', (15, 30))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('MMR', 'biological_process', 'GO:0006298', ('15', '18'))
10860	33883026	It was observed that the RASSF6 methylation was more frequent in B-Cell Acute Lymphoblastic Leukemia (B-ALL) cases compared with T-cell acute lymphoblastic leukaemia (T-ALL) cases, whereas the RASSF10 hyper methylation was more frequent in T-ALL compared with pre-B-ALL and B-ALL patients.	('T-ALL', 'Phenotype', 'HP:0006727', (167, 172))	('methylation', 'Var', (32, 43))	('T-cell acute lymphoblastic leukaemia', 'Phenotype', 'HP:0006727', (129, 165))	('RASSF6', 'Gene', (25, 31))	('T-cell acute lymphoblastic leukaemia', 'Disease', 'MESH:D054218', (129, 165))	('RASSF10', 'Gene', '644943', (193, 200))	('ALL', 'Phenotype', 'HP:0006721', (104, 107))	('RASSF10', 'Gene', (193, 200))	('B-ALL', 'Phenotype', 'HP:0004812', (102, 107))	('T-cell acute lymphoblastic leukaemia', 'Disease', (129, 165))	('-Cell Acute Lymphoblastic Leukemia', 'Phenotype', 'HP:0006727', (66, 100))	('ALL', 'Phenotype', 'HP:0006721', (276, 279))	('patients', 'Species', '9606', (280, 288))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('B-Cell Acute Lymphoblastic Leukemia', 'Phenotype', 'HP:0004812', (65, 100))	('B-Cell Acute Lymphoblastic Leukemia', 'Disease', (65, 100))	('ALL', 'Phenotype', 'HP:0006721', (242, 245))	('pre', 'molecular_function', 'GO:0003904', ('260', '263'))	('ALL', 'Phenotype', 'HP:0006721', (266, 269))	('acute lymphoblastic leukaemia', 'Phenotype', 'HP:0006721', (136, 165))	('methylation', 'biological_process', 'GO:0032259', ('207', '218'))	('B-ALL', 'Phenotype', 'HP:0004812', (274, 279))	('B-Cell Acute Lymphoblastic Leukemia', 'Disease', 'MESH:D015456', (65, 100))	('Acute Lymphoblastic Leukemia', 'Phenotype', 'HP:0006721', (72, 100))	('frequent', 'Reg', (53, 61))	('T-ALL', 'Phenotype', 'HP:0006727', (240, 245))	('B-ALL', 'Phenotype', 'HP:0004812', (264, 269))	('Leukemia', 'Phenotype', 'HP:0001909', (92, 100))	('Lymphoblastic Leukemia', 'Phenotype', 'HP:0005526', (78, 100))	('ALL', 'Phenotype', 'HP:0006721', (169, 172))	('RASSF6', 'Gene', '166824', (25, 31))
10861	33883026	Moreover, there was a significant correlation between RASSF6 hyper methylation and poor prognosis in pre-B-ALL patients which can be related to the NF-kB activation in the absence of RASSF6.	('RASSF6', 'Gene', (54, 60))	('ALL', 'Phenotype', 'HP:0006721', (107, 110))	('RASSF6', 'Gene', '166824', (183, 189))	('activation', 'PosReg', (154, 164))	('patients', 'Species', '9606', (111, 119))	('hyper methylation', 'Var', (61, 78))	('RASSF6', 'Gene', '166824', (54, 60))	('RASSF6', 'Gene', (183, 189))	('B-ALL', 'Phenotype', 'HP:0004812', (105, 110))	('poor prognosis', 'CPA', (83, 97))
10863	33883026	It has been reported that there were significant correlations between tumor sizes more than 2 cm, lymph node involvement, and HIC1 methylation among a sub population of Iranian breast cancer patients.	('breast cancer', 'Disease', (177, 190))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('HIC1', 'Gene', (126, 130))	('men', 'Species', '9606', (116, 119))	('patients', 'Species', '9606', (191, 199))	('HIC1', 'Gene', '3090', (126, 130))	('tumor', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('correlations', 'Interaction', (49, 61))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))	('methylation', 'Var', (131, 142))
10865	33883026	It was concluded that the HIC1 and RASSF1A hyper methylations can be used as prognostic markers of breast cancer in this population.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('HIC1', 'Gene', '3090', (26, 30))	('RASSF1A', 'Gene', (35, 42))	('hyper methylations', 'Var', (43, 61))	('breast cancer', 'Disease', (99, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('RASSF1A', 'Gene', '11186', (35, 42))	('HIC1', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
10866	33883026	Similarly, the RASSF1A methylation has been shown as an efficient prognostic marker in a sample of Saudi breast cancer patients.	('RASSF1A', 'Gene', '11186', (15, 22))	('Saudi breast cancer', 'Disease', (99, 118))	('methylation', 'Var', (23, 34))	('patients', 'Species', '9606', (119, 127))	('Saudi breast cancer', 'Disease', 'MESH:D001943', (99, 118))	('RASSF1A', 'Gene', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
10869	33883026	It has been reported that there were higher rates of p16, TSHR, and RASSF1A hyper methylations in a sample of Iranian malignant papillary thyroid tumors compared with benign tumors.	('TSHR', 'Gene', '7253', (58, 62))	('p16', 'Gene', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('higher', 'PosReg', (37, 43))	('malignant papillary thyroid tumors', 'Disease', (118, 152))	('benign tumors', 'Disease', 'MESH:D009369', (167, 180))	('RASSF1A', 'Gene', '11186', (68, 75))	('malignant papillary thyroid tumors', 'Disease', 'MESH:D000077273', (118, 152))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('p16', 'Gene', '1029', (53, 56))	('TSHR', 'Gene', (58, 62))	('benign tumors', 'Disease', (167, 180))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('hyper methylations', 'Var', (76, 94))	('papillary thyroid tumors', 'Phenotype', 'HP:0002895', (128, 152))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('RASSF1A', 'Gene', (68, 75))
10872	33883026	The alpha4 integrin hyper methylation was observed in the majority of an Iranian prostate cancer patients group.	('alpha4', 'Gene', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('Iranian prostate cancer', 'Disease', (73, 96))	('Iranian prostate cancer', 'Disease', 'MESH:D011471', (73, 96))	('hyper', 'Var', (20, 25))	('alpha4', 'Gene', '28898', (4, 10))	('prostate cancer', 'Phenotype', 'HP:0012125', (81, 96))	('patients', 'Species', '9606', (97, 105))
10875	33883026	It has been shown that the tumor tissues had higher rates of CDH1 hyper methylation compared with normal samples in Iranian breast cancer patients.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('CDH1', 'Gene', '999', (61, 65))	('hyper', 'Var', (66, 71))	('tumor', 'Disease', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('breast cancer', 'Disease', (124, 137))	('CDH1', 'Gene', (61, 65))	('higher', 'PosReg', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('patients', 'Species', '9606', (138, 146))
10883	33883026	It has been reported that there was higher ratio of p14ARF methylation in a sample of Iranian oral squamous cell carcinoma (OSCC) patients compared with controls which was also directly correlated with tumor stage.	('p14ARF', 'Gene', '1029', (52, 58))	('higher', 'PosReg', (36, 42))	('tumor', 'Disease', (202, 207))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 122))	('p14ARF', 'Gene', (52, 58))	('patients', 'Species', '9606', (130, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('methylation', 'Var', (59, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('oral squamous cell carcinoma', 'Disease', (94, 122))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
10884	33883026	Similarly, It was reported that there were significant associations between p14ARF hyper methylation, advanced stages, and lymph node involvement among Japanese OSCC patients.	('men', 'Species', '9606', (141, 144))	('advanced stages', 'CPA', (102, 117))	('hyper methylation', 'Var', (83, 100))	('p14ARF', 'Gene', '1029', (76, 82))	('p14ARF', 'Gene', (76, 82))	('lymph node involvement', 'CPA', (123, 145))	('patients', 'Species', '9606', (166, 174))
10886	33883026	MDM2 is an oncogene that inactivates p53 during tumorigenesis.	('tumor', 'Disease', (48, 53))	('inactivates', 'Var', (25, 36))	('MDM2', 'Gene', '4193', (0, 4))	('MDM2', 'Gene', (0, 4))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
10891	33883026	It has been observed that there was a significant inverse correlation between p16 hyper methylation and P53 expression in a sample of Iranian esophageal squamous cell carcinoma (ESCC) patients.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (142, 176))	('p16', 'Gene', (78, 81))	('inverse', 'NegReg', (50, 57))	('patients', 'Species', '9606', (184, 192))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('esophageal squamous cell carcinoma', 'Disease', (142, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('p16', 'Gene', '1029', (78, 81))	('P53', 'Gene', (104, 107))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('expression', 'MPA', (108, 118))	('hyper methylation', 'Var', (82, 99))	('P53', 'Gene', '7157', (104, 107))
10894	33883026	It was shown that the sporadic cases had higher ratio of p16 methylation compared with familial ESCC cases, while there was not any p16 methylation among controls.	('familial ESCC', 'Disease', (87, 100))	('methylation', 'Var', (61, 72))	('p16', 'Gene', (57, 60))	('p16', 'Gene', '1029', (132, 135))	('higher', 'PosReg', (41, 47))	('p16', 'Gene', '1029', (57, 60))	('p16', 'Gene', (132, 135))
10896	33883026	Another group has been reported that there were direct correlations between p16 hyper methylation, tumor grade, HP infection, and smoking in a subpopulation of Iranian OSCC cases.	('tumor', 'Disease', (99, 104))	('HP infection', 'Disease', 'MESH:C537262', (112, 124))	('p16', 'Gene', '1029', (76, 79))	('hyper methylation', 'Var', (80, 97))	('HP infection', 'Disease', (112, 124))	('methylation', 'biological_process', 'GO:0032259', ('86', '97'))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('p16', 'Gene', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('correlations', 'Interaction', (55, 67))	('Iranian OSCC', 'Disease', (160, 172))
10897	33883026	Another group has been reported that there was higher ratio of p16 and p15 methylations in tumors compared with normal margins in a sample of Iranian OSCC patients.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('p15', 'Gene', '1030', (71, 74))	('methylations', 'Var', (75, 87))	('p16', 'Gene', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('patients', 'Species', '9606', (155, 163))	('p15', 'Gene', (71, 74))	('p16', 'Gene', '1029', (63, 66))
10898	33883026	The aberrant methylation of the p15 and p16 have been also reported during OSCC progression among Japanese patients.	('methylation', 'MPA', (13, 24))	('p16', 'Gene', (40, 43))	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('reported', 'Reg', (59, 67))	('aberrant', 'Var', (4, 12))	('OSCC progression', 'Disease', (75, 91))	('p15', 'Gene', '1030', (32, 35))	('p16', 'Gene', '1029', (40, 43))	('p15', 'Gene', (32, 35))	('patients', 'Species', '9606', (107, 115))
10902	33883026	It has been reported that there was significantly higher frequency of DBC2 methylation in tumor and blood samples of a group of Iranian breast cancer patients compared with normal margins.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('higher', 'PosReg', (50, 56))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('methylation', 'Var', (75, 86))	('breast cancer', 'Disease', (136, 149))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('patients', 'Species', '9606', (150, 158))	('DBC2', 'Gene', (70, 74))	('DBC2', 'Gene', '23221', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
10912	33883026	It has been observed that there were higher levels of methylated UBE2Q1 in colorectal tumor samples compared with normal margins among a sub population of Iranian subjects.	('UBE2Q1', 'Gene', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('UBE2Q1', 'Gene', '55585', (65, 71))	('higher', 'PosReg', (37, 43))	('colorectal tumor', 'Disease', (75, 91))	('colorectal tumor', 'Disease', 'MESH:D015179', (75, 91))	('methylated', 'Var', (54, 64))
10913	33883026	Aberrant methylation of cell cycle regulators during tumor progressions among Iranian patients are illustrated in Fig.	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cell cycle', 'biological_process', 'GO:0007049', ('24', '34'))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('tumor', 'Disease', (53, 58))	('methylation', 'MPA', (9, 20))	('patients', 'Species', '9606', (86, 94))
10921	33883026	Moreover, there were significant correlations between DOK7 and VIM methylations and negative ER status.	('methylations', 'Var', (67, 79))	('DOK7', 'Gene', '285489', (54, 58))	('negative ER status', 'Disease', (84, 102))	('correlations', 'Interaction', (33, 45))	('VIM', 'Gene', '7431', (63, 66))	('DOK7', 'Gene', (54, 58))	('VIM', 'Gene', (63, 66))
10922	33883026	Another reports also showed DOK7 and VIM hyper methylations in Spanish and Australian breast cancer patients, respectively.	('VIM', 'Gene', '7431', (37, 40))	('DOK7', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('VIM', 'Gene', (37, 40))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('patients', 'Species', '9606', (100, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('hyper methylations', 'Var', (41, 59))	('breast cancer', 'Disease', (86, 99))	('DOK7', 'Gene', '285489', (28, 32))
10924	33883026	Ghrelin is associated with regulation of glucose and lipid metabolism and activates Ca2+ and P13K/AKT signaling pathways that are contributed with secretion of growth hormone in pituitary cells.	('growth hormone', 'Gene', (160, 174))	('growth hormone', 'Gene', '2688', (160, 174))	('Ghrelin', 'Chemical', 'MESH:D054439', (0, 7))	('glucose and lipid metabolism', 'Disease', 'MESH:D044882', (41, 69))	('activates', 'PosReg', (74, 83))	('P13K', 'Var', (93, 97))	('AKT', 'Gene', '207', (98, 101))	('Ca2+', 'Chemical', 'MESH:D000069285', (84, 88))	('Ghrelin', 'Gene', (0, 7))	('AKT', 'Gene', (98, 101))	('P13K', 'SUBSTITUTION', 'None', (93, 97))
10930	33883026	It has been reported that there was higher frequency of EDNRB hyper methylation in a sample of Iranian colorectal cancer tissues compared with normal margins.	('colorectal cancer', 'Disease', 'MESH:D015179', (103, 120))	('hyper methylation', 'Var', (62, 79))	('EDNRB', 'Gene', '1910', (56, 61))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('colorectal cancer', 'Disease', (103, 120))	('EDNRB', 'Gene', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))
10931	33883026	Similarly, the Chinese colorectal cancer tumors had significantly higher frequency of EDNRB promoter hyper methylation compared with normal tissues.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('EDNRB', 'Gene', '1910', (86, 91))	('colorectal cancer tumors', 'Disease', 'MESH:D015179', (23, 47))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('hyper methylation', 'Var', (101, 118))	('EDNRB', 'Gene', (86, 91))	('higher', 'PosReg', (66, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (23, 40))	('colorectal cancer tumors', 'Disease', (23, 47))
10933	33883026	DNA methylation of APC, AXIN2, SFRP, and DKK as important WNT inhibitors have been reported in colorectal cancer patients.	('APC', 'Gene', (19, 22))	('SFRP', 'Gene', (31, 35))	('APC', 'Gene', '324', (19, 22))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('colorectal cancer', 'Disease', (95, 112))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('reported', 'Reg', (83, 91))	('patients', 'Species', '9606', (113, 121))	('AXIN2', 'Gene', (24, 29))	('AXIN2', 'Gene', '8313', (24, 29))	('APC', 'cellular_component', 'GO:0005680', ('19', '22'))	('methylation', 'Var', (4, 15))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('DKK', 'Gene', (41, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
10934	33883026	It has been observed that there were significant correlations between APC and DDK3 aberrant promoter methylations and age and sex, respectively among a sub population of Iranian colorectal patients.	('APC', 'Gene', '324', (70, 73))	('APC', 'cellular_component', 'GO:0005680', ('70', '73'))	('DDK3', 'Gene', (78, 82))	('aberrant', 'Var', (83, 91))	('colorectal', 'Disease', 'MESH:D015179', (178, 188))	('DDK', 'cellular_component', 'GO:0031431', ('78', '81'))	('APC', 'Gene', (70, 73))	('colorectal', 'Disease', (178, 188))	('patients', 'Species', '9606', (189, 197))
10935	33883026	The SFRP4 and WIF1 promoter methylations were significantly associated with stage and grade.	('WIF1', 'Gene', (14, 18))	('WIF1', 'Gene', '11197', (14, 18))	('grade', 'CPA', (86, 91))	('stage', 'CPA', (76, 81))	('methylations', 'Var', (28, 40))	('SFRP4', 'Gene', (4, 9))	('SFRP4', 'Gene', '6424', (4, 9))	('associated', 'Reg', (60, 70))
10936	33883026	Moreover, there were significant correlations between SFRP2 and SFRP5 methylations and tumor type.	('SFRP2', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('correlations', 'Reg', (33, 45))	('tumor', 'Disease', (87, 92))	('SFRP5', 'Gene', '6425', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('methylations', 'Var', (70, 82))	('SFRP5', 'Gene', (64, 69))	('SFRP2', 'Gene', '6423', (54, 59))
10945	33883026	Similarly, there were also high levels of SFRP1 and SFRP2 hyper methylations among a group of Hungarian CRC patients.	('CRC', 'Disease', (104, 107))	('SFRP1', 'Gene', '6422', (42, 47))	('SFRP1', 'Gene', (42, 47))	('CRC', 'Phenotype', 'HP:0003003', (104, 107))	('CRC', 'Disease', 'MESH:D015179', (104, 107))	('SFRP2', 'Gene', '6423', (52, 57))	('SFRP2', 'Gene', (52, 57))	('patients', 'Species', '9606', (108, 116))	('hyper', 'Var', (58, 63))
10946	33883026	Phosphatase and tensin homolog (PTEN) is a suppressor of PI3K/AKT pathways which inhibits signal transduction from HER1, HER2, and IGFR growth factor receptors through the P13K/AKT signaling.	('inhibits', 'NegReg', (81, 89))	('AKT', 'Gene', (62, 65))	('HER2', 'Gene', '2064', (121, 125))	('HER1', 'Gene', (115, 119))	('AKT', 'Gene', '207', (177, 180))	('signal transduction', 'MPA', (90, 109))	('P13K', 'Var', (172, 176))	('PTEN', 'Gene', (32, 36))	('PTEN', 'Gene', '5728', (32, 36))	('AKT', 'Gene', (177, 180))	('IGFR growth factor receptors', 'Protein', (131, 159))	('P13K', 'SUBSTITUTION', 'None', (172, 176))	('HER1', 'Gene', '1956', (115, 119))	('AKT', 'Gene', '207', (62, 65))	('HER2', 'Gene', (121, 125))	('Phosphatase and tensin homolog', 'Gene', '5728', (0, 30))
10954	33883026	Another study on Iranian sporadic breast cancer patients showed that there were correlations between PTEN hyper methylation, advanced stages, and lymph node involvement.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('correlations', 'Interaction', (80, 92))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (25, 47))	('PTEN', 'Gene', (101, 105))	('PTEN', 'Gene', '5728', (101, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('patients', 'Species', '9606', (48, 56))	('hyper methylation', 'Var', (106, 123))	('sporadic breast cancer', 'Disease', (25, 47))	('men', 'Species', '9606', (164, 167))
10956	33883026	Iranian Kurdish breast cancer patients also had a higher frequency of PTEN methylation compared with healthy controls.	('methylation', 'biological_process', 'GO:0032259', ('75', '86'))	('methylation', 'Var', (75, 86))	('PTEN', 'Gene', (70, 74))	('PTEN', 'Gene', '5728', (70, 74))	('Kurdish breast cancer', 'Disease', 'MESH:D001943', (8, 29))	('patients', 'Species', '9606', (30, 38))	('Kurdish breast cancer', 'Disease', (8, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
10957	33883026	The female relatives of patients had also a significantly higher frequency of PTEN methylation compared with controls.	('methylation', 'Var', (83, 94))	('PTEN', 'Gene', (78, 82))	('PTEN', 'Gene', '5728', (78, 82))	('methylation', 'biological_process', 'GO:0032259', ('83', '94'))	('higher', 'PosReg', (58, 64))	('patients', 'Species', '9606', (24, 32))
10963	33883026	Deregulation of PAX5 has been observed in various types of human tumors.	('human', 'Species', '9606', (59, 64))	('PAX5', 'Gene', '5079', (16, 20))	('PAX5', 'Gene', (16, 20))	('Deregulation', 'Var', (0, 12))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
10969	33883026	It has been shown that there was a significant correlation between PAX5 methylation and survival in a sample of Chinese gastric cancer patients.	('PAX5', 'Gene', (67, 71))	('PAX5', 'Gene', '5079', (67, 71))	('patients', 'Species', '9606', (135, 143))	('survival', 'Disease', (88, 96))	('gastric cancer', 'Disease', (120, 134))	('gastric cancer', 'Disease', 'MESH:D013274', (120, 134))	('methylation', 'Var', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('gastric cancer', 'Phenotype', 'HP:0012126', (120, 134))
10971	33883026	MiR-192-2 induces the apoptosis through targeting SOX4 in gastric tumor cells.	('MiR-192-2', 'Chemical', '-', (0, 9))	('gastric tumor', 'Disease', 'MESH:D013274', (58, 71))	('gastric tumor', 'Phenotype', 'HP:0006753', (58, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('apoptosis', 'biological_process', 'GO:0006915', ('22', '31'))	('SOX4', 'Gene', (50, 54))	('SOX4', 'Gene', '6659', (50, 54))	('MiR-192-2', 'Var', (0, 9))	('apoptosis', 'CPA', (22, 31))	('gastric tumor', 'Disease', (58, 71))	('apoptosis', 'biological_process', 'GO:0097194', ('22', '31'))
10975	33883026	It has been observed that there was significantly higher ER4 methylation in tumors with P53 expression among a sub population of Iranian breast cancer patients.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('P53', 'Gene', (88, 91))	('higher', 'PosReg', (50, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('expression', 'Var', (92, 102))	('P53', 'Gene', '7157', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('patients', 'Species', '9606', (151, 159))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('methylation', 'MPA', (61, 72))	('ER4', 'Protein', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
10976	33883026	The ER5 methylation was observed in tumors with lymph node metastasis and higher grades.	('lymph node metastasis', 'CPA', (48, 69))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('ER5 methylation', 'Var', (4, 19))	('observed', 'Reg', (24, 32))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('methylation', 'Var', (8, 19))
10978	33883026	There was also significant higher frequency of ER5 methylation in Her-2+ tumors.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('Her-2', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('methylation', 'Var', (51, 62))	('higher', 'PosReg', (27, 33))	('tumors', 'Disease', (73, 79))	('ER5', 'Protein', (47, 50))	('Her-2', 'Gene', '2064', (66, 71))
10979	33883026	ER-alpha hyper methylation was frequently observed in invasive ductal cell carcinoma patients.	('hyper methylation', 'Var', (9, 26))	('ER-alpha', 'Gene', (0, 8))	('patients', 'Species', '9606', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('invasive ductal cell carcinoma', 'Disease', 'MESH:D044584', (54, 84))	('observed', 'Reg', (42, 50))	('ER-alpha', 'Gene', '2099', (0, 8))	('invasive ductal cell carcinoma', 'Disease', (54, 84))
10982	33883026	There was a correlation between ER-alpha methylation and poor prognosis in basal and Her2+ tumors.	('ER-alpha', 'Gene', (32, 40))	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('correlation', 'Reg', (12, 23))	('Her2', 'Gene', (85, 89))	('ER-alpha', 'Gene', '2099', (32, 40))	('methylation', 'Var', (41, 52))	('basal', 'Disease', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Her2', 'Gene', '2064', (85, 89))
10984	33883026	ER3 and ER5 methylations have been also reported in majority of a sample of Iranian ER negative breast tumors.	('ER5', 'Gene', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('breast tumors', 'Disease', (96, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('breast tumor', 'Phenotype', 'HP:0100013', (96, 108))	('breast tumors', 'Phenotype', 'HP:0100013', (96, 109))	('ER3', 'Gene', (0, 3))	('reported', 'Reg', (40, 48))	('methylations', 'Var', (12, 24))	('breast tumors', 'Disease', 'MESH:D001943', (96, 109))
10986	33883026	It has been reported that there was higher frequency of RARB hyper methylation in poor prognosis cases compared with good prognosis in a sample of Iranian prostate cancer patients.	('RARB', 'Gene', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('RARB', 'Gene', '5915', (56, 60))	('prostate cancer', 'Phenotype', 'HP:0012125', (155, 170))	('Iranian prostate cancer', 'Disease', 'MESH:D011471', (147, 170))	('patients', 'Species', '9606', (171, 179))	('Iranian prostate cancer', 'Disease', (147, 170))	('hyper methylation', 'Var', (61, 78))
10988	33883026	Similarly, RARB methylation was associated with a higher prostate cancer risk among American patients.	('prostate cancer', 'Disease', (57, 72))	('RARB', 'Gene', (11, 15))	('methylation', 'biological_process', 'GO:0032259', ('16', '27'))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('RARB', 'Gene', '5915', (11, 15))	('prostate cancer', 'Disease', 'MESH:D011471', (57, 72))	('prostate cancer', 'Phenotype', 'HP:0012125', (57, 72))	('patients', 'Species', '9606', (93, 101))	('methylation', 'Var', (16, 27))
10992	33883026	It has been shown that there was a significant association between the levels of APAF1 methylation, tumor stage, and grade in blood samples of a subpopulation of Iranian gastric cancer patients.	('gastric cancer', 'Disease', 'MESH:D013274', (170, 184))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('APAF1', 'Gene', '317', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Disease', (100, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (170, 184))	('methylation', 'biological_process', 'GO:0032259', ('87', '98'))	('APAF1', 'Gene', (81, 86))	('patients', 'Species', '9606', (185, 193))	('methylation', 'Var', (87, 98))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('gastric cancer', 'Disease', (170, 184))
10998	33883026	Moreover, it cleaves BID to generate truncated BID which enters to the mitochondria and triggers the mitochondrial apoptotic pathway.	('BID', 'Gene', (21, 24))	('triggers', 'Reg', (88, 96))	('mitochondrial apoptotic pathway', 'Pathway', (101, 132))	('BID', 'Gene', '637', (47, 50))	('enters', 'Reg', (57, 63))	('BID', 'Gene', '637', (21, 24))	('truncated', 'Var', (37, 46))	('BID', 'Gene', (47, 50))
10999	33883026	It has been observed that there was aberrant FAS promoter methylation in majority of a sample of Iranian oral squamous cell carcinoma patients, whereas the aberrant FADD methylation was observed in a minority of cases.	('methylation', 'MPA', (58, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('oral squamous cell carcinoma', 'Disease', (105, 133))	('patients', 'Species', '9606', (134, 142))	('aberrant', 'Var', (36, 44))	('FAS promoter', 'Protein', (45, 57))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 133))
11000	33883026	Ataxia telangiectasia mutated (ATM) is a serine threonine kinase which is activated by DNA double-strand break (DSB).	('DNA double-strand break', 'Var', (87, 110))	('Ataxia telangiectasia mutated', 'Gene', '472', (0, 29))	('ATM', 'Gene', '472', (31, 34))	('Ataxia telangiectasia mutated', 'Gene', (0, 29))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('serine', 'Chemical', 'MESH:D012694', (41, 47))	('telangiectasia', 'Phenotype', 'HP:0001009', (7, 21))	('Ataxia', 'Phenotype', 'HP:0001251', (0, 6))	('ATM', 'Gene', (31, 34))
11001	33883026	Deregulated expression of E2F1 transcription factor up regulates ATM that leads to the apoptosis induction, cell cycle regulation, and DNA repair via phosphorylation of CHK1, CHK2, P53, and CDC25.	('ATM', 'Gene', '472', (65, 68))	('CDC25', 'Gene', '995', (190, 195))	('phosphorylation', 'MPA', (150, 165))	('CDC25', 'Gene', (190, 195))	('Deregulated', 'Var', (0, 11))	('CHK1', 'Gene', '1111', (169, 173))	('CHK2', 'Gene', (175, 179))	('up regulates', 'PosReg', (52, 64))	('P53', 'Gene', (181, 184))	('E2F1', 'Gene', '1869', (26, 30))	('DNA repair', 'CPA', (135, 145))	('E2F1', 'Gene', (26, 30))	('apoptosis induction', 'CPA', (87, 106))	('cell cycle regulation', 'CPA', (108, 129))	('CHK1', 'Gene', (169, 173))	('CHK2', 'Gene', '11200', (175, 179))	('ATM', 'Gene', (65, 68))	('P53', 'Gene', '7157', (181, 184))
11005	33883026	Moreover, there was a significant association between D1853N polymorphism and ATM promoter methylation.	('D1853N', 'Var', (54, 60))	('ATM', 'Gene', (78, 81))	('D1853N', 'Mutation', 'rs1801516', (54, 60))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('ATM', 'Gene', '472', (78, 81))
11010	33883026	It has been observed that there was significantly higher frequency of CTLA4 promoter methylation in a sample of Iranian gastric cancer patients compared with normal margins.	('methylation', 'Var', (85, 96))	('higher', 'PosReg', (50, 56))	('patients', 'Species', '9606', (135, 143))	('CTLA4', 'Gene', '1493', (70, 75))	('gastric cancer', 'Disease', (120, 134))	('promoter', 'MPA', (76, 84))	('gastric cancer', 'Disease', 'MESH:D013274', (120, 134))	('CTLA4', 'Gene', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('gastric cancer', 'Phenotype', 'HP:0012126', (120, 134))
11012	33883026	Role of aberrant methylations in regulation of apoptosis during tumor progressions among Iranian patients are illustrated in Fig.	('aberrant methylations', 'Var', (8, 29))	('tumor', 'Disease', (64, 69))	('regulation of apoptosis', 'biological_process', 'GO:0042981', ('33', '56'))	('methylations', 'Var', (17, 29))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('patients', 'Species', '9606', (97, 105))
11015	33883026	It was frequently observed that the p16 and CDH1 aberrant promoter methylations can be involved in tumor progression of ESCC, thyroid, oral, breast, gastric, and prostate cancers.	('oral', 'Disease', (135, 139))	('breast', 'Disease', (141, 147))	('aberrant', 'Var', (49, 57))	('p16', 'Gene', '1029', (36, 39))	('prostate cancer', 'Phenotype', 'HP:0012125', (162, 177))	('prostate cancers', 'Phenotype', 'HP:0012125', (162, 178))	('CDH1', 'Gene', '999', (44, 48))	('prostate cancers', 'Disease', (162, 178))	('tumor', 'Disease', (99, 104))	('involved', 'Reg', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('CDH1', 'Gene', (44, 48))	('thyroid', 'Disease', (126, 133))	('ESCC', 'Disease', (120, 124))	('gastric', 'Disease', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('prostate cancers', 'Disease', 'MESH:D011471', (162, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('p16', 'Gene', (36, 39))
11018	33883026	Moreover, there were various reports of PTEN and ER-alpha promoter hyper methylations in Iranian BC patients which introduces them as methylation based markers of BC in this population.	('ER-alpha', 'Gene', '2099', (49, 57))	('hyper methylations', 'Var', (67, 85))	('PTEN', 'Gene', (40, 44))	('PTEN', 'Gene', '5728', (40, 44))	('Iranian BC', 'Disease', (89, 99))	('patients', 'Species', '9606', (100, 108))	('methylation', 'biological_process', 'GO:0032259', ('134', '145'))	('ER-alpha', 'Gene', (49, 57))
11024	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))	('HSPG', 'Gene', '960', (16, 20))	('expression levels', 'MPA', (82, 99))	('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))	('functions', 'MPA', (134, 143))	('activity', 'MPA', (171, 179))	('structure', 'MPA', (120, 129))
11043	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))
11055	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'))	('glucosamine', 'Chemical', 'MESH:D005944', (91, 102))	('iduronic acid', 'Chemical', 'MESH:D007067', (144, 157))	('sulfate', 'Chemical', 'MESH:D013431', (276, 283))	('glucosamine', 'Chemical', 'MESH:D005944', (210, 221))	('uronic acid', 'Chemical', 'MESH:D014574', (129, 140))	('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'))	('N-sulfation', 'MPA', (76, 87))	('modifications', 'Var', (32, 45))	('uronic acid', 'Chemical', 'MESH:D014574', (194, 205))	('glucosamine', 'Chemical', 'MESH:D005944', (285, 296))	('C-5', 'Var', (104, 107))	('sulfation', 'biological_process', 'GO:0051923', ('181', '190'))
11060	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))
11062	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))	('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))	('glucosamine', 'Chemical', 'MESH:D005944', (74, 85))	('3-OST', 'Gene', '9957', (213, 218))	('lung cancer', 'Disease', 'MESH:D008175', (275, 286))	('chondrosarcoma', 'Disease', 'MESH:D002813', (153, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (275, 286))	('chondrosarcoma', 'Disease', (153, 167))	('3-OST', 'Gene', (113, 118))
11065	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))
11066	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))
11067	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))	('non-melanoma skin cancer', 'Disease', (120, 144))	('HS chain synthesis', 'MPA', (73, 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))
11076	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))
11082	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))
11088	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))
11095	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))	('aberrant expression', 'Var', (4, 23))	('malignancy of the tumor', 'Disease', (163, 186))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))
11100	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))
11101	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))	('shedding', 'Var', (122, 130))	('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))
11102	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))
11116	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))	('PKC', 'Gene', (393, 396))	('extracellular signal-regulated kinase', 'Gene', (189, 226))	('FGF', 'Protein', (44, 47))	('extracellular signal-regulated kinase', 'Gene', '5594', (189, 226))	('phosphatidylinositol 3-kinase', 'Gene', '5293', (234, 263))	('tumor', 'Disease', (17, 22))	('ERK', 'Gene', '5594', (228, 231))	('protein kinase B', 'Gene', '2185', (271, 287))	('AKT', 'Gene', (289, 292))	('activation', 'PosReg', (95, 105))	('STAT', 'Gene', '6774', (364, 368))	('STAT', 'Gene', (364, 368))	('activator of transcription', 'Pathway', (336, 362))	('phosphatidylinositol 3-kinase', 'Gene', (234, 263))	('HSPG', 'Gene', '960', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('protein kinase B', 'Gene', (271, 287))	('binding', 'Var', (48, 55))	('HSPG', 'Gene', (29, 33))	('ERK', 'Gene', (228, 231))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('dimerization', 'Var', (69, 81))
11128	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))	('promotes', 'PosReg', (35, 43))	('shed', 'Var', (25, 29))	('SDC1', 'Gene', (30, 34))	('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'))
11130	32916872	Dysregulation of HSPG-regulated HGF/c-MET signaling in tumor microenvironment plays a key role in hepatocarcinoma.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('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))
11131	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))	('tumor', 'Disease', (62, 67))	('HB-EGF', 'Gene', (48, 54))	('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))
11202	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))	('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))
11211	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))	('M402', 'Chemical', '-', (42, 46))	('HS', 'Chemical', 'MESH:D006497', (12, 14))	('heparanase', 'Gene', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('PG545', 'Var', (31, 36))	('antimetastatic effects', 'CPA', (92, 114))	('anti-angiogenic', 'CPA', (72, 87))	('heparanase', 'Gene', '10855', (129, 139))	('inhibiting', 'NegReg', (118, 128))	('PG545', 'Chemical', 'MESH:C557899', (31, 36))
11217	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))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (76, 97))	('SULF1', 'Gene', (33, 38))	('SULF1', 'Gene', '23213', (33, 38))	('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))
11218	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))
11255	31921862	For example, overexpression of Drp1 was detected in breast cancer metastatic cells compared to the non-metastatic, whereas silencing of Drp1 or overexpression of Mfn1 resulted in mitochondrial elongation and significantly suppressed the metastatic properties of breast cancer cells.	('suppressed', 'NegReg', (222, 232))	('Mfn1', 'Gene', (162, 166))	('Drp1', 'Gene', (136, 140))	('Drp1', 'Gene', '10059', (31, 35))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('Mfn1', 'Gene', '55669', (162, 166))	('resulted in', 'Reg', (167, 178))	('breast cancer', 'Disease', 'MESH:D001943', (262, 275))	('breast cancer', 'Phenotype', 'HP:0003002', (262, 275))	('breast cancer', 'Disease', (52, 65))	('mitochondrial elongation', 'CPA', (179, 203))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (262, 275))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('Drp1', 'Gene', (31, 35))	('Drp1', 'Gene', '10059', (136, 140))	('silencing', 'Var', (123, 132))
11265	31921862	Another study has shown that inhibition of mitochondrial fusion may abolish invasion of syntaphilin-depleted prostate adenocarcinoma cells.	('mitochondrial', 'CPA', (43, 56))	('syntaphilin', 'Gene', (88, 99))	('syntaphilin', 'Gene', '9751', (88, 99))	('prostate adenocarcinoma', 'Disease', (109, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('abolish', 'NegReg', (68, 75))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (109, 132))	('inhibition', 'Var', (29, 39))	('invasion', 'CPA', (76, 84))
11268	31921862	Thereby, the silencing of both Mfn1, 2 and syntaphilin abolished mitochondrial trafficking and abrogated the migratory response.	('mitochondrial trafficking', 'CPA', (65, 90))	('Mfn1', 'Gene', (31, 35))	('Mfn1', 'Gene', '55669', (31, 35))	('abolished', 'NegReg', (55, 64))	('rat', 'Species', '10116', (112, 115))	('migratory response', 'CPA', (109, 127))	('syntaphilin', 'Gene', (43, 54))	('abrogated', 'NegReg', (95, 104))	('syntaphilin', 'Gene', '9751', (43, 54))	('silencing', 'Var', (13, 22))
11277	31921862	Since ROS can inactivate protein tyrosine phosphatases through oxidation of cysteine residues, ROS may have many yet-to-be discovered effects on diverse, mitogen-activated pathways that are normally inhibited by phosphatases.	('oxidation', 'MPA', (63, 72))	('ROS', 'Var', (6, 9))	('inactivate', 'NegReg', (14, 24))	('protein tyrosine phosphatases', 'Enzyme', (25, 54))	('tyrosine', 'Chemical', 'None', (33, 41))	('cysteine', 'Chemical', 'MESH:D003545', (76, 84))	('ROS', 'Var', (95, 98))	('mitogen-activated pathways', 'Pathway', (154, 180))
11278	31921862	ROS can stimulate the phosphorylation of MAPK and extracellular signal-regulated kinase (ERK), cyclin D1 expression and JUN N-terminal kinase (JNK) activation, all of which are linked to tumor cell survival and growth.	('cyclin', 'molecular_function', 'GO:0016538', ('95', '101'))	('activation', 'PosReg', (148, 158))	('ERK', 'Gene', '5594', (89, 92))	('JUN N-terminal kinase', 'Gene', '5599', (120, 141))	('tumor', 'Disease', (187, 192))	('MAPK', 'molecular_function', 'GO:0004707', ('41', '45'))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('JNK', 'Gene', (143, 146))	('expression', 'MPA', (105, 115))	('JNK', 'Gene', '5599', (143, 146))	('stimulate', 'PosReg', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('ERK', 'molecular_function', 'GO:0004707', ('89', '92'))	('JUN N-terminal kinase', 'Gene', (120, 141))	('ERK', 'Gene', (89, 92))	('cyclin D1', 'Gene', (95, 104))	('extracellular signal-regulated kinase', 'Gene', (50, 87))	('phosphorylation', 'MPA', (22, 37))	('ROS', 'Var', (0, 3))	('extracellular', 'cellular_component', 'GO:0005576', ('50', '63'))	('extracellular signal-regulated kinase', 'Gene', '5594', (50, 87))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cyclin D1', 'Gene', '595', (95, 104))	('MAPK', 'Protein', (41, 45))	('JNK', 'molecular_function', 'GO:0004705', ('143', '146'))
11288	31921862	Importantly, ROS accumulation leads to the stabilization of HIF-1 due to inhibition of the HIF-degrading enzyme prolyl hydroxylase.	('ROS', 'Var', (13, 16))	('stabilization', 'MPA', (43, 56))	('inhibition', 'NegReg', (73, 83))	('HIF-1', 'Gene', '3091', (60, 65))	('prolyl', 'Chemical', 'MESH:C065612', (112, 118))	('prolyl hydroxylase', 'Enzyme', (112, 130))	('HIF-1', 'Gene', (60, 65))
11291	31921862	ROS may affect the activation of TGF-beta downstream effector Smad, while treatment with the ROS scavenger N-acetyl cysteine (NAC) abolishes Smad phosphorylation.	('ROS', 'Var', (0, 3))	('N-acetyl cysteine', 'Chemical', 'MESH:D000111', (107, 124))	('affect', 'Reg', (8, 14))	('Smad', 'Protein', (62, 66))	('TGF-beta', 'Gene', '7040', (33, 41))	('NAC', 'Chemical', 'MESH:D000111', (126, 129))	('TGF-beta', 'Gene', (33, 41))	('phosphorylation', 'MPA', (146, 161))	('abolishes', 'NegReg', (131, 140))	('activation', 'MPA', (19, 29))
11298	31921862	In cervical carcinoma SiHa cells depletion of ROS leads to increase of E-cadherin and downregulation of Snail, the main negative regulator of E-cadherin.	('E-cadherin', 'Gene', (142, 152))	('E-cadherin', 'Gene', '999', (142, 152))	('depletion', 'Var', (33, 42))	('increase', 'PosReg', (59, 67))	('cadherin', 'molecular_function', 'GO:0008014', ('73', '81'))	('E-cadherin', 'Gene', (71, 81))	('E-cadherin', 'Gene', '999', (71, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('cervical carcinoma SiHa', 'Disease', (3, 26))	('Snail', 'Gene', (104, 109))	('downregulation', 'NegReg', (86, 100))	('cervical carcinoma SiHa', 'Disease', 'MESH:D002583', (3, 26))	('cadherin', 'molecular_function', 'GO:0008014', ('144', '152'))	('Snail', 'Gene', '6615', (104, 109))	('ROS', 'Gene', (46, 49))
11305	31921862	Recent data have demonstrated that Nrf2 activation can stimulate cancer cell migration and metastasis and Nrf2 deletion attenuates metastatic potential breast cancer cells suppressing RhoA GTPases activity.	('suppressing', 'NegReg', (172, 183))	('Nrf2', 'Gene', '4780', (35, 39))	('RhoA', 'Gene', '387', (184, 188))	('rat', 'Species', '10116', (24, 27))	('cancer', 'Disease', (65, 71))	('deletion', 'Var', (111, 119))	('cancer', 'Disease', (159, 165))	('rat', 'Species', '10116', (80, 83))	('Nrf2', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('activity', 'MPA', (197, 205))	('Nrf2', 'Gene', (35, 39))	('stimulate', 'PosReg', (55, 64))	('attenuates', 'NegReg', (120, 130))	('activation', 'PosReg', (40, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('RhoA', 'Gene', (184, 188))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Disease', (152, 165))	('Nrf2', 'Gene', '4780', (106, 110))
11309	31921862	It is known that mtDNA mutations can contribute to tumor initiation and progression.	('mtDNA', 'Gene', (17, 22))	('contribute', 'Reg', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor initiation', 'Disease', (51, 67))	('mutations', 'Var', (23, 32))	('progression', 'CPA', (72, 83))	('tumor initiation', 'Disease', 'MESH:D009369', (51, 67))
11310	31921862	Variations in copy number of mtDNA are associated with tumorigenesis and depend on tumor type.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (83, 88))	('mtDNA', 'Gene', (29, 34))	('tumor', 'Disease', (55, 60))	('Variations', 'Var', (0, 10))	('associated', 'Reg', (39, 49))	('copy number', 'Var', (14, 25))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
11312	31921862	On the other hand, increased copy number of mtDNA was found in prostate, head and neck, and colorectal cancers.	('colorectal cancers', 'Disease', (92, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('copy number', 'Var', (29, 40))	('mtDNA', 'Gene', (44, 49))	('increased', 'PosReg', (19, 28))	('prostate', 'Disease', (63, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('colorectal cancers', 'Disease', 'MESH:D015179', (92, 110))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))
11313	31921862	Mutations and variations in mtDNA content might be associated with regulation of the metastatic properties of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('variations', 'Var', (14, 24))	('associated', 'Reg', (51, 61))	('Mutations', 'Var', (0, 9))	('mtDNA content', 'Gene', (28, 41))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
11314	31921862	mtDNA mutations are also associated with EMT of cancer cells.	('associated', 'Reg', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('mtDNA', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
11316	31921862	Conversely, knockdown of mitochondrial transcription factor A (TFAM) leads to a decrease in mtDNA copy number, upregulation of E-cadherin expression, and suppression of cell migration rate in esophageal squamous cell carcinoma.	('mitochondrial transcription factor A', 'Gene', '7019', (25, 61))	('rat', 'Species', '10116', (184, 187))	('TFAM', 'Gene', (63, 67))	('expression', 'MPA', (138, 148))	('mitochondrial transcription factor A', 'Gene', (25, 61))	('upregulation', 'PosReg', (111, 123))	('knockdown', 'Var', (12, 21))	('esophageal squamous cell carcinoma', 'Disease', (192, 226))	('mtDNA', 'Gene', (92, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (203, 226))	('TFAM', 'Gene', '7019', (63, 67))	('copy number', 'MPA', (98, 109))	('suppression', 'NegReg', (154, 165))	('rat', 'Species', '10116', (177, 180))	('cell migration rate', 'CPA', (169, 188))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (192, 226))	('E-cadherin', 'Gene', (127, 137))	('E-cadherin', 'Gene', '999', (127, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('decrease', 'NegReg', (80, 88))
11318	31921862	Furthermore, mtDNA mutations contribute to the acquisition of an aggressive phenotype in oncocytic thyroid tumors leading to their bioenergetic crisis.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('oncocytic thyroid tumors', 'Disease', (89, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('mutations', 'Var', (19, 28))	('mtDNA', 'cellular_component', 'GO:0000262', ('13', '18'))	('mtDNA', 'Gene', (13, 18))	('bioenergetic crisis', 'MPA', (131, 150))	('oncocytic thyroid tumors', 'Disease', 'MESH:C535584', (89, 113))
11320	31921862	Thus, oxygen deprivation may provide positive selective pressure for cancer cells carrying damaging mtDNA mutations.	('mtDNA', 'Gene', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('oxygen', 'Chemical', 'MESH:D010100', (6, 12))	('mtDNA', 'cellular_component', 'GO:0000262', ('100', '105'))	('mutations', 'Var', (106, 115))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
11322	31921862	These data are consistent with the observation that in human mammary epithelial cells (hMECs) a decrease in mtDNA copy number promotes calcineurin-mediated mitochondrial retrograde signaling, which initiates EMT.	('mtDNA', 'Gene', (108, 113))	('promotes', 'PosReg', (126, 134))	('human', 'Species', '9606', (55, 60))	('decrease', 'NegReg', (96, 104))	('copy number', 'Var', (114, 125))
11324	31921862	A recent study has revealed that increased mtDNA copy number may sustain tumor progression and metastasis by upregulating OXPHOS function in cancer cells that rely on mitochondrial OXPHOS.	('upregulating', 'PosReg', (109, 121))	('sustain', 'PosReg', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mtDNA', 'Gene', (43, 48))	('tumor', 'Disease', (73, 78))	('metastasis', 'CPA', (95, 105))	('increased', 'PosReg', (33, 42))	('copy number', 'Var', (49, 60))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('OXPHOS function', 'MPA', (122, 137))	('cancer', 'Disease', (141, 147))
11326	31921862	Summing up, mtDNA mutations and variations of mtDNA copy number are associated with EMT, increased invasiveness and metastasis in different types of cancer.	('cancer', 'Disease', (149, 155))	('associated', 'Reg', (68, 78))	('mtDNA', 'Gene', (46, 51))	('mtDNA', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('invasiveness', 'CPA', (99, 111))	('EMT', 'CPA', (84, 87))	('metastasis', 'CPA', (116, 126))	('variations', 'Var', (32, 42))	('increased', 'PosReg', (89, 98))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('mutations', 'Var', (18, 27))
11354	31921862	Overexpression of Bcl-w is associated with the infiltrative morphotypes of gastric cancer and is overexpressed in patients with lung and breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (137, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('Bcl-w', 'Gene', '599', (18, 23))	('gastric cancer', 'Disease', (75, 89))	('overexpressed', 'PosReg', (97, 110))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('associated', 'Reg', (27, 37))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('rat', 'Species', '10116', (53, 56))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('Overexpression', 'Var', (0, 14))	('lung and breast cancers', 'Disease', 'MESH:D001943', (128, 151))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('patients', 'Species', '9606', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('Bcl-w', 'Gene', (18, 23))
11363	31921862	Thus, in human triple-negative breast cancer (TNBC) the lack of Bnip3 results in tumor progression and metastasis via storage of dysfunctional mitochondria and subsequent ROS accumulation; the events that, as was discussed earlier, lead to expression of HIF-inducible genes including metastasis-related angiogenesis genes.	('Bnip3', 'Gene', (64, 69))	('metastasis via storage of dysfunctional mitochondria', 'Disease', 'MESH:D009362', (103, 155))	('storage', 'biological_process', 'GO:0051235', ('118', '125'))	('human', 'Species', '9606', (9, 14))	('angiogenesis', 'biological_process', 'GO:0001525', ('303', '315'))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('lack', 'Var', (56, 60))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('breast cancer', 'Disease', (31, 44))	('expression', 'MPA', (240, 250))	('tumor', 'Disease', (81, 86))	('lead to', 'Reg', (232, 239))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('accumulation', 'PosReg', (175, 187))	('mitochondria', 'cellular_component', 'GO:0005739', ('143', '155'))	('HIF-inducible', 'PosReg', (254, 267))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('ROS', 'MPA', (171, 174))	('Bnip3', 'Gene', '664', (64, 69))	('results in', 'Reg', (70, 80))	('metastasis-related angiogenesis genes', 'Gene', (284, 321))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
11364	31921862	Conversely, in melanoma cells Bnip3 silencing reduces the formation of lamellipodia and filopodia as well as cell migration through the downregulation of integrin-associated glycoprotein CD47, Rac1 and Cdc42.	('Rac1', 'Gene', (193, 197))	('Bnip3', 'Gene', (30, 35))	('rat', 'Species', '10116', (117, 120))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('Cdc42', 'Gene', (202, 207))	('melanoma', 'Disease', (15, 23))	('downregulation', 'NegReg', (136, 150))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('Bnip3', 'Gene', '664', (30, 35))	('CD47', 'Gene', '961', (187, 191))	('Cdc42', 'Gene', '998', (202, 207))	('silencing', 'Var', (36, 45))	('CD47', 'Gene', (187, 191))	('cell migration', 'biological_process', 'GO:0016477', ('109', '123'))	('formation', 'biological_process', 'GO:0009058', ('58', '67'))	('reduces', 'NegReg', (46, 53))	('Rac1', 'Gene', '5879', (193, 197))	('cell migration', 'CPA', (109, 123))
11375	31921862	Methylation of Bim and Bnip3 genes is associated with metastasis and the gene methylation rate is increased among colorectal and pancreatic cancer patients compared to healthy individuals.	('colorectal and pancreatic cancer', 'Disease', 'MESH:D015179', (114, 146))	('associated', 'Reg', (38, 48))	('gene methylation rate', 'MPA', (73, 94))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('Methylation', 'Var', (0, 11))	('Bnip3', 'Gene', '664', (23, 28))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('patients', 'Species', '9606', (147, 155))	('methylation', 'biological_process', 'GO:0032259', ('78', '89'))	('increased', 'PosReg', (98, 107))	('metastasis', 'CPA', (54, 64))	('Bnip3', 'Gene', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Bim', 'Gene', (15, 18))	('Bim', 'Gene', '10018', (15, 18))	('rat', 'Species', '10116', (90, 93))
11399	31921862	Therefore, NCLX tightly regulates mitochondrial Ca2+ level and prevents excessive Ca2+ accumulation in mitochondria that can lead to the increase of the mtROS level and subsequent SOCE suppression via oxidation of redox-sensitive Cys195 of Orai1.	('mitochondria', 'cellular_component', 'GO:0005739', ('103', '115'))	('suppression', 'NegReg', (185, 196))	('mtROS level', 'MPA', (153, 164))	('Cys195', 'Var', (230, 236))	('Orai1', 'Gene', (240, 245))	('increase', 'PosReg', (137, 145))	('NCLX', 'Gene', '80024', (11, 15))	('oxidation', 'Var', (201, 210))	('Ca2+ accumulation', 'MPA', (82, 99))	('Orai1', 'Gene', '84876', (240, 245))	('SOCE', 'biological_process', 'GO:0002115', ('180', '184'))	('NCLX', 'Gene', (11, 15))
11401	31921862	The mutations in BH1 domain of Bcl-2 protein leads to STIM1, Orai1-3, TRPC1 overexpression and SOCE enhancement.	('SOCE', 'CPA', (95, 99))	('protein', 'cellular_component', 'GO:0003675', ('37', '44'))	('Bcl-2', 'Gene', (31, 36))	('Bcl-2', 'Gene', '596', (31, 36))	('Bcl-2', 'molecular_function', 'GO:0015283', ('31', '36'))	('Orai1-3', 'Gene', '84876;80228;93129', (61, 68))	('Orai1-3', 'Gene', (61, 68))	('STIM1', 'Gene', (54, 59))	('SOCE', 'biological_process', 'GO:0002115', ('95', '99'))	('TRPC1', 'Gene', '7220', (70, 75))	('TRPC1', 'Gene', (70, 75))	('mutations', 'Var', (4, 13))	('STIM1', 'Gene', '6786', (54, 59))	('enhancement', 'PosReg', (100, 111))	('overexpression', 'PosReg', (76, 90))
11402	31921862	It has been established, that hyperactive SOCE induced by STIM1 and Orai1 overexpression correlates with increased metastasis in different types of cancer.	('cancer', 'Disease', (148, 154))	('hyperactive', 'Disease', 'MESH:D006948', (30, 41))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('hyperactive', 'Disease', (30, 41))	('metastasis', 'CPA', (115, 125))	('STIM1', 'Gene', '6786', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('SOCE', 'MPA', (42, 46))	('Orai1', 'Gene', (68, 73))	('SOCE', 'biological_process', 'GO:0002115', ('42', '46'))	('Orai1', 'Gene', '84876', (68, 73))	('increased', 'PosReg', (105, 114))	('STIM1', 'Gene', (58, 63))	('overexpression', 'Var', (74, 88))
11409	31921862	Both Bcl-2 and Bcl-XL interact with VDAC1 through BH4 domain; however, Bcl-XL BH4 is more effective than Bcl-2-BH4 in targeting VDAC1 activity.	('VDAC1', 'Gene', (128, 133))	('BH4', 'Var', (78, 81))	('Bcl-XL', 'Gene', '598', (15, 21))	('VDAC1', 'Gene', (36, 41))	('Bcl-XL', 'Gene', (71, 77))	('Bcl-2', 'molecular_function', 'GO:0015283', ('5', '10'))	('VDAC1', 'Gene', '7416', (128, 133))	('Bcl-XL', 'Gene', (15, 21))	('Bcl-2', 'Gene', (105, 110))	('VDAC1', 'Gene', '7416', (36, 41))	('Bcl-2', 'Gene', (5, 10))	('Bcl-2', 'Gene', '596', (105, 110))	('Bcl-2', 'Gene', '596', (5, 10))	('Bcl-2', 'molecular_function', 'GO:0015283', ('105', '110'))	('activity', 'MPA', (134, 142))	('Bcl-XL', 'Gene', '598', (71, 77))
11415	31921862	It has been revealed, that inhibition of ryanodine receptor subtype IP3R3 and subsequent decrease in Ca2+ release results in suppression of the invasion and migration of glioblastoma cell lines and metastasis in glioblastoma mouse model.	('Ca2+ release', 'MPA', (101, 113))	('rat', 'Species', '10116', (160, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (170, 182))	('glioblastoma', 'Disease', (212, 224))	('decrease', 'NegReg', (89, 97))	('suppression', 'NegReg', (125, 136))	('IP3R3', 'Gene', (68, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (212, 224))	('mouse', 'Species', '10090', (225, 230))	('ryanodine', 'Chemical', 'MESH:D012433', (41, 50))	('inhibition', 'Var', (27, 37))	('metastasis in', 'CPA', (198, 211))	('glioblastoma', 'Phenotype', 'HP:0012174', (212, 224))	('ryanodine receptor', 'molecular_function', 'GO:0005219', ('41', '59'))	('glioblastoma', 'Disease', (170, 182))	('glioblastoma', 'Disease', 'MESH:D005909', (170, 182))
11416	31921862	Overexpression of IP3R3, but not of IP3R1 and IP3R2, leads to stimulation of the migration properties of breast cancer cells sustaining Ca2+ signaling.	('IP3R3', 'Var', (18, 23))	('IP3R1', 'Gene', (36, 41))	('rat', 'Species', '10116', (84, 87))	('stimulation', 'PosReg', (62, 73))	('IP3R2', 'Gene', '3709', (46, 51))	('IP3R2', 'Gene', (46, 51))	('IP3R1', 'Gene', '3708', (36, 41))	('migration properties', 'CPA', (81, 101))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
11422	31921862	Silencing of this uniporter results in decreased mitochondrial Ca2+ level and ROS production, as well as migratory and invasiveness capacities.	('rat', 'Species', '10116', (108, 111))	('ROS production', 'MPA', (78, 92))	('decreased', 'NegReg', (39, 48))	('Silencing', 'Var', (0, 9))	('mitochondrial Ca2+ level', 'MPA', (49, 73))
11423	31921862	MCU gene deletion reduces tumor metastasis in TNBC MDA-MB-231 xenografts via HIF-1-dependent gene expression.	('MCU', 'Gene', (0, 3))	('deletion', 'Var', (9, 17))	('gene expression', 'biological_process', 'GO:0010467', ('93', '108'))	('reduces', 'NegReg', (18, 25))	('HIF-1', 'Gene', '3091', (77, 82))	('MCU', 'Gene', '90550', (0, 3))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('HIF-1', 'Gene', (77, 82))	('tumor metastasis', 'Disease', 'MESH:D009362', (26, 42))	('tumor metastasis', 'Disease', (26, 42))
11451	31921862	For example, expression of hexokinase 2 (HK2), the embryonic isoform of hexokinase, the enzyme which defines the start of glycolysis, is associated with increased risk of recurrence, and adverse clinical outcome for breast cancer, pancreatic cancer, and neuroblastoma patients.	('neuroblastoma', 'Phenotype', 'HP:0003006', (254, 267))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('recurrence', 'CPA', (171, 181))	('associated with', 'Reg', (137, 152))	('breast cancer', 'Disease', (216, 229))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('pancreatic cancer', 'Disease', (231, 248))	('expression', 'Var', (13, 23))	('neuroblastoma', 'Disease', 'MESH:D009447', (254, 267))	('pancreatic cancer', 'Disease', 'MESH:D010190', (231, 248))	('HK2', 'Gene', (41, 44))	('neuroblastoma', 'Disease', (254, 267))	('patients', 'Species', '9606', (268, 276))	('clinical', 'Species', '191496', (195, 203))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (231, 248))
11461	31921862	Inhibition of glycolysis attenuates cell motility even while mitochondrial ATP synthesis remains intact, and inhibition of mitochondrial respiration reduces cell motility only minimally compared to inhibition of glycolysis.	('attenuates', 'NegReg', (25, 35))	('cell motility', 'CPA', (157, 170))	('inhibition', 'Var', (109, 119))	('rat', 'Species', '10116', (142, 145))	('ATP', 'Chemical', 'MESH:D000255', (75, 78))	('mitochondrial respiration', 'MPA', (123, 148))	('cell motility', 'CPA', (36, 49))
11464	31921862	In turn, inhibition of glycolysis suppresses the migration properties of prostate cancer cells.	('prostate cancer', 'Disease', (73, 88))	('rat', 'Species', '10116', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('suppresses', 'NegReg', (34, 44))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('glycolysis', 'MPA', (23, 33))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('inhibition', 'Var', (9, 19))
11466	31921862	In breast cancer, loss of fructose-1,6-bisphosphatase together with the loss of E-cadherin promotes cancer stem cell (CSC)-like features and cancer cell dissemination by enhancing beta-catenin signaling and the EMT program.	('loss', 'Var', (72, 76))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', (10, 16))	('promotes', 'PosReg', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', (141, 147))	('fructose', 'Chemical', 'MESH:D005632', (26, 34))	('EMT program', 'CPA', (211, 222))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('beta-catenin', 'Gene', (180, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('beta-catenin', 'Gene', '1499', (180, 192))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (100, 106))	('enhancing', 'PosReg', (170, 179))	('E-cadherin', 'Gene', (80, 90))	('E-cadherin', 'Gene', '999', (80, 90))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('loss', 'Var', (18, 22))	('breast cancer', 'Disease', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
11496	31921862	Importantly, a more recent study demonstrated that the use of modified lonidamine is significantly more efficacious in inhibiting mitochondrial bioenergetics in lung cancer cells, leading to suppression of lung cancer progression and metastasis.	('lonidamine', 'Chemical', 'MESH:C016371', (71, 81))	('lung cancer', 'Disease', 'MESH:D008175', (206, 217))	('inhibiting', 'NegReg', (119, 129))	('progression', 'CPA', (218, 229))	('mitochondrial bioenergetics', 'MPA', (130, 157))	('lung cancer', 'Disease', (161, 172))	('suppression of lung cancer', 'Disease', (191, 217))	('rat', 'Species', '10116', (40, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('lonidamine', 'Gene', (71, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('modified', 'Var', (62, 70))	('suppression of lung cancer', 'Disease', 'MESH:D008175', (191, 217))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))	('metastasis', 'CPA', (234, 244))
11497	31921862	Mitochondrial-lonidamine activates the generation of ROS in lung cancer cells, which leads to the inactivation of the Akt/mTOR/p70S6K signaling pathways and autophagic cell death.	('activates', 'PosReg', (25, 34))	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('Akt', 'Gene', (118, 121))	('rat', 'Species', '10116', (43, 46))	('p70S6K', 'Gene', (127, 133))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('p70S6K', 'Gene', '6198', (127, 133))	('Mitochondrial-lonidamine', 'Var', (0, 24))	('lonidamine', 'Chemical', 'MESH:C016371', (14, 24))	('Akt', 'Gene', '207', (118, 121))	('ROS', 'Protein', (53, 56))	('autophagic cell death', 'CPA', (157, 178))	('inactivation', 'NegReg', (98, 110))
11506	31921862	Furthermore, the treatment with NAC was shown to enhance the metastatic dissemination of human melanoma cells, providing evidence that oxidative stress may, in certain circumstances, stimulate metastasis.	('human', 'Species', '9606', (89, 94))	('NAC', 'Chemical', 'MESH:D000111', (32, 35))	('oxidative stress', 'MPA', (135, 151))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('enhance', 'PosReg', (49, 56))	('melanoma', 'Disease', (95, 103))	('metastasis', 'CPA', (193, 203))	('NAC', 'cellular_component', 'GO:0005854', ('32', '35'))	('NAC', 'Var', (32, 35))	('stimulate', 'PosReg', (183, 192))	('oxidative stress', 'Phenotype', 'HP:0025464', (135, 151))
11521	31921862	Furthermore, Ch282-5 provided suppression of colon cancer cell migration, invasion and liver metastasis.	('colon cancer', 'Disease', (45, 57))	('invasion', 'CPA', (74, 82))	('colon cancer', 'Phenotype', 'HP:0003003', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('colon cancer', 'Disease', 'MESH:D015179', (45, 57))	('Ch282-5', 'Var', (13, 20))	('suppression', 'NegReg', (30, 41))	('rat', 'Species', '10116', (66, 69))	('liver metastasis', 'CPA', (87, 103))
11523	31921862	Conversely, inhibition of Drp1 in combination with BH3-mimetic treatment significantly enhanced apoptotic response in melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('Drp1', 'Gene', (26, 30))	('inhibition', 'Var', (12, 22))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('apoptotic response', 'CPA', (96, 114))	('enhanced', 'PosReg', (87, 95))	('Drp1', 'Gene', '10059', (26, 30))
11524	31921862	Additionally, inhibition of Drp1 by Mdivi-1 increased the cytotoxic effect of combination treatment with A-1210477 and ABT-263 in different melanoma cell lines.	('Mdivi-1', 'Gene', (36, 43))	('Drp1', 'Gene', '10059', (28, 32))	('combination', 'Interaction', (78, 89))	('cytotoxic effect', 'CPA', (58, 74))	('ABT-263', 'Chemical', 'MESH:C528561', (119, 126))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('Drp1', 'Gene', (28, 32))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('increased', 'PosReg', (44, 53))	('A-1210477', 'Var', (105, 114))	('inhibition', 'NegReg', (14, 24))
11559	30042169	It has been proved that the aberrant expression of miRNAs is a common feature of human malignancy.	('malignancy', 'Disease', 'MESH:D009369', (87, 97))	('aberrant', 'Var', (28, 36))	('miR', 'Gene', '220972', (51, 54))	('malignancy', 'Disease', (87, 97))	('miR', 'Gene', (51, 54))	('human', 'Species', '9606', (81, 86))
11589	30042169	The native or mutant 3'UTR of CXXC4 was amplified and cloned into plasmid pMIR-Reporter (Thermo Fisher), generating the plasmids pMIR-wt and pMIR-mut, respectively.	('mutant', 'Var', (14, 20))	('CXXC4', 'Gene', (30, 35))	('CXXC4', 'Gene', '80319', (30, 35))
11594	30042169	After blocking, the membranes were incubated with primary antibodies against CXXC4 (ab105400, 1:500), BCL-2 (ab32124, 1:1000), Bax (ab32503, 1:1000), and beta-actin (ab8227, 1:3000) (Abcam, Cambridge, U.K.) overnight at 4 C. After that, the membranes were incubated with secondary antibody (ab205718) (Abcam) and exposed using an Ultrasensitive ECL Chemiluminescence kit (Sangon Biotech) according to the manual.	('Bax', 'Gene', '581', (127, 130))	('CXXC4', 'Gene', '80319', (77, 82))	('BCL-2', 'Gene', (102, 107))	('beta-actin', 'Gene', (154, 164))	('beta-actin', 'Gene', '728378', (154, 164))	('Bax', 'Gene', (127, 130))	('ab105400', 'Var', (84, 92))	('CXXC4', 'Gene', (77, 82))	('BCL-2', 'Gene', '596', (102, 107))
11623	30042169	However, miR-629-5p mimic or inhibitor showed no impact on the luciferase activities of the cells transfected with the mutant 3'UTR of CXXC4 (Figure 4D).	('CXXC4', 'Gene', (135, 140))	('miR-629', 'Gene', '693214', (9, 16))	('miR-629', 'Gene', (9, 16))	('CXXC4', 'Gene', '80319', (135, 140))	('activities', 'MPA', (74, 84))	('5p', 'Chemical', '-', (17, 19))	('mutant', 'Var', (119, 125))	('luciferase', 'Enzyme', (63, 73))
11626	30042169	To illustrate whether CXXC4 involves in the oncogenic function of miR-625-5p, si-CXXC4 was transfected with miR-625-5p inhibitor in LoVo cells to knockdown CXXC4 level.	('knockdown', 'Var', (146, 155))	('LoVo', 'CellLine', 'CVCL:0399', (132, 136))	('miR-625', 'Gene', (108, 115))	('CXXC4', 'Gene', (22, 27))	('CXXC4', 'Gene', (156, 161))	('miR-625', 'Gene', (66, 73))	('5p', 'Chemical', '-', (116, 118))	('miR-625', 'Gene', '693210', (66, 73))	('CXXC4', 'Gene', '80319', (156, 161))	('5p', 'Chemical', '-', (74, 76))	('CXXC4', 'Gene', (81, 86))	('miR-625', 'Gene', '693210', (108, 115))	('CXXC4', 'Gene', '80319', (22, 27))	('CXXC4', 'Gene', '80319', (81, 86))
11629	30042169	Besides, the enhanced cell apoptosis (Figure 5C), the aberrant expressions of Bcl-2 and Bax proteins (Figure 5D,E), and the enhanced ratio of Bax to Bcl-2 (Figure 5F) in the miR-625-5p inhibitor transfected cells were also partly abrogated by CXXC4 knockdown.	('transfected', 'Var', (195, 206))	('Bcl-2', 'Gene', (149, 154))	('expressions', 'MPA', (63, 74))	('Bcl-2', 'Gene', '596', (78, 83))	('ratio', 'MPA', (133, 138))	('miR-625', 'Gene', (174, 181))	('CXXC4', 'Gene', '80319', (243, 248))	('Bax', 'Gene', (88, 91))	('Bcl-2', 'Gene', '596', (149, 154))	('Bax', 'Gene', '581', (88, 91))	('Bcl-2', 'molecular_function', 'GO:0015283', ('149', '154'))	('apoptosis', 'biological_process', 'GO:0097194', ('27', '36'))	('apoptosis', 'biological_process', 'GO:0006915', ('27', '36'))	('Bax', 'Gene', (142, 145))	('enhanced', 'PosReg', (13, 21))	('miR-625', 'Gene', '693210', (174, 181))	('Bax', 'Gene', '581', (142, 145))	('enhanced', 'PosReg', (124, 132))	('Bcl-2', 'molecular_function', 'GO:0015283', ('78', '83'))	('CXXC4', 'Gene', (243, 248))	('cell apoptosis', 'CPA', (22, 36))	('Bcl-2', 'Gene', (78, 83))	('5p', 'Chemical', '-', (182, 184))
11676	29483219	Knocking down PRPK expression attenuated colorectal liver and lung metastasis of colon cancer cells in vivo.	('Knocking down', 'Var', (0, 13))	('colon cancer', 'Phenotype', 'HP:0003003', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('attenuated colorectal liver and lung metastasis of colon cancer', 'Disease', 'MESH:D015179', (30, 93))	('PRPK', 'Gene', (14, 18))
11688	29483219	PRPK is phosphorylated at Ser250 by Akt/PBK and by the T-LAK cell-originated protein kinase (TOPK).	('Ser250', 'Var', (26, 32))	('PBK', 'Gene', (40, 43))	('PRPK', 'Protein', (0, 4))	('T-LAK cell-originated protein kinase', 'Gene', '55872', (55, 91))	('TOPK', 'Gene', '55872', (93, 97))	('T-LAK cell-originated protein kinase', 'Gene', (55, 91))	('Akt', 'Gene', (36, 39))	('TOPK', 'Gene', (93, 97))	('Ser250', 'Chemical', '-', (26, 32))	('PBK', 'Gene', '55872', (40, 43))	('Akt', 'Gene', '207', (36, 39))
11693	29483219	For example, the p53 protein is also phosphorylated at Ser15 by ATR and ATM.	('ATR', 'Gene', '545', (64, 67))	('ATR', 'Gene', (64, 67))	('ATM', 'Gene', '472', (72, 75))	('Ser15', 'Chemical', '-', (55, 60))	('Ser15', 'Var', (55, 60))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))	('ATM', 'Gene', (72, 75))	('protein', 'Protein', (21, 28))
11696	29483219	Depletion of PRPK reportedly causes a p53-dependent and -independent increase in paclitaxel-induced caspase activation and p53 remains phosphorylated on Ser15 even after depletion of PRPK, suggesting that this is not a major role for PRPK in proliferating cells.	('increase', 'PosReg', (69, 77))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('paclitaxel-induced caspase', 'MPA', (81, 107))	('Depletion', 'Var', (0, 9))	('paclitaxel', 'Chemical', 'MESH:D017239', (81, 91))	('p53', 'Gene', (123, 126))	('PRPK', 'Gene', (13, 17))	('Ser15', 'Chemical', '-', (153, 158))	('p53', 'Gene', '7157', (123, 126))	('activation', 'PosReg', (108, 118))
11706	29483219	Anti-phosphor-survivin (Thr34; D2E11), phosphor-p53 (Ser15) (16G8) anti-mouse antibody were from Cell Signaling Technology, Inc. (Beverly, MA).	('p53', 'Gene', (48, 51))	('Signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('Thr34', 'Chemical', '-', (24, 29))	('antibody', 'cellular_component', 'GO:0019814', ('78', '86'))	('antibody', 'molecular_function', 'GO:0003823', ('78', '86'))	('p53', 'Gene', '7157', (48, 51))	('mouse', 'Species', '10090', (72, 77))	('survivin', 'Gene', (14, 22))	('Ser', 'cellular_component', 'GO:0005790', ('53', '56'))	('Thr34', 'Var', (24, 29))	('antibody', 'cellular_component', 'GO:0042571', ('78', '86'))	('Ser15', 'Chemical', '-', (53, 58))	('survivin', 'Gene', '11799', (14, 22))	('antibody', 'cellular_component', 'GO:0019815', ('78', '86'))
11729	29483219	The colon adenocarcinoma tissue arrays (HCol-Ade180Sur-03) and (HCol-Ade180Sur-05) had survival data, including TNM and pathology grade, 90 cases and NAT, 90 cases.	('Ade180Sur', 'Chemical', '-', (69, 78))	('TNM', 'Gene', '10178', (112, 115))	('HCol', 'Chemical', '-', (64, 68))	('Ade180Sur', 'Chemical', '-', (45, 54))	('HCol-Ade180Sur-03', 'Var', (40, 57))	('HCol-Ade180Sur-05', 'Var', (64, 81))	('TNM', 'Gene', (112, 115))	('HCol', 'Chemical', '-', (40, 44))	('colon adenocarcinoma', 'Disease', (4, 24))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (4, 24))
11730	29483219	Immunostaining was performed on the tissue array using antibodies to detect p-PRPK (1:100) or mutant p53 (1:50).	('p53', 'Gene', '7157', (101, 104))	('p-PRPK', 'Var', (76, 82))	('mutant', 'Var', (94, 100))	('p53', 'Gene', (101, 104))
11740	29483219	Next, we determined the effect of knocking down PRPK levels with sh-RNA on the invasion abilities of invasive cancer cell lines such as HCT116 and HCT15.	('knocking', 'Var', (34, 42))	('invasive cancer', 'Disease', 'MESH:D009362', (101, 116))	('HCT116', 'CellLine', 'CVCL:0291', (136, 142))	('PRPK levels', 'Protein', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('HCT15', 'CellLine', 'CVCL:0292', (147, 152))	('invasive cancer', 'Disease', (101, 116))
11744	29483219	The area of liver metastasis from mice expressing shPRPK#1/HCT116 was significantly decreased compared to shMock (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (59, 65))	('decreased', 'NegReg', (84, 93))	('mice', 'Species', '10090', (34, 38))	('shPRPK#1/HCT116', 'Var', (50, 65))
11745	29483219	The metastatic nodules were completely absent in livers from mice expressing shPRPK#1/HCT15 compared to shMock (Fig.	('HCT15', 'CellLine', 'CVCL:0292', (86, 91))	('metastatic nodules', 'CPA', (4, 22))	('mice', 'Species', '10090', (61, 65))	('shPRPK#1/HCT15', 'Var', (77, 91))	('absent', 'NegReg', (39, 45))
11747	29483219	Migration and invasion were inhibited in CT26 mouse colon cancer cells stably expressing shPRPK, as compared to shMock (Supplementary Fig.	('colon cancer', 'Disease', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('CT26', 'Gene', (41, 45))	('mouse', 'Species', '10090', (46, 51))	('inhibited', 'NegReg', (28, 37))	('colon cancer', 'Phenotype', 'HP:0003003', (52, 64))	('colon cancer', 'Disease', 'MESH:D015179', (52, 64))	('shPRPK', 'Var', (89, 95))	('CT26', 'Gene', '168400', (41, 45))
11749	29483219	The area of lung metastasis from mice expressing shMock in HCT116 cells (28 days) was greater compared to shPRPK#1 (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (59, 65))	('shMock', 'Var', (49, 55))	('lung metastasis', 'CPA', (12, 27))	('mice', 'Species', '10090', (33, 37))
11751	29483219	H&E staining of lungs with cells expressing shMock showed greater tumor metastasis compared with shPRPK (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('H&E', 'Chemical', '-', (0, 3))	('showed', 'PosReg', (51, 57))	('tumor metastasis', 'Disease', 'MESH:D009362', (66, 82))	('tumor metastasis', 'Disease', (66, 82))	('expressing', 'Var', (33, 43))
11753	29483219	2E) demonstrated that mice inoculated with shMock (n = 9, red line) exhibit dramatically decreased survival time compared to mice inoculated with shPRPK#1 (p = 0.0015).	('survival time', 'CPA', (99, 112))	('mice', 'Species', '10090', (125, 129))	('shMock', 'Var', (43, 49))	('mice', 'Species', '10090', (22, 26))	('decreased', 'NegReg', (89, 98))
11759	29483219	Mutation of survivin (Thr34Ala) can induce apoptosis and reduce angiogenesis, metastasis, and cell cycle progression.	('survivin', 'Gene', '11799', (12, 20))	('reduce', 'NegReg', (57, 63))	('apoptosis', 'CPA', (43, 52))	('angiogenesis', 'CPA', (64, 76))	('cell cycle progression', 'CPA', (94, 116))	('Thr34Ala', 'SUBSTITUTION', 'None', (22, 30))	('Mutation', 'Var', (0, 8))	('survivin', 'Gene', (12, 20))	('Thr34Ala', 'Var', (22, 30))	('metastasis', 'CPA', (78, 88))	('induce', 'PosReg', (36, 42))
11760	29483219	Wild-type and mutant His-survivin (Thr34Ala) proteins were analyzed for phosphorylation by PRPK.	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('Thr34Ala', 'SUBSTITUTION', 'None', (35, 43))	('survivin', 'Gene', (25, 33))	('mutant', 'Var', (14, 20))	('Thr34Ala', 'Var', (35, 43))	('phosphorylation', 'MPA', (72, 87))	('survivin', 'Gene', '11799', (25, 33))
11761	29483219	3B, right panel) results indicated that mutant T34A abrogated phosphorylation of survivin, confirming that PRPK phosphorylates survivin at Thr34.	('abrogated', 'NegReg', (52, 61))	('survivin', 'Gene', (127, 135))	('phosphorylation', 'MPA', (62, 77))	('survivin', 'Gene', '11799', (81, 89))	('survivin', 'Gene', '11799', (127, 135))	('Thr34', 'Chemical', '-', (139, 144))	('T34A', 'Gene', (47, 51))	('mutant', 'Var', (40, 46))	('T34A', 'Mutation', 'rs752988925', (47, 51))	('survivin', 'Gene', (81, 89))
11766	29483219	We found that this was indeed the case, as phosphorylation of PRPK (Ser250) and survivin (Thr34) was induced in a dose- and time-dependent manner by EGF (Supplementary Fig.	('survivin', 'Gene', '11799', (80, 88))	('phosphorylation', 'MPA', (43, 58))	('PRPK', 'Protein', (62, 66))	('Ser250', 'Chemical', '-', (68, 74))	('Thr34', 'Chemical', '-', (90, 95))	('EGF', 'Var', (149, 152))	('induced', 'PosReg', (101, 108))	('survivin', 'Gene', (80, 88))
11769	29483219	V5-PRPK and Flag-survivin were transfected alone or together into HEK293 cells and the expression of each protein was confirmed by anti-V5 or anti-Flag, respectively (Fig.	('anti-V5', 'Var', (131, 138))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('HEK293', 'CellLine', 'CVCL:0045', (66, 72))	('survivin', 'Gene', '11799', (17, 25))	('survivin', 'Gene', (17, 25))
11777	29483219	Survivin phosphorylation induced by EGF was decreased by knockdown of PRPK (shPRPK#1) in HCT116 or HCT15 cells (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('9', '24'))	('Survivin', 'Gene', '11799', (0, 8))	('phosphorylation', 'MPA', (9, 24))	('EGF', 'molecular_function', 'GO:0005154', ('36', '39'))	('HCT116', 'CellLine', 'CVCL:0291', (89, 95))	('Survivin', 'Gene', (0, 8))	('knockdown', 'Var', (57, 66))	('HCT15', 'CellLine', 'CVCL:0292', (99, 104))	('decreased', 'NegReg', (44, 53))
11779	29483219	EGF regulates survivin stability and survivin is stabilized by Thr34 phosphorylation.	('EGF', 'molecular_function', 'GO:0005154', ('0', '3'))	('Thr34', 'Chemical', '-', (63, 68))	('phosphorylation', 'biological_process', 'GO:0016310', ('69', '84'))	('survivin', 'Gene', '11799', (37, 45))	('survivin', 'Gene', (14, 22))	('regulates', 'Reg', (4, 13))	('Thr34', 'Var', (63, 68))	('survivin', 'Gene', (37, 45))	('survivin', 'Gene', '11799', (14, 22))	('stability', 'MPA', (23, 32))
11782	29483219	3F, left panels), suggesting that phosphorylation of survivin by PRPK enhances its stability.	('PRPK', 'Gene', (65, 69))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('stability', 'MPA', (83, 92))	('survivin', 'Gene', '11799', (53, 61))	('phosphorylation', 'Var', (34, 49))	('survivin', 'Gene', (53, 61))	('enhances', 'PosReg', (70, 78))
11783	29483219	Phosphorylation of survivin was almost absent in MutPRPK cells (Fig.	('survivin', 'Gene', '11799', (19, 27))	('MutPRPK', 'Var', (49, 56))	('Phosphorylation', 'MPA', (0, 15))	('absent', 'NegReg', (39, 45))	('survivin', 'Gene', (19, 27))
11784	29483219	These results demonstrate that mutation of PRPK markedly attenuates its phosphorylation of survivin.	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('phosphorylation of', 'MPA', (72, 90))	('survivin', 'Gene', '11799', (91, 99))	('mutation', 'Var', (31, 39))	('PRPK', 'Gene', (43, 47))	('survivin', 'Gene', (91, 99))	('attenuates', 'NegReg', (57, 67))
11788	29483219	The mutation of survivin (Thr34Ala) induces apoptosis, thus we compared the level of cleaved caspase-3, a marker of apoptosis in cells expressing either mutant or wild-type PRPK (Supplementary Fig.	('Thr34Ala', 'Var', (26, 34))	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('apoptosis', 'CPA', (44, 53))	('survivin', 'Gene', '11799', (16, 24))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('mutation', 'Var', (4, 12))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))	('Thr34Ala', 'SUBSTITUTION', 'None', (26, 34))	('survivin', 'Gene', (16, 24))	('induces', 'Reg', (36, 43))
11789	29483219	After 48 h of treatment with 5-FU, the level of cleaved caspase-3 was increased in cells expressing mutant PRPK, compared to cells expressing WT PRPK.	('level of cleaved caspase-3', 'MPA', (39, 65))	('PRPK', 'Gene', (107, 111))	('mutant', 'Var', (100, 106))	('increased', 'PosReg', (70, 79))	('5-FU', 'Chemical', 'MESH:D005472', (29, 33))
11790	29483219	This indicated that overexpression of the mutant PRPK induces apoptosis, and has a similar biological effect to the survivin T34A mutation.	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('PRPK', 'Gene', (49, 53))	('mutant', 'Var', (42, 48))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('T34A', 'Mutation', 'rs752988925', (125, 129))	('overexpression', 'PosReg', (20, 34))	('survivin', 'Gene', '11799', (116, 124))	('apoptosis', 'CPA', (62, 71))	('induces', 'Reg', (54, 61))	('survivin', 'Gene', (116, 124))
11791	29483219	Experiments were also performed with PRPK knockdown in HCT116 cells (Supplementary Figure 4F) and we did not observe dramatic differences in the levels of cleaved caspase 3 in cells with or without PRPK, thus apoptosis was not induced in the absence of 5-FU, which is consistent with our previous cell growth data.	('cell growth', 'biological_process', 'GO:0016049', ('297', '308'))	('apoptosis', 'biological_process', 'GO:0097194', ('209', '218'))	('PRPK', 'Gene', (37, 41))	('HCT116', 'CellLine', 'CVCL:0291', (55, 61))	('apoptosis', 'biological_process', 'GO:0006915', ('209', '218'))	('5-FU', 'Chemical', 'MESH:D005472', (253, 257))	('knockdown', 'Var', (42, 51))
11802	29483219	Computer modeling showed that FA fits into the ATP-binding pocket of PRPK and formed hydrogen bonds with Lys40, Ala45 or Lys60 and hydrophobic interactions with Val47/Val58 or Ile179/Ile182 of PRPK (Fig.	('fits', 'Disease', (33, 37))	('ATP', 'Chemical', 'MESH:D000255', (47, 50))	('Lys60', 'Chemical', '-', (121, 126))	('Ile179/Ile182', 'Var', (176, 189))	('formed', 'Reg', (78, 84))	('Ile179', 'Chemical', '-', (176, 182))	('Lys60', 'Var', (121, 126))	('Lys40', 'Chemical', '-', (105, 110))	('PRPK', 'Protein', (69, 73))	('hydrogen', 'Chemical', 'MESH:D006859', (85, 93))	('Lys40', 'Var', (105, 110))	('Ala45', 'Var', (112, 117))	('Val47/Val58', 'Var', (161, 172))	('Val47', 'Chemical', '-', (161, 166))	('Val58', 'Chemical', '-', (167, 172))	('PRPK', 'Protein', (193, 197))	('fits', 'Disease', 'MESH:D012640', (33, 37))	('hydrogen bonds', 'Interaction', (85, 99))	('hydrophobic', 'MPA', (131, 142))	('Ile182', 'Chemical', '-', (183, 189))	('Ala45', 'Chemical', '-', (112, 117))
11825	29483219	Results showed that p-survivin was dramatically decreased in lung tissues from groups treated with 5-FU or FA, as compared to the untreated group (Fig.	('5-FU', 'Chemical', 'MESH:D005472', (99, 103))	('survivin', 'Gene', '11799', (22, 30))	('decreased', 'NegReg', (48, 57))	('survivin', 'Gene', (22, 30))	('5-FU', 'Var', (99, 103))
11841	29483219	Next, we examined p-p53 or mutant p53 expression levels in the same tissue array with different tumor grades that we had used for the analysis of p-PRPK levels (Fig.	('p53', 'Gene', (34, 37))	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('p53', 'Gene', '7157', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('mutant', 'Var', (27, 33))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
11844	29483219	These results suggest that levels of mutated p53 are associated with colon cancer development in Stages I to II, but are not associated with colon metastasis (Stages III or IV).	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('colon metastasis', 'Disease', (141, 157))	('colon cancer', 'Disease', (69, 81))	('colon cancer', 'Disease', 'MESH:D015179', (69, 81))	('colon metastasis', 'Disease', 'MESH:D009362', (141, 157))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutated', 'Var', (37, 44))	('associated with', 'Reg', (53, 68))	('colon cancer', 'Phenotype', 'HP:0003003', (69, 81))
11853	29483219	The up-regulation of p53 activity suppresses cancer malignancy; however mutant p53 proteins not only lose their tumor suppressive activities, but often gain additional oncogenic functions.	('lose', 'NegReg', (101, 105))	('p53', 'Gene', (79, 82))	('proteins', 'Protein', (83, 91))	('p53', 'Gene', '7157', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('mutant', 'Var', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('p53', 'Gene', '7157', (21, 24))	('cancer malignancy', 'Disease', 'MESH:D009369', (45, 62))	('gain', 'PosReg', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer malignancy', 'Disease', (45, 62))	('oncogenic functions', 'CPA', (168, 187))	('tumor', 'Disease', (112, 117))	('p53', 'Gene', (21, 24))
11855	29483219	The cell lines HCT116 and DLD-1 express wild-type p53 and HCT15, HT-29 and WiDr cells express a mutant p53.	('mutant', 'Var', (96, 102))	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('HT-29', 'CellLine', 'CVCL:0320', (65, 70))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))	('HCT15', 'CellLine', 'CVCL:0292', (58, 63))	('HCT116', 'CellLine', 'CVCL:0291', (15, 21))
11862	29483219	For experiments, we used HCT116 cells, which express wild-type p53, and HCT15 cells, which express a mutant p53.	('HCT15', 'CellLine', 'CVCL:0292', (72, 77))	('p53', 'Gene', (63, 66))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('p53', 'Gene', '7157', (63, 66))	('HCT116', 'CellLine', 'CVCL:0291', (25, 31))	('mutant', 'Var', (101, 107))
11864	29483219	Knocking down PRPK expression prevented colorectal liver or lung metastasis of HCT116 and HCT15 colon cancer cells in vivo, and dramatically increased survival of mice.	('colorectal liver', 'Disease', (40, 56))	('HCT15', 'CellLine', 'CVCL:0292', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('prevented', 'NegReg', (30, 39))	('Knocking down', 'Var', (0, 13))	('increased', 'PosReg', (141, 150))	('survival', 'CPA', (151, 159))	('lung metastasis', 'CPA', (60, 75))	('colon cancer', 'Phenotype', 'HP:0003003', (96, 108))	('colon cancer', 'Disease', 'MESH:D015179', (96, 108))	('HCT116', 'CellLine', 'CVCL:0291', (79, 85))	('mice', 'Species', '10090', (163, 167))	('colon cancer', 'Disease', (96, 108))	('colorectal liver', 'Disease', 'MESH:D017093', (40, 56))	('PRPK', 'Gene', (14, 18))
11875	29483219	The phosphorylation of survivin at Thr34 is important for its therapeutic potential and its molecular mechanism of action.	('survivin', 'Gene', '11799', (23, 31))	('Thr34', 'Chemical', '-', (35, 40))	('Thr34', 'Var', (35, 40))	('survivin', 'Gene', (23, 31))	('phosphorylation', 'biological_process', 'GO:0016310', ('4', '19'))
11986	26511802	Sensitivity to 5-FU was defined as >= 20% reduction of ATP in 5-FU-treated cells compared with untreated controls, and resistance to 5-FU was defined as < 20% reduction in ATP.	('5-FU', 'Chemical', 'MESH:D005472', (133, 137))	('ATP', 'Chemical', 'MESH:D000255', (172, 175))	('5-FU', 'Chemical', 'MESH:D005472', (62, 66))	('ATP', 'Chemical', 'MESH:D000255', (55, 58))	('ATP', 'MPA', (55, 58))	('5-FU', 'Chemical', 'MESH:D005472', (15, 19))	('reduction', 'NegReg', (42, 51))	('5-FU-treated', 'Var', (62, 74))
11991	26511802	The rate of recurrence was higher in the 5-FU-resistant group, but without significance (p=0.053) (Table 1).	('5-FU', 'Chemical', 'MESH:D005472', (41, 45))	('5-FU-resistant', 'Var', (41, 55))	('higher', 'PosReg', (27, 33))
12007	26511802	Most of these studies focused on molecular characteristics of the primary tumor such as microsatellite instability (MSI), 18q deletions, mutations in KRAS and TP53, and thymidylate synthase gene expression.	('18q', 'Disease', (122, 125))	('thymidylate synthase', 'Gene', '7298', (169, 189))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('gene expression', 'biological_process', 'GO:0010467', ('190', '205'))	('TP53', 'Gene', '7157', (159, 163))	('mutations', 'Var', (137, 146))	('TP53', 'Gene', (159, 163))	('thymidylate synthase', 'Gene', (169, 189))	('tumor', 'Disease', (74, 79))	('KRAS', 'Gene', (150, 154))	('microsatellite', 'MPA', (88, 102))	('KRAS', 'Gene', '3845', (150, 154))
12031	26438061	Patients in the low-PNI group had a greater potential to have aggressive histological features, advanced tumors (T), nodal involvement (N), metastasis (M), and TNM stage than those in the high-PNI group.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('nodal', 'Gene', (117, 122))	('nodal', 'Gene', '4838', (117, 122))	('TNM', 'Gene', (160, 163))	('low-PNI', 'Var', (16, 23))	('Patients', 'Species', '9606', (0, 8))	('TNM', 'Gene', '10178', (160, 163))	('metastasis', 'CPA', (140, 150))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('aggressive histological features', 'CPA', (62, 94))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('men', 'Species', '9606', (130, 133))
12032	26438061	Furthermore, the PNI value was an independent prognostic factor for colorectal cancer in this study.	('colorectal cancer', 'Disease', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PNI value', 'Var', (17, 26))	('colorectal cancer', 'Disease', 'MESH:D015179', (68, 85))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('rectal cancer', 'Phenotype', 'HP:0100743', (72, 85))
12033	26438061	The OS was significantly lower in the low-PNI group than in the high-PNI group in patients with TNM stage II and III diseases.	('TNM', 'Gene', '10178', (96, 99))	('patients', 'Species', '9606', (82, 90))	('low-PNI', 'Var', (38, 45))	('lower', 'NegReg', (25, 30))	('TNM', 'Gene', (96, 99))	('III diseases', 'Disease', (113, 125))
12063	26438061	Older age (age >=60 years), larger tumor size, worse gross type, and poorly differentiated histological type were more frequently observed in the low-PNI group.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('low-PNI', 'Var', (146, 153))
12065	26438061	Moreover, patients in the low-PNI group were more likely to have advanced tumors (T), nodal involvement (N), metastasis (M), TNM stage, and Dukes stage.	('nodal', 'Gene', (86, 91))	('TNM', 'Gene', (125, 128))	('nodal', 'Gene', '4838', (86, 91))	('Dukes stage', 'CPA', (140, 151))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('TNM', 'Gene', '10178', (125, 128))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('metastasis', 'CPA', (109, 119))	('men', 'Species', '9606', (99, 102))	('patients', 'Species', '9606', (10, 18))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('low-PNI', 'Var', (26, 33))	('tumors', 'Disease', (74, 80))
12071	26438061	Multivariate analysis revealed that only the low PNI value (hazard ratio, 0.862; 95 % confidence interval, 0.527-0.932; P = 0.014), infiltrative gross type, advanced T stage, lymph node involvement, and distant metastasis were independent prognostic factors for adverse OS of colorectal cancer patients in this study.	('rectal cancer', 'Phenotype', 'HP:0100743', (280, 293))	('colorectal cancer', 'Disease', 'MESH:D015179', (276, 293))	('patients', 'Species', '9606', (294, 302))	('PNI value', 'MPA', (49, 58))	('men', 'Species', '9606', (193, 196))	('colorectal cancer', 'Phenotype', 'HP:0003003', (276, 293))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('colorectal cancer', 'Disease', (276, 293))	('low', 'Var', (45, 48))
12073	26438061	Low PNI was first found to be a predictor of a high risk of short-term postoperative complications in the gastrointestinal tract.	('gastrointestinal tract', 'Disease', (106, 128))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (106, 128))	('Low PNI', 'Var', (0, 7))
12074	26438061	Recently, increasing evidence revealed that low PNI was also related to reduced survival in various types of malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('reduced', 'NegReg', (72, 79))	('malignant tumors', 'Disease', (109, 125))	('malignant tumors', 'Disease', 'MESH:D018198', (109, 125))	('low', 'Var', (44, 47))	('PNI', 'MPA', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('survival', 'CPA', (80, 88))
12075	26438061	In this retrospective study, we demonstrated that low PNI was associated with older ages and aggressive clinicopathological features, which led to a worse overall survival for patients with colorectal cancer.	('PNI', 'MPA', (54, 57))	('patients', 'Species', '9606', (176, 184))	('rectal cancer', 'Phenotype', 'HP:0100743', (194, 207))	('low', 'Var', (50, 53))	('colorectal cancer', 'Disease', 'MESH:D015179', (190, 207))	('colorectal cancer', 'Phenotype', 'HP:0003003', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('colorectal cancer', 'Disease', (190, 207))
12080	26438061	However, for other kinds of malignant tumors, most studies usually set the cutoff value of PNI at 45, because PNI < 45 was regarded as malnutrition and was accompanied by a high risk of postoperative complications.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('malnutrition', 'Phenotype', 'HP:0004395', (135, 147))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('malignant tumors', 'Disease', 'MESH:D018198', (28, 44))	('PNI < 45', 'Var', (110, 118))	('malignant tumors', 'Disease', (28, 44))	('malnutrition', 'Disease', (135, 147))	('malnutrition', 'Disease', 'MESH:D044342', (135, 147))
12081	26438061	In our large cohort study, with the help of the ROC curve analysis for the 5-year overall survival of colorectal cancer patients, we found that the optimal cutoff point for PNI was 45, similar to the result of Mohri's study.	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('colorectal cancer', 'Disease', (102, 119))	('rectal cancer', 'Phenotype', 'HP:0100743', (106, 119))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('patients', 'Species', '9606', (120, 128))	('PNI', 'Var', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
12088	26438061	Our multivariate Cox analysis clearly demonstrated that PNI was an independent prognostic survival factor for patients with colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('rectal cancer', 'Phenotype', 'HP:0100743', (128, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('colorectal cancer', 'Disease', (124, 141))	('PNI', 'Var', (56, 59))	('patients', 'Species', '9606', (110, 118))	('colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))
12090	26438061	A similar result was found by Jiang et al., who found that when the cutoff value of PNI was set at 46, the 5-year survival rates were significantly lower in the low-PNI group among patients with stage II and III disease.	('lower', 'NegReg', (148, 153))	('patients', 'Species', '9606', (181, 189))	('low-PNI', 'Var', (161, 168))
12091	26438061	These results suggested that low PNI might be associated with a worse prognosis in patients with locally advanced cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('PNI', 'MPA', (33, 36))	('low', 'Var', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('patients', 'Species', '9606', (83, 91))	('cancer', 'Disease', (114, 120))
12114	26474403	The results of the phase III FIRE-3 study suggested cetuximab did not improve progression-free survival (PFS), but significantly improved response rate (RR) and overall survival (OS) in patients with K-RAS Exon 2 wild-type advanced colorectal cancer.	('colorectal cancer', 'Disease', (232, 249))	('cetuximab', 'Chemical', 'MESH:D000068818', (52, 61))	('OS', 'Chemical', '-', (179, 181))	('response rate', 'MPA', (138, 151))	('colorectal cancer', 'Disease', 'MESH:D015179', (232, 249))	('K-RAS', 'Gene', '3845', (200, 205))	('cetuximab', 'Var', (52, 61))	('colorectal cancer', 'Phenotype', 'HP:0003003', (232, 249))	('K-RAS', 'Gene', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('improved', 'PosReg', (129, 137))	('overall survival', 'CPA', (161, 177))	('patients', 'Species', '9606', (186, 194))
12197	26223867	Aberrant miR-106b expression has been reported in several cancers.	('miR-106b', 'Gene', '406900', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Aberrant', 'Var', (0, 8))	('reported', 'Reg', (38, 46))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('expression', 'MPA', (18, 28))	('miR-106b', 'Gene', (9, 17))	('cancers', 'Disease', (58, 65))
12205	26223867	Furthermore, survival analyses showed the patients with high mi-106b/low DLC1 had shorter overall survival (OS) and disease-free survival (DFS) rates, and confirmed miR-106b may be an independent prognostic factor for OS and DFS in CRC patients.	('disease-free survival', 'CPA', (116, 137))	('DLC1', 'Gene', '10395', (73, 77))	('CRC', 'Disease', (232, 235))	('overall survival', 'CPA', (90, 106))	('high mi-106b/low', 'Var', (56, 72))	('miR-106b', 'Gene', (165, 173))	('patients', 'Species', '9606', (236, 244))	('DLC1', 'Gene', (73, 77))	('CRC', 'Phenotype', 'HP:0003003', (232, 235))	('miR-106b', 'Gene', '406900', (165, 173))	('patients', 'Species', '9606', (42, 50))	('mi-106b/low', 'Var', (61, 72))	('shorter', 'NegReg', (82, 89))
12212	26223867	Furthermore, increasing numbers of miRNAs have been observed in various types of cancer and may be involved in modulating cancer cell behaviors.	('observed', 'Reg', (52, 60))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (122, 128))	('involved', 'Reg', (99, 107))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('modulating', 'Reg', (111, 121))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('miRNAs', 'Var', (35, 41))
12245	26223867	For luciferase reporter experiments, the wild-type and mutated 3'UTR of DLC1 mRNA were subcloned into the XhoI and NotI site of the psicheck-2 vector (Promega, Madison, WI, USA).	('mutated', 'Var', (55, 62))	('DLC1', 'Gene', '10395', (72, 76))	('DLC1', 'Gene', (72, 76))
12269	26223867	In contrast, miR-106b knockdown suppressed LoVo cell migration and invasion.	('invasion', 'CPA', (67, 75))	('miR-106b', 'Gene', '406900', (13, 21))	('knockdown', 'Var', (22, 31))	('LoVo', 'CellLine', 'CVCL:0399', (43, 47))	('LoVo cell migration', 'CPA', (43, 62))	('suppressed', 'NegReg', (32, 42))	('miR-106b', 'Gene', (13, 21))
12274	26223867	To confirm whether or not DLC-1 was a direct target of miR-106b, we inserted wild-type or mutant 3'UTR sequences immediately downstream of the luciferase reporter gene and co-expressed these with either miR-106b or anti-miR-106b in HEK293 cells.	('HEK293', 'CellLine', 'CVCL:0045', (232, 238))	('miR-106b', 'Gene', (203, 211))	('DLC-1', 'Gene', (26, 31))	('miR-106b', 'Gene', (220, 228))	('mutant', 'Var', (90, 96))	('miR-106b', 'Gene', (55, 63))	('miR-106b', 'Gene', '406900', (203, 211))	('miR-106b', 'Gene', '406900', (220, 228))	('miR-106b', 'Gene', '406900', (55, 63))	('DLC-1', 'Gene', '10395', (26, 31))
12276	26223867	In addition, mutation of the binding site of miR-106b in the 3'UTR of DLC-1 abolished both the effect of miR-106b and anti-miR-106b (Fig.	('miR-106b', 'Gene', (123, 131))	('miR-106b', 'Gene', '406900', (105, 113))	('DLC-1', 'Gene', '10395', (70, 75))	('miR-106b', 'Gene', '406900', (123, 131))	('mutation', 'Var', (13, 21))	('effect', 'MPA', (95, 101))	('miR-106b', 'Gene', (45, 53))	('abolished', 'NegReg', (76, 85))	('DLC-1', 'Gene', (70, 75))	('miR-106b', 'Gene', '406900', (45, 53))	('miR-106b', 'Gene', (105, 113))
12282	26223867	In agreement with the expression of target proteins, miR-106b mimics could augment the migratory and invasive ability of SW480 cells, and the decreased metastatic potential was also observed in DLC1-overexpressing cells compared with control cells (Fig.	('DLC1', 'Gene', (194, 198))	('miR-106b', 'Gene', '406900', (53, 61))	('metastatic potential', 'CPA', (152, 172))	('mimics', 'Var', (62, 68))	('decreased', 'NegReg', (142, 151))	('SW480', 'CellLine', 'CVCL:0546', (121, 126))	('DLC1', 'Gene', '10395', (194, 198))	('augment', 'PosReg', (75, 82))	('miR-106b', 'Gene', (53, 61))
12286	26223867	6a, DLC1 levels were lower in CRC tissues with lymph node metastasis compared with the lymph-node-negative primary CRC tissues (P < 0.05).	('DLC1', 'Gene', '10395', (4, 8))	('DLC1', 'Gene', (4, 8))	('lower', 'NegReg', (21, 26))	('lymph node metastasis', 'Var', (47, 68))	('CRC', 'Phenotype', 'HP:0003003', (115, 118))	('CRC', 'Phenotype', 'HP:0003003', (30, 33))
12291	26223867	The results showed that patients with high miR-106b expression had shorter overall survival (OS) and disease-free survival (DFS) than those with low miR-106b expression (P = 0.012 for OS, Fig.	('miR-106b', 'Gene', '406900', (149, 157))	('miR-106b', 'Gene', '406900', (43, 51))	('high', 'Var', (38, 42))	('disease-free survival', 'CPA', (101, 122))	('overall', 'MPA', (75, 82))	('shorter', 'NegReg', (67, 74))	('patients', 'Species', '9606', (24, 32))	('miR-106b', 'Gene', (149, 157))	('miR-106b', 'Gene', (43, 51))
12315	26223867	In a number of cancers, miRNAs regulate cell proliferation and metastasis by targeting deleted in liver cancer-1 (DLC1).	('liver cancer', 'Disease', (98, 110))	('metastasis', 'CPA', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('deleted', 'Var', (87, 94))	('cancers', 'Disease', (15, 22))	('regulate', 'Reg', (31, 39))	('DLC1', 'Gene', '10395', (114, 118))	('miR', 'Gene', '220972', (24, 27))	('miR', 'Gene', (24, 27))	('liver cancer', 'Phenotype', 'HP:0002896', (98, 110))	('cell proliferation', 'biological_process', 'GO:0008283', ('40', '58'))	('cell proliferation', 'CPA', (40, 58))	('DLC1', 'Gene', (114, 118))	('liver cancer', 'Disease', 'MESH:D006528', (98, 110))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
12325	26223867	This observation was confirmed by the fact that miR-106b overexpression diminished but miR-106b knockdown increased DLC1 mRNA and protein expression in CRC cells.	('knockdown', 'Var', (96, 105))	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('DLC1', 'Gene', (116, 120))	('miR-106b', 'Gene', (48, 56))	('miR-106b', 'Gene', (87, 95))	('miR-106b', 'Gene', '406900', (48, 56))	('CRC', 'Phenotype', 'HP:0003003', (152, 155))	('increased', 'PosReg', (106, 115))	('miR-106b', 'Gene', '406900', (87, 95))	('DLC1', 'Gene', '10395', (116, 120))
12328	26223867	A recent study reported that low DLC1 by itself did not have prognosis value in colon cancer patients, but there is a prognostic significance when low DLC1 was combined with low p15 or high Cdk6 in colon cancer patients.	('colon cancer', 'Disease', (80, 92))	('p15', 'Gene', '1030', (178, 181))	('low', 'Var', (147, 150))	('colon cancer', 'Disease', (198, 210))	('patients', 'Species', '9606', (93, 101))	('patients', 'Species', '9606', (211, 219))	('DLC1', 'Gene', '10395', (33, 37))	('DLC1', 'Gene', (33, 37))	('Cdk', 'molecular_function', 'GO:0004693', ('190', '193'))	('colon cancer', 'Phenotype', 'HP:0003003', (80, 92))	('DLC1', 'Gene', '10395', (151, 155))	('colon cancer', 'Phenotype', 'HP:0003003', (198, 210))	('DLC1', 'Gene', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('Cdk6', 'Gene', (190, 194))	('colon cancer', 'Disease', 'MESH:D015179', (80, 92))	('Cdk6', 'Gene', '1021', (190, 194))	('colon cancer', 'Disease', 'MESH:D015179', (198, 210))	('p15', 'Gene', (178, 181))	('high', 'Var', (185, 189))
12329	26223867	In line with these findings, we found that low DLC1 expression was not associated with OS in CRC patients.	('CRC', 'Disease', (93, 96))	('DLC1', 'Gene', (47, 51))	('low', 'Var', (43, 46))	('CRC', 'Phenotype', 'HP:0003003', (93, 96))	('expression', 'MPA', (52, 62))	('DLC1', 'Gene', '10395', (47, 51))	('patients', 'Species', '9606', (97, 105))
12335	26223867	In conclusion, this study demonstrates that miR-106b can significantly promote CRC cell migration and invasion by directly targeting DLC1, and revealed that high miR-106b expression could serve as an independent predictor of poor prognosis and recurrence in CRC patients.	('expression', 'MPA', (171, 181))	('miR-106b', 'Gene', '406900', (162, 170))	('promote', 'PosReg', (71, 78))	('miR-106b', 'Gene', '406900', (44, 52))	('patients', 'Species', '9606', (262, 270))	('CRC', 'Phenotype', 'HP:0003003', (258, 261))	('DLC1', 'Gene', (133, 137))	('CRC', 'Phenotype', 'HP:0003003', (79, 82))	('targeting', 'Reg', (123, 132))	('invasion', 'CPA', (102, 110))	('high', 'Var', (157, 161))	('miR-106b', 'Gene', (162, 170))	('CRC cell migration', 'CPA', (79, 97))	('miR-106b', 'Gene', (44, 52))	('CRC', 'Disease', (258, 261))	('DLC1', 'Gene', '10395', (133, 137))
12349	33028024	Alterations in the gut microbiota and its metabolites due to a diet that is poor in fiber can lead to dysfunction of the gut's epithelial barrier, production of pro-inflammatory cytokines (i.e., Interleukin 6 (IL6), Tumour Necrosis Factor alpha (TNF-alpha), Interleukin beta (IL1beta)), and increase of the gut's permeability.	("gut's permeability", 'CPA', (307, 325))	('IL6', 'Gene', '3569', (210, 213))	('Interleukin 6', 'Gene', '3569', (195, 208))	('production', 'MPA', (147, 157))	('Alterations', 'Var', (0, 11))	('Tumour Necrosis Factor', 'Disease', 'MESH:D009336', (216, 238))	('IL6', 'Gene', (210, 213))	('pro-inflammatory cytokines', 'MPA', (161, 187))	('TNF-alpha', 'Gene', '7124', (246, 255))	('IL1beta', 'Gene', (276, 283))	('dysfunction', 'CPA', (102, 113))	('increase', 'PosReg', (291, 299))	('Interleukin 6', 'Gene', (195, 208))	('Tumour Necrosis Factor', 'Disease', (216, 238))	('Tumour', 'Phenotype', 'HP:0002664', (216, 222))	('IL1beta', 'Gene', '3552', (276, 283))	('TNF-alpha', 'Gene', (246, 255))
12351	33028024	In animal models, a chronic or intermittent fiber deficiency leads to dysbiosis with erosion of the mucus layer and barrier dysfunctions that cannot be prevented by adding purified prebiotic fibers (e.g., inulin, arabinoxylan, beta-glucan).	('leads to', 'Reg', (61, 69))	('dysbiosis', 'Disease', (70, 79))	('dysbiosis', 'Disease', 'MESH:D064806', (70, 79))	('beta-glucan', 'Chemical', 'MESH:D047071', (227, 238))	('mucus layer', 'cellular_component', 'GO:0070701', ('100', '111'))	('deficiency', 'Var', (50, 60))
12361	33028024	Enrichment of Fusobacterium nucleatum has been observed to induce immunosuppressive activity mediated by the inhibition of T cells in colorectal carcinogenesis.	('Fusobacterium nucleatum', 'Species', '851', (14, 37))	('Fusobacterium nucleatum', 'Var', (14, 37))	('T cells', 'CPA', (123, 130))	('induce', 'PosReg', (59, 65))	('immunosuppressive activity', 'CPA', (66, 92))	('inhibition', 'NegReg', (109, 119))	('colorectal carcinogenesis', 'Disease', (134, 159))	('colorectal carcinogenesis', 'Disease', 'MESH:D015179', (134, 159))	('men', 'Species', '9606', (6, 9))
12387	33028024	Polycyclic aromatic hydrocarbons (PAHs), which are related with tobacco carcinogens, are responsible for the appearance of an increased risk of developing ACP, especially when they are in a high concentration.	('tobacco', 'Species', '4097', (64, 71))	('PAHs', 'Chemical', 'MESH:D011084', (34, 38))	('Polycyclic', 'Var', (0, 10))	('ACP', 'Gene', (155, 158))	('ACP', 'Gene', '60502', (155, 158))	('Polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (0, 32))
12456	33028024	The onset trigger of this sequence of "adenoma-carcinoma" is believed to be the inactivation of the adenomatous polyposis (APC) gene.	('adenoma-carcinoma', 'Disease', (39, 56))	('adenomatous polyposis', 'Disease', (100, 121))	('APC', 'Disease', 'MESH:D011125', (123, 126))	('APC', 'Disease', (123, 126))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (100, 121))	('adenomatous polyposis', 'Disease', 'MESH:D011125', (100, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('adenomatous polyp', 'Phenotype', 'HP:0005227', (100, 117))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (39, 56))	('inactivation', 'Var', (80, 92))
12458	33028024	The most frequent genetic variation in colorectal cancer was determined to be a mutation in the APC gene, with more than 3000 pathological mutations discovered so far.	('frequent', 'Reg', (9, 17))	('rectal cancer', 'Phenotype', 'HP:0100743', (43, 56))	('APC', 'Disease', 'MESH:D011125', (96, 99))	('colorectal cancer', 'Disease', 'MESH:D015179', (39, 56))	('APC', 'cellular_component', 'GO:0005680', ('96', '99'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (39, 56))	('APC', 'Disease', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutation', 'Var', (80, 88))	('colorectal cancer', 'Disease', (39, 56))
12459	33028024	Most of the mutations are identified within a cluster region (MCR (mobilized colistin resistance), codons 1286-1513), often giving rise to a truncated APC protein.	('giving rise to', 'Reg', (124, 138))	('mutations', 'Var', (12, 21))	('APC', 'Disease', 'MESH:D011125', (151, 154))	('APC', 'Disease', (151, 154))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('truncated', 'MPA', (141, 150))	('codons 1286-1513', 'Var', (99, 115))	('APC', 'cellular_component', 'GO:0005680', ('151', '154'))
12465	33028024	Furthermore, intrapartum antibiotic exposure leads to different gut colonization when compared with postnatal treatment, and the observed impact remains stable up to 6 months of age even when lactobacilli supplementation was implemented.	('gut colonization', 'CPA', (64, 80))	('men', 'Species', '9606', (230, 233))	('men', 'Species', '9606', (115, 118))	('men', 'Species', '9606', (211, 214))	('antibiotic', 'Var', (25, 35))
12469	33028024	It has been studied that the change in some gut bacteria can be determined by mutations of the host's genes, with these changes further promoting the development of pathologies.	('development of pathologies', 'CPA', (150, 176))	('died', 'Disease', 'MESH:D003643', (15, 19))	('mutations', 'Var', (78, 87))	('died', 'Disease', (15, 19))	('promoting', 'PosReg', (136, 145))	('men', 'Species', '9606', (157, 160))
12473	33028024	The relationship between the change of gut microbiota and the inactivation of APC mutations has been studied, showing that their association could potentially explain the role of gut microbiome in the transformation of APC mutant adenomatous polyps to CRC.	('mutant', 'Var', (223, 229))	('APC', 'Disease', 'MESH:D011125', (78, 81))	('adenomatous polyps', 'Disease', (230, 248))	('adenomatous polyp', 'Phenotype', 'HP:0005227', (230, 247))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (230, 248))	('APC', 'Disease', (78, 81))	('APC', 'Disease', 'MESH:D011125', (219, 222))	('adenomatous polyps', 'Disease', 'MESH:D018256', (230, 248))	('CRC', 'Phenotype', 'HP:0003003', (252, 255))	('APC', 'Disease', (219, 222))	('gut microbiome', 'Species', '749906', (179, 193))	('died', 'Disease', (104, 108))	('died', 'Disease', 'MESH:D003643', (104, 108))
12474	33028024	It has been demonstrated through these studies that lower levels of Faecalibacterium prausnitzii, Bifidobacterium pseudocatenulatum, and Ruminococcus sp 5 were found in patients with APC mutations.	('patients', 'Species', '9606', (169, 177))	('Bifidobacterium pseudocatenulatum', 'MPA', (98, 131))	('Ruminococcus sp 5', 'Species', '169436', (137, 154))	('lower', 'NegReg', (52, 57))	('Faecalibacterium prausnitzii', 'Species', '853', (68, 96))	('mutations', 'Var', (187, 196))	('APC', 'Disease', 'MESH:D011125', (183, 186))	('Bifidobacterium pseudocatenulatum', 'Species', '28026', (98, 131))	('APC', 'Disease', (183, 186))
12477	33028024	Different studies have documented that an alteration of SCFAs in gut composition has also been associated with colorectal cancer, among other pathologies.	('rectal cancer', 'Phenotype', 'HP:0100743', (115, 128))	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('SCFAs', 'Chemical', 'MESH:D005232', (56, 61))	('alteration', 'Var', (42, 52))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal cancer', 'Disease', (111, 128))	('associated', 'Reg', (95, 105))	('men', 'Species', '9606', (27, 30))
12480	33028024	However, iso-butyric, valeric, and iso-valeric acids are also present in lower amounts.	('iso-valeric', 'Var', (35, 46))	('valeric', 'MPA', (22, 29))	('iso-butyric, valeric, and iso-valeric acids', 'Chemical', '-', (9, 52))
12557	30694563	For analyses by tumour site, cancers were assigned to the following groups: colon, ICD-10 C18.0-18.9; colon right (proximal), C18.0 caecum to C18.4 transverse colon; colon left (distal), C18.5 splenic flexure to C18.7 sigmoid colon; rectum, C19-C20.	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('sigmoid colon', 'Disease', (218, 231))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('tumour', 'Disease', (16, 22))	('colon right', 'Disease', 'MESH:D015179', (102, 113))	('cancers', 'Disease', 'MESH:D009369', (29, 36))	('C18.0', 'Var', (126, 131))	('colon left', 'Disease', (166, 176))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancers', 'Disease', (29, 36))	('colon left', 'Disease', 'MESH:D015179', (166, 176))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('colon right', 'Disease', (102, 113))	('sigmoid colon', 'Disease', 'MESH:D012811', (218, 231))
12558	30694563	For analyses by morphological type, cancers were divided into 6 groups based on the WHO/IARC classification12 (Supporting Information Table SS1): (1) adenocarcinoma, ICD-O code M8140/3 (and 12 related codes); (2) mucinous adenocarcinoma, ICD-O M8480/3 (and 3 related codes); (3) signet ring cell carcinoma, ICD-O code M8490/3; (4) neuroendocrine tumours, including carcinoid, ICD-O codes M8246/3, M8240/3, M8243/3 and 6 related codes; (5) squamous cell, ICD-O code M8070/3 (and 2 related codes); and (6) other tumours: all remaining tumours, including other specified carcinoma, specified non-carcinoma tumours, and cancers of unspecified morphology.	('adenocarcinoma', 'Disease', (150, 164))	('carcinoma', 'Disease', (296, 305))	('tumours', 'Disease', (510, 517))	('tumours', 'Phenotype', 'HP:0002664', (346, 353))	('M8243/3', 'Var', (406, 413))	('tumours', 'Disease', 'MESH:D009369', (346, 353))	('tumours', 'Phenotype', 'HP:0002664', (510, 517))	('carcinoma', 'Disease', 'MESH:D002277', (227, 236))	('carcinoma', 'Disease', 'MESH:D002277', (155, 164))	('carcinoma', 'Disease', 'MESH:D002277', (568, 577))	('tumours', 'Disease', (533, 540))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('tumours', 'Disease', 'MESH:D009369', (510, 517))	('specified', 'Disease', (579, 588))	('cancers', 'Disease', 'MESH:D009369', (616, 623))	('adenocarcinoma', 'Disease', 'MESH:D000230', (222, 236))	('adenocarcinoma', 'Disease', 'MESH:D000230', (150, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (593, 602))	('M8240/3', 'Var', (397, 404))	('carcinoma', 'Disease', (593, 602))	('tumours', 'Phenotype', 'HP:0002664', (533, 540))	('tumours', 'Disease', 'MESH:D009369', (533, 540))	('carcinoma', 'Disease', 'MESH:D002277', (296, 305))	('tumour', 'Phenotype', 'HP:0002664', (510, 516))	('neuroendocrine tumours', 'Disease', 'MESH:D018358', (331, 353))	('neuroendocrine tumours', 'Disease', (331, 353))	('tumours', 'Disease', (603, 610))	('non-carcinoma tumours', 'Disease', (589, 610))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (213, 236))	('carcinoid', 'Phenotype', 'HP:0100570', (365, 374))	('tumour', 'Phenotype', 'HP:0002664', (533, 539))	('tumour', 'Phenotype', 'HP:0002664', (603, 609))	('unspecified', 'Species', '32644', (627, 638))	('tumours', 'Phenotype', 'HP:0002664', (603, 610))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('cancers', 'Phenotype', 'HP:0002664', (616, 623))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('non-carcinoma tumours', 'Disease', 'MESH:D009369', (589, 610))	('cancers', 'Disease', (616, 623))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('carcinoma', 'Disease', (227, 236))	('mucinous adenocarcinoma', 'Disease', (213, 236))	('tumours', 'Disease', 'MESH:D009369', (603, 610))	('cancers', 'Disease', (36, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (568, 577))	('carcinoma', 'Disease', 'MESH:D002277', (593, 602))	('carcinoma', 'Disease', (155, 164))	('carcinoma', 'Disease', (568, 577))	('cancer', 'Phenotype', 'HP:0002664', (616, 622))	('tumours', 'Disease', (346, 353))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumour', 'Phenotype', 'HP:0002664', (346, 352))	('adenocarcinoma', 'Disease', (222, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))
12622	29967641	Functionally, MUC2 inhibits the intestinal inflammatory response, thus suppressing the development of intestinal tumors.	('tumors', 'Disease', (113, 119))	('MUC2', 'Var', (14, 18))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('intestinal tumors', 'Disease', (102, 119))	('intestinal tumors', 'Disease', 'MESH:D007414', (102, 119))	('intestinal inflammatory response', 'CPA', (32, 64))	('inhibits', 'NegReg', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('suppressing', 'NegReg', (71, 82))
12630	29967641	found that the loss of MUC2 in CRC tissues was an adverse prognostic factor for survival in mismatch-repair- (MMR-) proficient and MLH1-negative CRC.	('MUC2', 'Protein', (23, 27))	('CRC', 'Phenotype', 'HP:0003003', (145, 148))	('CRC', 'Phenotype', 'HP:0003003', (31, 34))	('loss', 'Var', (15, 19))	('MLH1', 'Gene', '4292', (131, 135))	('MLH1', 'Gene', (131, 135))	('CRC', 'Disease', (145, 148))
12634	29754471	HT29, HCT116, SW480 and SW620) and normal colorectal mucosa cell line (NCM460) were also purchased.	('SW480', 'Var', (14, 19))	('colorectal mucosa', 'Disease', 'MESH:D015179', (42, 59))	('SW480', 'CellLine', 'CVCL:0546', (14, 19))	('SW620', 'Var', (24, 29))	('SW620', 'CellLine', 'CVCL:0547', (24, 29))	('HCT116', 'CellLine', 'CVCL:0291', (6, 12))	('colorectal mucosa', 'Disease', (42, 59))	('HT29', 'CellLine', 'CVCL:0320', (0, 4))
12635	29754471	Si-H19, si-NC, miR-29b-3p mimics, miR-29b-3p inhibitor, si-PGRN and negative control (NC) were, respectively, transfected into the CRC cells.	('Si-H19', 'Var', (0, 6))	('miR-29b', 'Gene', (15, 22))	('PGRN', 'Gene', '2896', (59, 63))	('si', 'Chemical', 'MESH:D012825', (8, 10))	('miR-29b', 'Gene', '407024', (34, 41))	('PGRN', 'Gene', (59, 63))	('miR-29b', 'Gene', '407024', (15, 22))	('miR-29b', 'Gene', (34, 41))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('si-NC', 'Var', (8, 13))
12639	29754471	Besides, transfection with si-H19, miR-29b-3p mimic or si-PGRN were correlated with elevated E-cadherin expression, decreased snail and vimentin expressions, as well as less-motivated cell proliferation and cell metastasis (P < 0.05).	('si', 'Chemical', 'MESH:D012825', (2, 4))	('elevated', 'PosReg', (84, 92))	('snail', 'Gene', (126, 131))	('E-cadherin', 'Gene', (93, 103))	('E-cadherin', 'Gene', '999', (93, 103))	('expression', 'MPA', (104, 114))	('vimentin', 'Gene', '7431', (136, 144))	('si', 'Chemical', 'MESH:D012825', (151, 153))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('vimentin', 'Gene', (136, 144))	('miR-29b', 'Gene', '407024', (35, 42))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('PGRN', 'Gene', '2896', (58, 62))	('cell metastasis', 'CPA', (207, 222))	('less-motivated cell proliferation', 'CPA', (169, 202))	('si', 'Chemical', 'MESH:D012825', (219, 221))	('decreased', 'NegReg', (116, 125))	('snail', 'Gene', '6615', (126, 131))	('miR-29b', 'Gene', (35, 42))	('PGRN', 'Gene', (58, 62))	('si-H19', 'Var', (27, 33))	('si', 'Chemical', 'MESH:D012825', (27, 29))
12641	29754471	Finally, addition of LiCl (Wnt/beta-catenin pathway activator) or XAV93920 (Wnt/beta-catenin pathway inhibitor) would cause remarkably altered E-cadherin, c-Myc, vimentin and snail expressions, as well as significantly changed transcriptional activity of beta-catenin/Tcf reporter plasmid (P < 0.05).	('beta-catenin', 'Gene', (255, 267))	('c-Myc', 'Gene', '4609', (155, 160))	('beta-catenin', 'Gene', '1499', (255, 267))	('vimentin', 'Gene', '7431', (162, 170))	('vimentin', 'Gene', (162, 170))	('vimentin', 'cellular_component', 'GO:0045099', ('162', '170'))	('XAV93920', 'Var', (66, 74))	('beta-catenin', 'Gene', (31, 43))	('LiCl', 'Chemical', 'MESH:D018021', (21, 25))	('beta-catenin', 'Gene', '1499', (31, 43))	('expressions', 'MPA', (181, 192))	('transcriptional activity', 'MPA', (227, 251))	('beta-catenin', 'Gene', (80, 92))	('altered', 'Reg', (135, 142))	('beta-catenin', 'Gene', '1499', (80, 92))	('Tcf', 'Gene', '3172', (268, 271))	('Tcf', 'Gene', (268, 271))	('snail', 'Gene', '6615', (175, 180))	('si', 'Chemical', 'MESH:D012825', (205, 207))	('cadherin', 'molecular_function', 'GO:0008014', ('145', '153'))	('vimentin', 'cellular_component', 'GO:0045098', ('162', '170'))	('LiCl', 'Var', (21, 25))	('si', 'Chemical', 'MESH:D012825', (187, 189))	('c-Myc', 'Gene', (155, 160))	('snail', 'Gene', (175, 180))	('E-cadherin', 'Gene', (143, 153))	('E-cadherin', 'Gene', '999', (143, 153))	('changed', 'Reg', (219, 226))
12650	29754471	rs2839698) was demonstrated to elevate susceptibility to CRC among a Chinese population.	('elevate', 'PosReg', (31, 38))	('rs2839698', 'Var', (0, 9))	('susceptibility', 'MPA', (39, 53))	('rs2839698', 'Mutation', 'rs2839698', (0, 9))	('CRC', 'Disease', (57, 60))
12653	29754471	For example, H19 negatively modifying tenogenic differentiation was achieved by direct target of miR-29b-3p and then suppression of TGF-beta1 and COL1A1 expressions.	('suppression', 'NegReg', (117, 128))	('H19', 'Var', (13, 16))	('si', 'Chemical', 'MESH:D012825', (159, 161))	('COL1A1', 'Gene', (146, 152))	('COL1A1', 'Gene', '1277', (146, 152))	('miR-29b', 'Gene', '407024', (97, 104))	('TGF-beta1', 'Gene', '7040', (132, 141))	('TGF-beta1', 'Gene', (132, 141))	('negatively', 'NegReg', (17, 27))	('expressions', 'MPA', (153, 164))	('modifying', 'Reg', (28, 37))	('si', 'Chemical', 'MESH:D012825', (124, 126))	('tenogenic differentiation', 'CPA', (38, 63))	('miR-29b', 'Gene', (97, 104))
12656	29754471	Besides, microRNA-29b could contribute to suppressed angiogenesis, invasion, and metastasis of hepatocellular carcinoma by targeting matrix metalloproteinase-2 (MMP-2).	('si', 'Chemical', 'MESH:D012825', (2, 4))	('matrix metalloproteinase-2', 'Gene', '4313', (133, 159))	('invasion', 'CPA', (67, 75))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('targeting', 'Reg', (123, 132))	('angiogenesis', 'biological_process', 'GO:0001525', ('53', '65'))	('MMP-2', 'Gene', '4313', (161, 166))	('microRNA-29b', 'Var', (9, 21))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('metastasis of hepatocellular carcinoma', 'Disease', (81, 119))	('si', 'Chemical', 'MESH:D012825', (62, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('MMP-2', 'molecular_function', 'GO:0004228', ('161', '166'))	('matrix metalloproteinase-2', 'Gene', (133, 159))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (95, 119))	('MMP-2', 'Gene', (161, 166))	('angiogenesis', 'CPA', (53, 65))	('suppressed', 'NegReg', (42, 52))	('metastasis of hepatocellular carcinoma', 'Disease', 'MESH:D009362', (81, 119))
12668	29754471	However, miR-29b-3p expression within HT29, HCT116, SW480 and SW620 was significantly lower than that within NCM460 (P < 0.05) (Fig.	('miR-29b', 'Gene', (9, 16))	('HCT116', 'CellLine', 'CVCL:0291', (44, 50))	('SW480', 'Var', (52, 57))	('expression', 'MPA', (20, 30))	('lower', 'NegReg', (86, 91))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('SW480', 'CellLine', 'CVCL:0546', (52, 57))	('miR-29b', 'Gene', '407024', (9, 16))	('SW620', 'CellLine', 'CVCL:0547', (62, 67))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('SW620', 'Var', (62, 67))	('HT29', 'CellLine', 'CVCL:0320', (38, 42))
12674	29754471	Besides, the regression analysis demonstrated that high H19 expression, low miR-29b-3p expression, poor differentiation, T3 + T4 stage and M1 distant cell presented high correlations with poor prognosis of CRC patients (P < 0.05) (Table 2).	('expression', 'MPA', (60, 70))	('miR-29b', 'Gene', (76, 83))	('si', 'Chemical', 'MESH:D012825', (29, 31))	('si', 'Chemical', 'MESH:D012825', (93, 95))	('si', 'Chemical', 'MESH:D012825', (2, 4))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('miR-29b', 'Gene', '407024', (76, 83))	('CRC', 'Disease', (206, 209))	('high', 'Var', (51, 55))	('patients', 'Species', '9606', (210, 218))	('si', 'Chemical', 'MESH:D012825', (199, 201))	('H19', 'Protein', (56, 59))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('low', 'NegReg', (72, 75))
12675	29754471	Additionally, Kaplan Meier analysis displayed that the overall survival (OS) rate of patients with under-expressed H19 and over-expressed miR-29b-3p performed far better than that of ones with over-expressed H19 and under-expressed miR-29b-3p (P < 0.05) (Fig.	('miR-29b', 'Gene', (232, 239))	('overall survival', 'MPA', (55, 71))	('miR-29b', 'Gene', '407024', (138, 145))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('miR-29b', 'Gene', '407024', (232, 239))	('patients', 'Species', '9606', (85, 93))	('H19', 'Var', (115, 118))	('better', 'PosReg', (163, 169))	('miR-29b', 'Gene', (138, 145))	('under-expressed H19', 'Var', (99, 118))
12677	29754471	The expression level of E-cadherin hiked, and Snail and Vimentin expressions fell off visibly in the si-H19 group, when compared with si-NC group (P < 0.05).	('expression level', 'MPA', (4, 20))	('Vimentin', 'Gene', (56, 64))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('si', 'Chemical', 'MESH:D012825', (134, 136))	('si-H19', 'Var', (101, 107))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('Vimentin', 'Gene', '7431', (56, 64))	('hiked', 'PosReg', (35, 40))	('expressions', 'MPA', (65, 76))	('E-cadherin', 'Gene', (24, 34))	('Snail', 'Gene', '6615', (46, 51))	('Snail', 'Gene', (46, 51))	('E-cadherin', 'Gene', '999', (24, 34))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('fell off', 'NegReg', (77, 85))
12679	29754471	Meanwhile, the MTT results went as that the cell viability of si-H19 group and miR-29b-3p mimic group declined evidently in comparison to the control group (P < 0.05).	('miR-29b', 'Gene', '407024', (79, 86))	('declined', 'NegReg', (102, 110))	('miR-29b', 'Gene', (79, 86))	('si-H19', 'Var', (62, 68))	('si', 'Chemical', 'MESH:D012825', (62, 64))	('MTT', 'Chemical', 'MESH:C070243', (15, 18))	('cell viability', 'CPA', (44, 58))
12681	29754471	Furthermore, the Transwell assay results indicated that the number of trans-membrane cells in the si-H19 group or in the miR-29b-3p mimic group was reduced remarkably (P < 0.05), whereas the number of trans-membrane cells in the miR-29b-3p inhibitor group picked up enormously than that in the control group (P < 0.05) (Fig.	('miR-29b', 'Gene', (229, 236))	('reduced', 'NegReg', (148, 155))	('miR-29b', 'Gene', '407024', (121, 128))	('miR-29b', 'Gene', '407024', (229, 236))	('si-H19', 'Var', (98, 104))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('miR-29b', 'Gene', (121, 128))
12684	29754471	In addition, the luciferase activity of H19 Wt+miR-29b-3p mimics group declined more notably than that of control group (P < 0.05).	('activity', 'MPA', (28, 36))	('miR-29b', 'Gene', (47, 54))	('declined', 'NegReg', (71, 79))	('luciferase', 'Enzyme', (17, 27))	('H19', 'Var', (40, 43))	('miR-29b', 'Gene', '407024', (47, 54))
12686	29754471	Moreover, qRT-PCR results demonstrated that addition of si-H19 could evidently increase the expression of miR-29b-3p (P < 0.05), but there was little change of H19 expression when miR-29b-3p expression was modified (P > 0.05) (Figs.	('increase', 'PosReg', (79, 87))	('si-H19', 'Var', (56, 62))	('si', 'Chemical', 'MESH:D012825', (170, 172))	('si', 'Chemical', 'MESH:D012825', (197, 199))	('miR-29b', 'Gene', (106, 113))	('miR-29b', 'Gene', '407024', (180, 187))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('miR-29b', 'Gene', '407024', (106, 113))	('miR-29b', 'Gene', (180, 187))	('expression', 'MPA', (92, 102))
12687	29754471	Silencing of miR-29b-3p fostered highly-expressed PGRN (P < 0.05), and the up-regulated miR-29b-3p expressions led to lowly-expressed PGRN (P < 0.05) (Fig.	('PGRN', 'Gene', (50, 54))	('PGRN', 'Gene', '2896', (134, 138))	('fostered highly-expressed', 'PosReg', (24, 49))	('miR-29b', 'Gene', (13, 20))	('miR-29b', 'Gene', (88, 95))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('PGRN', 'Gene', (134, 138))	('up-regulated', 'PosReg', (75, 87))	('miR-29b', 'Gene', '407024', (88, 95))	('PGRN', 'Gene', '2896', (50, 54))	('Silencing', 'Var', (0, 9))	('miR-29b', 'Gene', '407024', (13, 20))
12696	29754471	However, in comparison to H19 group, greatly reduced E-cadherin expression, accompanied with evidently elevated c-Myc, vimentin and Snail expressions were observed in the H19+XAV93920 and PGRN+XAV93920 groups (P < 0.05).	('si', 'Chemical', 'MESH:D012825', (70, 72))	('H19+XAV93920', 'Var', (171, 183))	('reduced', 'NegReg', (45, 52))	('E-cadherin', 'Gene', (53, 63))	('E-cadherin', 'Gene', '999', (53, 63))	('PGRN', 'Gene', (188, 192))	('c-Myc', 'Gene', '4609', (112, 117))	('si', 'Chemical', 'MESH:D012825', (144, 146))	('vimentin', 'Gene', '7431', (119, 127))	('c-Myc', 'Gene', (112, 117))	('vimentin', 'Gene', (119, 127))	('elevated', 'PosReg', (103, 111))	('Snail', 'Gene', '6615', (132, 137))	('Snail', 'Gene', (132, 137))	('PGRN', 'Gene', '2896', (188, 192))
12698	29754471	Correspondingly, the E-cadherin expressions of H19+LiCl and PGRN+XAV93920 groups were both on the rise in comparison to H19 group, while their c-Myc, vimentin and Snail expressions lessened terribly (P < 0.05).	('E-cadherin', 'Gene', (21, 31))	('E-cadherin', 'Gene', '999', (21, 31))	('PGRN', 'Gene', '2896', (60, 64))	('cadherin', 'molecular_function', 'GO:0008014', ('23', '31'))	('rise', 'PosReg', (98, 102))	('Snail', 'Gene', (163, 168))	('vimentin', 'cellular_component', 'GO:0045099', ('150', '158'))	('si', 'Chemical', 'MESH:D012825', (38, 40))	('si', 'Chemical', 'MESH:D012825', (175, 177))	('PGRN', 'Gene', (60, 64))	('c-Myc', 'Gene', (143, 148))	('LiCl', 'Chemical', 'MESH:D018021', (51, 55))	('H19+LiCl', 'Var', (47, 55))	('vimentin', 'Gene', '7431', (150, 158))	('c-Myc', 'Gene', '4609', (143, 148))	('Snail', 'Gene', '6615', (163, 168))	('vimentin', 'Gene', (150, 158))	('lessened', 'NegReg', (181, 189))	('vimentin', 'cellular_component', 'GO:0045098', ('150', '158'))
12721	29754471	More than that, interdiction of Wnt/beta-catenin pathway was accompanied by inhibited cell proliferation, promoted cell apoptosis and boosted EMT within pancreatic cancer animal models.	('interdiction', 'Var', (16, 28))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (153, 170))	('EMT within pancreatic cancer', 'Disease', (142, 170))	('EMT within pancreatic cancer', 'Disease', 'MESH:D001929', (142, 170))	('promoted', 'PosReg', (106, 114))	('si', 'Chemical', 'MESH:D012825', (126, 128))	('beta-catenin', 'Gene', (36, 48))	('cell proliferation', 'CPA', (86, 104))	('cell apoptosis', 'CPA', (115, 129))	('boosted', 'PosReg', (134, 141))	('inhibited', 'NegReg', (76, 85))	('beta-catenin', 'Gene', '1499', (36, 48))
12765	29754471	Next, miR-29b-3p mimics and miR-NC were, respectively, transfected into HT29 and SW480 cells that have been transfected with H19 Wt, H19 Mut, PGRN Wt, PGRN Mut and psiCHECK2.	('HT29', 'CellLine', 'CVCL:0320', (72, 76))	('PGRN', 'Gene', '2896', (151, 155))	('H19 Mut', 'Var', (133, 140))	('PGRN', 'Gene', (151, 155))	('PGRN', 'Gene', '2896', (142, 146))	('miR', 'Gene', (6, 9))	('miR', 'Gene', '220972', (6, 9))	('miR-29b', 'Gene', (6, 13))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))	('PGRN', 'Gene', (142, 146))	('si', 'Chemical', 'MESH:D012825', (165, 167))	('miR-29b', 'Gene', '407024', (6, 13))	('SW480', 'CellLine', 'CVCL:0546', (81, 86))
12768	29682198	Blood free-circulating DNA testing by highly sensitive methylation assay to diagnose colorectal neoplasias Although methylated TWIST1 is a biomarker of colorectal neoplasia, its detection from serum samples is very difficult by conventional bisulfite-based methylation assays.	('TWIST1', 'Gene', (127, 133))	('TWIST1', 'Gene', '7291', (127, 133))	('colorectal neoplasia', 'Disease', (152, 172))	('neoplasia', 'Phenotype', 'HP:0002664', (96, 105))	('neoplasias', 'Phenotype', 'HP:0002664', (96, 106))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (152, 172))	('colorectal neoplasias', 'Disease', 'MESH:D009369', (85, 106))	('colorectal neoplasias', 'Disease', (85, 106))	('neoplasia', 'Phenotype', 'HP:0002664', (163, 172))	('bisulfite', 'Chemical', 'MESH:C042345', (241, 250))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (85, 105))	('methylated', 'Var', (116, 126))
12780	29682198	The main approach to CRC screening throughout the world is the fecal immunochemical test for hemoglobin (FIT), and patients with fecal hemoglobin >20 mug hemoglobin/g feces (equivalent to a 100 ng/mL cutoff of hemoglobin in sample buffer) are referred for colonoscopy.	('CRC', 'Phenotype', 'HP:0003003', (21, 24))	('patients', 'Species', '9606', (115, 123))	('colonoscopy', 'Disease', (256, 267))	('mug', 'molecular_function', 'GO:0043739', ('150', '153'))	('CRC', 'Disease', (21, 24))	('>20', 'Var', (146, 149))
12786	29682198	In addition, as we were the first in the world to report that methylated TWIST1 is a biomarker of colorectal neoplasias, we evaluated the clinical performance of the serum CORD assay, targeting methylated TWIST1 in combination with and without FIT for the detection of colorectal neoplasia from serum samples, and compared clinical performance between TWIST1 and SEPT9 (a marker of the Epi proColon).	('neoplasias', 'Phenotype', 'HP:0002664', (109, 119))	('SEPT9', 'Gene', (363, 368))	('TWIST1', 'Gene', (73, 79))	('neoplasia', 'Phenotype', 'HP:0002664', (280, 289))	('TWIST1', 'Gene', '7291', (352, 358))	('man', 'Species', '9606', (153, 156))	('colorectal neoplasias', 'Disease', 'MESH:D009369', (98, 119))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (269, 289))	('methylated', 'Var', (62, 72))	('TWIST1', 'Gene', '7291', (73, 79))	('TWIST1', 'Gene', (205, 211))	('SEPT9', 'Gene', '10801', (363, 368))	('colorectal neoplasias', 'Disease', (98, 119))	('man', 'Species', '9606', (338, 341))	('TWIST1', 'Gene', '7291', (205, 211))	('Epi', 'Gene', (386, 389))	('TWIST1', 'Gene', (352, 358))	('Epi', 'Gene', '7035', (386, 389))	('neoplasia', 'Phenotype', 'HP:0002664', (109, 118))	('colorectal neoplasia', 'Disease', (269, 289))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (98, 118))
12794	29682198	In contrast, methylated TWIST1 copy numbers were independent of serum DNA concentration (Figure 3D).	('TWIST1', 'Gene', (24, 30))	('methylated', 'Var', (13, 23))	('TWIST1', 'Gene', '7291', (24, 30))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('serum DNA concentration', 'MPA', (64, 87))
12795	29682198	The median copy numbers of methylated TWIST1 were 0.0 (range, 0 to 11.4) in the control group, 1.9 (range, 0 to 11.2) in the non-advanced adenoma group, 1.7 (range, 0 to 26) in the advanced adenoma group, and 1.8 (range, 0 to 330) in the CRC group (Figure 4A).	('adenoma', 'Disease', (190, 197))	('TWIST1', 'Gene', (38, 44))	('TWIST1', 'Gene', '7291', (38, 44))	('adenoma', 'Disease', 'MESH:D000236', (138, 145))	('methylated', 'Var', (27, 37))	('CRC', 'Phenotype', 'HP:0003003', (238, 241))	('adenoma', 'Disease', 'MESH:D000236', (190, 197))	('adenoma', 'Disease', (138, 145))
12800	29682198	The median copy numbers of methylated SEPT9 were 2.0 (range, 0.0 to 13.2) in the control group, 2.0 (range, 0.0 to 50.0) in the non-advanced adenoma group, 3.6 (range, 0.0 to 46.0) in the advanced adenoma group, and 2.1 (range, 0.0 to 370.0) in the CRC group (Figure 4C).	('adenoma', 'Disease', 'MESH:D000236', (141, 148))	('methylated', 'Var', (27, 37))	('SEPT9', 'Gene', '10801', (38, 43))	('SEPT9', 'Gene', (38, 43))	('adenoma', 'Disease', (141, 148))	('adenoma', 'Disease', 'MESH:D000236', (197, 204))	('adenoma', 'Disease', (197, 204))	('CRC', 'Phenotype', 'HP:0003003', (249, 252))
12801	29682198	The best cutoff value to discriminate between the control group and CRC group was 7.6 copies of methylated SEPT9 by ROC curve analysis (Figure 4D).	('CRC', 'Phenotype', 'HP:0003003', (68, 71))	('methylated', 'Var', (96, 106))	('SEPT9', 'Gene', (107, 112))	('SEPT9', 'Gene', '10801', (107, 112))
12804	29682198	The combination of FIT and serum CORD assay of methylated TWIST1 resulted in a sensitivity of 40.0% (10/25) for non-advanced adenoma, 45.7% (32/70) for advanced adenoma, and 72.2% (13/18) for CRC, and the specificity was 84.0% (21/25) (Table 1 and Figure 1A).	('methylated', 'Var', (47, 57))	('CRC', 'Phenotype', 'HP:0003003', (192, 195))	('TWIST1', 'Gene', (58, 64))	('TWIST1', 'Gene', '7291', (58, 64))	('adenoma', 'Disease', 'MESH:D000236', (161, 168))	('CRC', 'Disease', (192, 195))	('adenoma', 'Disease', (161, 168))	('adenoma', 'Disease', 'MESH:D000236', (125, 132))	('adenoma', 'Disease', (125, 132))
12808	29682198	For methylated SEPT9, the combination of FIT and serum CORD assay resulted in a sensitivity of 28.0% (7/25) for non-advanced adenoma, 44.3% (31/70) for advanced adenoma, 42.9% (6/14) for stage I CRC, and 55.6% (10/18) for all-stages CRC, and the specificity was 80% (20/25) (Figure 1B).	('SEPT9', 'Gene', (15, 20))	('CRC', 'Phenotype', 'HP:0003003', (233, 236))	('CRC', 'Phenotype', 'HP:0003003', (195, 198))	('adenoma', 'Disease', 'MESH:D000236', (161, 168))	('methylated', 'Var', (4, 14))	('adenoma', 'Disease', (161, 168))	('adenoma', 'Disease', 'MESH:D000236', (125, 132))	('SEPT9', 'Gene', '10801', (15, 20))	('stage I CRC', 'Disease', (187, 198))	('adenoma', 'Disease', (125, 132))
12826	29682198	Because we frequently observed hypermethylation of TWIST1 in the tissues of colorectal adenoma and cancer, we thought methylated TWIST1 would be available as a biomarker of blood-based DNA testing for the detection of colorectal neoplasia including adenoma and cancer.	('TWIST1', 'Gene', (129, 135))	('adenoma', 'Disease', (249, 256))	('DNA', 'cellular_component', 'GO:0005574', ('185', '188'))	('colorectal adenoma', 'Disease', (76, 94))	('TWIST1', 'Gene', '7291', (51, 57))	('adenoma', 'Disease', 'MESH:D000236', (249, 256))	('TWIST1', 'Gene', '7291', (129, 135))	('hypermethylation', 'Var', (31, 47))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('colorectal adenoma', 'Disease', 'MESH:D015179', (76, 94))	('cancer', 'Disease', (261, 267))	('adenoma', 'Disease', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('observed', 'Reg', (22, 30))	('adenoma', 'Disease', 'MESH:D000236', (87, 94))	('colorectal neoplasia', 'Disease', (218, 238))	('neoplasia', 'Phenotype', 'HP:0002664', (229, 238))	('TWIST1', 'Gene', (51, 57))	('cancer', 'Disease', (99, 105))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (218, 238))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
12827	29682198	In the present study, the serum CORD assay of methylated TWIST1 resulted in a sensitivity of 36.0%, 30.0%, and 44.4% for the detection of non-advanced adenoma, advanced adenoma, and CRC, respectively, showing better performance compared with CEA (16.7%, 16.7%, and 17.6%, respectively) and equal or better performance compared with FIT (8.0%, 24.3%, and 44.4%, respectively).	('better', 'PosReg', (209, 215))	('man', 'Species', '9606', (312, 315))	('CEA', 'Gene', (242, 245))	('adenoma', 'Disease', 'MESH:D000236', (151, 158))	('man', 'Species', '9606', (222, 225))	('CEA', 'Gene', '1084', (242, 245))	('adenoma', 'Disease', 'MESH:D000236', (169, 176))	('CRC', 'Disease', (182, 185))	('adenoma', 'Disease', (151, 158))	('TWIST1', 'Gene', (57, 63))	('TWIST1', 'Gene', '7291', (57, 63))	('adenoma', 'Disease', (169, 176))	('methylated', 'Var', (46, 56))	('CRC', 'Phenotype', 'HP:0003003', (182, 185))
12831	29682198	In addition, the serum CORD assay of methylated TWIST1 showed moderate or better sensitivity as compared with those in previous reports of blood-based testing of methylated SEPT9 including the Epi proColon, in which the sensitivity is 7% for non-advanced adenoma, 11% for advanced adenoma, 48%-68% for CRC (35%-41% for CRC stage I, 63%-83% for CRC stage II, 46%-80 for CRC stage III, and 77%-100% for CRC stage IV).	('TWIST1', 'Gene', (48, 54))	('adenoma', 'Disease', (281, 288))	('adenoma', 'Disease', (255, 262))	('Epi', 'Gene', '7035', (193, 196))	('CRC', 'Phenotype', 'HP:0003003', (401, 404))	('SEPT9', 'Gene', (173, 178))	('adenoma', 'Disease', 'MESH:D000236', (281, 288))	('CRC', 'Disease', (369, 372))	('TWIST1', 'Gene', '7291', (48, 54))	('adenoma', 'Disease', 'MESH:D000236', (255, 262))	('CRC', 'Phenotype', 'HP:0003003', (344, 347))	('CRC', 'Phenotype', 'HP:0003003', (369, 372))	('CRC', 'Phenotype', 'HP:0003003', (319, 322))	('methylated', 'Var', (37, 47))	('CRC stage II', 'Disease', (344, 356))	('SEPT9', 'Gene', '10801', (173, 178))	('CRC', 'Disease', (302, 305))	('CRC', 'Phenotype', 'HP:0003003', (302, 305))	('CRC stage I', 'Disease', (319, 330))	('Epi', 'Gene', (193, 196))
12832	29682198	The 92% specificity of the serum CORD assay of methylated TWSIT1 was non-inferior to that of the 73%-93% achieved with blood testing of methylated SEPT9.	('methylated', 'Var', (47, 57))	('SEPT9', 'Gene', '10801', (147, 152))	('SEPT9', 'Gene', (147, 152))	('TWSIT1', 'Gene', (58, 64))
12835	29682198	However, the serum CORD assay seemed to complement FIT as a different screening modality for these tumor types because the results of FIT and serum CORD assay of methylated TWIST1, in part, seemed mutually exclusive.	('tumor', 'Disease', (99, 104))	('methylated', 'Var', (162, 172))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('TWIST1', 'Gene', (173, 179))	('TWIST1', 'Gene', '7291', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
12836	29682198	Therefore, we thought the combination of serum CORD assay of methylated TWIST1 and FIT might improve the sensitivity as compared to that by FIT alone.	('methylated', 'Var', (61, 71))	('TWIST1', 'Gene', (72, 78))	('TWIST1', 'Gene', '7291', (72, 78))	('improve', 'PosReg', (93, 100))	('sensitivity', 'MPA', (105, 116))
12839	29682198	In addition, the combination of serum CORD assay of methylated TWIST1 and FIT showed better sensitivity and specificity than that of serum CORD assay of methylated SEPT9 and FIT.	('sensitivity', 'MPA', (92, 103))	('SEPT9', 'Gene', '10801', (164, 169))	('TWIST1', 'Gene', (63, 69))	('TWIST1', 'Gene', '7291', (63, 69))	('methylated', 'Var', (52, 62))	('SEPT9', 'Gene', (164, 169))
12840	29682198	Thus, the combination test consisting of serum CORD assay of methylated TWIST1 and FIT may be useful as a laboratory test for the detection of early-stage CRC and non-advanced and advanced adenoma.	('methylated', 'Var', (61, 71))	('CRC', 'Phenotype', 'HP:0003003', (155, 158))	('TWIST1', 'Gene', (72, 78))	('TWIST1', 'Gene', '7291', (72, 78))	('adenoma', 'Disease', 'MESH:D000236', (189, 196))	('adenoma', 'Disease', (189, 196))	('non-advanced', 'Disease', (163, 175))
12844	29682198	In this study, detection of methylated TWIST1 from serum samples appeared to be useful for colorectal neoplasia screening.	('colorectal neoplasia', 'Disease', (91, 111))	('methylated', 'Var', (28, 38))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (91, 111))	('TWIST1', 'Gene', (39, 45))	('TWIST1', 'Gene', '7291', (39, 45))	('neoplasia', 'Phenotype', 'HP:0002664', (102, 111))
12845	29682198	However, we admit that hypermethylation of TWIST1 is associated with different types of cancer: breast, uterine cervix, ovary, bladder, gastric, lung, bone, pancreas, and brain.	('uterine cervix', 'Phenotype', 'HP:0030160', (104, 118))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('breast', 'Disease', (96, 102))	('pancreas', 'Disease', (157, 165))	('brain', 'Disease', (171, 176))	('bone', 'Disease', (151, 155))	('lung', 'Disease', (145, 149))	('pancreas', 'Disease', 'MESH:D010190', (157, 165))	('bladder', 'Disease', (127, 134))	('associated', 'Reg', (53, 63))	('TWIST1', 'Gene', (43, 49))	('TWIST1', 'Gene', '7291', (43, 49))	('hypermethylation', 'Var', (23, 39))	('uterine cervix', 'Disease', (104, 118))	('gastric', 'Disease', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ovary', 'Disease', (120, 125))
12852	29682198	To clarify the usefulness of DNA testing of methylated TWIST1 as a universal tumor marker from blood samples, retrospective and prospective cohort studies comprising various types of cancer are required.	('methylated', 'Var', (44, 54))	('cancer', 'Disease', (183, 189))	('TWIST1', 'Gene', (55, 61))	('TWIST1', 'Gene', '7291', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
12853	29682198	In conclusion, the combination of TWIST1 methylation analysis by serum CORD assay and FIT showed higher sensitivities for the detection of non-advanced adenoma, advanced adenoma, and early-stage CRC without great difference in the specificity as compared to those by FIT alone.	('adenoma', 'Disease', (170, 177))	('TWIST1', 'Gene', (34, 40))	('TWIST1', 'Gene', '7291', (34, 40))	('higher', 'PosReg', (97, 103))	('CRC', 'Phenotype', 'HP:0003003', (195, 198))	('methylation', 'Var', (41, 52))	('adenoma', 'Disease', 'MESH:D000236', (152, 159))	('adenoma', 'Disease', 'MESH:D000236', (170, 177))	('sensitivities', 'MPA', (104, 117))	('early-stage CRC', 'Disease', (183, 198))	('adenoma', 'Disease', (152, 159))
12854	29682198	Because this study suggests that the combination of serum DNA testing of methylated TWIST1 and FIT may be useful to detect individuals with colorectal neoplasia, confirmatory studies using independent data sets are needed to support our findings.	('neoplasia', 'Phenotype', 'HP:0002664', (151, 160))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('TWIST1', 'Gene', (84, 90))	('TWIST1', 'Gene', '7291', (84, 90))	('methylated', 'Var', (73, 83))	('colorectal neoplasia', 'Disease', (140, 160))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (140, 160))
12873	29682198	We performed multiplex droplet digital PCR to count the absolute copy numbers of hTERT, methylated TWIST1, and methylated SEPT9.	('SEPT9', 'Gene', '10801', (122, 127))	('SEPT9', 'Gene', (122, 127))	('hTERT', 'Gene', '7015', (81, 86))	('methylated', 'Var', (111, 121))	('methylated', 'Var', (88, 98))	('TWIST1', 'Gene', (99, 105))	('TWIST1', 'Gene', '7291', (99, 105))	('hTERT', 'Gene', (81, 86))
12894	27912775	Thus, it is of great importance for us to understand the biology, genetics and epigenetic alterations in CRC, especially the detailed mechanisms underlying distant metastasis, so as to improve the prognosis of CRC patients.	('patients', 'Species', '9606', (214, 222))	('CRC', 'Phenotype', 'HP:0003003', (210, 213))	('CRC', 'Disease', (105, 108))	('improve', 'PosReg', (185, 192))	('CRC', 'Phenotype', 'HP:0003003', (105, 108))	('epigenetic alterations', 'Var', (79, 101))	('CRC', 'Disease', (210, 213))
12895	27912775	The dysregulation of lncRNAs have also been shown to contribute to the initiation and progression of many types of cancers, including colorectal cancer.	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('contribute', 'Reg', (53, 63))	('colorectal cancer', 'Disease', (134, 151))	('cancers', 'Disease', (115, 122))	('dysregulation', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lncRNAs', 'Protein', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))
12945	27912775	The patients in the high lnc-GNAT1-1 expression group has a significant longer OS than those in the low expression group (55.75 vs. 68.59 months, p = 0.001).	('high lnc-GNAT1-1 expression', 'Var', (20, 47))	('patients', 'Species', '9606', (4, 12))	('longer', 'PosReg', (72, 78))
12957	27912775	In vitro experiments in SW480 cells showed that inhibition of lnc-GNAT1-1 promoted cell growth in CCK8 cell proliferation assay (Fig.	('promoted', 'PosReg', (74, 82))	('cell growth', 'biological_process', 'GO:0016049', ('83', '94'))	('SW480', 'CellLine', 'CVCL:0546', (24, 29))	('inhibition', 'Var', (48, 58))	('cell growth in CCK8 cell proliferation assay', 'CPA', (83, 127))	('cell proliferation', 'biological_process', 'GO:0008283', ('103', '121'))	('lnc-GNAT1-1', 'Gene', (62, 73))
12958	27912775	In flow cytometry analysis, the si-lnc-GNAT1-1 SW480 cells exhibited decreased apoptosis rate (10.16% vs. 17.71%, P < 0.001) and accelerated cell cycle (G0/G1%: 45.50% vs. 50.65%, P < 0.001) when compared with si-NC cells (Fig.	('SW480', 'CellLine', 'CVCL:0546', (47, 52))	('decreased', 'NegReg', (69, 78))	('accelerated', 'PosReg', (129, 140))	('apoptosis rate', 'CPA', (79, 93))	('si-lnc-GNAT1-1', 'Var', (32, 46))
12959	27912775	Finally, in the experiment of transwell migration and invasion assays, inhibition of lnc-GNAT1-1 could significantly enhance the migration and invasion abilities of SW480 cells (Fig.	('invasion abilities', 'CPA', (143, 161))	('inhibition', 'Var', (71, 81))	('SW480', 'CellLine', 'CVCL:0546', (165, 170))	('migration', 'CPA', (129, 138))	('enhance', 'PosReg', (117, 124))	('lnc-GNAT1-1', 'Gene', (85, 96))
12972	27912775	Then we detected the mRNA and protein expression levels of RKIP, with results showed that RKIP expression was decreased following lnc-GNAT1-1 knockdown, and vice versa (Fig.	('RKIP', 'Gene', '5037', (90, 94))	('RKIP', 'Gene', (90, 94))	('decreased', 'NegReg', (110, 119))	('lnc-GNAT1-1', 'Gene', (130, 141))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('RKIP', 'Gene', (59, 63))	('knockdown', 'Var', (142, 151))	('expression', 'MPA', (95, 105))	('RKIP', 'Gene', '5037', (59, 63))
12973	27912775	We further detected the expressions of NF-kappaB and Snail proteins in the above cells, with results showed that when lnc-GNAT1-1 was knocked down, expressions of NF-kappaB and Snail increased, while when lnc-GNAT1-1 was overexpressed, expression of the two proteins decreased (Fig.	('Snail', 'Gene', (53, 58))	('NF-kappaB', 'Gene', '4790', (39, 48))	('NF-kappaB', 'Gene', (163, 172))	('Snail', 'Gene', '6615', (177, 182))	('Snail', 'Gene', (177, 182))	('NF-kappaB', 'Gene', (39, 48))	('lnc-GNAT1-1', 'Gene', (118, 129))	('increased', 'PosReg', (183, 192))	('knocked', 'Var', (134, 141))	('NF-kappaB', 'Gene', '4790', (163, 172))	('expressions', 'MPA', (148, 159))	('Snail', 'Gene', '6615', (53, 58))
12983	27912775	Another important finding of this study is that lnc-GNAT1-1 is decreased in plasma of CRC patients than in healthy controls, with an AUC of 0.720 in the ROC analysis, which indicates that lnc-GNAT1-1 has a moderate to well efficiency for the diagnosis of CRC.	('lnc-GNAT1-1', 'Gene', (48, 59))	('CRC', 'Phenotype', 'HP:0003003', (255, 258))	('lnc-GNAT1-1', 'Var', (188, 199))	('CRC', 'Phenotype', 'HP:0003003', (86, 89))	('decreased', 'NegReg', (63, 72))	('CRC', 'Disease', (255, 258))	('patients', 'Species', '9606', (90, 98))	('CRC', 'Disease', (86, 89))
12990	27912775	Previous studies have shown a variety of interactions between lncRNAs and proteins, for instance, LOC389641 with E-cadherin, SNHG5 with MTA2, and CASC11 with hnRNP-K.	('MTA2', 'Gene', '9219', (136, 140))	('CASC11', 'Gene', '100270680', (146, 152))	('hnRNP-K', 'Gene', (158, 165))	('CASC11', 'Gene', (146, 152))	('interactions', 'Interaction', (41, 53))	('E-cadherin', 'Gene', (113, 123))	('MTA2', 'Gene', (136, 140))	('hnRNP-K', 'Gene', '3190', (158, 165))	('LOC389641', 'Var', (98, 107))	('E-cadherin', 'Gene', '999', (113, 123))	('SNHG5', 'Gene', (125, 130))	('SNHG5', 'Gene', '387066', (125, 130))
13087	25624117	Emerging Potential of Natural Products for Targeting Mucins for Therapy Against Inflammation and Cancer Deregulated mucin expression is a hallmark of several inflammatory and malignant pathologies.	('Inflammation', 'Disease', (80, 92))	('expression', 'MPA', (122, 132))	('Inflammation', 'Disease', 'MESH:D007249', (80, 92))	('Deregulated', 'Var', (104, 115))	('mucin', 'Protein', (116, 121))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))
13095	25624117	Somewhat paradoxically, for what evolved as a protective mechanism for epithelial cells under normal physiological conditions, aberrant and deregulated expression of mucins in epithelial malignancies contributes to tumorigenesis and metastasis.	('epithelial malignancies', 'Phenotype', 'HP:0031492', (176, 199))	('aberrant', 'Var', (127, 135))	('deregulated', 'Var', (140, 151))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('epithelial malignancies', 'Disease', (176, 199))	('mucins', 'Protein', (166, 172))	('epithelial malignancies', 'Disease', 'MESH:D002277', (176, 199))	('tumor', 'Disease', (215, 220))	('expression', 'MPA', (152, 162))
13097	25624117	Further, due to aberrant glycosylation in malignancies, mucins mediate cancer cell interactions with leukocytes, endothelial cells and platelets present in the tumor microenvironment during metastasis.	('aberrant', 'Var', (16, 24))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('malignancies', 'Disease', 'MESH:D009369', (42, 54))	('cancer', 'Disease', (71, 77))	('mucins', 'Protein', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('mediate', 'Reg', (63, 70))	('interactions', 'Interaction', (83, 95))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('malignancies', 'Disease', (42, 54))	('glycosylation', 'MPA', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (16, 38))	('tumor', 'Disease', (160, 165))
13100	25624117	These include immunotherapy to target epitopes presented by aberrantly expressed mucins on cancer cells, radioimmunotherapy to deliver cytotoxic radionuclides, or targeted therapy using anti-mucin antibodies or aptamers for delivering drugs toxins and nanoparticles specifically to mucin overexpressing cancer cells.	('cancer', 'Disease', (303, 309))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('radionuclides', 'Chemical', 'MESH:D011868', (145, 158))	('aberrantly', 'Var', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('aptamers', 'Protein', (211, 219))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
13113	25624117	Deregulated expression and aberrant glycosylation of mucins is a prominent characteristic of inflammatory diseases and malignancies and contributes to disease progression and pathogenesis.	('Deregulated', 'Var', (0, 11))	('aberrant', 'Var', (27, 35))	('glycosylation', 'MPA', (36, 49))	('malignancies', 'Disease', 'MESH:D009369', (119, 131))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (27, 49))	('malignancies', 'Disease', (119, 131))	('expression', 'MPA', (12, 22))	('mucins', 'Protein', (53, 59))	('inflammatory diseases', 'Disease', (93, 114))	('contributes', 'Reg', (136, 147))
13115	25624117	Both MUC1 and MUC4 physically interact with and stabilize ErbB family of growth factor receptor tyrosine kinases (RTKs) and potentiate ErbB-dependent signal transduction including extracellular signal regulated kinases (ERK1/2), MAPK and attenuate genotoxic stress induced apoptosis.	('ErbB', 'Gene', '1956', (58, 62))	('ErbB', 'Gene', (135, 139))	('ErbB', 'Gene', '1956', (135, 139))	('ERK1/2', 'Gene', (220, 226))	('ERK1/2', 'Gene', '5595;5594', (220, 226))	('MUC4', 'Gene', (14, 18))	('MUC1', 'Var', (5, 9))	('ErbB', 'Gene', (58, 62))	('potentiate', 'PosReg', (124, 134))	('extracellular signal regulated', 'MPA', (180, 210))	('genotoxic stress induced apoptosis', 'CPA', (248, 282))	('attenuate', 'NegReg', (238, 247))	('interact', 'Interaction', (30, 38))	('stabilize', 'PosReg', (48, 57))	('MAPK', 'CPA', (229, 233))
13123	25624117	have recently reported association and phosphorylation of cytoplasmic MUC16 (Tyr-22142) by SFKs such as c-Src and c-Yes.	('c-Src', 'Gene', (104, 109))	('association', 'Interaction', (23, 34))	('Tyr-22142', 'Var', (77, 86))	('phosphorylation', 'MPA', (39, 54))	('c-Yes', 'Gene', '7525', (114, 119))	('c-Src', 'Gene', '6714', (104, 109))	('reported', 'Reg', (14, 22))	('MUC16', 'Gene', '94025', (70, 75))	('phosphorylation', 'biological_process', 'GO:0016310', ('39', '54'))	('Tyr', 'Chemical', 'MESH:D014443', (77, 80))	('c-Yes', 'Gene', (114, 119))	('MUC16', 'Gene', (70, 75))
13127	25624117	Interestingly, similar to other mucins, MUC5AC knockdown was associated with decreased ERK1/2 signaling as evidenced by decreased pERK1/2 expression.	('decreased', 'NegReg', (120, 129))	('ERK1/2', 'Gene', (131, 137))	('ERK1/2', 'Gene', (87, 93))	('ERK1/2', 'Gene', '5595;5594', (131, 137))	('knockdown', 'Var', (47, 56))	('ERK1/2', 'Gene', '5595;5594', (87, 93))	('expression', 'MPA', (138, 148))	('MUC5AC', 'Gene', (40, 46))	('decreased', 'NegReg', (77, 86))
13139	25624117	Silencing the MUC1 or MUC4 gene reverses resistance to trastuzumab in HER2/ErbB2-positive gastric cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('MUC4', 'Gene', (22, 26))	('HER2', 'Gene', (70, 74))	('ErbB2', 'Gene', (75, 80))	('HER2', 'Gene', '2064', (70, 74))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('gastric cancers', 'Disease', 'MESH:D013274', (90, 105))	('ErbB2', 'Gene', '2064', (75, 80))	('resistance to trastuzumab', 'MPA', (41, 66))	('reverses', 'NegReg', (32, 40))	('trastuzumab', 'Chemical', 'MESH:D000068878', (55, 66))	('gastric cancers', 'Disease', (90, 105))	('gastric cancers', 'Phenotype', 'HP:0012126', (90, 105))	('MUC1', 'Gene', (14, 18))	('Silencing', 'Var', (0, 9))
13162	25624117	However, several environmental and/or intrinsic insults compromise this regulation leading to their aberrant expression resulting in diverse inflammatory and pathological disorders including cancer.	('resulting in', 'Reg', (120, 132))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('expression', 'MPA', (109, 119))	('aberrant', 'Var', (100, 108))	('compromise', 'NegReg', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('regulation', 'biological_process', 'GO:0065007', ('72', '82'))
13168	25624117	In addition, binding of Hypoxia Inducible Factor (HIF)-1alpha to HIF responsive elements (HRE) at -1488/-1485 and at -1510/-1507 of MUC1 promoter upregulates its expression.	('upregulates', 'PosReg', (146, 157))	('MUC1', 'Gene', (132, 136))	('binding', 'Interaction', (13, 20))	('expression', 'MPA', (162, 172))	('Hypoxia Inducible Factor (HIF)-1alpha', 'Gene', '3091', (24, 61))	('at -1510/-1507', 'Var', (114, 128))	('at -1488/-1485', 'Var', (95, 109))
13222	25624117	evaluated the chemopreventive effect of glycyrrhizin in DMH induced colon carcinogenesis in a rat model.	('glycyrrhizin', 'Chemical', 'MESH:D019695', (40, 52))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (68, 88))	('rat', 'Species', '10116', (94, 97))	('colon carcinogenesis', 'Disease', (68, 88))	('DMH', 'Chemical', 'MESH:D004111', (56, 59))	('DMH', 'Var', (56, 59))
13253	25624117	In airway epithelial cells, silibinin was demonstrated to inhibit mucin production and secretion.	('silibinin', 'Var', (28, 37))	('silibinin', 'Chemical', 'MESH:D000077385', (28, 37))	('mucin production', 'MPA', (66, 82))	('secretion', 'MPA', (87, 96))	('inhibit', 'NegReg', (58, 65))	('rat', 'Species', '10116', (49, 52))	('secretion', 'biological_process', 'GO:0046903', ('87', '96'))
13295	25624117	Imbalance in intestinal microflora is associated with and contributes to pathogenesis of inflammatory bowel diseases (IBD).	('Imbalance', 'Var', (0, 9))	('IBD', 'Phenotype', 'HP:0002037', (118, 121))	('associated', 'Reg', (38, 48))	('contributes', 'Reg', (58, 69))	('inflammatory bowel diseases', 'Disease', 'MESH:D015212', (89, 116))	('inflammatory bowel diseases', 'Phenotype', 'HP:0002037', (89, 116))	('pathogenesis', 'biological_process', 'GO:0009405', ('73', '85'))	('Imbalance', 'Phenotype', 'HP:0002172', (0, 9))	('inflammatory bowel diseases', 'Disease', (89, 116))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (89, 115))
13297	25624117	Epigenetic alterations including DNA methylation, histone modifications and micro-RNAs (miRNAs) have been shown to regulate mucin expression in various diseases including cancer (reviewed in.	('expression', 'MPA', (130, 140))	('rat', 'Species', '10116', (15, 18))	('histone', 'Protein', (50, 57))	('DNA methylation', 'biological_process', 'GO:0006306', ('33', '48'))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('cancer', 'Disease', (171, 177))	('DNA methylation', 'Var', (33, 48))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('mucin', 'Protein', (124, 129))	('regulate', 'Reg', (115, 123))
13397	24297651	In multivariate regression models, patients who underwent resection of primary tumor had improved overall (hazard ratio (HR), 0.42; 95 % confidence interval (CI) 0.40-0.44, p <0.0001) and colorectal cancer-specific survival (HR, 0.43; 95 % CI, 0.41-0.45; p <0.0001).	('improved', 'PosReg', (89, 97))	('colorectal cancer', 'Disease', (188, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))	('resection', 'Var', (58, 67))	('rectal cancer', 'Phenotype', 'HP:0100743', (192, 205))	('colorectal cancer', 'Disease', 'MESH:D015179', (188, 205))	('patients', 'Species', '9606', (35, 43))	('primary tumor', 'Disease', (71, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('primary tumor', 'Disease', 'MESH:D009369', (71, 84))
13433	24297651	In the full regression model, surgical resection of the primary tumor was associated with a statistically significant improvement in OS (hazard ratio (HR), 0.42; 95 % CI, 0.40-0.44; p <0.0001) (Table 3).	('primary tumor', 'Disease', (56, 69))	('improvement', 'PosReg', (118, 129))	('surgical resection', 'Var', (30, 48))	('primary tumor', 'Disease', 'MESH:D009369', (56, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
13435	24297651	Hispanic ethnicity was observed to have improved overall survival compared to Whites (8 % decreased risk of death from any cause).	('overall survival', 'MPA', (49, 65))	('Hispanic ethnicity', 'Var', (0, 18))	('decreased', 'NegReg', (90, 99))	('improved', 'PosReg', (40, 48))	('death', 'Disease', 'MESH:D003643', (108, 113))	('death', 'Disease', (108, 113))
13437	24297651	Resection of the primary tumor was associated with improvement in CRC-SS (HR, 0.43; 95 % CI, 0.41-0.45; p <0.0001).	('primary tumor', 'Disease', (17, 30))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('improvement', 'PosReg', (51, 62))	('Resection', 'Var', (0, 9))	('CRC-SS', 'Disease', (66, 72))	('primary tumor', 'Disease', 'MESH:D009369', (17, 30))	('CRC', 'Phenotype', 'HP:0003003', (66, 69))
13450	24297651	reported on a single-institution retrospective analysis of 64 patients and also found a significantly improved survival in the resection group compared to the non-resection group (15.2 vs. 12.3 months, p =0.003).	('patients', 'Species', '9606', (62, 70))	('survival', 'MPA', (111, 119))	('improved', 'PosReg', (102, 110))	('resection', 'Var', (127, 136))
13474	24297651	In summary, we report that resection of the primary tumor among chemotherapy-treated stage IV CRC patients is associated with improved OS and CRC-SS.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('primary tumor', 'Disease', 'MESH:D009369', (44, 57))	('improved', 'PosReg', (126, 134))	('resection', 'Var', (27, 36))	('CRC', 'Phenotype', 'HP:0003003', (142, 145))	('patients', 'Species', '9606', (98, 106))	('CRC', 'Phenotype', 'HP:0003003', (94, 97))	('CRC-SS', 'Disease', (142, 148))	('primary tumor', 'Disease', (44, 57))
13481	23284651	High density of TAM was significantly associated with late clinical staging in patients with breast cancer [risk ratio (RR)  = 1.20 (95% confidence interval (CI), 1.14-1.28)] and bladder cancer [RR = 3.30 (95%CI, 1.56-6.96)] and with early clinical staging in patients with ovarian cancer [RR = 0.52 (95%CI, 0.35-0.77)].	('TAM', 'Chemical', '-', (16, 19))	('bladder cancer', 'Phenotype', 'HP:0009725', (179, 193))	('ovarian cancer', 'Phenotype', 'HP:0100615', (274, 288))	('associated', 'Reg', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('High density', 'Var', (0, 12))	('ovarian cancer', 'Disease', 'MESH:D010051', (274, 288))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('patients', 'Species', '9606', (260, 268))	('ovarian cancer', 'Disease', (274, 288))	('bladder cancer', 'Disease', 'MESH:D001749', (179, 193))	('bladder cancer', 'Disease', (179, 193))	('breast cancer', 'Disease', (93, 106))	('patients', 'Species', '9606', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('late clinical staging', 'CPA', (54, 75))
13485	23284651	Although some modest bias cannot be excluded, high density of TAM seems to be associated with worse OS in patients with gastric cancer, urogenital cancer and head and neck cancer, with better OS in patients with colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('patients', 'Species', '9606', (198, 206))	('gastric cancer', 'Disease', 'MESH:D013274', (120, 134))	('head and neck cancer', 'Disease', 'MESH:D006258', (158, 178))	('neck', 'cellular_component', 'GO:0044326', ('167', '171'))	('urogenital cancer', 'Disease', 'MESH:D014565', (136, 153))	('OS', 'Chemical', '-', (192, 194))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('urogenital cancer', 'Disease', (136, 153))	('colorectal cancer', 'Disease', 'MESH:D015179', (212, 229))	('gastric cancer', 'Phenotype', 'HP:0012126', (120, 134))	('high density', 'Var', (46, 58))	('colorectal cancer', 'Disease', (212, 229))	('patients', 'Species', '9606', (106, 114))	('head and neck cancer', 'Phenotype', 'HP:0012288', (158, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('OS', 'Chemical', '-', (100, 102))	('gastric cancer', 'Disease', (120, 134))	('TAM', 'Chemical', '-', (62, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (212, 229))
13530	23284651	For overall population, high density of TAM was associated with a worse prognosis regarding overall survival (Figure 2B).	('overall survival', 'MPA', (92, 108))	('TAM', 'Chemical', '-', (40, 43))	('high density', 'Var', (24, 36))
13531	23284651	However, mortality was only 1.15-fold higher in high TAM patients with solid tumor, which showed modest effect.	('solid tumor', 'Disease', (71, 82))	('solid tumor', 'Disease', 'MESH:D009369', (71, 82))	('TAM', 'Chemical', '-', (53, 56))	('patients', 'Species', '9606', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('higher', 'PosReg', (38, 44))	('high TAM', 'Var', (48, 56))
13534	23284651	However, analysis of studies on colorectal cancer showed that there was a significant correlation between high density of TAM and longer OS [RR = 0.64 (95%CI, 0.43-0.96)].	('colorectal cancer', 'Disease', (32, 49))	('colorectal cancer', 'Disease', 'MESH:D015179', (32, 49))	('longer OS', 'Disease', (130, 139))	('TAM', 'Chemical', '-', (122, 125))	('high density', 'Var', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('colorectal cancer', 'Phenotype', 'HP:0003003', (32, 49))	('OS', 'Chemical', '-', (137, 139))
13536	23284651	Five studies reported that there was no significant correlation between M2-type TAM and OS [RR = 0.98 (95%CI, 0.71-1.35)], one study reported that the M1-type TAM density in the tumor islet is positively associated with extended survival in patients with lung cancer.	('M1-type', 'Var', (151, 158))	('tumor', 'Disease', (178, 183))	('TAM', 'Chemical', '-', (80, 83))	('lung cancer', 'Disease', (255, 266))	('lung cancer', 'Phenotype', 'HP:0100526', (255, 266))	('extended survival', 'CPA', (220, 237))	('associated with', 'Reg', (204, 219))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('lung cancer', 'Disease', 'MESH:D008175', (255, 266))	('OS', 'Chemical', '-', (88, 90))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('TAM', 'Chemical', '-', (159, 162))	('patients', 'Species', '9606', (241, 249))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
13543	23284651	Additionally, two of the studies on gastric cancer described that low density of TAM was significantly correlated with lymph node metastasis.	('gastric cancer', 'Disease', (36, 50))	('TAM', 'Chemical', '-', (81, 84))	('lymph node metastasis', 'CPA', (119, 140))	('low density', 'Var', (66, 77))	('TAM', 'Protein', (81, 84))	('gastric cancer', 'Disease', 'MESH:D013274', (36, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('correlated', 'Reg', (103, 113))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
13545	23284651	Similar phenomena were seen in bladder cancer and oral squamous group, and high density of TAM was significantly correlated with TNM stage, T status, lymph node metastasis and distant metastasis.	('distant metastasis', 'CPA', (176, 194))	('oral squamous group', 'Disease', (50, 69))	('TAM', 'Chemical', '-', (91, 94))	('high density', 'Var', (75, 87))	('T status', 'Disease', (140, 148))	('bladder cancer', 'Phenotype', 'HP:0009725', (31, 45))	('lymph node metastasis', 'CPA', (150, 171))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('correlated', 'Reg', (113, 123))	('men', 'Species', '9606', (13, 16))	('TNM stage', 'Disease', (129, 138))	('bladder cancer', 'Disease', 'MESH:D001749', (31, 45))	('bladder cancer', 'Disease', (31, 45))
13551	23284651	The present result showed that high density of TAM, as detected with immunohistochemistry, was significant associated with worse overall survival in solid tumor, with a global RR of 1.15.	('worse', 'NegReg', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('solid tumor', 'Disease', (149, 160))	('TAM', 'Chemical', '-', (47, 50))	('TAM', 'Protein', (47, 50))	('high density', 'Var', (31, 43))	('solid tumor', 'Disease', 'MESH:D009369', (149, 160))
13552	23284651	As potential bias exists between studies on different tumors, subgroup analysis was also performed, which suggested that high density of TAM was significant associated with OS in patients with gastric cancer [RR = 1.64 (95%CI, 1.24-2.16)], breast cancer [RR = 8.62 (95%CI, 3.10-23.95)], bladder caner [RR = 5.00 (95%CI, 1.98-12.63)], ovarian cancer [RR = 2.55 (95%CI, 1.60-4.06)], oral cancer [RR = 2.03 (95%CI, 1.47-2.80)] and thyroid cancer [RR = 2.72 (95%CI, 1.26-5.86)].	('gastric cancer', 'Disease', 'MESH:D013274', (193, 207))	('associated', 'Interaction', (157, 167))	('thyroid cancer', 'Phenotype', 'HP:0002890', (428, 442))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('ovarian cancer', 'Disease', 'MESH:D010051', (334, 348))	('gastric cancer', 'Phenotype', 'HP:0012126', (193, 207))	('patients', 'Species', '9606', (179, 187))	('tumors', 'Disease', (54, 60))	('thyroid cancer', 'Disease', (428, 442))	('cancer', 'Phenotype', 'HP:0002664', (436, 442))	('bladder caner', 'Disease', (287, 300))	('breast cancer', 'Phenotype', 'HP:0003002', (240, 253))	('TAM', 'Chemical', '-', (137, 140))	('OS', 'Chemical', '-', (173, 175))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('ovarian cancer', 'Disease', (334, 348))	('gastric cancer', 'Disease', (193, 207))	('breast cancer', 'Disease', 'MESH:D001943', (240, 253))	('oral cancer', 'Disease', 'MESH:D009062', (381, 392))	('breast cancer', 'Disease', (240, 253))	('oral cancer', 'Disease', (381, 392))	('ovarian cancer', 'Phenotype', 'HP:0100615', (334, 348))	('thyroid cancer', 'Disease', 'MESH:D013964', (428, 442))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('high', 'Var', (121, 125))
13558	23284651	In this meta-analysis, we reach a conclusion that high TAM infiltration is associated with worsen prognosis in patients with urogenital cancer or gastric cancer, not all cancer type.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('urogenital cancer', 'Disease', (125, 142))	('gastric cancer', 'Disease', 'MESH:D013274', (146, 160))	('urogenital cancer', 'Disease', 'MESH:D014565', (125, 142))	('gastric cancer', 'Disease', (146, 160))	('cancer', 'Disease', (170, 176))	('worsen', 'NegReg', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('gastric cancer', 'Phenotype', 'HP:0012126', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('TAM', 'Chemical', '-', (55, 58))	('high', 'Var', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('patients', 'Species', '9606', (111, 119))
13562	23284651	Interestingly, there also demonstrated a positive effect of TAM on lymph node metastasis in gastric and ovary cancer, which indicated that high density of TAM was associated with less probability of lymph node metastasis, however, significant negative effect was shown on overall survival.	('ovary cancer', 'Phenotype', 'HP:0100615', (104, 116))	('high density', 'Var', (139, 151))	('TAM', 'Chemical', '-', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('less', 'NegReg', (179, 183))	('TAM', 'Chemical', '-', (155, 158))	('lymph node metastasis', 'CPA', (199, 220))	('gastric and ovary cancer', 'Disease', 'MESH:D013274', (92, 116))
13579	23284651	However, we only included literatures evaluating TAM with the use of antibodies to the glycoprotein CD68.	('TAM', 'Chemical', '-', (49, 52))	('CD68', 'Gene', (100, 104))	('CD68', 'Gene', '968', (100, 104))	('antibodies', 'Var', (69, 79))
13619	33922305	While little is known on the molecular features of jejunal or ileal adenomas, the most frequent genetic alterations of intestinal-type NADAs involve APC and KRAS genes, similar to colorectal adenomas.	('alterations', 'Var', (104, 115))	('KRAS', 'Gene', '3845', (157, 161))	('adenomas', 'Disease', 'MESH:D000236', (191, 199))	('adenomas', 'Disease', 'MESH:D000236', (68, 76))	('adenomas', 'Disease', (191, 199))	('adenomas', 'Disease', (68, 76))	('NADAs', 'Chemical', '-', (135, 140))	('colorectal adenomas', 'Disease', (180, 199))	('APC', 'Disease', 'MESH:D011125', (149, 152))	('APC', 'Disease', (149, 152))	('KRAS', 'Gene', (157, 161))	('colorectal adenomas', 'Disease', 'MESH:D015179', (180, 199))
13623	33922305	found APC mutation in 53%, 59%, and 60% of low grade intestinal-type NADAs, high grade intestinal-type NADAs and intestinal-type intramucosal adenocarcinoma, respectively.	('intestinal-type intramucosal adenocarcinoma', 'Disease', (113, 156))	('low grade intestinal-type NADAs', 'Disease', (43, 74))	('NADAs', 'Chemical', '-', (103, 108))	('APC', 'Disease', 'MESH:D011125', (6, 9))	('NADAs', 'Chemical', '-', (69, 74))	('intestinal-type intramucosal adenocarcinoma', 'Disease', 'MESH:D000230', (113, 156))	('mutation', 'Var', (10, 18))	('APC', 'Disease', (6, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
13624	33922305	Most APC mutations are nonsense or frameshift mutations, mainly distributed in the mutation cluster regions (between codons 700 and 1200 or between codons 1400 and 1600), though a few missense mutations have also been identified.	('frameshift', 'Var', (35, 45))	('APC', 'Disease', 'MESH:D011125', (5, 8))	('APC', 'Disease', (5, 8))	('mutations', 'Var', (9, 18))	('APC', 'cellular_component', 'GO:0005680', ('5', '8'))
13625	33922305	The two more common mutational hotspots within APC gene in NADAs are T1556fs and R1450X.	('R1450X', 'Var', (81, 87))	('NADAs', 'Chemical', '-', (59, 64))	('APC', 'Disease', 'MESH:D011125', (47, 50))	('APC', 'Disease', (47, 50))	('T1556fs', 'Var', (69, 76))	('R1450X', 'Mutation', 'rs121913332', (81, 87))	('T1556fs', 'Mutation', 'rs587783031', (69, 76))
13626	33922305	Alterations in mutational cluster regions seem to be more common in intestinal-type NADAs (86%) in comparison with intestinal-type intramucosal adenocarcinomas (33%).	('common', 'Reg', (58, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('Alterations', 'Var', (0, 11))	('intestinal-type NADAs', 'Disease', (68, 89))	('NADAs', 'Chemical', '-', (84, 89))	('intestinal-type intramucosal adenocarcinomas', 'Disease', (115, 159))	('intestinal-type intramucosal adenocarcinomas', 'Disease', 'MESH:D000230', (115, 159))
13627	33922305	In addition, APC alterations have been found to be rarer in advanced duodenal carcinomas, suggesting that most NADAs have a low potential for malignant progression to duodenal adenocarcinomas and that the adenoma-carcinoma sequence may play a small role in the development of invasive duodenal adenocarcinomas.	('adenoma-carcinoma', 'Disease', (205, 222))	('duodenal adenocarcinomas', 'Disease', 'MESH:D000230', (285, 309))	('APC', 'cellular_component', 'GO:0005680', ('13', '16'))	('duodenal carcinomas', 'Phenotype', 'HP:0006771', (69, 88))	('duodenal adenocarcinoma', 'Phenotype', 'HP:0006771', (167, 190))	('APC', 'Disease', 'MESH:D011125', (13, 16))	('APC', 'Disease', (13, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('duodenal adenocarcinoma', 'Phenotype', 'HP:0006771', (285, 308))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (181, 191))	('alterations', 'Var', (17, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('duodenal adenocarcinomas', 'Phenotype', 'HP:0006771', (167, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (299, 308))	('duodenal adenocarcinomas', 'Phenotype', 'HP:0006771', (285, 309))	('NADAs', 'Chemical', '-', (111, 116))	('invasive duodenal adenocarcinomas', 'Disease', (276, 309))	('duodenal adenocarcinomas', 'Disease', (167, 191))	('duodenal carcinomas', 'Disease', (69, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('duodenal carcinomas', 'Disease', 'MESH:D004379', (69, 88))	('invasive duodenal adenocarcinomas', 'Disease', 'MESH:D000230', (276, 309))	('carcinomas', 'Phenotype', 'HP:0030731', (299, 309))	('men', 'Species', '9606', (268, 271))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (205, 222))	('duodenal adenocarcinomas', 'Disease', 'MESH:D000230', (167, 191))
13632	33922305	KRAS mutations were found in 18% of NADAs by Wagner et al., while they seem to be more common in ampullary adenomas (44%), likely as a result of the presence of bile and pancreatic secretions in the periampullary region.	('adenomas', 'Disease', (107, 115))	('common', 'Reg', (87, 93))	('mutations', 'Var', (5, 14))	('NADAs', 'Chemical', '-', (36, 41))	('KRAS', 'Gene', (0, 4))	('adenomas', 'Disease', 'MESH:D000236', (107, 115))	('KRAS', 'Gene', '3845', (0, 4))
13633	33922305	Interestingly, in the study by Matsubara et al., KRAS mutation was less frequent among intestinal-type adenomas in comparison with gastric-type adenomas with pyloric gland phenotype.	('adenomas', 'Disease', (103, 111))	('mutation', 'Var', (54, 62))	('KRAS', 'Gene', '3845', (49, 53))	('gastric-type adenomas', 'Disease', 'MESH:D000236', (131, 152))	('less', 'NegReg', (67, 71))	('adenomas', 'Disease', 'MESH:D000236', (144, 152))	('gastric-type adenomas', 'Disease', (131, 152))	('adenomas', 'Disease', (144, 152))	('adenomas', 'Disease', 'MESH:D000236', (103, 111))	('KRAS', 'Gene', (49, 53))
13634	33922305	As KRAS mutations are significantly rarer in low grade intestinal-type NADAs (3%) and high grade intestinal-type NADAs (7%) in comparison with intestinal-type intramucosal adenocarcinomas (40%), they seem to be related to neoplastic progression.	('related', 'Reg', (211, 218))	('intestinal-type intramucosal adenocarcinomas', 'Disease', (143, 187))	('KRAS', 'Gene', '3845', (3, 7))	('intestinal-type intramucosal adenocarcinomas', 'Disease', 'MESH:D000230', (143, 187))	('mutations', 'Var', (8, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('low grade intestinal-type NADAs', 'Disease', (45, 76))	('NADAs', 'Chemical', '-', (71, 76))	('KRAS', 'Gene', (3, 7))	('NADAs', 'Chemical', '-', (113, 118))
13635	33922305	GNAS mutations (mainly at codon 201) have never, or very rarely, been identified in intestinal-type NADAs.	('mutations', 'Var', (5, 14))	('GNAS', 'Gene', '2778', (0, 4))	('NADAs', 'Chemical', '-', (100, 105))	('GNAS', 'Gene', (0, 4))
13636	33922305	In contrast, both GNAS and KRAS alterations were significantly more common in gastric-type neoplasms.	('gastric-type neoplasms', 'Disease', (78, 100))	('KRAS', 'Gene', '3845', (27, 31))	('GNAS', 'Gene', '2778', (18, 22))	('neoplasms', 'Phenotype', 'HP:0002664', (91, 100))	('alterations', 'Var', (32, 43))	('GNAS', 'Gene', (18, 22))	('gastric-type neoplasms', 'Disease', 'MESH:D013274', (78, 100))	('neoplasm', 'Phenotype', 'HP:0002664', (91, 99))	('KRAS', 'Gene', (27, 31))	('common', 'Reg', (68, 74))
13637	33922305	BRAF alterations have been described in 6% of low grade intestinal-type NADAs and in 3% of high-grade intestinal type NADAs.	('NADAs', 'Chemical', '-', (72, 77))	('BRAF', 'Gene', '673', (0, 4))	('alterations', 'Var', (5, 16))	('NADAs', 'Chemical', '-', (118, 123))	('BRAF', 'Gene', (0, 4))	('low grade intestinal-type NADAs', 'Disease', (46, 77))
13638	33922305	BRAF V600E mutation has never been described in NADAs, while it may be present in up to 10% of BRAF-mutated small bowel adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('NADAs', 'Chemical', '-', (48, 53))	('BRAF', 'Gene', '673', (95, 99))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (95, 99))	('small bowel adenocarcinomas', 'Disease', (108, 135))	('BRAF', 'Gene', (0, 4))	('small bowel adenocarcinomas', 'Disease', 'MESH:D000230', (108, 135))
13639	33922305	ERBB2 mutations occur in less than 5% of NADAs, while the combined prevalence of mutations or copy number gains in any members of ERBB receptor family may reach 34%.	('ERBB', 'Gene', '1956', (0, 4))	('ERBB2', 'Gene', '2064', (0, 5))	('ERBB', 'Gene', (130, 134))	('ERBB2', 'Gene', (0, 5))	('NADAs', 'Chemical', '-', (41, 46))	('ERBB', 'Gene', (0, 4))	('copy number gains', 'Var', (94, 111))	('mutations', 'Var', (81, 90))	('ERBB', 'Gene', '1956', (130, 134))	('mutations', 'Var', (6, 15))
13640	33922305	ERBB2 mutations and/or amplifications have been detected in up to 23% of small bowel adenocarcinomas and they are associated with duodenal location and microsatellite instability.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('detected', 'Reg', (48, 56))	('duodenal location', 'Disease', (130, 147))	('ERBB2', 'Gene', '2064', (0, 5))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('microsatellite instability', 'Var', (152, 178))	('ERBB2', 'Gene', (0, 5))	('small bowel adenocarcinomas', 'Disease', (73, 100))	('associated', 'Reg', (114, 124))	('amplifications', 'Var', (23, 37))	('mutations', 'Var', (6, 15))	('small bowel adenocarcinomas', 'Disease', 'MESH:D000230', (73, 100))
13641	33922305	Interestingly ERBB2 inhibitors have been found to display anti-cancer activity in small bowel adenocarcinomas, both in vitro and in vivo.	('small bowel adenocarcinomas', 'Disease', (82, 109))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('small bowel adenocarcinomas', 'Disease', 'MESH:D000230', (82, 109))	('inhibitors', 'Var', (20, 30))	('ERBB2', 'Gene', '2064', (14, 19))	('ERBB2', 'Gene', (14, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
13645	33922305	In duodenal adenocarcinomas microsatellite instability may be associated with MLH1 methylation, however, epigenetic alterations of NADAs are poorly characterized.	('MLH1', 'Gene', '4292', (78, 82))	('carcinomas', 'Phenotype', 'HP:0030731', (17, 27))	('MLH1', 'Gene', (78, 82))	('adenocarcinomas microsatellite instability', 'Disease', (12, 54))	('associated', 'Reg', (62, 72))	('NADAs', 'Chemical', '-', (131, 136))	('duodenal adenocarcinoma', 'Phenotype', 'HP:0006771', (3, 26))	('adenocarcinomas microsatellite instability', 'Disease', 'MESH:D053842', (12, 54))	('duodenal adenocarcinomas', 'Disease', (3, 27))	('methylation', 'Var', (83, 94))	('duodenal adenocarcinomas', 'Disease', 'MESH:D000230', (3, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('duodenal adenocarcinomas', 'Phenotype', 'HP:0006771', (3, 27))
13646	33922305	MLH1 methylation has been recently observed in only 2% of intestinal-type NADAs/intramucosal adenocarcinomas, without a significant association with CpG island methylator phenotype (CIMP).	('methylation', 'Var', (5, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('MLH1', 'Gene', '4292', (0, 4))	('MLH1', 'Gene', (0, 4))	('adenocarcinomas', 'Disease', 'MESH:D000230', (93, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('adenocarcinomas', 'Disease', (93, 108))	('NADAs', 'Chemical', '-', (74, 79))	('CIMP', 'Chemical', '-', (182, 186))	('observed', 'Reg', (35, 43))
13647	33922305	In particular, MLH1 methylation was found in 3% of high grade and in no low grade NADAs by Ota et al.	('found', 'Reg', (36, 41))	('methylation', 'Var', (20, 31))	('NADAs', 'Chemical', '-', (82, 87))	('MLH1', 'Gene', '4292', (15, 19))	('MLH1', 'Gene', (15, 19))
13649	33922305	TP53 abnormalities are infrequent among intestinal-type NADAs.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('abnormalities', 'Var', (5, 18))	('NADAs', 'Chemical', '-', (56, 61))	('intestinal-type NADAs', 'Disease', (40, 61))
13662	33922305	found mutation in guanine nucleotide-binding protein alpha subunit (GNAS) gene in 4 out of 7 (57%) duodenal adenomas with gastric phenotype, and 2 of the 5 cases (40%) of pyloric gland adenomas, whereas APC, BRAF, KRAS, and CTNNB1 genes were wild-type in all investigated gastric-type adenomas.	('BRAF', 'Gene', '673', (208, 212))	('BRAF', 'Gene', (208, 212))	('gastric-type adenomas', 'Disease', (272, 293))	('adenomas', 'Disease', 'MESH:D000236', (108, 116))	('adenomas', 'Disease', (108, 116))	('CTNNB1', 'Gene', '1499', (224, 230))	('GNAS', 'Gene', (68, 72))	('APC', 'Disease', 'MESH:D011125', (203, 206))	('CTNNB1', 'Gene', (224, 230))	('APC', 'Disease', (203, 206))	('GNAS', 'Gene', '2778', (68, 72))	('adenomas', 'Disease', 'MESH:D000236', (185, 193))	('KRAS', 'Gene', '3845', (214, 218))	('adenomas', 'Disease', (185, 193))	('gastric-type adenomas', 'Disease', 'MESH:D000236', (272, 293))	('mutation', 'Var', (6, 14))	('KRAS', 'Gene', (214, 218))	('adenomas', 'Disease', 'MESH:D000236', (285, 293))	('adenomas', 'Disease', (285, 293))
13663	33922305	These findings support the hypothesis that GNAS mutation contributes to the pathogenesis of pyloric gland adenomas of the duodenum, as well as those of the stomach.	('GNAS', 'Gene', (43, 47))	('adenomas', 'Disease', 'MESH:D000236', (106, 114))	('mutation', 'Var', (48, 56))	('GNAS', 'Gene', '2778', (43, 47))	('pathogenesis', 'biological_process', 'GO:0009405', ('76', '88'))	('adenomas', 'Disease', (106, 114))	('contributes', 'Reg', (57, 68))
13664	33922305	Mutations in other oncogenes, like KRAS or in oncosuppressor genes like SMAD4 and TP53, have been observed by other authors.	('TP53', 'Gene', (82, 86))	('KRAS', 'Gene', (35, 39))	('SMAD4', 'Gene', '4089', (72, 77))	('KRAS', 'Gene', '3845', (35, 39))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (82, 86))	('SMAD4', 'Gene', (72, 77))
13666	33922305	In the case of missense mutations of GNAS gene, such as those resulting in R201H and R201C variants, the encoded protein is constitutionally active.	('R201H', 'Var', (75, 80))	('GNAS', 'Gene', (37, 41))	('active', 'MPA', (141, 147))	('R201H', 'Mutation', 'rs121913495', (75, 80))	('GNAS', 'Gene', '2778', (37, 41))	('R201C', 'Var', (85, 90))	('missense mutations', 'Var', (15, 33))
13667	33922305	Among gastrointestinal tract neoplasms, such GNAS gene alterations have been found in pancreatic intraductal papillary mucinous neoplasms (mostly of intestinal type) and colloid carcinomas, low-grade appendiceal mucinous neoplasms/pseudomyxoma peritonei, intestinal villous adenomas, in addition to gastric and duodenal pyloric gland adenomas and duodenal adenocarcinoma.	('neoplasms', 'Phenotype', 'HP:0002664', (29, 38))	('neoplasm', 'Phenotype', 'HP:0002664', (29, 37))	('gastrointestinal tract neoplasms', 'Phenotype', 'HP:0007378', (6, 38))	('intestinal villous', 'Phenotype', 'HP:0011473', (255, 273))	('gastrointestinal tract neoplasms', 'Disease', (6, 38))	('adenomas', 'Disease', 'MESH:D000236', (274, 282))	('duodenal adenocarcinoma', 'Disease', 'MESH:D000230', (347, 370))	('GNAS', 'Gene', (45, 49))	('adenomas', 'Disease', (274, 282))	('duodenal adenocarcinoma', 'Phenotype', 'HP:0006771', (347, 370))	('duodenal adenocarcinoma', 'Disease', (347, 370))	('mucinous neoplasms', 'Phenotype', 'HP:0031495', (119, 137))	('intestinal villous adenomas', 'Disease', (255, 282))	('GNAS', 'Gene', '2778', (45, 49))	('carcinomas', 'Disease', (178, 188))	('pancreatic intraductal papillary mucinous neoplasms', 'Disease', 'MESH:D000077779', (86, 137))	('neoplasm', 'Phenotype', 'HP:0002664', (128, 136))	('appendiceal mucinous neoplasms/pseudomyxoma peritonei', 'Disease', 'MESH:D011553', (200, 253))	('intestinal villous adenomas', 'Disease', 'MESH:D018253', (255, 282))	('gastrointestinal tract neoplasms', 'Disease', 'MESH:D004067', (6, 38))	('adenomas', 'Disease', 'MESH:D000236', (334, 342))	('appendiceal mucinous neoplasms', 'Phenotype', 'HP:0031499', (200, 230))	('mucinous neoplasms', 'Phenotype', 'HP:0031495', (212, 230))	('adenomas', 'Disease', (334, 342))	('carcinoma', 'Phenotype', 'HP:0030731', (361, 370))	('neoplasms', 'Phenotype', 'HP:0002664', (221, 230))	('neoplasms', 'Phenotype', 'HP:0002664', (128, 137))	('alterations', 'Var', (55, 66))	('found', 'Reg', (77, 82))	('neoplasm', 'Phenotype', 'HP:0002664', (221, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('carcinomas', 'Disease', 'MESH:D009369', (178, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (178, 188))
13668	33922305	Interestingly, in duodenal adenocarcinoma, GNAS mutation was associated with gastric phenotype, suggesting that pyloric gland adenomas might represent the precursor lesions of duodenal adenocarcinomas with gastric differentiation.	('duodenal adenocarcinomas', 'Disease', (176, 200))	('GNAS', 'Gene', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('duodenal adenocarcinomas', 'Disease', 'MESH:D000230', (176, 200))	('duodenal adenocarcinoma', 'Disease', 'MESH:D000230', (176, 199))	('duodenal adenocarcinomas', 'Phenotype', 'HP:0006771', (176, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (190, 200))	('adenomas', 'Disease', 'MESH:D000236', (126, 134))	('mutation', 'Var', (48, 56))	('gastric phenotype', 'Disease', (77, 94))	('duodenal adenocarcinoma', 'Disease', 'MESH:D000230', (18, 41))	('GNAS', 'Gene', '2778', (43, 47))	('duodenal adenocarcinoma', 'Phenotype', 'HP:0006771', (176, 199))	('duodenal adenocarcinoma', 'Phenotype', 'HP:0006771', (18, 41))	('associated', 'Reg', (61, 71))	('adenomas', 'Disease', (126, 134))	('duodenal adenocarcinoma', 'Disease', (18, 41))
13670	33922305	Despite the rarity of APC or CTNNB1 mutations, duodenal pyloric gland adenomas have been reported to express nuclear beta-catenin (a marker of Wnt pathway activation) by immunohistochemistry in a variable fraction of cases (up to 80%), suggesting that currently unknown molecular alterations other than CTNNB1 or APC mutation may be responsible for Wnt pathway activation.	('adenomas', 'Disease', 'MESH:D000236', (70, 78))	('APC', 'Disease', 'MESH:D011125', (22, 25))	('APC', 'Disease', (22, 25))	('adenomas', 'Disease', (70, 78))	('CTNNB1', 'Gene', '1499', (303, 309))	('APC', 'cellular_component', 'GO:0005680', ('22', '25'))	('beta-catenin', 'Gene', (117, 129))	('CTNNB1', 'Gene', '1499', (29, 35))	('beta-catenin', 'Gene', '1499', (117, 129))	('APC', 'Disease', 'MESH:D011125', (313, 316))	('CTNNB1', 'Gene', (303, 309))	('APC', 'Disease', (313, 316))	('APC', 'cellular_component', 'GO:0005680', ('313', '316'))	('Wnt', 'Gene', (349, 352))	('Wnt', 'Gene', (143, 146))	('mutations', 'Var', (36, 45))	('Wnt', 'Gene', '114487', (349, 352))	('CTNNB1', 'Gene', (29, 35))	('Wnt', 'Gene', '114487', (143, 146))
13671	33922305	The protein kinase A, activated by GNAS mutations, might play a role in Wnt pathway activation in pyloric gland adenomas by stabilizing beta-catenin.	('beta-catenin', 'Gene', '1499', (136, 148))	('activation', 'PosReg', (84, 94))	('Wnt', 'Gene', '114487', (72, 75))	('GNAS', 'Gene', '2778', (35, 39))	('adenomas', 'Disease', 'MESH:D000236', (112, 120))	('mutations', 'Var', (40, 49))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))	('adenomas', 'Disease', (112, 120))	('Wnt', 'Gene', (72, 75))	('GNAS', 'Gene', (35, 39))	('beta-catenin', 'Gene', (136, 148))	('stabilizing', 'NegReg', (124, 135))	('protein kinase A', 'Enzyme', (4, 20))
13674	33922305	described GNAS and KRAS gene mutations in 28% and 2% of gastric heterotopias, and in 17% and 37% of duodenal adenocarcinomas, respectively, supporting a pathogenetic link between gastric heterotopias and gastric-type adenomas or duodenal adenocarcinomas.	('GNAS', 'Gene', '2778', (10, 14))	('carcinomas', 'Phenotype', 'HP:0030731', (243, 253))	('heterotopia', 'Phenotype', 'HP:0002282', (187, 198))	('heterotopias', 'Phenotype', 'HP:0002282', (64, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('duodenal adenocarcinomas', 'Disease', 'MESH:D000230', (229, 253))	('KRAS', 'Gene', '3845', (19, 23))	('gastric heterotopias', 'Disease', (179, 199))	('gastric heterotopias', 'Disease', 'MESH:D013274', (179, 199))	('duodenal adenocarcinomas', 'Disease', 'MESH:D000230', (100, 124))	('gastric-type adenomas', 'Disease', 'MESH:D000236', (204, 225))	('KRAS', 'Gene', (19, 23))	('heterotopias', 'Phenotype', 'HP:0002282', (187, 199))	('duodenal adenocarcinoma', 'Phenotype', 'HP:0006771', (229, 252))	('mutations', 'Var', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('duodenal adenocarcinoma', 'Phenotype', 'HP:0006771', (100, 123))	('heterotopia', 'Phenotype', 'HP:0002282', (64, 75))	('gastric-type adenomas', 'Disease', (204, 225))	('duodenal adenocarcinomas', 'Phenotype', 'HP:0006771', (229, 253))	('gastric heterotopias', 'Disease', 'MESH:D013274', (56, 76))	('gastric heterotopias', 'Disease', (56, 76))	('duodenal adenocarcinomas', 'Phenotype', 'HP:0006771', (100, 124))	('duodenal adenocarcinomas', 'Disease', (229, 253))	('GNAS', 'Gene', (10, 14))	('duodenal adenocarcinomas', 'Disease', (100, 124))
13675	33922305	found GNAS and KRAS mutations in 41% and 26% of gastric foveolar metaplastic lesions of the duodenum, in keeping with other authors.	('gastric foveolar', 'Disease', (48, 64))	('KRAS', 'Gene', (15, 19))	('GNAS', 'Gene', (6, 10))	('KRAS', 'Gene', '3845', (15, 19))	('mutations', 'Var', (20, 29))	('GNAS', 'Gene', '2778', (6, 10))
13686	33922305	In one study including two foveolar adenomas of the duodenum, both harbored GNAS mutations, while no APC, KRAS, or CTNNB1 mutations were found.	('adenomas', 'Disease', 'MESH:D000236', (36, 44))	('KRAS', 'Gene', '3845', (106, 110))	('APC', 'Disease', (101, 104))	('CTNNB1', 'Gene', '1499', (115, 121))	('adenomas', 'Disease', (36, 44))	('GNAS', 'Gene', '2778', (76, 80))	('KRAS', 'Gene', (106, 110))	('mutations', 'Var', (81, 90))	('CTNNB1', 'Gene', (115, 121))	('APC', 'Disease', 'MESH:D011125', (101, 104))	('GNAS', 'Gene', (76, 80))	('harbored', 'Reg', (67, 75))
13697	33922305	Mutations in the APC gene have been found in adenomas and in early stage ampullary adenocarcinomas, identifying this alteration as an early event.	('APC', 'Disease', 'MESH:D011125', (17, 20))	('APC', 'Disease', (17, 20))	('found', 'Reg', (36, 41))	('adenocarcinomas', 'Disease', 'MESH:D000230', (83, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('adenocarcinomas', 'Disease', (83, 98))	('Mutations', 'Var', (0, 9))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('adenomas', 'Disease', 'MESH:D000236', (45, 53))	('adenomas', 'Disease', (45, 53))
13700	33922305	With regards to the MAP kinase pathway, KRAS mutations have been described in about 40% of ampullary adenocarcinomas as well as in ADAs (about 30%), even in areas of low-grade dysplasia.	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('mutations', 'Var', (45, 54))	('described', 'Reg', (65, 74))	('KRAS', 'Gene', (40, 44))	('MAP', 'molecular_function', 'GO:0004239', ('20', '23'))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('ADAs', 'Gene', (131, 135))	('KRAS', 'Gene', '3845', (40, 44))	('dysplasia', 'Disease', 'MESH:C536170', (176, 185))	('adenocarcinomas', 'Disease', 'MESH:D000230', (101, 116))	('adenocarcinomas', 'Disease', (101, 116))	('ADAs', 'Gene', '8540', (131, 135))	('dysplasia', 'Disease', (176, 185))
13701	33922305	Importantly, KRAS mutations have been found in a high percentage of ampullary adenomas (93%) when they are adjacent to invasive carcinomas.	('invasive carcinomas', 'Disease', 'MESH:D009361', (119, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('KRAS', 'Gene', (13, 17))	('adenomas', 'Disease', 'MESH:D000236', (78, 86))	('adenomas', 'Disease', (78, 86))	('found', 'Reg', (38, 43))	('invasive carcinomas', 'Disease', (119, 138))	('KRAS', 'Gene', '3845', (13, 17))	('mutations', 'Var', (18, 27))
13702	33922305	This finding supports the concept that adenomas are precancerous conditions and that KRAS alterations occur at an early stage of ampullary cancerogenesis.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancerous', 'Disease', (55, 64))	('alterations', 'Var', (90, 101))	('adenomas', 'Disease', 'MESH:D000236', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('adenomas', 'Disease', (39, 47))	('cancerous', 'Disease', 'MESH:D009369', (55, 64))	('KRAS', 'Gene', (85, 89))	('KRAS', 'Gene', '3845', (85, 89))	('cancer', 'Disease', (55, 61))	('cancer', 'Disease', (139, 145))
13708	33922305	The largest study on ampullary adenomas and adenocarcinomas showed MSI-H in 9% of adenomas (9/89) and in 10% of adenocarcinomas (15/144) with high levels of MSI concordance between the adenomatous component and adjacent invasive component, when present.	('adenoma', 'Disease', (82, 89))	('adenoma', 'Disease', (185, 192))	('adenocarcinomas', 'Disease', 'MESH:D000230', (44, 59))	('adenoma', 'Disease', 'MESH:D000236', (82, 89))	('adenocarcinomas', 'Disease', (44, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (49, 59))	('adenoma', 'Disease', 'MESH:D000236', (185, 192))	('adenoma', 'Disease', (31, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('adenoma', 'Disease', 'MESH:D000236', (31, 38))	('adenomas', 'Disease', 'MESH:D000236', (82, 90))	('adenomas', 'Disease', (82, 90))	('adenocarcinomas', 'Disease', 'MESH:D000230', (112, 127))	('MSI-H', 'Var', (67, 72))	('adenocarcinomas', 'Disease', (112, 127))	('adenomas', 'Disease', 'MESH:D000236', (31, 39))	('adenomas', 'Disease', (31, 39))
13709	33922305	A third of MSI-H adenomas showed MLH1 promoter hypermethylation while a further third of such adenomas showed loss of MSH6 (and could be part of LS).	('MSI-H adenomas', 'Disease', 'MESH:D000236', (11, 25))	('MLH1', 'Gene', (33, 37))	('MSI-H adenomas', 'Disease', (11, 25))	('loss', 'NegReg', (110, 114))	('promoter', 'MPA', (38, 46))	('adenomas', 'Disease', (94, 102))	('adenomas', 'Disease', 'MESH:D000236', (17, 25))	('MSH6', 'Gene', (118, 122))	('adenomas', 'Disease', (17, 25))	('MLH1', 'Gene', '4292', (33, 37))	('MSH6', 'Gene', '2956', (118, 122))	('hypermethylation', 'Var', (47, 63))	('adenomas', 'Disease', 'MESH:D000236', (94, 102))
13716	33922305	Recently three new entities of adenomatous polyposis syndromes have been described:the autosomal dominant polymerase proofreading-associated polyposis syndrome, caused by mutations in POLD1 (MIM:174761) and POLE (MIM: 174762) genes, the autosomal recessive NTHL1-associated polyposis (MIM: 616415), and the autosomal recessive MSH3-associated polyposis (MIM: 600887).	('adenomatous polyposis syndromes', 'Disease', 'MESH:D011125', (31, 62))	('polyposis', 'Disease', (274, 283))	('polyposis', 'Disease', 'MESH:D044483', (141, 150))	('NTHL1', 'Gene', '4913', (257, 262))	('caused by', 'Reg', (161, 170))	('polyposis', 'Disease', (343, 352))	('POLD1', 'Gene', (184, 189))	('polyposis syndrome', 'Disease', 'MESH:D011125', (43, 61))	('polyposis', 'Disease', 'MESH:D044483', (43, 52))	('polyposis syndrome', 'Disease', (141, 159))	('polyposis', 'Disease', 'MESH:D044483', (274, 283))	('polyposis', 'Disease', (141, 150))	('mutations', 'Var', (171, 180))	('polyposis', 'Disease', 'MESH:D044483', (343, 352))	('MSH3', 'Gene', (327, 331))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (31, 52))	('POLD1', 'Gene', '5424', (184, 189))	('MSH3', 'Gene', '4437', (327, 331))	('NTHL1', 'Gene', (257, 262))	('polyposis syndrome', 'Disease', 'MESH:D011125', (141, 159))	('adenomatous polyposis syndromes', 'Disease', (31, 62))	('polyposis', 'Disease', (43, 52))
13736	33922305	About 30% of all APC germ line alterations occur at codons 1061 and 1309, while the remaining mutations are spread rather uniformly between codons 200 and 1600.	('alterations', 'Var', (31, 42))	('APC', 'Disease', 'MESH:D011125', (17, 20))	('APC', 'Disease', (17, 20))
13743	33922305	The greater burden of somatic alterations and copy number variations observed in MAP adenomatous growths is the result of base excision repair defects in MAP patients.	('adenoma', 'Disease', (85, 92))	('copy number variations', 'Var', (46, 68))	('defects', 'NegReg', (143, 150))	('patients', 'Species', '9606', (158, 166))	('adenoma', 'Disease', 'MESH:D000236', (85, 92))
13744	33922305	The MUTYH gene, which is located on chromosome 1 (1p32.1-p34.3) and includes 16 exons, encodes for a glycosylase involved in base excision repair system and in repairing DNA mutations secondary to oxidative DNA damage.	('MUTYH', 'Gene', '4595', (4, 9))	('MUTYH', 'Gene', (4, 9))	('DNA', 'Gene', (170, 173))	('mutations', 'Var', (174, 183))	('p34', 'Gene', (57, 60))	('p34', 'Gene', '79719', (57, 60))	('encodes', 'Reg', (87, 94))
13745	33922305	More than 300 MUTYH pathogenic variants have been described in MAP individuals.	('MUTYH', 'Gene', (14, 19))	('MUTYH', 'Gene', '4595', (14, 19))	('variants', 'Var', (31, 39))	('MAP', 'molecular_function', 'GO:0004239', ('63', '66'))
13746	33922305	The Collaborative Group on MAP reported that the risk of duodenal polyposis in these patients is related to genotype, showing that p.Y179C homozygote patients have an increased risk.	('duodenal polyposis', 'Phenotype', 'HP:0004783', (57, 75))	('p.Y179C', 'Mutation', 'rs34612342', (131, 138))	('duodenal polyposis', 'Disease', 'MESH:D004382', (57, 75))	('patients', 'Species', '9606', (85, 93))	('p.Y179C', 'Var', (131, 138))	('patients', 'Species', '9606', (150, 158))	('duodenal polyposis', 'Disease', (57, 75))
13747	33922305	APC and MUTYH gene analysis are required by diagnostic protocols in the background of inherited adenomatous polyposis; furthermore, mutations in POLE, POLD1, NTLH1, and MSH3 genes are nowadays also screened by most laboratories.	('POLD1', 'Gene', '5424', (151, 156))	('MUTYH', 'Gene', '4595', (8, 13))	('MSH3', 'Gene', (169, 173))	('MSH3', 'Gene', '4437', (169, 173))	('APC', 'cellular_component', 'GO:0005680', ('0', '3'))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('mutations', 'Var', (132, 141))	('NTLH1', 'Gene', (158, 163))	('POLE', 'Gene', (145, 149))	('inherited adenomatous polyposis', 'Disease', 'MESH:D011125', (86, 117))	('APC', 'Disease', (0, 3))	('MUTYH', 'Gene', (8, 13))	('inherited adenomatous polyposis', 'Disease', (86, 117))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (96, 117))	('POLD1', 'Gene', (151, 156))
13749	33922305	To date, POLE and POLD1 germline mutations have been correlated with attenuated colorectal polyposis, while gastroduodenal adenomatous growths have been observed in about 57% of carriers.	('adenoma', 'Disease', 'MESH:D000236', (123, 130))	('colorectal polyposis', 'Phenotype', 'HP:0200063', (80, 100))	('adenoma', 'Disease', (123, 130))	('POLE', 'Gene', (9, 13))	('germline mutations', 'Var', (24, 42))	('attenuated colorectal polyposis', 'Disease', (69, 100))	('attenuated colorectal polyposis', 'Disease', 'MESH:C538265', (69, 100))	('POLD1', 'Gene', (18, 23))	('POLD1', 'Gene', '5424', (18, 23))
13752	33922305	Germline homozygous or compound heterozygous NTHL1 mutations have been associated with multiple colorectal adenomas but also with adenomas in extracolonic sites, including the duodenum.	('adenomas', 'Disease', (107, 115))	('mutations', 'Var', (51, 60))	('colonic', 'Disease', 'MESH:D003110', (147, 154))	('colorectal adenomas', 'Disease', (96, 115))	('duodenum', 'Disease', (176, 184))	('colonic', 'Disease', (147, 154))	('colorectal adenomas', 'Disease', 'MESH:D015179', (96, 115))	('compound heterozygous', 'Var', (23, 44))	('adenomas', 'Disease', 'MESH:D000236', (130, 138))	('NTHL1', 'Gene', '4913', (45, 50))	('NTHL1', 'Gene', (45, 50))	('adenomas', 'Disease', (130, 138))	('adenomas', 'Disease', 'MESH:D000236', (107, 115))	('associated', 'Reg', (71, 81))
13753	33922305	carried out whole exome sequencing on patients with unexplained adenomatous polyposis, and found two unrelated individuals showing different compound heterozygous mutations in MSH3, a gene involved in the MMR system.	('MSH3', 'Gene', (176, 180))	('MSH3', 'Gene', '4437', (176, 180))	('mutations', 'Var', (163, 172))	('adenomatous polyposis', 'Disease', (64, 85))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (64, 85))	('patients', 'Species', '9606', (38, 46))	('adenomatous polyposis', 'Disease', 'MESH:D011125', (64, 85))
13754	33922305	Interestingly, MSH3 mutation carriers may also feature duodenal adenomas.	('MSH3', 'Gene', (15, 19))	('feature', 'Reg', (47, 54))	('adenomas', 'Disease', 'MESH:D000236', (64, 72))	('mutation', 'Var', (20, 28))	('adenomas', 'Disease', (64, 72))	('MSH3', 'Gene', '4437', (15, 19))
13755	33922305	LS is an autosomal dominant syndrome due to a germline mutation of MMR genes and is related to an increased risk of large bowel carcinoma and of other neoplasms including small bowel cancer.	('germline mutation', 'Var', (46, 63))	('MMR', 'Gene', (67, 70))	('neoplasms', 'Disease', 'MESH:D009369', (151, 160))	('neoplasms', 'Disease', (151, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('bowel carcinoma', 'Disease', (122, 137))	('autosomal dominant syndrome', 'Disease', (9, 36))	('neoplasm', 'Phenotype', 'HP:0002664', (151, 159))	('large bowel', 'Phenotype', 'HP:0002037', (116, 127))	('small bowel cancer', 'Disease', 'MESH:D009369', (171, 189))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (9, 36))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('small bowel cancer', 'Disease', (171, 189))	('neoplasms', 'Phenotype', 'HP:0002664', (151, 160))	('due to', 'Reg', (37, 43))	('bowel carcinoma', 'Disease', 'MESH:D055496', (122, 137))
13757	33922305	In addition, deletion in the EPCAM gene may lead to MSH2 inactivation.	('lead', 'Reg', (44, 48))	('EPCAM', 'Gene', '4072', (29, 34))	('deletion', 'Var', (13, 21))	('MSH2', 'Gene', (52, 56))	('MSH2', 'Gene', '4436', (52, 56))	('inactivation', 'NegReg', (57, 69))	('EPCAM', 'Gene', (29, 34))
13771	33922305	On the contrary, MSI due to MLH1 hypermethylation, which is a common feature of CD-associated small bowel adenocarcinoma appears to be a late event in small bowel carcinogenesis in these patients, as it was solely detected in the preinvasive component of one case.	('patients', 'Species', '9606', (187, 195))	('small bowel adenocarcinoma', 'Disease', 'MESH:D000230', (94, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('small bowel adenocarcinoma', 'Disease', (94, 120))	('CD', 'Phenotype', 'HP:0002608', (80, 82))	('small bowel carcinogenesis', 'Disease', (151, 177))	('MLH1', 'Gene', '4292', (28, 32))	('hypermethylation', 'Var', (33, 49))	('MLH1', 'Gene', (28, 32))	('small bowel carcinogenesis', 'Disease', 'MESH:D063646', (151, 177))
13781	33922305	Similarly to CD-related dysplasia, microsatellite instability seems to play a minor role in early phases of the carcinogenic process in CrD-associated lesions also.	('CrD', 'Phenotype', 'HP:0100280', (136, 139))	('CrD-associated', 'Disease', (136, 150))	('carcinogenic', 'Disease', 'MESH:D063646', (112, 124))	('microsatellite instability', 'Var', (35, 61))	('carcinogenic', 'Disease', (112, 124))	('dysplasia', 'Disease', 'MESH:C536170', (24, 33))	('dysplasia', 'Disease', (24, 33))	('CD', 'Phenotype', 'HP:0002608', (13, 15))
13782	33922305	Molecular studies have described KRAS mutations in a small number of CrD-associated preinvasive growths (about 13%), found in exon 12 or, in only a single dysplastic lesion, in exon 37.	('CrD-associated', 'Gene', (69, 83))	('CrD', 'Phenotype', 'HP:0100280', (69, 72))	('KRAS', 'Gene', (33, 37))	('dysplastic lesion', 'Disease', (155, 172))	('KRAS', 'Gene', '3845', (33, 37))	('dysplastic lesion', 'Disease', 'MESH:D004416', (155, 172))	('preinvasive growths', 'Disease', (84, 103))	('mutations', 'Var', (38, 47))
13783	33922305	PIK3CA mutations were also found, mostly in "eosinophilic" type dysplasia.	('PIK3CA', 'Gene', (0, 6))	('dysplasia', 'Disease', 'MESH:C536170', (64, 73))	('PIK3CA', 'Gene', '5290', (0, 6))	('dysplasia', 'Disease', (64, 73))	('mutations', 'Var', (7, 16))
13784	33922305	On the contrary, no BRAF, NRAS, or EGFR mutations were reported.	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('NRAS', 'Gene', (26, 30))	('BRAF', 'Gene', '673', (20, 24))	('EGFR', 'molecular_function', 'GO:0005006', ('35', '39'))	('NRAS', 'Gene', '4893', (26, 30))	('BRAF', 'Gene', (20, 24))
13795	33922305	Molecular testing information, available for 8 Hyp-P from 2 different studies, has demonstrated KRAS mutation in 2, BRAF V600E mutation in 2, and no mutation for either gene in the remaining 4 polyps.	('V600E', 'Mutation', 'rs113488022', (121, 126))	('KRAS', 'Gene', '3845', (96, 100))	('polyps', 'Disease', 'MESH:D011127', (193, 199))	('mutation', 'Var', (101, 109))	('BRAF', 'Gene', '673', (116, 120))	('BRAF', 'Gene', (116, 120))	('Hyp-P', 'Disease', (47, 52))	('Hyp-P', 'Disease', 'MESH:C000656865', (47, 52))	('polyps', 'Disease', (193, 199))	('KRAS', 'Gene', (96, 100))
13801	33922305	Interestingly, unlike colorectal TSAs where the CIMP phenotype is concomitant with BRAF mutation, in duodenal TSAs, CIMP phenotype is an early and frequent molecular event unrelated to MLH1 loss and BRAF mutations.	('colorectal TSAs', 'Disease', (22, 37))	('mutation', 'Var', (88, 96))	('MLH1', 'Gene', '4292', (185, 189))	('colorectal TSAs', 'Disease', 'MESH:D015179', (22, 37))	('MLH1', 'Gene', (185, 189))	('BRAF', 'Gene', (199, 203))	('CIMP', 'Chemical', '-', (116, 120))	('BRAF', 'Gene', '673', (199, 203))	('BRAF', 'Gene', '673', (83, 87))	('BRAF', 'Gene', (83, 87))	('CIMP', 'Chemical', '-', (48, 52))
13805	33922305	The latter includes several conditions characterized by mutations in PTEN, a gene implicated in tumor suppression, the most common of which is Cowden Syndrome (CS).	('PTEN', 'Gene', '5728', (69, 73))	('Cowden Syndrome', 'Disease', (143, 158))	('mutations', 'Var', (56, 65))	('CS', 'Gene', '1431', (160, 162))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('Cowden Syndrome', 'Disease', 'MESH:D006223', (143, 158))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('PTEN', 'Gene', (69, 73))
13824	33922305	This hypothesis was based on the demonstration of genetic alterations in stromal cells of syndromic juvenile polyps but not in the epithelial component.	('genetic', 'Var', (50, 57))	('syndromic juvenile polyps', 'Disease', 'MESH:D011127', (90, 115))	('juvenile polyps', 'Phenotype', 'HP:0004784', (100, 115))	('syndromic juvenile polyps', 'Disease', (90, 115))	('juvenile polyp', 'Phenotype', 'HP:0004784', (100, 114))
13825	33922305	Several authors have tried to consolidate this hypothesis by studying genetic alterations in the stroma and epithelium of both syndromic juvenile and Peutz-Jeghers polyps, with inconclusive and contrasting results.	('polyps', 'Disease', (164, 170))	('syndromic juvenile', 'Disease', (127, 145))	('Peutz-Jeghers', 'Disease', (150, 163))	('genetic', 'Var', (70, 77))	('polyps', 'Disease', 'MESH:D011127', (164, 170))	('syndromic juvenile', 'Disease', 'MESH:C537702', (127, 145))
13828	33922305	More than 90% of patients fulfilling the diagnostic criteria for PJS and carry mutation in STK11, a tumor suppression gene, located at 19p13.3, which encodes for a serine/threonine kinase.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('STK11', 'Gene', (91, 96))	('serine', 'Chemical', 'MESH:D012694', (164, 170))	('tumor', 'Disease', (100, 105))	('STK11', 'Gene', '6794', (91, 96))	('mutation', 'Var', (79, 87))	('patients', 'Species', '9606', (17, 25))	('STK11', 'molecular_function', 'GO:0033868', ('91', '96'))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
13830	33922305	Missense/nonsense mutations, mutations in splicing sites, small insertions, deletions, and indel type mutations cover the majority (about 70%) of STK11 alterations in PJS.	('splicing', 'biological_process', 'GO:0045292', ('42', '50'))	('Missense/nonsense mutations', 'Var', (0, 27))	('alterations', 'Var', (152, 163))	('mutations', 'Var', (29, 38))	('STK11', 'Gene', (146, 151))	('STK11', 'molecular_function', 'GO:0033868', ('146', '151'))	('STK11', 'Gene', '6794', (146, 151))
13831	33922305	The remaining 30% of cases are represented by rearrangements for deletions, insertions, or combined mutations of larger fragments of the STK11 sequence.	('mutations', 'Var', (100, 109))	('men', 'Species', '9606', (55, 58))	('men', 'Species', '9606', (124, 127))	('STK11', 'Gene', (137, 142))	('insertions', 'Var', (76, 86))	('deletions', 'Var', (65, 74))	('STK11', 'Gene', '6794', (137, 142))	('STK11', 'molecular_function', 'GO:0033868', ('137', '142'))	('rearrangements', 'Var', (46, 60))
13832	33922305	Patients with clinical diagnosis of PJS and with wild-type STK11, have shown heterozygous mutation in a great variety of other genes, including APC and DNA MMR genes.	('heterozygous mutation', 'Var', (77, 98))	('STK11', 'Gene', (59, 64))	('DNA MMR genes', 'Gene', (152, 165))	('APC', 'Disease', 'MESH:D011125', (144, 147))	('APC', 'Disease', (144, 147))	('Patients', 'Species', '9606', (0, 8))	('STK11', 'Gene', '6794', (59, 64))	('PJS', 'Disease', (36, 39))
13833	33922305	Mutation type does not seem to correlate with cancer risk while, more recently, it has been suggested that hypomethylation of STK11 promoter in PJS polyps might represent a risk factor for gastrointestinal malignancy development.	('PJS polyps', 'Disease', 'MESH:D011127', (144, 154))	('men', 'Species', '9606', (224, 227))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('PJS polyps', 'Disease', (144, 154))	('gastrointestinal malignancy', 'Disease', 'MESH:D004067', (189, 216))	('STK11', 'Gene', (126, 131))	('cancer', 'Disease', (46, 52))	('risk factor', 'Reg', (173, 184))	('gastrointestinal malignancy', 'Disease', (189, 216))	('STK11', 'Gene', '6794', (126, 131))	('hypomethylation', 'Var', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('STK11', 'molecular_function', 'GO:0033868', ('126', '131'))
13838	33922305	Germline mutations in SMAD4 (18q21) and BMPR1A (10q22-23) gene, both part of the transforming growth factor-beta (TGF-beta) signaling pathway, have been detected in about 20-30% of cases respectively, as point mutations and, less frequently, large deletions.	('SMAD4', 'Gene', (22, 27))	('BMPR1A', 'Gene', '657', (40, 46))	('TGF-beta', 'Gene', (114, 122))	('transforming growth factor-beta', 'molecular_function', 'GO:0005160', ('81', '112'))	('transforming growth factor-beta', 'Gene', (81, 112))	('detected', 'Reg', (153, 161))	('TGF-beta', 'Gene', '7039', (114, 122))	('transforming growth factor-beta', 'Gene', '7124', (81, 112))	('SMAD4', 'Gene', '4089', (22, 27))	('BMPR1A', 'Gene', (40, 46))	('signaling pathway', 'biological_process', 'GO:0007165', ('124', '141'))	('point mutations', 'Var', (204, 219))
13841	33922305	Patients carrying SMAD4 mutations have an increased risk of developing juvenile polyps in the stomach and manifest symptoms later than patients with BMPR1A mutations, possibly reflecting different age-related penetrance; this probably also correlates with a higher risk of gastric cancer development.	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('juvenile polyps', 'Phenotype', 'HP:0004784', (71, 86))	('patients', 'Species', '9606', (135, 143))	('SMAD4', 'Gene', '4089', (18, 23))	('juvenile polyp', 'Phenotype', 'HP:0004784', (71, 85))	('gastric cancer', 'Disease', (273, 287))	('BMPR1A', 'Gene', (149, 155))	('gastric cancer', 'Disease', 'MESH:D013274', (273, 287))	('Patients', 'Species', '9606', (0, 8))	('juvenile polyps', 'Disease', (71, 86))	('men', 'Species', '9606', (295, 298))	('SMAD4', 'Gene', (18, 23))	('gastric cancer', 'Phenotype', 'HP:0012126', (273, 287))	('mutations', 'Var', (24, 33))	('juvenile polyps', 'Disease', 'MESH:D011127', (71, 86))	('BMPR1A', 'Gene', '657', (149, 155))
13847	33922305	Germline mutations in PTEN, located on 10q22-q23, are demonstrated in up to 80% of patients.	('Germline mutations', 'Var', (0, 18))	('patients', 'Species', '9606', (83, 91))	('PTEN', 'Gene', (22, 26))	('PTEN', 'Gene', '5728', (22, 26))
13849	33922305	All types of mutations can affect PTEN gene, mainly in exons 5, 7, and 8; nonsense mutations correlate with colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('colorectal cancer', 'Disease', (108, 125))	('mutations', 'Var', (13, 22))	('PTEN', 'Gene', (34, 38))	('affect', 'Reg', (27, 33))	('PTEN', 'Gene', '5728', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
13857	33922305	While approximately 50% of MEN1-associated duodenal NETs and microtumors show LOH on chromosome 11q13, the hyperplastic G cells consistently lack this finding.	('MEN1', 'Gene', '4221', (27, 31))	('LOH', 'Var', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('MEN1', 'Gene', (27, 31))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('NETs', 'Phenotype', 'HP:0100634', (52, 56))
13858	33922305	This is important as it suggests that hyperplastic cells, though they harbor MEN1 germline mutations, are not yet committed to neoplastic transformation and indeed, LOH on chromosome 11q13 is a crucial event in the etiopathogenesis of duodenal gastrinomas.	('LOH on', 'Var', (165, 171))	('duodenal gastrinomas', 'Disease', (235, 255))	('mutations', 'Var', (91, 100))	('MEN1', 'Gene', (77, 81))	('duodenal gastrinomas', 'Disease', 'MESH:D015408', (235, 255))	('MEN1', 'Gene', '4221', (77, 81))
13862	33922305	Allelic loss (LOH at 11q13) has also been detected in duodenal somatostatin, producing MEN1-associated tumors as small as 400 microns; the hyperplastic somatostatin cells, however, similarly to the hyperplastic G-cells, do not show chromosome 11q13 LOH.	('somatostatin', 'Gene', (152, 164))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('MEN1', 'Gene', (87, 91))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('MEN1', 'Gene', '4221', (87, 91))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('somatostatin', 'Gene', '6750', (63, 75))	('Allelic', 'Var', (0, 7))	('somatostatin', 'Gene', '6750', (152, 164))	('somatostatin', 'Gene', (63, 75))	('chromosome', 'cellular_component', 'GO:0005694', ('232', '242'))
13872	33771981	ZFAS1 knockdown was associated with decreased cellular proliferation, migration, and invasion in two colon cancer cell lines (HT29 and SW480).	('colon cancer', 'Disease', 'MESH:D015179', (101, 113))	('migration', 'CPA', (70, 79))	('colon cancer', 'Disease', (101, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cellular proliferation', 'CPA', (46, 68))	('ZFAS1', 'Gene', (0, 5))	('invasion', 'CPA', (85, 93))	('SW480', 'CellLine', 'CVCL:0546', (135, 140))	('knockdown', 'Var', (6, 15))	('HT29', 'CellLine', 'CVCL:0320', (126, 130))	('colon cancer', 'Phenotype', 'HP:0003003', (101, 113))	('decreased', 'NegReg', (36, 45))
13874	33771981	ZFAS1 knockdown regulated ZEB1 gene expression and downstream targets E-cadherin and vimentin.	('expression', 'MPA', (36, 46))	('E-cadherin', 'Gene', '999', (70, 80))	('gene expression', 'biological_process', 'GO:0010467', ('31', '46'))	('cadherin', 'molecular_function', 'GO:0008014', ('72', '80'))	('regulated', 'Reg', (16, 25))	('vimentin', 'cellular_component', 'GO:0045099', ('85', '93'))	('ZEB1', 'Gene', '6935', (26, 30))	('ZEB1', 'Gene', (26, 30))	('vimentin', 'cellular_component', 'GO:0045098', ('85', '93'))	('ZFAS1', 'Gene', (0, 5))	('vimentin', 'Gene', '7431', (85, 93))	('knockdown', 'Var', (6, 15))	('E-cadherin', 'Gene', (70, 80))	('vimentin', 'Gene', (85, 93))
13875	33771981	Knockdown of miR-200b or miR-200c reversed the effect of ZFAS1 knockdown in the ZEB1/E-cadherin, vimentin signaling cascade, and the effects of cellular migration and invasion, but not cellular proliferation.	('ZEB1', 'Gene', '6935', (80, 84))	('miR-200b', 'Gene', '406984', (13, 21))	('vimentin', 'Gene', '7431', (97, 105))	('ZEB1', 'Gene', (80, 84))	('miR-200b', 'Gene', (13, 21))	('vimentin', 'Gene', (97, 105))	('invasion', 'CPA', (167, 175))	('ZFAS1', 'Gene', (57, 62))	('E-cadherin', 'Gene', (85, 95))	('E-cadherin', 'Gene', '999', (85, 95))	('miR-200c', 'Gene', (25, 33))	('miR-200c', 'Gene', '406985', (25, 33))	('knockdown', 'Var', (63, 72))	('cellular migration', 'CPA', (144, 162))
13876	33771981	ZFAS1 knockdown was also associated with decreased tumor growth in an in vivo mouse model.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('decreased tumor', 'Disease', 'MESH:D002303', (41, 56))	('ZFAS1', 'Gene', (0, 5))	('mouse', 'Species', '10090', (78, 83))	('knockdown', 'Var', (6, 15))	('decreased tumor', 'Disease', (41, 56))
13886	33771981	A recent review described that the majority of studies report that ZFAS1 has an oncogenic role, but ZFAS1 has a tumor suppressor role in breast cancer, and conflicting mechanisms have been reported in hepatocellular cancer.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('112', '128'))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (201, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('tumor', 'Disease', (112, 117))	('ZFAS1', 'Var', (100, 105))	('tumor suppressor', 'biological_process', 'GO:0051726', ('112', '128'))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
13904	33771981	Following ZFAS1 knockdown, expression of both miR-200b and miR-200c was significantly increased compared to non-target siRNA (Fig.	('miR-200b', 'Gene', (46, 54))	('increased', 'PosReg', (86, 95))	('expression', 'MPA', (27, 37))	('knockdown', 'Var', (16, 25))	('miR-200b', 'Gene', '406984', (46, 54))	('miR-200c', 'Gene', '406985', (59, 67))	('miR-200c', 'Gene', (59, 67))	('ZFAS1', 'Gene', (10, 15))
13905	33771981	3c, d. ZFAS1 was inversely correlated with miR-200c (Spearman r = -0.120, p = 0.09), but not inversely correlated with miR-200b (Spearman r = -0.030, p = 0.65) in the TCGA data set (Fig.	('d. ZFAS1', 'Var', (4, 12))	('correlated', 'Interaction', (27, 37))	('miR-200c', 'Gene', (43, 51))	('miR-200b', 'Gene', (119, 127))	('miR-200c', 'Gene', '406985', (43, 51))	('inversely', 'NegReg', (17, 26))	('miR-200b', 'Gene', '406984', (119, 127))
13914	33771981	ZFAS1 knockdown, in turn, leads to decreased ZEB1 protein expression in both cell lines (Fig.	('decreased', 'NegReg', (35, 44))	('ZFAS1', 'Gene', (0, 5))	('ZEB1', 'Gene', (45, 49))	('knockdown', 'Var', (6, 15))	('ZEB1', 'Gene', '6935', (45, 49))
13915	33771981	Furthermore, dual knockdown of ZFAS1 and miR-200b or ZFAS1 and miR-200c reversed this effect on ZEB1 expression in both the HT29 and SW480 cell lines.	('ZFAS1', 'Var', (53, 58))	('HT29', 'CellLine', 'CVCL:0320', (124, 128))	('miR-200b', 'Gene', '406984', (41, 49))	('ZEB1', 'Gene', (96, 100))	('miR-200b', 'Gene', (41, 49))	('ZEB1', 'Gene', '6935', (96, 100))	('miR-200c', 'Gene', (63, 71))	('expression', 'MPA', (101, 111))	('miR-200c', 'Gene', '406985', (63, 71))	('SW480', 'CellLine', 'CVCL:0546', (133, 138))
13919	33771981	5c, d), high ZFAS1 expression is associated with worse overall survival in the setting of low miR-200b (p = 0.018) and low miR-200c (p = 0.048) expression.	('overall survival', 'MPA', (55, 71))	('high', 'Var', (8, 12))	('miR-200b', 'Gene', (94, 102))	('expression', 'MPA', (19, 29))	('miR-200b', 'Gene', '406984', (94, 102))	('worse', 'NegReg', (49, 54))	('low', 'Var', (119, 122))	('miR-200c', 'Gene', (123, 131))	('miR-200c', 'Gene', '406985', (123, 131))	('ZFAS1', 'Gene', (13, 18))	('low', 'NegReg', (90, 93))
13921	33771981	As hypothesized, downstream of ZEB1, ZFAS1 knockdown leads to increased E-cadherin expression as well as decreased vimentin protein expression (Fig.	('increased', 'PosReg', (62, 71))	('ZEB1', 'Gene', (31, 35))	('cadherin', 'molecular_function', 'GO:0008014', ('74', '82'))	('vimentin', 'cellular_component', 'GO:0045099', ('115', '123'))	('vimentin', 'Gene', '7431', (115, 123))	('knockdown', 'Var', (43, 52))	('vimentin', 'Gene', (115, 123))	('ZFAS1', 'Gene', (37, 42))	('vimentin', 'cellular_component', 'GO:0045098', ('115', '123'))	('expression', 'MPA', (83, 93))	('E-cadherin', 'Gene', (72, 82))	('E-cadherin', 'Gene', '999', (72, 82))	('decreased', 'NegReg', (105, 114))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('ZEB1', 'Gene', '6935', (31, 35))
13923	33771981	This regulatory effect on E-cadherin and vimentin expression was attenuated with dual transfection of ZFAS1 and miR-200b or ZFAS and miR-200c in both the HT29 and SW480 cell lines.	('miR-200b', 'Gene', '406984', (112, 120))	('ZFAS', 'Var', (124, 128))	('vimentin', 'cellular_component', 'GO:0045099', ('41', '49'))	('E-cadherin', 'Gene', (26, 36))	('miR-200c', 'Gene', (133, 141))	('attenuated', 'NegReg', (65, 75))	('miR-200b', 'Gene', (112, 120))	('miR-200c', 'Gene', '406985', (133, 141))	('vimentin', 'cellular_component', 'GO:0045098', ('41', '49'))	('ZFAS1', 'Gene', (102, 107))	('E-cadherin', 'Gene', '999', (26, 36))	('SW480', 'CellLine', 'CVCL:0546', (163, 168))	('vimentin', 'Gene', '7431', (41, 49))	('HT29', 'CellLine', 'CVCL:0320', (154, 158))	('expression', 'MPA', (50, 60))	('vimentin', 'Gene', (41, 49))	('cadherin', 'molecular_function', 'GO:0008014', ('28', '36'))
13927	33771981	To validate these signaling cascade results, we performed functional cellular assays with dual knockdown of both ZFAS1 and miR-200b or ZFAS1 and miR-200c.	('miR-200c', 'Gene', (145, 153))	('miR-200b', 'Gene', '406984', (123, 131))	('miR-200c', 'Gene', '406985', (145, 153))	('miR-200b', 'Gene', (123, 131))	('ZFAS1', 'Gene', (113, 118))	('ZFAS1', 'Var', (135, 140))
13928	33771981	In the HT29 cell line, there was no difference in cellular proliferation with dual knockdown of ZFAS1 and miR-200b compared to non-target.	('ZFAS1', 'Gene', (96, 101))	('miR-200b', 'Gene', '406984', (106, 114))	('cellular proliferation', 'CPA', (50, 72))	('miR-200b', 'Gene', (106, 114))	('HT29', 'CellLine', 'CVCL:0320', (7, 11))	('knockdown', 'Var', (83, 92))
13930	33771981	In the SW480 cell line, there was no difference in the doubling time following ZFAS1 and miR-200c knockdown compared to non-target, but there were significant differences in the individual cell counts at 96 h (p = 0.003) and 120 h (p = 0.02).	('knockdown', 'Var', (98, 107))	('SW480', 'CellLine', 'CVCL:0546', (7, 12))	('miR-200c', 'Gene', (89, 97))	('miR-200c', 'Gene', '406985', (89, 97))	('ZFAS1', 'Gene', (79, 84))
13931	33771981	Following knockdown with ZFAS1 and miR-200b, there was a slower doubling time of cells as compared to non-target (Fig.	('ZFAS1', 'Gene', (25, 30))	('slower', 'NegReg', (57, 63))	('miR-200b', 'Gene', '406984', (35, 43))	('miR-200b', 'Gene', (35, 43))	('knockdown', 'Var', (10, 19))
13932	33771981	In the HT29 cell line, there was a significant difference in the scratch closure of cells following dual ZFAS1 and miR-200c knockdown compared to non-target (p = 0.02), but there was no difference in the dual ZFAS1 and miR-200b knockdown.	('knockdown', 'Var', (124, 133))	('miR-200c', 'Gene', (115, 123))	('miR-200c', 'Gene', '406985', (115, 123))	('miR-200b', 'Gene', '406984', (219, 227))	('ZFAS1', 'Gene', (105, 110))	('miR-200b', 'Gene', (219, 227))	('HT29', 'CellLine', 'CVCL:0320', (7, 11))	('scratch closure of cells', 'CPA', (65, 89))
13935	33771981	Using a mouse model, ZFAS1 knockdown was associated with decreased tumor volume compared to non-target siRNA (Fig.	('knockdown', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('decreased tumor', 'Disease', (57, 72))	('mouse', 'Species', '10090', (8, 13))	('decreased tumor', 'Disease', 'MESH:D002303', (57, 72))	('ZFAS1', 'Gene', (21, 26))
13941	33771981	For example, it can act as a tumor suppressor by methylating miR-9 in hepatocellular carcinoma, but can also promote cancer metastasis through miR-150 binding.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('cancer metastasis', 'Disease', (117, 134))	('promote', 'PosReg', (109, 116))	('binding', 'Interaction', (151, 158))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (70, 94))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('miR-150', 'Gene', (143, 150))	('methylating', 'Var', (49, 60))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (70, 94))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('miR-9', 'Gene', (61, 66))	('hepatocellular carcinoma', 'Disease', (70, 94))	('cancer metastasis', 'Disease', 'MESH:D009362', (117, 134))	('miR-150', 'Gene', '406942', (143, 150))	('tumor', 'Disease', (29, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))
13948	33771981	We report that there is copy number amplification seen with ZFAS1 in the TCGA colon adenocarcinoma cohort.	('copy number amplification', 'Var', (24, 49))	('colon adenocarcinoma', 'Disease', (78, 98))	('ZFAS1', 'Gene', (60, 65))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (78, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))
13964	33771981	Knockdown of ZFAS1 can lead to a less aggressive phenotype in colon cancer cell lines, reduction in the mesenchymal marker vimentin, and an increase in the epithelial marker E-cadherin.	('mesenchymal', 'CPA', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Knockdown', 'Var', (0, 9))	('colon cancer', 'Disease', (62, 74))	('vimentin', 'Gene', '7431', (123, 131))	('colon cancer', 'Disease', 'MESH:D015179', (62, 74))	('E-cadherin', 'Gene', (174, 184))	('E-cadherin', 'Gene', '999', (174, 184))	('colon cancer', 'Phenotype', 'HP:0003003', (62, 74))	('ZFAS1', 'Gene', (13, 18))	('increase', 'PosReg', (140, 148))	('vimentin', 'Gene', (123, 131))	('reduction', 'NegReg', (87, 96))	('less aggressive phenotype', 'CPA', (33, 58))
13969	33771981	Two paired data sets (colon cancer tissue and normal colon mucosa from the same patient) GSE104836 (N = 10) and GSE95132 (N = 10), and one unpaired data set (colon cancer tissue and normal colon mucosa from different patients), GSE103512 (N = 70), were downloaded from the GEO database.	('N = 10', 'Gene', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('patient', 'Species', '9606', (217, 224))	('GSE95132', 'Var', (112, 120))	('N = 10', 'Gene', '3164', (100, 106))	('colon cancer', 'Disease', 'MESH:D015179', (22, 34))	('colon cancer', 'Phenotype', 'HP:0003003', (22, 34))	('colon cancer', 'Phenotype', 'HP:0003003', (158, 170))	('N = 10', 'Gene', (100, 106))	('colon cancer', 'Disease', 'MESH:D015179', (158, 170))	('N = 10', 'Gene', '3164', (122, 128))	('colon cancer', 'Disease', (22, 34))	('patients', 'Species', '9606', (217, 225))	('patient', 'Species', '9606', (80, 87))	('colon cancer', 'Disease', (158, 170))	('GSE104836', 'Var', (89, 98))
14014	33326448	Alternatively, downregulation of Ccnd1causes p21 (Cdkn1a) to dissociate from Cdk4 and inhibit Cdk2, triggering arrest of the cell cycle independent of p53.	('p21', 'Gene', '24525', (45, 48))	('arrest', 'Disease', 'MESH:D006323', (111, 117))	('p21', 'Gene', (45, 48))	('Cdk4', 'Gene', (77, 81))	('Cdk4', 'Gene', '94201', (77, 81))	('arrest', 'Disease', (111, 117))	('Ccnd1', 'Gene', (33, 38))	('p53', 'Gene', '301300', (151, 154))	('Ccnd1', 'Gene', '58919', (33, 38))	('Cdk2', 'Gene', (94, 98))	('Cdkn1a', 'Gene', (50, 56))	('triggering', 'Reg', (100, 110))	('Cdk2', 'Gene', '362817', (94, 98))	('Cdkn1a', 'Gene', '114851', (50, 56))	('inhibit', 'NegReg', (86, 93))	('downregulation', 'Var', (15, 29))	('p53', 'Gene', (151, 154))
14016	33326448	Mutations in the p53 gene usually lead to tumor development, and tumors lacking a functional p53 gene are often resistant to cancer drug treatment.	('p53', 'Gene', '301300', (17, 20))	('tumors', 'Disease', (65, 71))	('p53', 'Gene', (17, 20))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', (65, 70))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('cancer', 'Disease', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('men', 'Species', '9606', (55, 58))	('men', 'Species', '9606', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('lead to', 'Reg', (34, 41))	('p53', 'Gene', '301300', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('p53', 'Gene', (93, 96))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
14058	33326448	The proliferative zone was also decreased in the ethanol group compared to controls for both younger (P = 0.002) and older (P = 0.003) rats (Fig 2D).	('ethanol', 'Chemical', 'MESH:D000431', (49, 56))	('proliferative zone', 'CPA', (4, 22))	('ethanol', 'Var', (49, 56))	('rats', 'Species', '10116', (135, 139))	('decreased', 'NegReg', (32, 41))
14129	32633324	Furthermore, the aberrant expression of lncRNA was shown to be associated with the onset and development of cancers.	('lncRNA', 'Protein', (40, 46))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('associated', 'Reg', (63, 73))	('aberrant expression', 'Var', (17, 36))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))
14135	32633324	The abnormal expression of SNHG15 promoted the proliferation, invasion and epithelial-mesenchymal transition (EMT) of tumor cells as well.	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('75', '108'))	('SNHG15', 'Gene', (27, 33))	('abnormal', 'Var', (4, 12))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('EMT', 'biological_process', 'GO:0001837', ('110', '113'))	('promoted', 'PosReg', (34, 42))	('tumor', 'Disease', (118, 123))	('invasion', 'CPA', (62, 70))	('proliferation', 'CPA', (47, 60))	('SNHG15', 'Gene', '285958', (27, 33))
14151	32633324	Pooled HRs indicated an association between the high expression of SNHG15 and overall survival (HR = 2.07, 95% CI, 1.48-2.88; P<0.0001).	('overall survival', 'CPA', (78, 94))	('SNHG15', 'Gene', '285958', (67, 73))	('SNHG15', 'Gene', (67, 73))	('high expression', 'Var', (48, 63))
14161	32633324	The combined results indicated a significantly positive correlation between the high expression of SNHG15 and positive lymph node metastasis (HR = 2.41, 95%CI, 0.99-5.87; P=0.05).	('positive', 'PosReg', (47, 55))	('positive lymph node metastasis', 'CPA', (110, 140))	('SNHG15', 'Gene', '285958', (99, 105))	('high', 'Var', (80, 84))	('SNHG15', 'Gene', (99, 105))
14173	32633324	The abnormal expression of non-coding RNA was reported to be closely related to diseases, such as cancer, cardiovascular disease, inflammatory bowel disease and metabolic disease.	('non-coding', 'Var', (27, 37))	('metabolic disease', 'Disease', (161, 178))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (130, 156))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (106, 128))	('abnormal', 'Var', (4, 12))	('inflammatory bowel disease', 'Disease', (130, 156))	('cardiovascular disease', 'Disease', 'MESH:D002318', (106, 128))	('metabolic disease', 'Disease', 'MESH:D008659', (161, 178))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('cardiovascular disease', 'Disease', (106, 128))	('related', 'Reg', (69, 76))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (130, 156))
14186	32633324	discovered that SNHG15 regulated YAP1-Hippo signaling pathway by sponging miR-200a-3p, inducing the growth and migration of papillary thyroid carcinoma cells.	('papillary thyroid carcinoma', 'Disease', (124, 151))	('sponging', 'Var', (65, 73))	('inducing', 'PosReg', (87, 95))	('SNHG15', 'Gene', '285958', (16, 22))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (124, 151))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('38', '61'))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (124, 151))	('YAP1', 'Gene', '10413', (33, 37))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (134, 151))	('YAP1', 'Gene', (33, 37))	('SNHG15', 'Gene', (16, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
14189	32633324	demonstrated that MYC protein increased the expression of SNHG15 through binding to the transcription start point of SNHG15, and the high expression of SNHG15 activated the apoptosis induced factor (AIF) protein, thus promoting the proliferation, invasion and chemotherapy resistance in colorectal cancer.	('chemotherapy resistance', 'CPA', (260, 283))	('expression', 'MPA', (44, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (287, 304))	('protein', 'cellular_component', 'GO:0003675', ('204', '211'))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('increased', 'PosReg', (30, 39))	('SNHG15', 'Gene', (152, 158))	('binding', 'molecular_function', 'GO:0005488', ('73', '80'))	('colorectal cancer', 'Disease', (287, 304))	('SNHG15', 'Gene', (117, 123))	('SNHG15', 'Gene', '285958', (152, 158))	('MYC', 'Gene', (18, 21))	('invasion', 'CPA', (247, 255))	('promoting', 'PosReg', (218, 227))	('SNHG15', 'Gene', '285958', (117, 123))	('binding', 'Interaction', (73, 80))	('apoptosis', 'biological_process', 'GO:0097194', ('173', '182'))	('apoptosis', 'biological_process', 'GO:0006915', ('173', '182'))	('MYC', 'Gene', '4609', (18, 21))	('colorectal cancer', 'Phenotype', 'HP:0003003', (287, 304))	('activated', 'PosReg', (159, 168))	('SNHG15', 'Gene', (58, 64))	('high expression', 'Var', (133, 148))	('SNHG15', 'Gene', '285958', (58, 64))	('proliferation', 'CPA', (232, 245))	('transcription', 'biological_process', 'GO:0006351', ('88', '101'))	('apoptosis', 'Gene', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
14191	32633324	reported that SNHG15 regulated the vascular endothelial growth factor A (VEGFA) and the expression of Cdc42 by sponging miR-153, contributing to the occurrence and development of glioma.	('vascular endothelial growth factor A', 'Gene', '7422', (35, 71))	('contributing to', 'Reg', (129, 144))	('vascular endothelial growth factor A', 'Gene', (35, 71))	('VEGFA', 'Gene', (73, 78))	('expression', 'MPA', (88, 98))	('Cdc42', 'Gene', '998', (102, 107))	('SNHG15', 'Gene', (14, 20))	('glioma', 'Disease', 'MESH:D005910', (179, 185))	('VEGFA', 'Gene', '7422', (73, 78))	('glioma', 'Phenotype', 'HP:0009733', (179, 185))	('sponging miR-153', 'Var', (111, 127))	('miR-153', 'Chemical', '-', (120, 127))	('miR-153', 'Var', (120, 127))	('Cdc42', 'Gene', (102, 107))	('SNHG15', 'Gene', '285958', (14, 20))	('glioma', 'Disease', (179, 185))
14199	32633324	In addition, high expression level of SNHG15 was associated with shorter overall survival, progression-free survival and recurrence-free survival.	('recurrence-free survival', 'CPA', (121, 145))	('SNHG15', 'Gene', (38, 44))	('expression level', 'MPA', (18, 34))	('high', 'Var', (13, 17))	('overall', 'MPA', (73, 80))	('shorter', 'NegReg', (65, 72))	('SNHG15', 'Gene', '285958', (38, 44))	('progression-free survival', 'CPA', (91, 116))
14201	32633324	The results showed that high expression level of SNHG15 was associated with shorter overall survival in digestive, respiratory and female reproductive system cancers, and supported the positive association between high expression level of SNHG15 and poor prognosis in various cancer types.	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('SNHG15', 'Gene', (49, 55))	('high', 'Var', (24, 28))	('SNHG15', 'Gene', '285958', (49, 55))	('SNHG15', 'Gene', (239, 245))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('SNHG15', 'Gene', '285958', (239, 245))	('cancers', 'Disease', (158, 165))	('cancer', 'Disease', (158, 164))	('digestive', 'Disease', (104, 113))	('respiratory', 'Disease', (115, 126))	('shorter', 'NegReg', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', (276, 282))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('expression', 'MPA', (29, 39))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('overall', 'MPA', (84, 91))
14203	32633324	The present study is the first meta-analysis exploring the connection between the abnormal expression of SNHG15 and cancer prognosis.	('abnormal expression', 'Var', (82, 101))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('SNHG15', 'Gene', '285958', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('SNHG15', 'Gene', (105, 111))
14206	32633324	Detailed molecular biological mechanisms between the abnormal expression of SNHG15 and the development of cancers were also discussed and summarized.	('SNHG15', 'Gene', (76, 82))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('abnormal', 'Var', (53, 61))	('SNHG15', 'Gene', '285958', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
14210	32633324	SNHG15 could serve as the competitive endogenous RNA, interacting with miR-211-3p, miR-200a-3p, miR-153, miR-141-3p, miR-141 and so on, directly or indirectly acting on downstream signaling pathway, promoting the cell proliferation, migration, invasion or cycle arrest of most cancers, the high expression of SNHG15 manifested worse cancer prognosis, especially in the glioma.	('high expression', 'Var', (290, 305))	('glioma', 'Disease', (369, 375))	('arrest', 'Disease', (262, 268))	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('miR-141', 'Gene', '406933', (105, 112))	('glioma', 'Disease', 'MESH:D005910', (369, 375))	('SNHG15', 'Gene', (0, 6))	('miR-141', 'Gene', (105, 112))	('cancer', 'Disease', (277, 283))	('SNHG15', 'Gene', (309, 315))	('cancer', 'Disease', (333, 339))	('glioma', 'Phenotype', 'HP:0009733', (369, 375))	('SNHG15', 'Gene', '285958', (0, 6))	('SNHG15', 'Gene', '285958', (309, 315))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('arrest', 'Disease', 'MESH:D006323', (262, 268))	('cell proliferation', 'CPA', (213, 231))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('cancers', 'Disease', (277, 284))	('miR-211-3p', 'Gene', '100302164', (71, 81))	('worse', 'NegReg', (327, 332))	('miR-211-3p', 'Gene', (71, 81))	('migration', 'CPA', (233, 242))	('promoting', 'PosReg', (199, 208))	('miR-141', 'Gene', '406933', (117, 124))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (333, 339))	('miR-153', 'Chemical', '-', (96, 103))	('invasion', 'CPA', (244, 252))	('miR-141', 'Gene', (117, 124))
14336	31572011	Although the question of why a certain proportion of colorectal MALT lymphomas may respond to antibiotics remains unanswered, several crucial findings may support the following speculations: 1) HPE prescriptions can also eradicate other bacteria or bacteria similar to H. pylori associated with the development of human colon MALT lymphoma.	('lymphomas', 'Phenotype', 'HP:0002665', (69, 78))	('men', 'Species', '9606', (306, 309))	('human colon MALT lymphoma', 'Disease', (314, 339))	('human', 'Species', '9606', (314, 319))	('rectal MALT', 'Phenotype', 'HP:0100896', (57, 68))	('lymphoma', 'Phenotype', 'HP:0002665', (69, 77))	('H. pylori', 'Species', '210', (269, 278))	('prescriptions', 'Var', (198, 211))	('eradicate', 'NegReg', (221, 230))	('lymphoma', 'Phenotype', 'HP:0002665', (331, 339))
14341	31572011	In a B-cell lymphoma cell line derived from a BALB/c mouse model, O'Hara et al showed that clarithromycin inhibited cell viability and induced apoptosis through down-regulating BCL-2 expression.	('lymphoma', 'Phenotype', 'HP:0002665', (12, 20))	('clarithromycin', 'Var', (91, 105))	('BCL-2', 'molecular_function', 'GO:0015283', ('177', '182'))	('inhibited', 'NegReg', (106, 115))	('apoptosis', 'CPA', (143, 152))	('apoptosis', 'biological_process', 'GO:0097194', ('143', '152'))	('expression', 'MPA', (183, 193))	('down-regulating', 'NegReg', (161, 176))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (5, 20))	('mouse', 'Species', '10090', (53, 58))	('apoptosis', 'biological_process', 'GO:0006915', ('143', '152'))	('cell viability', 'CPA', (116, 130))	('clarithromycin', 'Chemical', 'MESH:D017291', (91, 105))	('BCL-2', 'Gene', '12043', (177, 182))	('BCL-2', 'Gene', (177, 182))
14342	31572011	Mizunoe et al showed that macrolides, either clarithromycin or azithromycin, caused apoptosis of activated lymphocytes through attenuation of BCL-XL expression.	('BCL-XL', 'Gene', '598', (142, 148))	('attenuation', 'NegReg', (127, 138))	('clarithromycin', 'Var', (45, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('84', '93'))	('clarithromycin', 'Chemical', 'MESH:D017291', (45, 59))	('apoptosis', 'biological_process', 'GO:0006915', ('84', '93'))	('macrolides', 'Chemical', 'MESH:D018942', (26, 36))	('BCL-XL', 'Gene', (142, 148))	('azithromycin', 'Chemical', 'MESH:D017963', (63, 75))	('azithromycin', 'Var', (63, 75))
14354	27848961	Butyrate has a remarkable array of colonic health-promoting and antineoplastic properties: it is the preferred energy source for colonocytes, it maintains mucosal integrity and it suppresses inflammation and carcinogenesis through effects on immunity, gene expression and epigenetic modulation.	('inflammation', 'Disease', 'MESH:D007249', (191, 203))	('carcinogenesis', 'Disease', (208, 222))	('carcinogenesis', 'Disease', 'MESH:D063646', (208, 222))	('gene', 'CPA', (252, 256))	('inflammation', 'Disease', (191, 203))	('Butyrate', 'Chemical', 'MESH:D002087', (0, 8))	('immunity', 'CPA', (242, 250))	('effects', 'Reg', (231, 238))	('suppresses', 'NegReg', (180, 190))	('epigenetic modulation', 'Var', (272, 293))	('mucosal', 'CPA', (155, 162))
14363	27848961	Genome-wide association studies have identified 14 loci harbouring common variants that influence the risk of developing colorectal cancer, but it took the inclusion of >9,000 cases and 9,000 controls before a statistically significant interaction between one of these loci and the intake of processed meat was found.	('influence', 'Reg', (88, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('rectal cancer', 'Phenotype', 'HP:0100743', (125, 138))	('colorectal cancer', 'Disease', (121, 138))	('variants', 'Var', (74, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))
14365	27848961	The World Cancer Research Fund's 2010 Continuous Update Report based on the systematic review and meta-analysis of 43 cohort or randomized controlled trials graded the evidence of linking dietary fibre with a decreased risk of colorectal cancer, and red and preserved meat with increased risk, as "convincing" : the strongest grade assigned.	('rectal cancer', 'Phenotype', 'HP:0100743', (231, 244))	('colorectal cancer', 'Phenotype', 'HP:0003003', (227, 244))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('colorectal cancer', 'Disease', (227, 244))	('Cancer', 'Phenotype', 'HP:0002664', (10, 16))	('Cancer', 'Disease', (10, 16))	('Cancer', 'Disease', 'MESH:D009369', (10, 16))	('dietary fibre', 'Var', (188, 201))	('fibre', 'Chemical', '-', (196, 201))	('colorectal cancer', 'Disease', 'MESH:D015179', (227, 244))	('decreased', 'NegReg', (209, 218))
14376	27848961	Evidence indicates that colorectal cancer arises from a stepwise disturbance of the composition of the gut microbiota, induced by food components or diet, plus genetic alterations in oncogenes and tumour-suppressor genes.	('tumour', 'Disease', 'MESH:D009369', (197, 203))	('oncogenes', 'Gene', (183, 192))	('colorectal cancer', 'Phenotype', 'HP:0003003', (24, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('genetic alterations', 'Var', (160, 179))	('tumour', 'Disease', (197, 203))	('rectal cancer', 'Phenotype', 'HP:0100743', (28, 41))	('colorectal cancer', 'Disease', (24, 41))	('composition', 'MPA', (84, 95))	('rat', 'Species', '10116', (172, 175))	('colorectal cancer', 'Disease', 'MESH:D015179', (24, 41))	('gut', 'Gene', (103, 106))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))	('gut', 'Gene', '110006', (103, 106))
14377	27848961	For example, most colorectal cancers harbour mutations in the gene encoding APC, a tumour suppressor that regulates Wnt signalling by controlling the levels of beta-catenin, which then regulates downstream inflammatory, cell cycle and proliferative pathways.	('beta-catenin', 'Gene', (160, 172))	('beta-catenin', 'Gene', '1499', (160, 172))	('signalling', 'biological_process', 'GO:0023052', ('120', '130'))	('inflammatory', 'Pathway', (206, 218))	('regulates', 'Reg', (185, 194))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('colorectal cancers', 'Disease', 'MESH:D015179', (18, 36))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('APC', 'cellular_component', 'GO:0005680', ('76', '79'))	('tumour', 'Disease', (83, 89))	('rat', 'Species', '10116', (242, 245))	('cell cycle', 'biological_process', 'GO:0007049', ('220', '230'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (18, 35))	('rectal cancer', 'Phenotype', 'HP:0100743', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('APC', 'Disease', 'MESH:D011125', (76, 79))	('APC', 'Disease', (76, 79))	('Wnt signalling', 'MPA', (116, 130))	('mutations', 'Var', (45, 54))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('proliferative pathways', 'Pathway', (235, 257))	('colorectal cancers', 'Disease', (18, 36))
14378	27848961	Mechanistic studies have shown that mutant Apc mice spontaneously develop adenomatous polyps.	('develop', 'PosReg', (66, 73))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (74, 92))	('Apc', 'Gene', (43, 46))	('adenomatous polyps', 'Disease', 'MESH:D018256', (74, 92))	('Apc', 'Gene', '11789', (43, 46))	('mutant', 'Var', (36, 42))	('adenomatous polyp', 'Phenotype', 'HP:0005227', (74, 91))	('mice', 'Species', '10090', (47, 51))	('adenomatous polyps', 'Disease', (74, 92))
14383	27848961	Microorganisms can induce chronic inflammation in a number of ways: adherence to the epithelium; activation of an immune response through binding to Toll-like receptors and/or activating regulatory T (Treg)cells; synthesis and secretion of cytotoxic biomolecules or metabolites; or by translocation into the body.	('translocation', 'Reg', (285, 298))	('inflammation', 'Disease', (34, 46))	('Microorganisms', 'Var', (0, 14))	('activation', 'PosReg', (97, 107))	('secretion', 'biological_process', 'GO:0046903', ('227', '236'))	('adherence', 'CPA', (68, 77))	('inflammation', 'biological_process', 'GO:0006954', ('34', '46'))	('synthesis', 'biological_process', 'GO:0009058', ('213', '222'))	('binding', 'Interaction', (138, 145))	('secretion', 'MPA', (227, 236))	('induce', 'Reg', (19, 25))	('inflammation', 'Disease', 'MESH:D007249', (34, 46))	('binding', 'molecular_function', 'GO:0005488', ('138', '145'))	('immune response', 'biological_process', 'GO:0006955', ('114', '129'))	('immune response', 'CPA', (114, 129))
14387	27848961	For example, a review of 31 original articles on the role of colon microbiota in colorectal cancer performed in humans and animals observed that, despite differences in methodology, some bacteria were consistently augmented (including Fusobacteria, Alistipes, Porphyromonadaceae, Coriobacteridae, Staphylococcaceae, Akkermansia spp.	('man', 'Species', '9606', (321, 324))	('Alistipes', 'CPA', (249, 258))	('men', 'Species', '9606', (217, 220))	('colorectal cancer', 'Disease', (81, 98))	('spp', 'molecular_function', 'GO:0042499', ('328', '331'))	('Coriobacteridae', 'Disease', (280, 295))	('Porphyromonadaceae', 'Var', (260, 278))	('humans', 'Species', '9606', (112, 118))	('rectal cancer', 'Phenotype', 'HP:0100743', (85, 98))	('Staphylococcaceae', 'Disease', (297, 314))	('bacteria', 'MPA', (187, 195))	('Fusobacteria', 'Disease', (235, 247))	('Akkermansia spp', 'Disease', (316, 331))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('augmented', 'PosReg', (214, 223))	('man', 'Species', '9606', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))
14403	27848961	in the neoplastic process; biopsy material from adenomas and adjacent normal mucosa in 19 patients showed 48% positivity for Fusobacterium in tumour tissue, which was higher than in the normal tissue.	('tumour', 'Disease', (142, 148))	('adenomas', 'Disease', (48, 56))	('Fusobacterium', 'Species', '851', (125, 138))	('Fusobacterium', 'Gene', (125, 138))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('positivity', 'Var', (110, 120))	('adenomas', 'Disease', 'MESH:D000236', (48, 56))	('patients', 'Species', '9606', (90, 98))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('neoplastic process', 'Phenotype', 'HP:0002664', (7, 25))
14405	27848961	Other studies have shown that F. nucleatum-high colorectal cancer tissues were inversely associated with the density of CD3+ T cells and had a strong association with microsatellite instability and CpG island methylator phenotype-linked cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('CpG', 'Var', (198, 201))	('F. nucleatum', 'Species', '851', (30, 42))	('colorectal cancer', 'Disease', (48, 65))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancers', 'Disease', (237, 244))	('inversely', 'NegReg', (79, 88))	('cancers', 'Disease', 'MESH:D009369', (237, 244))	('rectal cancer', 'Phenotype', 'HP:0100743', (52, 65))	('colorectal cancer', 'Disease', 'MESH:D015179', (48, 65))	('microsatellite', 'MPA', (167, 181))
14450	27848961	Ammonia can be absorbed and recycled in transamination pathways in the liver and can be taken up and detoxified by probiotic Lactobacilli; however, in high concentrations, ammonia interferes with cell metabolism, is cytotoxic and induces inflammation and epithelial proliferation.	('rat', 'Species', '10116', (163, 166))	('inflammation', 'Disease', 'MESH:D007249', (238, 250))	('ammonia', 'Chemical', 'MESH:D000641', (172, 179))	('interferes', 'NegReg', (180, 190))	('induces', 'Reg', (230, 237))	('inflammation', 'Disease', (238, 250))	('ammonia', 'Var', (172, 179))	('Ammonia', 'Chemical', 'MESH:D000641', (0, 7))	('rat', 'Species', '10116', (273, 276))	('inflammation', 'biological_process', 'GO:0006954', ('238', '250'))	('cell metabolism', 'CPA', (196, 211))	('epithelial proliferation', 'CPA', (255, 279))	('metabolism', 'biological_process', 'GO:0008152', ('201', '211'))
14457	27848961	However, exciting new studies in rats have shown that endogenous mucosal hydrogen sulfide increases ulcer healing and is anti-inflammatory.	('anti-inflammatory', 'CPA', (121, 138))	('endogenous', 'Var', (54, 64))	('increases ulcer healing', 'Disease', 'MESH:D014456', (90, 113))	('hydrogen sulfide', 'Chemical', 'MESH:D006862', (73, 89))	('increases ulcer healing', 'Disease', (90, 113))	('rats', 'Species', '10116', (33, 37))
14463	27848961	Theoretically, these changes could increase the susceptibility of the colonic epithelium to luminal carcinogens.	('colonic epithelium to luminal carcinogens', 'Disease', (70, 111))	('increase', 'PosReg', (35, 43))	('susceptibility', 'MPA', (48, 62))	('changes', 'Var', (21, 28))	('colonic epithelium to luminal carcinogens', 'Disease', 'MESH:C536309', (70, 111))
14465	27848961	For example, studies in humans have shown that fibre supplementation reduces feacal ammonia and p-cresol, and increases the colonic microbial uptake of nitrogenous metabolites.	('supplementation', 'Var', (53, 68))	('increases the colonic', 'Disease', 'MESH:D015179', (110, 131))	('p-cresol', 'Chemical', 'MESH:C032538', (96, 104))	('nitrogenous', 'Chemical', '-', (152, 163))	('reduces', 'NegReg', (69, 76))	('feacal ammonia', 'MPA', (77, 91))	('humans', 'Species', '9606', (24, 30))	('fibre', 'Chemical', '-', (47, 52))	('ammonia', 'Chemical', 'MESH:D000641', (84, 91))	('increases the colonic', 'Disease', (110, 131))	('men', 'Species', '9606', (59, 62))
14467	27848961	Furthermore, symbiotic supplementation (Lactobacillus rhamnosus GG, Bifidobacterium lactis BB12 and inulin) was associated with less DNA damage and reduced mucosal proliferation rates in patients who had undergone colonic polypectomy, supporting the view that cancer risk is determined by the balance between mucosa health-promoting and inflammatory or carcinogenic precursors.	('Bifidobacterium lactis BB12', 'Var', (68, 95))	('patients', 'Species', '9606', (187, 195))	('Lactobacillus rhamnosus GG', 'Species', '568703', (40, 66))	('carcinogenic', 'Disease', 'MESH:D063646', (353, 365))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('carcinogenic', 'Disease', (353, 365))	('reduced', 'NegReg', (148, 155))	('cancer', 'Disease', (260, 266))	('rat', 'Species', '10116', (171, 174))	('men', 'Species', '9606', (29, 32))	('Lactobacillus rhamnosus GG', 'Var', (40, 66))	('DNA damage', 'MPA', (133, 143))	('rat', 'Species', '10116', (178, 181))	('Bifidobacterium lactis', 'Species', '302911', (68, 90))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('mucosal proliferation rates', 'CPA', (156, 183))	('less', 'NegReg', (128, 132))
14484	27848961	First, miR-92a levels were established as sevenfold higher in sporadic human colorectal cancer tissue than in adjacent normal tissue.	('colorectal cancer', 'Disease', (77, 94))	('rectal cancer', 'Phenotype', 'HP:0100743', (81, 94))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('higher', 'PosReg', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('miR-92a', 'Var', (7, 14))	('human', 'Species', '9606', (71, 76))
14498	27848961	Evidence for the paradox includes the observation that increased butyrogenesis stimulates epithelial growth through its energy provision under starved or atrophic conditions, whereas enhanced butryogenesis under conditions of excess growth suppresses proliferation and cancer risk.	('epithelial growth', 'CPA', (90, 107))	('proliferation', 'CPA', (251, 264))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('energy provision', 'MPA', (120, 136))	('stimulates', 'PosReg', (79, 89))	('butyrogenesis', 'Var', (65, 78))	('atrophic conditions', 'Disease', (154, 173))	('suppresses', 'NegReg', (240, 250))	('atrophic conditions', 'Disease', 'MESH:D020966', (154, 173))	('rat', 'Species', '10116', (258, 261))	('butryogenesis', 'CPA', (192, 205))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
14501	27848961	Furthermore, in gnotobiotic mouse models colonized with wild-type or mutant strains of a butyrate-producing bacterium, fibre was demonstrated to have a potent tumour-suppressive effect but in a microbiota and butyrate-dependent manner.	('butyrate', 'Chemical', 'MESH:D002087', (209, 217))	('tumour', 'Disease', (159, 165))	('butyrate', 'Chemical', 'MESH:D002087', (89, 97))	('mouse', 'Species', '10090', (28, 33))	('mutant', 'Var', (69, 75))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('rat', 'Species', '10116', (213, 216))	('rat', 'Species', '10116', (136, 139))	('tumour', 'Disease', 'MESH:D009369', (159, 165))	('fibre', 'Chemical', '-', (119, 124))	('man', 'Species', '9606', (228, 231))	('rat', 'Species', '10116', (93, 96))
14502	27848961	However, it is not surprising to find studies that do not fit well with the idea that butyro-genesis suppresses carcinogenesis.	('butyro-genesis', 'Var', (86, 100))	('carcinogenesis', 'Disease', 'MESH:D063646', (112, 126))	('suppresses', 'NegReg', (101, 111))	('carcinogenesis', 'Disease', (112, 126))
14518	27848961	Critically, the inflammatory and proliferative effects induced by meat and bile acids, as well as the associated DNA damage and mutations, can be prevented by the simultaneous consumption of resistant starch.	('DNA', 'cellular_component', 'GO:0005574', ('113', '116'))	('mutations', 'Var', (128, 137))	('proliferative', 'CPA', (33, 46))	('rat', 'Species', '10116', (40, 43))	('inflammatory', 'CPA', (16, 28))	('starch', 'Chemical', 'MESH:D013213', (201, 207))	('bile acids', 'Chemical', 'MESH:D001647', (75, 85))
14524	27848961	A good example of the relationship between plant-cell breakdown, fibre metabolism and phytochemical release is given by a study that reported that the feeding of a high-protein, low-carbohydrate and low-fibre diet to human volunteers resulted in reduced levels of key butyrate-producers (Roseburia and Eubacterium rectale), a decrease in the proportion of butyrate in faecal SCFA concentrations, and greatly reduced concentrations of free phenolic acids in the gut.	('gut', 'Gene', '110006', (461, 464))	('Eubacterium rectale', 'Species', '39491', (302, 321))	('Roseburia', 'Disease', 'None', (288, 297))	('proportion of butyrate in', 'MPA', (342, 367))	('human', 'Species', '9606', (217, 222))	('fibre', 'Chemical', '-', (203, 208))	('butyrate', 'Chemical', 'MESH:D002087', (356, 364))	('fibre', 'Chemical', '-', (65, 70))	('butyrate', 'Chemical', 'MESH:D002087', (268, 276))	('carbohydrate', 'Chemical', 'MESH:D002241', (182, 194))	('rat', 'Species', '10116', (190, 193))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('breakdown', 'biological_process', 'GO:0009056', ('54', '63'))	('reduced', 'NegReg', (246, 253))	('rat', 'Species', '10116', (387, 390))	('concentrations of free phenolic acids', 'MPA', (416, 453))	('metabolism', 'biological_process', 'GO:0008152', ('71', '81'))	('gut', 'Gene', (461, 464))	('Roseburia', 'Disease', (288, 297))	('low-fibre', 'Var', (199, 208))	('decrease', 'NegReg', (326, 334))	('rat', 'Species', '10116', (360, 363))	('reduced', 'NegReg', (408, 415))	('rat', 'Species', '10116', (272, 275))	('rat', 'Species', '10116', (423, 426))	('levels', 'MPA', (254, 260))
14530	27848961	A wealth of experimental studies (reviewed elsewhere) have shown that polyphenols, particularly those derived from grapes, tea, coffee and cocoa or chocolate, have powerful anti-inflammatory, antiproliferative and tumour-inhibiting properties in the colon.	('tumour', 'Disease', (214, 220))	('men', 'Species', '9606', (18, 21))	('rat', 'Species', '10116', (203, 206))	('chocolate', 'Species', '3641', (148, 157))	('cocoa', 'Species', '3641', (139, 144))	('anti-inflammatory', 'CPA', (173, 190))	('polyphenols', 'Chemical', 'MESH:D059808', (70, 81))	('tumour', 'Disease', 'MESH:D009369', (214, 220))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('antiproliferative', 'CPA', (192, 209))	('polyphenols', 'Var', (70, 81))
14576	27848961	Mechanistically, a high-fat diet might increase colorectal cancer risk, both directly through its effect on inflammation, stem cell regulation and prostanoid metabolism, and indirectly through its effects on the gut microbiota.	('prostanoid', 'Chemical', 'MESH:D011453', (147, 157))	('colorectal cancer', 'Phenotype', 'HP:0003003', (48, 65))	('inflammation', 'Disease', (108, 120))	('colorectal cancer', 'Disease', 'MESH:D015179', (48, 65))	('colorectal cancer', 'Disease', (48, 65))	('gut', 'Gene', (212, 215))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('stem cell regulation', 'MPA', (122, 142))	('increase', 'PosReg', (39, 47))	('gut', 'Gene', '110006', (212, 215))	('effects', 'Reg', (197, 204))	('rectal cancer', 'Phenotype', 'HP:0100743', (52, 65))	('inflammation', 'Disease', 'MESH:D007249', (108, 120))	('effect', 'Reg', (98, 104))	('high-fat', 'Var', (19, 27))	('prostanoid metabolism', 'MPA', (147, 168))
14579	27848961	Strong experimental evidence suggests that the secondary bile acids lithocholic and deoxycholic acid are carcinogenic to the colon.	('carcinogenic to the colon', 'Disease', 'MESH:D015179', (105, 130))	('deoxycholic acid', 'Chemical', 'MESH:D003840', (84, 100))	('carcinogenic to the colon', 'Disease', (105, 130))	('lithocholic', 'Chemical', '-', (68, 79))	('deoxycholic acid', 'Var', (84, 100))	('bile acids', 'Chemical', 'MESH:D001647', (57, 67))	('men', 'Species', '9606', (13, 16))
14591	27848961	Although hydrogen sulfide has been shown to be genotoxic in experimental cell lines, the study in IL-10 deficient mice, in which only saturated fat and not polyunsaturated fat stimulated the growth of B. wadsworthia, suggests that all fats might not be equal.	('saturated', 'Chemical', '-', (134, 143))	('men', 'Species', '9606', (66, 69))	('IL-10', 'Gene', (98, 103))	('saturated', 'Chemical', '-', (162, 171))	('growth', 'CPA', (191, 197))	('IL-10', 'molecular_function', 'GO:0005141', ('98', '103'))	('B. wadsworthia', 'Species', '35833', (201, 215))	('mice', 'Species', '10090', (114, 118))	('hydrogen sulfide', 'Chemical', 'MESH:D006862', (9, 25))	('deficient', 'Var', (104, 113))	('stimulated', 'PosReg', (176, 186))
14689	29190912	Kaplan-Meier survival (Figure 2) indicated that the overall survival rate for patients with high serum RBP4 concentrations (>26.7 ug/mL) was significantly higher than that for patients with low serum RBP4 concentrations (<=26.7 ug/mL), while there was no significant difference between the overall survival rate for patients with high serum THBS2 concentrations (>14.85 ng/mL) and that for patients with low serum THBS2 concentrations (<=14.85 ng/mL).	('survival', 'CPA', (60, 68))	('patients', 'Species', '9606', (176, 184))	('high', 'Var', (92, 96))	('patients', 'Species', '9606', (390, 398))	('RBP4', 'Gene', '5950', (103, 107))	('RBP4', 'Gene', (103, 107))	('patients', 'Species', '9606', (78, 86))	('RBP4', 'Gene', (200, 204))	('RBP4', 'Gene', '5950', (200, 204))	('higher', 'PosReg', (155, 161))	('patients', 'Species', '9606', (316, 324))
14733	29190912	Similarly, alcohol drinking can decrease the serum retinol concentration in head and neck cancer.	('alcohol drinking', 'Var', (11, 27))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('decrease the serum retinol concentration', 'Phenotype', 'HP:0031032', (32, 72))	('serum retinol concentration', 'MPA', (45, 72))	('neck cancer', 'Disease', 'MESH:D006258', (85, 96))	('neck cancer', 'Disease', (85, 96))	('head and neck cancer', 'Phenotype', 'HP:0012288', (76, 96))	('alcohol', 'Chemical', 'MESH:D000438', (11, 18))	('retinol', 'Chemical', 'MESH:D014801', (51, 58))	('alcohol drinking', 'Phenotype', 'HP:0030955', (11, 27))	('decrease', 'NegReg', (32, 40))
14745	29190912	Knockdown of THBS2 led to increased MMP3 expression and interruption of the ERalpha mediated invasion suppression, providing further evidence of an ERalpha-THBS2-MMP3 axis in CAF.	('MMP3', 'Gene', '4314', (162, 166))	('Knockdown', 'Var', (0, 9))	('THBS2', 'Gene', (13, 18))	('MMP3', 'Gene', '4314', (36, 40))	('MMP3', 'molecular_function', 'GO:0004248', ('162', '166'))	('ERalpha', 'Gene', '2099', (148, 155))	('interruption', 'NegReg', (56, 68))	('MMP3', 'molecular_function', 'GO:0004248', ('36', '40'))	('invasion suppression', 'CPA', (93, 113))	('ERalpha', 'Gene', (148, 155))	('ERalpha', 'Gene', (76, 83))	('increased', 'PosReg', (26, 35))	('MMP3', 'Gene', (162, 166))	('ERalpha', 'Gene', '2099', (76, 83))	('MMP3', 'Gene', (36, 40))
14797	28778197	The number of patients with a primary tumour size of >10 cm was significantly higher in the non-resection group (82.4%) compared to the surgical group (55.8%).	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('non-resection', 'Var', (92, 105))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('tumour', 'Disease', (38, 44))	('patients', 'Species', '9606', (14, 22))
14840	28778197	In the group of liver resection, the site of primary ACC was more often on the right side (60%), whereas an equal distribution of the primary ACC to both sides was observed in all 77 patients with isolated liver metastases.	('isolated liver metastases', 'Disease', (197, 222))	('ACC', 'Phenotype', 'HP:0006744', (142, 145))	('ACC', 'Phenotype', 'HP:0006744', (53, 56))	('isolated liver metastases', 'Disease', 'MESH:D009362', (197, 222))	('liver resection', 'Var', (16, 31))	('patients', 'Species', '9606', (183, 191))
14884	28450390	The adenoma-carcinoma sequence describes the sequential accumulation of a series of genetic mutations leading to advanced adenomas and then invasive cancer.	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (4, 21))	('invasive cancer', 'Disease', (140, 155))	('adenoma-carcinoma', 'Disease', (4, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('invasive cancer', 'Disease', 'MESH:D009362', (140, 155))	('mutations', 'Var', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('leading to', 'Reg', (102, 112))	('adenomas', 'Disease', 'MESH:D000236', (122, 130))	('adenomas', 'Disease', (122, 130))
14889	28450390	When aberrant DNA methylation results in the transcriptional silencing of important tumour suppressor genes, neoplastic growth can be promoted.	('tumour', 'Disease', (84, 90))	('neoplastic growth', 'CPA', (109, 126))	('DNA', 'Protein', (14, 17))	('promoted', 'PosReg', (134, 142))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('aberrant', 'Var', (5, 13))	('tumour', 'Disease', 'MESH:D009369', (84, 90))	('transcriptional', 'MPA', (45, 60))
14896	28450390	Many benign sessile serrated polyps (SSPs) are BRAF mutant and are CIMP+, and analysis of SSLs with an adjacent region of cancer show shared immunohistochemical and molecular features between the benign and malignant foci.	('serrated polyps', 'Phenotype', 'HP:0032222', (20, 35))	('mutant', 'Var', (52, 58))	('serrated polyp', 'Phenotype', 'HP:0032222', (20, 34))	('CIMP', 'Chemical', '-', (67, 71))	('BRAF', 'Gene', (47, 51))	('cancer', 'Disease', (122, 128))	('BRAF', 'Gene', '673', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('sessile serrated', 'Phenotype', 'HP:0032222', (12, 28))	('polyps', 'Disease', (29, 35))	('SLs', 'Chemical', '-', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('polyps', 'Disease', 'MESH:D011127', (29, 35))
14898	28450390	This evidence has led to the establishment of a proposed serrated neoplasia pathway, where HPs initiated by BRAF or less commonly KRAS, mutation proceed to SSLs with the accumulation of epigenetic gene silencing, although it may be that SSLs arise de novo.	('serrated neoplasia', 'Phenotype', 'HP:0032222', (57, 75))	('SLs', 'Chemical', '-', (157, 160))	('SSLs', 'Disease', (156, 160))	('men', 'Species', '9606', (38, 41))	('neoplasia', 'Disease', 'MESH:D009369', (66, 75))	('mutation', 'Var', (136, 144))	('proceed', 'Reg', (145, 152))	('KRAS', 'Gene', '3845', (130, 134))	('neoplasia', 'Phenotype', 'HP:0002664', (66, 75))	('gene silencing', 'biological_process', 'GO:0016458', ('197', '211'))	('SLs', 'Chemical', '-', (238, 241))	('KRAS', 'Gene', (130, 134))	('epigenetic gene silencing', 'Var', (186, 211))	('BRAF', 'Gene', '673', (108, 112))	('accumulation', 'PosReg', (170, 182))	('BRAF', 'Gene', (108, 112))	('neoplasia', 'Disease', (66, 75))
14899	28450390	Inactivation of tumour suppressor genes causes the development of cellular atypia (SSL with dysplasia) with eventual progression to cancer.	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('causes', 'Reg', (40, 46))	('cancer', 'Disease', (132, 138))	('tumour', 'Disease', (16, 22))	('cellular atypia', 'Disease', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('dysplasia', 'Disease', (92, 101))	('dysplasia', 'Disease', 'MESH:D004476', (92, 101))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('men', 'Species', '9606', (58, 61))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('Inactivation', 'Var', (0, 12))
14901	28450390	Molecular features are not as clearly defined as SSLs, but includes KRAS or BRAF mutations  along with variable levels of CIMP positivity.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('KRAS', 'Gene', (68, 72))	('KRAS', 'Gene', '3845', (68, 72))	('CIMP', 'Chemical', '-', (122, 126))	('mutations', 'Var', (81, 90))	('SLs', 'Chemical', '-', (50, 53))
14978	28450390	The stool DNA assay measured beta-actin (a marker of total human DNA), mutant KRAS, aberrantly methylated BMP3 and NDRG4 and faecal haemoglobin.	('beta-actin', 'Protein', (29, 39))	('human', 'Species', '9606', (59, 64))	('aberrantly methylated', 'Var', (84, 105))	('BMP3', 'Gene', (106, 110))	('KRAS', 'Gene', (78, 82))	('mutant', 'Var', (71, 77))	('KRAS', 'Gene', '3845', (78, 82))	('NDRG4', 'Gene', '65009', (115, 120))	('NDRG4', 'Gene', (115, 120))	('BMP3', 'Gene', '651', (106, 110))
14980	28450390	In a recent large study in an average-risk cohort by Imperiale et al  using FIT versus FIT plus multitarget stool DNA testing, FIT plus DNA significantly outperformed FIT alone for the detection of serrated polyps 1 cm or more in size, 42.4% vs 5.1%, respectively, p<0.001.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('outperformed', 'NegReg', (154, 166))	('polyps', 'Disease', 'MESH:D011127', (207, 213))	('FIT plus', 'Var', (127, 135))	('serrated polyps', 'Phenotype', 'HP:0032222', (198, 213))	('serrated polyp', 'Phenotype', 'HP:0032222', (198, 212))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))	('polyps', 'Disease', (207, 213))
14998	28450390	Risk estimates do not seem to exceed those for Lynch syndrome and molecular mechanisms to CRC such as loss of DNA mismatch repair may be shared.	('loss', 'Var', (102, 106))	('Lynch syndrome', 'Disease', 'MESH:D003123', (47, 61))	('Lynch syndrome', 'Disease', (47, 61))
15018	28450390	Other studies also support SSA/P as an independent risk factor for CRC, with incidence significantly higher in patients with SSA than control patients with hyperplastic and adenomatous polyps.	('adenomatous polyps', 'Phenotype', 'HP:0005227', (173, 191))	('CRC', 'Disease', (67, 70))	('higher', 'PosReg', (101, 107))	('SSA', 'Var', (125, 128))	('adenomatous polyps', 'Disease', 'MESH:D018256', (173, 191))	('adenomatous polyp', 'Phenotype', 'HP:0005227', (173, 190))	('patients', 'Species', '9606', (142, 150))	('adenomatous polyps', 'Disease', (173, 191))	('patients', 'Species', '9606', (111, 119))
15051	28450390	Although many colitis-associated cancers may develop from sporadic adenomas (the adenoma-carcinoma sequence), it is recognised that a proportion of cancers in patients with colitis arise from an inflammation-cancer pathway involving a different frequency, sequence and timing of molecular events (eg, earlier loss of Adenomatous Polyposis Coli (APC) function and later p53 mutation) compared with sporadic, non-IBD-related carcinogenesis.	('colitis-associated cancers', 'Disease', 'MESH:D003092', (14, 40))	('p53', 'Gene', (369, 372))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('colitis', 'Phenotype', 'HP:0002583', (14, 21))	('colitis-associated cancers', 'Disease', (14, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('colitis', 'Disease', (173, 180))	('carcinogenesis', 'Disease', (423, 437))	('inflammation-cancer', 'Disease', 'MESH:D007249', (195, 214))	('adenomas', 'Disease', 'MESH:D000236', (67, 75))	('colitis', 'Disease', (14, 21))	('mutation', 'Var', (373, 381))	('colitis', 'Disease', 'MESH:D003092', (173, 180))	('adenomas', 'Disease', (67, 75))	('Adenomatous Polyposis Coli', 'Disease', 'MESH:D011125', (317, 343))	('carcinogenesis', 'Disease', 'MESH:D063646', (423, 437))	('APC', 'Disease', 'MESH:D011125', (345, 348))	('patients', 'Species', '9606', (159, 167))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (81, 98))	('loss', 'NegReg', (309, 313))	('APC', 'Disease', (345, 348))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('colitis', 'Disease', 'MESH:D003092', (14, 21))	('cancers', 'Disease', (148, 155))	('adenoma-carcinoma', 'Disease', (81, 98))	('Adenomatous Polyposis Coli', 'Disease', (317, 343))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('p53', 'Gene', '7157', (369, 372))	('Adenomatous Polyposis', 'Phenotype', 'HP:0005227', (317, 338))	('inflammation-cancer', 'Disease', (195, 214))	('colitis', 'Phenotype', 'HP:0002583', (173, 180))
15060	28450390	Aust et al  demonstrated activating BRAF mutations typical of SSPs were identified in 9% (3 out of 33) of colitis-associated cancers, consistent with the hypothesis that some colitis-associated cancers may arise through the serrated pathway.	('mutations', 'Var', (41, 50))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('BRAF', 'Gene', (36, 40))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('activating', 'PosReg', (25, 35))	('colitis', 'Phenotype', 'HP:0002583', (175, 182))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colitis', 'Phenotype', 'HP:0002583', (106, 113))	('colitis-associated cancers', 'Disease', (106, 132))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('colitis-associated cancers', 'Disease', (175, 201))	('colitis-associated cancers', 'Disease', 'MESH:D003092', (106, 132))	('colitis-associated cancers', 'Disease', 'MESH:D003092', (175, 201))	('BRAF', 'Gene', '673', (36, 40))
15062	28450390	Odze et al  found no significant difference in the prevalence of KRAS mutations, loss of heterozygosity of APC, 3p, p53 or p16, between chronic UC-associated HPs (not SSPs per se), sporadic HPs and inflamed colitic mucosa.	('mutations', 'Var', (70, 79))	('p16', 'Gene', (123, 126))	('chronic UC-associated HPs', 'Disease', (136, 161))	('inflamed colitic mucosa', 'Disease', (198, 221))	('KRAS', 'Gene', '3845', (65, 69))	('inflamed colitic mucosa', 'Disease', 'MESH:C531841', (198, 221))	('p53', 'Gene', '7157', (116, 119))	('APC', 'cellular_component', 'GO:0005680', ('107', '110'))	('APC', 'Disease', 'MESH:D011125', (107, 110))	('p16', 'Gene', '1029', (123, 126))	('APC', 'Disease', (107, 110))	('KRAS', 'Gene', (65, 69))	('p53', 'Gene', (116, 119))
15065	28450390	KRAS mutation was detected in 45% (5/11) polyps and the mucinous adenocarcinoma, more than expected for the standard serrated pathway.	('detected', 'Reg', (18, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('polyps', 'Disease', (41, 47))	('polyps', 'Disease', 'MESH:D011127', (41, 47))	('mucinous adenocarcinoma', 'Disease', (56, 79))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (56, 79))	('KRAS', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('KRAS', 'Gene', '3845', (0, 4))
15068	28450390	These included one HP and one TSA, both of which exhibited the V600E BRAF mutation without MSI or MMR deficiency.	('MSI', 'Disease', (91, 94))	('V600E', 'Var', (63, 68))	('TSA', 'molecular_function', 'GO:0033984', ('30', '33'))	('MMR', 'biological_process', 'GO:0006298', ('98', '101'))	('MMR deficiency', 'Disease', (98, 112))	('TSA', 'Chemical', '-', (30, 33))	('MMR deficiency', 'Disease', 'MESH:C536143', (98, 112))	('BRAF', 'Gene', '673', (69, 73))	('V600E', 'Mutation', 'rs113488022', (63, 68))	('MSI', 'Disease', 'None', (91, 94))	('BRAF', 'Gene', (69, 73))
15069	28450390	The TSA was close to a mucinous adenocarcinoma, which exhibited the BRAF mutation and MSI with loss of hMLH1.	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (23, 46))	('MSI', 'Disease', 'None', (86, 89))	('BRAF', 'Gene', '673', (68, 72))	('mucinous adenocarcinoma', 'Disease', (23, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('BRAF', 'Gene', (68, 72))	('hMLH1', 'Gene', (103, 108))	('MSI', 'Disease', (86, 89))	('hMLH1', 'Gene', '4292', (103, 108))	('TSA', 'Chemical', '-', (4, 7))	('mutation', 'Var', (73, 81))	('loss', 'Var', (95, 99))
15070	28450390	KRAS mutations are uncommon in the serrated pathway, but are observed preferentially in sporadic colorectal carcinogenesis.	('colorectal carcinogenesis', 'Disease', (97, 122))	('mutations', 'Var', (5, 14))	('observed', 'Reg', (61, 69))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (97, 122))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
15071	28450390	KRAS activating mutations occur very early in IBD-related carcinogenesis, as evidenced by KRAS mutations being detected in control inflammatory non-dysplastic mucosa.	('activating', 'PosReg', (5, 15))	('dysplastic mucosa', 'Disease', (148, 165))	('KRAS', 'Gene', (90, 94))	('carcinogenesis', 'Disease', 'MESH:D063646', (58, 72))	('mutations', 'Var', (16, 25))	('KRAS', 'Gene', '3845', (90, 94))	('carcinogenesis', 'Disease', (58, 72))	('dysplastic mucosa', 'Disease', 'MESH:D004416', (148, 165))	('IBD-related', 'Disease', (46, 57))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
15106	28367247	Fibronectin: How Its Aberrant Expression in Tumors May Improve Therapeutic Targeting Fibronectin is a matrix glycoprotein which has not only been found to be over-expressed in several cancers, but has been shown to participate in several steps of tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('over-expressed', 'PosReg', (158, 172))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('Tumors', 'Disease', (44, 50))	('Aberrant', 'Var', (21, 29))	('Fibronectin', 'Gene', (85, 96))	('cancers', 'Disease', (184, 191))	('Tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Disease', (247, 252))	('participate', 'Reg', (215, 226))	('cancers', 'Disease', 'MESH:D009369', (184, 191))	('Tumors', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Fibronectin', 'Gene', '2335', (0, 11))	('Tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Fibronectin', 'Gene', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('Fibronectin', 'Gene', '2335', (85, 96))
15107	28367247	The purpose of this review is to illustrate how aberrant fibronectin expression influences tumor growth, invasion, metastasis and therapy resistance.	('invasion', 'CPA', (105, 113))	('metastasis', 'CPA', (115, 125))	('fibronectin', 'Protein', (57, 68))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('influences', 'Reg', (80, 90))	('aberrant', 'Var', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('therapy resistance', 'CPA', (130, 148))	('tumor', 'Disease', (91, 96))
15113	28367247	With regard to cancer, fibronectin is not only increased in tumors where its altered expression has been shown to promote tumor growth, migration and invasion but fibronectin has also been reported to limit tumor cell responsiveness to therapy  (Figure 1).	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('altered', 'Var', (77, 84))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('promote', 'PosReg', (114, 121))	('limit', 'NegReg', (201, 206))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Disease', (15, 21))	('fibronectin', 'Var', (163, 174))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('tumors', 'Disease', (60, 66))	('expression', 'MPA', (85, 95))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('invasion', 'CPA', (150, 158))	('increased', 'PosReg', (47, 56))	('migration', 'CPA', (136, 145))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
15116	28367247	Work in our lab has shown that loss of caveolin-1, the main structural protein of caveolae, results in increased expression of fibronectin, tenascin-C and collagen in murine mammary glands (Thompson et al, unpublished data).	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('expression', 'MPA', (113, 123))	('caveolae', 'cellular_component', 'GO:0005901', ('82', '90'))	('increased expression of fibronectin', 'Phenotype', 'HP:0032463', (103, 138))	('increased', 'PosReg', (103, 112))	('murine', 'Species', '10090', (167, 173))	('loss', 'Var', (31, 35))	('tenascin-C', 'cellular_component', 'GO:0090733', ('140', '150'))	('caveolin-1', 'Gene', (39, 49))	('tenascin-C', 'Protein', (140, 150))	('collagen', 'Protein', (155, 163))	('collagen', 'molecular_function', 'GO:0005202', ('155', '163'))	('fibronectin', 'Protein', (127, 138))	('caveolin-1', 'Gene', '12389', (39, 49))
15117	28367247	The purpose of this review is to illustrate the mechanisms in which aberrant fibronectin expression influences tumorigenesis and therapy resistance.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('influences', 'Reg', (100, 110))	('tumor', 'Disease', (111, 116))	('fibronectin', 'Protein', (77, 88))	('therapy resistance', 'CPA', (129, 147))	('aberrant', 'Var', (68, 76))
15132	28367247	In an effort to delineate a role for fibronectin-integrin interactions on tumor cell resistance to apoptosis, Han et al used Wortmannin to block PI3-K in human bronchial epithelial BEAS-2B and 16-HBE cell lines following alpha5beta1 cellular engagement with fibronectin.	('human', 'Species', '9606', (154, 159))	('16-HBE', 'CellLine', 'CVCL:0112', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('PI3-K', 'Var', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('BEAS-2B', 'CellLine', 'CVCL:0168', (181, 188))	('Wortmannin', 'Chemical', 'MESH:D000077191', (125, 135))	('tumor', 'Disease', (74, 79))	('beta1', 'Gene', '146712', (227, 232))	('beta1', 'Gene', (227, 232))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('PI3-K', 'molecular_function', 'GO:0016303', ('145', '150'))
15143	28367247	While the full length form of fibronectin plays an important role in tumorigenesis, isoforms of fibronectin, such as the ED-A and ED-B variants, have been reported to regulate tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('ED-B', 'Gene', '2335', (130, 134))	('ED-A', 'Gene', (121, 125))	('regulate', 'Reg', (167, 175))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (176, 181))	('ED-B', 'Gene', (130, 134))	('variants', 'Var', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
15148	28367247	Aside from a role in angiogenesis, ED-A fibronectin was reported to be upregulated in patient colorectal tumors, especially those that were of advanced stage.	('colorectal tumors', 'Disease', 'MESH:D015179', (94, 111))	('colorectal tumors', 'Disease', (94, 111))	('patient', 'Species', '9606', (86, 93))	('ED-A', 'Var', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('upregulated', 'PosReg', (71, 82))
15151	28367247	In a more recent study, ED-A fibronectin was shown to increase the population of myeloid derived cells, known to impair immune responses to cancer cells, from osteoblasts.	('ED-A fibronectin', 'Var', (24, 40))	('increase', 'PosReg', (54, 62))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('population of myeloid derived cells', 'CPA', (67, 102))
15153	28367247	Tumor growth and the presence of myeloid cells in tumors were reduced in cKO animals but not in WT animals.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cKO', 'Var', (73, 76))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('Tumor growth', 'CPA', (0, 12))	('reduced', 'NegReg', (62, 69))
15154	28367247	Although the authors don't attribute these findings to a specific reduction in the ED-A fibronectin isoform, they go on to demonstrate that culture of myeloid cells from cKO animals with ED-A fibronectin resulted in a reduction of melanoma apoptosis, suggesting that this pro-tumor effect results from ED-A activation of myeloid cells.	('apoptosis', 'biological_process', 'GO:0097194', ('240', '249'))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('apoptosis', 'biological_process', 'GO:0006915', ('240', '249'))	('melanoma apoptosis', 'Disease', 'MESH:D008545', (231, 249))	('reduction', 'NegReg', (218, 227))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('ED-A', 'Var', (187, 191))	('tumor', 'Disease', (276, 281))	('melanoma apoptosis', 'Disease', (231, 249))
15168	28367247	The authors found that inhibiting 7-nAChR and COX-2 not only limited fibronectin expression, but also increased E-cadherin expression, reducing SW480 cell migration.	('limited', 'NegReg', (61, 68))	('COX-2', 'Gene', '4513', (46, 51))	('increased', 'PosReg', (102, 111))	('expression', 'MPA', (123, 133))	('fibronectin', 'Protein', (69, 80))	('COX-2', 'Gene', (46, 51))	('nAChR', 'Gene', (36, 41))	('E-cadherin', 'Gene', (112, 122))	('SW480', 'CellLine', 'CVCL:0546', (144, 149))	('E-cadherin', 'Gene', '999', (112, 122))	('nAChR', 'molecular_function', 'GO:0022848', ('36', '41'))	('cell migration', 'biological_process', 'GO:0016477', ('150', '164'))	('cadherin', 'molecular_function', 'GO:0008014', ('114', '122'))	('SW480 cell migration', 'CPA', (144, 164))	('reducing', 'NegReg', (135, 143))	('inhibiting', 'Var', (23, 33))	('nAChR', 'Gene', '1137', (36, 41))
15172	28367247	Here, the authors first showed that 3D co-culture of ovarian cancer cells with mesothelial cells supported fibronectin expression from mesothelial cells via activation of a TGF-betaR1/RAC1/SMAD3 signaling pathway, a phenomenon which was important for cancer cell adhesion, proliferation and invasion as silencing of fibronectin reduced these cellular responses.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('ovarian cancer', 'Disease', (53, 67))	('TGF-beta', 'Gene', (173, 181))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('ovarian cancer', 'Phenotype', 'HP:0100615', (53, 67))	('reduced', 'NegReg', (328, 335))	('RAC1', 'Gene', (184, 188))	('expression', 'MPA', (119, 129))	('RAC1', 'Gene', '5879', (184, 188))	('SMAD3', 'Gene', '4088', (189, 194))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('fibronectin', 'MPA', (107, 118))	('cancer', 'Disease', (251, 257))	('silencing', 'Var', (303, 312))	('ovarian cancer', 'Disease', 'MESH:D010051', (53, 67))	('SMAD3', 'Gene', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('TGF-beta', 'Gene', '7040', (173, 181))	('activation', 'PosReg', (157, 167))
15174	28367247	In-vivo, the authors found that treatment of mice with antibodies against alpha5 and beta1 reduced the number of metastases and tumor weight from orthotopically injected ovarian cancer cell lines.	('ovarian cancer', 'Disease', (170, 184))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mice', 'Species', '10090', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('alpha5', 'Protein', (74, 80))	('metastases', 'Disease', (113, 123))	('beta1', 'Gene', (85, 90))	('reduced', 'NegReg', (91, 98))	('beta1', 'Gene', '146712', (85, 90))	('antibodies', 'Var', (55, 65))	('tumor', 'Disease', (128, 133))	('ovarian cancer', 'Phenotype', 'HP:0100615', (170, 184))	('ovarian cancer', 'Disease', 'MESH:D010051', (170, 184))	('metastases', 'Disease', 'MESH:D009362', (113, 123))
15176	28367247	In a similar study, it was shown that inhibition of alpha5 and beta1 integrins significantly reduced ovarian tumor cell adhesion to a 3D model consisting of primary human mesothelial cells and fibroblasts and additionally limited the number of metastases in ovarian cancer xenografts.	('ovarian tumor', 'Phenotype', 'HP:0100615', (101, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (258, 272))	('human', 'Species', '9606', (165, 170))	('beta1 integrin', 'Gene', '3688', (63, 77))	('limited', 'NegReg', (222, 229))	('ovarian tumor', 'Disease', 'MESH:D010051', (101, 114))	('cell adhesion', 'biological_process', 'GO:0007155', ('115', '128'))	('beta1 integrin', 'Gene', (63, 77))	('reduced', 'NegReg', (93, 100))	('inhibition', 'Var', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('metastases in ovarian cancer', 'Disease', 'MESH:D009362', (244, 272))	('metastases in ovarian cancer', 'Disease', (244, 272))	('ovarian tumor', 'Disease', (101, 114))
15177	28367247	Downregulation of E-cadherin on ovarian cancer cells was specifically shown to augment alpha5 integrin expression via activation of FAK and Erk1.	('FAK', 'Gene', (132, 135))	('E-cadherin', 'Gene', (18, 28))	('activation', 'PosReg', (118, 128))	('E-cadherin', 'Gene', '999', (18, 28))	('ovarian cancer', 'Disease', (32, 46))	('Downregulation', 'Var', (0, 14))	('augment', 'PosReg', (79, 86))	('Erk1', 'Gene', '5595', (140, 144))	('ovarian cancer', 'Phenotype', 'HP:0100615', (32, 46))	('FAK', 'Gene', '5747', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ovarian cancer', 'Disease', 'MESH:D010051', (32, 46))	('Erk1', 'Gene', (140, 144))	('alpha5 integrin', 'Protein', (87, 102))
15191	28367247	Inhibition of ERK1/2 and PI3K resulted in a reduction of migrating and invasive A549 cells as a result of downregulation of MMP9, implicating a role for fibronectin-FAK-MMP9 in lung cancer invasion.	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('MMP9', 'molecular_function', 'GO:0004229', ('169', '173'))	('FAK', 'Gene', '5747', (165, 168))	('FAK', 'molecular_function', 'GO:0004717', ('165', '168'))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('PI3K', 'Var', (25, 29))	('MMP9', 'Gene', '4318', (124, 128))	('MMP9', 'Gene', (124, 128))	('A549', 'CellLine', 'CVCL:0023', (80, 84))	('MMP9', 'molecular_function', 'GO:0004229', ('124', '128'))	('reduction', 'NegReg', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('downregulation', 'NegReg', (106, 120))	('lung cancer', 'Disease', (177, 188))	('ERK1/2', 'Gene', (14, 20))	('PI3K', 'molecular_function', 'GO:0016303', ('25', '29'))	('ERK1/2', 'Gene', '5595;5594', (14, 20))	('MMP9', 'Gene', '4318', (169, 173))	('MMP9', 'Gene', (169, 173))	('FAK', 'Gene', (165, 168))	('ERK1', 'molecular_function', 'GO:0004707', ('14', '18'))
15198	28367247	Disrupting the interaction between the beta1-integrin and fibronectin reversed the conferred resistance, leading to drug-induced apoptosis of the tumor cells.	('resistance', 'MPA', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('leading to', 'Reg', (105, 115))	('tumor', 'Disease', (146, 151))	('beta1-integrin', 'Gene', '3688', (39, 53))	('Disrupting', 'Var', (0, 10))	('beta1-integrin', 'Gene', (39, 53))	('interaction', 'Interaction', (15, 26))	('drug-induced apoptosis', 'CPA', (116, 138))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
15201	28367247	Inhibition of beta1 improved tamoxifen sensitivity of resistant MCF7 cells and further reduced cellular migration following culture in the presence of conditioned media from carcinoma associated fibroblasts (CAFs).	('improved', 'PosReg', (20, 28))	('carcinoma', 'Disease', (174, 183))	('tamoxifen', 'Chemical', 'MESH:D013629', (29, 38))	('CAF', 'Gene', (208, 211))	('reduced', 'NegReg', (87, 94))	('CAF', 'Gene', '8850', (208, 211))	('carcinoma', 'Disease', 'MESH:D002277', (174, 183))	('MCF7', 'CellLine', 'CVCL:0031', (64, 68))	('Inhibition', 'Var', (0, 10))	('beta1', 'Gene', (14, 19))	('beta1', 'Gene', '146712', (14, 19))	('cellular migration', 'CPA', (95, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('tamoxifen sensitivity', 'MPA', (29, 50))
15205	28367247	The observed reduction of cytotoxicity was a result of tumor cell alpha5beta1 integrin engagement with fibronectin as silencing these integrins restored tumor cell sensitivity to cetuximab.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('restored', 'PosReg', (144, 152))	('cytotoxicity', 'Disease', (26, 38))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cetuximab', 'Chemical', 'MESH:D000068818', (179, 188))	('beta1 integrin', 'Gene', (72, 86))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (153, 158))	('silencing', 'Var', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('cytotoxicity', 'Disease', 'MESH:D064420', (26, 38))	('reduction', 'NegReg', (13, 22))	('beta1 integrin', 'Gene', '3688', (72, 86))
15206	28367247	Interestingly, cetuximab was also shown to promote increased fibronectin expression from both tumor cell lines, a finding which was reported to result from activation of the p38-MAPK-ATF2 signaling pathway.	('cetuximab', 'Var', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('promote increased', 'PosReg', (43, 60))	('ATF2', 'Gene', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('p38', 'Gene', '5594', (174, 177))	('fibronectin', 'Protein', (61, 72))	('cetuximab', 'Chemical', 'MESH:D000068818', (15, 24))	('tumor', 'Disease', (94, 99))	('ATF2', 'Gene', '1386', (183, 187))	('increased fibronectin', 'Phenotype', 'HP:0032463', (51, 72))	('p38', 'Gene', (174, 177))
15207	28367247	siRNA silencing of fibronectin improved cytotoxicity of cetuximab in H1299 and A549 tumor cell lines, demonstrating that excess fibronectin in combination with alpha5beta1 integrin engagement with fibronectin facilitates cetuximab resistance.	('A549 tumor', 'Disease', (79, 89))	('cytotoxicity', 'Disease', (40, 52))	('beta1 integrin', 'Gene', '3688', (166, 180))	('facilitates', 'PosReg', (209, 220))	('A549 tumor', 'Disease', 'MESH:D009369', (79, 89))	('cetuximab', 'Chemical', 'MESH:D000068818', (56, 65))	('cetuximab', 'Chemical', 'MESH:D000068818', (221, 230))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cytotoxicity', 'Disease', 'MESH:D064420', (40, 52))	('cetuximab', 'MPA', (221, 230))	('beta1 integrin', 'Gene', (166, 180))	('silencing', 'Var', (6, 15))	('H1299', 'CellLine', 'CVCL:0060', (69, 74))
15212	28367247	To overcome chemotherapy resistance from integrin-fibronectin interactions, Nam et al showed that disrupting the peptide bond between fibronectin and alpha5beta1-integrin in combination with radiation therapy promoted apoptosis and reduced the expression of alpha5beta1 in cultures of malignant human breast cancer cells cultured atop a 3D Matrigel.	('beta1', 'Gene', '146712', (156, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (301, 314))	('reduced', 'NegReg', (232, 239))	('beta1', 'Gene', '146712', (264, 269))	('beta1-integrin', 'Gene', (156, 170))	('disrupting', 'Var', (98, 108))	('radiation', 'Disease', 'MESH:D004194', (191, 200))	('breast cancer', 'Disease', 'MESH:D001943', (301, 314))	('Nam', 'Gene', (76, 79))	('human', 'Species', '9606', (295, 300))	('breast cancer', 'Disease', (301, 314))	('radiation', 'Disease', (191, 200))	('Nam', 'Gene', '246329', (76, 79))	('apoptosis', 'CPA', (218, 227))	('peptide bond', 'MPA', (113, 125))	('beta1', 'Gene', (156, 161))	('beta1-integrin', 'Gene', '3688', (156, 170))	('beta1', 'Gene', (264, 269))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('promoted', 'PosReg', (209, 217))	('expression', 'MPA', (244, 254))
15215	28367247	To determine whether inhibition of beta1 integrin improved therapeutic responses, the authors treated subcutaneously grown U87MG glioblastomas with alternating doses of a beta1 inhibitor and low dose (1mg/kg) bevacizumab.	('beta1', 'Gene', (35, 40))	('glioblastomas', 'Phenotype', 'HP:0012174', (129, 142))	('glioblastomas', 'Disease', 'MESH:D005909', (129, 142))	('beta1 integrin', 'Gene', (35, 49))	('glioblastomas', 'Disease', (129, 142))	('therapeutic responses', 'CPA', (59, 80))	('inhibition', 'Var', (21, 31))	('beta1', 'Gene', (171, 176))	('beta1', 'Gene', '146712', (171, 176))	('bevacizumab', 'Chemical', 'MESH:D000068258', (209, 220))	('beta1 integrin', 'Gene', '3688', (35, 49))	('beta1', 'Gene', '146712', (35, 40))
15223	28367247	For instance, Ilic et al reported that fibronectin fibrils were more sparse and thinner in FAK null embryos compared to wildtype littermates and fibroblasts, a result which was demonstrated to be independent of fibronectin gene or protein expression and synthesis, suggesting that FAK activity is necessary for fibronectin matrix organization.	('thinner', 'NegReg', (80, 87))	('FAK', 'Gene', (91, 94))	('FAK', 'Gene', '5747', (91, 94))	('sparse', 'NegReg', (69, 75))	('fibronectin fibrils', 'CPA', (39, 58))	('FAK', 'Gene', '5747', (281, 284))	('FAK', 'Gene', (281, 284))	('null', 'Var', (95, 99))
15227	28367247	Specifically, the authors reported that inhibition of Src resulted in decreased FAK phosphorylation suggesting that a reduction of FAK activity may be a useful strategy to reduce fibronectin mediated effects on tumor cell migration and invasion.	('cell migration', 'biological_process', 'GO:0016477', ('217', '231'))	('FAK', 'Gene', '5747', (80, 83))	('invasion', 'CPA', (236, 244))	('reduction', 'NegReg', (118, 127))	('phosphorylation', 'biological_process', 'GO:0016310', ('84', '99'))	('tumor', 'Disease', (211, 216))	('Src', 'Gene', (54, 57))	('FAK', 'Gene', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('FAK', 'molecular_function', 'GO:0004717', ('131', '134'))	('activity', 'MPA', (135, 143))	('reduce', 'NegReg', (172, 178))	('decreased FAK', 'Phenotype', 'HP:0032341', (70, 83))	('reduce fibronectin', 'Phenotype', 'HP:0032463', (172, 190))	('fibronectin', 'Protein', (179, 190))	('FAK', 'Gene', '5747', (131, 134))	('inhibition', 'Var', (40, 50))	('Src', 'Gene', '6714', (54, 57))	('FAK', 'molecular_function', 'GO:0004717', ('80', '83'))	('decreased', 'NegReg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('FAK', 'Gene', (80, 83))
15228	28367247	In addition to indirect targets of FAK, it may be possible to directly reduce FAK activity via use of a novel ATP competitive kinase inhibitor, PF-04554878, which was recently shown to promote apoptosis and reduce proliferation of pancreatic neuroendocrine tumor cells.	('reduce', 'NegReg', (207, 213))	('reduce', 'NegReg', (71, 77))	('FAK', 'molecular_function', 'GO:0004717', ('35', '38'))	('FAK', 'Gene', '5747', (78, 81))	('apoptosis', 'biological_process', 'GO:0097194', ('193', '202'))	('pancreatic neuroendocrine tumor', 'Disease', 'MESH:D018358', (231, 262))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (242, 262))	('proliferation', 'CPA', (214, 227))	('apoptosis', 'biological_process', 'GO:0006915', ('193', '202'))	('FAK', 'Gene', (35, 38))	('promote', 'PosReg', (185, 192))	('pancreatic neuroendocrine tumor', 'Disease', (231, 262))	('FAK', 'molecular_function', 'GO:0004717', ('78', '81'))	('FAK', 'Gene', '5747', (35, 38))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (231, 262))	('PF-04554878', 'Chemical', 'MESH:C584510', (144, 155))	('PF-04554878', 'Var', (144, 155))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('apoptosis', 'CPA', (193, 202))	('FAK', 'Gene', (78, 81))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('126', '142'))	('activity', 'MPA', (82, 90))	('ATP', 'Chemical', 'MESH:D000255', (110, 113))
15230	28367247	Levental et al demonstrated that expression of lysyl oxidase (LOX), an enzyme which cross-links collagen fibers, not only increased FAK expression, but augmented matrix rigidity and breast tumor progression, a phenomenon which was reversed upon treatment with an inhibitor of LOX.	('FAK', 'Gene', (132, 135))	('rigidity', 'Disease', 'MESH:D009127', (169, 177))	('breast tumor', 'Disease', (182, 194))	('LOX', 'Gene', (62, 65))	('lysyl oxidase', 'Gene', (47, 60))	('expression', 'Var', (33, 43))	('FAK', 'Gene', '5747', (132, 135))	('lysyl oxidase', 'Gene', '4015', (47, 60))	('augmented', 'PosReg', (152, 161))	('breast tumor', 'Phenotype', 'HP:0100013', (182, 194))	('LOX', 'Gene', '4015', (276, 279))	('rigidity', 'Phenotype', 'HP:0002063', (169, 177))	('rigidity', 'Disease', (169, 177))	('increased', 'PosReg', (122, 131))	('breast tumor', 'Disease', 'MESH:D001943', (182, 194))	('LOX', 'Gene', (276, 279))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('LOX', 'Gene', '4015', (62, 65))
15233	28367247	Although this work was conducted in cardiac fibroblasts, it's foreseeable that inhibiting LOX may be a means to reduce tumoral fibronectin expression.	('inhibiting', 'Var', (79, 89))	('LOX', 'Gene', '4015', (90, 93))	('tumoral', 'Disease', (119, 126))	('reduce', 'NegReg', (112, 118))	('tumoral', 'Disease', 'MESH:D009369', (119, 126))	('LOX', 'Gene', (90, 93))	('reduce tumoral fibronectin expression', 'Phenotype', 'HP:0032463', (112, 149))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
15236	28367247	Furthermore, Hielscher et al demonstrated that treatment of co-cultures of fibroblasts and breast cancer cells with pUR4B not only reduced fibronectin deposition and organization in the ECM, but also inhibited the deposition of other matrix proteins.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('fibronectin deposition', 'MPA', (139, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('organization in the ECM', 'CPA', (166, 189))	('reduced fibronectin deposition', 'Phenotype', 'HP:0032463', (131, 161))	('reduced', 'NegReg', (131, 138))	('deposition of other matrix proteins', 'MPA', (214, 249))	('pUR4B', 'Var', (116, 121))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('inhibited', 'NegReg', (200, 209))
15237	28367247	As such, direct inhibition of fibronectin polymerization via a small peptide may impair the assembly of other matrix proteins and capillaries, thus depriving tumors of a supportive scaffold and the oxygen and nutrients necessary for continued growth.	('tumors', 'Disease', (158, 164))	('assembly', 'MPA', (92, 100))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('small peptide', 'Var', (63, 76))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('inhibition', 'NegReg', (16, 26))	('fibronectin polymerization', 'Protein', (30, 56))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('oxygen', 'Chemical', 'MESH:D010100', (198, 204))	('depriving', 'NegReg', (148, 157))	('impair', 'NegReg', (81, 87))
15242	28367247	Previous studies have shown that silencing fibronectin reduced tumor cell proliferation and growth and tumor cell migration.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('reduced', 'NegReg', (55, 62))	('tumor', 'Disease', (103, 108))	('silencing', 'Var', (33, 42))	('cell migration', 'biological_process', 'GO:0016477', ('109', '123'))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('growth', 'CPA', (92, 98))	('fibronectin', 'Protein', (43, 54))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))
15380	26871465	Surprisingly, overexpressed HIF-3alpha1 was localized to the cytosol and increased phosphorylated signal transducer and activator of transcription 3 (p-STAT3).	('overexpressed', 'Var', (14, 27))	('increased', 'PosReg', (73, 82))	('transcription', 'biological_process', 'GO:0006351', ('133', '146'))	('signal transducer and activator of transcription 3', 'Gene', '6774', (98, 148))	('cytosol', 'cellular_component', 'GO:0005829', ('61', '68'))	('HIF-3alpha1', 'Gene', (28, 39))	('HIF-3alpha1', 'Gene', '64344', (28, 39))
15394	26871465	HIF-1alpha is required for pro-inflammatory regulation and promotes the survival of CRC cell lines under hypoxic condition, whereas HIF-2alpha increases genes important in proinflammatory response, tumor growth and invasion in mice.	('HIF-2alpha', 'Var', (132, 142))	('hypoxic condition', 'Disease', (105, 122))	('increases', 'PosReg', (143, 152))	('CRC', 'Phenotype', 'HP:0003003', (84, 87))	('invasion', 'CPA', (215, 223))	('hypoxic condition', 'Disease', 'MESH:D009135', (105, 122))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('mice', 'Species', '10090', (227, 231))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('promotes', 'PosReg', (59, 67))	('survival', 'CPA', (72, 80))	('genes', 'MPA', (153, 158))	('tumor', 'Disease', (198, 203))	('regulation', 'biological_process', 'GO:0065007', ('44', '54'))
15397	26871465	Interestingly, overexpressed HIF-3alpha1 is localized to the cytosol and can strongly activate the pro-survival signal transducer and activator of transcription 3 (STAT3) signaling, which is essential for HIF-3alpha-promoted CRC cell growth.	('pro-survival', 'biological_process', 'GO:0043066', ('99', '111'))	('signaling', 'biological_process', 'GO:0023052', ('171', '180'))	('transcription', 'biological_process', 'GO:0006351', ('147', '160'))	('signal transducer and activator of transcription 3', 'Gene', '6774', (112, 162))	('HIF-3alpha1', 'Gene', '64344', (29, 40))	('overexpressed', 'Var', (15, 28))	('activate', 'PosReg', (86, 94))	('cytosol', 'cellular_component', 'GO:0005829', ('61', '68'))	('CRC', 'Phenotype', 'HP:0003003', (225, 228))	('cell growth', 'biological_process', 'GO:0016049', ('229', '240'))	('HIF-3alpha1', 'Gene', (29, 40))
15398	26871465	Previously, we have reported that intestine-specific disruption of Vhl (VhlDeltaIE) activates HIF signaling, and when these mice are crossed to the Apcmin/+ intestinal tumor model (VhlDeltaIE/Apcmin/+), colorectal tumorigenesis is robustly increased compared with littermate control mice (VhlF/F/Apcmin/+).	('Vhl', 'Gene', (72, 75))	('HIF signaling', 'MPA', (94, 107))	('mice', 'Species', '10090', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('Vhl', 'Gene', (181, 184))	('mice', 'Species', '10090', (283, 287))	('disruption', 'Var', (53, 63))	('Vhl', 'Gene', (67, 70))	('colorectal tumor', 'Disease', 'MESH:D015179', (203, 219))	('activates', 'PosReg', (84, 93))	('Vhl', 'Gene', '7428', (72, 75))	('colorectal tumor', 'Disease', (203, 219))	('Vhl', 'Gene', (289, 292))	('increased', 'PosReg', (240, 249))	('tumor', 'Disease', (168, 173))	('Vhl', 'Gene', '7428', (181, 184))	('tumor', 'Disease', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('Vhl', 'Gene', '7428', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('Vhl', 'Gene', '7428', (289, 292))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
15409	26871465	By qPCR analysis, the HIF-3alpha mRNA expression was significantly increased in the lentiviral HIF-3alpha1 infected cells compared to the lentiviral empty vector (EV) infected cells in both HT29 and SW480 cells (Figure 2A).	('EV', 'Chemical', '-', (163, 165))	('HIF-3alpha1', 'Gene', (95, 106))	('HT29', 'CellLine', 'CVCL:0320', (190, 194))	('SW480', 'CellLine', 'CVCL:0546', (199, 204))	('lentiviral', 'Var', (84, 94))	('infected', 'Var', (107, 115))	('increased', 'PosReg', (67, 76))	('HIF-3alpha1', 'Gene', '64344', (95, 106))	('HIF-3alpha', 'Gene', (22, 32))
15412	26871465	A colony formation assay was performed to confirm these results, and as expected, the HIF-3alpha1 overexpressing cells formed more colonies compared to the EV cells (Figure 2D and 2E).	('overexpressing', 'Var', (98, 112))	('EV', 'Chemical', '-', (156, 158))	('formation', 'biological_process', 'GO:0009058', ('9', '18'))	('HIF-3alpha1', 'Gene', (86, 97))	('colonies', 'CPA', (131, 139))	('HIF-3alpha1', 'Gene', '64344', (86, 97))
15415	26871465	HIF-3alpha1 overexpression increased the P2.1 luciferase activity, and this was further potentiated by HIF-2alpha (Figure 3A).	('luciferase activity', 'molecular_function', 'GO:0050248', ('46', '65'))	('increased', 'PosReg', (27, 36))	('P2.1', 'Gene', (41, 45))	('luciferase activity', 'molecular_function', 'GO:0045289', ('46', '65'))	('P2.1', 'Gene', '644914', (41, 45))	('luciferase activity', 'molecular_function', 'GO:0047077', ('46', '65'))	('potentiated', 'PosReg', (88, 99))	('HIF-3alpha1', 'Gene', (0, 11))	('activity', 'MPA', (57, 65))	('HIF-2alpha', 'Var', (103, 113))	('luciferase activity', 'molecular_function', 'GO:0050397', ('46', '65'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('46', '65'))	('HIF-3alpha1', 'Gene', '64344', (0, 11))
15422	26871465	A robust increase in phosphorylated signal transducer and activator of transcription 3 (p-STAT3) was observed in HIF-3alpha1 overexpressing cells compared to EV.	('overexpressing', 'Var', (125, 139))	('HIF-3alpha1', 'Gene', (113, 124))	('signal transducer and activator of transcription 3', 'Gene', '6774', (36, 86))	('increase', 'PosReg', (9, 17))	('HIF-3alpha1', 'Gene', '64344', (113, 124))	('EV', 'Chemical', '-', (158, 160))
15426	26871465	To confirm the critical role of STAT3 in HIF-3alpha1-promoted cell growth, HT29 and SW480 EV and HIF-3alpha1 cells were treated with S3I-201, a STAT3 inhibitor (STAT3i).	('EV', 'Chemical', '-', (90, 92))	('HIF-3alpha1', 'Gene', '64344', (97, 108))	('HIF-3alpha1', 'Gene', '64344', (41, 52))	('S3I-201', 'Chemical', 'MESH:C520337', (133, 140))	('HIF-3alpha1', 'Gene', (41, 52))	('HT29', 'CellLine', 'CVCL:0320', (75, 79))	('cell growth', 'CPA', (62, 73))	('cell growth', 'biological_process', 'GO:0016049', ('62', '73'))	('SW480', 'CellLine', 'CVCL:0546', (84, 89))	('HIF-3alpha1', 'Gene', (97, 108))	('S3I-201', 'Var', (133, 140))
15430	26871465	The results of the colony formation assay showed that STAT3i significantly reduced HIF-3alpha1-enhanced colony growth.	('HIF-3alpha1', 'Gene', '64344', (83, 94))	('colony growth', 'CPA', (104, 117))	('reduced', 'NegReg', (75, 82))	('formation', 'biological_process', 'GO:0009058', ('26', '35'))	('STAT3i', 'Var', (54, 60))	('HIF-3alpha1', 'Gene', (83, 94))
15441	26871465	Furthermore, knocking down Arnt, a cofactor essential for the transcriptional activity of all isoforms of HIF-alpha, effectively reduces the protein levels of Arnt to about 30%-40% compared to scrambled control in both EV and HIF-3alpha overexpressing cell lines, but it did not reduce the HIF-3alpha-increased p-STAT3 level (Figure 6D).	('knocking down', 'Var', (13, 26))	('protein levels', 'MPA', (141, 155))	('Arnt', 'Gene', '405', (159, 163))	('Arnt', 'Gene', (159, 163))	('p-STAT3 level', 'MPA', (311, 324))	('EV', 'Chemical', '-', (219, 221))	('Arnt', 'Gene', '405', (27, 31))	('Arnt', 'Gene', (27, 31))	('reduces', 'NegReg', (129, 136))
15453	26871465	In the intestine, activation of HIF-1alpha does not increase tumorigenesis in mice, whereas HIF-2alpha promotes the development of CRC.	('HIF-2alpha', 'Var', (92, 102))	('CRC', 'Disease', (131, 134))	('mice', 'Species', '10090', (78, 82))	('development', 'CPA', (116, 127))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('CRC', 'Phenotype', 'HP:0003003', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('promotes', 'PosReg', (103, 111))	('tumor', 'Disease', (61, 66))
15457	26871465	Excess activation of STAT3 in enterocytes promotes, whereas ablation of STAT3 reduces tumor cell proliferation through G1 and G2/M cell cycle progression in mouse models of colitis-associated CRC.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('STAT3', 'Gene', (21, 26))	('CRC', 'Phenotype', 'HP:0003003', (192, 195))	('STAT3', 'Gene', (72, 77))	('cell cycle', 'biological_process', 'GO:0007049', ('131', '141'))	('ablation', 'Var', (60, 68))	('tumor', 'Disease', (86, 91))	('colitis', 'Disease', 'MESH:D003092', (173, 180))	('G2/M cell cycle progression', 'CPA', (126, 153))	('promotes', 'PosReg', (42, 50))	('colitis', 'Disease', (173, 180))	('colitis', 'Phenotype', 'HP:0002583', (173, 180))	('cell proliferation', 'biological_process', 'GO:0008283', ('92', '110'))	('mouse', 'Species', '10090', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('reduces', 'NegReg', (78, 85))
15466	26871465	Western blot analysis failed to detect the activation of phospho-JAK2 in HIF-3alpha1 overexpression cells, further studies are still needed to understand which isoform is responsible for HIF-3alpha-increased STAT3 activation and to dissect the precise mechanisms for how HIF-3alpha binds with JAK.	('HIF-3alpha1', 'Gene', '64344', (73, 84))	('JAK', 'molecular_function', 'GO:0004713', ('293', '296'))	('activation', 'PosReg', (214, 224))	('JAK2', 'Gene', '3717', (65, 69))	('HIF-3alpha-increased', 'Var', (187, 207))	('HIF-3alpha1', 'Gene', (73, 84))	('JAK', 'molecular_function', 'GO:0004713', ('65', '68'))	('STAT3', 'MPA', (208, 213))	('JAK2', 'Gene', (65, 69))
15526	23617249	In CSF1-null mice, the loss of CSF1 prevented the accumulation of macrophages in the tumor vicinity and delayed the development of invasive and metastatic carcinoma confirming the importance of the presence of macrophages in the TME.	('carcinoma', 'Disease', 'MESH:D002277', (155, 164))	('tumor', 'Disease', (85, 90))	('mice', 'Species', '10090', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('accumulation of macrophages in', 'MPA', (50, 80))	('delayed', 'NegReg', (104, 111))	('carcinoma', 'Disease', (155, 164))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('loss', 'Var', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('CSF1', 'Gene', (31, 35))	('prevented', 'NegReg', (36, 45))
15539	23617249	Furthermore, whereas cancer cells exhibit an enormous variety of genetic and epigenetic changes during tumorigenesis, changes in the cancer microenvironment are usually common among many tumor types, raising the hope that therapeutic targeting of these events could be generally applicable.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('epigenetic changes', 'Var', (77, 95))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Disease', (187, 192))	('cancer', 'Disease', (133, 139))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
15562	23617249	showed that inhibiting the COX2 in the involuting mammary gland reduced the collagen fibrillogenesis associated with involution and inhibited breast tumor growth and infiltration to the lung.	('inhibited', 'NegReg', (132, 141))	('breast tumor', 'Disease', 'MESH:D001943', (142, 154))	('COX2', 'Enzyme', (27, 31))	('collagen fibrillogenesis', 'MPA', (76, 100))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('breast tumor', 'Disease', (142, 154))	('inhibiting', 'Var', (12, 22))	('collagen', 'molecular_function', 'GO:0005202', ('76', '84'))	('reduced', 'NegReg', (64, 71))	('breast tumor', 'Phenotype', 'HP:0100013', (142, 154))
15587	23617249	Silibinin (C25H22O10, molecular weight, 482.44) is isolated from the seeds of Silybum marianum (L.) Gaertn (Family Asteraceae), and is one of the most-widely consumed dietary supplements for its hepatoprotective efficacy.	('C25H22O10', 'Chemical', '-', (11, 20))	('Silybum marianum (L.) Gaertn', 'Species', '92921', (78, 106))	('Silibinin', 'Chemical', 'MESH:D000077385', (0, 9))	('hepatoprotective', 'MPA', (195, 211))	('C25H22O10', 'Var', (11, 20))
15650	23617249	In our unpublished studies, we have observed that silibinin targets the fibronectin-prostate cancer cell interaction and inhibits integrins expression as well as down-stream signaling involved in actin-remodeling; thereby inhibits the formation of motile structures.	('down-stream', 'NegReg', (162, 173))	('prostate cancer', 'Disease', (84, 99))	('signaling', 'MPA', (174, 183))	('expression', 'MPA', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('inhibits', 'NegReg', (121, 129))	('formation of motile structures', 'CPA', (235, 265))	('silibinin', 'Var', (50, 59))	('silibinin', 'Chemical', 'MESH:D000077385', (50, 59))	('prostate cancer', 'Disease', 'MESH:D011471', (84, 99))	('integrins', 'Protein', (130, 139))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))	('inhibits', 'NegReg', (222, 230))
15711	23617249	Silibinin treatment has been shown to inhibit the formation of cyclooxygenase pathway metabolites (PGE2, prostacyclin, and thromoxanes) by human mononuclear cells, platelets, and endothelial cells stimulated with LPS or A23187.	('LPS', 'Var', (213, 216))	('thromoxanes', 'Chemical', '-', (123, 134))	('PGE2', 'Chemical', 'MESH:D015232', (99, 103))	('A23187', 'Var', (220, 226))	('Silibinin', 'Chemical', 'MESH:D000077385', (0, 9))	('oxygen', 'Chemical', 'MESH:D010100', (68, 74))	('prostacyclin', 'Chemical', 'MESH:D011464', (105, 117))	('human', 'Species', '9606', (139, 144))	('A23187', 'Chemical', 'MESH:D000001', (220, 226))	('inhibit', 'NegReg', (38, 45))	('formation of cyclooxygenase', 'MPA', (50, 77))
15712	23617249	Silibinin treatment also strongly inhibited the formation of 5-lipoxygenase metabolites by human granulocytes (leukotrienes LTB4, LTC4/D4/E4/F4) when stimulated with A23187, FMLP, or opsonized zymosan.	('A23187', 'Chemical', 'MESH:D000001', (166, 172))	('zymosan', 'Chemical', 'MESH:D015054', (193, 200))	('formation', 'biological_process', 'GO:0009058', ('48', '57'))	('E4/F4', 'Gene', (138, 143))	('Silibinin', 'Chemical', 'MESH:D000077385', (0, 9))	('inhibited', 'NegReg', (34, 43))	('A23187', 'Var', (166, 172))	('FMLP', 'Gene', (174, 178))	('5-lipoxygenase', 'Gene', '240', (61, 75))	('FMLP', 'Gene', '2357', (174, 178))	('E4/F4', 'Gene', '10277', (138, 143))	('5-lipoxygenase', 'Gene', (61, 75))	('leukotrienes', 'Chemical', 'MESH:D015289', (111, 123))	('human', 'Species', '9606', (91, 96))
15754	33332677	20  There are also many examples of miRNAs acting as oncogenes (oncomiRs) in tumourigenesis.	('miRNAs', 'Var', (36, 42))	('tumour', 'Disease', (77, 83))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('tumour', 'Disease', 'MESH:D009369', (77, 83))
15769	33332677	25  Hsa-miR-125b-1 is implicated in t(11;14)(q24;q32) and t(2;11)(p21;q23) chromosomal translocations, which leads to B-cell acute lymphoid leukaemia (B-ALL) and acute myeloid leukaemia (AML), respectively.	('lymphoid leukaemia', 'Phenotype', 'HP:0005526', (131, 149))	('t(2;11)(p21;q23)', 'STRUCTURAL_ABNORMALITY', 'None', (58, 74))	('acute myeloid leukaemia', 'Disease', 'MESH:D015470', (162, 185))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (162, 185))	('t(2;11)(p21;q23', 'Var', (58, 73))	('Hsa-miR-125b-1', 'Gene', '406911', (4, 18))	('ALL', 'Phenotype', 'HP:0006721', (153, 156))	('t(11;14)(q24;q32', 'Var', (36, 52))	('lymphoid leukaemia', 'Disease', (131, 149))	('cel', 'Gene', (120, 123))	('t(11;14)(q24;q32)', 'STRUCTURAL_ABNORMALITY', 'None', (36, 53))	('acute myeloid leukaemia', 'Disease', (162, 185))	('leads to', 'Reg', (109, 117))	('Hsa-miR-125b-1', 'Gene', (4, 18))	('acute lymphoid leukaemia', 'Phenotype', 'HP:0006721', (125, 149))	('AML', 'Disease', 'MESH:D015470', (187, 190))	('lymphoid leukaemia', 'Disease', 'MESH:D007945', (131, 149))	('AML', 'Phenotype', 'HP:0004808', (187, 190))	('AML', 'Disease', (187, 190))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (168, 185))	('cel', 'Gene', '1056', (120, 123))
15777	33332677	37 ,  38  One of miR-125b downstream targets is the tumour suppressor, adenomatous polyposis coli (APC), and loss-of-function mutations in APC have been linked to the progression of cancer.	('miR-125b', 'Gene', '100033636', (17, 25))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (71, 97))	('tumour', 'Disease', (52, 58))	('adenomatous polyposis coli', 'Gene', (71, 97))	('cancer', 'Disease', (182, 188))	('mutations', 'Var', (126, 135))	('APC', 'Phenotype', 'HP:0005227', (99, 102))	('APC', 'Disease', 'MESH:D011125', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('APC', 'Disease', (99, 102))	('adenomatous polyposis coli', 'Gene', '324', (71, 97))	('APC', 'Phenotype', 'HP:0005227', (139, 142))	('APC', 'Disease', 'MESH:D011125', (139, 142))	('loss-of-function', 'NegReg', (109, 125))	('APC', 'Disease', (139, 142))	('miR-125b', 'Gene', (17, 25))	('cancer', 'Disease', 'MESH:D009369', (182, 188))
15782	33332677	43   Similarly, the dysregulated activation of the PI3K/Akt signalling pathway is commonly associated with the proliferative ability of tumour cells in cancer progression, and miR-125b is also implicated in this signalling pathway (Figure 1).	('dysregulated', 'Var', (20, 32))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('proliferative ability', 'CPA', (111, 132))	('activation', 'PosReg', (33, 43))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('Akt', 'Gene', (56, 59))	('cel', 'Gene', (143, 146))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('tumour', 'Disease', (136, 142))	('miR-125b', 'Gene', '100033636', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('miR-125b', 'Gene', (176, 184))	('Akt', 'Gene', '207', (56, 59))	('cel', 'Gene', '1056', (143, 146))	('associated', 'Reg', (91, 101))
15792	33332677	50 ,  51  For example, the ectopic expression of miR-125b in human osteosarcoma cells can reverse their high rate of proliferation, migration and tumour formation by targeting STAT3.	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('miR-125b', 'Gene', '100033636', (49, 57))	('cel', 'Gene', '1056', (80, 83))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('ectopic expression', 'Var', (27, 45))	('osteosarcoma', 'Disease', (67, 79))	('tumour', 'Disease', 'MESH:D009369', (146, 152))	('cel', 'Gene', (80, 83))	('osteosarcoma', 'Disease', 'MESH:D012516', (67, 79))	('tumour', 'Disease', (146, 152))	('STAT3', 'Gene', '6774', (176, 181))	('migration', 'CPA', (132, 141))	('human', 'Species', '9606', (61, 66))	('targeting', 'Reg', (166, 175))	('STAT3', 'Gene', (176, 181))	('reverse', 'NegReg', (90, 97))	('miR-125b', 'Gene', (49, 57))	('high rate', 'MPA', (104, 113))	('osteosarcoma', 'Phenotype', 'HP:0002669', (67, 79))
15808	33332677	For example, in glioblastoma cells, miR-125b down-regulates p53 and the knockdown of miR-125b can lead to the activation of p53-related apoptosis.	('miR-125b', 'Gene', (36, 44))	('cel', 'Gene', (29, 32))	('activation', 'PosReg', (110, 120))	('miR-125b', 'Gene', '100033636', (85, 93))	('glioblastoma', 'Phenotype', 'HP:0012174', (16, 28))	('p53', 'Protein', (60, 63))	('p53-related apoptosis', 'CPA', (124, 145))	('apoptosis', 'biological_process', 'GO:0097194', ('136', '145'))	('miR-125b', 'Gene', (85, 93))	('down-regulates', 'NegReg', (45, 59))	('miR-125b', 'Gene', '100033636', (36, 44))	('apoptosis', 'biological_process', 'GO:0006915', ('136', '145'))	('cel', 'Gene', '1056', (29, 32))	('glioblastoma', 'Disease', (16, 28))	('knockdown', 'Var', (72, 81))	('glioblastoma', 'Disease', 'MESH:D005909', (16, 28))
15814	33332677	31 ,  32  The aberrant expression of miR-125b has been demonstrated to give rise to a wide range of malignancies.	('give rise to', 'Reg', (71, 83))	('malignancies', 'Disease', 'MESH:D009369', (100, 112))	('malignancies', 'Disease', (100, 112))	('aberrant expression', 'Var', (14, 33))	('miR-125b', 'Gene', '100033636', (37, 45))	('miR-125b', 'Gene', (37, 45))
15817	33332677	62  In addition, the ectopic overexpression of the heavy chain of ferritin, a nanocage protein, leads to the down-regulation of miR-125b in NSCLC via hypermethylation in the miR-125b promoter region (Figure 2).	('overexpression', 'PosReg', (29, 43))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('miR-125b', 'Gene', (174, 182))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('miR-125b', 'Gene', '100033636', (128, 136))	('down-regulation', 'NegReg', (109, 124))	('SCLC', 'Phenotype', 'HP:0030357', (141, 145))	('miR-125b', 'Gene', (128, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('hypermethylation', 'Var', (150, 166))	('miR-125b', 'Gene', '100033636', (174, 182))	('regulation', 'biological_process', 'GO:0065007', ('114', '124'))	('NSCLC', 'Disease', (140, 145))
15827	33332677	67  The subsequent knockdown of lncRNA HOXA-AS2 inhibits the capability of bladder cancer cell lines to proliferate and migrate in vitro as well as tumour development in vivo.	('tumour', 'Disease', (148, 154))	('inhibits', 'NegReg', (48, 56))	('HOXA-AS2', 'Gene', (39, 47))	('knockdown', 'Var', (19, 28))	('bladder cancer', 'Disease', (75, 89))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('cel', 'Gene', '1056', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('HOXA-AS2', 'Gene', '285943', (39, 47))	('cel', 'Gene', (90, 93))	('tumour', 'Disease', 'MESH:D009369', (148, 154))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))
15837	33332677	71  In addition, the expression of miR-125b is suppressed in nucleophosmin-anaplastic lymphoma kinase (NPM-ALK)+ systemic anaplastic large-cell lymphoma, due to hypermethylation of the miR-125b promoter region.	('cel', 'Gene', (139, 142))	('hypermethylation', 'Var', (161, 177))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (75, 94))	('miR-125b', 'Gene', '100033636', (185, 193))	('lymphoma', 'Disease', (86, 94))	('lymphoma', 'Disease', 'MESH:D008223', (86, 94))	('suppressed', 'NegReg', (47, 57))	('ALK', 'Gene', '238', (107, 110))	('lymphoma', 'Phenotype', 'HP:0002665', (144, 152))	('cell lymphoma', 'Phenotype', 'HP:0012191', (139, 152))	('ALK', 'Gene', (107, 110))	('miR-125b', 'Gene', (35, 43))	('cel', 'Gene', '1056', (139, 142))	('NPM', 'Gene', (103, 106))	('NPM', 'Gene', '4869', (103, 106))	('lymphoma', 'Phenotype', 'HP:0002665', (86, 94))	('lymphoma', 'Disease', (144, 152))	('anaplastic large-cell lymphoma', 'Phenotype', 'HP:0012193', (122, 152))	('miR-125b', 'Gene', '100033636', (35, 43))	('miR-125b', 'Gene', (185, 193))	('lymphoma', 'Disease', 'MESH:D008223', (144, 152))	('expression', 'MPA', (21, 31))
15840	33332677	Regarding the methylation of tumour suppressor genes, patients with promoter hypermethylation in genes such as PTEN and RASSF1A are also associated with down-regulated miR-125b levels.	('RASSF1A', 'Gene', (120, 127))	('tumour', 'Disease', (29, 35))	('PTEN', 'Gene', (111, 115))	('miR-125b', 'Gene', '100033636', (168, 176))	('PTEN', 'Gene', '5728', (111, 115))	('patients', 'Species', '9606', (54, 62))	('miR-125b', 'Gene', (168, 176))	('RASSF1A', 'Gene', '11186', (120, 127))	('promoter hypermethylation', 'Var', (68, 93))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('down-regulated', 'NegReg', (153, 167))	('tumour', 'Disease', 'MESH:D009369', (29, 35))
15843	33332677	75  In addition, the enhanced methylation of histones H3K9me3 and H3K27me3 is associated with the down-regulation of miR-125b-1 in breast cancer cells.	('histones H3K9me3', 'Protein', (45, 61))	('cel', 'Gene', '1056', (145, 148))	('enhanced', 'PosReg', (21, 29))	('regulation', 'biological_process', 'GO:0065007', ('103', '113'))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('miR-125b-1', 'Gene', '406911', (117, 127))	('miR-125b-1', 'Gene', (117, 127))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('cel', 'Gene', (145, 148))	('down-regulation', 'NegReg', (98, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('breast cancer', 'Disease', (131, 144))	('H3K9me3', 'Protein', (54, 61))	('methylation', 'MPA', (30, 41))	('H3K27me3', 'Var', (66, 74))
15850	33332677	Hexokinase-2 (HK-2) is an enzyme involved in catalysing the first rate-limiting step in glycolysis, and it is targeted by miR-125b-5p.	('miR-125b-5p', 'Var', (122, 133))	('HK-2', 'Gene', '3099', (14, 18))	('HK-2', 'Gene', (14, 18))	('Hexokinase-2', 'Gene', (0, 12))	('miR-125b-5p', 'Chemical', '-', (122, 133))	('Hexokinase-2', 'Gene', '3099', (0, 12))
15851	33332677	44 ,  78  In laryngeal squamous cell carcinoma (LSCC) cells, miR-125b-5p overexpression leads to the down-regulation of HK-2 and thus results in a decrease in lactate production and glucose consumption.	('regulation', 'biological_process', 'GO:0065007', ('106', '116'))	('cel', 'Gene', '1056', (54, 57))	('miR-125b-5p', 'Var', (61, 72))	('cel', 'Gene', (32, 35))	('decrease', 'NegReg', (147, 155))	('HK-2', 'Gene', '3099', (120, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('cel', 'Gene', (54, 57))	('glucose consumption', 'MPA', (182, 201))	('HK-2', 'molecular_function', 'GO:0008256', ('120', '124'))	('lactate production', 'MPA', (159, 177))	('down-regulation', 'NegReg', (101, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('overexpression', 'PosReg', (73, 87))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (23, 46))	('HK-2', 'Gene', (120, 124))	('miR-125b-5p', 'Chemical', '-', (61, 72))	('cel', 'Gene', '1056', (32, 35))	('glucose', 'Chemical', 'MESH:D005947', (182, 189))	('squamous cell carcinoma', 'Disease', (23, 46))	('lactate', 'Chemical', 'MESH:D019344', (159, 166))
15870	33332677	91  miR-125b overexpression or SIRT6 knockout leads to cellular senescence and apoptosis in hepatocellular carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (92, 116))	('miR-125b', 'Gene', '100033636', (4, 12))	('cel', 'Gene', '1056', (55, 58))	('cel', 'Gene', '1056', (117, 120))	('cel', 'Gene', (98, 101))	('knockout', 'Var', (37, 45))	('miR-125b', 'Gene', (4, 12))	('SIRT6', 'Gene', '51548', (31, 36))	('cel', 'Gene', (55, 58))	('apoptosis', 'CPA', (79, 88))	('overexpression', 'PosReg', (13, 27))	('cel', 'Gene', (117, 120))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (92, 116))	('hepatocellular carcinoma', 'Disease', (92, 116))	('cel', 'Gene', '1056', (98, 101))	('SIRT6', 'Gene', (31, 36))
15888	33332677	The ectopic expression of miR-125b has been shown to inhibit SAF-1 expression, and thus down-regulate the proliferative and invasive nature of breast cancer cells (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('miR-125b', 'Gene', '100033636', (26, 34))	('inhibit', 'NegReg', (53, 60))	('SAF-1', 'Gene', (61, 66))	('miR-125b', 'Gene', (26, 34))	('breast cancer', 'Disease', (143, 156))	('cel', 'Gene', (157, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('ectopic expression', 'Var', (4, 22))	('SAF-1', 'Gene', '4150', (61, 66))	('expression', 'MPA', (67, 77))	('cel', 'Gene', '1056', (157, 160))	('down-regulate', 'NegReg', (88, 101))
15896	33332677	116  A number of investigations have reported that the deregulation of miR-125b influences critical developmental checkpoints during haematopoiesis and thus leads to the development of cancer (Table 1).	('miR-125b', 'Gene', '100033636', (71, 79))	('haematopoiesis', 'Disease', 'None', (133, 147))	('leads to', 'Reg', (157, 165))	('miR-125b', 'Gene', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('deregulation', 'Var', (55, 67))	('haematopoiesis', 'Disease', (133, 147))	('influences', 'Reg', (80, 90))	('critical developmental checkpoints', 'CPA', (91, 125))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
15901	33332677	105  In addition, the ectopic expression of miR-125b contributes to the development of leukaemia and accelerates the maturation arrest in T-ALL xenograft mouse models in part via the inhibition of the T-lineage regulators, Ets1 and CBFbeta.	('mouse', 'Species', '10090', (154, 159))	('leukaemia', 'Disease', (87, 96))	('inhibition', 'NegReg', (183, 193))	('miR-125b', 'Gene', (44, 52))	('arrest', 'Disease', 'MESH:D006323', (128, 134))	('cel', 'Gene', '1056', (103, 106))	('ectopic expression', 'Var', (22, 40))	('Ets1', 'Gene', (223, 227))	('Ets1', 'Gene', '23871', (223, 227))	('ALL', 'Phenotype', 'HP:0006721', (140, 143))	('arrest', 'Disease', (128, 134))	('cel', 'Gene', (103, 106))	('leukaemia', 'Disease', 'MESH:D007938', (87, 96))	('CBFbeta', 'Gene', (232, 239))	('miR-125b', 'Gene', '100033636', (44, 52))	('CBFbeta', 'Gene', '12606', (232, 239))
15906	33332677	108  In addition, dysregulated expression of miR-125b initially reduces the production of B cells in the blood and spleen, and of pre-B cells in the bone marrow, by targeting S1PR1, but later promotes pre-B-cell lymphoma via the inhibition of IRF4 (Table 1).	('cel', 'Gene', '1056', (136, 139))	('targeting', 'NegReg', (165, 174))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (205, 220))	('IRF4', 'Gene', (243, 247))	('cel', 'Gene', (207, 210))	('pre', 'molecular_function', 'GO:0003904', ('130', '133'))	('miR-125b', 'Gene', (45, 53))	('cel', 'Gene', (136, 139))	('inhibition', 'NegReg', (229, 239))	('B-cell lymphoma', 'Disease', (205, 220))	('cel', 'Gene', '1056', (92, 95))	('reduces', 'NegReg', (64, 71))	('dysregulated', 'Var', (18, 30))	('miR-125b', 'Gene', '100033636', (45, 53))	('promotes', 'PosReg', (192, 200))	('lymphoma', 'Phenotype', 'HP:0002665', (212, 220))	('cell lymphoma', 'Phenotype', 'HP:0012191', (207, 220))	('pre', 'molecular_function', 'GO:0003904', ('201', '204'))	('cel', 'Gene', (92, 95))	('cel', 'Gene', '1056', (207, 210))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (205, 220))	('S1PR1', 'Gene', (175, 180))
15907	33332677	108  Besides that, miR-125b overexpression increases the number of early B-progenitor cells and induces the expansion and enrichment of the lymphoid-balanced and lymphoid-biased haematopoietic stem cell subset via negatively regulating pro-apoptotic targets, Bmf and KLF3, thereby conferring lymphoproliferative neoplasm.	('cel', 'Gene', '1056', (86, 89))	('Bmf', 'Gene', (259, 262))	('overexpression', 'Var', (28, 42))	('KLF3', 'Gene', (267, 271))	('lymphoproliferative neoplasm', 'Phenotype', 'HP:0005523', (292, 320))	('increases', 'PosReg', (43, 52))	('cel', 'Gene', '1056', (198, 201))	('conferring', 'Reg', (281, 291))	('KLF3', 'Gene', '16599', (267, 271))	('expansion', 'CPA', (108, 117))	('Bmf', 'Gene', '171543', (259, 262))	('lymphoproliferative neoplasm', 'Disease', 'MESH:D008232', (292, 320))	('cel', 'Gene', (86, 89))	('neoplasm', 'Phenotype', 'HP:0002664', (312, 320))	('cel', 'Gene', (198, 201))	('negatively', 'NegReg', (214, 224))	('regulating', 'Reg', (225, 235))	('enrichment', 'CPA', (122, 132))	('miR-125b', 'Gene', (19, 27))	('lymphoproliferative neoplasm', 'Disease', (292, 320))	('induces', 'Reg', (96, 103))	('miR-125b', 'Gene', '100033636', (19, 27))
15971	33332677	158  Furthermore, miRNA expression microarray analysis indicated that miR-125b is up-regulated in patient tissue samples containing EGFR mutation for gefitinib resistance as compared with samples containing EGFR mutation for gefitinib sensitivity.	('patient', 'Species', '9606', (98, 105))	('mutation', 'Var', (137, 145))	('miR-125b', 'Gene', '100033636', (70, 78))	('EGFR', 'Gene', (132, 136))	('gefitinib', 'Chemical', 'MESH:D000077156', (225, 234))	('miR-125b', 'Gene', (70, 78))	('up-regulated', 'PosReg', (82, 94))	('gefitinib', 'Chemical', 'MESH:D000077156', (150, 159))	('gefitinib resistance', 'MPA', (150, 170))
16021	32937891	Besides that, ROS activate signaling pathways associated with cell growth, e.g., p38MAPK, p70S6K, p90Rsk, JAK/STAT, JNK, ERK, RAS, AKT and phospholipase D. Moreover, ROS can oxidize cysteine residues in tyrosine phosphatases, for example PTEN and PTP-1B, and decrease their activities.	('AKT', 'Gene', '207', (131, 134))	('PTEN', 'Gene', '5728', (238, 242))	('activities', 'MPA', (274, 284))	('tyrosine phosphatases', 'Enzyme', (203, 224))	('RA', 'Chemical', 'MESH:C041376', (126, 128))	('decrease', 'NegReg', (259, 267))	('ERK', 'Gene', '5594', (121, 124))	('MAPK', 'molecular_function', 'GO:0004707', ('84', '88'))	('p38', 'Gene', (81, 84))	('ROS', 'Chemical', 'MESH:D017382', (166, 169))	('p70S6K', 'Gene', '6198', (90, 96))	('cysteine', 'Chemical', 'MESH:D003545', (182, 190))	('ERK', 'Gene', (121, 124))	('signaling', 'biological_process', 'GO:0023052', ('27', '36'))	('AKT', 'Gene', (131, 134))	('PTP-1B', 'Gene', (247, 253))	('oxidize cysteine residues', 'MPA', (174, 199))	('ROS', 'Chemical', 'MESH:D017382', (14, 17))	('ROS', 'Var', (166, 169))	('JNK', 'molecular_function', 'GO:0004705', ('116', '119'))	('JNK', 'Gene', (116, 119))	('cell growth', 'biological_process', 'GO:0016049', ('62', '73'))	('ERK', 'molecular_function', 'GO:0004707', ('121', '124'))	('JNK', 'Gene', '5599', (116, 119))	('p38', 'Gene', '1432', (81, 84))	('PTEN', 'Gene', (238, 242))	('p70S6K', 'Gene', (90, 96))	('JAK', 'molecular_function', 'GO:0004713', ('106', '109'))
16022	32937891	Such changes promote hyper-activation of the PI3K and AKT pathways.	('changes', 'Var', (5, 12))	('AKT', 'Gene', '207', (54, 57))	('PI3K', 'molecular_function', 'GO:0016303', ('45', '49'))	('AKT', 'Gene', (54, 57))	('hyper-activation', 'PosReg', (21, 37))
16025	32937891	In addition, iron-induced oxidative stress by ferric nitrilotriacetate (Fe-NTA) assesses in p16/p15 tumor suppressor genes deletion which results in carcinogenesis.	('ferric nitrilotriacetate', 'Chemical', 'MESH:C020326', (46, 70))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('100', '116'))	('carcinogenesis', 'Disease', (149, 163))	('p16', 'Gene', (92, 95))	('Fe-NTA', 'Chemical', 'MESH:C020326', (72, 78))	('tumor', 'Disease', (100, 105))	('p15', 'Gene', (96, 99))	('deletion', 'Var', (123, 131))	('oxidative stress', 'Phenotype', 'HP:0025464', (26, 42))	('p15', 'Gene', '1030', (96, 99))	('tumor suppressor', 'biological_process', 'GO:0051726', ('100', '116'))	('p16', 'Gene', '1029', (92, 95))	('carcinogenesis', 'Disease', 'MESH:D063646', (149, 163))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('iron', 'Chemical', 'MESH:D007501', (13, 17))	('results in', 'Reg', (138, 148))
16029	32937891	In fact, mutant p53 isoforms cannot apply antioxidant activities, and rather induce intracellular ROS and promote a pro-tumorigenic survival.	('induce', 'PosReg', (77, 83))	('ROS', 'Chemical', 'MESH:D017382', (98, 101))	('rat', 'Species', '10116', (70, 73))	('mutant', 'Var', (9, 15))	('p53', 'Gene', (16, 19))	('promote', 'PosReg', (106, 113))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('intracellular ROS', 'MPA', (84, 101))	('p53', 'Gene', '7157', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
16161	32937891	Primrose reduced H2O2-induced DNA damage in a concentration-dependent manner in fibroblast cells compared to the positive controls (only 20 muM H2O2 treatment).	('DNA', 'cellular_component', 'GO:0005574', ('30', '33'))	('DNA damage', 'MPA', (30, 40))	('reduced', 'NegReg', (9, 16))	('rat', 'Species', '10116', (53, 56))	('H2O2-induced', 'Var', (17, 29))	('men', 'Species', '9606', (154, 157))	('H2O2', 'Chemical', 'MESH:D006861', (17, 21))	('H2O2', 'Chemical', 'MESH:D006861', (144, 148))
16200	32937891	It was reported that P. granatum has the ability to down-regulate various signaling pathways like NF-KB, P13K/AKT/mTOR and Wnt, as well as reduece the expression of genes that are associated with cancer development, such as anti-apoptotic genes, MMPs, VEGF, c-met, pro-inflammatory cytokines, cyclines, and Cdks.	('men', 'Species', '9606', (210, 213))	('signaling pathways', 'Pathway', (74, 92))	('P13K', 'SUBSTITUTION', 'None', (105, 109))	('AKT', 'Gene', (110, 113))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('VEGF', 'Gene', (252, 256))	('anti-apoptotic genes', 'Gene', (224, 244))	('MMPs', 'Gene', (246, 250))	('NF-KB', 'Gene', (98, 103))	('Wnt', 'Gene', (123, 126))	('mTOR', 'Gene', (114, 118))	('down-regulate', 'NegReg', (52, 65))	('P13K', 'Var', (105, 109))	('AKT', 'Gene', '207', (110, 113))	('c-met', 'Gene', (258, 263))	('reduece', 'NegReg', (139, 146))	('expression', 'MPA', (151, 161))	('mTOR', 'Gene', '2475', (114, 118))	('cancer', 'Disease', (196, 202))	('P. granatum', 'Species', '22663', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('genes', 'Gene', (165, 170))	('VEGF', 'Gene', '7422', (252, 256))
16246	32937891	Furthermore, antioxidant properties of four Lamiaceae species have shown that M. officinalis has the highest total phenolic content and antioxidant activity compared to the other species.	('M. officinalis', 'Species', '39338', (78, 92))	('total phenolic content', 'MPA', (109, 131))	('antioxidant activity', 'MPA', (136, 156))	('M. officinalis', 'Var', (78, 92))	('antioxidant', 'MPA', (13, 24))
16268	32937891	Moreover, the extract and its active ingradients enhanced the antiproliferative effect (synergistic effect) of cisplatin in both A2780 and A2780CP70 cells.	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('enhanced', 'PosReg', (49, 57))	('extract', 'Chemical', '-', (14, 21))	('A2780', 'CellLine', 'CVCL:0134', (139, 144))	('A2780', 'CellLine', 'CVCL:0134', (129, 134))	('antiproliferative effect', 'MPA', (62, 86))	('rat', 'Species', '10116', (73, 76))	('A2780CP70', 'Var', (139, 148))
16270	32937891	Furthermore, A2780 cells were more sensitive to carnosol, carnosic acid and rosmarinic acid than A2780CP70 cells.	('rosmarinic acid', 'MPA', (76, 91))	('A2780', 'CellLine', 'CVCL:0134', (13, 18))	('A2780', 'Var', (13, 18))	('carnosic acid', 'MPA', (58, 71))	('A2780', 'CellLine', 'CVCL:0134', (97, 102))	('more', 'PosReg', (30, 34))	('carnosic acid', 'Chemical', 'MESH:C018381', (58, 71))	('sensitive to carnosol', 'MPA', (35, 56))	('rosmarinic acid', 'Chemical', 'MESH:C041376', (76, 91))	('carnosol', 'Chemical', 'MESH:C068623', (48, 56))
16280	32937891	In addition, Nrf2 gene silencing increased rosemary cytotoxic effects.	('gene silencing', 'biological_process', 'GO:0016458', ('18', '32'))	('rosemary cytotoxic effects', 'CPA', (43, 69))	('Nrf2', 'Gene', (13, 17))	('rosemary', 'Chemical', '-', (43, 51))	('increased', 'PosReg', (33, 42))	('gene silencing', 'Var', (18, 32))	('Nrf2', 'Gene', '4780', (13, 17))
16302	32937891	In contrast to a previous study which showed that ginger interferes with iron absorption, a recent study concluded that ginger improves iron absorption, and therefore, it is beneficial as a supplement in the therapy of anemia.	('ginger', 'Species', '94328', (120, 126))	('men', 'Species', '9606', (196, 199))	('anemia', 'Phenotype', 'HP:0001903', (219, 225))	('iron', 'Chemical', 'MESH:D007501', (73, 77))	('improves', 'PosReg', (127, 135))	('ginger', 'Var', (120, 126))	('anemia', 'Disease', (219, 225))	('anemia', 'Disease', 'MESH:D000740', (219, 225))	('ginger', 'Species', '94328', (50, 56))	('iron absorption', 'MPA', (136, 151))	('iron', 'Chemical', 'MESH:D007501', (136, 140))
16306	32937891	It was shown that H. sabdariffa has no significant effect on blood TC, HDL, and TG, however, H. sabdariffa was able to lower both FPG and LDL.	('LDL', 'MPA', (138, 141))	('lower', 'NegReg', (119, 124))	('H. sabdariffa', 'Species', '183260', (93, 106))	('H. sabdariffa', 'Species', '183260', (18, 31))	('TG', 'Chemical', 'MESH:D014280', (80, 82))	('H. sabdariffa', 'Var', (93, 106))	('blood TC', 'MPA', (61, 69))	('FPG', 'MPA', (130, 133))	('HDL', 'MPA', (71, 74))	('TC', 'Chemical', '-', (67, 69))
16308	32937891	For example, P. granatum seed oil exhibited a hormetic effect when applied to mouse mammary organ culture.	('oil', 'Chemical', 'MESH:D009821', (30, 33))	('P. granatum', 'Var', (13, 24))	('mouse', 'Species', '10090', (78, 83))	('P. granatum', 'Species', '22663', (13, 24))	('hormetic effect', 'MPA', (46, 61))
16329	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))
16335	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))
16339	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))
16340	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))
16356	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))
16358	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))
16361	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))
16363	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))
16367	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))
16369	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))
16370	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))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('cell death', 'CPA', (244, 254))	('tumor', 'Disease', (53, 58))	('CD133', 'Var', (124, 129))	('cell differentiation', 'CPA', (212, 232))	('tumor', 'Disease', (140, 145))
16372	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))
16377	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))	('mice', 'Species', '10090', (138, 142))	('suppressed', 'NegReg', (76, 86))	('glioblastoma tumor', 'Disease', 'MESH:D005909', (91, 109))	('glioblastoma tumor', 'Disease', (91, 109))
16378	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))
16379	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))
16386	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))
16392	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))	('decreased', 'NegReg', (121, 130))	('gene expressions', 'MPA', (187, 203))	('cyclin D1', 'Gene', '595', (258, 267))	('rat', 'Species', '10116', (241, 244))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cyclin D1', 'Gene', (258, 267))
16393	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))	('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))
16399	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))
16401	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))	('CD133', 'Var', (216, 221))	('metastasis', 'CPA', (277, 287))	('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))
16402	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'))
16403	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'))
16405	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))	('Slug', 'Gene', (250, 254))	('CD133', 'Gene', (73, 78))	('downregulation', 'NegReg', (156, 170))	('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))
16407	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))	('induced', 'PosReg', (56, 63))	('CD133', 'Gene', (50, 55))	('more', 'PosReg', (72, 76))	('EMT', 'CPA', (64, 67))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (95, 105))
16408	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))	('silencing', 'NegReg', (20, 29))	('PROM1', 'Gene', (33, 38))	('BAY 11-7085', 'Chemical', 'MESH:C416282', (157, 168))	('inhibition', 'NegReg', (61, 71))	('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))	('CD133 mediated invasiveness of MIA PaCa-2 cells', 'CPA', (202, 249))	('mutant', 'Var', (126, 132))
16413	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))	('CD133', 'Gene', (134, 139))	('cancer', 'Disease', (79, 85))	('ectopically expressed', 'Var', (112, 133))
16415	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))
16435	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))
16440	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))	('Overexpression', 'Var', (0, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))
16441	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))
16442	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))
16444	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))	('5-FU', 'Chemical', 'MESH:D005472', (92, 96))
16446	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))
16448	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))
16449	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))
16452	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))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('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))
16460	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))
16461	30399449	Another invention includes to conjugate anti-CD133 monoclonal antibody to nanoparticles that were loaded with anti-cancer drug paclitaxel.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('anti-CD133', 'Var', (40, 50))	('paclitaxel', 'Chemical', 'MESH:D017239', (127, 137))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
16466	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))
16479	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))	('cancers', 'Disease', (294, 301))	('cancer metastasis', 'Disease', (210, 227))	('results in', 'Reg', (82, 92))	('cancer', 'Disease', (294, 300))	('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))
16485	29755687	KRAS, BRAF and NRAS mutations were found in 335 (46%), 78 (11%) and 32 (4%) samples, respectively.	('KRAS', 'Gene', '3845', (0, 4))	('NRAS', 'Gene', (15, 19))	('BRAF', 'Gene', '673', (6, 10))	('NRAS', 'Gene', '4893', (15, 19))	('BRAF', 'Gene', (6, 10))	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (20, 29))	('found', 'Reg', (35, 40))
16486	29755687	Moreover, mutations and amplifications in potentially actionable genes were identified in 464 samples (64%), including mutations in PIK3CA (14%), ERBB2 (0.4%), AKT1 (0.6%), and MAP2K1 (0.1%), as well as amplifications of ERBB2 (0.3%) and EGFR (0.3%).	('MAP2K1', 'Gene', '5604', (177, 183))	('amplifications', 'Var', (203, 217))	('EGFR', 'molecular_function', 'GO:0005006', ('238', '242'))	('MAP2K1', 'Gene', (177, 183))	('MAP2K', 'molecular_function', 'GO:0004708', ('177', '182'))	('EGFR', 'Gene', '1956', (238, 242))	('AKT1', 'Gene', '207', (160, 164))	('EGFR', 'Gene', (238, 242))	('ERBB2', 'Gene', (146, 151))	('AKT1', 'Gene', (160, 164))	('ERBB2', 'Gene', '2064', (146, 151))	('PIK3CA', 'Gene', (132, 138))	('mutations', 'Var', (10, 19))	('mutations', 'Var', (119, 128))	('ERBB2', 'Gene', (221, 226))	('PIK3CA', 'Gene', '5290', (132, 138))	('ERBB2', 'Gene', '2064', (221, 226))
16493	29755687	Until recently, indications for standard-of-care molecular testing in colorectal carcinomas included testing for KRAS mutational status as a predictor of response to anti-EGFR agents.	('EGFR', 'Gene', (171, 175))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (70, 91))	('KRAS', 'Gene', (113, 117))	('mutational status', 'Var', (118, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('KRAS', 'Gene', '3845', (113, 117))	('EGFR', 'Gene', '1956', (171, 175))	('colorectal carcinomas', 'Disease', (70, 91))
16495	29755687	Indeed, not only is the benefit of anti-EGFR therapy confined to RAS wild type (wt) tumors, but treatment with anti-EGFR antibodies may even harm patients with a RAS mutation.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('EGFR', 'Gene', (116, 120))	('patients', 'Species', '9606', (146, 154))	('harm', 'NegReg', (141, 145))	('RAS', 'Gene', (162, 165))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('EGFR', 'Gene', '1956', (116, 120))	('mutation', 'Var', (166, 174))
16496	29755687	BRAF mutation is a strong negative prognostic biomarker and evidence is accumulating that patients with a BRAF mutant tumor do not benefit from anti-EGFR therapy.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('mutant', 'Var', (111, 117))	('BRAF', 'Gene', '673', (106, 110))	('EGFR', 'Gene', '1956', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (106, 110))	('tumor', 'Disease', (118, 123))	('EGFR', 'Gene', (149, 153))	('BRAF', 'Gene', (0, 4))	('patients', 'Species', '9606', (90, 98))
16498	29755687	International efforts to catalogue mutations for multiple forms of cancer, coupled with the successes of targeted agents in patients with molecularly defined tumors, have generated enthusiasm for incorporating genomic profiling into clinical cancer practice.	('tumors', 'Disease', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('patients', 'Species', '9606', (124, 132))	('mutations', 'Var', (35, 44))
16506	29755687	The most frequent mutations were found in TP53 (62%) and KRAS (46%) (Table 2 and Figure 3).	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', (42, 46))	('KRAS', 'Gene', (57, 61))	('KRAS', 'Gene', '3845', (57, 61))	('mutations', 'Var', (18, 27))
16507	29755687	Of successfully sequenced cases, 563 potentially actionable mutations were identified in 464 patients (64%), including 343 KRAS mutations, 32 NRAS mutations, 78 BRAF mutations, 101 PIK3CA mutations, 4 AKT1 mutations, 3 ERBB2 mutations, 1 EGFR mutation, and 1 MAP2K1 mutation.	('mutations', 'Var', (147, 156))	('NRAS', 'Gene', '4893', (142, 146))	('PIK3CA', 'Gene', (181, 187))	('EGFR', 'Gene', '1956', (238, 242))	('KRAS', 'Gene', (123, 127))	('patients', 'Species', '9606', (93, 101))	('MAP2K1', 'Gene', '5604', (259, 265))	('mutations', 'Var', (166, 175))	('MAP2K1', 'Gene', (259, 265))	('mutations', 'Var', (128, 137))	('AKT1', 'Gene', '207', (201, 205))	('NRAS', 'Gene', (142, 146))	('ERBB2', 'Gene', (219, 224))	('PIK3CA', 'Gene', '5290', (181, 187))	('AKT1', 'Gene', (201, 205))	('EGFR', 'Gene', (238, 242))	('mutations', 'Var', (188, 197))	('BRAF', 'Gene', (161, 165))	('BRAF', 'Gene', '673', (161, 165))	('ERBB2', 'Gene', '2064', (219, 224))	('mutations', 'Var', (60, 69))	('KRAS', 'Gene', '3845', (123, 127))
16508	29755687	The frequencies of these variants detected by NGS were consistent with frequencies reported in public databases (www.cbioportal.org; http://cancer.sanger.ac.uk/cosmic).	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('variants', 'Var', (25, 33))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))
16510	29755687	Furthermore, around 50% of cases showed KRAS and/or NRAS mutations for each category of tumor cell content (27/54 in cases with <10% tumor cell content; 278/553 in those with 10-50% tumor cells; or 59/117 in cases with >50% tumor cells).	('NRAS', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('NRAS', 'Gene', '4893', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('KRAS', 'Gene', (40, 44))	('tumor', 'Disease', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('mutations', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (133, 138))	('KRAS', 'Gene', '3845', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
16511	29755687	Using coverage analysis, potential EGFR or ERBB2 amplifications were suggested for 2 and 2 patients, respectively.	('ERBB2', 'Gene', '2064', (43, 48))	('patients', 'Species', '9606', (91, 99))	('ERBB2', 'Gene', (43, 48))	('amplifications', 'Var', (49, 63))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('EGFR', 'molecular_function', 'GO:0005006', ('35', '39'))
16518	29755687	We are able to identify potentially actionable mutations for 464 patients, most of them carrying KRAS and/or NRAS mutations (365).	('KRAS', 'Gene', (97, 101))	('mutations', 'Var', (114, 123))	('NRAS', 'Gene', (109, 113))	('KRAS', 'Gene', '3845', (97, 101))	('NRAS', 'Gene', '4893', (109, 113))	('patients', 'Species', '9606', (65, 73))
16519	29755687	According to international guidelines, the presence of a RAS mutation is a contraindication to anti-EGFR therapy.	('RAS', 'Gene', (57, 60))	('EGFR', 'Gene', '1956', (100, 104))	('mutation', 'Var', (61, 69))	('EGFR', 'Gene', (100, 104))
16520	29755687	Nevertheless, the discovery of particular mutations in rare genes can cause a change in the treatment of the patient by including him/her in a clinical trial or medical need program.	('patient', 'Species', '9606', (109, 116))	('change', 'Reg', (78, 84))	('mutations', 'Var', (42, 51))	('cause', 'Reg', (70, 75))
16527	29755687	Briefly, 10 ng of DNA was amplified using the Colon and Lung Cancer panel (Ampliseq , Life Technologies) in order to sequence 1825 hotspot mutations in 22 genes (90 amplicons) including AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, ERBB2, ERBB4, FBXW7, FGFR1, FGFR2, FGFR3, KRAS, MAP2K1, MET, NOTCH1, NRAS, PIK3CA, PTEN, SMAD4, STK11, TP53.	('FGFR2', 'Gene', (251, 256))	('MAP2K1', 'Gene', (271, 277))	('STK11', 'molecular_function', 'GO:0033868', ('319', '324'))	('FGFR', 'molecular_function', 'GO:0005007', ('244', '248'))	('ERBB4', 'Gene', (230, 235))	('EGFR', 'molecular_function', 'GO:0005006', ('217', '221'))	('CTNNB1', 'Gene', (203, 209))	('ERBB2', 'Gene', (223, 228))	('Colon and Lung Cancer', 'Disease', 'MESH:D008175', (46, 67))	('TP53', 'Gene', '7157', (326, 330))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('FGFR2', 'Gene', '2263', (251, 256))	('Lung Cancer', 'Phenotype', 'HP:0100526', (56, 67))	('EGFR', 'Gene', (217, 221))	('PTEN', 'Gene', (306, 310))	('NRAS', 'Gene', '4893', (292, 296))	('PIK3CA', 'Gene', (298, 304))	('NOTCH1', 'Gene', (284, 290))	('KRAS', 'Gene', '3845', (265, 269))	('AKT1', 'Gene', '207', (186, 190))	('FGFR3', 'Gene', (258, 263))	('ERBB2', 'Gene', '2064', (223, 228))	('FGFR1', 'Gene', (244, 249))	('FBXW7', 'Gene', (237, 242))	('ALK', 'Gene', '238', (192, 195))	('DDR2', 'Gene', '4921', (211, 215))	('FGFR3', 'Gene', '2261', (258, 263))	('FGFR', 'molecular_function', 'GO:0005007', ('258', '262'))	('SMAD4', 'Gene', (312, 317))	('STK11', 'Gene', (319, 324))	('KRAS', 'Gene', (265, 269))	('BRAF', 'Gene', (197, 201))	('ALK', 'Gene', (192, 195))	('NOTCH1', 'Gene', '4851', (284, 290))	('PTEN', 'Gene', '5728', (306, 310))	('BRAF', 'Gene', '673', (197, 201))	('AKT1', 'Gene', (186, 190))	('CTNNB1', 'Gene', '1499', (203, 209))	('NRAS', 'Gene', (292, 296))	('FGFR', 'molecular_function', 'GO:0005007', ('251', '255'))	('TP53', 'Gene', (326, 330))	('EGFR', 'Gene', '1956', (217, 221))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (139, 148))	('FBXW7', 'Gene', '55294', (237, 242))	('DDR2', 'Gene', (211, 215))	('PIK3CA', 'Gene', '5290', (298, 304))	('STK11', 'Gene', '6794', (319, 324))	('MAP2K1', 'Gene', '5604', (271, 277))	('SMAD4', 'Gene', '4089', (312, 317))	('MAP2K', 'molecular_function', 'GO:0004708', ('271', '276'))	('FGFR1', 'Gene', '2260', (244, 249))	('ERBB4', 'Gene', '2066', (230, 235))
16539	28903410	We found that low RASSF6 expression corresponds to a poor prognosis in colorectal cancer patients, and low RASSF6 expression is distinctly associated with tumour progression.	('low', 'Var', (103, 106))	('colorectal cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('expression', 'MPA', (25, 35))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('low', 'NegReg', (14, 17))	('patients', 'Species', '9606', (89, 97))	('associated', 'Reg', (139, 149))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('RASSF6', 'Gene', (18, 24))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('tumour', 'Disease', (155, 161))
16540	28903410	Our in vitro analysis revealed that RASSF6 suppresses the proliferation and metastasis of DLD1 cells, and RASSF6 knockdown in HCT116 cells confirmed these observations.	('RASSF6', 'Gene', (36, 42))	('HCT116', 'CellLine', 'CVCL:0291', (126, 132))	('suppresses', 'NegReg', (43, 53))	('RASSF6', 'Gene', (106, 112))	('knockdown', 'Var', (113, 122))
16541	28903410	Our mechanistic investigation revealed that RASSF6 inhibits the expression of the classical target genes of Wnt signalling, as demonstrated by the reduced expression of TCF1, c-Jun, and c-Myc in RASSF6-overexpressing DLD1 stable cell lines.	('expression', 'MPA', (64, 74))	('inhibits', 'NegReg', (51, 59))	('c-Myc', 'Gene', '4609', (186, 191))	('c-Jun', 'Gene', '3725', (175, 180))	('expression', 'MPA', (155, 165))	('c-Myc', 'Gene', (186, 191))	('TCF1', 'Gene', (169, 173))	('c-Jun', 'Gene', (175, 180))	('RASSF6', 'Var', (44, 50))	('reduced', 'NegReg', (147, 154))	('TCF1', 'Gene', '6932', (169, 173))
16543	28903410	Additionally, rescue assays revealed that the activation of Wnt signalling by LiCl treatment impaired the inhibitory effect of RASSF6 on the proliferation and metastasis of colorectal cancer cells, which implies that RASSF6 suppresses the tumorigenicity of colorectal cancer cells at least in part through inhibiting Wnt signalling pathway.	('colorectal cancer', 'Disease', (173, 190))	('impaired', 'NegReg', (93, 101))	('RASSF6', 'Var', (217, 223))	('colorectal cancer', 'Disease', 'MESH:D015179', (173, 190))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('colorectal cancer', 'Phenotype', 'HP:0003003', (257, 274))	('colorectal cancer', 'Disease', 'MESH:D015179', (257, 274))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('inhibiting', 'NegReg', (306, 316))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('Wnt signalling pathway', 'Pathway', (317, 339))	('colorectal cancer', 'Disease', (257, 274))	('inhibitory effect', 'MPA', (106, 123))	('tumor', 'Disease', (239, 244))	('colorectal cancer', 'Phenotype', 'HP:0003003', (173, 190))	('suppresses', 'NegReg', (224, 234))	('LiCl', 'Chemical', 'MESH:D018021', (78, 82))
16558	28903410	Despite a previous study indicating that RASSF6 inhibits cell growth and migration in HT29 and Lovo cell lines, further underlying mechanisms is needed to determine how RASSF6 suppress proliferation and metastasis in CRC, and to determine whether the expression level of RASSF6 correlates with the prognosis of CRC patients.	('proliferation', 'CPA', (185, 198))	('HT29', 'CellLine', 'CVCL:0320', (86, 90))	('RASSF6', 'Var', (41, 47))	('inhibits', 'NegReg', (48, 56))	('suppress', 'NegReg', (176, 184))	('CRC', 'Disease', (311, 314))	('CRC', 'Phenotype', 'HP:0003003', (217, 220))	('cell growth', 'biological_process', 'GO:0016049', ('57', '68'))	('patients', 'Species', '9606', (315, 323))	('CRC', 'Phenotype', 'HP:0003003', (311, 314))	('CRC', 'Disease', (217, 220))	('RASSF6', 'Gene', (169, 175))
16560	28903410	Previous studies have demonstrated that the dysregulation of the Wnt pathway is involved in many types malignant tumours and is an important regulator of biological processes, such as cell growth, migration and EMT process.	('malignant tumours', 'Disease', (103, 120))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('dysregulation', 'Var', (44, 57))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('Wnt pathway', 'Pathway', (65, 76))	('involved', 'Reg', (80, 88))	('malignant tumours', 'Disease', 'MESH:D009369', (103, 120))
16562	28903410	In the present study, we first determined the expression level of RASSF6 in eight CRC cell lines and in patient tissues, and we then investigated potential mechanisms to elucidate how RASSF6 inhibits CRC progression.	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('CRC', 'Disease', (200, 203))	('RASSF6', 'Var', (184, 190))	('inhibits', 'NegReg', (191, 199))	('RASSF6', 'Gene', (66, 72))	('patient', 'Species', '9606', (104, 111))	('CRC', 'Phenotype', 'HP:0003003', (200, 203))
16593	28903410	Results showed that both the weight and volume of tumours were significantly decreased in the RASSF6 group compared with the Vector group (Figure 5A and 5B).	('volume of tumours', 'Disease', (40, 57))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('RASSF6', 'Var', (94, 100))	('volume of tumours', 'Disease', 'MESH:D009369', (40, 57))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('decreased', 'NegReg', (77, 86))
16609	28903410	Secondly, except for negative correlation between RASSF6 expression and advanced TNM stage, we also found that low RASSF6 expression was significantly associated with tumour size (p = 0.042), lymph node status (p < 0.001), and the presence of distant metastasis (p < 0.001, Table 1), which provided more powerful evidence that RASSF6 suppresses CRC proliferation and metastasis.	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('expression', 'MPA', (122, 132))	('TNM', 'Gene', (81, 84))	('lymph node status', 'CPA', (192, 209))	('tumour', 'Disease', (167, 173))	('RASSF6', 'Var', (327, 333))	('distant metastasis', 'CPA', (243, 261))	('RASSF6', 'Gene', (115, 121))	('TNM', 'Gene', '10178', (81, 84))	('CRC', 'Phenotype', 'HP:0003003', (345, 348))	('CRC proliferation', 'CPA', (345, 362))	('low', 'NegReg', (111, 114))	('suppresses', 'NegReg', (334, 344))
16610	28903410	Addtionally, we first established both hepatic and lung metastasis models to demonstrate that RASSF6 inhibits metastasis of CRC cell lines in vivo to further confirm the role of RASSF6 in CRC (Figure 5E-5H), which has not been reported before.	('hepatic and lung metastasis', 'Disease', 'MESH:D009362', (39, 66))	('CRC', 'Phenotype', 'HP:0003003', (188, 191))	('metastasis of CRC cell lines', 'CPA', (110, 138))	('RASSF6', 'Var', (94, 100))	('CRC', 'Phenotype', 'HP:0003003', (124, 127))	('CRC', 'Disease', (188, 191))	('inhibits', 'NegReg', (101, 109))
16611	28903410	To the best of our knowledge, our study first emphasized the role of RASSF6 in predicting the prognosis of CRC patients, discovered that RASSF6 suppresses EMT process, and inhibits tumorigenesis of CRC at least in part, through suppressing Wnt signaling pathway.	('tumor', 'Disease', (181, 186))	('EMT', 'biological_process', 'GO:0001837', ('155', '158'))	('inhibits', 'NegReg', (172, 180))	('CRC', 'Disease', (198, 201))	('Wnt signaling pathway', 'Pathway', (240, 261))	('CRC', 'Phenotype', 'HP:0003003', (107, 110))	('suppresses', 'NegReg', (144, 154))	('EMT process', 'CPA', (155, 166))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('240', '261'))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('suppressing', 'NegReg', (228, 239))	('RASSF6', 'Var', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('CRC', 'Phenotype', 'HP:0003003', (198, 201))	('patients', 'Species', '9606', (111, 119))
16615	28903410	Moreover, to further validate whether RASSF6 indeed inhibits CRC tumorigenesis by modulating the Wnt pathway, we also performed rescue assays by treating cells with the Wnt activator LiCl.	('modulating', 'Reg', (82, 92))	('RASSF6', 'Var', (38, 44))	('tumor', 'Disease', (65, 70))	('inhibits', 'NegReg', (52, 60))	('CRC', 'Disease', (61, 64))	('LiCl', 'Chemical', 'MESH:D018021', (183, 187))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Wnt pathway', 'Pathway', (97, 108))	('CRC', 'Phenotype', 'HP:0003003', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
16618	28903410	Dysregulated Wnt signalling is widely implicated in various malignancies, especially in colorectal cancer, and this leads to cell changes that influence a vast array of biological processes, including embryonic development, cell proliferation, cell migration, stem cell maintenance, and tumourigenesis.	('malignancies', 'Disease', 'MESH:D009369', (60, 72))	('malignancies', 'Disease', (60, 72))	('colorectal cancer', 'Disease', (88, 105))	('embryonic development', 'CPA', (201, 222))	('tumour', 'Disease', (287, 293))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('stem cell maintenance', 'CPA', (260, 281))	('cell migration', 'CPA', (244, 258))	('cell proliferation', 'CPA', (224, 242))	('influence', 'Reg', (143, 152))	('Dysregulated', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('implicated', 'Reg', (38, 48))	('tumour', 'Phenotype', 'HP:0002664', (287, 293))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('tumour', 'Disease', 'MESH:D009369', (287, 293))	('leads to', 'Reg', (116, 124))
16619	28903410	Given that RASSF6 inhibiting Wnt signalling in CRC, we suspect that RASSF6 may also involve in other biological processes in CRC, such as stem cell maintenance, angiogenesis, and anti-tumour drug resistance, all of which require further investigation in future studies.	('CRC', 'Phenotype', 'HP:0003003', (47, 50))	('RASSF6', 'Var', (11, 17))	('RASSF6', 'Gene', (68, 74))	('involve', 'Reg', (84, 91))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('CRC', 'Phenotype', 'HP:0003003', (125, 128))	('inhibiting', 'NegReg', (18, 28))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('drug resistance', 'Phenotype', 'HP:0020174', (191, 206))	('Wnt signalling', 'MPA', (29, 43))	('tumour', 'Disease', (184, 190))
16620	28903410	Additionally, the canonical target genes mediate the effects of Wnt signalling in normal and diseased cells, and RASSF6 overexpression led to a distinct reduction in the Wnt signalling target genes c-Myc, c-Jun, and TCF1, along with a decrease in cell growth and motility; however, the specific target genes that mediate the ability of RASSF6 to act as a tumour suppressor in CRC have not been elucidated.	('decrease', 'NegReg', (235, 243))	('TCF1', 'Gene', (216, 220))	('RASSF6', 'Gene', (113, 119))	('CRC', 'Disease', (376, 379))	('c-Jun', 'Gene', '3725', (205, 210))	('reduction', 'NegReg', (153, 162))	('TCF1', 'Gene', '6932', (216, 220))	('c-Myc', 'Gene', '4609', (198, 203))	('tumour', 'Phenotype', 'HP:0002664', (355, 361))	('c-Jun', 'Gene', (205, 210))	('CRC', 'Phenotype', 'HP:0003003', (376, 379))	('motility', 'CPA', (263, 271))	('cell growth', 'CPA', (247, 258))	('tumour', 'Disease', 'MESH:D009369', (355, 361))	('c-Myc', 'Gene', (198, 203))	('overexpression', 'Var', (120, 134))	('tumour', 'Disease', (355, 361))
16622	28903410	For example, in melanoma, RASSF6 suppresses MAPK activation; whether RASSF6 also inhibits MAPK signalling in CRC, and whether Wnt is the primary mechanism that mediates the regulation of RASSF6 in CRC remains to be determined.	('inhibits', 'NegReg', (81, 89))	('suppresses', 'NegReg', (33, 43))	('MAPK', 'Gene', '5594', (90, 94))	('MAPK activation', 'biological_process', 'GO:0000187', ('44', '59'))	('MAPK', 'molecular_function', 'GO:0004707', ('90', '94'))	('MAPK signalling', 'biological_process', 'GO:0000165', ('90', '105'))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('MAPK', 'molecular_function', 'GO:0004707', ('44', '48'))	('MAPK', 'Gene', (90, 94))	('melanoma', 'Disease', (16, 24))	('MAPK', 'Gene', '5594', (44, 48))	('CRC', 'Phenotype', 'HP:0003003', (197, 200))	('RASSF6', 'Var', (26, 32))	('MAPK', 'Gene', (44, 48))	('regulation', 'biological_process', 'GO:0065007', ('173', '183'))	('CRC', 'Phenotype', 'HP:0003003', (109, 112))
16706	28877221	Collected tumour tissue was placed in cold PBS with antibiotics (500 U/ml penicillin, 500 mug/ml streptomycin, 100 mug/ml gentamicin and 2.5 mug/ml amphotericin B) and transported to the laboratory on ice.	('mug', 'molecular_function', 'GO:0043739', ('115', '118'))	('PBS', 'Chemical', 'MESH:D007854', (43, 46))	('500 U/ml', 'Var', (65, 73))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('penicillin', 'Chemical', 'MESH:D010406', (74, 84))	('mug', 'molecular_function', 'GO:0043739', ('90', '93'))	('streptomycin', 'Chemical', 'MESH:D013307', (97, 109))	('tumour', 'Disease', 'MESH:D009369', (10, 16))	('gentamicin', 'Chemical', 'MESH:D005839', (122, 132))	('tumour', 'Disease', (10, 16))	('mug', 'molecular_function', 'GO:0043739', ('141', '144'))	('amphotericin B', 'Chemical', 'MESH:D000666', (148, 162))
16756	28877221	The percentage of EpCAM-positive cells expressing Ki67 at day 3 varied from 9% to 63% for different spheroid cultures (Fig 2D).	('Ki67', 'Var', (50, 54))	('Ki67', 'Chemical', '-', (50, 54))	('EpCAM', 'Gene', '4072', (18, 23))	('EpCAM', 'Gene', (18, 23))
16831	28448473	In support of this view, several authors have reported that remodeling of Ca2+ signaling in different forms of cancer contributes to cancer hallmarks, including exaggerated cell proliferation, acquisition of cell migration and invasion capabilities, and enhanced resistance to cell death.	('cancer hallmarks', 'Disease', 'MESH:D009369', (133, 149))	('Ca2', 'Gene', '760', (74, 77))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cell migration', 'biological_process', 'GO:0016477', ('208', '222'))	('resistance to cell death', 'CPA', (263, 287))	('cancer', 'Disease', (111, 117))	('remodeling', 'Var', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('enhanced', 'PosReg', (254, 262))	('exaggerated', 'PosReg', (161, 172))	('Ca2', 'Gene', (74, 77))	('invasion capabilities', 'CPA', (227, 248))	('cell migration', 'CPA', (208, 222))	('cell death', 'biological_process', 'GO:0008219', ('277', '287'))	('cell proliferation', 'biological_process', 'GO:0008283', ('173', '191'))	('cancer', 'Disease', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cell proliferation', 'CPA', (173, 191))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer hallmarks', 'Disease', (133, 149))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('acquisition', 'PosReg', (193, 204))
16892	28448473	Interestingly, it has been shown recently that blockers of T-type channels may prevent colon cancer growth.	('colon cancer', 'Disease', (87, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('prevent', 'NegReg', (79, 86))	('T-type channels', 'Protein', (59, 74))	('colon cancer', 'Phenotype', 'HP:0003003', (87, 99))	('blockers', 'Var', (47, 55))	('colon cancer', 'Disease', 'MESH:D015179', (87, 99))
16932	28448473	In addition, it has been also reported that depletion of mutated K-Ras in a colon cancer cell line changes Ca2+ store content and susceptibility to apoptosis by promoting changes in expression of IP3R isoforms.	('Ca2', 'Gene', '760', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('colon cancer', 'Disease', 'MESH:D015179', (76, 88))	('expression', 'MPA', (182, 192))	('changes', 'Reg', (99, 106))	('Ca2', 'Gene', (107, 110))	('colon cancer', 'Disease', (76, 88))	('susceptibility', 'CPA', (130, 144))	('changes', 'Reg', (171, 178))	('IP3R', 'Gene', '3710', (196, 200))	('K-Ras', 'Gene', '3845', (65, 70))	('K-Ras', 'Gene', (65, 70))	('IP3R', 'Gene', (196, 200))	('depletion', 'MPA', (44, 53))	('apoptosis', 'CPA', (148, 157))	('mutated', 'Var', (57, 64))	('colon cancer', 'Phenotype', 'HP:0003003', (76, 88))	('promoting', 'PosReg', (161, 170))
16986	28219002	A BRAF mutation is required for predicting poor prognosis.	('BRAF', 'Gene', (2, 6))	('BRAF', 'Gene', '673', (2, 6))	('mutation', 'Var', (7, 15))
16987	28219002	Additionally, amplification of human epidermal growth factor receptor 2 (HER2) and MET is also associated with resistance to EGFR inhibitor in metastatic CRC patients.	('resistance', 'MPA', (111, 121))	('HER2', 'Protein', (73, 77))	('associated', 'Reg', (95, 105))	('EGFR', 'Gene', '1956', (125, 129))	('human', 'Species', '9606', (31, 36))	('EGFR', 'Gene', (125, 129))	('MET', 'Gene', (83, 86))	('metastatic CRC', 'Disease', (143, 157))	('epidermal growth factor receptor 2', 'Gene', '2064', (37, 71))	('patients', 'Species', '9606', (158, 166))	('CRC', 'Phenotype', 'HP:0003003', (154, 157))	('epidermal growth factor receptor 2', 'Gene', (37, 71))	('amplification', 'Var', (14, 27))
16988	28219002	The BRAF V600E mutation is found in sporadic microsatellite unstable CRCs, and thus is helpful for ruling out Lynch syndrome.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('microsatellite', 'Var', (45, 59))	('Lynch syndrome', 'Disease', (110, 124))	('CRC', 'Phenotype', 'HP:0003003', (69, 72))	('Lynch syndrome', 'Disease', 'MESH:D003123', (110, 124))	('V600E', 'Var', (9, 14))	('ruling', 'Disease', 'MESH:D065309', (99, 105))	('ruling', 'Disease', (99, 105))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))
16989	28219002	In addition, the KRAS mutation is a prognostic biomarker and the PIK3CA mutation is a molecular biomarker predicting response to phosphoinositide 3-kinase/AKT/mammalian target of rapamycin inhibitors and response to aspirin therapy in CRC patients.	('CRC', 'Phenotype', 'HP:0003003', (235, 238))	('AKT', 'Gene', (155, 158))	('mutation', 'Var', (22, 30))	('phosphoinositide 3-kinase', 'Gene', (129, 154))	('phosphoinositide 3-kinase', 'Gene', '5290', (129, 154))	('aspirin', 'Chemical', 'MESH:D001241', (216, 223))	('patients', 'Species', '9606', (239, 247))	('PIK3CA', 'Gene', (65, 71))	('KRAS', 'Gene', (17, 21))	('mutation', 'Var', (72, 80))	('AKT', 'Gene', '207', (155, 158))	('KRAS', 'Gene', '3845', (17, 21))	('mammalian target of rapamycin', 'Gene', '2475', (159, 188))	('mammalian target of rapamycin', 'Gene', (159, 188))	('PIK3CA', 'Gene', '5290', (65, 71))
16999	28219002	MSI testing is recommended in small intestinal adenocarcinoma, and KRAS and BRAF mutations are found in a subset of small intestinal adenocarcinoma.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('small intestinal adenocarcinoma', 'Disease', (30, 61))	('small intestinal adenocarcinoma', 'Disease', (116, 147))	('KRAS', 'Gene', (67, 71))	('found', 'Reg', (95, 100))	('small intestinal adenocarcinoma', 'Disease', 'MESH:C538260', (116, 147))	('small intestinal adenocarcinoma', 'Disease', 'MESH:C538260', (30, 61))	('mutations', 'Var', (81, 90))	('KRAS', 'Gene', '3845', (67, 71))	('men', 'Species', '9606', (20, 23))
17004	28219002	MSI is defined as a change in the microsatellite region within a tumor in comparison to that of normal tissue, resulting from either deletion or insertion of repeating units.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('deletion', 'Var', (133, 141))	('insertion', 'Var', (145, 154))	('repeating', 'Protein', (158, 167))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
17012	28219002	Additionally, the loss of epithelial cell adhesion molecule (EpCAM) expression has been demonstrated in a small subset of Lynch-syndrome-associated CRCs, which is caused by germline EpCAM deletions.	('Lynch-syndrome', 'Disease', (122, 136))	('loss', 'NegReg', (18, 22))	('epithelial cell adhesion molecule', 'Gene', '4072', (26, 59))	('caused by', 'Reg', (163, 172))	('expression', 'MPA', (68, 78))	('Lynch-syndrome', 'Disease', 'MESH:D003123', (122, 136))	('EpCAM', 'Gene', '4072', (61, 66))	('deletions', 'Var', (188, 197))	('EpCAM', 'Gene', '4072', (182, 187))	('CRC', 'Phenotype', 'HP:0003003', (148, 151))	('EpCAM', 'Gene', (61, 66))	('EpCAM', 'Gene', (182, 187))	('epithelial cell adhesion molecule', 'Gene', (26, 59))
17014	28219002	Sporadic MSI-H is observed in about 15%-20% of sporadic CRCs in Western countries and in about 5%-6% in Eastern countries and is caused by MLH1 promoter hypermethylation and MLH1 expression loss.	('MLH1', 'Gene', '4292', (139, 143))	('MLH1', 'Gene', (139, 143))	('expression', 'MPA', (179, 189))	('loss', 'NegReg', (190, 194))	('Sporadic MSI-H', 'Disease', (0, 14))	('CRCs', 'Disease', (56, 60))	('MLH1', 'Gene', '4292', (174, 178))	('CRC', 'Phenotype', 'HP:0003003', (56, 59))	('MLH1', 'Gene', (174, 178))	('promoter hypermethylation', 'Var', (144, 169))	('Sporadic MSI-H', 'Disease', 'MESH:D000848', (0, 14))
17022	28219002	It is generally accepted that a defective MMR system is associated with decreased therapeutic response to fluorouracil-based adjuvant chemotherapy in CRCs and GCs.	('CRCs', 'Disease', (150, 154))	('MMR system', 'Protein', (42, 52))	('decreased', 'NegReg', (72, 81))	('fluorouracil', 'Chemical', 'MESH:D005472', (106, 118))	('GC', 'Phenotype', 'HP:0012126', (159, 161))	('decreased therapeutic response', 'Phenotype', 'HP:0020173', (72, 102))	('response to fluorouracil', 'biological_process', 'GO:0036275', ('94', '118'))	('MMR', 'biological_process', 'GO:0006298', ('42', '45'))	('CRC', 'Phenotype', 'HP:0003003', (150, 153))	('defective', 'Var', (32, 41))
17030	28219002	Currently, the gold standard of MSI testing is the Bethesda panel, which uses PCR for the analysis of the fragment length of five markers: two mononucleotide repeats (BAT25 and BAT26) and three dinucleotide repeats (D5S346, D2S123, and D17S250).	('D17S250', 'Var', (236, 243))	('men', 'Species', '9606', (110, 113))	('mononucleotide', 'Chemical', '-', (143, 157))	('dinucleotide', 'Chemical', 'MESH:D015226', (194, 206))	('D5S346', 'Var', (216, 222))	('D2S123', 'Var', (224, 230))
17053	28219002	KRAS mutations have important roles in various aspects of carcinogenesis, and KRAS mutations in exon 2 at codons 12 and 13 have been reported to be detected in approximately 35%-45% of CRCs.	('mutations', 'Var', (83, 92))	('CRC', 'Phenotype', 'HP:0003003', (185, 188))	('CRCs', 'Disease', (185, 189))	('carcinogenesis', 'Disease', 'MESH:D063646', (58, 72))	('detected', 'Reg', (148, 156))	('KRAS', 'Gene', (78, 82))	('carcinogenesis', 'Disease', (58, 72))	('KRAS', 'Gene', '3845', (78, 82))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
17054	28219002	Negative correlations between KRAS mutations and MSI or BRAF mutations suggest that these molecular alterations are associated with a distinct subset of CRCs and have prognostic significance.	('BRAF', 'Gene', (56, 60))	('BRAF', 'Gene', '673', (56, 60))	('associated', 'Reg', (116, 126))	('mutations', 'Var', (61, 70))	('CRCs', 'Disease', (153, 157))	('CRC', 'Phenotype', 'HP:0003003', (153, 156))	('MSI', 'Gene', (49, 52))	('KRAS', 'Gene', (30, 34))	('KRAS', 'Gene', '3845', (30, 34))	('mutations', 'Var', (35, 44))
17059	28219002	KRAS mutations in exon 2 at codons 12 and 13 are associated with resistance to cetuximab and panitumumab, and with poor survival in chemo-refractory metastatic CRC patients.	('poor', 'NegReg', (115, 119))	('CRC', 'Phenotype', 'HP:0003003', (160, 163))	('associated', 'Reg', (49, 59))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (164, 172))	('cetuximab', 'Chemical', 'MESH:D000068818', (79, 88))	('KRAS', 'Gene', (0, 4))	('resistance', 'MPA', (65, 75))	('panitumumab', 'Chemical', 'MESH:D000077544', (93, 104))	('KRAS', 'Gene', '3845', (0, 4))
17060	28219002	Additionally, oncogenic mutations in KRAS codons 59, 61, 117, and 146 and NRAS codons 12, 13, and 61 have been reported in approximately 3%-5% of CRC samples.	('CRC', 'Disease', (146, 149))	('NRAS', 'Gene', (74, 78))	('KRAS', 'Gene', (37, 41))	('reported', 'Reg', (111, 119))	('NRAS', 'Gene', '4893', (74, 78))	('CRC', 'Phenotype', 'HP:0003003', (146, 149))	('mutations', 'Var', (24, 33))	('KRAS', 'Gene', '3845', (37, 41))
17061	28219002	Recent clinical trials have demonstrated that extended RAS mutation testing, including that for mutations in KRAS and NRAS exons 2 to 4, can be more predictable for lack of responsiveness to EGFR inhibitors than previously proven KRAS exon 2 testing in first-line chemotherapy for metastatic CRC patients.	('KRAS', 'Gene', '3845', (230, 234))	('lack', 'NegReg', (165, 169))	('clinical', 'Species', '191496', (7, 15))	('CRC', 'Phenotype', 'HP:0003003', (292, 295))	('EGFR', 'molecular_function', 'GO:0005006', ('191', '195'))	('NRAS', 'Gene', (118, 122))	('EGFR', 'Gene', '1956', (191, 195))	('KRAS', 'Gene', (109, 113))	('responsiveness', 'MPA', (173, 187))	('EGFR', 'Gene', (191, 195))	('NRAS', 'Gene', '4893', (118, 122))	('KRAS', 'Gene', '3845', (109, 113))	('KRAS', 'Gene', (230, 234))	('patients', 'Species', '9606', (296, 304))	('mutations', 'Var', (96, 105))
17063	28219002	The oncogenic BRAF mutation has a role in constitutive activation and downstream signaling along the MAPK signaling pathway.	('mutation', 'Var', (19, 27))	('constitutive activation', 'MPA', (42, 65))	('MAPK signaling pathway', 'Pathway', (101, 123))	('BRAF', 'Gene', '673', (14, 18))	('BRAF', 'Gene', (14, 18))
17064	28219002	BRAF mutations occur in approximately 5%-8% of CRCs and most are the BRAF V600E mutation, however, the BRAF V600E mutation almost never occurs in GCs.	('V600E', 'Mutation', 'rs113488022', (74, 79))	('CRC', 'Phenotype', 'HP:0003003', (47, 50))	('V600E', 'Mutation', 'rs113488022', (108, 113))	('BRAF', 'Gene', '673', (0, 4))	('GC', 'Phenotype', 'HP:0012126', (146, 148))	('V600E', 'Var', (74, 79))	('BRAF', 'Gene', '673', (69, 73))	('BRAF', 'Gene', '673', (103, 107))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', (69, 73))	('BRAF', 'Gene', (103, 107))	('CRCs', 'Disease', (47, 51))
17065	28219002	The BRAF mutation is an early molecular event in the serrated pathway of CRC.	('mutation', 'Var', (9, 17))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('CRC', 'Phenotype', 'HP:0003003', (73, 76))
17066	28219002	Molecular sequencing in serrated pathway CRCs has been reported as BRAF mutation/CpG island methylator phenotype (CIMP)/MSI-H or BRAF mutation/CIMP/MSS/p16 loss.	('CRC', 'Phenotype', 'HP:0003003', (41, 44))	('BRAF', 'Gene', '673', (67, 71))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('MSI-H', 'Disease', (120, 125))	('CIMP', 'Chemical', '-', (114, 118))	('p16', 'Gene', '1029', (152, 155))	('BRAF', 'Gene', (67, 71))	('loss', 'NegReg', (156, 160))	('CIMP', 'Chemical', '-', (143, 147))	('MSI-H', 'Disease', 'MESH:D000848', (120, 125))	('mutation/CpG', 'Var', (72, 84))	('p16', 'Gene', (152, 155))	('serrated pathway CRCs', 'Disease', (24, 45))
17067	28219002	Many previous studies have confirmed that the BRAF mutation is associated with poor prognosis in metastatic CRC patients.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('patients', 'Species', '9606', (112, 120))	('metastatic CRC', 'Disease', (97, 111))	('CRC', 'Phenotype', 'HP:0003003', (108, 111))	('mutation', 'Var', (51, 59))
17068	28219002	In addition to metastatic CRCs, earlier-stage CRC patients with mutated BRAF have been reported to show significantly worse overall survival than that of patients with wild-type BRAF.	('overall survival', 'MPA', (124, 140))	('BRAF', 'Gene', (72, 76))	('patients', 'Species', '9606', (50, 58))	('patients', 'Species', '9606', (154, 162))	('mutated', 'Var', (64, 71))	('CRC', 'Phenotype', 'HP:0003003', (46, 49))	('BRAF', 'Gene', (178, 182))	('worse', 'NegReg', (118, 123))	('BRAF', 'Gene', '673', (178, 182))	('BRAF', 'Gene', '673', (72, 76))	('CRC', 'Phenotype', 'HP:0003003', (26, 29))
17069	28219002	The BRAF V600E mutation is observed in approximately two thirds of microsatellite unstable CRCs caused by MLH1 hypermethylation and protein loss, but it never occurs in microsatellite unstable CRCs associated with Lynch syndrome.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('microsatellite unstable CRCs', 'Disease', (67, 95))	('MLH1', 'Gene', '4292', (106, 110))	('hypermethylation', 'Var', (111, 127))	('MLH1', 'Gene', (106, 110))	('V600E', 'Var', (9, 14))	('Lynch syndrome', 'Disease', (214, 228))	('protein', 'Protein', (132, 139))	('CRC', 'Phenotype', 'HP:0003003', (193, 196))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('Lynch syndrome', 'Disease', 'MESH:D003123', (214, 228))	('CRC', 'Phenotype', 'HP:0003003', (91, 94))	('caused by', 'Reg', (96, 105))	('loss', 'NegReg', (140, 144))
17070	28219002	Therefore, newly diagnosed CRC cases should be initially examined by MSI analysis with MMR protein IHC, and then Lynch syndrome can be excluded if both MLH1 loss by IHC and BRAF V600E mutation or MLH1 hypermethylation are observed.	('MLH1', 'Gene', (152, 156))	('CRC', 'Phenotype', 'HP:0003003', (27, 30))	('V600E', 'Var', (178, 183))	('BRAF', 'Gene', '673', (173, 177))	('MLH1 loss by IHC', 'Disease', 'MESH:D015431', (152, 168))	('MLH1', 'Gene', '4292', (196, 200))	('MLH1', 'Gene', (196, 200))	('BRAF', 'Gene', (173, 177))	('MLH1 loss by IHC', 'Disease', (152, 168))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('V600E', 'Mutation', 'rs113488022', (178, 183))	('Lynch syndrome', 'Disease', (113, 127))	('MMR', 'biological_process', 'GO:0006298', ('87', '90'))	('MLH1', 'Gene', '4292', (152, 156))	('Lynch syndrome', 'Disease', 'MESH:D003123', (113, 127))
17076	28219002	However, several clinical trials that combine BRAF and EGFR inhibitors with or without a third agent are currently ongoing or have recently been completed in BRAF mutated CRCs.	('BRAF', 'Gene', (46, 50))	('CRCs', 'Disease', (171, 175))	('BRAF', 'Gene', '673', (46, 50))	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'molecular_function', 'GO:0005006', ('55', '59'))	('mutated', 'Var', (163, 170))	('EGFR', 'Gene', (55, 59))	('BRAF', 'Gene', '673', (158, 162))	('BRAF', 'Gene', (158, 162))	('clinical', 'Species', '191496', (17, 25))	('CRC', 'Phenotype', 'HP:0003003', (171, 174))
17077	28219002	In addition to the RAS/RAF/MAPK signaling pathway, activated EGFR can also induce the phosphoinositide 3-kinase (PI3K)/AKT/PTEN pathway.	('AKT', 'Gene', '207', (119, 122))	('activated', 'Var', (51, 60))	('phosphoinositide 3-kinase', 'Gene', '5290', (86, 111))	('phosphoinositide 3-kinase', 'Gene', (86, 111))	('PTEN', 'Gene', (123, 127))	('PTEN', 'Gene', '5728', (123, 127))	('EGFR', 'Gene', '1956', (61, 65))	('AKT', 'Gene', (119, 122))	('RAF', 'Gene', '22882', (23, 26))	('RAF', 'Gene', (23, 26))	('induce', 'PosReg', (75, 81))	('EGFR', 'Gene', (61, 65))
17078	28219002	PIK3CA mutations in exon 9 and 20 have been studied as effectors of the EGFR downstream signaling pathway, similar to BRAF and RAS, and they might be related to resistance to EGFR inhibitors.	('BRAF', 'Gene', '673', (118, 122))	('EGFR', 'Gene', (175, 179))	('BRAF', 'Gene', (118, 122))	('EGFR', 'Gene', '1956', (72, 76))	('related', 'Reg', (150, 157))	('PIK3CA', 'Gene', (0, 6))	('EGFR', 'Gene', (72, 76))	('PIK3CA', 'Gene', '5290', (0, 6))	('EGFR', 'Gene', '1956', (175, 179))	('mutations', 'Var', (7, 16))
17079	28219002	However, PIK3CA mutations tend to occur together with KRAS mutations.	('occur', 'Reg', (34, 39))	('mutations', 'Var', (16, 25))	('KRAS', 'Gene', (54, 58))	('KRAS', 'Gene', '3845', (54, 58))	('PIK3CA', 'Gene', (9, 15))	('PIK3CA', 'Gene', '5290', (9, 15))
17080	28219002	Furthermore, confirmative evidence for a role of PIK3CA mutations in predicting response to cetuximab has not been shown.	('cetuximab', 'Chemical', 'MESH:D000068818', (92, 101))	('PIK3CA', 'Gene', (49, 55))	('mutations', 'Var', (56, 65))	('PIK3CA', 'Gene', '5290', (49, 55))
17082	28219002	The PI3K/AKT/mammalian target of rapamycin (mTOR) pathway is frequently dysregulated in human cancers initiated by various molecular alterations including PIK3CA mutations.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('AKT', 'Gene', '207', (9, 12))	('mutations', 'Var', (162, 171))	('mammalian target of rapamycin', 'Gene', '2475', (13, 42))	('mammalian target of rapamycin', 'Gene', (13, 42))	('initiated by', 'Reg', (102, 114))	('PIK3CA', 'Gene', '5290', (155, 161))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('mTOR', 'Gene', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mTOR', 'Gene', '2475', (44, 48))	('PIK3CA', 'Gene', (155, 161))	('AKT', 'Gene', (9, 12))	('dysregulated', 'Reg', (72, 84))	('human', 'Species', '9606', (88, 93))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
17083	28219002	performed early-phase clinical trials in which PI3K/AKT/mTOR inhibitors were administered to the patients with advanced tumors, and demonstrated that PIK3CA mutation was independently associated with a better response to PI3K/AKT/mTOR inhibitors.	('advanced tumors', 'Disease', 'MESH:D020178', (111, 126))	('advanced tumors', 'Disease', (111, 126))	('PIK3CA', 'Gene', '5290', (150, 156))	('better', 'PosReg', (202, 208))	('mTOR', 'Gene', (230, 234))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))	('AKT', 'Gene', (226, 229))	('mTOR', 'Gene', (56, 60))	('AKT', 'Gene', (52, 55))	('clinical', 'Species', '191496', (22, 30))	('mTOR', 'Gene', '2475', (230, 234))	('patients', 'Species', '9606', (97, 105))	('PI3K', 'molecular_function', 'GO:0016303', ('221', '225'))	('PIK3CA', 'Gene', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('mTOR', 'Gene', '2475', (56, 60))	('mutation', 'Var', (157, 165))	('AKT', 'Gene', '207', (226, 229))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('AKT', 'Gene', '207', (52, 55))
17084	28219002	Many previous studies have reported the prognostic implication of PIK3CA mutations in CRC; some studies have shown a significant correlation between PIK3CA mutations and patient survival, but other studies have not.	('CRC', 'Phenotype', 'HP:0003003', (86, 89))	('PIK3CA', 'Gene', (66, 72))	('patient', 'Species', '9606', (170, 177))	('PIK3CA', 'Gene', '5290', (149, 155))	('PIK3CA', 'Gene', (149, 155))	('PIK3CA', 'Gene', '5290', (66, 72))	('mutations', 'Var', (73, 82))	('CRC', 'Disease', (86, 89))
17085	28219002	Although World Health Organization (WHO) classification suggests that PIK3CA mutations are markers for poor prognosis, its practical role for predicting a patient's outcome remains uncertain.	('PIK3CA', 'Gene', (70, 76))	('PIK3CA', 'Gene', '5290', (70, 76))	('mutations', 'Var', (77, 86))	('patient', 'Species', '9606', (155, 162))
17089	28219002	The results of BRAF mutation testing are required for predicting a patients' prognosis in both metastatic and earlier stage CRC and for excluding Lynch syndrome in all CRC patients.	('BRAF', 'Gene', '673', (15, 19))	('earlier stage CRC', 'Disease', (110, 127))	('BRAF', 'Gene', (15, 19))	('patients', 'Species', '9606', (67, 75))	('Lynch syndrome', 'Disease', (146, 160))	('metastatic', 'Disease', (95, 105))	('mutation', 'Var', (20, 28))	('CRC', 'Phenotype', 'HP:0003003', (124, 127))	('Lynch syndrome', 'Disease', 'MESH:D003123', (146, 160))	('patients', 'Species', '9606', (172, 180))	('CRC', 'Phenotype', 'HP:0003003', (168, 171))
17091	28219002	Although the prognostic or predictive role of PIK3CA mutation is not clear, molecular testing for PIK3CA mutation may be necessary for predicting response to PI3K/AKT/mTOR inhibitors and aspirin therapy after CRC diagnosis.	('mutation', 'Var', (105, 113))	('PIK3CA', 'Gene', '5290', (46, 52))	('AKT', 'Gene', (163, 166))	('PIK3CA', 'Gene', (98, 104))	('PI3K', 'molecular_function', 'GO:0016303', ('158', '162'))	('PIK3CA', 'Gene', '5290', (98, 104))	('CRC', 'Disease', (209, 212))	('mTOR', 'Gene', '2475', (167, 171))	('mTOR', 'Gene', (167, 171))	('aspirin', 'Chemical', 'MESH:D001241', (187, 194))	('CRC', 'Phenotype', 'HP:0003003', (209, 212))	('AKT', 'Gene', '207', (163, 166))	('PIK3CA', 'Gene', (46, 52))
17095	28219002	Therefore, this technology has provided sufficient analytical sensitivity and specificity for identifying KRAS, NRAS, and BRAF mutations in FFPE samples, even those from tissues with low tumor cell contents.	('KRAS', 'Gene', '3845', (106, 110))	('BRAF', 'Gene', '673', (122, 126))	('low tumor', 'Disease', 'MESH:D009800', (183, 192))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('NRAS', 'Gene', (112, 116))	('BRAF', 'Gene', (122, 126))	('low tumor', 'Disease', (183, 192))	('KRAS', 'Gene', (106, 110))	('NRAS', 'Gene', '4893', (112, 116))	('mutations', 'Var', (127, 136))
17098	28219002	The detection of KRAS mutations using real-time PCR-based commercial kits has been suggested to be more reliable and sensitive than sequencing methods.	('KRAS', 'Gene', '3845', (17, 21))	('KRAS', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))
17101	28219002	reported that KRAS mutational status was discordant between primary and metastatic sites in 17.5% of samples, using the Sanger sequencing method.	('mutational', 'Var', (19, 29))	('KRAS', 'Gene', (14, 18))	('KRAS', 'Gene', '3845', (14, 18))
17103	28219002	The TheraScreen KRAS RGQ PCR Kit uses Scorpions and ARMS technologies and detects six mutations in codon 12 and one in codon 13 of KRAS.	('mutations', 'Var', (86, 95))	('KRAS', 'Gene', (131, 135))	('detects', 'Reg', (74, 81))	('KRAS', 'Gene', (16, 20))	('KRAS', 'Gene', '3845', (131, 135))	('KRAS', 'Gene', '3845', (16, 20))
17104	28219002	The COBAS KRAS mutation test kit (Roche Molecular Systems, Inc., Branchburg, NJ, USA) is a TaqMelt PCR assay and can detect 19 KRAS mutations in codons 12, 13, and 61.	('detect', 'Reg', (117, 123))	('KRAS', 'Gene', '3845', (10, 14))	('mutations', 'Var', (132, 141))	('KRAS', 'Gene', (127, 131))	('KRAS', 'Gene', '3845', (127, 131))	('KRAS', 'Gene', (10, 14))
17105	28219002	The COBAS test was also reported to have higher sensitivity than Sanger sequencing and can detect minor mutations including G13C, G13R, and Q61H, which are detected in less than 1% of CRCs.	('Q61H', 'Mutation', 'rs17851045', (140, 144))	('G13C', 'Mutation', 'rs121913535', (124, 128))	('Q61H', 'Var', (140, 144))	('CRC', 'Phenotype', 'HP:0003003', (184, 187))	('G13C', 'Var', (124, 128))	('G13R', 'Var', (130, 134))	('G13R', 'Mutation', 'rs121913535', (130, 134))
17108	28219002	For improving detection sensitivity, high-resolution melting analysis, mutant-enriched PCR (enriched PCR-restriction fragment length polymorphism assay), and co-amplification at lower denaturation temperature-PCR methods can be applied in clinical mutation tests.	('men', 'Species', '9606', (121, 124))	('mutant-enriched', 'Var', (71, 86))	('detection', 'MPA', (14, 23))	('improving', 'PosReg', (4, 13))	('clinical', 'Species', '191496', (239, 247))
17109	28219002	As mentioned above, mutations in the genes related to the EGFR signaling network may be responsible for resistance to EGFR inhibitors or worse overall survival in CRC patients, but it is difficult and less practical to test all related gene mutations including KRAS exon 2-4, NRAS exon 2-4, BRAF V600E, and PIK3CA in each individual metastatic CRC patient using conventional methods.	('KRAS', 'Gene', (261, 265))	('CRC', 'Phenotype', 'HP:0003003', (163, 166))	('NRAS', 'Gene', '4893', (276, 280))	('PIK3CA', 'Gene', (307, 313))	('EGFR', 'Gene', (58, 62))	('patient', 'Species', '9606', (167, 174))	('CRC', 'Phenotype', 'HP:0003003', (344, 347))	('EGFR', 'Gene', '1956', (118, 122))	('patient', 'Species', '9606', (348, 355))	('V600E', 'Mutation', 'rs113488022', (296, 301))	('NRAS', 'Gene', (276, 280))	('BRAF', 'Gene', (291, 295))	('BRAF', 'Gene', '673', (291, 295))	('mutations', 'Var', (20, 29))	('EGFR', 'Gene', '1956', (58, 62))	('PIK3CA', 'Gene', '5290', (307, 313))	('KRAS', 'Gene', '3845', (261, 265))	('patients', 'Species', '9606', (167, 175))	('EGFR', 'Gene', (118, 122))	('men', 'Species', '9606', (3, 6))
17134	28219002	HER2 gene amplification has been reported to be more frequent in rectal cancer than in right or left colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('frequent', 'Reg', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('left colon cancer', 'Disease', (96, 113))	('gene amplification', 'Var', (5, 23))	('HER2', 'Gene', (0, 4))	('rectal cancer', 'Phenotype', 'HP:0100743', (65, 78))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('colon cancer', 'Phenotype', 'HP:0003003', (101, 113))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('left colon cancer', 'Disease', 'MESH:D015179', (96, 113))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', (72, 78))
17140	28219002	In addition to RAS mutation, gene amplification of the receptor tyrosine kinases HER2 has been shown to bypass EGFR signaling and activate the MEK-ERK cascade, suggesting predictive roles of this gene.	('activate', 'PosReg', (130, 138))	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('MEK', 'Gene', (143, 146))	('ERK cascade', 'biological_process', 'GO:0070371', ('147', '158'))	('MEK', 'Gene', '5609', (143, 146))	('EGFR', 'Gene', '1956', (111, 115))	('bypass', 'NegReg', (104, 110))	('HER2', 'Gene', (81, 85))	('ERK', 'Gene', '5594', (147, 150))	('EGFR', 'Gene', (111, 115))	('gene amplification', 'Var', (29, 47))	('ERK', 'Gene', (147, 150))	('ERK', 'molecular_function', 'GO:0004707', ('147', '150'))	('signaling', 'biological_process', 'GO:0023052', ('116', '125'))
17141	28219002	This has been supported by a previous study that identified HER2 amplification in samples from metastatic CRC patients who did not benefit from EGFR inhibitor treatment.	('EGFR', 'Gene', (144, 148))	('CRC', 'Phenotype', 'HP:0003003', (106, 109))	('HER2', 'Protein', (60, 64))	('metastatic CRC', 'Disease', (95, 109))	('amplification', 'Var', (65, 78))	('EGFR', 'Gene', '1956', (144, 148))	('patients', 'Species', '9606', (110, 118))	('men', 'Species', '9606', (164, 167))
17142	28219002	Clinical trials using antibodies against FGFR2b are now being conducted in GC patients.	('FGFR2', 'Gene', (41, 46))	('Clinical', 'Species', '191496', (0, 8))	('antibodies', 'Var', (22, 32))	('FGFR2', 'Gene', '2263', (41, 46))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('patients', 'Species', '9606', (78, 86))	('GC', 'Phenotype', 'HP:0012126', (75, 77))
17143	28219002	Oncogenic activation of FGFR2 via gene amplification occurs in a subset of common cancers, especially diffuse type GC.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('FGFR2', 'Gene', '2263', (24, 29))	('gene amplification', 'Var', (34, 52))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('GC', 'Phenotype', 'HP:0012126', (115, 117))	('FGFR', 'molecular_function', 'GO:0005007', ('24', '28'))	('diffuse type GC', 'Disease', (102, 117))	('FGFR2', 'Gene', (24, 29))	('activation', 'PosReg', (10, 20))
17144	28219002	FGFR2 amplification has been detected in about 8% of gastroesophageal cancers.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('gastroesophageal cancers', 'Disease', (53, 77))	('detected', 'Reg', (29, 37))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('gastroesophageal cancers', 'Disease', 'MESH:D009369', (53, 77))	('amplification', 'Var', (6, 19))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))
17145	28219002	AZD4547 is a selective FGFR1-3 inhibitor with activity in FGFR2 amplified cancer models.	('FGFR1', 'Gene', (23, 28))	('amplified', 'PosReg', (64, 73))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('FGFR2', 'Gene', '2263', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('FGFR1', 'Gene', '2260', (23, 28))	('cancer', 'Disease', (74, 80))	('AZD4547', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('FGFR2', 'Gene', (58, 63))
17146	28219002	In the SHINE trial in advanced GC patients with FGFR2 amplification or polysomy, AZD4547 was well-tolerated, but there was no progression-free survival benefit in the AZD-treated group.	('FGFR2', 'Gene', (48, 53))	('FGFR2', 'Gene', '2263', (48, 53))	('amplification', 'Var', (54, 67))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('GC', 'Phenotype', 'HP:0012126', (31, 33))	('AZD', 'Chemical', 'MESH:C572463', (81, 84))	('patients', 'Species', '9606', (34, 42))	('AZD4547', 'Var', (81, 88))	('AZD', 'Chemical', 'MESH:C572463', (167, 170))	('polysomy', 'Var', (71, 79))	('AZD4547', 'Chemical', 'MESH:C572463', (81, 88))
17147	28219002	However, in a recent translational clinical trial, GCs with high-level clonal FGFR2 amplification have a high response rate to the selective FGFR2 inhibitor AZD4547.	('clinical', 'Species', '191496', (35, 43))	('AZD4547', 'Chemical', 'MESH:C572463', (157, 164))	('FGFR', 'molecular_function', 'GO:0005007', ('78', '82'))	('FGFR2', 'Gene', (141, 146))	('amplification', 'Var', (84, 97))	('FGFR2', 'Gene', '2263', (141, 146))	('GC', 'Phenotype', 'HP:0012126', (51, 53))	('FGFR2', 'Gene', (78, 83))	('FGFR2', 'Gene', '2263', (78, 83))	('FGFR', 'molecular_function', 'GO:0005007', ('141', '145'))	('response', 'MPA', (110, 118))
17148	28219002	In addition to HER2 amplification, MET amplification was also found in a small subset of RAS and BRAF wild-type metastatic patients and is suggested to be associated with resistance to cetuximab treatment.	('cetuximab', 'Chemical', 'MESH:D000068818', (185, 194))	('associated', 'Reg', (155, 165))	('HER2', 'Protein', (15, 19))	('patients', 'Species', '9606', (123, 131))	('MET amplification', 'Var', (35, 52))	('men', 'Species', '9606', (200, 203))	('RAS', 'Disease', (89, 92))	('BRAF', 'Gene', '673', (97, 101))	('BRAF', 'Gene', (97, 101))
17149	28219002	A recent study suggested MET amplification as a novel mechanism of the resistance to EGFR and BRAF combination blockade in BRAF-mutated CRCs; furthermore, the study showed that switching from EGFR to MET inhibition resulted in clinical response of the disease.	('EGFR', 'Gene', (85, 89))	('BRAF', 'Gene', (94, 98))	('EGFR', 'Gene', '1956', (85, 89))	('CRC', 'Phenotype', 'HP:0003003', (136, 139))	('EGFR', 'molecular_function', 'GO:0005006', ('192', '196'))	('clinical', 'Species', '191496', (227, 235))	('CRCs', 'Disease', (136, 140))	('EGFR', 'molecular_function', 'GO:0005006', ('85', '89'))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('BRAF', 'Gene', '673', (94, 98))	('clinical', 'MPA', (227, 235))	('switching', 'Var', (177, 186))	('EGFR', 'Gene', '1956', (192, 196))	('EGFR', 'Gene', (192, 196))
17150	28219002	KRAS gene amplification is observed in a minor subset of CRC cases (1%-2%) and has been reported to be nearly always mutually exclusive with KRAS mutations.	('CRC', 'Phenotype', 'HP:0003003', (57, 60))	('KRAS', 'Gene', (141, 145))	('KRAS', 'Gene', '3845', (141, 145))	('observed', 'Reg', (27, 35))	('CRC', 'Disease', (57, 60))	('amplification', 'Var', (10, 23))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
17154	28219002	The incidence of ROS1 rearrangement in gastric adenocarcinomas has been reported to be between 0.5% and 1%.	('ROS1', 'Gene', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('ROS1', 'Gene', '6098', (17, 21))	('men', 'Species', '9606', (31, 34))	('gastric adenocarcinomas', 'Disease', (39, 62))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (39, 62))	('rearrangement', 'Var', (22, 35))
17155	28219002	Neurotrophic tropomyosin receptor kinase (NTRK) gene rearrangements have oncogenic and transforming potential, and recently have emerged as targets for cancer therapy with developing selective inhibitors.	('men', 'Species', '9606', (62, 65))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('TRK', 'Gene', (43, 46))	('transforming potential', 'CPA', (87, 109))	('oncogenic', 'CPA', (73, 82))	('TRK', 'Gene', '7170', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('rearrangements', 'Var', (53, 67))
17157	28219002	A novel LMNA-NTRK1 rearrangement was reported in a metastatic CRC patient, who showed response to the pan-TRK inhibitor entrectinib.	('TRK', 'Gene', '7170', (106, 109))	('LMNA', 'Gene', (8, 12))	('men', 'Species', '9606', (28, 31))	('TRK', 'Gene', '7170', (14, 17))	('CRC', 'Phenotype', 'HP:0003003', (62, 65))	('LMNA', 'Gene', '4000', (8, 12))	('entrectinib', 'Chemical', 'MESH:C000607349', (120, 131))	('patient', 'Species', '9606', (66, 73))	('TRK', 'Gene', (106, 109))	('NTRK1', 'Gene', '4914', (13, 18))	('rearrangement', 'Var', (19, 32))	('TRK', 'Gene', (14, 17))	('NTRK1', 'Gene', (13, 18))
17174	28219002	Especially, heterogeneous HER2 expression is very common in GC and GEJ cancer, where upwards of 30% of HER2-positive GCs have been reported, and HER2 genetic status is closely correlated with HER2 expression status.	('GC', 'Phenotype', 'HP:0012126', (60, 62))	('GC', 'Phenotype', 'HP:0012126', (117, 119))	('heterogeneous', 'Var', (12, 25))	('GEJ cancer', 'Disease', 'MESH:D009369', (67, 77))	('common', 'Reg', (50, 56))	('GEJ cancer', 'Disease', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('HER2', 'Protein', (26, 30))
17187	28219002	Usually, the diagnostic criteria of gene amplification, including FGFR2 and MET in GC and HER2 and MET in CRC, have been defined as a target gene:reference gene ratio >2, and the positivity criteria have been adopted from the recommendations of the gastric HER2 test.	('HER2', 'Gene', (90, 94))	('FGFR2', 'Gene', (66, 71))	('FGFR2', 'Gene', '2263', (66, 71))	('CRC', 'Phenotype', 'HP:0003003', (106, 109))	('GC', 'Phenotype', 'HP:0012126', (83, 85))	('men', 'Species', '9606', (231, 234))	('FGFR', 'molecular_function', 'GO:0005007', ('66', '70'))	('MET', 'Var', (99, 102))
17194	28219002	By TCGA results, EBV-positive GCs have a tendency of CIMP, but do not show a MSI-H phenotype or hMLH1 hypermethylation.	('CIMP', 'Disease', (53, 57))	('MSI-H', 'Disease', (77, 82))	('hMLH1', 'Gene', (96, 101))	('EBV-positive', 'Var', (17, 29))	('MSI-H', 'Disease', 'MESH:D000848', (77, 82))	('CIMP', 'Chemical', '-', (53, 57))	('hMLH1', 'Gene', '4292', (96, 101))	('EBV', 'Species', '10376', (17, 20))	('GC', 'Phenotype', 'HP:0012126', (30, 32))
17195	28219002	EBV-positive GCs were strongly associated with CDKN2A (p16INK4A) promoter hypermethylation and PIK3CA mutation.	('GC', 'Phenotype', 'HP:0012126', (13, 15))	('PIK3CA', 'Gene', (95, 101))	('PIK3CA', 'Gene', '5290', (95, 101))	('mutation', 'Var', (102, 110))	('CDKN2A', 'Gene', (47, 53))	('associated', 'Reg', (31, 41))	('p16', 'Gene', (55, 58))	('EBV', 'Species', '10376', (0, 3))	('p16', 'Gene', '1029', (55, 58))
17203	28219002	Furthermore, although EBV and MSI are mutually exclusive in GCs, microsatellite unstable GCs are also associated with lymphocyte-rich histology.	('GC', 'Phenotype', 'HP:0012126', (60, 62))	('associated', 'Reg', (102, 112))	('microsatellite unstable', 'Var', (65, 88))	('EBV', 'Species', '10376', (22, 25))	('GC', 'Phenotype', 'HP:0012126', (89, 91))
17222	28219002	The non-hypermutated tumor includes genomically stable and chromosomally unstable subtypes.	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('non-hypermutated', 'Var', (4, 20))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', (21, 26))
17223	28219002	EBV-positive and MSI-H subtypes represent the hypermutated tumor and have frequent mutations in PIK3CA and ARID1A.	('MSI-H', 'Disease', 'MESH:D000848', (17, 22))	('mutations', 'Var', (83, 92))	('tumor', 'Disease', (59, 64))	('ARID1A', 'Gene', '8289', (107, 113))	('ARID1A', 'Gene', (107, 113))	('MSI-H', 'Disease', (17, 22))	('PIK3CA', 'Gene', (96, 102))	('PIK3CA', 'Gene', '5290', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('EBV', 'Species', '10376', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
17225	28219002	The gene mutations that contribute to gastric carcinoma, which have been revealed in previous large-scale studies, are listed in Table 2.	('gastric carcinoma', 'Phenotype', 'HP:0012126', (38, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('gastric carcinoma', 'Disease', 'MESH:D013274', (38, 55))	('mutations', 'Var', (9, 18))	('gastric carcinoma', 'Disease', (38, 55))
17229	28219002	Recurrent mutation of TP53, KRAS, APC, and PIK3CA has been consistently reported in previous studies and it is notable that the significantly frequent KRAS mutation is identified in non-hypermutated tumors (Table 3).	('KRAS', 'Gene', '3845', (151, 155))	('KRAS', 'Gene', (28, 32))	('TP53', 'Gene', (22, 26))	('PIK3CA', 'Gene', '5290', (43, 49))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('KRAS', 'Gene', '3845', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('mutation', 'Var', (156, 164))	('APC', 'Disease', 'MESH:D011125', (34, 37))	('mutation', 'Var', (10, 18))	('APC', 'Disease', (34, 37))	('TP53', 'Gene', '7157', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('KRAS', 'Gene', (151, 155))	('PIK3CA', 'Gene', (43, 49))
17247	28316601	Our results indicate a high radioresistance of Caco-2 in the investigated dose range, and an increased permeability of the tumoral cell layer due to the presence of PBMC.	('PBMC', 'Gene', (165, 169))	('tumor', 'Disease', (123, 128))	('increased', 'PosReg', (93, 102))	('presence', 'Var', (153, 161))	('Caco-2', 'Gene', (47, 53))	('Caco-2', 'CellLine', 'CVCL:0025', (47, 53))	('permeability', 'MPA', (103, 115))	('radioresistance', 'CPA', (28, 43))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
17303	28316601	Results for the sham-irradiated Caco-2 show that 3 cytokines are secreted only without coculture with PBMC, whereas the presence of PBMC induces the production and release in the culture medium of nine unique cytokines (Table 2).	('induces', 'Reg', (137, 144))	('PBMC', 'Var', (132, 136))	('Caco-2', 'CellLine', 'CVCL:0025', (32, 38))	('release', 'MPA', (164, 171))	('production', 'MPA', (149, 159))	('presence', 'Var', (120, 128))
17316	28316601	The 10 Gy-irradiation causes a reduction of afadin compared to the sham in absence of PBMC; the presence of PBMC enhances this effect, leading to a reduction of the 50% compared to what observed in the sham not cocultured cells (Figure 4).	('presence', 'Var', (96, 104))	('reduction', 'NegReg', (148, 157))	('afadin', 'Gene', (44, 50))	('reduction', 'NegReg', (31, 40))	('enhances', 'PosReg', (113, 121))	('PBMC', 'Gene', (108, 112))	('afadin', 'Gene', '4301', (44, 50))
17335	28316601	Our results show that IR and coculture add their effects in the case of IL-4, while radiation only acts in reducing release of IL-5; in this case the presence of PBMC completely stops the release of this cytokine.	('IL-5', 'Gene', '3567', (127, 131))	('IL-5', 'Gene', (127, 131))	('IL-4', 'Gene', '3565', (72, 76))	('release', 'MPA', (188, 195))	('stops', 'NegReg', (178, 183))	('PBMC', 'Gene', (162, 166))	('IL-4', 'Gene', (72, 76))	('presence', 'Var', (150, 158))
17358	26866579	Oncologists' and Cancer Patients' Views on Whole-Exome Sequencing and Incidental Findings: Results from The CanSeq Study While targeted sequencing improves outcomes for many cancer patients, how somatic and germline whole-exome sequencing (WES) will integrate into care remains uncertain.	('Cancer', 'Disease', (17, 23))	('outcomes', 'MPA', (156, 164))	('improves', 'PosReg', (147, 155))	('cancer', 'Disease', (174, 180))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('patients', 'Species', '9606', (181, 189))	('sequencing', 'Var', (136, 146))	('targeted sequencing', 'Var', (127, 146))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('Patients', 'Species', '9606', (24, 32))
17379	26866579	The eligible population for the CanSeq patient study includes patients who 1) have stage IV lung or colorectal adenocarcinoma, 2) consent to companion genotyping protocols (to allow variant confirmation by a complementary technology), 3) have a life expectancy of at least 6 months, 4) have an Eastern Cooperative Oncology Group (ECOG) performance status of zero or one, 5) have sufficient tumor DNA for WES, 6) have a treating oncologist who is participating in the study, 7) speak English, 8) consent to participation and 9) receive ongoing care at DFCI.	('Oncology', 'Phenotype', 'HP:0002664', (314, 322))	('patient', 'Species', '9606', (39, 46))	('men', 'Species', '9606', (214, 217))	('DFCI', 'Chemical', '-', (551, 555))	('tumor', 'Disease', 'MESH:D009369', (390, 395))	('colorectal adenocarcinoma', 'Disease', (100, 125))	('patient', 'Species', '9606', (62, 69))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (100, 125))	('tumor', 'Phenotype', 'HP:0002664', (390, 395))	('lung', 'Disease', (92, 96))	('tumor', 'Disease', (390, 395))	('variant', 'Var', (182, 189))	('DNA', 'cellular_component', 'GO:0005574', ('396', '399'))	('patients', 'Species', '9606', (62, 70))
17397	26866579	We also asked about intentions to disclose germline cancer risk alterations (with and without available risk-reduction strategies), pharmacogenetic polymorphisms (cancer and non-cancer related), alterations that conferred increased risk of developing a non-cancer condition (with and without available risk-reduction strategies), and carrier status.	('alterations', 'Var', (195, 206))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('non-cancer', 'Disease', (253, 263))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (178, 184))	('non-cancer', 'Disease', (174, 184))	('alterations', 'Var', (64, 75))	('non-cancer', 'Disease', 'MESH:D009369', (253, 263))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('non-cancer', 'Disease', 'MESH:D009369', (174, 184))	('cancer', 'Disease', (257, 263))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
17427	26866579	Additionally, men were more likely to indicate a high preference for the return of germline sequencing results than women (92% vs. 76%, adjusted RR 1.06, 95% CI 1.00-1.12, p=0.04).	('men', 'Species', '9606', (14, 17))	('women', 'Species', '9606', (116, 121))	('men', 'Species', '9606', (118, 121))	('RR 1', 'Gene', '6240', (145, 149))	('germline', 'Var', (83, 91))	('RR 1', 'Gene', (145, 149))
17442	26866579	This use of pharmacogenetic testing is notable because the reported uptake of pharmacogenetic testing generally is estimated to be low despite the fact that pharmacogenetic tests (e.g., DPYD, UGT1A1) are available, polymorphisms in these genes are associated with drug metabolism, and the FDA includes pharmacogenetic information in the label of drugs including 5-fluorouracil and irinotecan.	('UGT1A1', 'Gene', '54658', (192, 198))	('uptake', 'biological_process', 'GO:0098657', ('68', '74'))	('polymorphisms', 'Var', (215, 228))	('DPYD', 'Gene', (186, 190))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (362, 376))	('UGT1A1', 'Gene', (192, 198))	('associated', 'Reg', (248, 258))	('DPYD', 'Gene', '1806', (186, 190))	('drug metabolism', 'biological_process', 'GO:0017144', ('264', '279'))	('irinotecan', 'Chemical', 'MESH:D000077146', (381, 391))	('uptake', 'biological_process', 'GO:0098739', ('68', '74'))
17476	26576139	The five-year overall survival rate was significantly lower for patients with SRC than for those with NMAC (46.0% vs. 88.7%, hazard ratio, 6.99; 95% confidence interval, 2.33-20.95, P=0.001).	('SRC', 'Var', (78, 81))	('overall survival', 'CPA', (14, 30))	('patients', 'Species', '9606', (64, 72))	('NMAC', 'Chemical', '-', (102, 106))	('lower', 'NegReg', (54, 59))
17505	26576139	The tumor depth in all patients with SRC was T2 or greater (T2 in 1 patient, T3 in 9 patients, T4a in 1 patient, and T4b in 2 patients).	('tumor', 'Disease', (4, 9))	('patient', 'Species', '9606', (85, 92))	('patient', 'Species', '9606', (68, 75))	('patients', 'Species', '9606', (23, 31))	('patient', 'Species', '9606', (126, 133))	('patients', 'Species', '9606', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('patient', 'Species', '9606', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('T4a', 'Var', (95, 98))	('patients', 'Species', '9606', (126, 134))	('T4b', 'Var', (117, 120))	('patient', 'Species', '9606', (23, 30))
17516	26576139	In univariate analysis, the hazard ratio for death was 6.99 for the SRC group (95% CI, 2.33-20.95; P=0.001) compared with the NMAC group.	('NMAC', 'Chemical', '-', (126, 130))	('SRC', 'Var', (68, 71))	('death', 'Disease', 'MESH:D003643', (45, 50))	('death', 'Disease', (45, 50))
17547	25197175	We will focus the discussion on the monoclonal antibodies cetuximab and panitumumab : and especially in the current role of extended testing for mutations in the RAS oncogene.	('mutations', 'Var', (145, 154))	('cetuximab', 'Chemical', 'MESH:D000068818', (58, 67))	('panitumumab', 'Chemical', 'MESH:D000077544', (72, 83))	('RAS oncogene', 'Gene', (162, 174))
17552	25197175	RAS mutations occur early in the transition from normal to transformed epithelium, in the progression from polyps to invasive carcinoma.	('RAS', 'Gene', (0, 3))	('polyps to invasive carcinoma', 'Disease', 'MESH:D011127', (107, 135))	('polyps to invasive carcinoma', 'Disease', (107, 135))	('mutations', 'Var', (4, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))
17554	25197175	In the last 2 years, we have accumulated evidence that not only mutations in KRAS exon 2, which we have been testing for several years to select the most appropriate patients for treatment with EGFR inhibitors, but also those in KRAS exons 3, and 4, and NRAS exons 2, 3, and 4 are important and confer resistance to treatment with cetuximab and panitumumab.	('panitumumab', 'Chemical', 'MESH:D000077544', (345, 356))	('cetuximab', 'Chemical', 'MESH:D000068818', (331, 340))	('EGFR', 'Gene', '1950', (194, 198))	('KRAS', 'Gene', (229, 233))	('patients', 'Species', '9606', (166, 174))	('KRAS', 'Gene', (77, 81))	('KRAS', 'Gene', '3845', (229, 233))	('mutations', 'Var', (64, 73))	('NRAS', 'Gene', (254, 258))	('EGFR', 'Gene', (194, 198))	('KRAS', 'Gene', '3845', (77, 81))	('NRAS', 'Gene', '4893', (254, 258))
17556	25197175	Of these patients, 17% had mutations in KRAS exons 3 and 4 or in NRAS.	('mutations', 'Var', (27, 36))	('patients', 'Species', '9606', (9, 17))	('NRAS', 'Gene', '4893', (65, 69))	('KRAS', 'Gene', (40, 44))	('KRAS', 'Gene', '3845', (40, 44))	('NRAS', 'Gene', (65, 69))
17557	25197175	The original results showed better progression-free survival and a trend towards better overall survival with the EGFR inhibitor.	('better', 'PosReg', (81, 87))	('inhibitor', 'Var', (119, 128))	('better', 'PosReg', (28, 34))	('EGFR', 'Gene', '1950', (114, 118))	('EGFR', 'Gene', (114, 118))	('progression-free survival', 'CPA', (35, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('114', '118'))	('overall', 'MPA', (88, 95))
17558	25197175	With the exclusion of individuals with mutations in extended RAS testing, the results for overall survival became more evident and statistically significant: 20.2 versus 26.0 months, with a hazard ratio (HR) of 0.78, and a P = 0.02, compared with 19.7 versus 23.9 months, with a HR of 0.83, and P = 0.072 in the original analysis.	('rat', 'Species', '10116', (197, 200))	('extended RAS', 'Protein', (52, 64))	('mutations', 'Var', (39, 48))
17560	25197175	Eighteen percent of patients without mutations in KRAS exon 2 had other RAS mutations in extended testing.	('patients', 'Species', '9606', (20, 28))	('KRAS', 'Gene', '3845', (50, 54))	('mutations', 'Var', (76, 85))	('KRAS', 'Gene', (50, 54))
17562	25197175	Similarly, in the Crystal trial, which compared treatment with FOLFIRI in the first line with or without cetuximab, overall survival improved from 20.2 to 28.4 months (HR: 0.69, P = 0.0024) for patients without mutations in extended RAS testing, when compared to an improvement from 20 to 23.5 months (HR: 0.796, P = 0.0093) in patients without KRAS exon 2 mutations only.	('patients', 'Species', '9606', (194, 202))	('KRAS', 'Gene', (345, 349))	('patients', 'Species', '9606', (328, 336))	('mutations', 'Var', (211, 220))	('KRAS', 'Gene', '3845', (345, 349))	('overall survival', 'MPA', (116, 132))	('cetuximab', 'Chemical', 'MESH:D000068818', (105, 114))	('improved', 'PosReg', (133, 141))	('extended RAS', 'Protein', (224, 236))	('FOLFIRI', 'Chemical', '-', (63, 70))
17572	25197175	These clinical results were even more significant when patients with mutations in KRAS exons 3 and 4 and NRAS were also excluded.	('mutations', 'Var', (69, 78))	('NRAS', 'Gene', (105, 109))	('patients', 'Species', '9606', (55, 63))	('NRAS', 'Gene', '4893', (105, 109))	('KRAS', 'Gene', (82, 86))	('KRAS', 'Gene', '3845', (82, 86))
17573	25197175	For the 170 patients with wild type RAS in extended testing, overall survival improved from 28.9 months with the VEGF inhibitor to 41.3 months with the EGFR inhibitor.	('patients', 'Species', '9606', (12, 20))	('EGFR', 'Gene', '1950', (152, 156))	('inhibitor', 'Var', (118, 127))	('VEGF', 'Gene', (113, 117))	('EGFR', 'Gene', (152, 156))	('overall survival', 'MPA', (61, 77))	('VEGF', 'Gene', '7422', (113, 117))	('improved', 'PosReg', (78, 86))	('EGFR', 'molecular_function', 'GO:0005006', ('152', '156'))
17578	25197175	Unfortunately, results with extended RAS testing have not yet been reported, hampering our ability to make a final determination if chemotherapy treatment with EGFR inhibitors is superior to treatment with bevacizumab.	('EGFR', 'Gene', '1950', (160, 164))	('inhibitors', 'Var', (165, 175))	('bevacizumab', 'Chemical', 'MESH:D000068258', (206, 217))	('EGFR', 'Gene', (160, 164))
17582	25197175	Those studies in which patients received cetuximab with a fluoropyrimidine in infusional regimens showed clinical benefit with the monoclonal antibody, while those that used fluoropyrimidines by bolus or oral administration did not show a significant benefit.	('monoclonal', 'Var', (131, 141))	('cetuximab', 'Chemical', 'MESH:D000068818', (41, 50))	('fluoropyrimidine', 'Chemical', '-', (58, 74))	('patients', 'Species', '9606', (23, 31))	('benefit', 'PosReg', (114, 121))	('fluoropyrimidine', 'Chemical', '-', (174, 190))	('fluoropyrimidines', 'Chemical', '-', (174, 191))	('rat', 'Species', '10116', (217, 220))
17589	25197175	Approximately, 55% of patients with metastatic colorectal cancer have mutations in KRAS or NRAS and these patients should not be treated with cetuximab or panitumumab as they do not derive benefit - and may in some cases be harmed-with the use of EGFR inhibitors.	('KRAS', 'Gene', (83, 87))	('mutations', 'Var', (70, 79))	('KRAS', 'Gene', '3845', (83, 87))	('colorectal cancer', 'Disease', (47, 64))	('cetuximab', 'Chemical', 'MESH:D000068818', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('patients', 'Species', '9606', (22, 30))	('NRAS', 'Gene', (91, 95))	('colorectal cancer', 'Disease', 'MESH:D015179', (47, 64))	('EGFR', 'Gene', '1950', (247, 251))	('patients', 'Species', '9606', (106, 114))	('panitumumab', 'Chemical', 'MESH:D000077544', (155, 166))	('NRAS', 'Gene', '4893', (91, 95))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))	('EGFR', 'Gene', (247, 251))
17592	25197175	We eagerly await the results of extended RAS testing for the CALGB 80405 study to help clarify if EGFR inhibitors are superior to bevacizumab when combined to chemotherapy in the first line treatment of wild type patients or not.	('EGFR', 'Gene', (98, 102))	('bevacizumab', 'Chemical', 'MESH:D000068258', (130, 141))	('EGFR', 'Gene', '1950', (98, 102))	('inhibitors', 'Var', (103, 113))	('patients', 'Species', '9606', (213, 221))
17694	23720162	However, little is understood about the interplay between G and E. Some exceptions include an observed interactions between smoking and the GSTM1 deletion and a tag SNP in NAT2 in bladder cancer, ADH7 variants and alcohol consumption in upper aerodigestive cancers or GRIN2A variants and coffee consumption in Parkinson's disease.	('NAT2', 'Gene', '10', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	("Parkinson's disease", 'Disease', 'MESH:D010300', (310, 329))	('GRIN2A', 'Gene', '2903', (268, 274))	('variants', 'Var', (201, 209))	('GSTM1', 'Gene', (140, 145))	('ADH7', 'Gene', (196, 200))	('NAT2', 'Gene', (172, 176))	('ADH7', 'Gene', '131', (196, 200))	('ADH', 'molecular_function', 'GO:0004022', ('196', '199'))	('alcohol consumption in upper aerodigestive cancers', 'Disease', 'MESH:D006258', (214, 264))	('bladder cancer', 'Disease', 'MESH:D001749', (180, 194))	('bladder cancer', 'Disease', (180, 194))	('GRIN2A', 'Gene', (268, 274))	('GSTM1', 'Gene', '2944', (140, 145))	('bladder cancer', 'Phenotype', 'HP:0009725', (180, 194))	('interactions', 'Interaction', (103, 115))	("Parkinson's disease", 'Disease', (310, 329))	('alcohol consumption in upper aerodigestive cancers', 'Disease', (214, 264))	('deletion', 'Var', (146, 154))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('ADH', 'molecular_function', 'GO:0047636', ('196', '199'))	('variants', 'Var', (275, 283))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))
17701	23720162	It is known to interact with the TGF-beta receptor and several SNPs in this region have been found to associate with colorectal cancer risk.	('colorectal cancer', 'Disease', 'MESH:D015179', (117, 134))	('interact', 'Reg', (15, 23))	('TGF-beta receptor', 'Protein', (33, 50))	('colorectal cancer', 'Phenotype', 'HP:0003003', (117, 134))	('colorectal cancer', 'Disease', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('SNPs', 'Var', (63, 67))	('associate', 'Reg', (102, 111))
17703	23720162	We chose two SNPs rs4939827 and rs7351039 from the 21 SNPs and make them the hidden causal SNPs in the simulation.	('rs7351039', 'Var', (32, 41))	('rs4939827', 'Mutation', 'rs4939827', (18, 27))	('rs7351039', 'Mutation', 'rs7351039', (32, 41))	('rs4939827', 'Var', (18, 27))
17704	23720162	The two SNPs were chosen such that one is common (rs4939827, MAF=0.49) and one is less common (rs7351039, 11 MAF=0.08).	('MAF', 'Gene', '4094', (61, 64))	('MAF', 'Gene', (109, 112))	('rs4939827', 'Var', (50, 59))	('MAF', 'Gene', (61, 64))	('rs7351039', 'Mutation', 'rs7351039', (95, 104))	('MAF', 'Gene', '4094', (109, 112))	('rs4939827', 'Mutation', 'rs4939827', (50, 59))
17706	23720162	Gi1 and Gi2 are the simulated genotypes (=0,1, or 2) for rs4939827 and rs7351039, respectively.	('rs7351039', 'Var', (71, 80))	('rs4939827', 'Mutation', 'rs4939827', (57, 66))	('rs4939827', 'Var', (57, 66))	('rs7351039', 'Mutation', 'rs7351039', (71, 80))
17732	23720162	In addition, when exploring which SNPs contribute to the interaction signal in the marker set, we found that rs10936599 shows the strongest evidence - it was selected by the correlation screening of SBERIA and it also has the smallest interaction p-value in min-p.	('smallest', 'NegReg', (226, 234))	('rs10936599', 'Var', (109, 119))	('rs10936599', 'Mutation', 'rs10936599', (109, 119))	('interaction', 'Interaction', (235, 246))
17734	23720162	rs10936599, the SNP showing the strongest signal, is located at 3q26.2 in the MYNN gene.	('MYNN', 'Gene', (78, 82))	('MYNN', 'Gene', '55892', (78, 82))	('rs10936599', 'Mutation', 'rs10936599', (0, 10))	('rs10936599', 'Var', (0, 10))
17743	33627078	Variation rs9929218 and risk of the colorectal Cancer and adenomas: A meta-analysis Genome-wide association studies (GWAS) have identified multiple common CRC-related (colorectal cancer) SNPs (single nucleotide polymorphisms) including the Cadherin 1(CDH1) rs9929218 may act by increasing the risk of colorectal cancer, colorectal adenoma, or both.	('CDH1', 'Gene', '999', (251, 255))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('CRC', 'Phenotype', 'HP:0003003', (155, 158))	('Cadherin', 'molecular_function', 'GO:0008014', ('240', '248'))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))	('CDH1', 'Gene', (251, 255))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('rs9929218', 'Mutation', 'rs9929218', (10, 19))	('colorectal adenoma', 'Disease', (320, 338))	('rs9929218', 'Mutation', 'rs9929218', (257, 266))	('colorectal cancer', 'Disease', (168, 185))	('Cadherin 1', 'Gene', (240, 250))	('colorectal cancer', 'Disease', 'MESH:D015179', (301, 318))	('CRC-related', 'Disease', (155, 166))	('colorectal Cancer', 'Disease', 'MESH:D015179', (36, 53))	('colorectal cancer', 'Disease', (301, 318))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))	('rs9929218', 'Var', (10, 19))	('colorectal adenoma', 'Disease', 'MESH:D015179', (320, 338))	('rs9929218', 'Var', (257, 266))	('adenomas', 'Disease', 'MESH:D000236', (58, 66))	('adenomas', 'Disease', (58, 66))	('colorectal Cancer', 'Phenotype', 'HP:0003003', (36, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('increasing', 'PosReg', (278, 288))	('colorectal Cancer', 'Disease', (36, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (301, 318))	('Cadherin 1', 'Gene', '999', (240, 250))
17744	33627078	Meta-analysis implied considerable association between CRC and rs9929218 (OR = 1.21, 95%CI 1.04-1.42 for GG versus AA; OR = 1.22, 95%CI 1.05-1.42 for GG/AG versus AA).	('rs9929218', 'Mutation', 'rs9929218', (63, 72))	('CRC', 'Gene', (55, 58))	('rs9929218', 'Var', (63, 72))	('CRC', 'Phenotype', 'HP:0003003', (55, 58))
17745	33627078	In summary, our meta-analysis studies in different populations confirmed that SNP rs9929218 is significantly associated with CRC risk and that this variant may have a greater impact on Europeans.	('associated', 'Reg', (109, 119))	('CRC', 'Disease', (125, 128))	('CRC', 'Phenotype', 'HP:0003003', (125, 128))	('SNP', 'Var', (78, 81))	('rs9929218', 'Mutation', 'rs9929218', (82, 91))
17750	33627078	Single nucleotide polymorphism associated with CRC may increase the risk of colorectal cancer, colorectal adenomas, or both.	('increase', 'PosReg', (55, 63))	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('CRC', 'Phenotype', 'HP:0003003', (47, 50))	('Single nucleotide polymorphism', 'Var', (0, 30))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('colorectal adenomas', 'Disease', 'MESH:D015179', (95, 114))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('colorectal cancer', 'Disease', (76, 93))	('colorectal adenomas', 'Disease', (95, 114))	('CRC', 'Gene', (47, 50))
17752	33627078	Among these SNPs, rs9929218 (16p22.1), located in the intron region of the gene cadherin 1 (CDH1), was identified to be associated with CRC risk.	('associated', 'Reg', (120, 130))	('CRC', 'Phenotype', 'HP:0003003', (136, 139))	('rs9929218', 'Mutation', 'rs9929218', (18, 27))	('CDH1', 'Gene', (92, 96))	('rs9929218', 'Var', (18, 27))	('cadherin 1', 'Gene', (80, 90))	('CRC', 'Disease', (136, 139))	('cadherin 1', 'Gene', '999', (80, 90))	('cadherin', 'molecular_function', 'GO:0008014', ('80', '88'))	('CDH1', 'Gene', '999', (92, 96))
17753	33627078	conducted a meta-analysis of rs9929218 including 16 studies (n = 131,768) which emphasizes a significant association between rs9929218 polymorphism and CRC susceptibility.	('CRC', 'Disease', (152, 155))	('rs9929218', 'Mutation', 'rs9929218', (125, 134))	('CRC', 'Phenotype', 'HP:0003003', (152, 155))	('rs9929218', 'Var', (125, 134))	('rs9929218', 'Mutation', 'rs9929218', (29, 38))
17754	33627078	The rs9929218 has been identified as an aroused general interest for CRC susceptibility by recent genome-wide association studies and this polymorphism has shown that the G allele is associated with an increased risk of colorectal cancer.	('rs9929218', 'Mutation', 'rs9929218', (4, 13))	('colorectal cancer', 'Phenotype', 'HP:0003003', (220, 237))	('CRC', 'Phenotype', 'HP:0003003', (69, 72))	('rs9929218', 'Var', (4, 13))	('colorectal cancer', 'Disease', (220, 237))	('colorectal cancer', 'Disease', 'MESH:D015179', (220, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
17755	33627078	We, therefore, performed a meta-analysis of the published studies to clarify this antilogy and constitute a comprehensive map of the relationship between 16q22.1 (rs9929218) polymorphism and the CRC susceptibility.	('rs9929218', 'Var', (163, 172))	('CRC', 'Phenotype', 'HP:0003003', (195, 198))	('CRC', 'Disease', (195, 198))	('rs9929218', 'Mutation', 'rs9929218', (163, 172))
17756	33627078	Embase, PubMed, and ScienceDirect database were hunted invoking the semesters: 'rs9929218', 'Single Nucleotide Polymorphism ','colorectal cancer 'and 'colorectal adenoma 'to gather eligible articles.	('colorectal adenoma', 'Disease', (151, 169))	("'Single Nucleotide Polymorphism '", 'Var', (92, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('colorectal cancer', 'Disease', (127, 144))	('colorectal adenoma', 'Disease', 'MESH:D015179', (151, 169))	('rs9929218', 'Mutation', 'rs9929218', (80, 89))	('colorectal cancer', 'Disease', 'MESH:D015179', (127, 144))
17757	33627078	The combinations of following keywords were used: 'Neoplasms, Colorectal' or 'Colorectal Neoplasm' or 'Neoplasm, Colorectal' or 'Colorectal Tumors' or 'Colorectal Tumor' or 'Tumor, Colorectal' or 'Tumors, Colorectal' or 'Colorectal Carcinoma' or 'Carcinoma, Colorectal' or 'Carcinomas, Colorectal' or 'Colorectal Carcinomas' or 'Colorectal Cancer' or 'Cancer, Colorectal' or 'Cancers, Colorectal' or 'Colorectal Cancers'; 'Nucleotide Polymorphism, Single' or 'Nucleotide Polymorphisms, Single' or 'Polymorphisms, Single Nucleotide' or 'Single Nucleotide Polymorphisms' or 'SNPs' or 'Single Nucleotide Polymorphism'; 'rs9929218'.	('Neoplasms', 'Disease', (51, 60))	('Colorectal', 'Disease', (329, 339))	('Colorectal', 'Disease', (360, 370))	('Cancer', 'Disease', (340, 346))	('Colorectal', 'Disease', 'MESH:D015179', (205, 215))	('Colorectal', 'Disease', (385, 395))	('Colorectal', 'Disease', 'MESH:D015179', (258, 268))	('Tumor', 'Phenotype', 'HP:0002664', (174, 179))	('Colorectal', 'Disease', (129, 139))	("Colorectal Carcinoma' or 'Carcinoma", 'Disease', 'MESH:D015179', (221, 256))	('Colorectal Tumors', 'Disease', (129, 146))	('Carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('Carcinomas', 'Disease', 'MESH:D009369', (313, 323))	('Cancer', 'Disease', 'MESH:D009369', (340, 346))	('Cancer', 'Disease', (376, 382))	("Single' or 'Polymorphisms", 'Var', (486, 511))	('Carcinomas', 'Disease', (313, 323))	('Colorectal', 'Disease', 'MESH:D015179', (385, 395))	('Tumor', 'Phenotype', 'HP:0002664', (163, 168))	('Carcinomas', 'Phenotype', 'HP:0030731', (274, 284))	('Neoplasms', 'Disease', 'MESH:D009369', (51, 60))	('Colorectal', 'Disease', 'MESH:D015179', (129, 139))	('Cancer', 'Disease', 'MESH:D009369', (376, 382))	('Colorectal', 'Disease', 'MESH:D015179', (286, 296))	('Colorectal', 'Disease', (205, 215))	('Colorectal', 'Disease', (401, 411))	('Cancer', 'Disease', (412, 418))	("Colorectal' or 'Cancers", 'Disease', (360, 383))	('Cancer', 'Phenotype', 'HP:0002664', (340, 346))	("Colorectal Carcinoma' or 'Carcinoma", 'Disease', (221, 256))	('Colorectal', 'Disease', (258, 268))	('Colorectal Tumors', 'Disease', 'MESH:D015179', (129, 146))	('Colorectal Cancers', 'Disease', 'MESH:D015179', (401, 419))	('Cancer', 'Disease', 'MESH:D009369', (412, 418))	('Colorectal Neoplasm', 'Disease', 'MESH:D015179', (78, 97))	('Colorectal Carcinomas', 'Disease', 'MESH:D015179', (302, 323))	('Colorectal', 'Disease', 'MESH:D015179', (401, 411))	('Colorectal', 'Disease', 'MESH:D015179', (78, 88))	('Cancer', 'Phenotype', 'HP:0002664', (376, 382))	('Carcinomas', 'Disease', 'MESH:D009369', (274, 284))	("Colorectal' or 'Cancers", 'Disease', 'MESH:D015179', (360, 383))	('Carcinomas', 'Disease', (274, 284))	('Colorectal', 'Disease', (286, 296))	('Cancer', 'Disease', (352, 358))	('Carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('Neoplasm', 'Phenotype', 'HP:0002664', (89, 97))	("Single' or 'Nucleotide Polymorphisms", 'Var', (448, 484))	('Carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('Colorectal', 'Disease', 'MESH:D015179', (302, 312))	('Colorectal', 'Disease', (221, 231))	('Tumors', 'Disease', 'MESH:D009369', (197, 203))	('Cancer', 'Disease', 'MESH:D009369', (352, 358))	('Tumors', 'Disease', 'MESH:D009369', (140, 146))	('Colorectal Tumor', 'Disease', (152, 168))	('Colorectal', 'Disease', (78, 88))	("Single Nucleotide'", 'Var', (513, 531))	('Colorectal', 'Disease', 'MESH:D015179', (62, 72))	('Cancers', 'Phenotype', 'HP:0002664', (412, 419))	('Colorectal', 'Disease', 'MESH:D015179', (221, 231))	('Colorectal Cancers', 'Disease', (401, 419))	('Cancer', 'Phenotype', 'HP:0002664', (352, 358))	('Colorectal Carcinomas', 'Disease', (302, 323))	('Colorectal', 'Disease', (302, 312))	('Tumor', 'Phenotype', 'HP:0002664', (197, 202))	('Tumor', 'Phenotype', 'HP:0002664', (140, 145))	('Tumors', 'Disease', (197, 203))	('Tumors', 'Disease', (140, 146))	('Cancer', 'Phenotype', 'HP:0002664', (412, 418))	('Neoplasm', 'Phenotype', 'HP:0002664', (103, 111))	('Colorectal', 'Disease', (62, 72))	('Colorectal', 'Disease', 'MESH:D015179', (113, 123))	('rs9929218', 'Mutation', 'rs9929218', (617, 626))	("'Nucleotide Polymorphism", 'Var', (422, 446))	('Colorectal', 'Disease', 'MESH:D015179', (152, 162))	('Carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('Colorectal', 'Disease', 'MESH:D015179', (181, 191))	('Neoplasm', 'Phenotype', 'HP:0002664', (51, 59))	('Colorectal Tumor', 'Disease', 'MESH:D015179', (129, 145))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (329, 346))	('Colorectal Cancer', 'Disease', (329, 346))	('Tumors', 'Phenotype', 'HP:0002664', (197, 203))	('Tumors', 'Phenotype', 'HP:0002664', (140, 146))	('Colorectal', 'Disease', (113, 123))	('Colorectal', 'Disease', 'MESH:D015179', (329, 339))	('Colorectal', 'Disease', 'MESH:D015179', (360, 370))	('Colorectal Tumor', 'Disease', 'MESH:D015179', (152, 168))	('Colorectal', 'Disease', (152, 162))	('Colorectal', 'Disease', (181, 191))	('Cancers', 'Phenotype', 'HP:0002664', (376, 383))	('Carcinomas', 'Phenotype', 'HP:0030731', (313, 323))	('Colorectal Neoplasm', 'Disease', (78, 97))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (401, 418))
17758	33627078	Studies in our meta-analysis ought to meet the following inclusion standards: (1) assess the association between colorectal cancer risk and the rs9929218 polymorphism; (2) the studies were designed as case-control studies; (3) include the detailed frequency of each genotype.	('colorectal cancer', 'Disease', (113, 130))	('rs9929218', 'Mutation', 'rs9929218', (144, 153))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('rs9929218', 'Var', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('association', 'Interaction', (93, 104))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))
17759	33627078	The strength of the association between the CRC risk and rs9929218 polymorphism was measured through odds ratios (ORs) with 95% confidence intervals (CIs).	('CRC', 'Disease', (44, 47))	('rs9929218', 'Mutation', 'rs9929218', (57, 66))	('CRC', 'Phenotype', 'HP:0003003', (44, 47))	('rs9929218', 'Var', (57, 66))
17762	33627078	For the increased risk of CRC and rs9929218 polymorphism, there was no significant evidence shows that the correlations were found between them when all eligible studies were integrated into the meta-analysis.	('rs9929218', 'Var', (34, 43))	('CRC', 'Phenotype', 'HP:0003003', (26, 29))	('rs9929218', 'Mutation', 'rs9929218', (34, 43))	('CRC', 'Disease', (26, 29))
17767	33627078	GWAS has different common single nucleotide polymorphism (SNP) associated with colorectal cancer risk.	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('associated', 'Reg', (63, 73))	('colorectal cancer', 'Disease', (79, 96))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))	('single nucleotide polymorphism', 'Var', (26, 56))
17774	33627078	observed significant interactions between alcohol consumption and rs9929218.	('rs9929218', 'Mutation', 'rs9929218', (66, 75))	('interactions', 'Interaction', (21, 33))	('rs9929218', 'Var', (66, 75))	('alcohol', 'Chemical', 'MESH:D000438', (42, 49))
17775	33627078	In summary, we did a meta-analysis of the relationship between rs9929218 and increased susceptibility to CRC / CRA.	('CRA', 'Gene', (111, 114))	('rs9929218', 'Mutation', 'rs9929218', (63, 72))	('rs9929218', 'Var', (63, 72))	('CRC', 'Phenotype', 'HP:0003003', (105, 108))	('CRA', 'Gene', '51747', (111, 114))
17776	33627078	Rs9929218 is situated in the intron zone of CDH1, which encodes a calcium-dependent glycoprotein (E-cadherin).	('Rs9929218', 'Mutation', 'Rs9929218', (0, 9))	('cadherin', 'molecular_function', 'GO:0008014', ('100', '108'))	('E-cadherin', 'Gene', (98, 108))	('E-cadherin', 'Gene', '999', (98, 108))	('Rs9929218', 'Var', (0, 9))	('CDH1', 'Gene', (44, 48))	('calcium', 'Chemical', 'MESH:D002118', (66, 73))	('CDH1', 'Gene', '999', (44, 48))
17782	33627078	The combined results demonstrated that the rs9929218 polymorphism was an increased risk factor for CRC in European populations and there was no significant heterogeneity throughout the study.	('rs9929218', 'Var', (43, 52))	('CRC', 'Disease', (99, 102))	('risk', 'Reg', (83, 87))	('CRC', 'Phenotype', 'HP:0003003', (99, 102))	('rs9929218', 'Mutation', 'rs9929218', (43, 52))
17783	33627078	When stratified by ethnicity, significant associations between rs9929218 polymorphism and increased incidence of CRC were observed in Europeans.	('rs9929218', 'Mutation', 'rs9929218', (63, 72))	('CRC', 'Phenotype', 'HP:0003003', (113, 116))	('rs9929218', 'Var', (63, 72))	('CRC', 'Disease', (113, 116))
17785	33627078	In summary, our meta-analysis studies in different populations confirmed that SNP rs9929218 is significantly associated with CRC risk and that this variant may have a greater impact on Europeans than Asians and Others.	('associated', 'Reg', (109, 119))	('CRC', 'Disease', (125, 128))	('CRC', 'Phenotype', 'HP:0003003', (125, 128))	('SNP', 'Var', (78, 81))	('rs9929218', 'Mutation', 'rs9929218', (82, 91))
17786	33627078	GWAS Genome-wide association studies SNPs Single nucleotide polymorphisms CRC Colorectal cancer CRA Colorectal adenomas CDH1 Cadherin 1 ORs Odds ratios CIs Confidence intervals Cadherin Calcium-dependent glycoprotein EMT Epithelial-mesenchymal transition PRISMA Preferred reporting items for systematic review and meta-analysis HW collected data and performed statistical analysis and was a major contributor in writing the manuscript.	('Colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('Epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('221', '254'))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Cadherin 1', 'Gene', '999', (125, 135))	('Calcium', 'Chemical', 'MESH:D002118', (186, 193))	('Colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('CRC', 'Phenotype', 'HP:0003003', (74, 77))	('Cadherin', 'molecular_function', 'GO:0008014', ('177', '185'))	('Single nucleotide polymorphisms', 'Var', (42, 73))	('Colorectal adenomas', 'Disease', (100, 119))	('Cadherin', 'molecular_function', 'GO:0008014', ('125', '133'))	('Cadherin 1', 'Gene', (125, 135))	('Colorectal cancer', 'Disease', (78, 95))	('CRA', 'Gene', (96, 99))	('Colorectal adenomas', 'Disease', 'MESH:D015179', (100, 119))	('CDH1', 'Gene', '999', (120, 124))	('EMT', 'biological_process', 'GO:0001837', ('217', '220'))	('CRA', 'Gene', '51747', (96, 99))	('CDH1', 'Gene', (120, 124))
17796	32977434	Our review shows that there are promising results with beta blockers, statins and metformin, whereas data concerning antidepressants and antibacterial antibiotics seem to show a potentially harmful effect.	('metformin', 'Var', (82, 91))	('beta', 'Var', (55, 59))	('metformin', 'Chemical', 'MESH:D008687', (82, 91))
17854	32977434	Focusing on 1511 patients with colorectal cancer treated with ARB/ACEi vs. 7291 colorectal cancer controls treated with other antihypertensive drugs, there was no increase for cancer-specific mortality (OR: 0.82, 95% CI: 0.64-1.07 and OR: 0.78, 95% CI: 0.66-0.92 respectively for ARB and ACEi).	('ARB/ACEi', 'Chemical', '-', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (31, 48))	('mortality', 'Disease', 'MESH:D003643', (192, 201))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('hypertensive', 'Disease', (130, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('colorectal cancer', 'Disease', (80, 97))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('colorectal cancer', 'Disease', 'MESH:D015179', (31, 48))	('rectal cancer', 'Phenotype', 'HP:0100743', (84, 97))	('ARB/ACEi', 'Var', (62, 70))	('colorectal cancer', 'Disease', (31, 48))	('patients', 'Species', '9606', (17, 25))	('mortality', 'Disease', (192, 201))	('hypertensive', 'Disease', 'MESH:D006973', (130, 142))	('cancer', 'Disease', (91, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('cancer', 'Disease', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (176, 182))	('rectal cancer', 'Phenotype', 'HP:0100743', (35, 48))
17875	32977434	Risk-benefit assessment concerning use of non-aspirin-NSAIDs (NA-NSAIDs) for colorectal cancer prevention is still unknown: clinically relevant protective effects of NA-NSAIDs use have been found in women (19% relative risk reduction), distal colon cancer (22% relative risk reduction) and white people (risk reduction from 31% to 41%).	('people', 'Species', '9606', (296, 302))	('colorectal cancer', 'Disease', (77, 94))	('distal colon cancer', 'Disease', 'MESH:D015179', (236, 255))	('colon cancer', 'Phenotype', 'HP:0003003', (243, 255))	('rectal cancer', 'Phenotype', 'HP:0100743', (81, 94))	('distal colon cancer', 'Disease', (236, 255))	('NA-NSAIDs', 'Var', (166, 175))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('women', 'Species', '9606', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('aspirin', 'Chemical', 'MESH:D001241', (46, 53))	('reduction', 'NegReg', (275, 284))
17879	32977434	The study showed that, in vitro, ASA significantly enhances the cisplatin-mediated inhibition of cell proliferation, migration and invasion and induces apoptosis in colon cancer cells.	('ASA', 'Var', (33, 36))	('invasion', 'CPA', (131, 139))	('inhibition', 'NegReg', (83, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('152', '161'))	('apoptosis', 'biological_process', 'GO:0006915', ('152', '161'))	('colon cancer', 'Phenotype', 'HP:0003003', (165, 177))	('colon cancer', 'Disease', 'MESH:D015179', (165, 177))	('induces', 'Reg', (144, 151))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('83', '115'))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('enhances', 'PosReg', (51, 59))	('colon cancer', 'Disease', (165, 177))	('apoptosis', 'CPA', (152, 161))	('cisplatin-mediated', 'MPA', (64, 82))	('ASA', 'Chemical', 'MESH:D001241', (33, 36))
17880	32977434	The combined treatment of aspirin and cisplatin suppresses the expression of the antiapoptotic protein Bcl-2 and the EMT-related proteins, upregulates the levels of the cleaved PARP and Bax, blocks the PI3K/AKT and RAF-MEK-ERK signalling pathways, and inhibits the binding activity of NF-kappaB to the COX-2 promoter.	('ERK', 'Gene', '2048', (223, 226))	('COX-2', 'Gene', (302, 307))	('Bcl-2', 'Gene', '596', (103, 108))	('Bax', 'Gene', (186, 189))	('upregulates', 'PosReg', (139, 150))	('RAF', 'Gene', '22882', (215, 218))	('Bax', 'Gene', '581', (186, 189))	('COX-2', 'Gene', '4513', (302, 307))	('AKT', 'Gene', '207', (207, 210))	('binding', 'Interaction', (265, 272))	('MEK', 'Gene', '5609', (219, 222))	('cisplatin', 'Var', (38, 47))	('suppresses', 'NegReg', (48, 58))	('RAF', 'Gene', (215, 218))	('inhibits', 'NegReg', (252, 260))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))	('NF-kappaB', 'Gene', (285, 294))	('levels', 'MPA', (155, 161))	('antiapoptotic protein', 'MPA', (81, 102))	('aspirin', 'Chemical', 'MESH:D001241', (26, 33))	('MEK', 'Gene', (219, 222))	('PARP', 'Gene', '142', (177, 181))	('expression', 'MPA', (63, 73))	('NF-kappaB', 'Gene', '4790', (285, 294))	('blocks', 'NegReg', (191, 197))	('PARP', 'Gene', (177, 181))	('ERK', 'Gene', (223, 226))	('cleaved', 'MPA', (169, 176))	('Bcl-2', 'Gene', (103, 108))	('AKT', 'Gene', (207, 210))
17882	32977434	When it comes to patients who have already developed colorectal cancer, data concerning clinical usefulness of NSAIDs are rarer; use of aspirin seems to improve survival particularly in patients with colorectal cancer harbouring PIK3CA mutations.	('colorectal cancer', 'Disease', 'MESH:D015179', (200, 217))	('rectal cancer', 'Phenotype', 'HP:0100743', (57, 70))	('PIK3CA', 'Gene', '5290', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('rectal cancer', 'Phenotype', 'HP:0100743', (204, 217))	('colorectal cancer', 'Disease', 'MESH:D015179', (53, 70))	('mutations', 'Var', (236, 245))	('improve', 'PosReg', (153, 160))	('patients', 'Species', '9606', (17, 25))	('colorectal cancer', 'Disease', (200, 217))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('survival', 'MPA', (161, 169))	('colorectal cancer', 'Phenotype', 'HP:0003003', (200, 217))	('aspirin', 'Chemical', 'MESH:D001241', (136, 143))	('colorectal cancer', 'Phenotype', 'HP:0003003', (53, 70))	('PIK3CA', 'Gene', (229, 235))	('patients', 'Species', '9606', (186, 194))	('colorectal cancer', 'Disease', (53, 70))
17891	32977434	There are currently ongoing clinical trials (mostly focused on colon cancer patients harbouring PIK3CA mutations) that will look into this matter in detail.	('patients', 'Species', '9606', (76, 84))	('mutations', 'Var', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('colon cancer', 'Phenotype', 'HP:0003003', (63, 75))	('colon cancer', 'Disease', 'MESH:D015179', (63, 75))	('PIK3CA', 'Gene', (96, 102))	('PIK3CA', 'Gene', '5290', (96, 102))	('colon cancer', 'Disease', (63, 75))
17895	32977434	The study showed that antibiotic use was associated with an 18% relative risk increase of cancer.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('antibiotic', 'Var', (22, 32))	('increase', 'PosReg', (78, 86))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
17923	32977434	have shown that, in human HT29 and HCT116 colon carcinoma cells, TCAs reduce cell viability in a concentration-dependent manner and cause apoptotic cell death through either a non-mitochondrial or a mitochondrial pathway.	('mitochondrial pathway', 'Pathway', (199, 220))	('human', 'Species', '9606', (20, 25))	('TCAs', 'Var', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('colon carcinoma', 'Disease', (42, 57))	('TCAs', 'Chemical', 'MESH:D014238', (65, 69))	('HCT116', 'CellLine', 'CVCL:0291', (35, 41))	('reduce', 'NegReg', (70, 76))	('HT29', 'CellLine', 'CVCL:0320', (26, 30))	('colon carcinoma', 'Disease', 'MESH:D003110', (42, 57))	('death', 'Disease', 'MESH:D003643', (153, 158))	('death', 'Disease', (153, 158))	('cell viability', 'CPA', (77, 91))	('cause', 'Reg', (132, 137))	('non-mitochondrial', 'Pathway', (176, 193))
17951	32977434	Conversely, multiple epidemiological studies have demonstrated an association between metformin and reduced cancer incidence and mortality.	('mortality', 'Disease', 'MESH:D003643', (129, 138))	('reduced', 'NegReg', (100, 107))	('mortality', 'Disease', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('metformin', 'Var', (86, 95))	('metformin', 'Chemical', 'MESH:D008687', (86, 95))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
17954	32977434	On the whole, metformin can induce anticancer activity through two main routes: a direct mechanism resulting from the inhibition of mitochondrial complex I and consequent suppression of adenosine triphosphate (ATP) production in prenoplastic and neoplastic cells and an indirect mechanism related to metformin insulin-lowering activity, which may slow tumour development in hyperinsulinemic patients.	('insulin', 'Gene', (310, 317))	('hyperinsulinemic', 'Disease', (374, 390))	('adenosine', 'Chemical', 'MESH:D000241', (186, 195))	('mitochondrial complex I', 'Enzyme', (132, 155))	('cancer', 'Disease', (39, 45))	('inhibition', 'NegReg', (118, 128))	('ATP', 'Chemical', 'MESH:D000255', (210, 213))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Phenotype', 'HP:0002664', (352, 358))	('tumour', 'Disease', 'MESH:D009369', (352, 358))	('insulin', 'Gene', '3630', (379, 386))	('tumour', 'Disease', (352, 358))	('insulin', 'Gene', '3630', (310, 317))	('patients', 'Species', '9606', (391, 399))	('hyperinsulinemic', 'Disease', 'MESH:D044903', (374, 390))	('suppression', 'NegReg', (171, 182))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('metformin', 'Var', (14, 23))	('metformin', 'Chemical', 'MESH:D008687', (14, 23))	('slow', 'NegReg', (347, 351))	('metformin', 'Chemical', 'MESH:D008687', (300, 309))	('insulin', 'Gene', (379, 386))
17964	32977434	To conclude, metformin use might be associated with improved survival for patients with colorectal cancer, but its impact in patients with mCRC has still not been proven.	('colorectal cancer', 'Disease', (88, 105))	('metformin', 'Var', (13, 22))	('patients', 'Species', '9606', (74, 82))	('improved', 'PosReg', (52, 60))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('rectal cancer', 'Phenotype', 'HP:0100743', (92, 105))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('survival', 'MPA', (61, 69))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('patients', 'Species', '9606', (125, 133))
17991	32977434	Indeed, the newest addition is the one represented by B-raf inhibitors for patients harbouring B-raf V600E mutations and we could still argue that it is still based on inhibition of a crucial target of RAS-RAF-MEK-ERK pathway.	('RAF', 'Gene', '22882', (206, 209))	('V600E mutations', 'Var', (101, 116))	('B-raf', 'Gene', '673', (54, 59))	('V600E', 'Mutation', 'rs113488022', (101, 106))	('B-raf', 'Gene', (95, 100))	('RAF', 'Gene', (206, 209))	('B-raf', 'Gene', (54, 59))	('B-raf', 'Gene', '673', (95, 100))	('MEK', 'Gene', (210, 213))	('patients', 'Species', '9606', (75, 83))	('MEK', 'Gene', '5609', (210, 213))	('ERK', 'Gene', (214, 217))	('ERK', 'Gene', '2048', (214, 217))
18005	32977434	Despite these differences, survival outcomes for patients who received beta blockers were still better compared to other drugs or to patients who did not receive any antihypertensive medication, independently from age of colorectal cancer diagnosis.	('colorectal cancer', 'Disease', 'MESH:D015179', (221, 238))	('rectal cancer', 'Phenotype', 'HP:0100743', (225, 238))	('antihypertensive medication', 'Phenotype', 'HP:0000822', (166, 193))	('patients', 'Species', '9606', (133, 141))	('better', 'PosReg', (96, 102))	('hypertensive', 'Disease', 'MESH:D006973', (170, 182))	('beta', 'Var', (71, 75))	('colorectal cancer', 'Phenotype', 'HP:0003003', (221, 238))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('patients', 'Species', '9606', (49, 57))	('hypertensive', 'Disease', (170, 182))	('colorectal cancer', 'Disease', (221, 238))	('survival outcomes', 'CPA', (27, 44))
18062	33080755	In these studies, there was no apparent heterogeneity (I2 = 15.60%, P = .291), thus we applied the fixed-effects model, which revealed that high expression of Oct4 was remarkably associated with to poor DFS/RFS/PFS in patients with solid tumors.	('solid tumors', 'Disease', (232, 244))	('associated', 'Reg', (179, 189))	('RFS', 'Disease', 'MESH:D005198', (207, 210))	('patients', 'Species', '9606', (218, 226))	('solid tumors', 'Disease', 'MESH:D009369', (232, 244))	('high', 'Var', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('Oct4', 'Gene', (159, 163))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('RFS', 'Disease', (207, 210))
18067	33080755	Results indicated that patients overexpressing Oct4 had poorer DFS/RFS/PFS, including HCC (pooled HR: 1.92; 95% CI: 1.30-2.85; P = .001), cervical cancer (pooled HR: 2.77; 95% CI: 1.33-5.79; P = .007), colorectal cancer (pooled HR: 3.22; 95% CI: 1.68-6.16; P < .001), others (pooled HR: 2.39; 95% CI: 1.74-3.27; P < .001).	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('RFS', 'Disease', 'MESH:D005198', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('colorectal cancer', 'Phenotype', 'HP:0003003', (202, 219))	('patients', 'Species', '9606', (23, 31))	('poorer', 'NegReg', (56, 62))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))	('colorectal cancer', 'Disease', (202, 219))	('colorectal cancer', 'Disease', 'MESH:D015179', (202, 219))	('RFS', 'Disease', (67, 70))	('HCC', 'Disease', (86, 89))	('cervical cancer', 'Disease', 'MESH:D002583', (138, 153))	('cervical cancer', 'Disease', (138, 153))	('Oct4', 'Var', (47, 51))
18085	33080755	Interestingly, in HCC, Oct4 has been revealed to confer chemoresistance on HCC cells through protein kinase B Akt-mediated upregulation of ATP-binding cassette transporter G2, while it promoted cancer cell proliferation and migration via the survivin/STAT3 pathway, leading to poor prognosis.	('HCC', 'Phenotype', 'HP:0001402', (18, 21))	('ATP-binding cassette transporter', 'molecular_function', 'GO:0140359', ('139', '171'))	('chemoresistance', 'CPA', (56, 71))	('Akt', 'Gene', (110, 113))	('cell proliferation', 'biological_process', 'GO:0008283', ('201', '219'))	('protein kinase B', 'Gene', '2185', (93, 109))	('ATP-binding cassette transporter G2', 'Gene', (139, 174))	('ATP-binding cassette transporter G2', 'Gene', '9429', (139, 174))	('Akt', 'Gene', '207', (110, 113))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('protein kinase B', 'Gene', (93, 109))	('protein', 'cellular_component', 'GO:0003675', ('93', '100'))	('STAT3', 'Gene', (251, 256))	('HCC', 'Phenotype', 'HP:0001402', (75, 78))	('upregulation', 'PosReg', (123, 135))	('STAT3', 'Gene', '6774', (251, 256))	('Oct4', 'Var', (23, 27))	('migration', 'CPA', (224, 233))	('cancer', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('promoted', 'PosReg', (185, 193))
18093	33080755	On the other hand, Oct4 knockdown could significantly reduce migration and progression in pancreatic cancer and colorectal cancer and cause breast CSC-like cell apoptosis, this strongly suggested that targeting Oct4 might offer vital clinical applications in cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('Oct4', 'Gene', (19, 23))	('colorectal cancer', 'Disease', (112, 129))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('cause', 'Reg', (134, 139))	('reduce', 'NegReg', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('breast CSC-like cell apoptosis', 'CPA', (140, 170))	('cancer', 'Disease', (259, 265))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('knockdown', 'Var', (24, 33))	('progression', 'CPA', (75, 86))	('cancer', 'Disease', (101, 107))	('pancreatic cancer', 'Disease', (90, 107))	('cancer', 'Disease', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
18096	33080755	High expression of Oct4 was dramatically associated with worse OS and DFS/RFS/PFS in patients with solid tumors.	('RFS', 'Disease', (74, 77))	('associated', 'Reg', (41, 51))	('High', 'Var', (0, 4))	('RFS', 'Disease', 'MESH:D005198', (74, 77))	('solid tumors', 'Disease', 'MESH:D009369', (99, 111))	('patients', 'Species', '9606', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('worse OS', 'Disease', (57, 65))	('Oct4', 'Gene', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('solid tumors', 'Disease', (99, 111))
18099	33080755	Notably, only 2 studies revealed that patients exhibiting high expression of Oct4 survived longer and had a lower recurrence rate in hypopharyngeal squamous cell carcinoma, and OSCC patients expressing high levels of Oct4 had better cumulative OS, the underlying mechanism is unclear, thus, additional in-depth researches are needed.	('high levels', 'Var', (202, 213))	('hypopharyngeal squamous cell carcinoma', 'Disease', (133, 171))	('cumulative OS', 'CPA', (233, 246))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('better', 'PosReg', (226, 232))	('high expression', 'Var', (58, 73))	('hypopharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (133, 171))	('hypopharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (133, 171))	('lower', 'NegReg', (108, 113))	('patients', 'Species', '9606', (182, 190))	('patients', 'Species', '9606', (38, 46))	('Oct4', 'Gene', (77, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
18110	31226844	Genomic Profiling of KRAS/NRAS/BRAF/PIK3CA Wild-Type Metastatic Colorectal Cancer Patients Reveals Novel Mutations in Genes Potentially Associated with Resistance to Anti-EGFR Agents Previous findings suggest that metastatic colorectal carcinoma (mCRC) patients with KRAS/NRAS/BRAF/PIK3CA wild-type (quadruple-wt) tumors are highly sensitive to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs).	('EGFR', 'Gene', (171, 175))	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('epidermal growth factor receptor', 'Gene', (350, 382))	('KRAS', 'Gene', '3845', (267, 271))	('PIK3CA', 'Gene', (282, 288))	('patients', 'Species', '9606', (253, 261))	('Patients', 'Species', '9606', (82, 90))	('epidermal growth factor receptor', 'Gene', '1956', (350, 382))	('KRAS', 'Gene', (267, 271))	('NRAS', 'Gene', (272, 276))	('PIK3CA', 'Gene', (36, 42))	('EGFR', 'Gene', (384, 388))	('Type Metastatic Colorectal Cancer', 'Disease', 'MESH:D015179', (48, 81))	('BRAF', 'Gene', '673', (277, 281))	('BRAF', 'Gene', (277, 281))	('Mutations', 'Var', (105, 114))	('NRAS', 'Gene', (26, 30))	('Type Metastatic Colorectal Cancer', 'Disease', (48, 81))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('EGFR', 'Gene', '1956', (171, 175))	('BRAF', 'Gene', '673', (31, 35))	('BRAF', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('colorectal carcinoma', 'Disease', (225, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('tumors', 'Disease', (314, 320))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (225, 245))	('PIK3CA', 'Gene', '5290', (282, 288))	('EGFR', 'Gene', '1956', (384, 388))	('KRAS', 'Gene', '3845', (21, 25))	('NRAS', 'Gene', '4893', (26, 30))	('PIK3CA', 'Gene', '5290', (36, 42))	('NRAS', 'Gene', '4893', (272, 276))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (64, 81))	('tumors', 'Disease', 'MESH:D009369', (314, 320))	('KRAS', 'Gene', (21, 25))
18112	31226844	Tumor samples were analyzed with a targeted sequencing panel covering single nucleotide variants (SNVs), insertions/deletions (Indels), copy number variations (CNVs), and gene fusions in 143 cancer-related genes.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('single nucleotide variants', 'Var', (70, 96))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('copy number variations', 'Var', (136, 158))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('insertions/deletions', 'Var', (105, 125))	('gene fusions', 'Var', (171, 183))
18115	31226844	Quadruple-wt mCRC from patients with the shorter progression free survival (PFS) were enriched with peculiar genetic alterations in KRAS, FBXW7, MAP2K1, and NF1 genes as compared with patients with longer PFS.	('alterations', 'Var', (117, 128))	('KRAS', 'Gene', (132, 136))	('shorter', 'NegReg', (41, 48))	('KRAS', 'Gene', '3845', (132, 136))	('MAP2K1', 'Gene', (145, 151))	('patients', 'Species', '9606', (184, 192))	('patients', 'Species', '9606', (23, 31))	('FBXW7', 'Gene', '55294', (138, 143))	('FBXW7', 'Gene', (138, 143))	('NF1', 'Gene', (157, 160))	('NF1', 'Gene', '4763', (157, 160))	('progression', 'MPA', (49, 60))	('MAP2K1', 'Gene', '5604', (145, 151))
18119	31226844	Treatment with anti-EGFR agents is currently recommended only for mCRC patients with KRAS/NRAS/BRAF wild type (wt) tumors, because mutations in these genes have been shown to determine resistance to anti-EGFR therapies.	('EGFR', 'Gene', (20, 24))	('patients', 'Species', '9606', (71, 79))	('KRAS', 'Gene', (85, 89))	('NRAS', 'Gene', (90, 94))	('BRAF', 'Gene', '673', (95, 99))	('resistance', 'MPA', (185, 195))	('BRAF', 'Gene', (95, 99))	('EGFR', 'Gene', '1956', (204, 208))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('EGFR', 'Gene', '1956', (20, 24))	('EGFR', 'molecular_function', 'GO:0005006', ('204', '208'))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('EGFR', 'molecular_function', 'GO:0005006', ('20', '24'))	('tumors', 'Disease', (115, 121))	('mutations', 'Var', (131, 140))	('determine', 'Reg', (175, 184))	('NRAS', 'Gene', '4893', (90, 94))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('EGFR', 'Gene', (204, 208))	('KRAS', 'Gene', '3845', (85, 89))
18122	31226844	Indeed, a number of genetic alterations might play a role in the de novo resistance to anti-EGFR agents in mCRC.	('resistance', 'MPA', (73, 83))	('play', 'Reg', (46, 50))	('EGFR', 'molecular_function', 'GO:0005006', ('92', '96'))	('mCRC', 'Disease', (107, 111))	('role', 'Reg', (53, 57))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('genetic alterations', 'Var', (20, 39))
18123	31226844	In particular, single nucleotide variants (SNVs), copy number variations (CNVs) and/or rearrangements in PIK3CA, PTEN, ERBB2, MAP2K1, NTRK1-3, RET, AKT1, ALK, and ROS1, have been claimed to be associated with resistance to anti-EGFR MoAbs.	('rearrangements', 'Var', (87, 101))	('AKT1', 'Gene', '207', (148, 152))	('single nucleotide variants', 'Var', (15, 41))	('PIK3CA', 'Gene', '5290', (105, 111))	('MAP2K1', 'Gene', '5604', (126, 132))	('ALK', 'Gene', '238', (154, 157))	('MAP2K1', 'Gene', (126, 132))	('ROS1', 'Gene', '6098', (163, 167))	('RET', 'Gene', '5979', (143, 146))	('ALK', 'Gene', (154, 157))	('ERBB2', 'Gene', (119, 124))	('EGFR', 'Gene', '1956', (228, 232))	('PTEN', 'Gene', (113, 117))	('AKT1', 'Gene', (148, 152))	('PIK3CA', 'Gene', (105, 111))	('RET', 'Gene', (143, 146))	('ERBB2', 'Gene', '2064', (119, 124))	('copy number variations', 'Var', (50, 72))	('NTRK1', 'Gene', '4914', (134, 139))	('PTEN', 'Gene', '5728', (113, 117))	('ROS1', 'Gene', (163, 167))	('NTRK1', 'Gene', (134, 139))	('EGFR', 'Gene', (228, 232))	('associated', 'Reg', (193, 203))
18128	31226844	The availability of these tumor samples with annotated clinical data offers the possibility to identify novel genetic alterations that might be associated with de novo resistance to anti-EGFR MoAbs.	('associated', 'Reg', (144, 154))	('alterations', 'Var', (118, 129))	('EGFR', 'Gene', '1956', (187, 191))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('EGFR', 'Gene', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('EGFR', 'molecular_function', 'GO:0005006', ('187', '191'))
18132	31226844	In particular, we tested the tumor specimens with the Oncomine Comprehensive Panel that provides information on hotspot mutations of 73 oncogenes, CNVs of 49 genes, full-length sequence of 26 tumor suppressor genes, and sequence of 22 driver gene fusions (see Materials and Methods).	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('Oncomine', 'Chemical', '-', (54, 62))	('tumor suppressor', 'biological_process', 'GO:0051726', ('192', '208'))	('oncogenes', 'Gene', (136, 145))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('mutations', 'Var', (120, 129))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('192', '208'))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
18135	31226844	Of the 54 SNVs and insertions/deletions (Indels) identified, 35% and 41% were APC and TP53 variants, respectively (Figure 1).	('APC', 'Disease', 'MESH:D011125', (78, 81))	('TP53', 'Gene', '7157', (86, 90))	('APC', 'Disease', (78, 81))	('TP53', 'Gene', (86, 90))	('insertions/deletions', 'Var', (19, 39))	('APC', 'cellular_component', 'GO:0005680', ('78', '81'))
18136	31226844	Nineteen patients (90.47%) had at least one TP53 SNV or Indel, whereas 15/21 (71.43%) patients carried APC mutations.	('patients', 'Species', '9606', (9, 17))	('Indel', 'Var', (56, 61))	('APC', 'cellular_component', 'GO:0005680', ('103', '106'))	('TP53', 'Gene', '7157', (44, 48))	('APC', 'Disease', 'MESH:D011125', (103, 106))	('APC', 'Disease', (103, 106))	('TP53', 'Gene', (44, 48))	('patients', 'Species', '9606', (86, 94))
18137	31226844	All cases with APC mutations had also TP53 variants.	('APC', 'Disease', (15, 18))	('APC', 'Disease', 'MESH:D011125', (15, 18))	('TP53', 'Gene', (38, 42))	('APC', 'cellular_component', 'GO:0005680', ('15', '18'))	('mutations', 'Var', (19, 28))	('variants', 'Var', (43, 51))	('TP53', 'Gene', '7157', (38, 42))
18139	31226844	Two different variants in TP53 (c.275_276insGGCC and c.837_838InsG) and three in APC (c.4467_4468insCATTTTG, c.4098_4099delTCinsAT, and c.589_590insGAGTT) have not been reported in any other sample in public databases to date (;  cosmic, last accessed 03/14/2019).	('TP53', 'Gene', (26, 30))	('c.837_838InsG', 'Var', (53, 66))	('APC', 'Disease', (81, 84))	('c.4467_4468insCATTTTG', 'Mutation', 'c.4467_4468insCATTTTG', (86, 107))	('APC', 'cellular_component', 'GO:0005680', ('81', '84'))	('c.837_838InsG', 'Mutation', 'c.837_838I>G', (53, 66))	('c.275_276insGGCC', 'Var', (32, 48))	('c.4098_4099delTCinsAT', 'Mutation', 'c.4098_4099delinsTC,AT', (109, 130))	('c.589_590insGAGTT', 'Mutation', 'c.589_590insGAGTT', (136, 153))	('c.589_590insGAGTT', 'Var', (136, 153))	('c.4467_4468insCATTTTG', 'Var', (86, 107))	('c.275_276insGGCC', 'Mutation', 'c.275_276insGGCC', (32, 48))	('TP53', 'Gene', '7157', (26, 30))	('c.4098_4099delTCinsAT', 'Var', (109, 130))	('APC', 'Disease', 'MESH:D011125', (81, 84))
18140	31226844	Mutations were also detected in FBXW7 (n. 3), NF1 (n. 2), MAP2K1 (n. 1), KRAS (n. 1), PTPN11 (n. 1), ATM (n. 1), CTNNB1 (n. 1), PIK3R1 (n. 1), PTEN (n. 1), and CDKN2A (n. 1).	('NF1', 'Gene', '4763', (46, 49))	('PIK3R1', 'Gene', '5295', (128, 134))	('PTPN11', 'Gene', (86, 92))	('CTNNB1', 'Gene', '1499', (113, 119))	('FBXW7', 'Gene', (32, 37))	('NF1', 'Gene', (46, 49))	('KRAS', 'Gene', '3845', (73, 77))	('PTPN11', 'Gene', '5781', (86, 92))	('ATM', 'Gene', '472', (101, 104))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (73, 77))	('CTNNB1', 'Gene', (113, 119))	('CDKN2A', 'Gene', (160, 166))	('PIK3R1', 'Gene', (128, 134))	('PTEN', 'Gene', (143, 147))	('MAP2K1', 'Gene', '5604', (58, 64))	('FBXW7', 'Gene', '55294', (32, 37))	('ATM', 'Gene', (101, 104))	('MAP2K1', 'Gene', (58, 64))	('CDKN2A', 'Gene', '1029', (160, 166))	('PTEN', 'Gene', '5728', (143, 147))
18142	31226844	In particular, one case showed deletions of both APC and PIK3R1 (P6), two had deletions of either APC (P15) or TP53 (P14).	('P15', 'Gene', (103, 106))	('APC', 'Disease', 'MESH:D011125', (98, 101))	('APC', 'Disease', (49, 52))	('TP53', 'Gene', '7157', (111, 115))	('P15', 'Gene', '1030', (103, 106))	('APC', 'cellular_component', 'GO:0005680', ('49', '52'))	('APC', 'Disease', (98, 101))	('APC', 'Disease', 'MESH:D011125', (49, 52))	('TP53', 'Gene', (111, 115))	('deletions', 'Var', (31, 40))	('P14', 'Gene', '1029', (117, 120))	('APC', 'cellular_component', 'GO:0005680', ('98', '101'))	('P14', 'Gene', (117, 120))	('PIK3R1', 'Gene', (57, 63))	('PIK3R1', 'Gene', '5295', (57, 63))
18143	31226844	Three tumors (30%) had several amplified or deleted genes (Table S1 and Figure 2).	('amplified', 'Var', (31, 40))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
18147	31226844	Interestingly, we observed that patients with the shorter PFS (<median PFS) had peculiar genetic alterations in genes involved in the RAS/MEK and mTOR pathways that might be associated with resistance to anti-EGFR drugs.	('mTOR', 'Gene', '2475', (146, 150))	('patients', 'Species', '9606', (32, 40))	('associated', 'Reg', (174, 184))	('EGFR', 'Gene', (209, 213))	('genes', 'Gene', (112, 117))	('mTOR', 'Gene', (146, 150))	('MEK', 'Gene', (138, 141))	('MEK', 'Gene', '5609', (138, 141))	('genetic alterations', 'Var', (89, 108))	('EGFR', 'Gene', '1956', (209, 213))
18149	31226844	All variants were at an allelic frequency >5% with the exception of a KRAS variant (c.183A>T; p.Gln61His) that was identified in the tumor tissue from patient P7 (PFS 3.93 months) at an allelic frequency of 0.4%.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('KRAS', 'Gene', (70, 74))	('patient', 'Species', '9606', (151, 158))	('KRAS', 'Gene', '3845', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('c.183A>T', 'Mutation', 'rs17851045', (84, 92))	('p.Gln61His', 'Mutation', 'rs17851045', (94, 104))	('tumor', 'Disease', (133, 138))	('p.Gln61His', 'Var', (94, 104))	('c.183A>T; p.Gln61His', 'Var', (84, 104))
18153	31226844	Patient P3 (PFS 6.63 months) carried the variant c.169A>G in the MAP2K1 gene coding for the MEK1 protein.	('MEK1', 'molecular_function', 'GO:0004708', ('92', '96'))	('c.169A>G', 'Var', (49, 57))	('MAP2K1', 'Gene', (65, 71))	('MEK1', 'Gene', '5604', (92, 96))	('protein', 'cellular_component', 'GO:0003675', ('97', '104'))	('MEK1', 'Gene', (92, 96))	('c.169A>G', 'Mutation', 'rs397516790', (49, 57))	('MAP2K', 'molecular_function', 'GO:0004708', ('65', '70'))	('MAP2K1', 'Gene', '5604', (65, 71))	('Patient', 'Species', '9606', (0, 7))
18154	31226844	It results in the substitution of an amino acid residue (p.Lys57Glu) in the MEK1 negative regulatory domain and it has been associated with a gain of function of the protein.	('p.Lys57Glu', 'Var', (57, 67))	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('MEK1', 'molecular_function', 'GO:0004708', ('76', '80'))	('p.Lys57Glu', 'Mutation', 'rs397516790', (57, 67))	('MEK1', 'Gene', '5604', (76, 80))	('gain of function', 'PosReg', (142, 158))	('MEK1', 'Gene', (76, 80))
18155	31226844	Two patients (P20 and P21) had variants in NF1, a negative regulator of RAS, inactivated by mutation in various cancers.	('P21', 'Gene', '644914', (22, 25))	('variants', 'Var', (31, 39))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('P21', 'Gene', (22, 25))	('NF1', 'Gene', (43, 46))	('P20', 'Gene', '51673', (14, 17))	('P20', 'Gene', (14, 17))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('NF1', 'Gene', '4763', (43, 46))	('cancers', 'Disease', (112, 119))	('patients', 'Species', '9606', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
18156	31226844	Specifically, we found an insertion (c.638_639insA; p.Asn214Lys fs*2) in the tumor from patient P20 (PFS 2.83 months) and a SNV (c.5101A>T; p.Lys1701Ter) in the tumor from patient P21 (PFS 3.73 months).	('c.5101A>T; p.Lys1701Ter', 'Var', (129, 152))	('p.Lys1701Ter', 'Var', (140, 152))	('P21', 'Gene', (180, 183))	('P20', 'Gene', '51673', (96, 99))	('P20', 'Gene', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('p.Lys1701Ter', 'Mutation', 'p.K1701X', (140, 152))	('c.5101A>T', 'Mutation', 'c.5101A>T', (129, 138))	('p.Asn214Lys', 'SUBSTITUTION', 'None', (52, 63))	('PFS 2', 'Gene', (101, 106))	('tumor', 'Disease', (161, 166))	('patient', 'Species', '9606', (88, 95))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('p.Asn214Lys', 'Var', (52, 63))	('c.638_639insA', 'Mutation', 'c.638_639insA', (37, 50))	('patient', 'Species', '9606', (172, 179))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('P21', 'Gene', '644914', (180, 183))	('PFS 2', 'Gene', '51659', (101, 106))	('tumor', 'Disease', (77, 82))
18157	31226844	Both NF1 mutations lead to the formation of a premature stop codon with consequent loss of function and increased activation of the RAS signaling pathway.	('activation', 'PosReg', (114, 124))	('premature stop codon', 'MPA', (46, 66))	('NF1', 'Gene', (5, 8))	('mutations', 'Var', (9, 18))	('NF1', 'Gene', '4763', (5, 8))	('loss of function', 'NegReg', (83, 99))	('RAS signaling pathway', 'Pathway', (132, 153))	('signaling pathway', 'biological_process', 'GO:0007165', ('136', '153'))	('formation', 'biological_process', 'GO:0009058', ('31', '40'))
18159	31226844	Of the three missense mutations detected in FBXW7, two were found in patients with a PFS shorter than median PFS.	('FBXW7', 'Gene', '55294', (44, 49))	('FBXW7', 'Gene', (44, 49))	('missense mutations', 'Var', (13, 31))	('found', 'Reg', (60, 65))	('patients', 'Species', '9606', (69, 77))
18160	31226844	Patient P14 (PFS 8.07 months) carried the c.1798G>A variant (p.Asp600Asn) and patient P18 (PFS 1.73 months) the c.1513C>T SNV (p.Arg505Cys).	('P18', 'Gene', (86, 89))	('patient', 'Species', '9606', (78, 85))	('c.1798G>A', 'Mutation', 'c.1798G>A', (42, 51))	('p.Asp600Asn', 'Mutation', 'p.D600N', (61, 72))	('p.Arg505Cys', 'Mutation', 'rs149680468', (127, 138))	('P18', 'Gene', '100689229', (86, 89))	('P14', 'Gene', '1029', (8, 11))	('P14', 'Gene', (8, 11))	('c.1513C>T', 'Var', (112, 121))	('Patient', 'Species', '9606', (0, 7))	('c.1513C>T', 'Mutation', 'c.1513C>T', (112, 121))	('c.1798G>A', 'Var', (42, 51))
18162	31226844	In contrast, the FBXW7 p.Arg505Cys mutation has been reported in several cancer types and leads to loss of function of the protein.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('p.Arg505Cys', 'Mutation', 'rs149680468', (23, 34))	('FBXW7', 'Gene', '55294', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('p.Arg505Cys', 'Var', (23, 34))	('FBXW7', 'Gene', (17, 22))	('loss of function', 'NegReg', (99, 115))	('protein', 'Protein', (123, 130))
18166	31226844	Within this cohort, patient P16 had a significant copy number gain of ERBB2 (78.99) that was confirmed by FISH analysis (data not shown).	('copy number', 'Var', (50, 61))	('gain', 'PosReg', (62, 66))	('P16', 'Gene', (28, 31))	('patient', 'Species', '9606', (20, 27))	('ERBB2', 'Gene', '2064', (70, 75))	('ERBB2', 'Gene', (70, 75))	('P16', 'Gene', '1029', (28, 31))
18168	31226844	Patient P4 (PFS 17.93 months), carrying both GAS6 copy gain (5.59) and a FBXW7 variant (c.1268G>T; p.Gly423Val), had a complete response to first-line therapy.	('GAS', 'molecular_function', 'GO:0034005', ('45', '48'))	('c.1268G>T', 'Mutation', 'rs1157879635', (88, 97))	('copy gain', 'Disease', 'MESH:D015430', (50, 59))	('GAS6', 'Gene', (45, 49))	('FBXW7', 'Gene', '55294', (73, 78))	('GAS6', 'Gene', '2621', (45, 49))	('p.Gly423Val', 'Mutation', 'rs1157879635', (99, 110))	('copy gain', 'Disease', (50, 59))	('FBXW7', 'Gene', (73, 78))	('Patient', 'Species', '9606', (0, 7))	('c.1268G>T;', 'Var', (88, 98))
18169	31226844	The tumor from patient P17 carried several genetic alterations, including an Indel in PTEN.	('tumor', 'Disease', (4, 9))	('patient', 'Species', '9606', (15, 22))	('P17', 'Gene', (23, 26))	('PTEN', 'Gene', (86, 90))	('PTEN', 'Gene', '5728', (86, 90))	('P17', 'Gene', '653820', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('Indel', 'Var', (77, 82))
18172	31226844	Although we identified MAP2K1, FBXW7, and NF1 variants in patients with relatively short PFS, this finding could be due to a prognostic rather than a predictive value.	('MAP2K1', 'Gene', '5604', (23, 29))	('FBXW7', 'Gene', '55294', (31, 36))	('variants', 'Var', (46, 54))	('FBXW7', 'Gene', (31, 36))	('MAP2K1', 'Gene', (23, 29))	('patients', 'Species', '9606', (58, 66))	('NF1', 'Gene', '4763', (42, 45))	('NF1', 'Gene', (42, 45))
18173	31226844	Therefore, we interrogated public databases and data available at our biobank to assess the frequency in CRC of variants in MAP2K1, FBXW7, and NF1 and the correlation with clinical-pathological features.	('MAP2K1', 'Gene', (124, 130))	('NF1', 'Gene', (143, 146))	('NF1', 'Gene', '4763', (143, 146))	('FBXW7', 'Gene', '55294', (132, 137))	('MAP2K', 'molecular_function', 'GO:0004708', ('124', '129'))	('MAP2K1', 'Gene', '5604', (124, 130))	('FBXW7', 'Gene', (132, 137))	('variants', 'Var', (112, 120))
18174	31226844	In particular, we investigated whether these variants are found in left-sided tumors, in which the use of anti-EGFR monoclonal antibodies is highly recommended, as well as their prognostic significance.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('EGFR', 'Gene', '1956', (111, 115))	('variants', 'Var', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('EGFR', 'Gene', (111, 115))
18175	31226844	In the cBioPortal database, variants of the MAP2K1 gene are reported at frequencies of 1.7% in CRC patients (Table 1) and correlated with worse disease/progression-free survival (Logrank Test P-Value: 1.815e-3), but not with overall survival.	('disease/progression-free survival', 'CPA', (144, 177))	('variants', 'Var', (28, 36))	('MAP2K1', 'Gene', '5604', (44, 50))	('CRC', 'Disease', (95, 98))	('worse', 'NegReg', (138, 143))	('patients', 'Species', '9606', (99, 107))	('MAP2K1', 'Gene', (44, 50))
18176	31226844	Although MAP2K1 mutations were more frequent in right-sided tumors, they were also detected in left colon tumors (Table 1).	('MAP2K1', 'Gene', '5604', (9, 15))	('frequent', 'Reg', (36, 44))	('left colon tumors', 'Disease', 'MESH:D015179', (95, 112))	('detected', 'Reg', (83, 91))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('MAP2K', 'molecular_function', 'GO:0004708', ('9', '14'))	('tumors', 'Disease', (106, 112))	('MAP2K1', 'Gene', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('mutations', 'Var', (16, 25))	('left colon tumors', 'Disease', (95, 112))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('colon tumors', 'Phenotype', 'HP:0100273', (100, 112))	('tumors', 'Disease', (60, 66))
18177	31226844	MAP2K1 variants were also more frequent among KRAS/NRAS/BRAF wt patients as compared with unselected CRC (Table 1).	('MAP2K1', 'Gene', (0, 6))	('patients', 'Species', '9606', (64, 72))	('BRAF', 'Gene', '673', (56, 60))	('KRAS', 'Gene', (46, 50))	('variants', 'Var', (7, 15))	('KRAS', 'Gene', '3845', (46, 50))	('frequent', 'Reg', (31, 39))	('MAP2K', 'molecular_function', 'GO:0004708', ('0', '5'))	('NRAS', 'Gene', (51, 55))	('MAP2K1', 'Gene', '5604', (0, 6))	('NRAS', 'Gene', '4893', (51, 55))	('BRAF', 'Gene', (56, 60))
18178	31226844	The MAP2K1 mutations previously reported to be associated with de novo and acquired resistance to anti-EGFR MoAbs reside in the negative regulatory domain of the MEK1 protein and are associated with a gain of function of the protein.	('MEK1', 'molecular_function', 'GO:0004708', ('162', '166'))	('mutations', 'Var', (11, 20))	('EGFR', 'Gene', '1956', (103, 107))	('MAP2K', 'molecular_function', 'GO:0004708', ('4', '9'))	('MAP2K1', 'Gene', (4, 10))	('protein', 'cellular_component', 'GO:0003675', ('167', '174'))	('EGFR', 'Gene', (103, 107))	('protein', 'cellular_component', 'GO:0003675', ('225', '232'))	('protein', 'Protein', (225, 232))	('MAP2K1', 'Gene', '5604', (4, 10))	('EGFR', 'molecular_function', 'GO:0005006', ('103', '107'))	('MEK1', 'Gene', '5604', (162, 166))	('gain of function', 'PosReg', (201, 217))	('MEK1', 'Gene', (162, 166))
18179	31226844	Among 939 CRC cases tested at our laboratory for MAP2K1 mutations within clinical practice and clinical research, only 2 (0.2%) showed MEK1 gain of function variants (c.199G>A, p.Asp67Asn; c.169A>G, p.Lys57Glu), thus confirming the rarity of these specific genetic alterations in CRC.	('mutations', 'Var', (56, 65))	('MAP2K', 'molecular_function', 'GO:0004708', ('49', '54'))	('MEK1', 'Gene', (135, 139))	('MAP2K1', 'Gene', (49, 55))	('c.199G>A', 'Mutation', 'rs727504317', (167, 175))	('gain of function', 'PosReg', (140, 156))	('p.Lys57Glu', 'Mutation', 'rs397516790', (199, 209))	('c.169A>G', 'Mutation', 'rs397516790', (189, 197))	('p.Asp67Asn; c.169A>G', 'Var', (177, 197))	('p.Asp67Asn', 'Mutation', 'rs727504317', (177, 187))	('c.199G>A', 'Var', (167, 175))	('MEK1', 'Gene', '5604', (135, 139))	('MAP2K1', 'Gene', '5604', (49, 55))	('c.169A>G', 'Var', (189, 197))	('MEK1', 'molecular_function', 'GO:0004708', ('135', '139'))
18181	31226844	The frequency of these mutations is higher in right-sided tumors, without any significant difference between unselected CRC and KRAS/NRAS/BRAF wt carcinomas (Table 1).	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('KRAS', 'Gene', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('BRAF', 'Gene', '673', (138, 142))	('KRAS', 'Gene', '3845', (128, 132))	('NRAS', 'Gene', (133, 137))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('carcinomas', 'Disease', (146, 156))	('mutations', 'Var', (23, 32))	('carcinomas', 'Disease', 'MESH:D002277', (146, 156))	('NRAS', 'Gene', '4893', (133, 137))	('BRAF', 'Gene', (138, 142))
18182	31226844	Finally, we interrogated the cBioPortal database for the frequency of FBXW7 variants in CRC.	('FBXW7', 'Gene', '55294', (70, 75))	('variants', 'Var', (76, 84))	('CRC', 'Gene', (88, 91))	('FBXW7', 'Gene', (70, 75))
18183	31226844	Mutations in this gene are described in 12.5% of CRC patients and do not show correlation with survival.	('Mutations', 'Var', (0, 9))	('CRC', 'Disease', (49, 52))	('patients', 'Species', '9606', (53, 61))
18184	31226844	The frequency of FBXW7 variants is slightly higher in right-sided tumors (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('FBXW7', 'Gene', '55294', (17, 22))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('higher', 'Reg', (44, 50))	('FBXW7', 'Gene', (17, 22))	('variants', 'Var', (23, 31))
18185	31226844	These mutations also showed a slightly lower frequency in tumors that did not carry mutations in KRAS, NRAS, and BRAF genes (Table 1).	('BRAF', 'Gene', '673', (113, 117))	('NRAS', 'Gene', '4893', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('BRAF', 'Gene', (113, 117))	('KRAS', 'Gene', (97, 101))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('KRAS', 'Gene', '3845', (97, 101))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('NRAS', 'Gene', (103, 107))	('mutations', 'Var', (6, 15))
18189	31226844	Although we could analyze a limited number of patients for which tumor samples were available, we identified variants in several genes that might be potentially involved in the resistance to anti-EGFR agents.	('EGFR', 'Gene', (196, 200))	('patients', 'Species', '9606', (46, 54))	('tumor', 'Disease', (65, 70))	('involved', 'Reg', (161, 169))	('EGFR', 'Gene', '1956', (196, 200))	('variants', 'Var', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
18190	31226844	Among patients with the shorter PFS, we detected variants in genes that have been already associated with resistance to anti-EGFR MoAbs in CRC, such as KRAS, MAP2K1, and FBXW7, as well as in the new candidate gene NF1.	('variants', 'Var', (49, 57))	('EGFR', 'Gene', '1956', (125, 129))	('KRAS', 'Gene', (152, 156))	('NF1', 'Gene', '4763', (214, 217))	('NF1', 'Gene', (214, 217))	('associated', 'Reg', (90, 100))	('EGFR', 'Gene', (125, 129))	('KRAS', 'Gene', '3845', (152, 156))	('MAP2K1', 'Gene', '5604', (158, 164))	('patients', 'Species', '9606', (6, 14))	('resistance', 'MPA', (106, 116))	('FBXW7', 'Gene', '55294', (170, 175))	('MAP2K1', 'Gene', (158, 164))	('FBXW7', 'Gene', (170, 175))
18191	31226844	However, the mutations that we identified are mechanistically linked to EGFR-signaling, suggesting that they are good candidates as possible drivers of resistance to anti-EGFR agents.	('EGFR', 'Gene', (171, 175))	('EGFR', 'Gene', '1956', (72, 76))	('EGFR', 'Gene', (72, 76))	('EGFR', 'Gene', '1956', (171, 175))	('mutations', 'Var', (13, 22))
18192	31226844	In addition, data from public database suggest that FBXW7 and NF1 mutations are not associated with worse prognosis in CRC.	('mutations', 'Var', (66, 75))	('FBXW7', 'Gene', '55294', (52, 57))	('CRC', 'Disease', (119, 122))	('NF1', 'Gene', (62, 65))	('NF1', 'Gene', '4763', (62, 65))	('FBXW7', 'Gene', (52, 57))
18193	31226844	We found that a patient with KRAS p.Gln61 mutation at a very low allelic frequency in the tumor tissue and a liquid biopsy positive for the same KRAS variant had a quite short PFS.	('KRAS', 'Gene', (145, 149))	('KRAS', 'Gene', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('p.Gln61 mutation', 'Var', (34, 50))	('KRAS', 'Gene', '3845', (145, 149))	('KRAS', 'Gene', '3845', (29, 33))	('patient', 'Species', '9606', (16, 23))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
18194	31226844	Sub-clonal KRAS mutations have been reported to occur in CRC.	('KRAS', 'Gene', (11, 15))	('occur', 'Reg', (48, 53))	('KRAS', 'Gene', '3845', (11, 15))	('mutations', 'Var', (16, 25))	('CRC', 'Disease', (57, 60))
18195	31226844	KRAS variants at low allelic frequency are unlikely to determine resistance to anti-EGFR MoAbs in mCRC patients.	('EGFR', 'Gene', '1956', (84, 88))	('variants', 'Var', (5, 13))	('patients', 'Species', '9606', (103, 111))	('EGFR', 'Gene', (84, 88))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
18196	31226844	However, we and other groups described that some RAS wt mCRC patients with clinical resistance to anti-EGFR agents had a liquid biopsy positive for KRAS mutations and carried the same variant at very low allelic frequency in the primary tumor.	('KRAS', 'Gene', (148, 152))	('EGFR', 'Gene', '1956', (103, 107))	('tumor', 'Disease', (237, 242))	('mutations', 'Var', (153, 162))	('EGFR', 'Gene', (103, 107))	('patients', 'Species', '9606', (61, 69))	('KRAS', 'Gene', '3845', (148, 152))	('EGFR', 'molecular_function', 'GO:0005006', ('103', '107'))	('positive', 'Reg', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
18198	31226844	Therefore, we hypothesize that minor tumor clones carrying KRAS variants might be enriched during tumor progression in the metastatic sites, thus determining resistance to anti-EGFR MoAbs and positivity of liquid biopsy.	('KRAS', 'Gene', '3845', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('177', '181'))	('EGFR', 'Gene', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('resistance', 'MPA', (158, 168))	('EGFR', 'Gene', '1956', (177, 181))	('tumor', 'Disease', (98, 103))	('determining', 'Reg', (146, 157))	('KRAS', 'Gene', (59, 63))	('variants', 'Var', (64, 72))
18200	31226844	Mutations in p.Lys57 of MEK1 have been previously found to be associated with de novo and acquired resistance to anti-EGFR agents.	('associated', 'Reg', (62, 72))	('MEK1', 'Gene', '5604', (24, 28))	('EGFR', 'Gene', '1956', (118, 122))	('MEK1', 'Gene', (24, 28))	('EGFR', 'Gene', (118, 122))	('p.Lys57', 'Var', (13, 20))
18201	31226844	Mechanistically, these variants lead to constitutive activation of MEK1 and increased downstream signaling.	('MEK1', 'Gene', '5604', (67, 71))	('activation', 'PosReg', (53, 63))	('increased', 'PosReg', (76, 85))	('downstream signaling', 'MPA', (86, 106))	('MEK1', 'Gene', (67, 71))	('variants', 'Var', (23, 31))
18202	31226844	Although mutations in this site are quite rare in CRC, their identification might lead to a better identification of patients with primary resistance to anti-EGFR MoAbs.	('EGFR', 'Gene', (158, 162))	('mutations', 'Var', (9, 18))	('patients', 'Species', '9606', (117, 125))	('EGFR', 'Gene', '1956', (158, 162))	('EGFR', 'molecular_function', 'GO:0005006', ('158', '162'))
18203	31226844	In addition, combinations of anti-EGFR MoAbs, BRAF, and MEK inhibitors, that are highly active in patients with BRAF mutations, might be effective also in patients carrying MAP2K1 activating variants.	('BRAF', 'Gene', (46, 50))	('mutations', 'Var', (117, 126))	('BRAF', 'Gene', '673', (46, 50))	('combinations', 'Interaction', (13, 25))	('EGFR', 'Gene', (34, 38))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('activating', 'PosReg', (180, 190))	('patients', 'Species', '9606', (98, 106))	('MAP2K1', 'Gene', (173, 179))	('MEK', 'Gene', (56, 59))	('patients', 'Species', '9606', (155, 163))	('MEK', 'Gene', '5609', (56, 59))	('EGFR', 'Gene', '1956', (34, 38))	('MAP2K1', 'Gene', '5604', (173, 179))
18207	31226844	Variants in FBXW7 have been described in 6% to 10% of CRC.	('Variants', 'Var', (0, 8))	('FBXW7', 'Gene', (12, 17))	('CRC', 'Disease', (54, 57))	('FBXW7', 'Gene', '55294', (12, 17))	('described', 'Reg', (28, 37))
18208	31226844	In patients with mCRC, FBXW7 missense mutations are associated with PIK3CA mutations and with a shorter overall survival (OS).	('FBXW7', 'Gene', (23, 28))	('PIK3CA', 'Gene', (68, 74))	('shorter', 'NegReg', (96, 103))	('associated', 'Reg', (52, 62))	('PIK3CA', 'Gene', '5290', (68, 74))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (75, 84))	('FBXW7', 'Gene', '55294', (23, 28))	('overall survival', 'MPA', (104, 120))
18209	31226844	By using gene expression data, loss of FBXW7 was also correlated with a gene expression profile of RAS activation and resistance to anti-EGFR MoAbs in CRC.	('EGFR', 'Gene', (137, 141))	('FBXW7', 'Gene', (39, 44))	('RAS', 'Protein', (99, 102))	('gene expression', 'biological_process', 'GO:0010467', ('9', '24'))	('loss', 'Var', (31, 35))	('FBXW7', 'Gene', '55294', (39, 44))	('EGFR', 'Gene', '1956', (137, 141))	('activation', 'PosReg', (103, 113))	('EGFR', 'molecular_function', 'GO:0005006', ('137', '141'))	('gene expression', 'biological_process', 'GO:0010467', ('72', '87'))
18210	31226844	In agreement with these data, FBXW7 variants were identified in cases with resistance to anti-EGFR MoAbs in a retrospective study of 67 mCRC patients treated with different anti-EGFR MoAbs and chemotherapy regimens.	('FBXW7', 'Gene', '55294', (30, 35))	('EGFR', 'Gene', '1956', (178, 182))	('FBXW7', 'Gene', (30, 35))	('EGFR', 'Gene', '1956', (94, 98))	('EGFR', 'Gene', (178, 182))	('EGFR', 'Gene', (94, 98))	('variants', 'Var', (36, 44))	('patients', 'Species', '9606', (141, 149))
18211	31226844	Interestingly, in this study the majority of the FBXW7 mutations correlating with patients' outcome were in the WD40 domain, which is involved in FBXW7 binding to its substrates.	('mutations', 'Var', (55, 64))	('patients', 'Species', '9606', (82, 90))	('FBXW7', 'Gene', '55294', (146, 151))	('FBXW7', 'Gene', '55294', (49, 54))	('binding', 'molecular_function', 'GO:0005488', ('152', '159'))	('binding', 'Interaction', (152, 159))	('FBXW7', 'Gene', (146, 151))	('FBXW7', 'Gene', (49, 54))
18212	31226844	All the FBXW7 mutations identified in our study occurred in the WD40 domain.	('FBXW7', 'Gene', (8, 13))	('occurred', 'Reg', (48, 56))	('FBXW7', 'Gene', '55294', (8, 13))	('mutations', 'Var', (14, 23))
18213	31226844	A FBXW7 variant was found in our study in a patient with a good response to cetuximab-based therapy.	('variant', 'Var', (8, 15))	('patient', 'Species', '9606', (44, 51))	('cetuximab', 'Chemical', 'MESH:D000068818', (76, 85))	('FBXW7', 'Gene', (2, 7))	('FBXW7', 'Gene', '55294', (2, 7))
18214	31226844	The tumor of this patient carried also an amplification of GAS6, whose elevated expression has been previously associated with a favorable prognosis in CRC.	('tumor', 'Disease', (4, 9))	('CRC', 'Disease', (152, 155))	('GAS6', 'Gene', (59, 63))	('elevated', 'PosReg', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('patient', 'Species', '9606', (18, 25))	('GAS6', 'Gene', '2621', (59, 63))	('expression', 'MPA', (80, 90))	('amplification', 'Var', (42, 55))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('GAS', 'molecular_function', 'GO:0034005', ('59', '62'))
18216	31226844	Our data also point out to NF1 variants as a possible new biomarker of resistance to EGFR MoAbs.	('EGFR', 'Gene', (85, 89))	('EGFR', 'Gene', '1956', (85, 89))	('variants', 'Var', (31, 39))	('NF1', 'Gene', (27, 30))	('NF1', 'Gene', '4763', (27, 30))
18217	31226844	NF1 mutations are reported in 4.9% of KRAS/NRAS/BRAF wt CRC in the cBioPortal database (Table 1).	('KRAS', 'Gene', '3845', (38, 42))	('NRAS', 'Gene', '4893', (43, 47))	('NRAS', 'Gene', (43, 47))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('NF1', 'Gene', '4763', (0, 3))	('KRAS', 'Gene', (38, 42))
18218	31226844	Interestingly, both variants identified in our study have not been previously described, underlying the need to use technologies that cover the full-length gene for the analysis of NF1 mutations.	('mutations', 'Var', (185, 194))	('NF1', 'Gene', '4763', (181, 184))	('NF1', 'Gene', (181, 184))
18219	31226844	In a recent study of cetuximab-based therapy in a small cohort of Chinese mCRC patients (n. 33), the presence of NF1 mutations was associated with the shortest PFS.	('cetuximab', 'Chemical', 'MESH:D000068818', (21, 30))	('mutations', 'Var', (117, 126))	('NF1', 'Gene', (113, 116))	('NF1', 'Gene', '4763', (113, 116))	('patients', 'Species', '9606', (79, 87))
18222	31226844	We observed that a patient with ERBB2 copy number gain had a very good response to first line cetuximab-based therapy.	('ERBB2', 'Gene', (32, 37))	('patient', 'Species', '9606', (19, 26))	('ERBB2', 'Gene', '2064', (32, 37))	('cetuximab', 'Chemical', 'MESH:D000068818', (94, 103))	('copy number', 'Var', (38, 49))	('gain', 'PosReg', (50, 54))
18225	31226844	Previous studies have shown activity of anti-EGFR agents in CRC patients with partial ERBB2 amplification.	('EGFR', 'Gene', (45, 49))	('partial', 'Var', (78, 85))	('activity', 'MPA', (28, 36))	('patients', 'Species', '9606', (64, 72))	('CRC', 'Disease', (60, 63))	('ERBB2', 'Gene', '2064', (86, 91))	('ERBB2', 'Gene', (86, 91))	('EGFR', 'Gene', '1956', (45, 49))
18236	31226844	In fact, CNVs are more frequent in tumors related to the chromosomal instability pathway that have been suggested to be more sensitive to anti-EGFR agents.	('EGFR', 'Gene', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('frequent', 'Reg', (23, 31))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('CNVs', 'Var', (9, 13))	('chromosomal instability pathway', 'Pathway', (57, 88))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('EGFR', 'Gene', '1956', (143, 147))	('chromosomal instability', 'Phenotype', 'HP:0040012', (57, 80))
18243	31226844	In the first-line treatment, about 600 patients were screened for KRAS mutations to identify 340 eligible patients.	('patients', 'Species', '9606', (39, 47))	('KRAS', 'Gene', '3845', (66, 70))	('mutations', 'Var', (71, 80))	('patients', 'Species', '9606', (106, 114))	('KRAS', 'Gene', (66, 70))
18251	31226844	Further studies are required to confirm the role of the identified genetic alterations as biomarkers predictive of response to anti-EGFR MoAbs.	('EGFR', 'molecular_function', 'GO:0005006', ('132', '136'))	('genetic alterations', 'Var', (67, 86))	('EGFR', 'Gene', '1956', (132, 136))	('EGFR', 'Gene', (132, 136))
18253	31226844	; Analysis of tumor samples: A.M.R., M.L., F.F., C.R., A.I.	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', (14, 19))	('C.R.', 'Var', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
18340	30828825	Comparing patients with no neoplasia and high grade neoplasia, ions probably arising from hydrogen sulphide, dimethyl sulphide and dimethyl disulphide were significantly higher in samples from high risk compared to low risk subjects.	('dimethyl sulphide', 'Chemical', 'MESH:C004784', (109, 126))	('higher', 'PosReg', (170, 176))	('neoplasia', 'Disease', (27, 36))	('dimethyl', 'Var', (131, 139))	('neoplasia', 'Disease', 'MESH:D009369', (52, 61))	('neoplasia', 'Disease', 'MESH:D009369', (27, 36))	('neoplasia', 'Phenotype', 'HP:0002664', (27, 36))	('neoplasia', 'Phenotype', 'HP:0002664', (52, 61))	('dimethyl disulphide', 'Chemical', '-', (131, 150))	('hydrogen sulphide', 'Chemical', 'MESH:D006862', (90, 107))	('patients', 'Species', '9606', (10, 18))	('ions', 'MPA', (63, 67))	('dimethyl sulphide', 'MPA', (109, 126))	('neoplasia', 'Disease', (52, 61))
18503	29346117	To understand the molecular mechanism of FBW7 regulation in these cancers, we employed proteomics and identified the deubiquitinase (DUB) USP9X as an FBW7 interactor.	('interactor', 'Interaction', (155, 165))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('USP9X', 'Var', (138, 143))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
18506	29346117	In addition, Usp9x inactivation impaired intestinal regeneration and increased tumor burden in colitis-associated intestinal cancer.	('Usp9x', 'Gene', '22284', (13, 18))	('increased', 'PosReg', (69, 78))	('tumor', 'Disease', (79, 84))	('colitis', 'Phenotype', 'HP:0002583', (95, 102))	('impaired', 'NegReg', (32, 40))	('colitis-associated intestinal cancer', 'Disease', 'MESH:D007414', (95, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('intestinal regeneration', 'CPA', (41, 64))	('Usp9x', 'Gene', (13, 18))	('colitis-associated intestinal cancer', 'Disease', (95, 131))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('inactivation', 'Var', (19, 31))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
18507	29346117	c-Myc heterozygosity abrogated increased progenitor proliferation and tumor burden in Usp9x-deficient mice, suggesting that Usp9x suppresses tumor formation by regulating Fbw7 protein stability and thereby reducing c-Myc.	('Usp9x', 'Gene', (124, 129))	('Fbw7', 'Gene', (171, 175))	('mice', 'Species', '10090', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('regulating', 'Reg', (160, 170))	('suppresses', 'NegReg', (130, 140))	('protein', 'Protein', (176, 183))	('heterozygosity', 'Var', (6, 20))	('c-Myc', 'MPA', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('reducing', 'NegReg', (206, 214))	('Usp9x', 'Gene', '22284', (86, 91))	('progenitor proliferation', 'CPA', (41, 65))	('stability', 'MPA', (184, 193))	('abrogated', 'NegReg', (21, 30))	('Usp9x', 'Gene', '22284', (124, 129))	('Usp9x', 'Gene', (86, 91))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
18508	29346117	Thus, we identify a tumor suppressor mechanism in the mammalian intestine that arises from the posttranslational regulation of FBW7 by USP9X independent of somatic FBW7 mutations.	('mammalian', 'Species', '9606', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('FBW7', 'Gene', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('USP9X', 'Var', (135, 140))	('tumor', 'Disease', (20, 25))
18512	29346117	The importance of Wnt signaling in gut homeostasis is highlighted by the recurring mutations of the adenomatous polyposis coli (APC) gene, encoding a negative regulator of Wnt signaling, in human colorectal cancers (CRCs).	('mutations', 'Var', (83, 92))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('colorectal cancers', 'Disease', 'MESH:D015179', (196, 214))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (100, 126))	('APC', 'cellular_component', 'GO:0005680', ('128', '131'))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (100, 126))	('signaling', 'biological_process', 'GO:0023052', ('22', '31'))	('signaling', 'biological_process', 'GO:0023052', ('176', '185'))	('colorectal cancers', 'Disease', (196, 214))	('adenomatous polyposis coli', 'Disease', (100, 126))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('human', 'Species', '9606', (190, 195))	('homeostasis', 'biological_process', 'GO:0042592', ('39', '50'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (196, 213))
18514	29346117	Mutant APC fails to target beta-catenin for proteasomal degradation and thus results in increased downstream Wnt signaling, including increased c-Myc expression.	('downstream Wnt signaling', 'MPA', (98, 122))	('beta-catenin', 'Gene', '12387', (27, 39))	('increased', 'PosReg', (88, 97))	('c-Myc expression', 'MPA', (144, 160))	('Mutant', 'Var', (0, 6))	('increased', 'PosReg', (134, 143))	('beta-catenin', 'Gene', (27, 39))
18516	29346117	In addition to somatic APC mutations, chronic inflammatory conditions including Crohn's disease and ulcerative colitis also predispose patients to CRC.	('mutations', 'Var', (27, 36))	('patients', 'Species', '9606', (135, 143))	('predispose', 'Reg', (124, 134))	("Crohn's disease", 'Phenotype', 'HP:0100280', (80, 95))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (100, 118))	('ulcerative colitis', 'Disease', 'MESH:D003093', (100, 118))	("Crohn's disease", 'Disease', 'MESH:D003424', (80, 95))	("Crohn's disease", 'Disease', (80, 95))	('CRC', 'Disease', (147, 150))	('colitis', 'Phenotype', 'HP:0002583', (111, 118))	('ulcerative colitis', 'Disease', (100, 118))	('APC', 'cellular_component', 'GO:0005680', ('23', '26'))
18517	29346117	Although mechanisms linking inflammatory colitis to CRC are incompletely understood, these cancers may also show activation of Wnt signaling, including activating beta-catenin mutations, or amplification of c-MYC.	('c-MYC', 'Gene', '4609', (207, 212))	('colitis', 'Disease', 'MESH:D003092', (41, 48))	('CRC', 'Disease', (52, 55))	('mutations', 'Var', (176, 185))	('amplification', 'Var', (190, 203))	('beta-catenin', 'Gene', (163, 175))	('colitis', 'Disease', (41, 48))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('Wnt signaling', 'Pathway', (127, 140))	('activation', 'PosReg', (113, 123))	('colitis', 'Phenotype', 'HP:0002583', (41, 48))	('c-MYC', 'Gene', (207, 212))	('beta-catenin', 'Gene', '12387', (163, 175))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('activating', 'PosReg', (152, 162))
18519	29346117	Consistent with this function, FBW7 is one of the most frequently mutated genes in human CRC, altered in approximately 10% of tumors, and Fbw7 inactivation accelerates tumorigenesis in Apcmin/+ mice.	('accelerates', 'PosReg', (156, 167))	('inactivation', 'Var', (143, 155))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Disease', (168, 173))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('human', 'Species', '9606', (83, 88))	('Fbw7', 'Gene', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('mice', 'Species', '10090', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Disease', (126, 131))
18522	29346117	Thus, deregulation of either ubiquitylation or deubiquitylation may result in cancer.	('deregulation', 'Var', (6, 18))	('result', 'Reg', (68, 74))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('deubiquitylation', 'MPA', (47, 63))	('ubiquitylation', 'MPA', (29, 43))
18527	29346117	Colitis-driven tumor formation was greatly accelerated in mice with intestine-specific deletion of Usp9x.	('Usp9x', 'Gene', '22284', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('Usp9x', 'Gene', (99, 104))	('accelerated', 'PosReg', (43, 54))	('mice', 'Species', '10090', (58, 62))	('Colitis', 'Disease', (0, 7))	('tumor', 'Disease', (15, 20))	('Usp', 'molecular_function', 'GO:0051748', ('99', '102'))	('formation', 'biological_process', 'GO:0009058', ('21', '30'))	('Colitis', 'Phenotype', 'HP:0002583', (0, 7))	('deletion', 'Var', (87, 95))	('Colitis', 'Disease', 'MESH:D003092', (0, 7))
18539	29346117	Conversely, multiple different shRNAs targeting USP9X caused a sharp decrease in endogenous FBW7, whereas RBX1 and SKP1 protein and FBW7 mRNA levels were unaffected (Figure 2, A and B).	('USP', 'molecular_function', 'GO:0051748', ('48', '51'))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('endogenous FBW7', 'MPA', (81, 96))	('RBX1', 'Gene', '56438', (106, 110))	('RBX1', 'Gene', (106, 110))	('SKP1', 'Gene', (115, 119))	('decrease', 'NegReg', (69, 77))	('USP9X', 'Var', (48, 53))	('SKP1', 'Gene', '21402', (115, 119))
18541	29346117	Indeed, levels of Flag-FBW7alpha and Flag-FBW7beta were restored by MG132 in USP9X-silenced cells (Figure 2C and Supplemental Figure 1C).	('levels', 'MPA', (8, 14))	('MG132', 'Var', (68, 73))	('USP', 'molecular_function', 'GO:0051748', ('77', '80'))	('MG132', 'Chemical', 'MESH:C072553', (68, 73))
18542	29346117	In addition, USP9X depletion resulted in a striking reduction in Flag-FBW7alpha protein stability, as judged by a cycloheximide time course experiment (Figure 2, D and E).	('depletion', 'Var', (19, 28))	('cycloheximide', 'Chemical', 'MESH:D003513', (114, 127))	('protein', 'Protein', (80, 87))	('USP9X depletion', 'Var', (13, 28))	('Flag-FBW7alpha', 'Gene', (65, 79))	('reduction', 'NegReg', (52, 61))
18544	29346117	FBW7 protein levels are regulated by proteasomal degradation, suggesting that FBW7alpha is polyubiquitylated via Lys48 (K48) linkage.	('Lys48', 'Chemical', '-', (113, 118))	('protein', 'cellular_component', 'GO:0003675', ('5', '12'))	('polyubiquitylated', 'MPA', (91, 108))	('Lys48 (K48) linkage', 'Var', (113, 132))	('degradation', 'biological_process', 'GO:0009056', ('49', '60'))	('FBW7alpha', 'Gene', (78, 87))
18545	29346117	To formally demonstrate this, we performed a ubiquitin chain restriction analysis (Ubi-CRest) using purified polyubiquitylated Flag-FBW7alpha as a substrate for K48- and K63-specific DUBs (OTUB1 and AMSH, respectively) and USP9X.	('AMSH', 'Gene', (199, 203))	('OTUB1', 'Gene', '107260', (189, 194))	('K63-specific', 'Var', (170, 182))	('OTUB1', 'Gene', (189, 194))	('AMSH', 'Gene', '70527', (199, 203))	('Flag-FBW7alpha', 'Gene', (127, 141))	('K48-', 'Var', (161, 165))
18547	29346117	In addition, only OTUB1 and USP9X, but not AMSH, cleaved conjugated ubiquitins off FBW7alpha, suggesting that the majority of polyubiquitylated FBW7alpha is linked via K48.	('conjugated ubiquitins', 'MPA', (57, 78))	('AMSH', 'Gene', '70527', (43, 47))	('linked', 'Interaction', (157, 163))	('polyubiquitylated', 'Var', (126, 143))	('OTUB1', 'Gene', '107260', (18, 23))	('OTUB1', 'Gene', (18, 23))	('AMSH', 'Gene', (43, 47))
18549	29346117	Additionally, mUsp9x expression greatly reduced ubiquitylation of Flag-FBW7alpha, whereas the catalytically dead mutant V5-C1566S slightly increased FBW7 ubiquitylation, perhaps indicating a dominant negative effect (Figure 2J).	('V5-C1566S', 'Var', (120, 129))	('C1566S', 'Mutation', 'p.C1566S', (123, 129))	('Usp9x', 'Gene', (15, 20))	('ubiquitylation', 'MPA', (154, 168))	('increased', 'PosReg', (139, 148))	('ubiquitylation', 'MPA', (48, 62))	('reduced', 'NegReg', (40, 47))	('Usp9x', 'Gene', '22284', (15, 20))	('Flag-FBW7alpha', 'Gene', (66, 80))
18551	29346117	Protein levels of USP28, another DUB previously reported to differentially regulate FBW7 stability, were unaffected by USP9X knockdown (Figure 3A).	('knockdown', 'Var', (125, 134))	('USP28', 'Gene', (18, 23))	('USP9X', 'Var', (119, 124))	('USP28', 'Gene', '235323', (18, 23))	('FBW7', 'Gene', (84, 88))	('Protein levels', 'MPA', (0, 14))
18553	29346117	In vitro deletion of Usp9x in MAFs resulted in a decrease in the level of Fbw7 protein and accumulation of SCF(Fbw7) substrates (Figure 3B).	('deletion', 'Var', (9, 17))	('Usp9x', 'Gene', '22284', (21, 26))	('Usp', 'molecular_function', 'GO:0051748', ('21', '24'))	('decrease', 'NegReg', (49, 57))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('level of Fbw7 protein', 'MPA', (65, 86))	('Usp9x', 'Gene', (21, 26))	('SCF', 'molecular_function', 'GO:0005173', ('107', '110'))	('accumulation', 'PosReg', (91, 103))
18555	29346117	In addition, shRNA-mediated ITCH knockdown, unlike USP9X knockdown, did not result in stabilization of SCF(FBW7) substrates (Figure 3C).	('ITCH', 'Phenotype', 'HP:0000989', (28, 32))	('knockdown', 'Var', (33, 42))	('stabilization', 'MPA', (86, 99))	('ITCH', 'Gene', (28, 32))	('ITCH', 'Gene', '16396', (28, 32))
18556	29346117	To confirm the relevance of FBW7 in the regulation of SCF(FBW7) substrates by USP9X, we knocked down USP9X using 2 different shRNAs in HCT116-FBW7+/+ and HCT116-FBW7Delta/Delta cells.	('HCT116', 'CellLine', 'CVCL:0291', (154, 160))	('USP', 'molecular_function', 'GO:0051748', ('101', '104'))	('regulation', 'biological_process', 'GO:0065007', ('40', '50'))	('SCF', 'molecular_function', 'GO:0005173', ('54', '57'))	('knocked', 'Var', (88, 95))	('USP', 'molecular_function', 'GO:0051748', ('78', '81'))	('USP9X', 'Gene', (101, 106))	('HCT116', 'CellLine', 'CVCL:0291', (135, 141))
18557	29346117	Whereas USP9X knockdown increased NICD1, cyclin E, c-MYC, and c-JUN protein levels in HCT116-FBW7+/+ cells, in HCT116-FBW7Delta/Delta cells the protein levels of these substrates were already increased and were not further affected by USP9X knockdown (Figure 3D).	('c-MYC', 'Gene', (51, 56))	('c-JUN protein levels', 'MPA', (62, 82))	('NICD1', 'MPA', (34, 39))	('cyclin E', 'MPA', (41, 49))	('c-MYC', 'Gene', '4609', (51, 56))	('HCT116', 'CellLine', 'CVCL:0291', (111, 117))	('HCT116', 'CellLine', 'CVCL:0291', (86, 92))	('knockdown', 'Var', (14, 23))	('USP9X', 'Gene', (8, 13))	('increased', 'PosReg', (24, 33))	('increased', 'PosReg', (192, 201))
18558	29346117	Consistent with the notion that USP9X negatively regulates c-MYC protein stability, c-MYC ubiquitylation was reduced in USP9X-knockdown cells, with no effect on its mRNA (Figure 3, E and F).	('c-MYC', 'Gene', '4609', (84, 89))	('c-MYC', 'Gene', (59, 64))	('USP', 'molecular_function', 'GO:0051748', ('120', '123'))	('c-MYC', 'Gene', (84, 89))	('c-MYC', 'Gene', '4609', (59, 64))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('reduced', 'NegReg', (109, 116))	('USP9X-knockdown', 'Var', (120, 135))	('USP', 'molecular_function', 'GO:0051748', ('32', '35'))
18559	29346117	In agreement with these findings, USP9X silencing using 2 different siRNAs increased c-MYC transcriptional activity in HCT116-FBW7+/+ but not in HCT116-FBW7Delta/Delta cells, as indicated by a dual luciferase c-MYC reporter assay (Figure 3G).	('HCT116', 'CellLine', 'CVCL:0291', (119, 125))	('c-MYC', 'Gene', '4609', (85, 90))	('c-MYC', 'Gene', '4609', (209, 214))	('HCT116-FBW7+/+', 'Var', (119, 133))	('silencing', 'NegReg', (40, 49))	('HCT116', 'CellLine', 'CVCL:0291', (145, 151))	('increased', 'PosReg', (75, 84))	('c-MYC', 'Gene', (85, 90))	('c-MYC', 'Gene', (209, 214))
18560	29346117	Thus, USP9X negatively regulates c-MYC activity via direct stabilization of FBW7.	('regulates', 'Reg', (23, 32))	('FBW7', 'Gene', (76, 80))	('USP9X', 'Var', (6, 11))	('c-MYC', 'Gene', (33, 38))	('negatively', 'NegReg', (12, 22))	('stabilization', 'Reg', (59, 72))	('c-MYC', 'Gene', '4609', (33, 38))
18569	29346117	Deletion of one c-Myc, but not one c-Jun allele, was sufficient to reduce TA cell numbers to WT levels, whereas neither c-Myc nor c-Jun heterozygosity had any effect on the goblet cell numbers in Usp9xDeltaG intestine (Figure 4F and Supplemental Figure 5A).	('reduce', 'NegReg', (67, 73))	('c-Jun', 'Gene', (35, 40))	('Usp9x', 'Gene', '22284', (196, 201))	('c-Jun', 'Gene', '16476', (130, 135))	('c-Myc', 'Gene', (16, 21))	('c-Jun', 'Gene', '16476', (35, 40))	('c-Jun', 'Gene', (130, 135))	('Usp9x', 'Gene', (196, 201))	('TA cell numbers', 'MPA', (74, 89))	('goblet cell numbers', 'CPA', (173, 192))	('Deletion', 'Var', (0, 8))
18584	29346117	Both the Usp9xDeltaG and Fbw7DeltaG/+ mice showed reduced body weight throughout the experimental period, suggestive of a more advanced disease (Supplemental Figure 6, A and B).	('mice', 'Species', '10090', (38, 42))	('Fbw7DeltaG/+', 'Var', (25, 37))	('body weight', 'CPA', (58, 69))	('reduced body weight', 'Phenotype', 'HP:0004325', (50, 69))	('Usp', 'molecular_function', 'GO:0051748', ('9', '12'))	('Usp9x', 'Gene', '22284', (9, 14))	('reduced', 'NegReg', (50, 57))	('Usp9x', 'Gene', (9, 14))
18587	29346117	Indeed, c-Myc heterozygosity was sufficient to reduce the tumor burden to WT levels in Usp9xDeltaG mice, with a clear reduction of c-Myc staining in c-MycDeltaG/+ Usp9xDeltaG tumors (Figure 6, F and G).	('Usp9x', 'Gene', (163, 168))	('tumors', 'Disease', (175, 181))	('reduce', 'NegReg', (47, 53))	('reduction', 'NegReg', (118, 127))	('Usp9x', 'Gene', '22284', (87, 92))	('heterozygosity', 'Var', (14, 28))	('c-Myc heterozygosity', 'Var', (8, 28))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('Usp9x', 'Gene', (87, 92))	('mice', 'Species', '10090', (99, 103))	('tumor', 'Disease', (175, 180))	('c-Myc staining', 'MPA', (131, 145))	('Usp9x', 'Gene', '22284', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
18588	29346117	Thus, negative regulation of c-Myc by Usp9x via direct stabilization of Fbw7 protects mice from colitis-mediated CRC.	('colitis', 'Disease', 'MESH:D003092', (96, 103))	('regulation', 'biological_process', 'GO:0065007', ('15', '25'))	('colitis', 'Disease', (96, 103))	('Usp9x', 'Gene', '22284', (38, 43))	('negative regulation', 'NegReg', (6, 25))	('mice', 'Species', '10090', (86, 90))	('c-Myc', 'Protein', (29, 34))	('Fbw7', 'Gene', (72, 76))	('colitis', 'Phenotype', 'HP:0002583', (96, 103))	('Usp9x', 'Gene', (38, 43))	('Usp', 'molecular_function', 'GO:0051748', ('38', '41'))	('stabilization', 'Var', (55, 68))
18589	29346117	To test the relationship between USP9X and FBW7 in human cancers, we stained serial sections of human colon cancer TMAs for USP9X and FBW7 (Figure 7A).	('USP', 'molecular_function', 'GO:0051748', ('124', '127'))	('TMA', 'Chemical', '-', (115, 118))	('human', 'Species', '9606', (96, 101))	('colon cancer', 'Phenotype', 'HP:0003003', (102, 114))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('human', 'Species', '9606', (51, 56))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('colon cancer', 'Disease', 'MESH:D015179', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('colon cancer', 'Disease', (102, 114))	('FBW7', 'Gene', (134, 138))	('USP9X', 'Var', (124, 129))	('USP', 'molecular_function', 'GO:0051748', ('33', '36'))
18590	29346117	In CRC tumor tissue, USP9X and FBW7 showed a strong correlation in staining intensity, with 72% showing concomitant downregulation (Figure 7A, case 1, and Figure 7B).	('USP', 'molecular_function', 'GO:0051748', ('21', '24'))	('FBW7', 'Gene', (31, 35))	('CRC tumor', 'Disease', (3, 12))	('downregulation', 'NegReg', (116, 130))	('CRC tumor', 'Disease', 'MESH:D015179', (3, 12))	('staining intensity', 'MPA', (67, 85))	('USP9X', 'Var', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
18593	29346117	Moreover, USP9X was mutated in a small percentage of CRC patients.	('patients', 'Species', '9606', (57, 65))	('CRC', 'Disease', (53, 56))	('USP9X', 'Var', (10, 15))
18594	29346117	Interestingly, concurrent FBW7 mutations predominantly occurred in females (Fisher's exact test, P = 0.01) and not in males (P = 1) (Figure 7E), suggesting that incomplete USP9X inactivation caused by random X inactivation in females may favor a second genetic mutation in the FBW7 gene to fully inactivate the function of the USP9X-FBW7 axis.	('function', 'MPA', (311, 319))	('USP', 'molecular_function', 'GO:0051748', ('327', '330'))	('USP', 'molecular_function', 'GO:0051748', ('172', '175'))	('P = 1', 'Gene', '22673', (125, 130))	('USP9X-FBW7', 'Gene', '22284;50754', (327, 337))	('FBW7', 'Gene', (277, 281))	('inactivation', 'NegReg', (178, 190))	('inactivate', 'NegReg', (296, 306))	('USP9X', 'Var', (172, 177))	('P = 1', 'Gene', (125, 130))	('USP9X-FBW7', 'Gene', (327, 337))
18595	29346117	Taken together, these data support the notion that USP9X acts as a tumor suppressor in the intestine via positive regulation of FBW7.	('FBW7', 'Gene', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('positive regulation', 'PosReg', (105, 124))	('tumor', 'Disease', (67, 72))	('USP9X', 'Var', (51, 56))
18599	29346117	Thus, USP9X functions indirectly as a tumor suppressor, by controlling the protein stability of FBW7.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('USP', 'molecular_function', 'GO:0051748', ('6', '9'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('38', '54'))	('USP9X', 'Var', (6, 11))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('controlling', 'Reg', (59, 70))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('protein stability', 'MPA', (75, 92))	('tumor suppressor', 'biological_process', 'GO:0051726', ('38', '54'))	('FBW7', 'Gene', (96, 100))
18600	29346117	USP9X can have both pro- and antitumorigenic functions depending on tumor type.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('USP9X', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
18602	29346117	Our data demonstrate that in addition to the pancreas, USP9X is also a tumor suppressor in the intestine.	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('USP9X', 'Var', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
18603	29346117	Although the E3 ligase Itch was shown to mediate the antitumor effects of USP9X in the pancreas, our data demonstrate that USP9X can prevent intestinal cancer by directly regulating the stability of FBW7 protein.	('regulating', 'Reg', (171, 181))	('prevent', 'NegReg', (133, 140))	('intestinal cancer', 'Disease', (141, 158))	('USP9X', 'Var', (123, 128))	('Itch', 'Phenotype', 'HP:0000989', (23, 27))	('FBW7 protein', 'Protein', (199, 211))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('stability', 'MPA', (186, 195))	('protein', 'cellular_component', 'GO:0003675', ('204', '211'))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Itch', 'Gene', '16396', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('USP', 'molecular_function', 'GO:0051748', ('74', '77'))	('tumor', 'Disease', (57, 62))	('USP', 'molecular_function', 'GO:0051748', ('123', '126'))	('intestinal cancer', 'Disease', 'MESH:D007414', (141, 158))	('Itch', 'Gene', (23, 27))
18606	29346117	As in Fbw7DeltaG intestine, c-Myc and Notch1 appear to be the main mediators of the Usp9xDeltaG phenotypes.	('Usp9x', 'Gene', (84, 89))	('Notch1', 'Gene', (38, 44))	('Notch1', 'Gene', '18128', (38, 44))	('Usp', 'molecular_function', 'GO:0051748', ('84', '87'))	('Fbw7DeltaG', 'Var', (6, 16))	('Usp9x', 'Gene', '22284', (84, 89))
18607	29346117	The positive regulation of FBW7 by USP9X reinforces the importance of protein turnover and regulation in tissue homeostasis and cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('positive regulation', 'PosReg', (4, 23))	('USP', 'molecular_function', 'GO:0051748', ('35', '38'))	('tissue homeostasis', 'biological_process', 'GO:0001894', ('105', '123'))	('regulation', 'biological_process', 'GO:0065007', ('91', '101'))	('protein', 'cellular_component', 'GO:0003675', ('70', '77'))	('regulation', 'biological_process', 'GO:0065007', ('13', '23'))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('USP9X', 'Var', (35, 40))	('FBW7', 'Gene', (27, 31))	('cancer', 'Disease', (128, 134))
18613	29346117	Importantly, the regulation of FBW7 by USP9X has implications in human intestinal cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('human', 'Species', '9606', (65, 70))	('FBW7', 'Gene', (31, 35))	('intestinal cancer', 'Disease', 'MESH:D007414', (71, 88))	('intestinal cancer', 'Disease', (71, 88))	('USP9X', 'Var', (39, 44))	('implications', 'Reg', (49, 61))
18615	29346117	In these patients FBW7 function appears to be compromised regardless of FBW7 mutations.	('function', 'MPA', (23, 31))	('patients', 'Species', '9606', (9, 17))	('FBW7', 'Gene', (72, 76))	('mutations', 'Var', (77, 86))	('FBW7', 'Gene', (18, 22))
18616	29346117	Of 56 patients with low FBW7 IHC staining, 49 had low USP9X protein levels (Figure 7B).	('low', 'NegReg', (50, 53))	('USP9X protein levels', 'MPA', (54, 74))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('USP', 'molecular_function', 'GO:0051748', ('54', '57'))	('patients', 'Species', '9606', (6, 14))	('low', 'Var', (20, 23))	('FBW7', 'Gene', (24, 28))
18617	29346117	The strong and direct correlation between USP9X and FBW7 in human CRC, together with our biochemical characterization of FBW7 as a USP9X substrate, strongly suggests a causal role for USP9X loss in intestinal tumorigenesis.	('FBW7', 'Gene', (52, 56))	('tumor', 'Disease', (209, 214))	('loss', 'NegReg', (190, 194))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('USP9X', 'Var', (184, 189))	('human', 'Species', '9606', (60, 65))
18618	29346117	Consistent with this idea, we found that low USP9X expression was strongly associated with poor survival in colon cancer (Figure 7D).	('colon cancer', 'Disease', (108, 120))	('colon cancer', 'Phenotype', 'HP:0003003', (108, 120))	('poor', 'NegReg', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('colon cancer', 'Disease', 'MESH:D015179', (108, 120))	('low USP9X expression', 'Var', (41, 61))
18619	29346117	One plausible explanation for this apparent sex bias is the presence of tumor suppressor genes on the X chromosome that protect females from the effects of loss-of-function mutations.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor suppressor', 'biological_process', 'GO:0051726', ('72', '88'))	('tumor', 'Disease', (72, 77))	('X chromosome', 'cellular_component', 'GO:0000805', ('102', '114'))	('mutations', 'Var', (173, 182))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('72', '88'))	('loss-of-function', 'NegReg', (156, 172))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
18620	29346117	In agreement with this idea, we find that a significant percentage of female, but not male, colon cancer patients with USP9X mutations carry a concomitant FBW7 mutation (Figure 7E).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (125, 134))	('mutation', 'Var', (160, 168))	('patients', 'Species', '9606', (105, 113))	('FBW7', 'Gene', (155, 159))	('USP9X', 'Gene', (119, 124))	('colon cancer', 'Disease', 'MESH:D015179', (92, 104))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('colon cancer', 'Disease', (92, 104))	('USP', 'molecular_function', 'GO:0051748', ('119', '122'))
18622	29346117	Thus, USP9X is a crucial regulator of FBW7 protein levels and function, and the degradation of FBW7 in the absence of USP9X is a mechanism of tumor promotion.	('USP', 'molecular_function', 'GO:0051748', ('6', '9'))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('degradation', 'MPA', (80, 91))	('tumor', 'Disease', (142, 147))	('FBW7', 'Gene', (95, 99))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('USP', 'molecular_function', 'GO:0051748', ('118', '121'))	('degradation', 'biological_process', 'GO:0009056', ('80', '91'))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('absence', 'Var', (107, 114))
18632	29346117	HEK293, HCT116-FBW7+/+ and HCT116-FBW7Delta/Delta, COL205, HT29, HCT115, SW620, SW480, SW837, and SNUC1 cell lines were obtained from Cell Services at the Francis Crick Institute.	('HCT116-FBW7+/+', 'Var', (8, 22))	('SW837', 'CellLine', 'CVCL:1729', (87, 92))	('HCT116', 'CellLine', 'CVCL:0291', (27, 33))	('SNUC1', 'CellLine', 'CVCL:1708', (98, 103))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('SW480', 'CellLine', 'CVCL:0546', (80, 85))	('HCT116-FBW7Delta/Delta', 'Var', (27, 49))	('HT29', 'CellLine', 'CVCL:0320', (59, 63))	('SW620', 'CellLine', 'CVCL:0547', (73, 78))	('HCT116', 'CellLine', 'CVCL:0291', (8, 14))
18635	29346117	In HEK293 cells, 6x-His-ubiquitin was overexpressed along with Flag-FBW7 and a control or USP9X-specific shRNA (shU9 #3+4).	('overexpressed', 'PosReg', (38, 51))	('6x-His', 'Chemical', '-', (17, 23))	('HEK293', 'CellLine', 'CVCL:0045', (3, 9))	('6x-His-ubiquitin', 'Var', (17, 33))
18664	29346117	Data for 831 exome-sequenced colorectal adenocarcinoma patient samples with corresponding sex information were downloaded from cBioPortal to test for co-occurrence of USP9X and FBW7 mutations using a Fisher's exact test.	('USP9X', 'Gene', (167, 172))	('FBW7', 'Gene', (177, 181))	('test', 'Reg', (141, 145))	('colorectal adenocarcinoma', 'Disease', (29, 54))	('patient', 'Species', '9606', (55, 62))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (29, 54))	('mutations', 'Var', (182, 191))
18727	28373923	Laboratory tests showed anemia, malnutrition, and elevated levels of tumor markers (CEA: 74.2 ng/mL, CA19-9: 43.4 U/mL, and CA-125: 1037.4 U/mL).	('malnutrition', 'Disease', 'MESH:D044342', (32, 44))	('anemia', 'Phenotype', 'HP:0001903', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('malnutrition', 'Phenotype', 'HP:0004395', (32, 44))	('CA19-9', 'Var', (101, 107))	('elevated', 'PosReg', (50, 58))	('tumor', 'Disease', (69, 74))	('levels of', 'MPA', (59, 68))	('CEA', 'Gene', (84, 87))	('anemia', 'Disease', (24, 30))	('CA19-9', 'Chemical', 'MESH:C086528', (101, 107))	('CEA', 'Gene', '1084', (84, 87))	('anemia', 'Disease', 'MESH:D000740', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('malnutrition', 'Disease', (32, 44))
18740	28373923	Taken together with the previous reports, the present cases indicate that a rupture of surface layer of the ovary, such as ovulation and heterotopic endometriosis, triggers ovarian metastasis from colorectal cancer associated with peritoneal dissemination.	('colorectal cancer', 'Disease', (197, 214))	('ovulation', 'biological_process', 'GO:0030728', ('123', '132'))	('colorectal cancer', 'Disease', 'MESH:D015179', (197, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('heterotopic endometriosis', 'Disease', (137, 162))	('heterotopic endometriosis', 'Disease', 'MESH:D004715', (137, 162))	('ovarian metastasis', 'Disease', (173, 191))	('rectal cancer', 'Phenotype', 'HP:0100743', (201, 214))	('triggers', 'Reg', (164, 172))	('colorectal cancer', 'Phenotype', 'HP:0003003', (197, 214))	('endometriosis', 'Phenotype', 'HP:0030127', (149, 162))	('rupture', 'Var', (76, 83))	('ovarian metastasis', 'Disease', 'MESH:D009362', (173, 191))
18767	27058412	The knockdown of Cat S significantly suppressed the migration and invasion of GC cells.	('C', 'Chemical', 'MESH:D002244', (17, 18))	('Cat S', 'Gene', (17, 22))	('knockdown', 'Var', (4, 13))	('Cat S', 'Gene', '1520', (17, 22))	('GC', 'Phenotype', 'HP:0012126', (78, 80))	('C', 'Chemical', 'MESH:D002244', (79, 80))	('suppressed', 'NegReg', (37, 47))
18771	27058412	Serum biomarkers, for example, CEA, CA72-4, CA19-9, lack sufficient sensitivity and specificity.	('CA72-4', 'Chemical', '-', (36, 42))	('CEA', 'Gene', '1084', (31, 34))	('CA19-9', 'Var', (44, 50))	('CA19-9', 'Chemical', 'MESH:C086528', (44, 50))	('CA72-4', 'Var', (36, 42))	('CEA', 'Gene', (31, 34))
18786	27058412	High Cat L expression has been found in gastrointestinal stromal tumors.	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (40, 71))	('Cat L', 'Gene', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('gastrointestinal stromal tumors', 'Disease', (40, 71))	('Cat L', 'Gene', '1514', (5, 10))	('found', 'Reg', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (40, 71))
18803	27058412	In contrast, the AUCs of the traditional biomarkers of CEA, CA724 and CA199 were 0.626, 0.575, and 0.564, respectively.	('CEA', 'Gene', (55, 58))	('CEA', 'Gene', '1084', (55, 58))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('CA724', 'Chemical', '-', (60, 65))	('C', 'Chemical', 'MESH:D002244', (55, 56))	('C', 'Chemical', 'MESH:D002244', (19, 20))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('CA199', 'Var', (70, 75))	('CA199', 'Chemical', '-', (70, 75))
18805	27058412	The combination of Cat S, CEA, CA724 and CA199 resulted in a better AUC of 0.851 with a specificity of 91.2% and a sensitivity of 72.6% (Figure 2A).	('C', 'Chemical', 'MESH:D002244', (31, 32))	('CA199', 'Chemical', '-', (41, 46))	('C', 'Chemical', 'MESH:D002244', (41, 42))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('CA724', 'Var', (31, 36))	('Cat S', 'Gene', '1520', (19, 24))	('CEA', 'Gene', (26, 29))	('AUC', 'MPA', (68, 71))	('C', 'Chemical', 'MESH:D002244', (19, 20))	('C', 'Chemical', 'MESH:D002244', (26, 27))	('CEA', 'Gene', '1084', (26, 29))	('CA724', 'Chemical', '-', (31, 36))	('CA199', 'Var', (41, 46))	('Cat S', 'Gene', (19, 24))
18837	27058412	The knockdown of Cat S clearly reduced both the migration ability and the invasive nature of the GC cells and even elicited significant reductions compared to the wild-type Cat S cells (Figure 5C and 5D).	('C', 'Chemical', 'MESH:D002244', (17, 18))	('reduced', 'NegReg', (31, 38))	('C', 'Chemical', 'MESH:D002244', (194, 195))	('Cat S', 'Gene', (173, 178))	('Cat S', 'Gene', (17, 22))	('Cat S', 'Gene', '1520', (173, 178))	('invasive nature of the GC cells', 'CPA', (74, 105))	('reductions', 'NegReg', (136, 146))	('C', 'Chemical', 'MESH:D002244', (173, 174))	('migration ability', 'CPA', (48, 65))	('C', 'Chemical', 'MESH:D002244', (98, 99))	('GC', 'Phenotype', 'HP:0012126', (97, 99))	('knockdown', 'Var', (4, 13))	('Cat S', 'Gene', '1520', (17, 22))
18882	27058412	In summary, we observed high levels of expression of Cat S in GC, and the knockdown Cat S suppressed GC cell migration and invasion.	('Cat S', 'Gene', (53, 58))	('Cat', 'molecular_function', 'GO:0004096', ('84', '87'))	('GC', 'Phenotype', 'HP:0012126', (62, 64))	('Cat S', 'Gene', '1520', (84, 89))	('Cat S', 'Gene', '1520', (53, 58))	('knockdown', 'Var', (74, 83))	('C', 'Chemical', 'MESH:D002244', (84, 85))	('cell migration', 'biological_process', 'GO:0016477', ('104', '118'))	('GC', 'Phenotype', 'HP:0012126', (101, 103))	('Cat', 'molecular_function', 'GO:0004096', ('53', '56'))	('C', 'Chemical', 'MESH:D002244', (53, 54))	('C', 'Chemical', 'MESH:D002244', (102, 103))	('suppressed', 'NegReg', (90, 100))	('Cat S', 'Gene', (84, 89))	('C', 'Chemical', 'MESH:D002244', (63, 64))
18905	27058412	After being blocked with 5% non-fat dry milk in PBS containing 0.05% Tween-20, the blotted membranes were incubated with anti-human Cat S antibody (sc74429, Santa Cruz; 1:100) and then secondary antibody (1:5000, Boster, China).	('human', 'Species', '9606', (126, 131))	('PBS', 'Disease', (48, 51))	('sc74429', 'Var', (148, 155))	('C', 'Chemical', 'MESH:D002244', (221, 222))	('Cat S', 'Gene', '1520', (132, 137))	('C', 'Chemical', 'MESH:D002244', (163, 164))	('Tween-20', 'Chemical', 'MESH:D011136', (69, 77))	('C', 'Chemical', 'MESH:D002244', (132, 133))	('Cat S', 'Gene', (132, 137))	('PBS', 'Disease', 'MESH:D011535', (48, 51))
18931	25788983	CENP-A nucleosomes localize to transcription factor hotspots and subtelomeric sites in human cancer cells The histone H3 variant CENP-A is normally tightly regulated to ensure only one centromere exists per chromosome.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('CENP-A', 'Gene', (129, 135))	('variant', 'Var', (121, 128))	('CENP-A', 'Gene', (0, 6))	('H3', 'Chemical', 'MESH:C012616', (118, 120))	('human', 'Species', '9606', (87, 92))	('CENP-A', 'Gene', '1058', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('CENP-A', 'Gene', '1058', (0, 6))
18933	25788983	Consequently, CENP-A misregulation is thought to contribute to genome instability in human cancers.	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('misregulation', 'Var', (21, 34))	('genome instability', 'MPA', (63, 81))	('contribute', 'Reg', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('human', 'Species', '9606', (85, 90))
18940	25788983	We show this 8q24 accumulation of CENP-A can also be seen in early stage primary colorectal tumors.	('CENP-A', 'Gene', (34, 40))	('accumulation', 'PosReg', (18, 30))	('8q24', 'Var', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('colorectal tumors', 'Disease', 'MESH:D015179', (81, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal tumors', 'Disease', (81, 98))
18943	25788983	While the mechanistic basis for these events remains under investigation, such events have been attributed to DNA methylation changes , telomere disruption , repair and DNA damage pathway protein defects , replication distress , and misregulation of the centromere-specific histone H3 variant, CENP-A .	('misregulation', 'Var', (233, 246))	('protein defects', 'Disease', 'MESH:D011488', (188, 203))	('telomere', 'CPA', (136, 144))	('changes', 'Reg', (126, 133))	('protein defects', 'Disease', (188, 203))	('H3', 'Chemical', 'MESH:C012616', (282, 284))	('CENP-A', 'Gene', (294, 300))
18945	25788983	Consequently, mislocalization of CENP-A to noncentromere regions is believed to be a prognostic marker for aneuploidies driven by chromosomal breakage and rearrangements, emanating from bicentric chromosomes .	('chromosomal breakage', 'Phenotype', 'HP:0040012', (130, 150))	('driven by', 'Reg', (120, 129))	('ran', 'Gene', (159, 162))	('ran', 'Gene', '5901', (159, 162))	('CENP-A', 'Gene', (33, 39))	('aneuploidies', 'Disease', (107, 119))	('aneuploidies', 'Disease', 'MESH:D000782', (107, 119))	('mislocalization', 'Var', (14, 29))	('chromosomal breakage', 'Var', (130, 150))
18955	25788983	Taken together, our data uncover a new role for a classical histone variant in human cancer cell lines.	('human', 'Species', '9606', (79, 84))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('variant', 'Var', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
18973	25788983	Although no appreciable increase in H2A.Z was seen in the ectopic fraction of CENP-A, a threefold enrichment of canonical histone H3 in ectopic CENP-A IP was observed in SW480 compared to HeLa or normal colon cells.	('H2A.Z', 'Gene', '3015', (36, 41))	('H3', 'Chemical', 'MESH:C012616', (130, 132))	('SW480', 'Var', (170, 175))	('HeLa', 'CellLine', 'CVCL:0030', (188, 192))	('H2A.Z', 'Gene', (36, 41))	('SW480', 'CellLine', 'CVCL:0546', (170, 175))
18975	25788983	A recent study has reported that artificially overexpressed tagged CENP-A associates with the H3.3 chaperone DAXX in HeLa cells .	('DAXX', 'Gene', '1616', (109, 113))	('tagged', 'Var', (60, 66))	('associates', 'Interaction', (74, 84))	('CENP-A', 'Gene', (67, 73))	('HeLa', 'CellLine', 'CVCL:0030', (117, 121))	('DAXX', 'Gene', (109, 113))	('H3', 'Chemical', 'MESH:C012616', (94, 96))
18981	25788983	Given the association of ectopic CENP-A and H3 above, we were curious whether such nucleosomes, or their chromatin fibers, might present an alteration of nucleosomal features.	('chromatin', 'cellular_component', 'GO:0000785', ('105', '114'))	('association', 'Interaction', (10, 21))	('CENP-A', 'Gene', (33, 39))	('ectopic', 'Var', (25, 32))	('H3', 'Chemical', 'MESH:C012616', (44, 46))	('H3 above', 'Gene', (44, 52))
19014	25788983	A mechanistic question that arises from the correlation between ectopic CENP-A and DHS, was whether ectopic CENP-A creates DNase I sites once it binds to chromatin, or whether such sites precede CENP-A occupancy.	('binds', 'Interaction', (145, 150))	('sites', 'MPA', (131, 136))	('CENP-A', 'Var', (108, 114))	('DNase', 'Protein', (123, 128))	('ectopic CENP-A', 'Var', (100, 114))	('chromatin', 'cellular_component', 'GO:0000785', ('154', '163'))	('DHS', 'Chemical', '-', (83, 86))	('DNase I', 'molecular_function', 'GO:0004530', ('123', '130'))
19034	25788983	Thus, in the colorectal cancer cell line possessing the highest amount of CENP-A protein (Figure  1A), CENP-A localizes to 8q24 in a large fraction of cells.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('colorectal cancer', 'Disease', (13, 30))	('localizes', 'MPA', (110, 119))	('CENP-A', 'Var', (103, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (13, 30))	('protein', 'cellular_component', 'GO:0003675', ('81', '88'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (13, 30))
19048	25788983	Regardless of the absolute amount of ectopic CENP-A, in normal colon cells, and in the cancer cell lines examined, there is a connection between DHS/transcription factor binding sites and ectopic CENP-A (Figures  5 and 6).	('DHS', 'Chemical', '-', (145, 148))	('cancer', 'Disease', (87, 93))	('ran', 'Gene', '5901', (150, 153))	('ectopic', 'Var', (188, 195))	('connection', 'Reg', (126, 136))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('binding', 'Interaction', (170, 177))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('ran', 'Gene', (150, 153))
19057	25788983	Not mutually exclusive to this explanation is the interesting possibility that defects in the timing of CENP-A expression, or promiscuous binding of CENP-A to other chaperones, coupled to defects in proteolysis, might cumulatively conspire to permit increased CENP-A accumulation at transcription factor binding sites in cells.	('CENP-A', 'Gene', (104, 110))	('ran', 'Gene', '5901', (284, 287))	('defects', 'Var', (79, 86))	('ran', 'Gene', (284, 287))
19061	25788983	At the vast majority of genes in vivo, octameric H3 nucleosomes, with specific N-terminal tail modifications, dominate the epigenetic regulatory landscape .	('epigenetic regulatory', 'MPA', (123, 144))	('octameric', 'Var', (39, 48))	('H3', 'Chemical', 'MESH:C012616', (49, 51))
19062	25788983	Ectopic CENP-A nucleosomes would lack known H3 N-terminal tail modifications, and could potentially circumvent traditional epigenetic regulatory cascades.	('H3 N-terminal', 'Protein', (44, 57))	('circumvent', 'NegReg', (100, 110))	('CENP-A', 'Gene', (8, 14))	('H3', 'Chemical', 'MESH:C012616', (44, 46))	('Ectopic', 'Var', (0, 7))	('lack', 'NegReg', (33, 37))
19064	25788983	Ongoing studies are focused on whether recruitment of transcriptional activator or repressor complexes is altered in the presence of ectopic CENP-A nucleosomes, and whether such events influence gene expression patterns specifically in the cancer context.	('altered', 'Reg', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('ectopic', 'Var', (133, 140))	('influence', 'Reg', (185, 194))	('ran', 'Gene', (55, 58))	('ran', 'Gene', '5901', (55, 58))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('recruitment', 'MPA', (39, 50))	('cancer', 'Disease', (240, 246))	('gene expression patterns', 'MPA', (195, 219))
19146	24245549	http://ClinicalTrials.gov number NCT00808743 Familial adenomatous polyposis (FAP), characterized by the development of numerous premalignant colorectal adenomatous polyps, is caused by a germline mutation in the tumor suppressor adenomatous polyposis coli (APC) gene.	('adenomatous polyps', 'Phenotype', 'HP:0005227', (152, 170))	('numerous premalignant colorectal adenomatous polyps', 'Phenotype', 'HP:0005227', (119, 170))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (229, 255))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (229, 255))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('adenomatous polyposis coli', 'Disease', (229, 255))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('212', '228'))	('APC', 'Gene', '324', (257, 260))	('Familial adenomatous polyposis', 'Disease', (45, 75))	('caused by', 'Reg', (175, 184))	('numerous premalignant colorectal adenomatous polyps', 'Disease', 'MESH:D018256', (119, 170))	('FAP', 'Disease', (77, 80))	('APC', 'cellular_component', 'GO:0005680', ('257', '260'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('212', '228'))	('FAP', 'Disease', 'MESH:C567782', (77, 80))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (54, 75))	('Familial adenomatous polyposis', 'Disease', 'MESH:D011125', (45, 75))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (229, 250))	('tumor', 'Disease', (212, 217))	('germline mutation', 'Var', (187, 204))	('APC', 'Gene', (257, 260))	('tumor', 'Disease', 'MESH:D009369', (212, 217))
19159	24245549	While disruptions in the Wnt signaling pathway are involved in tumor initiation, abnormal expression of cyclooxygenase-2 (COX-2) observed in the majority of adenomas and carcinomas, is thought to play a crucial role in tumor progression by increasing the levels of prostaglandin E2 (PGE2).	('cyclooxygenase-2', 'Gene', (104, 120))	('tumor', 'Disease', (219, 224))	('carcinomas', 'Phenotype', 'HP:0030731', (170, 180))	('levels', 'MPA', (255, 261))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (265, 281))	('adenomas and carcinomas', 'Disease', 'MESH:D000236', (157, 180))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('COX-2', 'Gene', (122, 127))	('cyclooxygenase-2', 'Gene', '5743', (104, 120))	('tumor initiation', 'Disease', 'MESH:D009369', (63, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('25', '46'))	('tumor initiation', 'Disease', (63, 79))	('Wnt signaling pathway', 'Pathway', (25, 46))	('COX-2', 'Gene', '5743', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('increasing', 'PosReg', (240, 250))	('PGE2', 'Chemical', 'MESH:D015232', (283, 287))	('abnormal', 'Var', (81, 89))
19160	24245549	Overexpression of COX-2 is linked to reduced apoptosis, enhanced cell growth, tumor angiogenesis, and tissue invasion and metastasis.	('cell growth', 'CPA', (65, 76))	('COX-2', 'Gene', '5743', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('enhanced', 'PosReg', (56, 64))	('reduced', 'NegReg', (37, 44))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', (78, 83))	('apoptosis', 'CPA', (45, 54))	('COX-2', 'Gene', (18, 23))
19263	25023548	Using a database of 735 colon and rectal cancers in the Nurse's Health Study and the Health Professionals Follow-up Study, we examined the relationship of tumor SMO expression (assessed by immunohistochemistry) to prognosis, and to clinical, pathological and tumor molecular features, including mutations of KRAS, BRAF and PIK3CA, microsatellite instability, CpG island methylator phenotype (CIMP), LINE-1 methylation, and expression of phosphorylated AKT and CTNNB1.	('colon and rectal cancers', 'Disease', 'MESH:D012004', (24, 48))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('tumor', 'Disease', (155, 160))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('PIK3CA', 'Gene', (323, 329))	('mutations', 'Var', (295, 304))	('AKT', 'Gene', (452, 455))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('SMO', 'Gene', '6608', (161, 164))	('CTNNB1', 'Gene', '1499', (460, 466))	('CIMP', 'Chemical', '-', (392, 396))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('AKT', 'Gene', '207', (452, 455))	('KRAS', 'Gene', '3845', (308, 312))	('SMO', 'Gene', (161, 164))	('PIK3CA', 'Gene', '5290', (323, 329))	('BRAF', 'Gene', (314, 318))	('BRAF', 'Gene', '673', (314, 318))	('CTNNB1', 'Gene', (460, 466))	('KRAS', 'Gene', (308, 312))	('rectal cancer', 'Phenotype', 'HP:0100743', (34, 47))	('tumor', 'Disease', (259, 264))
19274	25023548	Hedgehog signaling has been implicated in the pathogenesis of various human cancers, either through hedgehog ligand-dependent activation, or through ligand-independent activation, i.e., by loss of function mutations in PTCH1, or gain of function mutations in the proto-oncogene SMO.	('mutations', 'Var', (206, 215))	('gain of function', 'PosReg', (229, 245))	('SMO', 'Gene', '6608', (278, 281))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('PTCH1', 'Gene', (219, 224))	('hedgehog', 'Protein', (100, 108))	('SMO', 'Gene', (278, 281))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('activation', 'PosReg', (126, 136))	('human', 'Species', '9606', (70, 75))	('mutations', 'Var', (246, 255))	('PTCH1', 'Gene', '5727', (219, 224))	('loss', 'NegReg', (189, 193))
19277	25023548	We therefore utilized a molecular pathological epidemiology database, derived from colorectal cancers arising in two U.S. nationwide prospective cohort studies, to examine SMO expression status in colorectal cancer, and to assess the relationships between SMO expression and other important molecular features, including: microsatellite instability (MSI); CpG island methylation phenotype (CIMP); long interspersed nucleotide element-1 (LINE-1) methylation; and KRAS, BRAF, and PIK3CA mutations.	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('BRAF', 'Gene', '673', (468, 472))	('BRAF', 'Gene', (468, 472))	('rectal cancer', 'Phenotype', 'HP:0100743', (87, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (197, 214))	('PIK3CA', 'Gene', '5290', (478, 484))	('mutations', 'Var', (485, 494))	('SMO', 'Gene', (172, 175))	('colorectal cancer', 'Phenotype', 'HP:0003003', (83, 100))	('colorectal cancers', 'Disease', (83, 101))	('SMO', 'Gene', '6608', (256, 259))	('KRAS', 'Gene', '3845', (462, 466))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('men', 'Species', '9606', (429, 432))	('colorectal cancer', 'Disease', 'MESH:D015179', (197, 214))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('PIK3CA', 'Gene', (478, 484))	('KRAS', 'Gene', (462, 466))	('rectal cancer', 'Phenotype', 'HP:0100743', (201, 214))	('SMO', 'Gene', (256, 259))	('colorectal cancer', 'Disease', 'MESH:D015179', (83, 100))	('CIMP', 'Chemical', '-', (390, 394))	('colorectal cancer', 'Disease', (197, 214))	('colorectal cancers', 'Disease', 'MESH:D015179', (83, 101))	('SMO', 'Gene', '6608', (172, 175))
19316	25023548	The model initially included age at diagnosis (continuous), sex, year of diagnosis (continuous), body mass index, tumor location (proximal vs. distal colon vs. rectum), tumor grade, MSI (high vs. low/MSS), CIMP (high vs. low/0), LINE-1 methylation (continuous), BRAF mutation, KRAS mutation, and PIK3CA mutation, in addition to CTNNB1 and phosphorylated AKT expression.	('MSS', 'Chemical', '-', (200, 203))	('methylation', 'biological_process', 'GO:0032259', ('236', '247'))	('BRAF', 'Gene', '673', (262, 266))	('BRAF', 'Gene', (262, 266))	('CTNNB1', 'Gene', '1499', (328, 334))	('AKT', 'Gene', (354, 357))	('tumor', 'Disease', (114, 119))	('PIK3CA', 'Gene', (296, 302))	('tumor', 'Disease', (169, 174))	('mutation', 'Var', (303, 311))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('CTNNB1', 'Gene', (328, 334))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('AKT', 'Gene', '207', (354, 357))	('KRAS', 'Gene', '3845', (277, 281))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('KRAS', 'Gene', (277, 281))	('PIK3CA', 'Gene', '5290', (296, 302))	('CIMP', 'Chemical', '-', (206, 210))
19321	25023548	SMO expression was positively associated with KRAS mutation (P = 0.0027), and inversely associated with phosphorylated AKT expression (P < 0.0001), BRAF mutation (P = 0.0026), CTNNB1 nuclear localization (P = 0.0005) and CIMP-high status (P = 0.0035) (Table 1).	('CTNNB1', 'Gene', '1499', (176, 182))	('CIMP', 'Chemical', '-', (221, 225))	('localization', 'biological_process', 'GO:0051179', ('191', '203'))	('phosphorylated', 'MPA', (104, 118))	('KRAS', 'Gene', (46, 50))	('associated', 'Interaction', (30, 40))	('AKT', 'Gene', '207', (119, 122))	('KRAS', 'Gene', '3845', (46, 50))	('mutation', 'Var', (51, 59))	('CTNNB1', 'Gene', (176, 182))	('SMO', 'Gene', (0, 3))	('AKT', 'Gene', (119, 122))	('BRAF', 'Gene', '673', (148, 152))	('associated', 'Interaction', (88, 98))	('SMO', 'Gene', '6608', (0, 3))	('mutation', 'Var', (153, 161))	('BRAF', 'Gene', (148, 152))
19338	25023548	The development and progression of colorectal neoplasia is attributable to the accumulation of genetic and epigenetic changes and the complex interaction of aberrations in various signaling pathways.	('colorectal neoplasia', 'Disease', 'MESH:D009369', (35, 55))	('neoplasia', 'Phenotype', 'HP:0002664', (46, 55))	('epigenetic changes', 'Var', (107, 125))	('colorectal neoplasia', 'Disease', (35, 55))	('men', 'Species', '9606', (11, 14))
19357	25023548	BRAF mutation is present in 10-15% of colorectal cancers and associated with inferior prognosis.	('colorectal cancer', 'Phenotype', 'HP:0003003', (38, 55))	('colorectal cancers', 'Disease', 'MESH:D015179', (38, 56))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('colorectal cancers', 'Disease', (38, 56))	('rectal cancer', 'Phenotype', 'HP:0100743', (42, 55))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('mutation', 'Var', (5, 13))
19375	24244261	The combination of lenalidomide and cetuximab appeared to be well tolerated but did not have clinically meaningful activity in KRAS-mutant metastatic colorectal cancer patients.	('colorectal cancer', 'Disease', (150, 167))	('rat', 'Species', '10116', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('KRAS-mutant', 'Gene', (127, 138))	('KRAS-mutant', 'Var', (127, 138))	('colorectal cancer', 'Disease', 'MESH:D015179', (150, 167))	('lenalidomide', 'Chemical', 'MESH:D000077269', (19, 31))	('patients', 'Species', '9606', (168, 176))	('cetuximab', 'Chemical', 'MESH:D000068818', (36, 45))	('colorectal cancer', 'Phenotype', 'HP:0003003', (150, 167))
19380	24244261	For patients with KRAS-mutated mCRC that is resistant to or has relapsed after fluoropyrimidine-, oxaliplatin-, and irinotecan-containing therapies, treatment beyond best supportive care is very limited.	('irinotecan', 'Chemical', 'MESH:D000077146', (116, 126))	('KRAS-mutated', 'Var', (18, 30))	('men', 'Species', '9606', (154, 157))	('CRC', 'Phenotype', 'HP:0003003', (32, 35))	('patients', 'Species', '9606', (4, 12))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (98, 109))	('mCRC', 'Gene', (31, 35))	('fluoropyrimidine', 'Chemical', '-', (79, 95))
19386	24244261	Genetic variation in FcgammaRs is suggested to play an important role in disorders of the host defense system, immunohematologic disease, and systemic autoimmune disease, as well as in the efficacy of mAbs, at least for those that have an immunoglobulin (Ig)G1 structure.	('FcgammaRs', 'Gene', (21, 30))	('role', 'Reg', (65, 69))	('Genetic variation', 'Var', (0, 17))	('immunohematologic disease', 'Phenotype', 'HP:0001871', (111, 136))	('immunohematologic disease', 'Disease', (111, 136))	('systemic autoimmune disease', 'Disease', 'MESH:D020274', (142, 169))	('systemic autoimmune disease', 'Disease', (142, 169))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('239', '253'))	('autoimmune disease', 'Phenotype', 'HP:0002960', (151, 169))	('immunohematologic disease', 'Disease', 'MESH:D004194', (111, 136))
19393	24244261	This effect was not observed with the combination of lenalidomide and panitumumab, this finding being justifiable by the fact that panitumumab is an IgG2 anti-EGFR mAb without ADCC-inducing capacity.	('panitumumab', 'Chemical', 'MESH:D000077544', (131, 142))	('EGFR', 'Gene', '1956', (159, 163))	('panitumumab', 'Var', (131, 142))	('EGFR', 'Gene', (159, 163))	('lenalidomide', 'Chemical', 'MESH:D000077269', (53, 65))	('panitumumab', 'Chemical', 'MESH:D000077544', (70, 81))
19397	24244261	Patients were eligible to participate in this study if they were diagnosed with metastatic colorectal adenocarcinoma with a confirmed KRAS mutation status.	('colorectal adenocarcinoma', 'Disease', (91, 116))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (91, 116))	('mutation status', 'Var', (139, 154))	('Patients', 'Species', '9606', (0, 8))	('KRAS', 'Gene', (134, 138))
19423	24244261	A biomarker and pharmacodynamic marker analysis including FcgammaR genotyping, EGFR copy number, and immunomodulation was performed in this study.	('FcgammaR', 'Gene', (58, 66))	('copy number', 'Var', (84, 95))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))
19487	24244261	Following these preclinical results, we hypothesized that the combination of lenalidomide and cetuximab could be active in patients with KRAS-mutated mCRC.	('KRAS-mutated', 'Var', (137, 149))	('CRC', 'Phenotype', 'HP:0003003', (151, 154))	('mCRC', 'Disease', (150, 154))	('cetuximab', 'Chemical', 'MESH:D000068818', (94, 103))	('patients', 'Species', '9606', (123, 131))	('lenalidomide', 'Chemical', 'MESH:D000077269', (77, 89))
19500	24244261	A SNP found in FcgammaRIIIA results in two allotypes with either valine (V) or phenylalanine (F) at codon 158.	('phenylalanine', 'Chemical', 'MESH:D010649', (79, 92))	('valine', 'Chemical', 'MESH:D014633', (65, 71))	('valine', 'Var', (65, 71))	('phenylalanine', 'MPA', (79, 92))	('FcgammaRIIIA', 'Gene', '2214', (15, 27))	('FcgammaRIIIA', 'Gene', (15, 27))
19506	24244261	Therefore, EGFR copy number might be of value as a prognostic marker.	('copy number', 'Var', (16, 27))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))
19507	24244261	For subjects treated with lenalidomide plus cetuximab combination therapy, this finding is consistent with published reports of improved survival in patients with mCRC and high EGFR copy numbers who receive treatment with cetuximab.	('patients', 'Species', '9606', (149, 157))	('CRC', 'Phenotype', 'HP:0003003', (164, 167))	('EGFR', 'molecular_function', 'GO:0005006', ('177', '181'))	('improved', 'PosReg', (128, 136))	('copy numbers', 'Var', (182, 194))	('EGFR', 'Gene', '1956', (177, 181))	('cetuximab', 'Chemical', 'MESH:D000068818', (44, 53))	('cetuximab', 'Chemical', 'MESH:D000068818', (222, 231))	('high', 'Var', (172, 176))	('lenalidomide', 'Chemical', 'MESH:D000077269', (26, 38))	('EGFR', 'Gene', (177, 181))	('mCRC', 'Gene', (163, 167))	('men', 'Species', '9606', (212, 215))
19508	24244261	However, the observation of an association between high EGFR copy number and OS in the lenalidomide monotherapy arm is inconclusive because of the small sample size.	('copy number', 'Var', (61, 72))	('lenalidomide', 'Chemical', 'MESH:D000077269', (87, 99))	('EGFR', 'Gene', '1956', (56, 60))	('EGFR', 'Gene', (56, 60))	('high', 'Var', (51, 55))	('OS', 'Chemical', '-', (77, 79))
19512	24244261	Despite preclinical evidence, present clinical data suggest the modulating effect of lenalidomide is unable to overcome primary resistance of KRAS-mutant mCRC to EGFR targeted inhibition by cetuximab.	('KRAS-mutant', 'Var', (142, 153))	('CRC', 'Phenotype', 'HP:0003003', (155, 158))	('EGFR', 'Gene', '1956', (162, 166))	('cetuximab', 'Chemical', 'MESH:D000068818', (190, 199))	('EGFR', 'Gene', (162, 166))	('EGFR', 'molecular_function', 'GO:0005006', ('162', '166'))	('mCRC', 'Gene', (154, 158))	('lenalidomide', 'Chemical', 'MESH:D000077269', (85, 97))
19542	24199171	Overexpression of the HER2 protein and/or amplification of the HER2-encoding gene have been associated with an unfavorable prognosis in several types of cancer, including breast, gastric, and pancreatic cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('gastric', 'Disease', (179, 186))	('HER2', 'Gene', '2064', (63, 67))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (192, 209))	('breast', 'Disease', (171, 177))	('HER2', 'Gene', (22, 26))	('protein', 'cellular_component', 'GO:0003675', ('27', '34'))	('cancer', 'Disease', (203, 209))	('HER2', 'Gene', '2064', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('amplification', 'Var', (42, 55))	('HER2', 'Gene', (63, 67))	('pancreatic cancer', 'Disease', 'MESH:D010190', (192, 209))	('associated', 'Reg', (92, 102))	('pancreatic cancer', 'Disease', (192, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
19545	24199171	Since gene-amplification is the primary cause of HER2 overexpression, both FISH- (or CISH-) and IHC-based companion diagnostic devices have been approved by the FDA.	('gene-amplification', 'Var', (6, 24))	('cause', 'Reg', (40, 45))	('overexpression', 'PosReg', (54, 68))	('HER2', 'Gene', (49, 53))	('HER2', 'Gene', '2064', (49, 53))
19558	24199171	While the immunohistochemical detection of EGFR expression did not prove to be decisive in determining the clinical response, promising data has been generated in support of using the EGFR gene copy number as a predictive biomarker for EGFR-targeted therapy.	('copy number', 'Var', (194, 205))	('EGFR', 'Gene', '1956', (184, 188))	('EGFR', 'Gene', (184, 188))	('EGFR', 'Gene', '1956', (43, 47))	('EGFR', 'Gene', '1956', (236, 240))	('EGFR', 'Gene', (43, 47))	('EGFR', 'Gene', (236, 240))
19560	24199171	In contrast to colorectal cancer, mutations within the EGFR in NSCLC are common and mutational testing is recommended for all NSCLC cases.	('NSCLC', 'Disease', (63, 68))	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'molecular_function', 'GO:0005006', ('55', '59'))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('EGFR', 'Gene', (55, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (15, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('colorectal cancer', 'Phenotype', 'HP:0003003', (15, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('colorectal cancer', 'Disease', (15, 32))	('mutations', 'Var', (34, 43))	('NSCLC', 'Disease', (126, 131))
19568	24199171	Activating mutations within the KIT gene and, to a lesser degree, PDGFR, are commonly found in patients with GIST and depending on their location within the coding region of the respective gene, they are highly correlated with the likelihood of a response to imatinib mesylate treatment.	('PDGFR', 'Gene', '5159', (66, 71))	('mutations', 'Var', (11, 20))	('response to imatinib mesylate treatment', 'MPA', (247, 286))	('Activating', 'PosReg', (0, 10))	('GIST', 'Phenotype', 'HP:0100723', (109, 113))	('patients', 'Species', '9606', (95, 103))	('KIT', 'Gene', (32, 35))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (259, 276))	('correlated with', 'Reg', (211, 226))	('PDGFR', 'Gene', (66, 71))
19572	24199171	Second-line treatment of NSCLC patients with confirmed ALK rearrangements, using the small molecule inhibitor crizotinib, has recently been shown to significantly prolong progression-free survival compared to standard chemotherapy.	('progression-free survival', 'CPA', (171, 196))	('prolong', 'PosReg', (163, 170))	('ALK', 'Gene', '238', (55, 58))	('NSCLC', 'Disease', (25, 30))	('rearrangements', 'Var', (59, 73))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('patients', 'Species', '9606', (31, 39))	('ALK', 'Gene', (55, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))	('crizotinib', 'Chemical', 'MESH:D000077547', (110, 120))
19585	24199171	Mutations of the associated gene occur in a range of human malignancies including cutaneous melanoma, colorectal cancer, NSCLC, papillary thyroid cancer, and hairy-cell leukemia.	('cutaneous melanoma', 'Disease', 'MESH:C562393', (82, 100))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('papillary thyroid cancer', 'Disease', (128, 152))	('occur', 'Reg', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('hairy-cell leukemia', 'Disease', (158, 177))	('Mutations', 'Var', (0, 9))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (128, 152))	('colorectal cancer', 'Disease', (102, 119))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('human', 'Species', '9606', (53, 58))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (128, 152))	('thyroid cancer', 'Phenotype', 'HP:0002890', (138, 152))	('malignancies', 'Disease', 'MESH:D009369', (59, 71))	('NSCLC', 'Disease', (121, 126))	('malignancies', 'Disease', (59, 71))	('leukemia', 'Phenotype', 'HP:0001909', (169, 177))	('hairy-cell leukemia', 'Disease', 'MESH:D007943', (158, 177))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('cutaneous melanoma', 'Disease', (82, 100))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (82, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
19586	24199171	By far, the most common BRAF mutation results in the substitution of valine for glutamic acid at position 600 (V600E), leading to the constitutive activation of the protein's kinase domain.	('mutation', 'Var', (29, 37))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('protein', 'Protein', (165, 172))	('substitution', 'Var', (53, 65))	('V600E', 'Var', (111, 116))	('valine for glutamic acid at position 600', 'Mutation', 'rs113488022', (69, 109))	('V600E', 'Mutation', 'rs113488022', (111, 116))	('BRAF', 'Gene', (24, 28))	('activation', 'PosReg', (147, 157))	('constitutive', 'MPA', (134, 146))
19587	24199171	In human cutaneous melanoma, mutated BRAF has been detected in 40-50% of cases, with up 90% of these alterations concerning the V-E substitution at codon 600.	('human', 'Species', '9606', (3, 8))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('cutaneous melanoma', 'Disease', (9, 27))	('BRAF', 'Gene', (37, 41))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (9, 27))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (9, 27))	('mutated', 'Var', (29, 36))
19588	24199171	Vemurafenib and dabrafenib are two potent small molecule inhibitor drugs that specifically target BRAF V600E and have demonstrated remarkable response rates in metastatic melanoma patients.	('V600E', 'Var', (103, 108))	('dabrafenib', 'Chemical', 'MESH:C561627', (16, 26))	('BRAF', 'Gene', (98, 102))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Disease', (171, 179))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('V600E', 'Mutation', 'rs113488022', (103, 108))	('patients', 'Species', '9606', (180, 188))
19591	24199171	The results obtained from using this antibody to determine the BRAF mutational status in melanoma and thyroid cancer samples were identical to those achieved following DNA sequencing-based profiling.	('thyroid cancer', 'Disease', 'MESH:D013964', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('thyroid cancer', 'Phenotype', 'HP:0002890', (102, 116))	('thyroid cancer', 'Disease', (102, 116))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('mutational status', 'Var', (68, 85))	('BRAF', 'Gene', (63, 67))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
19594	24199171	With regard to the intra-tumor heterogeneity of BRAF V600E, only few cases with non-homogenous expression have been observed following immunohistochemical detection.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('V600E', 'Mutation', 'rs113488022', (53, 58))	('BRAF', 'Var', (48, 52))	('intra-tumor', 'Disease', 'MESH:D009369', (19, 30))	('intra-tumor', 'Disease', (19, 30))
19595	24199171	These results are in direct contrast to previous reports describing significant variability of BRAF mutational status among individual cells within a tumor and warrant further investigation.	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('BRAF', 'Gene', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('mutational', 'Var', (100, 110))
19598	24199171	Epidermal growth factor receptor mutations have been detected in 2-17% of NSCLC patients from Europe and the United States, however, the mutational frequency increases to 30% when analyzing cases from East Asia.	('patients', 'Species', '9606', (80, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('Epidermal growth factor', 'molecular_function', 'GO:0005154', ('0', '23'))	('mutations', 'Var', (33, 42))	('NSCLC', 'Disease', (74, 79))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))
19599	24199171	Specific mutations, in particular those affecting the EGFR kinase domain, have been associated with response to gefitinib and erlotinib treatment.	('mutations', 'Var', (9, 18))	('EGFR', 'Gene', '1956', (54, 58))	('associated', 'Reg', (84, 94))	('response', 'MPA', (100, 108))	('erlotinib', 'Chemical', 'MESH:D000069347', (126, 135))	('EGFR', 'Gene', (54, 58))	('gefitinib', 'Chemical', 'MESH:D000077156', (112, 121))
19600	24199171	The two most common types of EGFR mutations are in-frame deletions of exon 19 and a leucine to arginine substitution at codon 858 (L858R) in exon 21.	('in-frame deletions', 'Var', (48, 66))	('leucine to arginine substitution at codon 858', 'Mutation', 'rs121434568', (84, 129))	('EGFR', 'molecular_function', 'GO:0005006', ('29', '33'))	('EGFR', 'Gene', '1956', (29, 33))	('L858R', 'Mutation', 'rs121434568', (131, 136))	('EGFR', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))
19601	24199171	Taken together, alterations at these sites account for up to 90% of all EGFR mutations.	('EGFR', 'Gene', '1956', (72, 76))	('EGFR', 'Gene', (72, 76))	('mutations', 'Var', (77, 86))
19602	24199171	For example, E746_A750del results in a five amino acid deletion in the corresponding protein and is the most common deletion detected, occurring in approximately 70% of cases.	('E746_A750del', 'Mutation', 'p.746,750delA', (13, 25))	('results in', 'Reg', (26, 36))	('E746_A750del', 'Var', (13, 25))	('protein', 'Protein', (85, 92))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
19603	24199171	The application of mutation-specific antibodies designed to target L858R and the E746_A750del modification, have yielded varying levels of detection specificity and sensitivity.	('E746_A750del', 'Var', (81, 93))	('E746_A750del', 'Mutation', 'p.746,750delA', (81, 93))	('L858R', 'Mutation', 'rs121434568', (67, 72))	('L858R', 'Var', (67, 72))
19606	24199171	While initial attempts to determine optimal tissue preparation and staining evaluation have been presented, additional steps toward a standardized protocol for the detection of EGFR mutations using IHC should be undertaken.	('EGFR', 'Gene', '1956', (177, 181))	('EGFR', 'Gene', (177, 181))	('mutations', 'Var', (182, 191))
19609	24199171	Confirming the importance of EGFR-mutational status for treatment response, positive IHC staining has been associated with longer progression-free survival compared to IHC-negative or -equivocal cases.	('longer', 'PosReg', (123, 129))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('positive', 'Var', (76, 84))	('progression-free survival', 'CPA', (130, 155))	('IHC', 'Gene', (85, 88))
19610	24199171	In addition, high mutant EGFR expression (as defined by the sum of scores for fraction and intensity) was significantly related to elevated progression-free survival but not overall survival and a fraction of positive tumor cells exceeding 50% of all cells predicted better response to EGFR inhibition treatment in univariate but not multivariate analysis.	('elevated', 'PosReg', (131, 139))	('progression-free survival', 'CPA', (140, 165))	('expression', 'MPA', (30, 40))	('EGFR', 'Gene', (25, 29))	('EGFR', 'Gene', '1956', (286, 290))	('EGFR', 'molecular_function', 'GO:0005006', ('286', '290'))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('mutant', 'Var', (18, 24))	('EGFR', 'Gene', (286, 290))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (218, 223))	('high mutant', 'Var', (13, 24))	('EGFR', 'molecular_function', 'GO:0005006', ('25', '29'))	('EGFR', 'Gene', '1956', (25, 29))
19611	24199171	Furthermore, EGFR-mutation-specific antibodies have been shown to occasionally detect mutations associated with EGFR-inhibitor resistance via mechanisms that are not yet fully understood.	('EGFR', 'Gene', (112, 116))	('mutations', 'Var', (86, 95))	('EGFR', 'Gene', '1956', (112, 116))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
19663	33902503	Incomplete polyp resection, especially when larger lesions are removed in piecemeal fashion, significantly increases the tumour recurrence probability and might be the cause of post-colonoscopy CRC in up to 50% of the cases.	('increases', 'PosReg', (107, 116))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('cause', 'Reg', (168, 173))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('post-colonoscopy CRC', 'Disease', (177, 197))	('tumour', 'Disease', (121, 127))	('Incomplete polyp resection', 'Var', (0, 26))
19750	33671932	Differential Effects of Trp53 Alterations in Murine Colorectal Cancer Although colorectal cancer is among the most frequent malignant tumors, there are currently no mouse models available that reliably mimic both tumor biology as well as treatment response.	('Trp53', 'Gene', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (52, 69))	('malignant tumors', 'Disease', (124, 140))	('Colorectal Cancer', 'Disease', (52, 69))	('Murine', 'Species', '10090', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('malignant tumors', 'Disease', 'MESH:D009369', (124, 140))	('Alterations', 'Var', (30, 41))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))	('mouse', 'Species', '10090', (165, 170))	('colorectal cancer', 'Disease', (79, 96))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (52, 69))	('Cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', (213, 218))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('Trp53', 'Gene', '22059', (24, 29))
19751	33671932	In this article, we describe a novel mouse model in which mutations relevant to colorectal cancer are induced in mice, leading to tumor formation in the distal colon.	('mutations', 'Var', (58, 67))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('leading to', 'Reg', (119, 129))	('mouse', 'Species', '10090', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancer', 'Disease', (80, 97))	('mice', 'Species', '10090', (113, 117))	('tumor', 'Disease', (130, 135))
19755	33671932	The effects of different mutations in the Trp53 gene on tumor cells show striking differences, similar to the effects in other tumor diseases.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mutations', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('effects', 'Reg', (4, 11))	('Trp53', 'Gene', (42, 47))	('tumor diseases', 'Disease', (127, 141))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (56, 61))	('tumor diseases', 'Disease', 'MESH:D009369', (127, 141))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
19759	33671932	We aimed to develop and characterize a genetically engineered mouse model (GEMM) of Apc/Kras/Trp53 mutant CRC, the most frequent genetic subtype of CRC.	('mouse', 'Species', '10090', (62, 67))	('CRC', 'Disease', (106, 109))	('mutant', 'Var', (99, 105))	('Apc', 'cellular_component', 'GO:0005680', ('84', '87'))	('Apc/Kras/Trp53', 'Gene', (84, 98))
19760	33671932	Methods: Tumors were induced in mice with conditional mutations or knockouts in Apc, Kras, and Trp53 by a segmental adeno-cre viral infection, monitored via colonoscopy and characterized on multiple levels via immunohistochemistry and next-generation sequencing.	('Trp53', 'Gene', (95, 100))	('viral infection', 'Disease', 'MESH:D001102', (126, 141))	('viral infection', 'biological_process', 'GO:0016032', ('126', '141'))	('Apc', 'Gene', (80, 83))	('viral infection', 'Disease', (126, 141))	('mutations', 'Var', (54, 63))	('knockouts', 'Var', (67, 76))	('Kras', 'Gene', (85, 89))	('Tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mice', 'Species', '10090', (32, 36))	('Tumors', 'Disease', (9, 15))	('Tumors', 'Disease', 'MESH:D009369', (9, 15))	('Apc', 'cellular_component', 'GO:0005680', ('80', '83'))	('Tumors', 'Phenotype', 'HP:0002664', (9, 15))
19762	33671932	The Trp53 R172H hotspot mutation leads to significantly increased metastatic capacity.	('Trp53', 'Gene', (4, 9))	('increased', 'PosReg', (56, 65))	('metastatic capacity', 'CPA', (66, 85))	('R172H', 'Var', (10, 15))	('R172H', 'Mutation', 'rs372604524', (10, 15))
19763	33671932	The effects of Trp53 alterations, as well as the response to treatment of this model, are similar to human CRC.	('human', 'Species', '9606', (101, 106))	('Trp53', 'Protein', (15, 20))	('alterations', 'Var', (21, 32))
19764	33671932	Exome sequencing revealed spontaneous protein-modifying alterations in multiple CRC-related genes and oncogenic pathways, resulting in a genetic landscape resembling human CRC.	('CRC-related genes', 'Gene', (80, 97))	('human', 'Species', '9606', (166, 171))	('protein-modifying', 'Reg', (38, 55))	('alterations', 'Var', (56, 67))
19767	33671932	Canonical CRC evolution starts with mutations in the APC gene, often followed by oncogenic KRAS and TP53 mutations.	('APC', 'Disease', 'MESH:D011125', (53, 56))	('APC', 'Disease', (53, 56))	('TP53', 'Gene', (100, 104))	('mutations', 'Var', (36, 45))	('KRAS', 'Gene', '16653', (91, 95))	('KRAS', 'Gene', (91, 95))
19769	33671932	It describes three subtypes, among which CCS1 is the most frequent (49% of CRC cases), featuring simultaneous mutations in APC, KRAS, and TP53.	('KRAS', 'Gene', (128, 132))	('APC', 'cellular_component', 'GO:0005680', ('123', '126'))	('KRAS', 'Gene', '16653', (128, 132))	('CCS', 'molecular_function', 'GO:0052728', ('41', '44'))	('mutations', 'Var', (110, 119))	('APC', 'Disease', 'MESH:D011125', (123, 126))	('APC', 'Disease', (123, 126))	('CCS1', 'Gene', (41, 45))	('CRC', 'Disease', (75, 78))	('TP53', 'Gene', (138, 142))	('CCS', 'molecular_function', 'GO:0034019', ('41', '44'))	('CCS1', 'Gene', '110138', (41, 45))	('CCS', 'molecular_function', 'GO:0052727', ('41', '44'))
19778	33671932	In addition, although most Trp53 (the murine counterpart of human TP53) alterations involve mutations rather than complete Trp53 loss, no CRC GEMM of mutant Trp53 has been described yet.	('Trp53', 'Gene', (27, 32))	('alterations', 'Var', (72, 83))	('mutations', 'Var', (92, 101))	('murine', 'Species', '10090', (38, 44))	('human', 'Species', '9606', (60, 65))
19779	33671932	We here present and comprehensively characterize a novel GEMM of compound Apc/Kras/Trp53 mutated CRC (CCS1) that enables valid research of the biology and treatment response of the most common human CRC subtype.	('CCS1', 'Gene', '110138', (102, 106))	('CCS1', 'Gene', (102, 106))	('human', 'Species', '9606', (193, 198))	('mutated', 'Var', (89, 96))
19780	33671932	Using this mouse model, we evaluated the differential effects of various genetic alterations in the Trp53 gene in CTC.	('CTC', 'Disease', (114, 117))	('Trp53', 'Gene', (100, 105))	('mouse', 'Species', '10090', (11, 16))	('genetic alterations', 'Var', (73, 92))
19797	33671932	The addition of the oncogenic Kras G12D mutation (AK mice) accelerated adenoma formation and increased the frequency of intramucosal carcinoma.	('adenoma', 'Disease', (71, 78))	('carcinoma', 'Disease', 'MESH:D009369', (133, 142))	('increased', 'PosReg', (93, 102))	('G12D', 'Mutation', 'rs121913529', (35, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('formation', 'biological_process', 'GO:0009058', ('79', '88'))	('Kras G12D', 'Var', (30, 39))	('adenoma', 'Disease', 'MESH:D000236', (71, 78))	('accelerated', 'PosReg', (59, 70))	('mice', 'Species', '10090', (53, 57))	('carcinoma', 'Disease', (133, 142))
19798	33671932	Alterations in Trp53 led to the early development of invasive tumors.	('led to', 'Reg', (21, 27))	('invasive tumors', 'Disease', (53, 68))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Alterations', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('invasive tumors', 'Disease', 'MESH:D009361', (53, 68))	('Trp53', 'Gene', (15, 20))
19801	33671932	Again, Trp53 alterations led to faster progression, resulting in the majority of Trp53 mutant (AKPr) or Trp53 deficient (AKPfl) tumors being classified as invasive adenocarcinomas.	('invasive adenocarcinomas', 'Disease', 'MESH:D000230', (155, 179))	('invasive adenocarcinomas', 'Disease', (155, 179))	('Trp53', 'Gene', (7, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('deficient', 'NegReg', (110, 119))	('Trp53', 'Gene', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mutant', 'Var', (87, 93))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('alterations', 'Var', (13, 24))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('Trp53', 'Gene', (81, 86))
19803	33671932	Mice with alterations in the Trp53 gene showed significantly more invasive tumors than Trp53 WT mice.	('invasive tumors', 'Disease', 'MESH:D009361', (66, 81))	('alterations', 'Var', (10, 21))	('mice', 'Species', '10090', (96, 100))	('more', 'PosReg', (61, 65))	('Trp53', 'Gene', (29, 34))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('invasive tumors', 'Disease', (66, 81))
19804	33671932	Most tumors exhibited poor or anaplastic differentiation, especially in Trp53 mutant mice, in which no well-differentiated tumors were seen (Figure S1).	('mice', 'Species', '10090', (85, 89))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('poor', 'CPA', (22, 26))	('Trp53', 'Gene', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('anaplastic differentiation', 'CPA', (30, 56))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('mutant', 'Var', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
19807	33671932	As expected, the knockout of Apc led to strong accumulation of beta-catenin in all tumors and metastatic lesions (Figure 3B,C,J).	('beta-catenin', 'Gene', (63, 75))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (83, 89))	('Apc', 'Gene', (29, 32))	('knockout', 'Var', (17, 25))	('beta-catenin', 'Gene', '12387', (63, 75))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('Apc', 'cellular_component', 'GO:0005680', ('29', '32'))	('accumulation', 'PosReg', (47, 59))
19809	33671932	Partial nuclear positivity for CDX2 corroborated the colorectal origin of the examined tumors and distant metastases (Figure 3E,H,M).	('metastases', 'Disease', 'MESH:D009362', (106, 116))	('CDX2', 'Gene', '12591', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('colorectal', 'Disease', (53, 63))	('Partial nuclear positivity', 'Var', (0, 26))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('CDX2', 'Gene', (31, 35))	('metastases', 'Disease', (106, 116))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
19810	33671932	In AKPfl tumor cells, the expression of p53 protein was entirely lost (Figure 3N), whereas the mutant p53 protein accumulated in the nuclei of AKPr tumor cells (Figure 3G,O), a phenomenon well-known for many mutant forms of p53, including p53 R172H/R175H.	('protein', 'Protein', (106, 113))	('R172H', 'SUBSTITUTION', 'None', (243, 248))	('AKPr tumor', 'Disease', 'MESH:D009369', (143, 153))	('accumulated', 'PosReg', (114, 125))	('p53', 'Gene', '22059', (102, 105))	('expression', 'MPA', (26, 36))	('p53', 'Gene', (224, 227))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('p53', 'Gene', (40, 43))	('p53', 'Gene', (239, 242))	('R175H', 'Var', (249, 254))	('AKPr tumor', 'Disease', (143, 153))	('mutant', 'Var', (95, 101))	('p53', 'Gene', (102, 105))	('R175H', 'SUBSTITUTION', 'None', (249, 254))	('protein', 'Protein', (44, 51))	('AKPfl tumor', 'Disease', (3, 14))	('p53', 'Gene', '22059', (224, 227))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('lost', 'NegReg', (65, 69))	('AKPfl tumor', 'Disease', 'MESH:D009369', (3, 14))	('R172H', 'Var', (243, 248))	('p53', 'Gene', '22059', (40, 43))	('p53', 'Gene', '22059', (239, 242))
19812	33671932	We observed an increase in locally advanced tumors with increasingly complex genotypes (Figure 1J, p = 0.15), which underscores the role of acquired Kras and Trp53 mutations during the adenoma-carcinoma sequence.	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (185, 202))	('tumors', 'Disease', (44, 50))	('Kras', 'Gene', (149, 153))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('Trp53', 'Gene', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('increase', 'PosReg', (15, 23))	('adenoma-carcinoma', 'Disease', (185, 202))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mutations', 'Var', (164, 173))
19813	33671932	Interestingly, while AKPfl mice developed highly anaplastic but non-metastatic tumors (Figure 2E), AKPr mice exhibited more differentiated tumors as well as mesenteric lymph node (Figure 2G) and hepatic metastases (Figure 1F and Figure 2H, Table S7.	('metastases', 'Disease', 'MESH:D009362', (203, 213))	('AKPr', 'Var', (99, 103))	('mice', 'Species', '10090', (27, 31))	('more', 'PosReg', (119, 123))	('mice', 'Species', '10090', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (79, 85))	('mesenteric lymph node', 'CPA', (157, 178))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('metastases', 'Disease', (203, 213))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
19815	33671932	While the addition of oncogenic Kras to Apc mice (=AK mice) did not influence median survival (258 (Apc) vs. 302 (AK) days, p = 0.97), mice with an additional oncogenic mutation of Trp53 (AKPr mice) had a borderline significant shorter median survival (186 days, p = 0.16).	('median survival', 'MPA', (236, 251))	('mutation', 'Var', (169, 177))	('oncogenic', 'PosReg', (159, 168))	('mice', 'Species', '10090', (193, 197))	('mice', 'Species', '10090', (135, 139))	('shorter', 'NegReg', (228, 235))	('mice', 'Species', '10090', (54, 58))	('mice', 'Species', '10090', (44, 48))	('Trp53', 'Gene', (181, 186))
19816	33671932	When compared to Trp53 WT mice, the hotspot point mutant of Trp53 (R172H) did not significantly reduce survival in the GEMM (186 vs. 282 days, p = 0.13) (Figure 4B).	('R172H', 'Var', (67, 72))	('R172H', 'Mutation', 'rs372604524', (67, 72))	('survival', 'CPA', (103, 111))	('reduce', 'NegReg', (96, 102))	('Trp53', 'Gene', (60, 65))	('mice', 'Species', '10090', (26, 30))
19820	33671932	This is in line with data from other groups describing the increased invasive activity of tumor cells harboring the Trp53 R172H hotspot mutation.	('invasive activity', 'MPA', (69, 86))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('R172H', 'Mutation', 'rs372604524', (122, 127))	('R172H', 'Var', (122, 127))	('increased', 'PosReg', (59, 68))	('Trp53', 'Gene', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
19829	33671932	We next analyzed the impact of different Trp53 alterations on the mutational landscape of the resulting tumors via next-generation exome sequencing.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Trp53', 'Gene', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('alterations', 'Var', (47, 58))
19830	33671932	All GEMMs developed numerous new single nucleotide variants (SNVs) over time, demonstrating that the GEMM recapitulates the genetic progression observed in human CRC.	('human', 'Species', '9606', (156, 161))	('single nucleotide variants', 'Var', (33, 59))	('CRC', 'Disease', (162, 165))
19831	33671932	As expected, both the average number of mutated genes (Figure 5A-C) and mutations (Figure S3A-C) were significantly higher in Trp53-mutant tumors than in Apc and AK mice (Figure 5A-C).	('mutations', 'Var', (72, 81))	('mice', 'Species', '10090', (165, 169))	('higher', 'PosReg', (116, 122))	('Trp53-mutant', 'Gene', (126, 138))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
19833	33671932	Here, again, Trp53 mutant tumors exhibited a higher number of mutated genes as compared to Trp53 WT tumors (2430 vs. 132.5, p < 0.0001).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('WT tumors', 'Disease', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('WT tumors', 'Disease', 'MESH:C536751', (97, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('mutant', 'Var', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('higher', 'PosReg', (45, 51))	('mutated genes', 'MPA', (62, 75))	('Trp53', 'Gene', (13, 18))	('tumors', 'Disease', (26, 32))
19835	33671932	Although, in general, there was only ~5% mutational overlap (4.2-6.1%) between murine and human CRC (Table 1A, Table S1), many important driver mutations known in human CRC spontaneously developed in the murine tumors.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('murine', 'Species', '10090', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('human', 'Species', '9606', (90, 95))	('human', 'Species', '9606', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('murine', 'Species', '10090', (79, 85))	('developed', 'Reg', (187, 196))	('mutations', 'Var', (144, 153))
19836	33671932	Despite relatively stable genomes in Apc and AK mice, the addition of the oncogenic Kras G12D mutation consistently induced mutations in Casc1 (Cancer susceptibility candidate 1), an anti-apoptotic gene.	('mutations', 'Var', (124, 133))	('Kras', 'Gene', (84, 88))	('Cancer', 'Phenotype', 'HP:0002664', (144, 150))	('mice', 'Species', '10090', (48, 52))	('induced', 'Reg', (116, 123))	('Casc1', 'Gene', '320662', (137, 142))	('Apc', 'cellular_component', 'GO:0005680', ('37', '40'))	('Cancer susceptibility candidate 1', 'Gene', '320662', (144, 177))	('Casc1', 'Gene', (137, 142))	('G12D', 'Mutation', 'rs121913529', (89, 93))	('Cancer susceptibility candidate 1', 'Gene', (144, 177))	('mutation', 'Var', (94, 102))	('G12D mutation', 'Var', (89, 102))
19837	33671932	This is in line with previous data from both human and murine lung cancer, in which CASC1/Casc1 mutations were shown to often coincide with oncogenic KRAS/Kras.	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('CASC1', 'Gene', (84, 89))	('Casc1', 'Gene', (90, 95))	('Casc1', 'Gene', '320662', (90, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('lung cancer', 'Disease', (62, 73))	('human', 'Species', '9606', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('CASC1', 'Gene', '320662', (84, 89))	('KRAS', 'Gene', '16653', (150, 154))	('KRAS', 'Gene', (150, 154))	('mutations', 'Var', (96, 105))	('murine', 'Species', '10090', (55, 61))
19838	33671932	Both Trp53 R172H and loss of Trp53 triggered multiple new oncogenic mutations (Supplementary Table S1) well-known for their role in CRC, including protein-modifying mutations in Arid1a, Arid1b, Atm, Kmt2a/b/d (Mll1/2/4), Cdh1, Cdk4/6, Erbb2 and Jak3, which are among the most frequent oncogenic mutations in human CRC.	('Mll1/2/4', 'Gene', (210, 218))	('CRC', 'Disease', (132, 135))	('Cdk4/6', 'Gene', '1019;1021', (227, 233))	('R172H', 'Mutation', 'rs372604524', (11, 16))	('Arid1b', 'Gene', (186, 192))	('Erbb2', 'Gene', (235, 240))	('Cdh1', 'Gene', '999', (221, 225))	('Arid1b', 'Gene', '57492', (186, 192))	('Atm', 'Gene', (194, 197))	('loss', 'Var', (21, 25))	('Arid1a', 'Gene', '8289', (178, 184))	('Jak3', 'Gene', '3718', (245, 249))	('Trp53', 'Gene', (29, 34))	('mutations', 'Var', (165, 174))	('human', 'Species', '9606', (308, 313))	('Mll1/2/4', 'Gene', '4297;8085', (210, 218))	('Kmt2a/b/d', 'Gene', (199, 208))	('R172H', 'Var', (11, 16))	('Trp53 R172H', 'Var', (5, 16))	('Erbb2', 'Gene', '2064', (235, 240))	('Cdh1', 'Gene', (221, 225))	('Arid1a', 'Gene', (178, 184))	('Atm', 'Gene', '472', (194, 197))	('Cdk4/6', 'Gene', (227, 233))	('Jak3', 'Gene', (245, 249))	('Kmt2a/b/d', 'Gene', '4297', (199, 208))
19840	33671932	Interestingly, AKPr but not AKPfl mice presented mutations in migration and survival pathways (Table 1C and Table 2), which coincides with a strikingly increased migratory activity measured in AKPr vs. AKPfl cells (Figure S2).	('migration', 'CPA', (62, 71))	('mice', 'Species', '10090', (34, 38))	('mutations', 'Var', (49, 58))	('increased', 'PosReg', (152, 161))	('survival pathways', 'Pathway', (76, 93))	('migratory activity', 'CPA', (162, 180))
19841	33671932	In addition, immune modulating pathways, such as IL-2 and Dap12, were altered in AKPr which may enable circulating tumor cells to survive in circulation.	('AKPr', 'Var', (81, 85))	('altered', 'Reg', (70, 77))	('enable', 'PosReg', (96, 102))	('IL-2', 'Gene', '16183', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('IL-2', 'Gene', (49, 53))	('tumor', 'Disease', (115, 120))	('Dap12', 'Gene', '22177', (58, 63))	('Dap12', 'Gene', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('immune modulating pathways', 'Pathway', (13, 39))
19846	33671932	As several mutations in mismatch-repair (MMR) genes were found in the Trp53-altered genotypes, including Msi2 and Msh3 (AKPr) and Msi2, Msh4, Msh5, Msh3 (AKPfl) (Table S1), we aimed to determine the MSI status of the sequenced tumors using a set of three long mononucleotide microsatellites (>=23 repetitive units) as a diagnostic marker panel (Table S6) as described previously.	('mutations', 'Var', (11, 20))	('Msh4', 'Gene', (136, 140))	('Msi2', 'Gene', (105, 109))	('Msh3', 'Gene', (114, 118))	('Msi2', 'Gene', '76626', (105, 109))	('Msi2', 'Gene', (130, 134))	('Msh5', 'Gene', (142, 146))	('Msi2', 'Gene', '76626', (130, 134))	('Msh5', 'Gene', '17687', (142, 146))	('found', 'Reg', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('Msh3', 'Gene', '17686', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('Msh3', 'Gene', (148, 152))	('tumors', 'Disease', (227, 233))	('Trp53-altered', 'Gene', (70, 83))	('MMR) genes', 'Gene', (41, 51))	('mononucleotide', 'Chemical', '-', (260, 274))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('Msh3', 'Gene', '17686', (148, 152))	('Msh4', 'Gene', '55993', (136, 140))
19848	33671932	This tumor also exhibited protein-altering mutations in the MMR genes Msi2, Msh4 and Msh5.	('Msi2', 'Gene', (70, 74))	('Msi2', 'Gene', '76626', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('Msh5', 'Gene', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('MMR', 'biological_process', 'GO:0006298', ('60', '63'))	('mutations', 'Var', (43, 52))	('Msh4', 'Gene', (76, 80))	('Msh5', 'Gene', '17687', (85, 89))	('Msh4', 'Gene', '55993', (76, 80))	('tumor', 'Disease', (5, 10))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('protein-altering', 'Reg', (26, 42))
19855	33671932	In human CRC, the initial and rate-limiting mutation is the inactivation of APC leading to adenoma formation.	('adenoma', 'Disease', (91, 98))	('human', 'Species', '9606', (3, 8))	('APC', 'cellular_component', 'GO:0005680', ('76', '79'))	('adenoma', 'Disease', 'MESH:D000236', (91, 98))	('APC', 'Disease', 'MESH:D011125', (76, 79))	('APC', 'Disease', (76, 79))	('formation', 'biological_process', 'GO:0009058', ('99', '108'))	('inactivation', 'Var', (60, 72))
19856	33671932	Similar to the human disease, in GEMM this initial step is followed by multiple new mutations, recapitulating the genetic progression of CRC.	('mutations', 'Var', (84, 93))	('CRC', 'Disease', (137, 140))	('human', 'Species', '9606', (15, 20))
19857	33671932	In addition, the GEMM tumors exhibit similar biological and clinical changes upon mutations in Kras and Trp53 in comparison to human CRC, including genomic destabilization, faster progression, de-differentiation and increased metastatic activity.	('metastatic activity', 'CPA', (226, 245))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('human', 'Species', '9606', (127, 132))	('de-differentiation', 'CPA', (193, 211))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('Kras', 'Gene', (95, 99))	('Trp53', 'Gene', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('faster', 'PosReg', (173, 179))	('mutations', 'Var', (82, 91))	('tumors', 'Disease', (22, 28))	('increased', 'PosReg', (216, 225))
19861	33671932	In contrast, tumors with point mutations in the Trp53 gene proliferate slower but exhibit increased metastatic capacity.	('slower', 'NegReg', (71, 77))	('proliferate', 'CPA', (59, 70))	('tumors', 'Disease', (13, 19))	('Trp53', 'Gene', (48, 53))	('increased', 'PosReg', (90, 99))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('point mutations', 'Var', (25, 40))	('metastatic capacity', 'CPA', (100, 119))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
19862	33671932	In line with previous investigations on Trp53 mutations, this indicates not only incomplete dominant negative effects of the mutant P53 protein and some retained function of the WT allele but also functional gains of Trp53 R172H, increasing the metastatic activity of tumor cells with this mutation.	('R172H', 'Mutation', 'rs372604524', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('Trp53', 'Gene', (217, 222))	('mutant', 'Var', (125, 131))	('tumor', 'Disease', (268, 273))	('P53', 'Gene', (132, 135))	('gains', 'PosReg', (208, 213))	('increasing', 'PosReg', (230, 240))	('function', 'MPA', (162, 170))	('negative', 'NegReg', (101, 109))	('protein', 'Protein', (136, 143))	('R172H', 'Var', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (268, 273))	('P53', 'Gene', '22059', (132, 135))
19863	33671932	Exome sequencing of AKPr revealed numerous mutations and pathways involved in migration and invasion of cancer cells as well as immune modulating pathways, which may increase the metastatic activity as well as the chance of tumor cell survival during the process of metastasis.	('metastatic activity', 'CPA', (179, 198))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('AKPr', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('increase', 'PosReg', (166, 174))	('invasion', 'CPA', (92, 100))	('tumor', 'Disease', (224, 229))	('mutations', 'Var', (43, 52))	('involved', 'Reg', (66, 74))	('migration', 'CPA', (78, 87))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
19866	33671932	While the data presented here is derived from mice with four different genotypes, the model can be easily adapted for multiple other CRC subtypes by introducing other conditional mutations such as Pik3ca, Pten, or Smad4.	('Pten', 'Gene', (205, 209))	('Pten', 'Gene', '19211', (205, 209))	('Pik3ca', 'Gene', (197, 203))	('Pik3ca', 'Gene', '18706', (197, 203))	('Smad4', 'Gene', (214, 219))	('mice', 'Species', '10090', (46, 50))	('mutations', 'Var', (179, 188))	('Smad4', 'Gene', '17128', (214, 219))
19870	33671932	The following are available online at , Table S1: List of genes which are mutated in both the GEMM and the The Cancer Genome Atlas (TCGA) human CRC dataset, Table S2: List of mutated genes shared between different genotypes, Table S3: List of unique and common TCGA >1% genes between AKPr and AKPfl tumors, Table S4: Overview of all the enriched pathways between AKPfl and AKPr, Table S5: Comparison of enriched pathways between human and mouse for AKPfl and AKPr genotypes, Table S6: Mutations in mismatch repair genes and MSI analysis, Table S7: Overview of the metastatic pattern seen in the different genotypes, Figure S1: Poorly differentiated and anaplastic tumors are more frequent in Trp53-mutant GEMMs, Figure S2: Tumor cells derived from AKPr mice have higher migration ability in comparison with tumor cells derived from AKPfl mice, Figure S3.	('tumor', 'Disease', (807, 812))	('AKPfl tumors', 'Disease', (293, 305))	('mismatch repair', 'biological_process', 'GO:0006298', ('498', '513'))	('tumor', 'Disease', 'MESH:D009369', (664, 669))	('tumors', 'Phenotype', 'HP:0002664', (664, 670))	('tumor', 'Disease', 'MESH:D009369', (807, 812))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('human', 'Species', '9606', (429, 434))	('mice', 'Species', '10090', (838, 842))	('tumor', 'Phenotype', 'HP:0002664', (664, 669))	('tumors', 'Phenotype', 'HP:0002664', (299, 305))	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))	('migration ability', 'CPA', (770, 787))	('tumor', 'Phenotype', 'HP:0002664', (807, 812))	('frequent', 'Reg', (680, 688))	('Cancer', 'Disease', (111, 117))	('AKPfl tumors', 'Disease', 'MESH:D009369', (293, 305))	('Trp53-mutant', 'Gene', (692, 704))	('mouse', 'Species', '10090', (439, 444))	('tumor', 'Disease', (299, 304))	('Trp53-mutant', 'Var', (692, 704))	('anaplastic tumors', 'Disease', 'MESH:D002277', (653, 670))	('human', 'Species', '9606', (138, 143))	('Tumor', 'Phenotype', 'HP:0002664', (723, 728))	('tumor', 'Disease', (664, 669))	('mice', 'Species', '10090', (753, 757))	('anaplastic tumors', 'Disease', (653, 670))	('Cancer', 'Disease', 'MESH:D009369', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('higher', 'PosReg', (763, 769))
19871	33671932	The GEMMs recapitulate the increased mutation number observed in TP53-mutant human CRC.	('mutation', 'MPA', (37, 45))	('increased', 'PosReg', (27, 36))	('human', 'Species', '9606', (77, 82))	('TP53-mutant', 'Var', (65, 76))
19881	33530546	Changes in lipid metabolism, so-called "lipid metabolic reprogramming", can affect cellular functions including the cell cycle, proliferation, growth, and differentiation, leading to carcinogenesis.	('cellular functions', 'CPA', (83, 101))	('affect', 'Reg', (76, 82))	('leading to', 'Reg', (172, 182))	('growth', 'CPA', (143, 149))	('lipid', 'Chemical', 'MESH:D008055', (40, 45))	('carcinogenesis', 'Disease', (183, 197))	('differentiation', 'CPA', (155, 170))	('lipid', 'Chemical', 'MESH:D008055', (11, 16))	('proliferation', 'CPA', (128, 141))	('Changes', 'Var', (0, 7))	('carcinogenesis', 'Disease', 'MESH:D063646', (183, 197))	('lipid metabolism', 'MPA', (11, 27))	('cell cycle', 'CPA', (116, 126))
19921	33530546	Overexpression of CPT1 is associated with tumor progression in several types of cancers such as breast cancer, gastric cancer, and prostate cancer.	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('CPT1', 'Gene', '1376', (18, 22))	('CPT', 'molecular_function', 'GO:0004095', ('18', '21'))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Disease', (96, 109))	('Overexpression', 'Var', (0, 14))	('associated with', 'Reg', (26, 41))	('gastric cancer', 'Disease', 'MESH:D013274', (111, 125))	('tumor', 'Disease', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('CPT1', 'Gene', (18, 22))	('CPT', 'molecular_function', 'GO:0004142', ('18', '21'))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('cancers', 'Disease', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('prostate cancer', 'Disease', 'MESH:D011471', (131, 146))	('prostate cancer', 'Phenotype', 'HP:0012125', (131, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('gastric cancer', 'Disease', (111, 125))	('prostate cancer', 'Disease', (131, 146))
19928	33530546	Glioblastoma cells store excess FAs into triglycerides and lipid droplets (LDs) by upregulating diacylglycerol-acyltransferase 1 (DGAT1), and inhibition of DGAT1 promotes glioblastoma cell death through excessive FAO-mediated reactive oxidative species (ROS) production.	('ROS', 'Chemical', '-', (254, 257))	('lipid', 'Chemical', 'MESH:D008055', (59, 64))	('DGAT1', 'Gene', '8694', (156, 161))	('upregulating', 'PosReg', (83, 95))	('DGAT1', 'Gene', '8694', (130, 135))	('diacylglycerol-acyltransferase 1', 'Gene', (96, 128))	('FAs', 'Chemical', 'MESH:D005227', (32, 35))	('diacylglycerol-acyltransferase 1', 'Gene', '8694', (96, 128))	('Glioblastoma', 'Disease', (0, 12))	('glioblastoma cell death', 'Disease', 'MESH:D005909', (171, 194))	('DGAT1', 'Gene', (156, 161))	('DGAT1', 'Gene', (130, 135))	('glioblastoma', 'Phenotype', 'HP:0012174', (171, 183))	('promotes', 'PosReg', (162, 170))	('cell death', 'biological_process', 'GO:0008219', ('184', '194'))	('glioblastoma cell death', 'Disease', (171, 194))	('reactive oxidative species', 'Chemical', '-', (226, 252))	('inhibition', 'Var', (142, 152))	('triglycerides', 'Chemical', 'MESH:D014280', (41, 54))	('FAO-mediated reactive oxidative species', 'MPA', (213, 252))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('excessive', 'PosReg', (203, 212))
19931	33530546	Therefore, specific metabolites generated by the altered lipid metabolism may be biomarkers for cancer.	('altered', 'Var', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lipid metabolism', 'MPA', (57, 73))	('cancer', 'Disease', (96, 102))	('lipid metabolism', 'biological_process', 'GO:0006629', ('57', '73'))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('lipid', 'Chemical', 'MESH:D008055', (57, 62))
19954	33530546	Furthermore, loss of SQLE leads to the upstream accumulation of squalene, which protects cells from ferroptosis by maintaining an appropriate composition of membranous polyunsaturated fatty acids (PUFAs).	('PUFAs', 'Chemical', 'MESH:D005231', (197, 202))	('SQLE', 'Gene', '6713', (21, 25))	('squalene', 'Chemical', 'MESH:D013185', (64, 72))	('SQLE', 'Gene', (21, 25))	('ferroptosis', 'Disease', (100, 111))	('polyunsaturated fatty acids', 'Chemical', 'MESH:D005231', (168, 195))	('loss', 'Var', (13, 17))
19960	33530546	On the other hand, oxidized sterols are known to be LXR ligands and inhibit cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('76', '94'))	('oxidized', 'Var', (19, 27))	('inhibit', 'NegReg', (68, 75))	('cell proliferation', 'CPA', (76, 94))	('sterols', 'Chemical', 'MESH:D013261', (28, 35))
19961	33530546	27HC, 24(R/S), and 25-epoxycholesterol inhibit growth and metastasis of gastric cancer by activating LXR signaling.	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('inhibit growth and metastasis of gastric cancer', 'Phenotype', 'HP:0006753', (39, 86))	('inhibit', 'NegReg', (39, 46))	('LXR signaling', 'MPA', (101, 114))	('25-epoxycholesterol', 'Chemical', '-', (19, 38))	('27HC', 'Chemical', 'MESH:C076996', (0, 4))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('25-epoxycholesterol', 'Var', (19, 38))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('activating', 'PosReg', (90, 100))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('gastric cancer', 'Disease', (72, 86))
19969	33530546	In prostate cancer, loss of phosphatase and tensin homolog (PTEN) activates the PI3K-Akt pathway and increases cholesterol uptake and esterification, leading to CE accumulation.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('cholesterol uptake', 'MPA', (111, 129))	('PTEN', 'Gene', (60, 64))	('Akt', 'Gene', (85, 88))	('prostate cancer', 'Disease', (3, 18))	('increases cholesterol', 'Phenotype', 'HP:0003124', (101, 122))	('Akt', 'Gene', '207', (85, 88))	('PTEN', 'Gene', '5728', (60, 64))	('cholesterol', 'Chemical', 'MESH:D002784', (111, 122))	('PI3K', 'molecular_function', 'GO:0016303', ('80', '84'))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('28', '58'))	('loss', 'Var', (20, 24))	('esterification', 'MPA', (134, 148))	('CE accumulation', 'MPA', (161, 176))	('phosphatase', 'molecular_function', 'GO:0016791', ('28', '39'))	('activates', 'PosReg', (66, 75))	('increases', 'PosReg', (101, 110))	('phosphatase and tensin homolog', 'Gene', '5728', (28, 58))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cholesterol uptake', 'biological_process', 'GO:0070508', ('111', '129'))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
19971	33530546	Inhibition of cholesterol metabolism has been considered a feasible anti-tumor therapy.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('cholesterol metabolism', 'MPA', (14, 36))	('cholesterol', 'Chemical', 'MESH:D002784', (14, 25))	('Inhibition', 'Var', (0, 10))
19978	33530546	Inhibition of cholesterol esterification is also an effective approach.	('cholesterol esterification', 'MPA', (14, 40))	('cholesterol', 'Chemical', 'MESH:D002784', (14, 25))	('Inhibition', 'Var', (0, 10))
20012	33530546	Microtubule-associated protein 1S (MAP1S)-mediated lipophagy promotes the elimination of lipid droplets, and high expression of MAP1S is associated with the suppression of tumor growth and metastasis and an improved prognosis in clear-cell renal cell carcinoma.	('Microtubule-associated protein 1S', 'Gene', '55201', (0, 33))	('MAP1S', 'Gene', (128, 133))	('high expression', 'Var', (109, 124))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('lipid', 'Chemical', 'MESH:D008055', (89, 94))	('tumor', 'Disease', (172, 177))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (229, 260))	('elimination of lipid droplets', 'MPA', (74, 103))	('clear-cell renal cell carcinoma', 'Disease', (229, 260))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (240, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('Microtubule-associated protein 1S', 'Gene', (0, 33))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (229, 260))	('MAP1S', 'Gene', '55201', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('suppression', 'NegReg', (157, 168))	('MAP1S', 'Gene', '55201', (128, 133))	('MAP1S', 'Gene', (35, 40))
20015	33530546	Re-expression of LAL in the liver and lungs improves inflammation and prevents metastasis to the same areas.	('metastasis to the same areas', 'CPA', (79, 107))	('LAL', 'Gene', (17, 20))	('improves', 'PosReg', (44, 52))	('inflammation', 'Disease', 'MESH:D007249', (53, 65))	('Re-expression', 'Var', (0, 13))	('inflammation', 'Disease', (53, 65))	('inflammation', 'biological_process', 'GO:0006954', ('53', '65'))	('prevents', 'NegReg', (70, 78))
20045	33530546	Overexpression of LPCAT1 has been shown to increase cell proliferation, migration, and metastasis in clear cell renal cell carcinoma and HCC cell lines.	('migration', 'CPA', (72, 81))	('metastasis', 'CPA', (87, 97))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (101, 132))	('clear cell renal cell carcinoma', 'Disease', (101, 132))	('cell proliferation', 'CPA', (52, 70))	('LPCAT1', 'Gene', '79888', (18, 24))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (112, 132))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (101, 132))	('HCC', 'Phenotype', 'HP:0001402', (137, 140))	('increase', 'PosReg', (43, 51))	('Overexpression', 'Var', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('LPCAT1', 'Gene', (18, 24))
20052	33530546	Loss of LPCAT3 in the mouse gut reduces the composition of polyunsaturated phospholipids and promotes tumor development and growth in Apcmin mice.	('LPCAT3', 'Gene', (8, 14))	('tumor', 'Disease', (102, 107))	('growth', 'CPA', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('polyunsaturated phospholipids', 'Chemical', '-', (59, 88))	('reduces', 'NegReg', (32, 39))	('mice', 'Species', '10090', (141, 145))	('mouse', 'Species', '10090', (22, 27))	('promotes', 'PosReg', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Loss', 'Var', (0, 4))	('composition of polyunsaturated phospholipids', 'MPA', (44, 88))
20065	33530546	Inhibition of ACAT1 in CD8 T cells alters cholesterol synthesis and leads to an accumulation of free cholesterol in the plasma membrane.	('cholesterol synthesis', 'MPA', (42, 63))	('CD8', 'Gene', (23, 26))	('ACAT1', 'Gene', '38', (14, 19))	('CD8', 'Gene', '925', (23, 26))	('plasma membrane', 'cellular_component', 'GO:0005886', ('120', '135'))	('cholesterol synthesis', 'biological_process', 'GO:0006695', ('42', '63'))	('Inhibition', 'Var', (0, 10))	('cholesterol', 'Chemical', 'MESH:D002784', (42, 53))	('accumulation', 'PosReg', (80, 92))	('alters', 'Reg', (35, 41))	('ACAT1', 'Gene', (14, 19))	('cholesterol', 'Chemical', 'MESH:D002784', (101, 112))	('free cholesterol in the plasma membrane', 'MPA', (96, 135))
20069	33530546	On the other hand, cholesterol accumulation in TME has been shown to induce ER stress and further increase T cell exhaustion.	('cholesterol', 'Chemical', 'MESH:D002784', (19, 30))	('T cell exhaustion', 'CPA', (107, 124))	('induce', 'Reg', (69, 75))	('increase T cell', 'Phenotype', 'HP:0100828', (98, 113))	('increase', 'PosReg', (98, 106))	('T cell exhaustion', 'Phenotype', 'HP:0005435', (107, 124))	('ER', 'Gene', '2069', (76, 78))	('cholesterol accumulation', 'Var', (19, 43))
20073	33530546	Inactivation of LXR-alpha ligand through the inhibition of cholesterol synthesis or expression of SULT2B1b (an enzyme that converts oxysterol to inactive sulfated oxysterol) in tumor-bearing mice restores dendritic cell function and antitumor response.	('inhibition', 'NegReg', (45, 55))	('tumor', 'Disease', (237, 242))	('oxysterol', 'Chemical', 'MESH:D000072376', (132, 141))	('fat', 'Gene', '948', (157, 160))	('oxysterol', 'Chemical', 'MESH:D000072376', (163, 172))	('fat', 'Gene', (157, 160))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('restores', 'PosReg', (196, 204))	('cholesterol', 'Chemical', 'MESH:D002784', (59, 70))	('SULT2B1b', 'Gene', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('dendritic cell function', 'CPA', (205, 228))	('mice', 'Species', '10090', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Disease', (177, 182))	('cholesterol synthesis', 'MPA', (59, 80))	('Inactivation', 'Var', (0, 12))
20078	33530546	22HC is abundant in the conditioned medium of various cancer cells and can mobilize CD11bhighGr1high neutrophils.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('CD11bhighGr1high', 'Var', (84, 100))	('mobilize', 'MPA', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
20082	33530546	27HC promotes metastasis by attracting polymorphonuclear neutrophils and gammadelta T cells and reducing cytotoxic CD8 T cells in a high-cholesterol diet-fed breast cancer model.	('CD8', 'Gene', '925', (115, 118))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('high-cholesterol', 'Phenotype', 'HP:0003124', (132, 148))	('metastasis', 'CPA', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Disease', (158, 171))	('reducing', 'NegReg', (96, 104))	('cholesterol', 'Chemical', 'MESH:D002784', (137, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('27HC', 'Chemical', 'MESH:C076996', (0, 4))	('27HC', 'Var', (0, 4))	('attracting', 'PosReg', (28, 38))	('promotes', 'PosReg', (5, 13))	('CD8', 'Gene', (115, 118))
20084	33530546	Overexpression of LOX-1 has been found in several cancers and is associated with a poor prognosis.	('found', 'Reg', (33, 38))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('LOX-1', 'Gene', '4973', (18, 23))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('Overexpression', 'Var', (0, 14))	('LOX-1', 'Gene', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
20088	33530546	Thus, STAT3 or STAT5 inhibition, or CD36 deletion, are known to downregulate lipid metabolism and prevent the immunosuppressive functions of MDSCs.	('immunosuppressive functions', 'CPA', (110, 137))	('STAT3', 'MPA', (6, 11))	('prevent', 'NegReg', (98, 105))	('CD36', 'Gene', (36, 40))	('downregulate', 'NegReg', (64, 76))	('lipid metabolism', 'MPA', (77, 93))	('deletion', 'Var', (41, 49))	('CD36', 'Species', '42374', (36, 40))	('lipid', 'Chemical', 'MESH:D008055', (77, 82))
20134	32214837	Association of XRCC1, XRCC2 and XRCC3 Gene Polymorphism with Esophageal Cancer Risk The X-ray repair cross-complementing (XRCC) gene polymorphisms influence esophageal carcinogenesis by altering the DNA repair capacity.	('DNA repair capacity', 'MPA', (199, 218))	('polymorphisms', 'Var', (133, 146))	('XRCC3', 'Gene', (32, 37))	('Esophageal Cancer', 'Disease', (61, 78))	('esophageal carcinogenesis', 'Disease', (157, 182))	('XRCC2', 'Gene', (22, 27))	('XRCC3', 'Gene', '7517', (32, 37))	('XRCC1', 'Gene', '7515', (15, 20))	('altering', 'Reg', (186, 194))	('influence', 'Reg', (147, 156))	('men', 'Species', '9606', (113, 116))	('XRCC2', 'Gene', '7516', (22, 27))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (61, 78))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (157, 182))	('XRCC1', 'Gene', (15, 20))
20135	32214837	The present study was designed to screen five single nucleotide polymorphisms (SNPs) of XRCC genes for their susceptibility to esophageal cancer (EC) risk.	('susceptibility', 'Reg', (109, 123))	('esophageal cancer', 'Disease', (127, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('XRCC genes', 'Gene', (88, 98))	('single nucleotide polymorphisms', 'Var', (46, 77))
20138	32214837	For XRCC1 p.Arg399Gln, a decreased risk for EC was associated with the AA genotype [OR (95% CI): 0.53 (0.3-0.95), p=0.03] even after adjusting for various covariates [OR (95% CI): 0.49 (0.26-0.9), p=0.024] and with the recessive model [OR (95% CI): 0.49 (0.27-0.8), p=0.016].	('p.Arg399Gln', 'Var', (10, 21))	('XRCC1', 'Gene', (4, 9))	('p.Arg399Gln', 'Mutation', 'rs25487', (10, 21))	('decreased', 'NegReg', (25, 34))
20140	32214837	The two XRCC1 polymorphisms, p.Arg399Gln and p.Arg194Trp were in slight LD among EC patients (D=0.845, r2=0.042).	('XRCC1 p', 'Gene', '7515', (8, 15))	('p.Arg399Gln', 'Var', (29, 40))	('p.Arg399Gln', 'Mutation', 'rs25487', (29, 40))	('patients', 'Species', '9606', (84, 92))	('p.Arg194Trp', 'Mutation', 'rs1799782', (45, 56))	('p.Arg194Trp', 'Var', (45, 56))	('XRCC1 p', 'Gene', (8, 15))
20141	32214837	XRCC2 and XRCC3 polymorphisms were not associated with EC risk.	('polymorphisms', 'Var', (16, 29))	('XRCC2', 'Gene', '7516', (0, 5))	('XRCC2', 'Gene', (0, 5))	('XRCC3', 'Gene', (10, 15))	('XRCC3', 'Gene', '7517', (10, 15))
20142	32214837	XRCC1 p.Arg399Gln plays a protective role in the development of the EC.	('p.Arg399Gln', 'Mutation', 'rs25487', (6, 17))	('XRCC1', 'Gene', (0, 5))	('men', 'Species', '9606', (56, 59))	('p.Arg399Gln', 'Var', (6, 17))
20143	32214837	The study is the first report from India, providing baseline data about genetic polymorphisms in DNA repair genes XRCC1, XRCC2 and XRCC3 modulating overall EC risk.	('XRCC3', 'Gene', '7517', (131, 136))	('modulating', 'Reg', (137, 147))	('XRCC1', 'Gene', '7515', (114, 119))	('XRCC2', 'Gene', '7516', (121, 126))	('polymorphisms', 'Var', (80, 93))	('XRCC2', 'Gene', (121, 126))	('XRCC3', 'Gene', (131, 136))	('XRCC1', 'Gene', (114, 119))
20148	32214837	XRCC1 protein as a part of Base excision repair (BER) pathway plays an efficient role in repairing DNA single-strand breaks.	('XRCC1 p', 'Gene', (0, 7))	('DNA', 'Var', (99, 102))	('repairing', 'MPA', (89, 98))	('XRCC1 p', 'Gene', '7515', (0, 7))
20150	32214837	Two XRCC1 polymorphisms, p.Arg194Trp (exon 6) and p. Arg280His (exon 9) affect the function of the protein.	('Arg280His', 'Var', (53, 62))	('affect', 'Reg', (72, 78))	('p.Arg194Trp', 'Mutation', 'rs1799782', (25, 36))	('XRCC1 p', 'Gene', (4, 11))	('p.Arg194Trp', 'Var', (25, 36))	('XRCC1 p', 'Gene', '7515', (4, 11))	('Arg280His', 'SUBSTITUTION', 'None', (53, 62))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('function of the protein', 'MPA', (83, 106))
20151	32214837	XRCC1 p.Arg399Gln polymorphism in exon 10 has been associated with breast, lung and head and neck cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('XRCC1', 'Gene', (0, 5))	('neck cancers', 'Disease', (93, 105))	('head and neck cancer', 'Disease', 'MESH:D006258', (84, 104))	('p.Arg399Gln', 'Var', (6, 17))	('associated', 'Reg', (51, 61))	('p.Arg399Gln', 'Mutation', 'rs25487', (6, 17))	('neck cancers', 'Disease', 'MESH:D006258', (93, 105))	('breast', 'Disease', (67, 73))	('head and neck cancer', 'Phenotype', 'HP:0012288', (84, 104))	('lung', 'Disease', (75, 79))	('head and neck cancers', 'Phenotype', 'HP:0012288', (84, 105))
20153	32214837	XRCC2 p.Arg188His polymorphism located in exon3 has been associated with cancers like pancreatic, ovarian, oral and upper aerodigestive tract cancers.	('cancers', 'Disease', (73, 80))	('pancreatic', 'Disease', (86, 96))	('upper aerodigestive tract cancers', 'Disease', (116, 149))	('upper aerodigestive tract cancers', 'Disease', 'MESH:D006258', (116, 149))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('XRCC2', 'Gene', '7516', (0, 5))	('p.Arg188His', 'Mutation', 'rs3218536', (6, 17))	('p.Arg188His', 'Var', (6, 17))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('XRCC2', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('pancreatic', 'Disease', 'MESH:D010195', (86, 96))	('ovarian', 'Disease', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('associated', 'Reg', (57, 67))
20155	32214837	Variation in expression of XRCC3 has been reported in various cancers, like gastric, breast, lung, skin and colorectal.	('colorectal', 'Disease', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('expression', 'MPA', (13, 23))	('reported', 'Reg', (42, 50))	('lung', 'Disease', (93, 97))	('XRCC3', 'Gene', (27, 32))	('skin', 'Disease', (99, 103))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('gastric', 'Disease', (76, 83))	('XRCC3', 'Gene', '7517', (27, 32))	('breast', 'Disease', (85, 91))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('Variation', 'Var', (0, 9))
20156	32214837	The most common polymorphism in XRCC3 p.Thr241Met in exon 7 can influence the ability to repair DNA.	('XRCC3', 'Gene', (32, 37))	('p.Thr241Met', 'Var', (38, 49))	('ability', 'MPA', (78, 85))	('XRCC3', 'Gene', '7517', (32, 37))	('influence', 'Reg', (64, 73))	('p.Thr241Met', 'Mutation', 'rs861539', (38, 49))
20157	32214837	Allelic variants of XRCC1, XRCC2, and XRCC3 are associated with risk of different types of cancer among different populations all over the world.	('associated', 'Reg', (48, 58))	('XRCC1', 'Gene', (20, 25))	('cancer', 'Disease', (91, 97))	('Allelic variants', 'Var', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('XRCC2', 'Gene', '7516', (27, 32))	('XRCC3', 'Gene', (38, 43))	('XRCC2', 'Gene', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('XRCC3', 'Gene', '7517', (38, 43))	('XRCC1', 'Gene', '7515', (20, 25))
20160	32214837	Therefore, the present study was carried out to explore the role of five polymorphisms of XRCC genes; XRCC1 (p.Arg399Gln, p.Arg194Trp, p.Arg280His), XRCC2 (p.Arg188His) and XRCC3 (p.Thr241Met) in the risk of EC in the population of Punjab, India.	('p.Arg280His', 'Var', (135, 146))	('p.Arg399Gln', 'Var', (109, 120))	('XRCC3', 'Gene', (173, 178))	('XRCC3', 'Gene', '7517', (173, 178))	('p.Arg280His', 'Mutation', 'rs25489', (135, 146))	('p.Arg399Gln', 'Mutation', 'rs25487', (109, 120))	('p.Arg194Trp', 'Mutation', 'rs1799782', (122, 133))	('XRCC1', 'Gene', (102, 107))	('p.Arg194Trp', 'Var', (122, 133))	('p.Thr241Met', 'Mutation', 'rs861539', (180, 191))	('XRCC genes', 'Gene', (90, 100))	('p.Arg188His', 'Mutation', 'rs3218536', (156, 167))	('p.Arg188His', 'Var', (156, 167))	('XRCC1', 'Gene', '7515', (102, 107))	('p.Thr241Met', 'Var', (180, 191))	('XRCC2', 'Gene', '7516', (149, 154))	('XRCC2', 'Gene', (149, 154))
20165	32214837	Previously published primer sequences for XRCC1 p.Arg399Gln, XRCC1 p.Arg194Trp, XRCC1 p.Arg280His, XRCC2 p.Arg188His and XRCC3 p.Thr241Met polymorphisms were used to amplify the target region.	('XRCC1', 'Gene', (61, 66))	('p.Arg194Trp', 'Mutation', 'rs1799782', (67, 78))	('p.Thr241Met', 'Var', (127, 138))	('XRCC2', 'Gene', '7516', (99, 104))	('XRCC2', 'Gene', (99, 104))	('XRCC1', 'Gene', (42, 47))	('XRCC3', 'Gene', '7517', (121, 126))	('p.Arg399Gln', 'Var', (48, 59))	('p.Arg280His', 'Var', (86, 97))	('p.Arg399Gln', 'Mutation', 'rs25487', (48, 59))	('p.Arg194Trp', 'Var', (67, 78))	('p.Thr241Met', 'Mutation', 'rs861539', (127, 138))	('p.Arg188His', 'Var', (105, 116))	('XRCC1', 'Gene', (80, 85))	('p.Arg280His', 'Mutation', 'rs25489', (86, 97))	('XRCC3', 'Gene', (121, 126))	('p.Arg188His', 'Mutation', 'rs3218536', (105, 116))
20172	32214837	In the present study 5 polymorphisms; XRCC1 (p.Arg399Gln, p.Arg280His, p.Arg194Trp), XRCC2 (p.Arg188His) and XRCC3 (p.Thr241Met) were studied for the association with risk of esophageal cancer (EC).	('p.Thr241Met', 'Var', (116, 127))	('XRCC2', 'Gene', '7516', (85, 90))	('XRCC1', 'Gene', (38, 43))	('p.Arg399Gln', 'Var', (45, 56))	('XRCC3', 'Gene', '7517', (109, 114))	('p.Arg280His', 'Mutation', 'rs25489', (58, 69))	('p.Arg194Trp', 'Mutation', 'rs1799782', (71, 82))	('p.Arg188His', 'Mutation', 'rs3218536', (92, 103))	('p.Arg188His', 'Var', (92, 103))	('p.Arg194Trp', 'Var', (71, 82))	('XRCC1', 'Gene', '7515', (38, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('XRCC2', 'Gene', (85, 90))	('XRCC3', 'Gene', (109, 114))	('p.Thr241Met', 'Mutation', 'rs861539', (116, 127))	('esophageal cancer', 'Disease', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('p.Arg280His', 'Var', (58, 69))	('p.Arg399Gln', 'Mutation', 'rs25487', (45, 56))
20173	32214837	For XRCC1 p.Arg280His polymorphism, A allele was associated with an increased risk of EC (OR=1.60, 95% CI= 1.02-2.52, p=0.04).	('XRCC1', 'Gene', (4, 9))	('p.Arg280His', 'Var', (10, 21))	('p.Arg280His', 'Mutation', 'rs25489', (10, 21))
20179	32214837	No significant difference in allele (p=0.54) and genotype (p=0.52) frequencies of XRCC1 p.Arg194Trp polymorphism was observed.	('p.Arg194Trp', 'Var', (88, 99))	('XRCC1', 'Gene', (82, 87))	('p.Arg194Trp', 'Mutation', 'rs1799782', (88, 99))
20180	32214837	No association with EC risk was observed for XRCC2 p.Arg188His and XRCC3 p.Thr241Met polymorphism (p=0.53) in the subjects.	('p.Thr241Met', 'Mutation', 'rs861539', (73, 84))	('XRCC3', 'Gene', (67, 72))	('XRCC3', 'Gene', '7517', (67, 72))	('p.Arg188His', 'Mutation', 'rs3218536', (51, 62))	('p.Thr241Met', 'Var', (73, 84))	('p.Arg188His', 'Var', (51, 62))	('XRCC2', 'Gene', '7516', (45, 50))	('XRCC2', 'Gene', (45, 50))
20181	32214837	Genetic model analysis of XRCC1 p.Arg399Gln and XRCC3p.Thr241Met (Table 6) revealed a decreased risk of EC under the recessive model AA vs GG+GA (OR=0.55, 95% CI=0.32-0.95, p=0.027) for XRCC1p.Arg399Gln polymorphism which became more significant after adjustment with binomial logistic regression (OR=0.49, 95% CI=0.27-0.88, p=0.016).	('p.Arg399Gln', 'Mutation', 'rs25487', (191, 202))	('men', 'Species', '9606', (258, 261))	('XRCC1', 'Gene', (26, 31))	('p.Arg399Gln', 'SUBSTITUTION', 'None', (32, 43))	('p.Arg399Gln', 'SUBSTITUTION', 'None', (191, 202))	('p.Thr241Met', 'Var', (53, 64))	('decreased', 'NegReg', (86, 95))	('p.Thr241Met', 'SUBSTITUTION', 'None', (53, 64))	('p.Arg399Gln', 'Var', (32, 43))	('p.Arg399Gln', 'Var', (191, 202))	('p.Arg399Gln', 'Mutation', 'rs25487', (32, 43))
20182	32214837	For p.Thr241Met polymorphism no genotype combination was associated with EC.	('p.Thr241Met', 'Mutation', 'rs861539', (4, 15))	('p.Thr241Met', 'Var', (4, 15))	('associated', 'Reg', (57, 67))
20184	32214837	Based on the measures of linkage disequilibrium (LD), the two polymorphisms of XRCC1gene, p.Arg399Gln and p.Arg194Trp, were in slight LD among EC patients (D=0.845, r2=0.042) (Figure 1A).	('XRCC1', 'Gene', '7515', (79, 84))	('p.Arg194Trp', 'Var', (106, 117))	('p.Arg194Trp', 'Mutation', 'rs1799782', (106, 117))	('XRCC1', 'Gene', (79, 84))	('p.Arg399Gln', 'Var', (90, 101))	('p.Arg399Gln', 'Mutation', 'rs25487', (90, 101))	('patients', 'Species', '9606', (146, 154))
20185	32214837	The haplotype GGT (p.Arg399Gln, p.Arg280His, and p.Arg194Trp) was predominant in EC cases as compared to controls, but the difference was statistically non-significant (p=0.1).	('p.Arg280His', 'Var', (32, 43))	('p.Arg399Gln', 'Mutation', 'rs25487', (19, 30))	('p.Arg280His', 'Mutation', 'rs25489', (32, 43))	('p.Arg194Trp', 'Mutation', 'rs1799782', (49, 60))	('p.Arg194Trp', 'Var', (49, 60))	('p.Arg399Gln', 'Var', (19, 30))
20187	32214837	The combinations comprising the AA genotype (p.Arg399Gln) occurred significantly more often in controls than patients, with AA-CC-CC combination associated with significantly decreased risk of EC (OR=0.5, 95% CI=0.29-0.91, p=0.020).	('p.Arg399Gln', 'Mutation', 'rs25487', (45, 56))	('decreased', 'NegReg', (175, 184))	('p.Arg399Gln', 'Var', (45, 56))	('patients', 'Species', '9606', (109, 117))
20188	32214837	According to MDR analysis, the best MDR model included all the five studied polymorphisms XRCC1 (p.Arg399Gln, p.Arg194Trp, p.Arg280His), XRCC2 (p.Arg188His) and XRCC3 (p.Thr241Met).	('p.Arg188His', 'Var', (144, 155))	('XRCC1', 'Gene', '7515', (90, 95))	('p.Arg280His', 'Var', (123, 134))	('p.Thr241Met', 'Var', (168, 179))	('XRCC3', 'Gene', (161, 166))	('p.Arg194Trp', 'Var', (110, 121))	('XRCC2', 'Gene', '7516', (137, 142))	('XRCC2', 'Gene', (137, 142))	('XRCC3', 'Gene', '7517', (161, 166))	('p.Arg280His', 'Mutation', 'rs25489', (123, 134))	('p.Arg194Trp', 'Mutation', 'rs1799782', (110, 121))	('p.Thr241Met', 'Mutation', 'rs861539', (168, 179))	('XRCC1', 'Gene', (90, 95))	('p.Arg399Gln', 'Var', (97, 108))	('p.Arg399Gln', 'Mutation', 'rs25487', (97, 108))	('p.Arg188His', 'Mutation', 'rs3218536', (144, 155))
20191	32214837	In India, the inter-individual differences in susceptibility to cancer due to the genetic polymorphisms in XRCC1 previously found.	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('XRCC1 p', 'Gene', (107, 114))	('susceptibility', 'MPA', (46, 60))	('polymorphisms', 'Var', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('XRCC1 p', 'Gene', '7515', (107, 114))
20192	32214837	As DNA-repair gene polymorphisms play a very important role in carcinogenesis, we carried out this case-control study to evaluate whether XRCC1 (p.Arg399Gln, p.Arg194Trp and p.Arg280His), XRCC2 (p.Arg188His), and XRCC3 (p.Thr241Met) gene polymorphisms modulate the risk of esophageal cancer.	('XRCC2', 'Gene', '7516', (188, 193))	('modulate', 'Reg', (252, 260))	('p.Arg399Gln', 'Mutation', 'rs25487', (145, 156))	('carcinogenesis', 'Disease', 'MESH:D063646', (63, 77))	('p.Arg194Trp', 'Mutation', 'rs1799782', (158, 169))	('esophageal cancer', 'Disease', 'MESH:D004938', (273, 290))	('p.Arg188His', 'Mutation', 'rs3218536', (195, 206))	('p.Arg188His', 'Var', (195, 206))	('p.Arg280His', 'Var', (174, 185))	('XRCC3', 'Gene', (213, 218))	('XRCC1', 'Gene', (138, 143))	('p.Arg399Gln', 'Var', (145, 156))	('p.Thr241Met', 'Mutation', 'rs861539', (220, 231))	('esophageal cancer', 'Disease', (273, 290))	('p.Arg194Trp', 'Var', (158, 169))	('p.Arg280His', 'Mutation', 'rs25489', (174, 185))	('XRCC2', 'Gene', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('XRCC1', 'Gene', '7515', (138, 143))	('p.Thr241Met', 'Var', (220, 231))	('XRCC3', 'Gene', '7517', (213, 218))	('carcinogenesis', 'Disease', (63, 77))
20193	32214837	The XRCC1p.Arg399Gln polymorphism is involved in various protein-protein interactions and higher sister chromatid exchanges and DNA adducts.	('p.Arg399Gln', 'Var', (9, 20))	('p.Arg399Gln', 'SUBSTITUTION', 'None', (9, 20))	('protein-protein interactions', 'Protein', (57, 85))	('higher', 'PosReg', (90, 96))	('involved', 'Reg', (37, 45))
20194	32214837	In the present study, we found that A allele and the AA genotype of XRCC1p.Arg399Gln polymorphism was associated with a decreased risk of esophageal cancer.	('decreased', 'NegReg', (120, 129))	('esophageal cancer', 'Disease', (138, 155))	('p.Arg399Gln', 'SUBSTITUTION', 'None', (73, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('p.Arg399Gln', 'Var', (73, 84))
20195	32214837	Very few studies relating the XRCC1 Arg399Gln polymorphism with esophageal cancer risk are available from which only one is from India.	('XRCC1', 'Gene', (30, 35))	('esophageal cancer', 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('XRCC1', 'Gene', '7515', (30, 35))	('Arg399Gln', 'Var', (36, 45))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))	('Arg399Gln', 'SUBSTITUTION', 'None', (36, 45))
20196	32214837	Among previous reports from North India on EC; a study of Chandigarh region found association with a decreased risk of XRCC1 p.Arg399Gln, another study from Uttar Pradesh also reported Arg/Gln (p=0.03, OR= 0.62) and Gln/Gln (p=0.003, OR=0.37) genotype to be associated with a decreased risk of gall bladder cancer; a study from Kashmir on colorectal cancer also reported a protective role of AA genotype.	('colorectal cancer', 'Phenotype', 'HP:0003003', (339, 356))	('Gln', 'Chemical', 'MESH:D005973', (189, 192))	('colorectal cancer', 'Disease', 'MESH:D015179', (339, 356))	('Arg', 'Chemical', 'MESH:D001120', (185, 188))	('colorectal cancer', 'Disease', (339, 356))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('decreased', 'NegReg', (101, 110))	('XRCC1', 'Gene', (119, 124))	('Arg', 'Chemical', 'MESH:D001120', (127, 130))	('gall bladder cancer', 'Disease', (294, 313))	('Gln', 'Chemical', 'MESH:D005973', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('bladder cancer', 'Phenotype', 'HP:0009725', (299, 313))	('gall bladder cancer', 'Disease', 'MESH:D005706', (294, 313))	('p.Arg399Gln', 'Var', (125, 136))	('Gln', 'Chemical', 'MESH:D005973', (216, 219))	('p.Arg399Gln', 'Mutation', 'rs25487', (125, 136))	('Gln', 'Chemical', 'MESH:D005973', (220, 223))
20198	32214837	Contrary to the results of the present study, some previous studies from North India have reported an increased risk with AA genotype of XRCC1p.Arg399Gln polymorphism in lung cancer, head and neck cancer, colorectal cancer and prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (227, 242))	('head and neck cancer', 'Disease', 'MESH:D006258', (183, 203))	('p.Arg399Gln', 'SUBSTITUTION', 'None', (142, 153))	('colorectal cancer', 'Disease', 'MESH:D015179', (205, 222))	('prostate cancer', 'Phenotype', 'HP:0012125', (227, 242))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('lung cancer', 'Disease', 'MESH:D008175', (170, 181))	('colorectal cancer', 'Phenotype', 'HP:0003003', (205, 222))	('head and neck cancer', 'Phenotype', 'HP:0012288', (183, 203))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('neck', 'cellular_component', 'GO:0044326', ('192', '196'))	('prostate cancer', 'Disease', (227, 242))	('colorectal cancer', 'Disease', (205, 222))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lung cancer', 'Disease', (170, 181))	('p.Arg399Gln', 'Var', (142, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
20200	32214837	However, few studies from South India reported no association of XRCC1p.Arg399Gln polymorphism with any of cancer (Table 1).	('p.Arg399Gln', 'SUBSTITUTION', 'None', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('p.Arg399Gln', 'Var', (70, 81))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('association', 'Interaction', (50, 61))	('cancer', 'Disease', (107, 113))
20201	32214837	Results of the present study on XRCC1 p.Arg399Gln polymorphism is in agreement with the studies from different parts of the globe like esophageal cancer in Han Chinese, colorectal adenocarcinoma in Norwegian population, gallbladder cancer, and non-melanoma skin cancers.	('gallbladder cancer', 'Disease', (220, 238))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('men', 'Species', '9606', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('non-melanoma skin cancers', 'Disease', 'MESH:D012878', (244, 269))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (169, 194))	('skin cancer', 'Phenotype', 'HP:0008069', (257, 268))	('bladder cancer', 'Phenotype', 'HP:0009725', (224, 238))	('cancers', 'Phenotype', 'HP:0002664', (262, 269))	('non-melanoma skin cancers', 'Disease', (244, 269))	('gallbladder cancer', 'Disease', 'MESH:D005706', (220, 238))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('p.Arg399Gln', 'Mutation', 'rs25487', (38, 49))	('skin cancers', 'Phenotype', 'HP:0008069', (257, 269))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('p.Arg399Gln', 'Var', (38, 49))	('esophageal cancer', 'Disease', (135, 152))	('colorectal adenocarcinoma', 'Disease', (169, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('melanoma', 'Phenotype', 'HP:0002861', (248, 256))	('XRCC1', 'Gene', (32, 37))
20202	32214837	In contrast, some previous studies have reported the association of Arg399Gln polymorphism with an increased risk of esophageal, stomach and oral cancers, colorectal cancers in Korean, Egyptian and Japanese populations, lung cancer and breast cancer.	('oral cancers', 'Disease', (141, 153))	('oral cancers', 'Disease', 'MESH:D009062', (141, 153))	('esophageal', 'Disease', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('association', 'Reg', (53, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (236, 249))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('lung cancer', 'Disease', (220, 231))	('stomach', 'Disease', (129, 136))	('colorectal cancers', 'Disease', (155, 173))	('breast cancer', 'Disease', 'MESH:D001943', (236, 249))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('breast cancer', 'Disease', (236, 249))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))	('Arg399Gln', 'SUBSTITUTION', 'None', (68, 77))	('colorectal cancers', 'Disease', 'MESH:D015179', (155, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('Arg399Gln', 'Var', (68, 77))
20203	32214837	However, three studies did not find any association between p.Arg399Gln polymorphism and cancer of the esophagus, gall bladder and breast.	('gall bladder', 'Disease', 'MESH:D005705', (114, 126))	('p.Arg399Gln', 'Var', (60, 71))	('p.Arg399Gln', 'Mutation', 'rs25487', (60, 71))	('gall bladder', 'Disease', (114, 126))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('breast', 'Disease', (131, 137))	('cancer', 'Disease', (89, 95))	('cancer of the esophagus', 'Phenotype', 'HP:0100751', (89, 112))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
20205	32214837	Among international studies, no association of XRCC1 p.Arg194Trp has been reported with EC risk in the population of North Carolina, gastric cancer in Korean population and breast cancer in Caucasian women.	('women', 'Species', '9606', (200, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('gastric cancer', 'Phenotype', 'HP:0012126', (133, 147))	('XRCC1', 'Gene', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('gastric cancer', 'Disease', 'MESH:D013274', (133, 147))	('gastric cancer', 'Disease', (133, 147))	('p.Arg194Trp', 'Var', (53, 64))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('p.Arg194Trp', 'Mutation', 'rs1799782', (53, 64))	('breast cancer', 'Disease', (173, 186))
20206	32214837	On the contrary, Trp allele has been reported to be associated with an increased risk of gastric cancer in the Chinese population.	('associated', 'Reg', (52, 62))	('Trp', 'Gene', (17, 20))	('Trp', 'Chemical', 'MESH:D014364', (17, 20))	('gastric cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (89, 103))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (71, 103))	('allele', 'Var', (21, 27))	('gastric cancer', 'Phenotype', 'HP:0012126', (89, 103))
20208	32214837	In the present study, we observed a lower risk of esophageal cancer associated with p.Arg399Gln polymorphism of XRCC1.	('p.Arg399Gln', 'Var', (84, 95))	('p.Arg399Gln', 'Mutation', 'rs25487', (84, 95))	('XRCC1', 'Gene', (112, 117))	('XRCC1', 'Gene', '7515', (112, 117))	('esophageal cancer', 'Disease', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))
20209	32214837	A relationship between polymorphism in XRCC1Arg399Gln and increased rate of apoptosis has been reported in patients of ulcerative colitis and in schizophrenia patients.	('ulcerative colitis', 'Disease', (119, 137))	('schizophrenia', 'Disease', 'MESH:D012559', (145, 158))	('colitis', 'Phenotype', 'HP:0002583', (130, 137))	('increased', 'PosReg', (58, 67))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('patients', 'Species', '9606', (159, 167))	('schizophrenia', 'Phenotype', 'HP:0100753', (145, 158))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (119, 137))	('polymorphism', 'Var', (23, 35))	('apoptosis', 'CPA', (76, 85))	('XRCC1Arg399Gln', 'Gene', (39, 53))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))	('patients', 'Species', '9606', (107, 115))	('schizophrenia', 'Disease', (145, 158))	('ulcerative colitis', 'Disease', 'MESH:D003093', (119, 137))	('rate', 'MPA', (68, 72))
20210	32214837	The increased rates of the apoptosis results into the elimination of potential premalignant cells and hence, the XRCC1 Gln399 may play a protective role in esophageal cancer risk.	('rates', 'MPA', (14, 19))	('XRCC1', 'Gene', (113, 118))	('Gln399', 'Var', (119, 125))	('esophageal cancer', 'Disease', (156, 173))	('apoptosis', 'CPA', (27, 36))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('Gln399', 'Chemical', '-', (119, 125))	('XRCC1', 'Gene', '7515', (113, 118))
20211	32214837	The A allele of XRCC1p.Arg280His was associated with an increased risk of esophageal cancer in the present study.	('esophageal cancer', 'Disease', (74, 91))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('p.Arg280His', 'Var', (21, 32))	('p.Arg280His', 'SUBSTITUTION', 'None', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
20213	32214837	From the North Indian population, p.Arg280His has been associated with an increased risk of hepatocellular carcinoma but no association has been reported with SCC head and neck.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('SCC', 'Gene', (159, 162))	('p.Arg280His', 'Var', (34, 45))	('SCC', 'Phenotype', 'HP:0002860', (159, 162))	('p.Arg280His', 'Mutation', 'rs25489', (34, 45))	('neck', 'cellular_component', 'GO:0044326', ('172', '176'))	('SCC', 'Gene', '6317', (159, 162))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (92, 116))	('hepatocellular carcinoma', 'Disease', (92, 116))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (92, 116))	('increased risk of hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (74, 116))
20215	32214837	A meta-analysis within the Asian population has reported an association of p.Arg280His polymorphism with bladder cancer risk.	('p.Arg280His', 'Var', (75, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('p.Arg280His', 'Mutation', 'rs25489', (75, 86))	('bladder cancer', 'Disease', 'MESH:D001749', (105, 119))	('bladder cancer', 'Disease', (105, 119))	('association', 'Interaction', (60, 71))
20218	32214837	A study on the Chinese population reported no association between p.Arg280His polymorphism and ESCC.	('SCC', 'Gene', (96, 99))	('SCC', 'Phenotype', 'HP:0002860', (96, 99))	('p.Arg280His', 'Mutation', 'rs25489', (66, 77))	('SCC', 'Gene', '6317', (96, 99))	('p.Arg280His', 'Var', (66, 77))
20220	32214837	No association of XRCC2 p.Arg188His with EC has been observed in the present study, which is the first report from India for esophageal cancer risk.	('p.Arg188His', 'Mutation', 'rs3218536', (24, 35))	('p.Arg188His', 'Var', (24, 35))	('esophageal cancer', 'Disease', (125, 142))	('XRCC2', 'Gene', '7516', (18, 23))	('XRCC2', 'Gene', (18, 23))	('esophageal cancer', 'Disease', 'MESH:D004938', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
20221	32214837	In previous reports from India, no association of XRCC2 p.Arg188His polymorphism was reported with nasopharyngeal carcinoma whereas another study found an association of GA genotype with increased risk of SCC head and neck.	('XRCC2', 'Gene', '7516', (50, 55))	('XRCC2', 'Gene', (50, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (99, 123))	('SCC', 'Gene', (205, 208))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (99, 123))	('p.Arg188His', 'Var', (56, 67))	('p.Arg188His', 'Mutation', 'rs3218536', (56, 67))	('SCC', 'Phenotype', 'HP:0002860', (205, 208))	('nasopharyngeal carcinoma', 'Disease', (99, 123))	('SCC', 'Gene', '6317', (205, 208))
20222	32214837	The contradictory reports from different parts of the world have shown that XRCC2 p.Arg188His polymorphism was associated with a significantly increased risk of pharyngeal cancer and breast cancer but not with bladder cancer, colorectal adenoma, skin cancer, thyroid cancer and breast cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (210, 224))	('bladder cancer', 'Disease', (210, 224))	('skin cancer', 'Disease', 'MESH:D012878', (246, 257))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('breast cancer', 'Disease', 'MESH:D001943', (278, 291))	('associated', 'Reg', (111, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (210, 224))	('breast cancer', 'Disease', (278, 291))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('thyroid cancer', 'Disease', 'MESH:D013964', (259, 273))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('XRCC2', 'Gene', '7516', (76, 81))	('breast cancer', 'Disease', (183, 196))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('colorectal adenoma', 'Disease', 'MESH:D015179', (226, 244))	('thyroid cancer', 'Phenotype', 'HP:0002890', (259, 273))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Disease', (285, 291))	('skin cancer', 'Disease', (246, 257))	('p.Arg188His', 'Mutation', 'rs3218536', (82, 93))	('cancer', 'Disease', (267, 273))	('p.Arg188His', 'Var', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (161, 178))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (251, 257))	('skin cancer', 'Phenotype', 'HP:0008069', (246, 257))	('XRCC2', 'Gene', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Disease', (218, 224))	('thyroid cancer', 'Disease', (259, 273))	('breast cancer', 'Phenotype', 'HP:0003002', (278, 291))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('colorectal adenoma', 'Disease', (226, 244))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
20224	32214837	XRCC3 gene mainly repairs using the HR pathway and in vitro studies revealed high sensitivity to DNA damaging agents in cells with XRCC3 gene knockouts.	('knockouts', 'Var', (142, 151))	('XRCC3', 'Gene', '7517', (131, 136))	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('XRCC3', 'Gene', '7517', (0, 5))	('XRCC3', 'Gene', (0, 5))	('XRCC3', 'Gene', (131, 136))	('sensitivity to DNA damaging agents', 'MPA', (82, 116))
20225	32214837	No association of XRCC3 p.Thr241Met polymorphism with esophageal cancer has been observed in the present study.	('XRCC3', 'Gene', (18, 23))	('p.Thr241Met', 'Var', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('esophageal cancer', 'Disease', (54, 71))	('XRCC3', 'Gene', '7517', (18, 23))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('p.Thr241Met', 'Mutation', 'rs861539', (24, 35))
20228	32214837	For XRCC3 p.Thr241Met polymorphism, no association was reported with gastric cancer in Italian population and with colorectal cancer in the West Algerian population but an association with an increased risk was reported for lung cancer in an Italian population, oral SCC in Thai population, and gastric cancer in the Chinese population.	('SCC', 'Gene', '6317', (267, 270))	('XRCC3', 'Gene', '7517', (4, 9))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (295, 309))	('SCC', 'Gene', (267, 270))	('lung cancer', 'Disease', 'MESH:D008175', (224, 235))	('p.Thr241Met', 'Var', (10, 21))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('lung cancer', 'Phenotype', 'HP:0100526', (224, 235))	('colorectal cancer', 'Phenotype', 'HP:0003003', (115, 132))	('gastric cancer', 'Phenotype', 'HP:0012126', (295, 309))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('gastric cancer', 'Disease', (69, 83))	('XRCC3', 'Gene', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('SCC', 'Phenotype', 'HP:0002860', (267, 270))	('colorectal cancer', 'Disease', 'MESH:D015179', (115, 132))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('lung cancer', 'Disease', (224, 235))	('gastric cancer', 'Disease', (295, 309))	('colorectal cancer', 'Disease', (115, 132))	('p.Thr241Met', 'Mutation', 'rs861539', (10, 21))
20230	32214837	The haplotype analysis in the present study shows an association of haplotype GGT of XRCC1 gene (Arg399-Arg280-194Trp of p.Arg399Gln, p.Arg280His, and p.Arg194Trp polymorphisms) with a risk of EC, however, the association was not statistically significant (Table 7).	('p.Arg280His', 'Mutation', 'rs25489', (134, 145))	('p.Arg194Trp', 'Mutation', 'rs1799782', (151, 162))	('p.Arg280His', 'Var', (134, 145))	('XRCC1', 'Gene', (85, 90))	('p.Arg194Trp', 'Var', (151, 162))	('Arg399-Arg280-194Trp', 'Var', (97, 117))	('p.Arg399Gln', 'Var', (121, 132))	('p.Arg399Gln', 'Mutation', 'rs25487', (121, 132))	('Arg399-Arg280-194Trp', 'Mutation', 'p.R,R399,280-194W', (97, 117))	('association', 'Interaction', (53, 64))	('XRCC1', 'Gene', '7515', (85, 90))
20232	32214837	However, a study from West Bengal (East India) reported CAG haplotype (Arg194-His280-Arg399) to have reduced risk against gastric cancer.	('His280', 'Chemical', '-', (78, 84))	('Arg194', 'Chemical', '-', (71, 77))	('Arg194-His280-Arg399', 'Var', (71, 91))	('gastric cancer', 'Disease', (122, 136))	('reduced', 'NegReg', (101, 108))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('Arg399', 'Chemical', '-', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))
20233	32214837	A study from Uttar Pradesh (North India) reported CGA and CAG haplotype of XRCC1 (Arg194-His280-Arg399) to be associated with prostate cancer and haplotype CGA to be associated with bladder cancer.	('CGA', 'Gene', '1113', (156, 159))	('CGA', 'Gene', (50, 53))	('CGA', 'Gene', '1113', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('associated', 'Reg', (110, 120))	('Arg194', 'Chemical', '-', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('associated', 'Reg', (166, 176))	('bladder cancer', 'Disease', 'MESH:D001749', (182, 196))	('bladder cancer', 'Disease', (182, 196))	('XRCC1', 'Gene', (75, 80))	('bladder cancer', 'Phenotype', 'HP:0009725', (182, 196))	('prostate cancer', 'Disease', 'MESH:D011471', (126, 141))	('Arg399', 'Chemical', '-', (96, 102))	('His280', 'Chemical', '-', (89, 95))	('prostate cancer', 'Phenotype', 'HP:0012125', (126, 141))	('CGA', 'Gene', (156, 159))	('Arg194-His280-Arg399', 'Var', (82, 102))	('prostate cancer', 'Disease', (126, 141))	('XRCC1', 'Gene', '7515', (75, 80))
20235	32214837	The XRCC1 codon 399 Arg/Arg genotype has been associated with increased risk of acute radiation dermatitis in nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy.	('Arg', 'Chemical', 'MESH:D001120', (20, 23))	('patients', 'Species', '9606', (135, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('Arg', 'Chemical', 'MESH:D001120', (24, 27))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (110, 134))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (110, 134))	('XRCC1', 'Gene', (4, 9))	('nasopharyngeal carcinoma', 'Disease', (110, 134))	('dermatitis', 'Phenotype', 'HP:0011123', (96, 106))	('radiation dermatitis', 'Disease', 'MESH:D004194', (86, 106))	('radiation dermatitis', 'Disease', (86, 106))	('codon 399 Arg/Arg', 'Var', (10, 27))	('XRCC1', 'Gene', '7515', (4, 9))
20237	32214837	The present study indicates a protective role of the XRCC1 p.Arg399Gln towards the development of EC.	('p.Arg399Gln', 'Mutation', 'rs25487', (59, 70))	('XRCC1', 'Gene', (53, 58))	('p.Arg399Gln', 'Var', (59, 70))	('men', 'Species', '9606', (90, 93))
20239	32214837	The present study being the first report from India, providing baseline data about five genetic polymorphisms in three DNA repair genes XRCC1, XRCC2 and XRCC3 modulating overall esophageal cancer susceptibility in ethnic Punjabi Indian subjects.	('XRCC3', 'Gene', (153, 158))	('esophageal cancer', 'Disease', (178, 195))	('XRCC3', 'Gene', '7517', (153, 158))	('XRCC1', 'Gene', (136, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('modulating', 'Reg', (159, 169))	('XRCC2', 'Gene', '7516', (143, 148))	('XRCC2', 'Gene', (143, 148))	('polymorphisms', 'Var', (96, 109))	('XRCC1', 'Gene', '7515', (136, 141))
20243	32214837	The results suggest a role of XRCC gene polymorphisms in esophageal cancer risk and a need to confirm our findings with higher sample size in different ethnic groups inhabiting different geographical areas of India.	('esophageal cancer', 'Disease', 'MESH:D004938', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('role', 'Reg', (22, 26))	('polymorphisms', 'Var', (40, 53))	('XRCC gene', 'Gene', (30, 39))	('esophageal cancer', 'Disease', (57, 74))
20258	32059485	However, what is not known is whether the abundance of TILs decreases the risk of tumour dissemination by reducing the release of circulating tumour cells (CTCs), which have metastatic potential.	('decreases', 'NegReg', (60, 69))	('tumour', 'Disease', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('CTCs', 'Chemical', '-', (156, 160))	('TILs', 'Var', (55, 59))	('reducing', 'NegReg', (106, 114))	('abundance', 'Var', (42, 51))	('tumour dissemination', 'Disease', (82, 102))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('tumour dissemination', 'Disease', 'MESH:D009103', (82, 102))	('tumour', 'Disease', 'MESH:D009369', (142, 148))
20259	32059485	In MSI-H CRC, the resultant microsatellite alterations result in frameshifts that truncate proteins and may lead to inactivation of affected coding regions.	('inactivation', 'NegReg', (116, 128))	('result in', 'Reg', (55, 64))	('microsatellite alterations', 'Var', (28, 54))	('CRC', 'Disease', (9, 12))	('MSI', 'Disease', 'MESH:D053842', (3, 6))	('frameshifts', 'Var', (65, 76))	('MSI', 'Disease', (3, 6))	('proteins', 'Protein', (91, 99))	('CRC', 'Disease', 'MESH:D015179', (9, 12))	('truncate', 'NegReg', (82, 90))
20339	32059485	Collinearity between MSI-H status and TILs has been shown in clinicopathological data, including the data from our own cohort study, and has been traditionally associated with a better prognosis.	('MSI', 'Disease', 'MESH:D053842', (21, 24))	('MSI', 'Disease', (21, 24))	('associated', 'Reg', (160, 170))	('Collinearity', 'Var', (0, 12))
20347	32059485	The MSI hyper-mutational state is also thought to be the reason for poor differentiation and other adverse pathological features of the tumour.	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('MSI', 'Disease', 'MESH:D053842', (4, 7))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('MSI', 'Disease', (4, 7))	('tumour', 'Disease', (136, 142))	('hyper-mutational', 'Var', (8, 24))
20348	32059485	The higher grade of tumour associated with hyper-mutational state may be the reason for the increased peri-operative release of CTCs.	('CTCs', 'Chemical', '-', (128, 132))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('tumour', 'Disease', (20, 26))	('hyper-mutational state', 'Var', (43, 65))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
20379	31906589	Patient outcome data revealed that CLU expression is associated with both lower patient survival and an increase in disease recurrence.	('increase', 'PosReg', (104, 112))	('CLU expression', 'Var', (35, 49))	('patient survival', 'CPA', (80, 96))	('lower', 'NegReg', (74, 79))	('disease recurrence', 'CPA', (116, 134))	('patient', 'Species', '9606', (80, 87))	('Patient', 'Species', '9606', (0, 7))
20392	31906589	However, specific targeted ablation of LGR5+ cells in cancerous tissues revealed that the LGR5+ stem cell population is dispensable for primary tumour maintenance.	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('cancerous', 'Disease', (54, 63))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('tumour', 'Disease', (144, 150))	('ablation', 'Var', (27, 35))	('cancerous', 'Disease', 'MESH:D009369', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
20396	31906589	However, colon tumours with elevated levels of BMI1 have been associated with reduced overall patient survival.	('colon tumours', 'Disease', (9, 22))	('BMI1', 'Gene', (47, 51))	('colon tumours', 'Disease', 'MESH:D003110', (9, 22))	('reduced', 'NegReg', (78, 85))	('levels', 'Var', (37, 43))	('patient', 'Species', '9606', (94, 101))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))
20456	31906589	High KRT20 expression was significantly associated with lower AUC values, conferring sensitivity to treatment.	('KRT20', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('AUC values', 'MPA', (62, 72))	('lower', 'NegReg', (56, 61))	('KRT20', 'Gene', '54474', (5, 10))
20487	31906589	We have identified that CLU, a marker of the revival stem cell population, is enriched in PDCOs resistant to 5-FU and this is consistent with overall patient data showing that CLU correlates with lower survival and an increase in disease recurrence.	('disease recurrence', 'CPA', (230, 248))	('patient', 'Species', '9606', (150, 157))	('lower', 'NegReg', (196, 201))	('survival', 'CPA', (202, 210))	('increase', 'PosReg', (218, 226))	('CLU', 'Var', (176, 179))	('5-FU', 'Chemical', 'MESH:D005472', (109, 113))
20502	32002283	TP53 mutation was more frequent in IS-TB type I (ISATBhigh) patients, while IS-TB type IV (ISBTBlow) harbored high number of CTNNB1 mutation.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('IS-TB type I', 'Disease', (35, 47))	('patients', 'Species', '9606', (60, 68))	('frequent', 'Reg', (23, 31))	('CTNNB1', 'Gene', (125, 131))	('mutation', 'Var', (5, 13))	('CTNNB1', 'Gene', '1499', (125, 131))
20519	32002283	For example, in HCC, the pioneering studies demonstrated that CD8+ and CD45RO+ T-cell infiltration were independent favorable prognostic factors indicating patient survival.	('HCC', 'Disease', 'MESH:D006528', (16, 19))	('HCC', 'Disease', (16, 19))	('CD8', 'Gene', (62, 65))	('HCC', 'Phenotype', 'HP:0001402', (16, 19))	('CD8', 'Gene', '925', (62, 65))	('CD45RO+', 'Var', (71, 78))	('patient', 'Species', '9606', (156, 163))
20547	32002283	We utilized the LASSO COX model to identify the most significant prognostic parameters out of 11 features for lymphocytes (CD3, CD20, CD8, CD45RO, CD45RA, CD57, CD68, FOXP3, Tryptase, PD1 and PD-L1), and then constructed a classifier according to multiple immune parameters for predicting DFS in the training cohort.	('LASSO', 'Chemical', 'MESH:C000188', (16, 21))	('CD8', 'Gene', (134, 137))	('Tryptase', 'Gene', (174, 182))	('CD8', 'Gene', '925', (134, 137))	('Tryptase', 'Gene', '397389', (174, 182))	('CD20', 'Gene', '54474', (128, 132))	('CD45RO', 'Var', (139, 145))	('CD57', 'Gene', (155, 159))	('CD20', 'Gene', (128, 132))	('CD3', 'Gene', '397455', (123, 126))	('CD45RA', 'Var', (147, 153))	('CD57', 'Gene', '27087', (155, 159))	('CD3', 'Gene', (123, 126))
20565	32002283	In the validation cohort, 3-year OS and DFS rates for cases with low-grade tumor budding were also significantly higher than they were for cases with high-grade budding (OS: 84.2% vs. 58.4%; DFS: 70.2% vs. 48.4%).	('DFS', 'MPA', (40, 43))	('low-grade', 'Var', (65, 74))	('higher', 'PosReg', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
20575	32002283	High-grade tumor budding was significantly correlated with high stromal CD8+ (P = .002), CD20+ (P = .009), CD45RO+ (P = .003) and CD45RA+ (P = .026) lymphocyte infiltration (Figure 4(g)).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('budding', 'biological_process', 'GO:0007114', ('17', '24'))	('CD20', 'Gene', '54474', (89, 93))	('CD45RA+', 'Var', (130, 137))	('CD45RO+', 'Var', (107, 114))	('tumor', 'Disease', (11, 16))	('CD20', 'Gene', (89, 93))	('correlated', 'Reg', (43, 53))	('CD8', 'Gene', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('CD8', 'Gene', '925', (72, 75))
20576	32002283	Noticeably, high-grade tumor budding was also positively correlated with PD1+ (P < .001) and CD68+ (P < .001) immune cells.	('CD68+', 'Var', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('correlated', 'Reg', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('PD1+', 'Var', (73, 77))
20578	32002283	LASSO COX was used to establish a prognostic score for DFS in the training group, which combined five parameters (CD8stromal, PD-L1stromal, Mast-cellstromal, CD68stromal, and FOXP3stromal) out of the 11 types of immune markers (Figure S4).	('CD8', 'Gene', '925', (114, 117))	('CD68stromal', 'Var', (158, 169))	('CD8', 'Gene', (114, 117))	('LASSO', 'Chemical', 'MESH:C000188', (0, 5))
20580	32002283	On the basis of the Z-score of the personalized levels of the five parameters, the immunoscore is = (-0.25 x CD8stromal) + (0.03 x PD-L1stromal) + (0.01 x Mast-cellstromal) + (0.21 x CD68stromal) + (0.20 x FOXP3stromal).	('CD8', 'Gene', (109, 112))	('-0.25', 'Var', (101, 106))	('CD8', 'Gene', '925', (109, 112))
20588	32002283	TP53 mutation was more frequent in IS-TB type I (ISATBhigh) patients.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('IS-TB type I', 'Disease', (35, 47))	('patients', 'Species', '9606', (60, 68))	('frequent', 'Reg', (23, 31))	('mutation', 'Var', (5, 13))
20591	32002283	Especially, IS-TB type IV (ISBTBlow) harbored high number of CTNNB1 mutation.	('mutation', 'Var', (68, 76))	('CTNNB1', 'Gene', (61, 67))	('CTNNB1', 'Gene', '1499', (61, 67))
20610	32002283	In this study, immune score integrated five types of immune cells (CD68+, CD8+, FOXP3+, mast cell, and PD-L1+) in HCC could predict patient survival efficiently (Figure S4).	('CD8', 'Gene', '925', (74, 77))	('predict', 'Reg', (124, 131))	('HCC', 'Phenotype', 'HP:0001402', (114, 117))	('CD68+', 'Var', (67, 72))	('patient', 'Species', '9606', (132, 139))	('HCC', 'Disease', (114, 117))	('HCC', 'Disease', 'MESH:D006528', (114, 117))	('CD8', 'Gene', (74, 77))
20623	32002283	In comparison, in some other tumor types such as melanoma, mutational load was correlated with the degree of survival benefit.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mutational load', 'Var', (59, 74))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
20627	32002283	TP53 (mainly within IS-TB type I) and CTNNB1 (mainly within IS-TB type IV) mutation in HCC dominated two distinct HCC phenotypes, associated with different immune and pathological characteristics.	('HCC', 'Phenotype', 'HP:0001402', (87, 90))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('HCC', 'Disease', 'MESH:D006528', (114, 117))	('HCC', 'Phenotype', 'HP:0001402', (114, 117))	('mutation', 'Var', (75, 83))	('CTNNB1', 'Gene', (38, 44))	('HCC', 'Disease', 'MESH:D006528', (87, 90))	('HCC', 'Disease', (114, 117))	('HCC', 'Disease', (87, 90))	('CTNNB1', 'Gene', '1499', (38, 44))
20628	32002283	We found that CTNNB1 mutation was associated with impaired anti-tumor immunity (immune type B).	('tumor', 'Disease', (64, 69))	('CTNNB1', 'Gene', '1499', (14, 20))	('impaired', 'NegReg', (50, 58))	('mutation', 'Var', (21, 29))	('CTNNB1', 'Gene', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
20631	32002283	In addition, we observed that CTNNB1 mutated tumors were well differentiated, with pseudoglandular pattern, mature stroma, and low alpha-SMA (fibroblast activation protein) expression.	('alpha-SMA', 'Gene', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('CTNNB1', 'Gene', (30, 36))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('fibroblast activation', 'biological_process', 'GO:0072537', ('142', '163'))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('CTNNB1', 'Gene', '1499', (30, 36))	('expression', 'MPA', (173, 183))	('mutated', 'Var', (37, 44))	('pseudoglandular pattern', 'CPA', (83, 106))	('alpha-SMA', 'Gene', '58', (131, 140))
20632	32002283	As reported previously, CTNNB1 mutations activating beta-catenin are oncogenic driver mutations related to a specific HCC subtype presented in well-differentiated tumors with pseudoglandular pattern and other specific pathological features.	('mutations', 'Var', (31, 40))	('HCC', 'Disease', (118, 121))	('beta-catenin', 'Gene', (52, 64))	('activating', 'PosReg', (41, 51))	('HCC', 'Phenotype', 'HP:0001402', (118, 121))	('CTNNB1', 'Gene', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('beta-catenin', 'Gene', '1499', (52, 64))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('CTNNB1', 'Gene', '1499', (24, 30))	('HCC', 'Disease', 'MESH:D006528', (118, 121))
20633	32002283	In this study, we revealed the relationship of CTNNB1 mutation and tumor-stromal features in HCC firstly.	('CTNNB1', 'Gene', (47, 53))	('mutation', 'Var', (54, 62))	('HCC', 'Phenotype', 'HP:0001402', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('CTNNB1', 'Gene', '1499', (47, 53))	('tumor', 'Disease', (67, 72))	('HCC', 'Disease', 'MESH:D006528', (93, 96))	('HCC', 'Disease', (93, 96))
20635	32002283	TP53 mutation was poorly differentiated and with thick-trabecular pattern.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
20642	32002283	Altogether, we report five major observations: first, we have shown significant relations between tumor budding and patient prognosis; second, tumor budding was associated with specific pathological patterns and immune cell infiltrations in HCC; third, the IS-TB type based on immune score and tumor budding was an independent prognostic factor, integrating IS-TB type and other clinical parameters could predict patient prognosis efficiently; fourth, IS-TB type was correlated with HCC molecular alterations; fifth, TP53 (mainly corresponds to IS-TB type I) and CTNNB1 (mainly corresponds to IS-TB type IV) mutation in HCC constituted two distinct HCC phenotypes, associated with distinct immune and pathological features.	('HCC', 'Disease', (620, 623))	('HCC', 'Phenotype', 'HP:0001402', (620, 623))	('TP53', 'Gene', '7157', (517, 521))	('HCC', 'Disease', 'MESH:D006528', (241, 244))	('mutation', 'Var', (608, 616))	('tumor', 'Disease', (98, 103))	('patient', 'Species', '9606', (413, 420))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('HCC', 'Disease', (483, 486))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('HCC', 'Phenotype', 'HP:0001402', (483, 486))	('HCC', 'Disease', (649, 652))	('CTNNB1', 'Gene', '1499', (563, 569))	('HCC', 'Phenotype', 'HP:0001402', (649, 652))	('HCC', 'Disease', 'MESH:D006528', (620, 623))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('HCC', 'Disease', (241, 244))	('TP53', 'Gene', (517, 521))	('HCC', 'Phenotype', 'HP:0001402', (241, 244))	('tumor', 'Disease', (294, 299))	('HCC', 'Disease', 'MESH:D006528', (483, 486))	('tumor', 'Disease', (143, 148))	('patient', 'Species', '9606', (116, 123))	('CTNNB1', 'Gene', (563, 569))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('HCC', 'Disease', 'MESH:D006528', (649, 652))	('tumor', 'Disease', 'MESH:D009369', (143, 148))
20662	29691298	However, CAIX is up-regulated in hypoxic cells and is over-expressed in approximately 90% of clear-cell renal cell carcinomas, as a result of von Hippel-Lindau inactivation.	('CAIX', 'Gene', (9, 13))	('von Hippel-Lindau', 'Disease', (142, 159))	('clear-cell renal cell carcinomas', 'Disease', 'MESH:C538614', (93, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('clear-cell renal cell carcinomas', 'Disease', (93, 125))	('clear-cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (93, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (142, 159))	('inactivation', 'Var', (160, 172))	('over-expressed', 'PosReg', (54, 68))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (104, 124))	('up-regulated', 'PosReg', (17, 29))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (93, 124))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (104, 125))
20767	29691298	We compared the anticancer activity of compounds AAZ-ValCit-MMAE (1) and AAZ+-ValCit-MMAE (2) in BALB/c nude mice, bearing subcutaneously-grafted SKRC-52 renal cell carcinomas.	('AAZ+-ValCit-MMAE', 'Chemical', '-', (73, 89))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (154, 174))	('SKRC-52', 'CellLine', 'CVCL:6198', (146, 153))	('nude mice', 'Species', '10090', (104, 113))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (154, 175))	('AAZ+-ValCit-MMAE', 'Var', (73, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('renal cell carcinomas', 'Disease', (154, 175))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (154, 175))	('cancer', 'Disease', (20, 26))	('Val', 'Chemical', 'MESH:D014633', (78, 81))	('MMAE', 'Chemical', 'MESH:C495575', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('MMAE', 'Chemical', 'MESH:C495575', (85, 89))	('Val', 'Chemical', 'MESH:D014633', (53, 56))	('AAZ', 'Chemical', 'MESH:D000086', (49, 52))	('AAZ', 'Chemical', 'MESH:D000086', (73, 76))
20787	29691298	CAIX quantification by FACS analysis indicates that CT26.3E10 has a slightly lower surface density of CAIX, compared to SKRC-52 cells [Supplementary Figure 11].	('lower', 'NegReg', (77, 82))	('SKRC-52', 'CellLine', 'CVCL:6198', (120, 127))	('surface', 'MPA', (83, 90))	('CT26.3E10', 'CellLine', 'CVCL:7254', (52, 61))	('CT26.3E10', 'Var', (52, 61))	('FACS', 'Gene', (23, 27))	('FACS', 'Gene', '14081', (23, 27))
20788	29691298	Furthermore, mice bearing CT26.3E10 tumors showed a preferential uptake of the near-infrared fluorophore conjugate AAZ-IRdye680RD in the neoplastic mass 6 hours after intravenous injection, compared to similar experiments performed in mice bearing CT26.wt tumors [Figure 5D].	('mice', 'Species', '10090', (13, 17))	('CT26', 'Gene', '168400', (248, 252))	('AAZ-IRdye680RD', 'Var', (115, 129))	('preferential', 'PosReg', (52, 64))	('mice', 'Species', '10090', (235, 239))	('tumors', 'Disease', 'MESH:D009369', (256, 262))	('CT26', 'Gene', '168400', (26, 30))	('neoplastic mass', 'Phenotype', 'HP:0002664', (137, 152))	('CT26.3E10', 'CellLine', 'CVCL:7254', (26, 35))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('uptake', 'MPA', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('CT26', 'Gene', (248, 252))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('tumors', 'Disease', (36, 42))	('AAZ', 'Chemical', 'MESH:D000086', (115, 118))	('CT26', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumors', 'Disease', (256, 262))
20803	29691298	The targeted delivery of linker-payload combinations to the extracellular environment is attractive, as it may promote an efficient drug release process, triggered by high local concentration of glutathione (released by dying tumor cells) or by proteases.	('glutathione', 'Chemical', 'MESH:D005978', (195, 206))	('promote', 'PosReg', (111, 118))	('tumor', 'Disease', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('drug release process', 'MPA', (132, 152))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('rat', 'Species', '10116', (185, 188))	('combinations', 'Var', (40, 52))
20830	30090047	However, EFB prior to ER may sometimes result in submucosal fibrosis, making lifting of the lesion with submucosal injection difficult.	('EFB', 'Var', (9, 12))	('result in', 'Reg', (39, 48))	('submucosal fibrosis', 'Disease', 'MESH:D005355', (49, 68))	('submucosal fibrosis', 'Disease', (49, 68))	('EFB', 'Chemical', '-', (9, 12))
20889	30090047	Inherited CRC syndromes such as familial polyposis and hereditary nonpolyposis CRC support such evidence and recent findings on ras gene mutation and chromosomal deletions additionally provide biological evidence of the adenoma-carcinoma sequence.	('ras', 'Gene', (128, 131))	('hereditary nonpolyposis', 'Disease', 'MESH:D003123', (55, 78))	('mutation', 'Var', (137, 145))	('familial polyposis', 'Disease', 'MESH:D011125', (32, 50))	('CRC', 'Phenotype', 'HP:0003003', (79, 82))	('CRC', 'Phenotype', 'HP:0003003', (10, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('adenoma-carcinoma', 'Disease', (220, 237))	('familial polyposis', 'Disease', (32, 50))	('hereditary nonpolyposis', 'Disease', (55, 78))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (220, 237))
20895	30090047	However, indiscriminate EFB prior to polypectomy may lead to submucosal fibrosis and non-lifting of lesions, which makes the complete excision of the lesion more difficult.	('submucosal fibrosis', 'Disease', 'MESH:D005355', (61, 80))	('lead to', 'Reg', (53, 60))	('submucosal fibrosis', 'Disease', (61, 80))	('non-lifting of lesions', 'CPA', (85, 107))	('EFB', 'Var', (24, 27))	('indiscriminate', 'Var', (9, 23))	('EFB', 'Chemical', '-', (24, 27))
20915	30090047	Interestingly, our study showed that polyp size was also associated with OD by EFB.	('EFB', 'Chemical', '-', (79, 82))	('polyp size', 'Var', (37, 47))	('associated', 'Reg', (57, 67))
20944	29698444	At 48 hours there is a significant increase in C/G->T/A mutations that is not represented in DNA treated with UNG.	('C/G->T/A mutations', 'Var', (47, 65))	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('UNG', 'Gene', '7374', (110, 113))	('UNG', 'Gene', (110, 113))
20985	29698444	BRAF genotypes are often assayed in colon cancer, either by immunohistochemistry or other molecular assays as activating BRAF mutations are also a relative contraindication to EGFR targeted therapy, and BRAF status may play an additional role in Lynch syndrome screening.	('BRAF', 'Gene', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('colon cancer', 'Disease', 'MESH:D015179', (36, 48))	('EGFR', 'Gene', '1956', (176, 180))	('colon cancer', 'Disease', (36, 48))	('Lynch syndrome', 'Disease', (246, 260))	('BRAF', 'Gene', '673', (203, 207))	('BRAF', 'Gene', '673', (0, 4))	('EGFR', 'Gene', (176, 180))	('activating', 'PosReg', (110, 120))	('mutations', 'Var', (126, 135))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (121, 125))	('Lynch syndrome', 'Disease', 'MESH:D003123', (246, 260))	('BRAF', 'Gene', (203, 207))	('colon cancer', 'Phenotype', 'HP:0003003', (36, 48))
20993	29698444	After UNG treatment the number of C/G->T/A events was decreased by a median of 32, 17 and 35 mutations per sample for patients 1, 2 and 3 respectively, supporting the hypothesis that the variants resulted due to deamination from formalin treatment.	('C/G->T/A', 'Var', (34, 42))	('UNG', 'Gene', '7374', (6, 9))	('formalin', 'Chemical', 'MESH:D005557', (229, 237))	('UNG', 'Gene', (6, 9))	('variants', 'Var', (187, 195))	('decreased', 'NegReg', (54, 63))	('patients', 'Species', '9606', (118, 126))
20995	29698444	Similarly to the 48 hour fixation time, when not treated with UNG, the number of deamination variants increased with sample age as compared to all other mutation types, with a median increase of 15 deamination variants between 1994 and 2014.	('variants', 'Var', (93, 101))	('deamination variants', 'Var', (81, 101))	('UNG', 'Gene', '7374', (62, 65))	('UNG', 'Gene', (62, 65))
21005	29698444	If the variant was repeatedly detected in one or a subset of FFPE blocks but not all patient tumor samples, this was indicative of intratumoral heterogeneity (ITH).	('patient', 'Species', '9606', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('variant', 'Var', (7, 14))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
21013	29698444	Although these results are reassuring to molecular pathology and clinical oncology practitioners, they do highlight the potential risks associated when working with very low tumor content samples, or reporting very low frequency mutational events.	('tumor', 'Disease', (174, 179))	('oncology', 'Phenotype', 'HP:0002664', (74, 82))	('mutational events', 'Var', (229, 246))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
21015	29698444	As our study shows, UNG treatment is not sufficient to eliminate false positive mutations arising from deamination effects in samples for mutations with VAFs <5%, nor does it mitigate poor read quality, with prolonged formalin fixation.	('UNG', 'Gene', '7374', (20, 23))	('VAF', 'Chemical', '-', (153, 156))	('formalin', 'Chemical', 'MESH:D005557', (218, 226))	('UNG', 'Gene', (20, 23))	('deamination', 'Var', (103, 114))	('VAFs', 'Gene', (153, 157))	('mutations', 'Var', (138, 147))
21016	29698444	Methylated cytosine, as found at CpG sites, is deaminated directly to thymine, and would not be affected by UNG treatment.	('UNG', 'Gene', '7374', (108, 111))	('UNG', 'Gene', (108, 111))	('thymine', 'Chemical', 'MESH:D013941', (70, 77))	('Methylated', 'Var', (0, 10))	('cytosine', 'Chemical', 'MESH:D003596', (11, 19))
21022	29698444	Our results show that samples fixed for 48 hours have increased variants likely arising from the deamination of cytosine during the formalin fixation process.	('formalin', 'Chemical', 'MESH:D005557', (132, 140))	('cytosine', 'Chemical', 'MESH:D003596', (112, 120))	('deamination', 'MPA', (97, 108))	('arising', 'Reg', (80, 87))	('variants', 'Var', (64, 72))
21034	29050349	High DBIL had higher percentage of lymph node metastasis and lymphovascular invasion as compared with low DBIL levels (P < 0.05).	('lymphovascular invasion', 'CPA', (61, 84))	('DBIL', 'Chemical', '-', (106, 110))	('lymph node metastasis', 'Disease', 'MESH:D009362', (35, 56))	('lymph node metastasis', 'Disease', (35, 56))	('High DBIL', 'Var', (0, 9))	('DBIL', 'Chemical', '-', (5, 9))
21035	29050349	Multivariate cox regression analyses confirmed that high DBIL level was an independently prognostic factor for both OS (HR: 1.337, 95% CI: 1.022-1.748, P = 0.034) and DFS (HR: 1.312, 95% CI: 1.049-1.643, P = 0.018).	('DBIL', 'MPA', (57, 61))	('DBIL', 'Chemical', '-', (57, 61))	('high', 'Var', (52, 56))	('DFS', 'Disease', (167, 170))
21060	29050349	In addition, patients with poor differentiated caicinoma (P < 0.001), with advanced T stage (P < 0.001) and N stage (P < 0.001), with less than 12 lymph node retrieval (P = 0.005), presented with lymphovascular invasion (P < 0.001) and perineural invasion (P < 0.001) suffered a shorter 5-year DFS (Table 4).	('5-year DFS', 'CPA', (287, 297))	('shorter', 'NegReg', (279, 286))	('patients', 'Species', '9606', (13, 21))	('less than 12 lymph node', 'Phenotype', 'HP:0002732', (134, 157))	('poor', 'Var', (27, 31))	('perineural invasion', 'CPA', (236, 255))	('lymphovascular invasion', 'CPA', (196, 219))
21099	26637808	Long non-coding RNAs in colorectal cancer Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (24, 41))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (24, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('colorectal cancer', 'Disease', (24, 41))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('Long non-coding RNAs', 'Var', (0, 20))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (42, 59))	('Colorectal cancer', 'Disease', 'MESH:D015179', (42, 59))	('cancer', 'Disease', (35, 41))	('Colorectal cancer', 'Disease', (42, 59))
21115	26637808	This is in contrast to the small ncRNAs, such as siRNAs, miRNAs, and piRNAs, which are highly conserved and involved in transcriptional and post-transcriptional gene silencing through specific base pairing with their targets.	('base pairing', 'Var', (193, 205))	('miR', 'Gene', '220972', (57, 60))	('miR', 'Gene', (57, 60))	('silencing', 'NegReg', (166, 175))
21119	26637808	To date, an increasing number of studies have shown abnormal expression of lncRNAs may inhibit tumor suppressor genes or cancer-promoting genes in the development of CRC.	('CRC', 'Disease', (166, 169))	('lncRNAs', 'Protein', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('expression', 'Var', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Disease', (121, 127))	('tumor', 'Disease', (95, 100))	('inhibit', 'NegReg', (87, 94))
21120	26637808	For example, loc285194 acts as a tumor suppressor but HOTAIR is the first identified lncRNA that plays a critical oncogenic role through epigenetic regulatory mechanisms.	('loc285194', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('HOTAIR', 'Gene', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('HOTAIR', 'Gene', '100124700', (54, 60))
21126	26637808	It can form multiple double stem-loop structures to bind to the lysine-specific demethylase 1 (LSD1) and polycomb repressive complex 2 (PRC2) to form histone modification complexes, which stimulate the two complexes' integration with the corresponding specificity genomic loci and cause H3K27me3 (histone H3 tri-methylated at lysine 27) and H3K4me2 (histone H3 dimethyl Lys4) methylation, leading to HOXD silencing.	('H3K4me2', 'Var', (341, 348))	('HOXD', 'Gene', (400, 404))	('polycomb', 'Gene', '12416', (105, 113))	('cause', 'Reg', (281, 286))	('lysine', 'Chemical', 'MESH:D008239', (326, 332))	('Lys4', 'Chemical', '-', (370, 374))	('HOXD', 'Gene', '3230', (400, 404))	('H3K27me3', 'Var', (287, 295))	('stimulate', 'PosReg', (188, 197))	('lysine', 'Chemical', 'MESH:D008239', (64, 70))	('lysine-specific demethylase 1', 'Gene', (64, 93))	('polycomb', 'Gene', (105, 113))	('lysine-specific demethylase 1', 'Gene', '23028', (64, 93))	('LSD1', 'Gene', '23028', (95, 99))	('LSD1', 'Gene', (95, 99))	('integration', 'MPA', (217, 228))
21134	26637808	After H19 gene is knocked out, the capacity for tumor growth, invasion and metastasis is enhanced in murine models of colon tumorigenesis.	('knocked out', 'Var', (18, 29))	('colon tumor', 'Disease', 'MESH:D015179', (118, 129))	('tumor', 'Disease', (48, 53))	('enhanced', 'PosReg', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('murine', 'Species', '10090', (101, 107))	('colon tumor', 'Phenotype', 'HP:0100273', (118, 129))	('H19 gene', 'Gene', (6, 14))	('tumor', 'Disease', (124, 129))	('colon tumor', 'Disease', (118, 129))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
21135	26637808	Therefore, abnormal expression of the H19 gene is related to the generation of CRC, and it dually functions as an oncogene and tumor suppressor gene through a variety of mechanisms.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor suppressor', 'biological_process', 'GO:0051726', ('127', '143'))	('related', 'Reg', (50, 57))	('H19', 'Gene', (38, 41))	('expression', 'MPA', (20, 30))	('tumor', 'Disease', (127, 132))	('abnormal', 'Var', (11, 19))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('127', '143'))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('CRC', 'Disease', (79, 82))
21137	26637808	Multiple mechanisms contribute to the decreased expression of MEG3 in tumors, including gene deletion, promoter hypermethylation, and hypermethylation of the intergenic differentially methylated region.	('decreased', 'NegReg', (38, 47))	('MEG3', 'Gene', '55384', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('promoter', 'MPA', (103, 111))	('expression', 'MPA', (48, 58))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('gene deletion', 'Var', (88, 101))	('MEG3', 'Gene', (62, 66))	('hypermethylation', 'Var', (134, 150))
21141	26637808	The loss of MEG3 expression, its deletion from genomic DNA and the degree of promoter methylation are associated with aggressive tumor growth.	('associated', 'Reg', (102, 112))	('MEG3', 'Gene', (12, 16))	('expression', 'MPA', (17, 27))	('deletion', 'Var', (33, 41))	('MEG3', 'Gene', '55384', (12, 16))	('aggressive tumor', 'Disease', 'MESH:D001523', (118, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('aggressive tumor', 'Disease', (118, 134))	('loss', 'NegReg', (4, 8))
21143	26637808	Experimental data demonstrate that p53 is a target of MEG3 and that transfection of MEG3 induces a significant increase in p53 protein levels in human cancer cell lines.	('increase', 'PosReg', (111, 119))	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('transfection', 'Var', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('MEG3', 'Gene', (84, 88))	('MEG3', 'Gene', (54, 58))	('human', 'Species', '9606', (145, 150))	('MEG3', 'Gene', '55384', (84, 88))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('MEG3', 'Gene', '55384', (54, 58))	('p53', 'Gene', (123, 126))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('p53', 'Gene', '7157', (123, 126))
21150	26637808	The overall survival rate of the patients with high expression of PCAT-1 is significantly lower than those with low expression.	('patients', 'Species', '9606', (33, 41))	('PCAT-1', 'Gene', (66, 72))	('high expression', 'Var', (47, 62))	('lower', 'NegReg', (90, 95))	('PCAT-1', 'Gene', '100750225', (66, 72))
21165	26637808	Loc285194, also called LSAMP antisense RNA 3, is an lncRNA of more than 2 kb in length that consists of 4 exons located at osteo3q13.31.	('LSAMP', 'Gene', (23, 28))	('LSAMP', 'Gene', '4045', (23, 28))	('Loc285194', 'Var', (0, 9))
21166	26637808	Loc285194 functions as a potential tumor suppressor.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('Loc285194', 'Var', (0, 9))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('tumor', 'Disease', (35, 40))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))
21167	26637808	Study showed that loc285194 is a direct transcriptional target of p53 with two binding sites of miR-211in its exon 4.	('miR-211', 'Gene', (96, 103))	('p53', 'Gene', '7157', (66, 69))	('loc285194', 'Var', (18, 27))	('binding', 'Interaction', (79, 86))	('p53', 'Gene', (66, 69))	('miR-211', 'Gene', '406993', (96, 103))
21168	26637808	Loc285194 is also consistently down-regulated in colon tumor specimens compared with normal specimens and is a direct target of p53 through the negative regulation of miR-211.	('regulation', 'biological_process', 'GO:0065007', ('153', '163'))	('colon tumor', 'Phenotype', 'HP:0100273', (49, 60))	('Loc285194', 'Var', (0, 9))	('p53', 'Gene', (128, 131))	('negative regulation', 'NegReg', (144, 163))	('p53', 'Gene', '7157', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('colon tumor', 'Disease', (49, 60))	('down-regulated', 'NegReg', (31, 45))	('miR-211', 'Gene', '406993', (167, 174))	('miR-211', 'Gene', (167, 174))	('colon tumor', 'Disease', 'MESH:D015179', (49, 60))
21170	26637808	For example, H19 can promote EMT progression and accelerate tumor growth by acting as competing endogenous RNA (ceRNA) for miR-138 and miR-200a in CRC.	('miR', 'Gene', (135, 138))	('H19', 'Var', (13, 16))	('EMT progression', 'CPA', (29, 44))	('EMT', 'biological_process', 'GO:0001837', ('29', '32'))	('miR', 'Gene', '220972', (123, 126))	('miR', 'Gene', (123, 126))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('promote', 'PosReg', (21, 28))	('RNA', 'cellular_component', 'GO:0005562', ('107', '110'))	('accelerate', 'PosReg', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('miR-200a', 'Gene', (135, 143))	('tumor', 'Disease', (60, 65))	('miR-200a', 'Gene', '406983', (135, 143))	('miR', 'Gene', '220972', (135, 138))
21177	26637808	Colon cancer-associated transcript (CCAT) family members and some novel lncRNA transcripts map to the highly conserved 8q24.21 region that encompasses rs6983267.	('rs6983267', 'Var', (151, 160))	('Colon cancer', 'Phenotype', 'HP:0003003', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('Colon cancer', 'Disease', (0, 12))	('lncRNA', 'Gene', (72, 78))	('rs6983267', 'Mutation', 'rs6983267', (151, 160))	('CCAT', 'Gene', '2805', (36, 40))	('Colon cancer', 'Disease', 'MESH:D015179', (0, 12))	('CCAT', 'Gene', (36, 40))
21195	26637808	Moreover, microsatellite-stable (MSS) cancers have higher CCAT2 expression than microsatellite-unstable (MSI-H) tumors and the adjacent normal colon mucosa.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('expression', 'MPA', (64, 74))	('CCAT2', 'Gene', (58, 63))	('microsatellite-stable', 'Var', (10, 31))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('MSI-H) tumors', 'Disease', 'MESH:D009369', (105, 118))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('higher', 'PosReg', (51, 57))	('cancers', 'Disease', (38, 45))	('CCAT2', 'Gene', '101805488', (58, 63))
21200	26637808	One study showed that p53 is a target gene of MEG3 andoverexpression of MEG3 leads to a significant increase in p53 protein levels in human cancer cell lines.	('MEG3', 'Gene', (72, 76))	('human', 'Species', '9606', (134, 139))	('MEG3', 'Gene', (46, 50))	('MEG3', 'Gene', '55384', (72, 76))	('p53', 'Gene', (22, 25))	('MEG3', 'Gene', '55384', (46, 50))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('p53', 'Gene', '7157', (112, 115))	('p53', 'Gene', '7157', (22, 25))	('p53', 'Gene', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('andoverexpression', 'Var', (51, 68))	('increase', 'PosReg', (100, 108))
21206	26637808	Studies have found that a particular sequence (fragment 6918 nt-8441 nt), located at the 3' end of MALAT-1 is correlated with several biological processes: cell proliferation, migration, and invasion of human colorectal malignant neoplasms.	('invasion', 'CPA', (191, 199))	('migration', 'CPA', (176, 185))	('fragment 6918 nt-8441 nt', 'Var', (47, 71))	('correlated', 'Reg', (110, 120))	('human', 'Species', '9606', (203, 208))	('MALAT-1', 'Gene', '378938', (99, 106))	('colorectal malignant neoplasms', 'Disease', 'MESH:D015179', (209, 239))	('neoplasms', 'Phenotype', 'HP:0002664', (230, 239))	('MALAT-1', 'Gene', (99, 106))	('colorectal malignant neoplasms', 'Disease', (209, 239))	('cell proliferation', 'CPA', (156, 174))
21217	26637808	MEG3 is found to be abnormal CpG methylation in CRC, in which its expression is decreased.	('CRC', 'Disease', (48, 51))	('methylation', 'Var', (33, 44))	('expression', 'MPA', (66, 76))	('decreased', 'NegReg', (80, 89))	('MEG3', 'Gene', (0, 4))	('MEG3', 'Gene', '55384', (0, 4))
21218	26637808	The hypermethylation in the MEG3 promoter region as well as the intergenic germ line-derived differentially methylated region (IG-DMR) would cause proliferation of cancer cells and blood vessels and then accelerate tumor metastasis and malignant.	('tumor metastasis', 'Disease', (215, 231))	('MEG3', 'Gene', '55384', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('proliferation', 'CPA', (147, 160))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('accelerate', 'PosReg', (204, 214))	('cause', 'Reg', (141, 146))	('tumor metastasis', 'Disease', 'MESH:D009362', (215, 231))	('MEG3', 'Gene', (28, 32))	('malignant', 'CPA', (236, 245))	('hypermethylation', 'Var', (4, 20))
21229	26637808	Indeed CCAT1-L, CCAT2, MEG3, Loc285194 and MALAT-1 promoter region have protein binding sites.	('CCAT1', 'Gene', (7, 12))	('protein', 'Protein', (72, 79))	('MEG3', 'Gene', (23, 27))	('MALAT-1', 'Gene', '378938', (43, 50))	('CCAT2', 'Gene', '101805488', (16, 21))	('CCAT1', 'Gene', '100507056', (7, 12))	('MALAT-1', 'Gene', (43, 50))	('CCAT2', 'Gene', (16, 21))	('binding', 'Interaction', (80, 87))	('MEG3', 'Gene', '55384', (23, 27))	('Loc285194', 'Var', (29, 38))
21234	26637808	Fox example, H19 as the precursor of miR-675, can decrease the level of RB.	('H19', 'Var', (13, 16))	('miR-675', 'Gene', (37, 44))	('level of RB', 'MPA', (63, 74))	('miR-675', 'Gene', '100033819', (37, 44))	('decrease', 'NegReg', (50, 58))
21246	26637808	Another lncRNAs, CCAT2 may also be served as a diagnostic biomarker since its expression is significantly higher in the tumor tissues as compared with the adjacent mucosae of 215 CRC and 94 paired non-neoplastic mucosal specimens obtained from patients from four different geographical regions; Therefore, lncRNAs transcripts in the cancer tissues and in the plasma of patients are promising biomarkers for CRC.	('patients', 'Species', '9606', (369, 377))	('expression', 'MPA', (78, 88))	('CCAT2', 'Gene', (17, 22))	('CRC', 'Disease', (407, 410))	('cancer', 'Disease', 'MESH:D009369', (333, 339))	('lncRNAs', 'Var', (306, 313))	('cancer', 'Disease', (333, 339))	('higher', 'PosReg', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('patients', 'Species', '9606', (244, 252))	('CCAT2', 'Gene', '101805488', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('tumor', 'Disease', (120, 125))
21381	26462034	Furthermore, the association between the pathways affected by altered expression of miRNAs and CRC was evaluated.	('altered', 'Var', (62, 69))	('miR', 'Gene', '220972', (84, 87))	('miR', 'Gene', (84, 87))	('CRC', 'Disease', (95, 98))	('CRC', 'Phenotype', 'HP:0003003', (95, 98))
21384	23168910	chromosomal instability, driven primarily by APC mutation induced deregulated Wnt signaling, and microsatellite instability (MSI) caused by mismatch repair (MMR) inactivation, together account for greater than 90% of late-onset colorectal cancer.	('Wnt signaling', 'Pathway', (78, 91))	('chromosomal instability', 'Phenotype', 'HP:0040012', (0, 23))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('chromosomal', 'MPA', (0, 11))	('colorectal cancer', 'Disease', 'MESH:D015179', (228, 245))	('APC', 'Gene', (45, 48))	('APC', 'Gene', '324', (45, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (228, 245))	('inactivation', 'Var', (162, 174))	('account', 'Reg', (185, 192))	('deregulated', 'MPA', (66, 77))	('microsatellite', 'MPA', (97, 111))	('colorectal cancer', 'Disease', (228, 245))
21397	23168910	Additional common genetic aberrations, including activating KRAS and inactivating TP53 mutations, may occur sequentially after APC mutation during adenoma to carcinoma transition.	('inactivating', 'Var', (69, 81))	('TP53', 'Gene', (82, 86))	('adenoma to carcinoma', 'Disease', 'MESH:D000236', (147, 167))	('APC', 'Gene', (127, 130))	('activating', 'PosReg', (49, 59))	('adenoma to carcinoma', 'Disease', (147, 167))	('APC', 'Gene', '324', (127, 130))	('rat', 'Species', '10116', (30, 33))	('KRAS', 'Gene', (60, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('KRAS', 'Gene', '3845', (60, 64))	('TP53', 'Gene', '7157', (82, 86))	('mutations', 'Var', (87, 96))	('APC', 'cellular_component', 'GO:0005680', ('127', '130'))
21399	23168910	MSI in sporadic CRC is primarily caused by inactivation of the mismatch repair (MMR) gene MLH1, induced by bi-allelic promoter CpG methylation.	('mismatch repair', 'biological_process', 'GO:0006298', ('63', '78'))	('caused by', 'Reg', (33, 42))	('MMR', 'Gene', (80, 83))	('MMR', 'biological_process', 'GO:0006298', ('80', '83'))	('methylation', 'biological_process', 'GO:0032259', ('131', '142'))	('MSI', 'Disease', (0, 3))	('sporadic CRC', 'Disease', (7, 19))	('MLH1', 'Gene', '4292', (90, 94))	('inactivation', 'Var', (43, 55))	('MLH1', 'Gene', (90, 94))
21401	23168910	Taken together, either deregulated Wnt signaling or MMR inactivation appears to drive a majority of colorectal tumors.	('MMR', 'Gene', (52, 55))	('deregulated', 'Var', (23, 34))	('colorectal tumors', 'Disease', (100, 117))	('colorectal tumors', 'Disease', 'MESH:D015179', (100, 117))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('inactivation', 'Var', (56, 68))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('Wnt signaling', 'Pathway', (35, 48))	('drive', 'PosReg', (80, 85))
21425	23168910	The MSI status was determined for a subset of samples for which Wnt status was already determined (74 Wnt+, 60 Wnt- and 8 Wnt unclassified) by using the NCI panel of 5 microsatellites (BAT25, BAT26, D5S346, D17S250, D2S123), since several samples did not yield DNA of sufficient quality/quantity to accurately analyze instability status for all five microsatellites (especially for D2S123 and D17S250 since these amplicons were comparatively of higher molecular size than the other three).	('D17S250', 'Var', (393, 400))	('D17S250', 'Var', (207, 214))	('rat', 'Species', '10116', (433, 436))	('rat', 'Species', '10116', (303, 306))	('as', 'Chemical', 'MESH:D001151', (130, 132))	('as', 'Chemical', 'MESH:D001151', (16, 18))	('D2S123', 'Var', (382, 388))	('DNA', 'cellular_component', 'GO:0005574', ('261', '264'))	('D5S346', 'Var', (199, 205))	('as', 'Chemical', 'MESH:D001151', (76, 78))	('D2S123', 'Var', (216, 222))
21427	23168910	Screening for mutations in the APC mutation cluster region (MCR; codons 1286-1513) and in KRAS exon 2 were performed by PCR-DNA sequencing on the 3100 genetic analyzer (ABI Inc., USA) as described in methods S1, using DNA isolated from tumor samples.	('KRAS', 'Gene', (90, 94))	('KRAS', 'Gene', '3845', (90, 94))	('APC', 'Gene', (31, 34))	('tumor', 'Disease', (236, 241))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('APC', 'Gene', '324', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('as', 'Chemical', 'MESH:D001151', (184, 186))	('mutations', 'Var', (14, 23))
21437	23168910	In addition, 8 of 15 Wnt+ samples but only 1 of 19 Wnt- samples harbored mutation in the APC MCR region, further confirming the Wnt status.	('APC', 'Gene', (89, 92))	('mutation', 'Var', (73, 81))	('APC', 'Gene', '324', (89, 92))	('harbored', 'Reg', (64, 72))
21438	23168910	The APC mutations detected in the study are listed in Table S1 and representative sequencing results are depicted in figure S2.	('APC', 'Gene', (4, 7))	('APC', 'Gene', '324', (4, 7))	('mutations', 'Var', (8, 17))
21441	23168910	The proportion of MSI+ samples was higher in early-onset (40%; 25/62) when compared to late-onset (30%; 14/47) samples (Table S2); the difference however was not significant.	('as', 'Chemical', 'MESH:D001151', (32, 34))	('higher', 'PosReg', (35, 41))	('as', 'Chemical', 'MESH:D001151', (155, 157))	('MSI+', 'Var', (18, 22))
21448	23168910	We screened the KRAS second exon for mutations; KRAS codons 12 and 13 located in the second exon account for 90 % of all mutations detected in CRC and are known to render anti-EGFR therapy ineffective.	('KRAS', 'Gene', (48, 52))	('mutations', 'Var', (121, 130))	('KRAS', 'Gene', '3845', (48, 52))	('EGFR', 'Gene', '1956', (176, 180))	('EGFR', 'Gene', (176, 180))	('KRAS', 'Gene', (16, 20))	('CRC', 'Disease', (143, 146))	('KRAS', 'Gene', '3845', (16, 20))
21449	23168910	Of the 173 samples tested, KRAS mutation was detected in 51 (29.5%) (Table 1; representative sequencing results are depicted in figure S2), lower than the frequency identified from the West.	('detected', 'Reg', (45, 53))	('KRAS', 'Gene', '3845', (27, 31))	('as', 'Chemical', 'MESH:D001151', (42, 44))	('KRAS', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))
21452	23168910	Interestingly, the frequency of KRAS mutation was lower (29.4%%; 19/65) than p53 nuclear stabilization (66%; 43/65) when analyzed exclusively in Wnt+ samples (Table 2) indicating perhaps that KRAS may not sequentially follow Wnt deregulation during CRC progression among Indian patients, as against the classical CRC progression sequence.	('mutation', 'Var', (37, 45))	('as', 'Chemical', 'MESH:D001151', (288, 290))	('as', 'Chemical', 'MESH:D001151', (305, 307))	('KRAS', 'Gene', (32, 36))	('as', 'Chemical', 'MESH:D001151', (47, 49))	('CRC', 'Disease', (249, 252))	('KRAS', 'Gene', '3845', (32, 36))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('KRAS', 'Gene', (192, 196))	('patients', 'Species', '9606', (278, 286))	('KRAS', 'Gene', '3845', (192, 196))
21456	23168910	The Wnt status determined by beta-Catenin IHC was confirmed by transcript profiling of AXIN2 and DKK-1 and by APC mutation screening.	('beta-Catenin', 'Gene', (29, 41))	('beta-Catenin', 'Gene', '1499', (29, 41))	('as', 'Chemical', 'MESH:D001151', (47, 49))	('AXIN2', 'Gene', (87, 92))	('AXIN2', 'Gene', '8313', (87, 92))	('APC', 'Gene', (110, 113))	('DKK-1', 'Gene', '22943', (97, 102))	('APC', 'cellular_component', 'GO:0005680', ('110', '113'))	('mutation', 'Var', (114, 122))	('DKK-1', 'Gene', (97, 102))	('APC', 'Gene', '324', (110, 113))
21459	23168910	APC-MCR mutation screening identified mutations in 53% of Wnt+ samples; mutations in other regions of APC or in other components of the APC degradation complex such as AXIN1/2 or CTNNB1, may account for Wnt activation in rest of the Wnt+ samples.	('mutations', 'Var', (72, 81))	('Wnt', 'MPA', (203, 206))	('CTNNB1', 'Gene', '1499', (179, 185))	('APC', 'Gene', (102, 105))	('APC', 'Gene', (136, 139))	('APC', 'Gene', (0, 3))	('APC', 'cellular_component', 'GO:0005680', ('0', '3'))	('APC', 'Gene', '324', (102, 105))	('APC', 'cellular_component', 'GO:0005680', ('136', '139'))	('AXIN1/2', 'Gene', '8312;8313', (168, 175))	('CTNNB1', 'Gene', (179, 185))	('AXIN1/2', 'Gene', (168, 175))	('APC', 'Gene', '324', (136, 139))	('APC', 'Gene', '324', (0, 3))	('as', 'Chemical', 'MESH:D001151', (165, 167))	('mutations', 'Var', (38, 47))	('degradation', 'biological_process', 'GO:0009056', ('140', '151'))	('APC', 'cellular_component', 'GO:0005680', ('102', '105'))
21461	23168910	Greater than 90% of colorectal tumors have been shown to harbor genetic or epigenetic aberrations in Wnt pathway gene(s).	('genetic', 'Var', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('colorectal tumors', 'Disease', (20, 37))	('epigenetic aberrations', 'Var', (75, 97))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('colorectal tumors', 'Disease', 'MESH:D015179', (20, 37))	('Wnt pathway', 'Pathway', (101, 112))	('rat', 'Species', '10116', (90, 93))
21462	23168910	Up-regulation of Wnt target genes in MSI+ tumors, due to mutations in APC/CTNNB1 or perturbation of a microsatellite located in the last exon of TCF4, has been documented.	('regulation', 'biological_process', 'GO:0065007', ('3', '13'))	('CTNNB1', 'Gene', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('perturbation', 'NegReg', (84, 96))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('as', 'Chemical', 'MESH:D001151', (133, 135))	('MSI+ tumors', 'Disease', 'MESH:D009369', (37, 48))	('APC', 'cellular_component', 'GO:0005680', ('70', '73'))	('CTNNB1', 'Gene', '1499', (74, 80))	('Up-regulation', 'PosReg', (0, 13))	('TCF4', 'Gene', (145, 149))	('MSI+ tumors', 'Disease', (37, 48))	('APC', 'Gene', (70, 73))	('mutations', 'Var', (57, 66))	('TCF4', 'Gene', '6925', (145, 149))	('APC', 'Gene', '324', (70, 73))	('as', 'Chemical', 'MESH:D001151', (152, 154))
21470	23168910	A combined effect of APC inactivation and mutation-induced KRAS activation in augmenting CRC initiation has been proposed.	('KRAS', 'Gene', '3845', (59, 63))	('as', 'Chemical', 'MESH:D001151', (105, 107))	('APC', 'Gene', (21, 24))	('KRAS', 'Gene', (59, 63))	('APC', 'cellular_component', 'GO:0005680', ('21', '24'))	('APC', 'Gene', '324', (21, 24))	('CRC', 'Disease', (89, 92))	('activation', 'PosReg', (64, 74))	('augmenting', 'PosReg', (78, 88))	('mutation-induced', 'Var', (42, 58))
21480	33431054	Comprehensive assessments of germline deletion structural variants reveal the association between prognostic MUC4 and CEP72 deletions and immune response gene expression in colorectal cancer patients Functional disruptions by large germline genomic structural variants in susceptible genes are known risks for cancer.	('colorectal cancer', 'Disease', (173, 190))	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', (310, 316))	('disruptions', 'NegReg', (211, 222))	('CEP72', 'Gene', (118, 123))	('colorectal cancer', 'Disease', 'MESH:D015179', (173, 190))	('MUC4', 'Gene', '4585', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('expression', 'MPA', (159, 169))	('colorectal cancer', 'Phenotype', 'HP:0003003', (173, 190))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('immune response gene', 'Gene', (138, 158))	('CEP72', 'Gene', '55722', (118, 123))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('deletions', 'Var', (124, 133))	('MUC4', 'Gene', (109, 113))
21481	33431054	We used deletion structural variants (DSVs) generated from germline whole-genome sequencing (WGS) and DSV immune-related association tumor microenvironment (TME) to predict cancer risk and prognosis.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('cancer', 'Disease', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Disease', (133, 138))	('predict', 'Reg', (165, 172))	('deletion', 'Var', (8, 16))
21494	33431054	The causal inference model showed that deleting the CEP72 DSV gene affect the recurrence-free survival (RFS) of IFIT1 expression.	('deleting', 'Var', (39, 47))	('CEP', 'molecular_function', 'GO:0047849', ('52', '55'))	('recurrence-free survival', 'CPA', (78, 102))	('affect', 'Reg', (67, 73))	('CEP72', 'Gene', '55722', (52, 57))	('IFIT1', 'Gene', (112, 117))	('CEP72', 'Gene', (52, 57))	('IFIT1', 'Gene', '3434', (112, 117))
21497	33431054	Large-scale germline structural variants, especially deletion structural variants (DSVs), can affect gene expression with a partial or complete loss of gene function and increased cancer risk in patients.	('gene', 'MPA', (152, 156))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('affect', 'Reg', (94, 100))	('increased', 'PosReg', (170, 179))	('patients', 'Species', '9606', (195, 203))	('deletion structural', 'Var', (53, 72))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('loss', 'NegReg', (144, 148))	('cancer', 'Disease', (180, 186))	('gene expression', 'MPA', (101, 116))
21508	33431054	Germline genomic DSVs are known to be associated with increased risk for cancer, and several studies have reportedly applied machine learning tools for developing prediction models.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('associated', 'Reg', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Germline genomic DSVs', 'Var', (0, 21))
21512	33431054	In total, 671 of 2919 significant DSVs were selected for the prediction of cancer risk with positive weights from the attention-weighted model (Supplementary Table 1A).	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (75, 81))	('DSVs', 'Var', (34, 38))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
21513	33431054	The size and distribution of deletions on each chromosome were no different between cancer patients and non-cancer subjects (Supplementary Fig.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('non-cancer', 'Disease', 'MESH:D009369', (104, 114))	('patients', 'Species', '9606', (91, 99))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('deletions', 'Var', (29, 38))	('cancer', 'Disease', (108, 114))	('non-cancer', 'Disease', (104, 114))
21519	33431054	The result indicated that the DSVs in SNTG2, PCMT1, DACT2, CBX3, ATP11A, and SHC2 were associated with breast cancer.	('DACT2', 'Gene', (52, 57))	('DSVs', 'Var', (30, 34))	('SHC2', 'Gene', '25759', (77, 81))	('PCMT1', 'Gene', (45, 50))	('SNTG2', 'Gene', (38, 43))	('CBX3', 'Gene', '11335', (59, 63))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('ATP11A', 'Gene', (65, 71))	('associated', 'Reg', (87, 97))	('SNTG2', 'Gene', '54221', (38, 43))	('breast cancer', 'Disease', (103, 116))	('ATP11A', 'Gene', '23250', (65, 71))	('DACT2', 'Gene', '168002', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('CBX3', 'Gene', (59, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('PCMT1', 'Gene', '5110', (45, 50))	('SHC2', 'Gene', (77, 81))
21529	33431054	Deletions in the FANCA, POLD1, and STK11 genes were observed in cancer patients only.	('observed', 'Reg', (52, 60))	('patients', 'Species', '9606', (71, 79))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('STK11', 'Gene', (35, 40))	('FANCA', 'Gene', '2175', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('STK11', 'molecular_function', 'GO:0033868', ('35', '40'))	('FANCA', 'Gene', (17, 22))	('POLD1', 'Gene', (24, 29))	('POLD1', 'Gene', '5424', (24, 29))	('Deletions', 'Var', (0, 9))	('STK11', 'Gene', '6794', (35, 40))
21540	33431054	MGAT4C, HSPA4L, ZSCAN5A, LOC100505841, and NALCN gene deletions were associated with cancer patients without FCH (p < 0.05), while SMYD3 and NKD2DSV genes were associated with cancer patients with FCH (p < 0.05).	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('NALCN', 'Gene', (43, 48))	('ZSCAN5A', 'Gene', '79149', (16, 23))	('NALCN', 'Gene', '259232', (43, 48))	('FCH', 'Chemical', '-', (197, 200))	('FCH', 'Chemical', '-', (109, 112))	('NKD2', 'Gene', (141, 145))	('patients', 'Species', '9606', (92, 100))	('SMYD3', 'Gene', (131, 136))	('SMYD3', 'Gene', '64754', (131, 136))	('NKD2', 'Gene', '85409', (141, 145))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('LOC100505841', 'Gene', (25, 37))	('FCH', 'Disease', (197, 200))	('ZSCAN5A', 'Gene', (16, 23))	('cancer', 'Disease', (85, 91))	('LOC100505841', 'Gene', '100505841', (25, 37))	('HSPA4L', 'Gene', (8, 14))	('deletions', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('patients', 'Species', '9606', (183, 191))	('MGAT4C', 'Gene', (0, 6))	('HSPA4L', 'Gene', '22824', (8, 14))	('MGAT4C', 'Gene', '25834', (0, 6))	('cancer', 'Disease', (176, 182))
21547	33431054	A total of 57 DSV genes were correlated with the six functional immune response categories; the PTPRN2 gene deletion had the highest frequency (Fig.	('PTPRN2', 'Gene', '5799', (96, 102))	('PTPRN2', 'Gene', (96, 102))	('immune response', 'biological_process', 'GO:0006955', ('64', '79'))	('deletion', 'Var', (108, 116))
21549	33431054	5a) were related to lymphocyte regulation and housekeeping (p-adjusted value less than 0.05), while CEP72 and ZZEF1 gene deletions had high occurrences in the housekeeping and cytokine signaling categories, respectively (Fig.	('ZZEF1', 'Gene', '23140', (110, 115))	('ZZEF1', 'Gene', (110, 115))	('housekeeping', 'MPA', (159, 171))	('CEP', 'molecular_function', 'GO:0047849', ('100', '103'))	('signaling', 'biological_process', 'GO:0023052', ('185', '194'))	('CEP72', 'Gene', '55722', (100, 105))	('deletions', 'Var', (121, 130))	('CEP72', 'Gene', (100, 105))	('lymphocyte regulation', 'MPA', (20, 41))	('regulation', 'biological_process', 'GO:0065007', ('31', '41'))
21560	33431054	Moreover, the MUC4 gene deletion was positively correlated with MAGE1 expression, which indicated that SV deletion resulted in increased MAGE1 expression (Fig.	('MAGE1', 'Gene', '4100', (64, 69))	('expression', 'MPA', (143, 153))	('MUC4', 'Gene', (14, 18))	('MAGE1', 'Gene', '4100', (137, 142))	('deletion', 'Var', (106, 114))	('MAGE1', 'Gene', (64, 69))	('MAGE1', 'Gene', (137, 142))	('deletion', 'Var', (24, 32))	('MUC4', 'Gene', '4585', (14, 18))	('increased', 'PosReg', (127, 136))
21562	33431054	The functional protein association networks indicated that the MUC4 gene deletion might influence the expression of MAGE1.We hypothesized that germline DSVs could affect immune MAGEA1 expression and correlate with a poor prognosis.	('MAGE1', 'Gene', '4100', (116, 121))	('immune', 'MPA', (170, 176))	('MUC4', 'Gene', '4585', (63, 67))	('MAGEA1', 'Gene', (177, 183))	('affect', 'Reg', (163, 169))	('MAGE1', 'Gene', (116, 121))	('MUC4', 'Gene', (63, 67))	('MAGEA1', 'Gene', '4100', (177, 183))	('expression', 'MPA', (184, 194))	('deletion', 'Var', (73, 81))
21564	33431054	In our cohort, the eight prognostic deletions were correlated with immune gene expression and survival in colorectal cancer stage III patients (Supplementary Fig.	('deletions', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('colorectal cancer', 'Disease', (106, 123))	('patients', 'Species', '9606', (134, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (106, 123))	('immune gene expression', 'MPA', (67, 89))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))	('correlated', 'Reg', (51, 61))
21565	33431054	Our results showed that deletion of the oncogene CEP72 could affect RFS by IFIT1 immune expression.	('RFS', 'Disease', (68, 71))	('CEP', 'molecular_function', 'GO:0047849', ('49', '52'))	('IFIT1', 'Gene', '3434', (75, 80))	('affect', 'Reg', (61, 67))	('CEP72', 'Gene', '55722', (49, 54))	('deletion', 'Var', (24, 32))	('CEP72', 'Gene', (49, 54))	('IFIT1', 'Gene', (75, 80))
21567	33431054	In this study, we demonstrated the possible biological relevance of the MUC4 gene deletion and MAGE1 expression and found the causal relationships among CEP72 gene deletion, IFIT1, and RFS (Fig.	('CEP72', 'Gene', (153, 158))	('MAGE1', 'Gene', '4100', (95, 100))	('IFIT1', 'Gene', '3434', (174, 179))	('MUC4', 'Gene', '4585', (72, 76))	('MAGE1', 'Gene', (95, 100))	('MUC4', 'Gene', (72, 76))	('CEP72', 'Gene', '55722', (153, 158))	('deletion', 'Var', (164, 172))	('IFIT1', 'Gene', (174, 179))
21579	33431054	Using population-based designs, we identified 671 DSVs associated with the risk of cancer.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('associated', 'Reg', (55, 65))	('DSVs', 'Var', (50, 54))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
21581	33431054	We found that the deletion occur in the LHFPL3 gene, which is relevant to colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (74, 91))	('LHFPL3', 'Gene', (40, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('LHFPL3', 'Gene', '375612', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('deletion', 'Var', (18, 26))	('colorectal cancer', 'Disease', (74, 91))
21582	33431054	The study has found that LHFPL3, the expression of miR-218-5p and miR-138-5p, was downregulated, which correlates to a reduction in cell activity, proliferation, and invasive human ability glioma cells.	('human', 'Species', '9606', (175, 180))	('reduction', 'NegReg', (119, 128))	('downregulated', 'NegReg', (82, 95))	('glioma', 'Disease', (189, 195))	('miR-138-5p', 'Var', (66, 76))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('miR-218-5p', 'Gene', (51, 61))	('glioma', 'Disease', 'MESH:D005910', (189, 195))	('cell activity', 'CPA', (132, 145))	('expression', 'MPA', (37, 47))	('LHFPL3', 'Gene', (25, 31))	('LHFPL3', 'Gene', '375612', (25, 31))
21583	33431054	The deletion in LHFPL3 leads to gene loss of function, which caused a worsening prognosis in colorectal cancer patients.	('loss of function', 'NegReg', (37, 53))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('LHFPL3', 'Gene', (16, 22))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('LHFPL3', 'Gene', '375612', (16, 22))	('deletion', 'Var', (4, 12))	('colorectal cancer', 'Disease', (93, 110))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('patients', 'Species', '9606', (111, 119))
21585	33431054	The result indicated that the deletion in CBX3 was associated with breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('CBX3', 'Gene', '11335', (42, 46))	('associated', 'Reg', (51, 61))	('deletion', 'Var', (30, 38))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('CBX3', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))
21587	33431054	CBX3 mRNA high expression was correlated to worsening RFS for all breast cancer patients.	('RFS', 'Disease', (54, 57))	('worsening', 'NegReg', (44, 53))	('patients', 'Species', '9606', (80, 88))	('CBX3', 'Gene', '11335', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('mRNA high expression', 'Var', (5, 25))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('CBX3', 'Gene', (0, 4))
21588	33431054	Many hereditary cancer syndromes have now been defined and attributed to specific germline-inherited mutations.	('hereditary cancer syndrome', 'Disease', (5, 31))	('hereditary cancer syndrome', 'Disease', 'MESH:D061325', (5, 31))	('mutations', 'Var', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
21594	33431054	Initially, they inherited nine DSV genes:CAB39L, GPR45, LOC1001291138, ACTR3BP5, ANP32AP1, ZBTB45, SALRNA1, XPO1, and HHIPL2:and developed cancer after acquiring five DSV genes:MGAT4A, HSPA4L, ZSCAN5A, LOC100505841, and NALCN.	('ZSCAN5A', 'Gene', '79149', (193, 200))	('ANP32AP1', 'Gene', (81, 89))	('SALRNA1', 'Gene', '104548971', (99, 106))	('NALCN', 'Gene', '259232', (220, 225))	('LOC1001291138', 'Var', (56, 69))	('GPR45', 'Gene', (49, 54))	('LOC100505841', 'Gene', (202, 214))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('AP1', 'cellular_component', 'GO:0005907', ('86', '89'))	('MGAT4A', 'Gene', '11320', (177, 183))	('HHIPL2', 'Gene', (118, 124))	('CAB39L', 'Gene', '81617', (41, 47))	('LOC100505841', 'Gene', '100505841', (202, 214))	('ZSCAN5A', 'Gene', (193, 200))	('XPO1', 'Gene', (108, 112))	('ACTR3BP5', 'Gene', '399746', (71, 79))	('ZBTB45', 'Gene', '84878', (91, 97))	('CAB39L', 'Gene', (41, 47))	('HSPA4L', 'Gene', (185, 191))	('ANP32AP1', 'Gene', '723972', (81, 89))	('developed', 'PosReg', (129, 138))	('MGAT4A', 'Gene', (177, 183))	('cancer', 'Disease', (139, 145))	('GPR45', 'Gene', '11250', (49, 54))	('ACTR3BP5', 'Gene', (71, 79))	('HHIPL2', 'Gene', '79802', (118, 124))	('HSPA4L', 'Gene', '22824', (185, 191))	('ZBTB45', 'Gene', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('XPO1', 'Gene', '7514', (108, 112))	('SALRNA1', 'Gene', (99, 106))	('NALCN', 'Gene', (220, 225))
21599	33431054	We hypothesized that germline DSVs mold the tumor microenvironment and immune gene expression, impacting the clinical outcome.	('impacting', 'Reg', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('germline DSVs', 'Var', (21, 34))	('mold', 'Reg', (35, 39))	('clinical outcome', 'MPA', (109, 125))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
21602	33431054	There were significantly poorer prognostic deletions in the tumor characterization category and better prognostic deletions in the lymphocyte regulation category.	('deletions', 'Var', (43, 52))	('lymphocyte regulation', 'MPA', (131, 152))	('regulation', 'biological_process', 'GO:0065007', ('142', '152'))	('poorer', 'NegReg', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
21603	33431054	Eight prognostic deletions associated with immune gene expression were identified, including HGF, CDKN2A, and ITGB1.	('ITGB1', 'Gene', '3688', (110, 115))	('deletions', 'Var', (17, 26))	('CDKN2A', 'Gene', (98, 104))	('ITGB1', 'Gene', (110, 115))	('gene expression', 'biological_process', 'GO:0010467', ('50', '65'))	('HGF', 'Gene', (93, 96))	('CDKN2A', 'Gene', '1029', (98, 104))	('HGF', 'Gene', '3082', (93, 96))
21613	33431054	The NCKUH institutional review board approved this study (A-ER-103-395 and A-ER-104-153), and all participants provided written informed consent.	('A-ER-103-395', 'Var', (58, 70))	('participants', 'Species', '9606', (98, 110))	('A-ER-104-153', 'Var', (75, 87))
21621	33431054	In the genetic features of colorectal cancers, there was no significant difference between recurrence and Mismatch Repair (MMR), KRAS, and TP53 status.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (27, 44))	('TP53', 'Gene', '7157', (139, 143))	('colorectal cancers', 'Disease', 'MESH:D015179', (27, 45))	('KRAS', 'Gene', (129, 133))	('colorectal cancers', 'Disease', (27, 45))	('KRAS', 'Gene', '3845', (129, 133))	('TP53', 'Gene', (139, 143))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('MMR', 'biological_process', 'GO:0006298', ('123', '126'))	('Mismatch', 'Var', (106, 114))	('Mismatch Repair', 'biological_process', 'GO:0006298', ('106', '121'))
21625	33431054	Third, we aimed to observe whether genes with DSVs would impact the tumor microenvironment's immune response gene expression.	('tumor', 'Disease', (68, 73))	('impact', 'Reg', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('DSVs', 'Var', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('immune response gene expression', 'MPA', (93, 124))
21631	33431054	We detected germline DSVs in cancer and non-cancer subjects simultaneously with PopDel from whole-genome DNA sequencing data.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', (44, 50))	('non-cancer', 'Disease', (40, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('non-cancer', 'Disease', 'MESH:D009369', (40, 50))	('DNA', 'cellular_component', 'GO:0005574', ('105', '108'))	('germline', 'Var', (12, 20))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
21639	33431054	All authors agree for publication This work was supported in part by the Ministry of Science and Technology (MOST), Taiwan under Research Grant of MOST-108-2634-F-006-006 and MOST 108-2634-F-006-011 and Ministry of Health and Welfare (MOHW108-TDU-B-211-124018 and MOHW108-TDU-B-211-133003).	('MOHW108-TDU-B-211-133003', 'Var', (264, 288))	('MOST-108-2634', 'CellLine', 'CVCL:9K47', (147, 160))	('MOHW108-TDU-B-211-124018', 'Var', (235, 259))
21683	32375670	The histological diagnosis of this patient was papillary thyroid carcinoma pT1aN0M0, Stage I, and multiple metastatic rectal adenocarcinoma rT4bN1M1b, stage IVB.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('pT1aN0M0', 'Var', (75, 83))	('papillary thyroid carcinoma', 'Disease', (47, 74))	('patient', 'Species', '9606', (35, 42))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (57, 74))	('adenocarcinoma', 'Disease', (125, 139))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (47, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (47, 74))	('adenocarcinoma', 'Disease', 'MESH:D000230', (125, 139))
21684	32375670	Due to metastatic rectal adenocarcinoma, RAS, BRAF V600E and PI3K molecular assay was performed and revealed that NRAS, BRAF V600E and PI3K was wild type but KRAS exons 2 had a mutation.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('KRAS', 'Gene', '3845', (158, 162))	('NRAS', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (120, 124))	('NRAS', 'Gene', '4893', (114, 118))	('BRAF', 'Gene', (120, 124))	('adenocarcinoma', 'Disease', (25, 39))	('PI3K', 'Var', (135, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('adenocarcinoma', 'Disease', 'MESH:D000230', (25, 39))	('KRAS', 'Gene', (158, 162))	('V600E', 'Mutation', 'rs113488022', (51, 56))	('V600E', 'Mutation', 'rs113488022', (125, 130))
21750	32375670	This hereditary syndrome results from a germline mutation in one of the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2).	('PMS2', 'Gene', (127, 131))	('MMR', 'Gene', (93, 96))	('MLH1', 'Gene', (105, 109))	('PMS2', 'Gene', '5395', (127, 131))	('MSH6', 'Gene', (117, 121))	('germline mutation', 'Var', (40, 57))	('MSH6', 'Gene', '2956', (117, 121))	('results from', 'Reg', (25, 37))	('MSH2', 'Gene', (111, 115))	('hereditary syndrome', 'Disease', (5, 24))	('hereditary syndrome', 'Disease', 'MESH:D061325', (5, 24))	('MSH2', 'Gene', '4436', (111, 115))	('MLH1', 'Gene', '4292', (105, 109))
21751	32375670	Pelizzo et al., revealed that both colonic and thyroid cancers were more likely to occur in association with MLH1 or MSH2 germ-line mutations in HNPCC patients.	('MLH1', 'Gene', '4292', (109, 113))	('HNPCC', 'Gene', '4436', (145, 150))	('MLH1', 'Gene', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mutations', 'Var', (132, 141))	('patients', 'Species', '9606', (151, 159))	('thyroid cancer', 'Phenotype', 'HP:0002890', (47, 61))	('MSH2', 'Gene', (117, 121))	('HNPCC', 'Gene', (145, 150))	('colonic and thyroid cancers', 'Disease', 'MESH:D015179', (35, 62))	('MSH2', 'Gene', '4436', (117, 121))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('association', 'Interaction', (92, 103))
21782	32038612	Depletion of NK cell populations prior to tumor transplantation has been shown to cause a more aggressive phenotype with metastatic tumors.	('cause', 'Reg', (82, 87))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('Depletion of NK cell populations', 'Phenotype', 'HP:0040218', (0, 32))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('Depletion', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
21789	32038612	The lack of TLR3 signaling downregulates NK cell function following cytokine stimulation, leading to defective immune responses unable to constrain metastatic diseases.	('NK cell function', 'CPA', (41, 57))	('TLR3', 'Gene', '142980', (12, 16))	('downregulates', 'NegReg', (27, 40))	('lack', 'Var', (4, 8))	('immune responses', 'MPA', (111, 127))	('defective immune responses', 'Phenotype', 'HP:0002721', (101, 127))	('TLR3', 'Gene', (12, 16))
21824	32038612	Melanoma cells isolated from metastatic lymph nodes were efficiently lysed by circulating NK cells expressing high levels of NKG2D, NKp30, DNAM-1, and CD62L.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('NKG2D', 'Var', (125, 130))	('Melanoma', 'Disease', (0, 8))	('NKp30', 'Gene', '259197', (132, 137))	('CD62L', 'Gene', (151, 156))	('CD62L', 'Gene', '6402', (151, 156))	('NKp30', 'Gene', (132, 137))
21835	32038612	An early study reported that low NK cell cytotoxicity was predictive of colon cancer recurrence, independently of other prognostic factors.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colon cancer', 'Disease', (72, 84))	('low', 'Var', (29, 32))	('low NK cell', 'Phenotype', 'HP:0040218', (29, 40))	('cytotoxicity', 'Disease', (41, 53))	('colon cancer', 'Phenotype', 'HP:0003003', (72, 84))	('colon cancer', 'Disease', 'MESH:D015179', (72, 84))	('cytotoxicity', 'Disease', 'MESH:D064420', (41, 53))
21851	32038612	These evidence indicate that infiltration of functional NK cells in hepatocellular carcinoma tissues may represent the host reaction to cancer and that TME impairs NK cell function during disease progression.	('impairs', 'NegReg', (156, 163))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (68, 92))	('cancer', 'Disease', (136, 142))	('TME', 'Var', (152, 155))	('NK cell function', 'CPA', (164, 180))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (68, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('hepatocellular carcinoma', 'Disease', (68, 92))
21887	32038612	The authors showed that pharmacological inhibition of FBP1 can revert the dysfunctional phenotype of NK cells during tumor promotion, but not during tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('FBP1', 'Gene', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('dysfunctional phenotype', 'MPA', (74, 97))	('tumor', 'Disease', (149, 154))	('pharmacological inhibition', 'Var', (24, 50))	('FBP1', 'Gene', '14121', (54, 58))	('revert', 'NegReg', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
21900	32038612	Preclinical studies show that the blocking of PGE2 in a murine model of metastatic breast cancer and in human gastric cancer cells restores NK cell function against tumor.	('gastric cancer', 'Disease', (110, 124))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('restores', 'PosReg', (131, 139))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('blocking', 'Var', (34, 42))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', (83, 96))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('human', 'Species', '9606', (104, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('PGE2', 'Chemical', 'MESH:D015232', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('PGE2', 'Gene', (46, 50))	('murine', 'Species', '10090', (56, 62))	('tumor', 'Disease', (165, 170))
21904	32038612	L-Kynurenine is known to affect NK cell activity by interfering with the IL-2-driven upregulation of NKp46 and NKG2D.	('L-Kynurenine', 'Var', (0, 12))	('IL-2', 'Gene', '3558', (73, 77))	('IL-2', 'molecular_function', 'GO:0005134', ('73', '77'))	('IL-2', 'Gene', (73, 77))	('L-Kynurenine', 'Chemical', 'MESH:C029366', (0, 12))	('interfering', 'NegReg', (52, 63))	('upregulation', 'PosReg', (85, 97))	('affect', 'Reg', (25, 31))	('NKp46', 'Gene', (101, 106))
21915	32038612	The acidification of the TME has been shown to induce apoptosis of liver-resident NK cells in colorectal cancer liver metastases.	('apoptosis', 'CPA', (54, 63))	('apoptosis of liver', 'Phenotype', 'HP:0001404', (54, 72))	('colorectal cancer liver metastases', 'Disease', 'MESH:D015179', (94, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('colorectal cancer liver metastases', 'Disease', (94, 128))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('acidification', 'Var', (4, 17))
21921	32038612	In a murine model, the neutralization of soluble NKG2D ligands such as MICA and MICB with mAb B10G5 was effective against prostate carcinoma and metastasis, leading to the enhanced NK cell infiltration in the tumor parenchyma, and improving CTLA-4 blockade therapy.	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('improving', 'PosReg', (231, 240))	('metastasis', 'CPA', (145, 155))	('neutralization', 'Var', (23, 37))	('CTLA-4 blockade therapy', 'MPA', (241, 264))	('enhanced', 'PosReg', (172, 180))	('murine', 'Species', '10090', (5, 11))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (122, 140))	('tumor parenchyma', 'Disease', (209, 225))	('prostate carcinoma', 'Disease', (122, 140))	('tumor parenchyma', 'Disease', 'MESH:D009369', (209, 225))	('prostate carcinoma', 'Disease', 'MESH:D011471', (122, 140))	('soluble', 'cellular_component', 'GO:0005625', ('41', '48'))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
21924	32038612	This therapeutic approach is very promising even in challenging pediatric tumors, such as neuroblastoma, in which amplification of the MYCN oncogene, clinically associated with poor prognosis, has been correlated with the reduced tumor susceptibility to NK cell-mediated killing.	('tumor', 'Disease', (230, 235))	('amplification', 'Var', (114, 127))	('neuroblastoma', 'Disease', (90, 103))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('neuroblastoma', 'Phenotype', 'HP:0003006', (90, 103))	('challenging pediatric tumors', 'Disease', 'MESH:D063766', (52, 80))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('MYCN', 'Gene', (135, 139))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Disease', (74, 79))	('challenging pediatric tumors', 'Disease', (52, 80))	('MYCN', 'Gene', '4613', (135, 139))	('reduced', 'NegReg', (222, 229))	('neuroblastoma', 'Disease', 'MESH:D009447', (90, 103))
21927	32038612	In a xenograft model, anti-PD1 suppressed the tumor growth of digestive cancers in an NK cell-dependent manner, suggesting a crucial role of PD1 in NK cell function.	('anti-PD1', 'Var', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', (46, 51))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('suppressed', 'NegReg', (31, 41))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
21928	32038612	Moreover, anti-CTLA-4 combined with IL-15/IL-15Ralpha enhances the NK cell tumor infiltration, improving the tumor growth control in xenograft murine models of solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (160, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('anti-CTLA-4', 'Var', (10, 21))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('murine', 'Species', '10090', (143, 149))	('IL-15', 'molecular_function', 'GO:0016170', ('42', '47'))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('enhances', 'PosReg', (54, 62))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('solid tumors', 'Disease', (160, 172))	('IL-15Ralpha', 'Gene', '16169', (42, 53))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('IL-15', 'molecular_function', 'GO:0016170', ('36', '41'))	('improving', 'PosReg', (95, 104))	('IL-15Ralpha', 'Gene', (42, 53))	('tumor', 'Disease', (109, 114))
21929	32038612	Melanoma patients treated with anti-CTLA-4 (ipilimumab) had higher intratumoral CD56 expression.	('patients', 'Species', '9606', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('higher', 'PosReg', (60, 66))	('tumor', 'Disease', (72, 77))	('Melanoma', 'Disease', (0, 8))	('anti-CTLA-4', 'Var', (31, 42))	('CD56', 'Gene', '4684', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('CD56', 'Gene', (80, 84))
21933	32038612	In preclinical studies, the murine model anti-TIGIT is able to improve the antitumor effect of anti-HER2 mAb alone, and in combination with PD1/PD-L1 inhibitors.	('tumor', 'Disease', (79, 84))	('anti-TIGIT', 'Var', (41, 51))	('improve', 'PosReg', (63, 70))	('murine', 'Species', '10090', (28, 34))	('anti-HER2 mAb', 'Protein', (95, 108))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
21934	32038612	Preclinical studies showed that CD96 blocking combined with anti-PD1 or anti-CTLA-4 enhances NK cell infiltration and IFN-gamma production, thus reducing tumor lung metastases.	('tumor lung metastases', 'Disease', 'MESH:D009362', (154, 175))	('tumor lung', 'Phenotype', 'HP:0100526', (154, 164))	('enhances', 'PosReg', (84, 92))	('NK cell infiltration', 'CPA', (93, 113))	('tumor lung metastases', 'Disease', (154, 175))	('anti-CTLA-4', 'Var', (72, 83))	('IFN-gamma', 'Gene', (118, 127))	('IFN-gamma', 'Gene', '3458', (118, 127))	('reducing', 'NegReg', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('CD96', 'Gene', (32, 36))	('CD96', 'Gene', '10225', (32, 36))
21935	32038612	The blockade of TIM-3 was also found to enhance NK cell function against melanoma cells.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('blockade', 'Var', (4, 12))	('TIM-3', 'Gene', (16, 21))	('enhance', 'PosReg', (40, 47))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
21936	32038612	The therapeutic efficacy of the combined use of different immune checkpoint inhibitors, such as anti-TIM-3 and anti-TIGIT, is currently tested in ongoing phase I and II clinical trials in solid tumor patients (Table 1).	('patients', 'Species', '9606', (200, 208))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('anti-TIM-3', 'Var', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))
21943	32038612	Thus, haploidentical allogenic NK cells represent an optimal cellular immunotherapy product, mainly for immunocompromising diseases, including solid tumors, whose patients can scantly count on their own cells and often need donor NK cells.	('solid tumors', 'Disease', (143, 155))	('patients', 'Species', '9606', (163, 171))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('solid tumors', 'Disease', 'MESH:D009369', (143, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('haploidentical', 'Var', (6, 20))	('donor', 'Species', '9606', (224, 229))
22039	31423233	Approximately 50% of human miRNA genes are located in genomic regions that have fragile sites, and these locations contain chromosomal abnormalities, such as deletions and amplifications.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (123, 148))	('chromosomal abnormalities', 'Disease', (123, 148))	('deletions', 'Var', (158, 167))	('human', 'Species', '9606', (21, 26))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('amplifications', 'Var', (172, 186))	('contain', 'Reg', (115, 122))
22044	31423233	In cancer cells, alteration of miRNA expression levels can be abnormally down- or upregulated, to function as either tumor suppressors or oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('upregulated', 'PosReg', (82, 93))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('alteration', 'Var', (17, 27))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('cancer', 'Disease', (3, 9))	('down-', 'NegReg', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
22071	31423233	Forward primers (Table II) were designed by first converting the miRNA sequences to DNA and adjusting the melting temperature of the primer to 60 C, either by adding a thymine to the 3' of the primer or removing a nucleotide from the 5' end of the primer.	('removing', 'Var', (203, 211))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('thymine', 'Chemical', 'MESH:D013941', (168, 175))	('adding', 'Reg', (159, 165))	('nucleotide', 'MPA', (214, 224))
22073	31423233	The amplification reaction (10 microl) included 2X SYBR Green PCR master mix (5 microl), universal primer (250 nM), miRNA-specific primer (250 nM), RNase-free water (1.75 microl) and cDNA (2 microl).	('250', 'Var', (139, 142))	('SYBR Green', 'Chemical', '-', (51, 61))	('miR', 'Gene', '220972', (116, 119))	('miR', 'Gene', (116, 119))	('water', 'Chemical', 'MESH:D014867', (159, 164))
22132	28954418	The updated meta-analysis confirms an important inverse association between adherence to a MedD and cancer mortality and risk of several cancer types, especially colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('colorectal cancer', 'Disease', 'MESH:D015179', (162, 179))	('cancer', 'Disease', (173, 179))	('colorectal cancer', 'Phenotype', 'HP:0003003', (162, 179))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('adherence', 'Var', (76, 85))	('colorectal cancer', 'Disease', (162, 179))	('cancer', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('inverse', 'NegReg', (48, 55))
22146	28954418	Some specific bioactive compounds from foods with tumor-preventive potential have been characterized in the past, e.g., polyphenols, n-3 fatty acids, or monounsaturated fatty acids.	('n-3 fatty acids', 'Chemical', 'MESH:D015525', (133, 148))	('monounsaturated', 'Var', (153, 168))	('polyphenols', 'Chemical', 'MESH:D059808', (120, 131))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('monounsaturated fatty acids', 'Chemical', 'MESH:D005229', (153, 180))	('tumor', 'Disease', (50, 55))
22174	28954418	Pooled estimates for the single components of the Mediterranean dietary pattern shown in Figure 1 revealed an inverse association for fruit consumption (RR: 0.93, 95% CI 0.89 to 0.97, I2 = 60%, n = 13 studies), vegetable intake (RR: 0.96, 95% CI 0.93 to 0.98, I2 = 0%, n = 14 studies), whole grain intake (RR: 0.91, 95% CI 0.87 to 0.95, I2 = 31%, n = 9 studies), and moderate alcohol consumption (within the range) (RR: 0.89, 95% CI 0.85 to 0.93), compared to higher intakes and cancer risk.	('cancer', 'Disease', (479, 485))	('cancer', 'Disease', 'MESH:D009369', (479, 485))	('moderate alcohol consumption', 'Var', (367, 395))	('inverse', 'NegReg', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (479, 485))	('alcohol', 'Chemical', 'MESH:D000438', (376, 383))
22178	28954418	Following the synthesis of data from RCTs as well as cohort and case-control studies in the present systematic review, strongest adherence to a MedD was inversely associated with cancer mortality and risk of colorectal, breast, gastric, liver, head and neck, gallbladder, and biliary tract cancer.	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('colorectal', 'Disease', (208, 218))	('breast', 'Disease', (220, 226))	('MedD', 'Gene', (144, 148))	('adherence', 'Var', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', (290, 296))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (276, 296))	('gastric', 'Disease', (228, 235))	('gallbladder', 'Disease', (259, 270))	('liver', 'Disease', (237, 242))	('associated with', 'Reg', (163, 178))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('cancer', 'Disease', (179, 185))	('inversely', 'NegReg', (153, 162))	('biliary tract cancer', 'Disease', 'MESH:D001661', (276, 296))	('biliary tract cancer', 'Disease', (276, 296))
22180	28954418	Consequently, the Greek cohort of the EPIC study revealed that the inverse association between adherence to a MedD and cancer risk is not due to any single component of this diet but rather an effect of the complete pattern.	('inverse', 'NegReg', (67, 74))	('adherence', 'Var', (95, 104))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
22213	28954418	In some studies, the inverse association between adherence to a MedD and risk of tobacco-related cancers was significantly more pronounced in the subgroup of active smokers.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('tobacco', 'Species', '4097', (81, 88))	('inverse', 'NegReg', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('adherence', 'Var', (49, 58))
22222	28954418	In conclusion, the present update of our systematic review and meta-analyses provided additional important evidence for a beneficial effect of high adherence to MedD with respect to primary prevention overall cancer risk and specific types of cancer, especially colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (262, 279))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('colorectal cancer', 'Phenotype', 'HP:0003003', (262, 279))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Disease', (243, 249))	('high adherence', 'Var', (143, 157))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('colorectal cancer', 'Disease', (262, 279))	('cancer', 'Disease', (209, 215))	('beneficial', 'PosReg', (122, 132))	('MedD', 'Gene', (161, 165))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
22240	28460459	In some cases, mesothelin expression has been associated with increased tumor aggressiveness and poor clinical outcome, however, its impact on the clinical outcome of malignant pleural mesothelioma patients has not been extensively evaluated.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (72, 92))	('increased', 'PosReg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('malignant pleural mesothelioma', 'Disease', (167, 197))	('patients', 'Species', '9606', (198, 206))	('mesothelin', 'Protein', (15, 25))	('expression', 'Var', (26, 36))	('aggressiveness', 'Phenotype', 'HP:0000718', (78, 92))	('tumor aggressiveness', 'Disease', (72, 92))	('associated', 'Reg', (46, 56))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (177, 197))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (167, 197))
22243	28460459	Although the mechanism(s) and/or tumor biological significances were unclear, high mesothelin expression was associated with KRAS gene mutation in lung adenocarcinoma.	('associated', 'Reg', (109, 119))	('KRAS', 'Gene', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('high', 'PosReg', (78, 82))	('KRAS', 'Gene', '3845', (125, 129))	('mesothelin', 'Protein', (83, 93))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (147, 166))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('expression', 'MPA', (94, 104))	('tumor', 'Disease', (33, 38))	('mutation', 'Var', (135, 143))	('lung adenocarcinoma', 'Disease', (147, 166))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (147, 166))
22274	28460459	Multivariable Cox hazards regression analysis revealed diffuse membranous mesothelin expression in mesothelioma tumor cells to be a favorable prognostic factor (HR, 0.36; 95% CI, 0.21-0.64; P < 0.001) (Table 4).	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (99, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mesothelioma tumor', 'Disease', (99, 117))	('diffuse', 'Var', (55, 62))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (99, 117))
22277	28460459	Arbitrary selected 75 colorectal tumors were analyzed for BRAF, KRAS, and NRAS gene mutations.	('NRAS', 'Gene', (74, 78))	('KRAS', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mutations', 'Var', (84, 93))	('NRAS', 'Gene', '4893', (74, 78))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('colorectal tumors', 'Disease', (22, 39))	('colorectal tumors', 'Disease', 'MESH:D015179', (22, 39))	('BRAF', 'Gene', '673', (58, 62))	('KRAS', 'Gene', '3845', (64, 68))	('BRAF', 'Gene', (58, 62))
22279	28460459	Only one case showed mutation in the NRAS gene.	('NRAS', 'Gene', '4893', (37, 41))	('NRAS', 'Gene', (37, 41))	('mutation', 'Var', (21, 29))
22310	28460459	In case of lung adenocarcinoma high-level of mesothelin expression is associated with aggressiveness, poor prognosis and KRAS gene mutation status.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (11, 30))	('aggressiveness', 'Phenotype', 'HP:0000718', (86, 100))	('KRAS', 'Gene', (121, 125))	('KRAS', 'Gene', '3845', (121, 125))	('high-level', 'Var', (31, 41))	('aggressiveness', 'Disease', 'MESH:D001523', (86, 100))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (11, 30))	('associated', 'Reg', (70, 80))	('expression', 'MPA', (56, 66))	('aggressiveness', 'Disease', (86, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('lung adenocarcinoma', 'Disease', (11, 30))
22311	28460459	Based on these observations, in the present study, gene mutation analyses were performed in colorectal adenocarcinomas since they commonly harbor KRAS mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('harbor', 'Reg', (139, 145))	('KRAS', 'Gene', (146, 150))	('KRAS', 'Gene', '3845', (146, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('colorectal adenocarcinomas', 'Disease', (92, 118))	('mutations', 'Var', (151, 160))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (92, 118))
22312	28460459	Among 75 arbitrarily selected colorectal adenocarcinomas, 20 and 31 tumors carried BRAF and RAS mutations, respectively.	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (30, 56))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('colorectal adenocarcinomas', 'Disease', (30, 56))	('BRAF', 'Gene', '673', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mutations', 'Var', (96, 105))	('BRAF', 'Gene', (83, 87))	('RAS', 'Gene', (92, 95))
22337	27708224	A module of inflammatory cytokines defines resistance of colorectal cancer to EGFR inhibitors Epidermal Growth Factor Receptor (EGFR) activates a robust signalling network to which colon cancer tumours often become addicted.	('tumours', 'Phenotype', 'HP:0002664', (194, 201))	('colorectal cancer', 'Disease', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (57, 74))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (94, 126))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('colon cancer', 'Phenotype', 'HP:0003003', (181, 193))	('colon cancer tumours', 'Disease', (181, 201))	('colon cancer tumours', 'Disease', 'MESH:D009369', (181, 201))	('Epidermal Growth Factor Receptor', 'Gene', (94, 126))	('colorectal cancer', 'Disease', 'MESH:D015179', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('activates', 'PosReg', (134, 143))	('EGFR', 'Gene', '1956', (78, 82))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('EGFR', 'Gene', (78, 82))	('inhibitors', 'Var', (83, 93))
22340	27708224	Mechanisms of cancer cell resistance include either acquisition of new mutations or non genomic activation of alternative signalling routes.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (71, 80))	('signalling', 'biological_process', 'GO:0023052', ('122', '132'))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
22345	27708224	Collectively, these results highlight the contribution of inflammatory cytokines to reduced sensitivity to EGFR blockade and suggest that inhibition of this panel of cytokines in combination with cetuximab might yield an effective treatment strategy for CRC patients refractory to anti-EGFR targeting.	('sensitivity', 'MPA', (92, 103))	('EGFR', 'Gene', '1956', (107, 111))	('EGFR', 'Gene', '1956', (286, 290))	('EGFR', 'Gene', (107, 111))	('reduced', 'NegReg', (84, 91))	('EGFR', 'Gene', (286, 290))	('inhibition', 'Var', (138, 148))	('patients', 'Species', '9606', (258, 266))	('CRC patients', 'Disease', (254, 266))	('cetuximab', 'Chemical', 'MESH:D000068818', (196, 205))
22351	27708224	EGFR antibodies in combination with chemotherapy prolong survival in subjects with mCRC and are a standard component of therapy of such individuals.	('EGFR', 'Gene', (0, 4))	('antibodies', 'Var', (5, 15))	('mCRC', 'Disease', (83, 87))	('EGFR', 'Gene', '1956', (0, 4))	('prolong', 'PosReg', (49, 56))	('survival', 'CPA', (57, 65))
22352	27708224	The genetic evaluation for KRAS and NRAS mutations currently represents the main clinical criterion predicting treatment efficacy, since mutations in these genes foresees an individual's intrinsic resistance to the monoclonal antibodies.	('mutations', 'Var', (41, 50))	('KRAS', 'Gene', '3845', (27, 31))	('NRAS', 'Gene', (36, 40))	('resistance', 'MPA', (197, 207))	('NRAS', 'Gene', '4893', (36, 40))	('mutations', 'Var', (137, 146))	('KRAS', 'Gene', (27, 31))
22379	27708224	These findings support the notion that the adaptation to cetuximab leads to resistant cells characterized by a more malignant phenotype, which enables the cells to grow in suspension.	('adaptation', 'Var', (43, 53))	('cetuximab', 'Chemical', 'MESH:D000068818', (57, 66))	('resistant cells', 'CPA', (76, 91))
22384	27708224	Under monolayer conditions, the autocrine ligands HBEGF and TGFA were slightly increased upon cetuximab administration and up-regulated in cetuximab-resistant cells, which also displayed increased levels of negative feedback regulators (Figure 3A).	('increased', 'PosReg', (79, 88))	('cetuximab', 'Chemical', 'MESH:D000068818', (94, 103))	('cetuximab', 'Chemical', 'MESH:D000068818', (139, 148))	('levels', 'MPA', (197, 203))	('TGFA', 'Gene', '7039', (60, 64))	('increased', 'PosReg', (187, 196))	('HBEGF', 'Gene', (50, 55))	('HBEGF', 'Gene', '1839', (50, 55))	('TGFA', 'Gene', (60, 64))	('cetuximab', 'Var', (94, 103))	('up-regulated', 'PosReg', (123, 135))
22415	27708224	These results support the hypothesis that NF-kB is a key player in resistance to CX treatment, likely for its ability of inducing pro-inflammatory cytokines production (such as IL1A, IL1B and IL8), which in turn activates a NF-kappaB dependent feed-forward loop, as reported in pancreatic tumors.	('IL1B', 'Gene', (183, 187))	('pro-inflammatory cytokines production', 'MPA', (130, 167))	('pancreatic tumors', 'Disease', (278, 295))	('NF-kappaB', 'Gene', '4790', (224, 233))	('IL1A', 'Gene', '3552', (177, 181))	('inducing', 'Reg', (121, 129))	('IL1B', 'Gene', '3553', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (278, 295))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('IL8', 'Gene', (192, 195))	('NF-kappaB', 'Gene', (224, 233))	('activates', 'PosReg', (212, 221))	('NF-kB', 'Var', (42, 47))	('IL8', 'Gene', '3576', (192, 195))	('IL1A', 'Gene', (177, 181))	('pancreatic tumors', 'Disease', 'MESH:D010190', (278, 295))	('CX', 'Chemical', 'MESH:D000068818', (81, 83))
22418	27708224	Gene expression information was analysed in colorectal tumorgrafts from 98 patients with wild type KRAS, BRAF, NRAS, and PIK3CA genotypes ("quadruple negative" tumors) and from 61 individuals with KRAS (G12) mutation.	('NRAS', 'Gene', '4893', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('KRAS', 'Gene', (197, 201))	('tumors', 'Disease', (160, 166))	('KRAS', 'Gene', '3845', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('PIK3CA', 'Gene', (121, 127))	('KRAS', 'Gene', (99, 103))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('colorectal tumorgrafts', 'Disease', (44, 66))	('NRAS', 'Gene', (111, 115))	('mutation', 'Var', (208, 216))	('patients', 'Species', '9606', (75, 83))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('BRAF', 'Gene', '673', (105, 109))	('colorectal tumorgrafts', 'Disease', 'MESH:D015179', (44, 66))	('BRAF', 'Gene', (105, 109))	('PIK3CA', 'Gene', '5290', (121, 127))	('KRAS', 'Gene', '3845', (197, 201))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
22425	27708224	Interestingly, the pattern of increased expression of this module of inflammatory cytokines was maintained in the group of KRAS mutant tumours, which by definition are resistant to treatment.	('expression', 'MPA', (40, 50))	('tumours', 'Disease', 'MESH:D009369', (135, 142))	('tumours', 'Disease', (135, 142))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('mutant', 'Var', (128, 134))	('KRAS', 'Gene', (123, 127))	('increased', 'PosReg', (30, 39))	('KRAS', 'Gene', '3845', (123, 127))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))
22434	27708224	Notably, TGCA data show a lack of correlations of the reported cytokines with KRAS mutation and our in vitro model confirms a RAS wild-type status in the resistant condition.	('mutation', 'Var', (83, 91))	('KRAS', 'Gene', '3845', (78, 82))	('KRAS', 'Gene', (78, 82))
22448	27708224	Importantly, our data clearly show that patients with an alteration in the panel of pro-inflammatory cytokines are not sensitive to cetuximab treatment, recapitulating the trend of KRAS resistant patients.	('alteration', 'Var', (57, 67))	('patients', 'Species', '9606', (40, 48))	('cetuximab', 'Chemical', 'MESH:D000068818', (132, 141))	('patients', 'Species', '9606', (196, 204))	('KRAS', 'Gene', (181, 185))	('KRAS', 'Gene', '3845', (181, 185))
22527	26478796	Patients with N1 regional LN, M0 level of metastasis and Adjuvant therapy had higher survival.	('Patients', 'Species', '9606', (0, 8))	('higher', 'PosReg', (78, 84))	('M0 level', 'Var', (30, 38))	('survival', 'MPA', (85, 93))
22566	26147805	T4 tumors, lymphatic vessel invasion, blood vessel invasion, high-grade histology, presentation with obstruction/perforation and inadequate lymph node sampling were defined as high-risk Stage II disease.	('blood vessel invasion', 'CPA', (38, 59))	('obstruction', 'Disease', 'MESH:D000402', (101, 112))	('inadequate lymph node', 'Phenotype', 'HP:0002732', (129, 150))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumors', 'Disease', (3, 9))	('obstruction', 'Disease', (101, 112))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('lymphatic vessel invasion', 'CPA', (11, 36))	('high-grade histology', 'Var', (61, 81))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
22682	25538788	The pathologic results of patient 1-5 came as colorectal adenocarcinoma with pathologic stage T3N0M0, T3N0M0, T3N1bM0 (metastasis in two regional lymph node), T3N1aM0 (metastasis in one regional lymph node), T3N0M0; transurethral cell cancer with pathologic stage T2aN0M0, T2bN0M0, T2bN0M0, T2aN0M0, T2aN0M0.	('T2bN0M0', 'Var', (273, 280))	('T2aN0M0', 'Var', (300, 307))	('T2aN0M0', 'Var', (264, 271))	('transurethral cell cancer', 'Disease', (216, 241))	('patient', 'Species', '9606', (26, 33))	('T2bN0M0', 'Var', (282, 289))	('T2aN0M0', 'Var', (291, 298))	('colorectal adenocarcinoma', 'Disease', (46, 71))	('transurethral cell cancer', 'Disease', 'MESH:C538614', (216, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (46, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
22711	24941225	Genetic Variations Affecting Serum Carcinoembryonic Antigen Levels and Status of Regional Lymph Nodes in Patients with Sporadic Colorectal Cancer from Southern China Serum carcinoembryonic antigen (sCEA) level might be an indicator of disease.	('Sporadic Colorectal Cancer', 'Disease', (119, 145))	('carcinoembryonic antigen', 'Gene', (172, 196))	('Carcinoembryonic Antigen', 'Gene', '1084', (35, 59))	('Patients', 'Species', '9606', (105, 113))	('Sporadic Colorectal Cancer', 'Disease', 'MESH:D015179', (119, 145))	('sCEA', 'Chemical', '-', (198, 202))	('Carcinoembryonic Antigen', 'Gene', (35, 59))	('Genetic Variations', 'Var', (0, 18))	('carcinoembryonic antigen', 'Gene', '1084', (172, 196))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (128, 145))	('Cancer', 'Phenotype', 'HP:0002664', (139, 145))
22717	24941225	The rs1047781 (chr19- FUT2) (A/T) was associated with elevated sCEA levels, and rs8176746 (chr9- ABO) was associated with the regional lymph metastasis in the CRC patients.	('patients', 'Species', '9606', (163, 171))	('sCEA levels', 'MPA', (63, 74))	('associated', 'Reg', (106, 116))	('rs8176746', 'Mutation', 'rs8176746', (80, 89))	('elevated', 'PosReg', (54, 62))	('CRC', 'Phenotype', 'HP:0003003', (159, 162))	('ABO', 'Gene', (97, 100))	('rs8176746', 'Var', (80, 89))	('rs1047781', 'Var', (4, 13))	('rs1047781', 'Mutation', 'rs1047781', (4, 13))	('FUT2', 'Gene', (22, 26))	('ABO', 'Gene', '28', (97, 100))	('regional lymph metastasis', 'CPA', (126, 151))	('sCEA', 'Chemical', '-', (63, 67))	('FUT2', 'Gene', '2524', (22, 26))	('CRC', 'Disease', (159, 162))
22719	24941225	The sCEA level in rs1047781-T carriers was higher than that in the A carriers in CRC patients without lymph node metastasis (P = 0.006).	('sCEA level', 'MPA', (4, 14))	('higher', 'PosReg', (43, 49))	('patients', 'Species', '9606', (85, 93))	('rs1047781', 'Mutation', 'rs1047781', (18, 27))	('CRC', 'Phenotype', 'HP:0003003', (81, 84))	('rs1047781-T', 'Var', (18, 29))	('sCEA', 'Chemical', '-', (4, 8))
22720	24941225	The regional lymph node metastasis in patients with homozygote AA of rs8176746 was more common than that in the heterozygote AG carriers (P = 0.022).	('rs8176746', 'Mutation', 'rs8176746', (69, 78))	('rs8176746', 'Var', (69, 78))	('common', 'Reg', (88, 94))	('patients', 'Species', '9606', (38, 46))	('regional lymph node metastasis', 'CPA', (4, 34))
22722	24941225	We found candidate SNPs associated with elevated sCEA levels in both healthy males and CRC population.	('SNPs', 'Var', (19, 23))	('sCEA levels', 'MPA', (49, 60))	('elevated', 'PosReg', (40, 48))	('CRC', 'Phenotype', 'HP:0003003', (87, 90))	('sCEA', 'Chemical', '-', (49, 53))
22723	24941225	Rs1047781 (chr19- FUT2) may be the susceptible locus for recurrence of CRC in a population from Southern China.	('FUT2', 'Gene', (18, 22))	('CRC', 'Disease', (71, 74))	('Rs1047781', 'Var', (0, 9))	('FUT2', 'Gene', '2524', (18, 22))	('CRC', 'Phenotype', 'HP:0003003', (71, 74))	('Rs1047781', 'Mutation', 'Rs1047781', (0, 9))
22734	24941225	Genome mutations associated with the elevated CEA level in CRC is present in the tumor itself, so such mutations could not be served as a genetic marker for CEA level for diagnostic purposes.	('associated', 'Reg', (17, 27))	('elevated', 'PosReg', (37, 45))	('CRC', 'Phenotype', 'HP:0003003', (59, 62))	('CEA', 'Gene', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('CEA', 'Gene', '1084', (46, 49))	('elevated CEA', 'Phenotype', 'HP:0031029', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CEA', 'Gene', (157, 160))	('CEA', 'Gene', '1084', (157, 160))	('tumor', 'Disease', (81, 86))	('mutations', 'Var', (7, 16))
22746	24941225	Nine candidate SNPs from the 25 SNPs that reached genome-wide significance were selected for genotyping in CRC patients: rs8176746 (chr9- ABO), rs1047781 (chr19-FUT2), rs3760775 (chr19-FUT6), rs441810 (chr21-FAM3B), rs12608544 (chr19-DBP), rs3786749 (chr19- SULT2B1), rs2071699 (chr19- FUT1), rs507666 (chr9- ABO) and rs687289 (chr9- ABO).	('rs3760775', 'Mutation', 'rs3760775', (168, 177))	('rs8176746', 'Mutation', 'rs8176746', (121, 130))	('ABO', 'Gene', (309, 312))	('rs1047781', 'Mutation', 'rs1047781', (144, 153))	('ABO', 'Gene', '28', (138, 141))	('rs1047781', 'Var', (144, 153))	('rs507666', 'Var', (293, 301))	('FUT1', 'Gene', '2523', (286, 290))	('rs687289', 'Var', (318, 326))	('rs12608544', 'Mutation', 'rs12608544', (216, 226))	('rs3786749', 'Mutation', 'rs3786749', (240, 249))	('FUT2', 'Gene', '2524', (161, 165))	('rs3760775', 'Var', (168, 177))	('rs441810', 'Var', (192, 200))	('CRC', 'Phenotype', 'HP:0003003', (107, 110))	('ABO', 'Gene', '28', (334, 337))	('rs2071699', 'Var', (268, 277))	('FAM3B', 'Gene', '54097', (208, 213))	('rs12608544', 'Var', (216, 226))	('rs507666', 'Mutation', 'rs507666', (293, 301))	('rs687289', 'Mutation', 'rs687289', (318, 326))	('ABO', 'Gene', '28', (309, 312))	('DBP', 'Gene', (234, 237))	('ABO', 'Gene', (138, 141))	('SULT2B1', 'Gene', (258, 265))	('FUT1', 'Gene', (286, 290))	('FUT6', 'Gene', (185, 189))	('SULT2B1', 'Gene', '6820', (258, 265))	('rs3786749', 'Var', (240, 249))	('FUT6', 'Gene', '2528', (185, 189))	('rs8176746', 'Var', (121, 130))	('DBP', 'Gene', '1628', (234, 237))	('ABO', 'Gene', (334, 337))	('FAM3B', 'Gene', (208, 213))	('rs2071699', 'Mutation', 'rs2071699', (268, 277))	('FUT2', 'Gene', (161, 165))	('rs441810', 'Mutation', 'rs441810', (192, 200))	('patients', 'Species', '9606', (111, 119))
22759	24941225	In patients without regional lymph nodes metastasis, subgroups with rs1047781 (chr19- FUT2) AT and TT allele had a significantly higher CEA level than the AA carriers (AA:1.73 ng/ml, AT: 3.49 ng/ml and TT: 4.11 ng/ml; P = 0.006).	('CEA', 'Gene', '1084', (136, 139))	('AT', 'Disease', 'None', (183, 185))	('FUT2', 'Gene', (86, 90))	('higher', 'PosReg', (129, 135))	('rs1047781', 'Var', (68, 77))	('rs1047781', 'Mutation', 'rs1047781', (68, 77))	('AT', 'Disease', 'None', (92, 94))	('FUT2', 'Gene', '2524', (86, 90))	('patients', 'Species', '9606', (3, 11))	('CEA', 'Gene', (136, 139))
22763	24941225	For rs1047781 (chr19- FUT2), the allelic genotype TT was associated with the highest sCEA level, and the difference in the sCEA level between allele T carriers and homozygote AA was significantly different (AA vs. AT: P = 0.008; AA vs. TT: P = 0.006; AT vs. TT: P = 0.787; respectively) ( Table 4 ).	('AT', 'Disease', 'None', (214, 216))	('rs1047781', 'Var', (4, 13))	('rs1047781', 'Mutation', 'rs1047781', (4, 13))	('sCEA', 'Chemical', '-', (123, 127))	('FUT2', 'Gene', (22, 26))	('sCEA', 'Chemical', '-', (85, 89))	('AT', 'Disease', 'None', (251, 253))	('sCEA level', 'MPA', (85, 95))	('FUT2', 'Gene', '2524', (22, 26))
22764	24941225	The rate of regional lymph node (RLN) metastasis in the allelic subgroup AT was the highest in the three subgroups of rs1047781 (AA: 12.8%, AT: 19.6%, TT: 9.0%; AA vs. AT: P = 0.961, AA vs. TT: P = 0.046, AT vs. TT: P<0.001; respectively).	('rs1047781', 'Var', (118, 127))	('highest', 'Reg', (84, 91))	('rs1047781', 'Mutation', 'rs1047781', (118, 127))	('AT', 'Disease', 'None', (205, 207))	('AT', 'Disease', 'None', (168, 170))	('AT', 'Disease', 'None', (140, 142))	('AT', 'Disease', 'None', (73, 75))
22765	24941225	The rates of distant organ metastasis in the three allelic subgroups of rs1047781 were not significantly different (AA vs. AT: P = 0.651; AA vs. TT: P = 0.607; AT vs. TT: P = 0.888, respectively) ( Table 4 ).	('AT', 'Disease', 'None', (160, 162))	('rs1047781', 'Mutation', 'rs1047781', (72, 81))	('AT', 'Disease', 'None', (123, 125))	('distant organ metastasis', 'CPA', (13, 37))	('rs1047781', 'Var', (72, 81))
22766	24941225	The frequency of RLN metastases was significantly different in the allelic subgroups of rs8176746 (chr9-ABO) (P = 0.022).	('metastases', 'Disease', 'MESH:D009362', (21, 31))	('ABO', 'Gene', '28', (104, 107))	('ABO', 'Gene', (104, 107))	('rs8176746', 'Mutation', 'rs8176746', (88, 97))	('RLN', 'Disease', (17, 20))	('metastases', 'Disease', (21, 31))	('rs8176746', 'Var', (88, 97))
22770	24941225	SNPs associated with the CEA level and regional lymph metastasis, rs1047781 (chr19- FUT2) and rs8176746 (chr9- ABO), were not the independent contributors to disease-free survival ( Figure 3  ,  4 ).	('CEA', 'Gene', '1084', (25, 28))	('rs8176746', 'Mutation', 'rs8176746', (94, 103))	('FUT2', 'Gene', (84, 88))	('rs8176746', 'Var', (94, 103))	('rs1047781', 'Mutation', 'rs1047781', (66, 75))	('ABO', 'Gene', '28', (111, 114))	('ABO', 'Gene', (111, 114))	('rs1047781', 'Var', (66, 75))	('FUT2', 'Gene', '2524', (84, 88))	('CEA', 'Gene', (25, 28))
22771	24941225	We used the combination of SNPs (rs1047781 and rs8176746) as the genetic marker in survival analysis and the disease-free times was significantly different between rs1047781-AA and rs1047781 (AT+TT) genotype carriers among rs8176746 (AA+AG) carriers (P = 0.023) (Figure 5 ).	('rs8176746', 'Var', (223, 232))	('rs1047781', 'Mutation', 'rs1047781', (164, 173))	('rs1047781-AA', 'Var', (164, 176))	('rs1047781', 'Mutation', 'rs1047781', (181, 190))	('different', 'Reg', (146, 155))	('AT', 'Disease', 'None', (192, 194))	('rs8176746', 'Mutation', 'rs8176746', (47, 56))	('rs8176746', 'Mutation', 'rs8176746', (223, 232))	('rs1047781', 'Mutation', 'rs1047781', (33, 42))
22775	24941225	In support of a previous report on healthy volunteers in the United States, we found that cigarette-smoking is associated with CEA levels.	('cigarette-smoking', 'Var', (90, 107))	('CEA', 'Gene', (127, 130))	('associated', 'Reg', (111, 121))	('CEA', 'Gene', '1084', (127, 130))
22804	24941225	The strongest CEA level-associated SNP was rs1047781 at 19q13, a missense change (A->T, Ile->Phe) within the FUT2 gene that encodes a fucosyltransferase catalyzing the production of the H antigen and determines the secretion status of the ABO and Lewis histo-blood group antigens.	('ABO', 'Gene', '28', (239, 242))	('blood group antigen', 'Phenotype', 'HP:0010970', (259, 278))	('rs1047781', 'Mutation', 'rs1047781', (43, 52))	('CEA', 'Gene', (14, 17))	('CEA', 'Gene', '1084', (14, 17))	('rs1047781', 'Var', (43, 52))	('secretion', 'biological_process', 'GO:0046903', ('215', '224'))	('Phe', 'Chemical', 'MESH:D010649', (93, 96))	('FUT2', 'Gene', (109, 113))	('FUT2', 'Gene', '2524', (109, 113))	('Ile', 'Chemical', 'MESH:D007532', (88, 91))	('ABO', 'Gene', (239, 242))
22805	24941225	It was reported that the T allele of this SNP represents a de facto inactivated mutant of the FUT2 enzyme and was causally associated with the non-secretor phenotype in a Japanese population.	('associated', 'Reg', (123, 133))	('FUT2', 'Gene', (94, 98))	('T allele', 'Var', (25, 33))	('FUT2', 'Gene', '2524', (94, 98))
22811	24941225	nlm.nih.gov), an associated study revealed that rs507666 is a surrogate for type A1 histo-blood group antigen, rs687289 is a marker for the O allele, rs8176746 is a marker for the B allele and rs8176704 is a marker for the A2 allele.	('rs8176704', 'Var', (193, 202))	('blood group antigen', 'molecular_function', 'GO:0005555', ('90', '109'))	('rs507666', 'Var', (48, 56))	('rs687289', 'Var', (111, 119))	('rs8176746', 'Mutation', 'rs8176746', (150, 159))	('rs8176704', 'Mutation', 'rs8176704', (193, 202))	('rs507666', 'Mutation', 'rs507666', (48, 56))	('rs8176746', 'Var', (150, 159))	('rs687289', 'Mutation', 'rs687289', (111, 119))	('blood group antigen', 'Phenotype', 'HP:0010970', (90, 109))
22817	24941225	We inferred that SNPs were associated with elevated sCEA levels in healthy and CRC population from the same region.	('CRC', 'Phenotype', 'HP:0003003', (79, 82))	('sCEA levels', 'MPA', (52, 63))	('SNPs', 'Var', (17, 21))	('elevated', 'PosReg', (43, 51))	('sCEA', 'Chemical', '-', (52, 56))
22819	24941225	Rs8176746, rs376077, rs12608544, rs3786749, rs2071699, rs441810 and rs507666 were subsequently included in the genotyping of CRC patients.	('rs12608544', 'Mutation', 'rs12608544', (21, 31))	('rs507666', 'Var', (68, 76))	('CRC', 'Disease', (125, 128))	('rs2071699', 'Var', (44, 53))	('patients', 'Species', '9606', (129, 137))	('rs441810', 'Mutation', 'rs441810', (55, 63))	('rs376077', 'Mutation', 'rs376077', (11, 19))	('rs2071699', 'Mutation', 'rs2071699', (44, 53))	('rs507666', 'Mutation', 'rs507666', (68, 76))	('Rs8176746', 'Mutation', 'Rs8176746', (0, 9))	('CRC', 'Phenotype', 'HP:0003003', (125, 128))	('Rs8176746', 'Var', (0, 9))	('rs3786749', 'Var', (33, 42))	('rs3786749', 'Mutation', 'rs3786749', (33, 42))	('rs441810', 'Var', (55, 63))	('rs12608544', 'Var', (21, 31))	('rs376077', 'Var', (11, 19))
22821	24941225	Stratification analysis showed that rs1047781 (chr19- FUT2) was the associated loci in CRC patients.	('CRC', 'Disease', (87, 90))	('patients', 'Species', '9606', (91, 99))	('rs1047781', 'Mutation', 'rs1047781', (36, 45))	('CRC', 'Phenotype', 'HP:0003003', (87, 90))	('rs1047781', 'Var', (36, 45))	('FUT2', 'Gene', (54, 58))	('FUT2', 'Gene', '2524', (54, 58))
22822	24941225	In accordance with the results from the GWAS analysis in healthy population, the rs1047781 was a susceptible locus for elevated CEA level in CRC patients.	('patients', 'Species', '9606', (145, 153))	('CEA', 'Gene', (128, 131))	('rs1047781', 'Mutation', 'rs1047781', (81, 90))	('CEA', 'Gene', '1084', (128, 131))	('CRC', 'Phenotype', 'HP:0003003', (141, 144))	('elevated', 'PosReg', (119, 127))	('rs1047781', 'Var', (81, 90))	('elevated CEA', 'Phenotype', 'HP:0031029', (119, 131))	('CRC', 'Disease', (141, 144))
22824	24941225	Similarly, genotype AA carriers had the lowest CEA levels in the CRC patients without tumor metastasis.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('lowest', 'NegReg', (40, 46))	('tumor metastasis', 'Disease', 'MESH:D009362', (86, 102))	('CRC', 'Phenotype', 'HP:0003003', (65, 68))	('genotype AA', 'Var', (11, 22))	('tumor metastasis', 'Disease', (86, 102))	('CEA', 'Gene', (47, 50))	('patients', 'Species', '9606', (69, 77))	('CEA', 'Gene', '1084', (47, 50))
22826	24941225	The other study in FAMHES showed rs1047781 to be a locus associated with vitamin B12 levels in healthy people.	('people', 'Species', '9606', (103, 109))	('rs1047781', 'Var', (33, 42))	('vitamin B12', 'Chemical', 'MESH:D014805', (73, 84))	('rs1047781', 'Mutation', 'rs1047781', (33, 42))	('vitamin B12 levels', 'MPA', (73, 91))	('associated', 'Reg', (57, 67))
22830	24941225	We observed that AT and TT genotypes of rs1047781 (FUT2), and not the AA genotype, are associated with higher serum CEA levels.	('FUT2', 'Gene', '2524', (51, 55))	('rs1047781', 'Var', (40, 49))	('rs1047781', 'Mutation', 'rs1047781', (40, 49))	('higher serum CEA levels', 'Phenotype', 'HP:0031029', (103, 126))	('AT', 'Disease', 'None', (17, 19))	('higher', 'PosReg', (103, 109))	('CEA', 'Gene', (116, 119))	('FUT2', 'Gene', (51, 55))	('CEA', 'Gene', '1084', (116, 119))
22831	24941225	Interestingly, the CRC patients with T allele exhibited a different prognosis from those with the AA genotype.	('patients', 'Species', '9606', (23, 31))	('T allele', 'Var', (37, 45))	('CRC', 'Disease', (19, 22))	('CRC', 'Phenotype', 'HP:0003003', (19, 22))
22849	24941225	As shown in Table 3, rs1047781-TT carriers had lower CEA levels and fewer RLN metastases, supporting the association between CEA levels and prognosis.	('metastases', 'Disease', 'MESH:D009362', (78, 88))	('lower', 'NegReg', (47, 52))	('rs1047781-TT', 'Var', (21, 33))	('CEA', 'Gene', (125, 128))	('CEA', 'Gene', '1084', (125, 128))	('CEA', 'Gene', (53, 56))	('rs1047781', 'Mutation', 'rs1047781', (21, 30))	('CEA', 'Gene', '1084', (53, 56))	('metastases', 'Disease', (78, 88))	('fewer', 'NegReg', (68, 73))
22850	24941225	Since rs8176746 was associated with lymph node metastasis, the combination of rs1047781 and rs8176746 as genetic markers of disease-free survival was applied for further analysis.	('associated', 'Reg', (20, 30))	('rs8176746', 'Var', (6, 15))	('lymph node metastasis', 'CPA', (36, 57))	('rs1047781', 'Mutation', 'rs1047781', (78, 87))	('rs8176746', 'Mutation', 'rs8176746', (92, 101))	('rs8176746', 'Mutation', 'rs8176746', (6, 15))
22851	24941225	As suggested by Figure 3, rs1047781 (AT+TT) carriers had worse disease-free survival than the AA carriers.	('AT', 'Disease', 'None', (37, 39))	('rs1047781', 'Var', (26, 35))	('rs1047781', 'Mutation', 'rs1047781', (26, 35))	('disease-free survival', 'CPA', (63, 84))	('worse', 'NegReg', (57, 62))
22852	24941225	It is in accordance with the higher CEA levels among mutant type rs1047781 carriers.	('higher', 'PosReg', (29, 35))	('CEA', 'Gene', (36, 39))	('CEA', 'Gene', '1084', (36, 39))	('rs1047781', 'Var', (65, 74))	('rs1047781', 'Mutation', 'rs1047781', (65, 74))
22853	24941225	Although these SNPs might associate with tumor recurrence in CRC, the overall survival of CRC patients was not significantly different in 5 years when grouped by rs1047781 or rs8176746 (Figure S4, S5).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('rs8176746', 'Var', (175, 184))	('patients', 'Species', '9606', (94, 102))	('tumor', 'Disease', (41, 46))	('CRC', 'Phenotype', 'HP:0003003', (90, 93))	('CRC', 'Disease', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('rs1047781', 'Mutation', 'rs1047781', (162, 171))	('rs8176746', 'Mutation', 'rs8176746', (175, 184))	('associate', 'Reg', (26, 35))	('rs1047781', 'Var', (162, 171))	('CRC', 'Phenotype', 'HP:0003003', (61, 64))
22855	24941225	Therefore it is worthwhile to test if rs1047781 is a prognostic marker of tumor recurrence among CRC patients.	('patients', 'Species', '9606', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CRC', 'Phenotype', 'HP:0003003', (97, 100))	('rs1047781', 'Var', (38, 47))	('rs1047781', 'Mutation', 'rs1047781', (38, 47))	('tumor', 'Disease', (74, 79))
22860	24941225	The mutation in the tumor cell's CEA gene (PELPK motif; Pro-Glu-Leu-Pro-Lys) might induce high CEA levels by its hepatic clearance; mutation in the PELK motif could alter structural stability and binding affinity to Kupffer's cell receptor in the liver.	('structural stability', 'MPA', (171, 191))	('hepatic clearance', 'MPA', (113, 130))	('alter', 'Reg', (165, 170))	('induce', 'PosReg', (83, 89))	('CEA', 'Gene', (33, 36))	('mutation', 'Var', (4, 12))	('binding affinity', 'Interaction', (196, 212))	('CEA', 'Gene', (95, 98))	('CEA', 'Gene', '1084', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('CEA', 'Gene', '1084', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mutation', 'Var', (132, 140))	('tumor', 'Disease', (20, 25))
22862	24941225	Another study indentified rs10318 (GREM1), rs6983267 (POU5F1P1, DQ515897, MYC) and rs4464148 (SMAD7) associated with clinic outcome in patients with stage II and stage III CRC treated with 5-FU-based adjuvant chemotherapy.	('CRC', 'Phenotype', 'HP:0003003', (172, 175))	('patients', 'Species', '9606', (135, 143))	('GREM1', 'Gene', '26585', (35, 40))	('MYC', 'Gene', (74, 77))	('GREM1', 'Gene', (35, 40))	('SMAD7', 'Gene', '4092', (94, 99))	('rs4464148', 'Mutation', 'rs4464148', (83, 92))	('POU5F1P1', 'Gene', (54, 62))	('clinic', 'MPA', (117, 123))	('rs6983267', 'Var', (43, 52))	('rs10318', 'Var', (26, 33))	('MYC', 'Gene', '4609', (74, 77))	('POU5F1P1', 'Gene', '5462', (54, 62))	('rs6983267', 'Mutation', 'rs6983267', (43, 52))	('rs4464148', 'Var', (83, 92))	('5-FU', 'Chemical', 'MESH:D005472', (189, 193))	('rs10318', 'Mutation', 'rs10318', (26, 33))	('SMAD7', 'Gene', (94, 99))	('associated with', 'Reg', (101, 116))
22871	24941225	We found that the rs1047781 is the susceptible locus for elevated sCEA level whereas rs8176746 is associated with the status of regional lymph node metastasis.	('rs8176746', 'Var', (85, 94))	('sCEA level', 'MPA', (66, 76))	('elevated', 'PosReg', (57, 65))	('rs1047781', 'Var', (18, 27))	('rs1047781', 'Mutation', 'rs1047781', (18, 27))	('rs8176746', 'Mutation', 'rs8176746', (85, 94))	('sCEA', 'Chemical', '-', (66, 70))	('associated', 'Reg', (98, 108))
22873	24941225	The SNP rs1047781 might be a predictor for tumor recurrence in TNM stage II and III CRC patients.	('rs1047781', 'Var', (8, 17))	('TNM', 'Gene', '10178', (63, 66))	('patients', 'Species', '9606', (88, 96))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('III CRC', 'Disease', (80, 87))	('TNM', 'Gene', (63, 66))	('CRC', 'Phenotype', 'HP:0003003', (84, 87))	('tumor', 'Disease', (43, 48))	('rs1047781', 'Mutation', 'rs1047781', (8, 17))
22898	24259307	Furthermore, many post-translational modifications affect the chemokine receptor signaling, receptor specificity as well as chemotactic property of chemokines and thus affect their biological functions.	('al', 'Chemical', 'MESH:D000535', (34, 36))	('biological functions', 'MPA', (181, 201))	('affect', 'Reg', (51, 57))	('chemotactic property', 'MPA', (124, 144))	('al', 'Chemical', 'MESH:D000535', (189, 191))	('chemokine receptor', 'Gene', '7852', (62, 80))	('post-translational modifications', 'Var', (18, 50))	('chemokine receptor', 'Gene', (62, 80))	('affect', 'Reg', (168, 174))	('al', 'Chemical', 'MESH:D000535', (85, 87))	('receptor specificity', 'MPA', (92, 112))
22903	24259307	This alteration occurs due to inactivation of the tumor suppressor genes or constitutive activation of the oncogenes that play a role in the regulation of the chemokines.	('rat', 'Species', '10116', (9, 12))	('inactivation', 'Var', (30, 42))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('activation', 'PosReg', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('al', 'Chemical', 'MESH:D000535', (5, 7))	('oncogenes', 'Gene', (107, 116))	('tumor', 'Disease', (50, 55))
22904	24259307	Furthermore, deregulated expression of the transcription factors also affects the levels of chemokine and receptors regulated by them and promotes tumorigenesis.	('levels of chemokine', 'MPA', (82, 101))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('al', 'Chemical', 'MESH:D000535', (65, 67))	('deregulated', 'Var', (13, 24))	('expression', 'MPA', (25, 35))	('affects', 'Reg', (70, 77))	('promotes', 'PosReg', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
22913	24259307	However, the loss of chemokine receptor CXCR2 reduces oncogene induced senescence along with the DNA damage response.	('DNA', 'cellular_component', 'GO:0005574', ('97', '100'))	('CXCR2', 'Gene', (40, 45))	('oncogene', 'Gene', (54, 62))	('chemokine receptor', 'Gene', '7852', (21, 39))	('CXCR2', 'Gene', '3579', (40, 45))	('chemokine receptor', 'Gene', (21, 39))	('reduces', 'NegReg', (46, 53))	('loss', 'Var', (13, 17))	('al', 'Chemical', 'MESH:D000535', (82, 84))	('senescence', 'biological_process', 'GO:0010149', ('71', '81'))	('DNA damage response', 'biological_process', 'GO:0006974', ('97', '116'))
22915	24259307	Also, the reintroduction of the chemokine receptor CXCR2 leads to premature senescence by a p53 dependent mechanism.	('reintroduction', 'Var', (10, 24))	('chemokine receptor', 'Gene', (32, 50))	('premature senescence', 'MPA', (66, 86))	('CXCR2', 'Gene', '3579', (51, 56))	('p53', 'Gene', (92, 95))	('CXCR2', 'Gene', (51, 56))	('p53', 'Gene', '7157', (92, 95))	('senescence', 'biological_process', 'GO:0010149', ('76', '86'))	('chemokine receptor', 'Gene', '7852', (32, 50))
22918	24259307	However, mutations in CXCR2 or downregulation of CXCR2 expression may affect the ability of this chemokine receptor to induce senescence.	('affect', 'Reg', (70, 76))	('chemokine receptor', 'Gene', '7852', (97, 115))	('CXCR2', 'Gene', '3579', (49, 54))	('ability', 'MPA', (81, 88))	('mutations', 'Var', (9, 18))	('senescence', 'CPA', (126, 136))	('CXCR2', 'Gene', (49, 54))	('CXCR2', 'Gene', '3579', (22, 27))	('downregulation', 'NegReg', (31, 45))	('CXCR2', 'Gene', (22, 27))	('chemokine receptor', 'Gene', (97, 115))
22920	24259307	The inability to induce senescence by mutated CXCR2 may in fact promote tumorigenesis instead of blocking it.	('mutated', 'Var', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('promote', 'PosReg', (64, 71))	('senescence', 'MPA', (24, 34))	('tumor', 'Disease', (72, 77))	('CXCR2', 'Gene', '3579', (46, 51))	('CXCR2', 'Gene', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
22930	24259307	Furthermore, the knockdown of CXCR4 in these cells or treatment with CXCR4 antagonist leads to a decrease in cell migration.	('rat', 'Species', '10116', (117, 120))	('CXCR4', 'molecular_function', 'GO:0038147', ('30', '35'))	('CXCR4', 'molecular_function', 'GO:0038147', ('69', '74'))	('cell migration', 'biological_process', 'GO:0016477', ('109', '123'))	('knockdown', 'Var', (17, 26))	('decrease', 'NegReg', (97, 105))	('cell migration', 'CPA', (109, 123))
22935	24259307	The authors suggest that inhibiting CXCL8 signaling may help inhibit EMT by targeting the cells with the mesenchymal and invasive phenotype.	('signaling', 'biological_process', 'GO:0023052', ('42', '51'))	('EMT', 'biological_process', 'GO:0001837', ('69', '72'))	('inhibiting', 'Var', (25, 35))	('EMT', 'CPA', (69, 72))	('inhibit', 'NegReg', (61, 68))	('al', 'Chemical', 'MESH:D000535', (114, 116))	('al', 'Chemical', 'MESH:D000535', (46, 48))	('CXCL8', 'Gene', '3576', (36, 41))	('CXCL8', 'Gene', (36, 41))
22936	24259307	A recent study demonstrated that using a CXCR7 antagonist, CCX733 drastically reduced EMT in bladder cancer, which suggests the importance of CXCR7 in regulating EMT and in the development of bladder cancer.	('reduced EMT', 'Phenotype', 'HP:0032198', (78, 89))	('bladder cancer', 'Disease', 'MESH:D001749', (93, 107))	('bladder cancer', 'Disease', (93, 107))	('rat', 'Species', '10116', (22, 25))	('CXCR7', 'Gene', '57007', (41, 46))	('CXCR7', 'Gene', '57007', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('bladder cancer', 'Phenotype', 'HP:0009725', (192, 206))	('CXCR7', 'Gene', (142, 147))	('al', 'Chemical', 'MESH:D000535', (73, 75))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('CXCR7', 'Gene', (41, 46))	('reduced', 'NegReg', (78, 85))	('bladder cancer', 'Disease', (192, 206))	('bladder cancer', 'Disease', 'MESH:D001749', (192, 206))	('bladder cancer', 'Phenotype', 'HP:0009725', (93, 107))	('CCX733', 'Var', (59, 65))	('EMT', 'CPA', (86, 89))
23006	24259307	Additional studies demonstrate that de novo expression of CXCR4 is sufficient to increase tumor invasion and metastasis in an organ-specific manner.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('CXCR4', 'Var', (58, 63))	('rat', 'Species', '10116', (26, 29))	('al', 'Chemical', 'MESH:D000535', (8, 10))	('metastasis', 'CPA', (109, 119))	('increase', 'PosReg', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
23011	24259307	CXCR4 expression in prostate cancer enhances the invasive, metastatic ability of tumor cells in the presence of CXCL12 ligand, while inhibition of CXCR4 decreases metastatic ability.	('enhances', 'PosReg', (36, 44))	('prostate cancer', 'Disease', 'MESH:D011471', (20, 35))	('prostate cancer', 'Phenotype', 'HP:0012125', (20, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('CXCL12', 'Gene', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('prostate cancer', 'Disease', (20, 35))	('CXCL12', 'Gene', '6387', (112, 118))	('CXCR4 expression', 'Var', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('invasive', 'CPA', (49, 57))	('tumor', 'Disease', (81, 86))
23013	24259307	Additionally, CXCR4 mediates prostate tumor cell adhesion through the alpha5 and beta3 integrins.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('prostate tumor', 'Phenotype', 'HP:0100787', (29, 43))	('prostate tumor', 'Disease', (29, 43))	('CXCR4', 'Var', (14, 19))	('cell adhesion', 'biological_process', 'GO:0007155', ('44', '57'))	('al', 'Chemical', 'MESH:D000535', (70, 72))	('al', 'Chemical', 'MESH:D000535', (8, 10))	('prostate tumor', 'Disease', 'MESH:D011471', (29, 43))	('CXCR4', 'molecular_function', 'GO:0038147', ('14', '19'))	('beta3 integrins', 'Protein', (81, 96))
23021	24259307	In breast cancer, CXCR4 promotes metastasis to the lungs, liver, and lymph nodes.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('CXCR4', 'Var', (18, 23))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('CXCR4', 'molecular_function', 'GO:0038147', ('18', '23'))	('metastasis to the lungs', 'CPA', (33, 56))	('promotes', 'PosReg', (24, 32))
23022	24259307	In gastric cancer, studies show that CXCR4 promotes metastasis to the lymph nodes.	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('promotes', 'PosReg', (43, 51))	('metastasis to the lymph nodes', 'CPA', (52, 81))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('CXCR4', 'molecular_function', 'GO:0038147', ('37', '42'))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('CXCR4', 'Var', (37, 42))
23023	24259307	Also, a study demonstrates that CXCR4 expression in esophageal cancer enhances metastasis to the lymph nodes and bone marrow.	('CXCR4', 'molecular_function', 'GO:0038147', ('32', '37'))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('esophageal cancer', 'Disease', (52, 69))	('CXCR4 expression', 'Var', (32, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (52, 69))	('rat', 'Species', '10116', (21, 24))	('enhances', 'PosReg', (70, 78))
23035	24259307	Interestingly, expression of CCR7 in B16 melanoma cells induces metastasis to the lymph nodes, while, as previously discussed, expression of CXCR4 in murine B16 cells increases metastasis to the lungs.	('CCR7', 'Gene', (29, 33))	('expression', 'Var', (15, 25))	('murine', 'Species', '10090', (150, 156))	('metastasis to the lymph nodes', 'CPA', (64, 93))	('metastasis', 'CPA', (177, 187))	('melanoma', 'Disease', (41, 49))	('induces', 'Reg', (56, 63))	('B16', 'CellLine', 'CVCL:N540', (37, 40))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('increases', 'PosReg', (167, 176))	('B16', 'CellLine', 'CVCL:N540', (157, 160))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))
23037	24259307	High CCR7 expression in human non-Hodgkin's lymphoma induces metastatic spread through the PI3K/Akt signal pathway.	('lymphoma', 'Phenotype', 'HP:0002665', (44, 52))	('human', 'Species', '9606', (24, 29))	('High', 'Var', (0, 4))	('al', 'Chemical', 'MESH:D000535', (104, 106))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (30, 52))	("non-Hodgkin's lymphoma", 'Disease', (30, 52))	('metastatic spread', 'CPA', (61, 78))	('CCR', 'molecular_function', 'GO:0043880', ('5', '8'))	('Akt', 'Gene', '207', (96, 99))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (34, 52))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (30, 52))	('PI3K', 'molecular_function', 'GO:0016303', ('91', '95'))	('CCR7', 'Gene', (5, 9))	('Akt', 'Gene', (96, 99))	('induces', 'Reg', (53, 60))
23038	24259307	CCR7 expression also induces lymphatic spread in human pancreatic ductal adenocarcinoma.	('lymphatic spread', 'CPA', (29, 45))	('induces', 'Reg', (21, 28))	('CCR7', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('human', 'Species', '9606', (49, 54))	('expression', 'Var', (5, 15))	('al', 'Chemical', 'MESH:D000535', (70, 72))	('al', 'Chemical', 'MESH:D000535', (16, 18))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (55, 87))	('CCR', 'molecular_function', 'GO:0043880', ('0', '3'))	('pancreatic ductal adenocarcinoma', 'Disease', (55, 87))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (55, 87))
23042	24259307	Similar to CXCR4, CCR7-CCL21 interactions induces directional invasion of breast tumor cells, pseudopodia formation, and actin polymerization which increases the invasiveness of tumor cells.	('actin polymerization', 'biological_process', 'GO:0030041', ('121', '141'))	('breast tumor', 'Phenotype', 'HP:0100013', (74, 86))	('breast tumor', 'Disease', (74, 86))	('tumor', 'Disease', (178, 183))	('pseudopodia formation', 'CPA', (94, 115))	('CCL21', 'Gene', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('CCL', 'molecular_function', 'GO:0044101', ('23', '26'))	('directional invasion', 'CPA', (50, 70))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('al', 'Chemical', 'MESH:D000535', (59, 61))	('CCR', 'molecular_function', 'GO:0043880', ('18', '21'))	('increases', 'PosReg', (148, 157))	('breast tumor', 'Disease', 'MESH:D001943', (74, 86))	('CCL21', 'Gene', '6366', (23, 28))	('induces', 'Reg', (42, 49))	('formation', 'biological_process', 'GO:0009058', ('106', '115'))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CXCR4', 'molecular_function', 'GO:0038147', ('11', '16'))	('interactions', 'Var', (29, 41))	('actin polymerization', 'CPA', (121, 141))
23050	24259307	Expressing oncogenic Notch 1 causes mice to develop characteristic pathological features of T-ALL and infiltration of the leptomeningeal spaces of the brain, demonstrating that oncogenic Notch1 is capable of inducing T-ALL and targeting transformed cells to the CNS.	('rat', 'Species', '10116', (108, 111))	('oncogenic Notch1', 'Var', (177, 193))	('Notch1', 'Var', (187, 193))	('Notch 1', 'Gene', '18128', (21, 28))	('al', 'Chemical', 'MESH:D000535', (134, 136))	('inducing', 'PosReg', (208, 216))	('ALL', 'Phenotype', 'HP:0006721', (219, 222))	('ALL', 'Phenotype', 'HP:0006721', (94, 97))	('mice', 'Species', '10090', (36, 40))	('al', 'Chemical', 'MESH:D000535', (77, 79))	('rat', 'Species', '10116', (165, 168))	('Notch 1', 'Gene', (21, 28))	('T-ALL', 'CPA', (217, 222))
23051	24259307	Analysis of primary T-ALL samples as well as T-ALL cell-lines containing Notch1-activating mutations have CCR7 upregulation caused by Notch1 signaling.	('CCR7', 'Gene', (106, 110))	('upregulation', 'PosReg', (111, 123))	('ALL', 'Phenotype', 'HP:0006721', (22, 25))	('ALL', 'Phenotype', 'HP:0006721', (47, 50))	('al', 'Chemical', 'MESH:D000535', (145, 147))	('signaling', 'biological_process', 'GO:0023052', ('141', '150'))	('Notch1', 'Var', (134, 140))	('Notch1-activating', 'Gene', (73, 90))	('al', 'Chemical', 'MESH:D000535', (2, 4))	('mutations', 'Var', (91, 100))	('CCR', 'molecular_function', 'GO:0043880', ('106', '109'))
23058	24259307	Inhibition of CCR7, PI3K, Akt and mTOR successfully stops phosphorylation and DNA-binding.	('Akt', 'Gene', '207', (26, 29))	('CCR7', 'Gene', (14, 18))	('phosphorylation', 'MPA', (58, 73))	('DNA-binding', 'Interaction', (78, 89))	('Akt', 'Gene', (26, 29))	('Inhibition', 'Var', (0, 10))	('stops', 'NegReg', (52, 57))	('mTOR', 'Gene', '2475', (34, 38))	('mTOR', 'Gene', (34, 38))
23073	24259307	Given the role of CCR10-CCL27 in leukocyte migration to the skin, it is likely that CCR10 expression in melanoma induces metastasis to the skin.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('induces', 'Reg', (113, 120))	('melanoma', 'Disease', (104, 112))	('rat', 'Species', '10116', (46, 49))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('metastasis to the skin', 'CPA', (121, 143))	('CCR10', 'Gene', (18, 23))	('CCR10', 'Gene', '2826', (18, 23))	('CCL27', 'Gene', (24, 29))	('leukocyte migration to the skin', 'CPA', (33, 64))	('CCR10', 'Gene', (84, 89))	('CCL27', 'Gene', '10850', (24, 29))	('expression', 'Var', (90, 100))	('CCR10', 'Gene', '2826', (84, 89))
23074	24259307	However, another study suggests that CCR10 expression in melanoma promotes metastasis to the lymph nodes in addition to enhancing invasion, growth, and immune escape of tumor cells.	('CCR10', 'Gene', '2826', (37, 42))	('enhancing', 'PosReg', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('expression', 'Var', (43, 53))	('invasion', 'CPA', (130, 138))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('promotes', 'PosReg', (66, 74))	('tumor', 'Disease', (169, 174))	('CCR10', 'Gene', (37, 42))	('metastasis to the lymph nodes', 'CPA', (75, 104))	('CCR', 'molecular_function', 'GO:0043880', ('37', '40'))	('growth', 'CPA', (140, 146))
23080	24259307	al demonstrate that expressing CXCR3 in a colon cancer cell line increases in vivo metastasis to the lymph nodes, but not to the liver or lungs.	('metastasis to the lymph nodes', 'CPA', (83, 112))	('al', 'Chemical', 'MESH:D000535', (0, 2))	('increases', 'PosReg', (65, 74))	('CXCR3', 'Var', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('colon cancer', 'Phenotype', 'HP:0003003', (42, 54))	('colon cancer', 'Disease', 'MESH:D015179', (42, 54))	('rat', 'Species', '10116', (10, 13))	('expressing CXCR3', 'Var', (20, 36))	('colon cancer', 'Disease', (42, 54))
23084	24259307	In osteosarcoma, studies suggest that CXCR3 and its ligands induce metastasis to the lungs and later stimulate growth and expansion of the metastases.	('growth', 'CPA', (111, 117))	('osteosarcoma', 'Disease', (3, 15))	('metastases', 'Disease', (139, 149))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('expansion', 'CPA', (122, 131))	('metastases', 'Disease', 'MESH:D009362', (139, 149))	('metastasis to the lungs', 'CPA', (67, 90))	('stimulate', 'PosReg', (101, 110))	('CXCR3', 'Var', (38, 43))
23103	24259307	Meanwhile, expression of CCR7 in DND41 cells is sufficient to induce brain and spinal cord infiltration, while silencing CCR7 successfully inhibits T-ALL CNS metastasis.	('T-ALL CNS metastasis', 'Disease', 'MESH:D009362', (148, 168))	('rat', 'Species', '10116', (97, 100))	('silencing', 'Var', (111, 120))	('ALL', 'Phenotype', 'HP:0006721', (150, 153))	('induce', 'PosReg', (62, 68))	('al', 'Chemical', 'MESH:D000535', (83, 85))	('DND41', 'CellLine', 'CVCL:2022', (33, 38))	('CCR', 'molecular_function', 'GO:0043880', ('25', '28'))	('CCR7', 'Gene', (121, 125))	('T-ALL CNS metastasis', 'Disease', (148, 168))	('CCR', 'molecular_function', 'GO:0043880', ('121', '124'))	('inhibits', 'NegReg', (139, 147))
23176	30873708	PTX3 acted as a regulator of C3-deposition on cancer cells by interacting with the Complement inhibitor Factor H. Interestingly, PTX3-deficiency resulted in increased DNA damage, as shown by more mutations of Trp53, one of the genes targeted by 3-MCA, oxidative DNA damage and expression of DNA damage markers.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('3-MCA', 'Chemical', 'MESH:D008748', (245, 250))	('C3-deposition', 'Disease', 'MESH:C565169', (29, 42))	('PTX3', 'Gene', (129, 133))	('PTX3', 'Gene', '5806', (129, 133))	('DNA damage', 'MPA', (167, 177))	('PTX3-deficiency', 'Disease', 'MESH:D007153', (129, 144))	('cancer', 'Disease', (46, 52))	('PTX3', 'Gene', (0, 4))	('C3-deposition', 'Phenotype', 'HP:0012576', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PTX3', 'Gene', '5806', (0, 4))	('Factor H', 'Gene', '3075', (104, 112))	('mutations', 'Var', (196, 205))	('Trp53', 'Gene', (209, 214))	('PTX3-deficiency', 'Disease', (129, 144))	('Trp53', 'Gene', '7157', (209, 214))	('increased', 'PosReg', (157, 166))	('Factor H', 'Gene', (104, 112))	('C3-deposition', 'Disease', (29, 42))	('oxidative', 'MPA', (252, 261))
23177	30873708	Importantly, in selected human mesenchymal and epithelial tumors, the PTX3 promoter and regulatory regions were highly methylated and this epigenetic modification resulted in transcriptional inactivation and silencing of PTX3 expression.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('PTX3', 'Gene', '5806', (70, 74))	('PTX3', 'Gene', '5806', (221, 225))	('silencing', 'NegReg', (208, 217))	('epithelial tumors', 'Disease', (47, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('expression', 'MPA', (226, 236))	('epigenetic', 'Var', (139, 149))	('human', 'Species', '9606', (25, 30))	('epithelial tumors', 'Disease', 'MESH:D002277', (47, 64))	('PTX3', 'Gene', (70, 74))	('PTX3', 'Gene', (221, 225))	('transcriptional', 'MPA', (175, 190))
23178	30873708	In colorectal cancer PTX3 gene methylation and silencing was detected as an early event, already identified in adenomas and stage 1 neoplastic lesions, an observation consistent with an important role in pathogenesis.	('adenomas', 'Disease', 'MESH:D000236', (111, 119))	('neoplastic lesions', 'Disease', 'MESH:D007680', (132, 150))	('neoplastic lesions', 'Disease', (132, 150))	('adenomas', 'Disease', (111, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('silencing', 'NegReg', (47, 56))	('PTX3', 'Gene', (21, 25))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (132, 150))	('methylation', 'Var', (31, 42))	('colorectal cancer', 'Disease', (3, 20))	('PTX3', 'Gene', '5806', (21, 25))	('pathogenesis', 'biological_process', 'GO:0009405', ('204', '216'))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
23184	30873708	Along the same line, in myeloproliferative neoplasms, PTX3 levels correlated with mutant JAK2 (JAK2V617F) allele burden, which is well esteblished to sustain leukocyte activation.	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (24, 52))	('correlated', 'Reg', (66, 76))	('PTX3', 'Gene', (54, 58))	('JAK2', 'Gene', '3717', (95, 99))	('JAK2V617F', 'Gene', '3717', (95, 104))	('leukocyte activation', 'biological_process', 'GO:0045321', ('158', '178'))	('neoplasms', 'Phenotype', 'HP:0002664', (43, 52))	('JAK2V617F', 'Gene', (95, 104))	('JAK', 'molecular_function', 'GO:0004713', ('89', '92'))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (24, 52))	('JAK2', 'Gene', '3717', (89, 93))	('PTX3', 'Gene', '5806', (54, 58))	('JAK2', 'Gene', (95, 99))	('myeloproliferative neoplasms', 'Disease', (24, 52))	('JAK2', 'Gene', (89, 93))	('JAK', 'molecular_function', 'GO:0004713', ('95', '98'))	('mutant', 'Var', (82, 88))
23209	30873708	Blocking IL-1 resulted in an increase in lean body mass, improved parameters of quality of life, decreased pain and decreased constitutional symptoms.. Reducing IL-1alpha may also reduce inflammation-mediated immunosuppression, both impacting on increased survival and immune-mediated tumor regression.	('inflammation', 'Disease', 'MESH:D007249', (187, 199))	('pain', 'Phenotype', 'HP:0012531', (107, 111))	('survival', 'CPA', (256, 264))	('reduce', 'NegReg', (180, 186))	('decreased pain', 'Disease', 'MESH:D010146', (97, 111))	('IL-1alpha', 'Gene', '3552', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('Reducing', 'Var', (152, 160))	('decreased pain', 'Phenotype', 'HP:0007328', (97, 111))	('inflammation', 'Disease', (187, 199))	('IL-1', 'Gene', '3552', (161, 165))	('decreased pain', 'Disease', (97, 111))	('IL-1', 'Gene', '3552', (9, 13))	('IL-1', 'Gene', (161, 165))	('IL-1alpha', 'Gene', (161, 170))	('constitutional symptoms', 'Phenotype', 'HP:0025142', (126, 149))	('tumor', 'Disease', (285, 290))	('impacting', 'Reg', (233, 242))	('IL-1', 'Gene', (9, 13))	('increased', 'PosReg', (246, 255))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
23211	30873708	In the seminal CANTOS study with 10,061 patients with atherosclerosis and high CRP levels, anti-IL-1beta (Canakinumab) resulted in a major (>50%) reduction in the incidence and mortality from lung cancer.	('CRP', 'Gene', '1401', (79, 82))	('anti-IL-1beta', 'Var', (91, 104))	('atherosclerosis', 'Disease', 'MESH:D050197', (54, 69))	('atherosclerosis', 'Phenotype', 'HP:0002621', (54, 69))	('lung cancer', 'Disease', (192, 203))	('IL-1', 'molecular_function', 'GO:0005149', ('96', '100'))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('mortality', 'Disease', (177, 186))	('patients', 'Species', '9606', (40, 48))	('atherosclerosis', 'Disease', (54, 69))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lung cancer', 'Disease', 'MESH:D008175', (192, 203))	('CRP', 'Gene', (79, 82))	('mortality', 'Disease', 'MESH:D003643', (177, 186))	('reduction', 'NegReg', (146, 155))
23218	30873708	Inhibition of IL-1R8 unleashed NK cell-mediated resistance against liver and lung carcinogenesis and metastasis, two NK cell rich anatomical sites.	('lung carcinogenesis', 'Disease', 'MESH:D063646', (77, 96))	('IL-1R', 'molecular_function', 'GO:0004908', ('14', '19'))	('IL-1R8', 'Gene', (14, 20))	('unleashed', 'Reg', (21, 30))	('IL-1R8', 'Gene', '59307', (14, 20))	('Inhibition', 'Var', (0, 10))	('lung carcinogenesis', 'Disease', (77, 96))
23230	30873708	Interestingly, signals which orient TAM in a protumor direction (M2-like) do not inhibit their ADCC and ADCP effector function, or actually increase it.	('TAM', 'Chemical', '-', (36, 39))	('tumor', 'Disease', (48, 53))	('signals', 'Var', (15, 22))	('inhibit', 'NegReg', (81, 88))	('ADCP', 'Chemical', '-', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('increase', 'PosReg', (140, 148))	('ADCC', 'MPA', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('ADCP effector function', 'MPA', (104, 126))
23420	29212274	And positive pN were demonstrated as high-risk postoperative factors for synchronous metastases (Table 3).	('pN', 'Chemical', 'MESH:C070006', (13, 15))	('positive pN', 'Var', (4, 15))	('synchronous metastases', 'Disease', (73, 95))	('synchronous metastases', 'Disease', 'MESH:D009362', (73, 95))
23426	29212274	demonstrated that incidence of confirmed distant metastases was significantly greater in the rectal cancer group with positive EMVI (28/135, 20.7%) compared to the group with negative EMVI (4/95, 4.2%), with odds ratio of 6.0 (95% CI 2.0-17.6).	('metastases', 'Disease', 'MESH:D009362', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('rectal cancer', 'Disease', 'MESH:D012004', (93, 106))	('positive', 'Var', (118, 126))	('rectal cancer', 'Disease', (93, 106))	('rectal cancer', 'Phenotype', 'HP:0100743', (93, 106))	('greater', 'PosReg', (78, 85))	('metastases', 'Disease', (49, 59))
23436	29212274	While in our study, three quarters of patients were proven pathological T4 stage, and all of the synchronous metastases were occurred in patients with pathological T4 status.	('synchronous metastases', 'Disease', (97, 119))	('T4 status', 'Var', (164, 173))	('occurred', 'Reg', (125, 133))	('patients', 'Species', '9606', (137, 145))	('synchronous metastases', 'Disease', 'MESH:D009362', (97, 119))	('patients', 'Species', '9606', (38, 46))
23443	29212274	Some studies have shown that high-resolution MR diagnosis of EMVI positive can be used as a predictor of lymph node metastasis in colorectal cancer, suggesting that mrEMVI has a significant correlation with lymph node metastasis.	('colorectal cancer', 'Phenotype', 'HP:0003003', (130, 147))	('mrEMVI', 'Var', (165, 171))	('lymph node metastasis', 'CPA', (207, 228))	('colorectal cancer', 'Disease', (130, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('rectal cancer', 'Phenotype', 'HP:0100743', (134, 147))	('colorectal cancer', 'Disease', 'MESH:D015179', (130, 147))	('correlation', 'Interaction', (190, 201))
23487	28918047	Moreover, BC032913 enhanced the mRNA and protein expression of TIMP3 and inhibited Wnt/beta-catenin pathway activity, thus suppressing CRC metastasis in vitro and in vivo.	('BC032913', 'Chemical', '-', (10, 18))	('si', 'Chemical', 'MESH:D012825', (146, 148))	('suppressing', 'NegReg', (123, 134))	('BC032913', 'Var', (10, 18))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('CRC metastasis', 'CPA', (135, 149))	('inhibited', 'NegReg', (73, 82))	('TIMP3', 'Gene', (63, 68))	('CRC', 'Phenotype', 'HP:0003003', (135, 138))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('Wnt/beta-catenin pathway', 'Pathway', (83, 107))	('enhanced', 'PosReg', (19, 27))
23488	28918047	Collectively, the obtained data show that BC032913 plays an inhibitory role in CRC aggression by upregulating TIMP3, followed by inactivation of the Wnt/beta-catenin pathway.	('BC032913', 'Chemical', '-', (42, 50))	('CRC aggression', 'Disease', 'MESH:D015179', (79, 93))	('CRC', 'Phenotype', 'HP:0003003', (79, 82))	('Wnt/beta-catenin pathway', 'Pathway', (149, 173))	('BC032913', 'Var', (42, 50))	('inactivation', 'NegReg', (129, 141))	('CRC aggression', 'Disease', (79, 93))	('upregulating', 'PosReg', (97, 109))	('TIMP3', 'MPA', (110, 115))	('aggression', 'Phenotype', 'HP:0000718', (83, 93))	('aggression', 'biological_process', 'GO:0002118', ('83', '93'))
23489	28918047	Our findings indicate that the novel lncRNA BC032913 could serve as a novel prognostic marker and effective therapeutic target for CRC.	('CRC', 'Phenotype', 'HP:0003003', (131, 134))	('BC032913', 'Chemical', '-', (44, 52))	('CRC', 'Disease', (131, 134))	('BC032913', 'Var', (44, 52))
23497	28918047	In recent years, increasing evidence has demonstrated that lncRNAs participate in the pathogenesis of multiple diseases through various mechanisms of downstream gene regulation, such as epigenetic, post-transcriptional, and transcriptional regulation.	('epigenetic', 'Var', (186, 196))	('participate', 'Reg', (67, 78))	('multiple diseases', 'Disease', (102, 119))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('lncRNAs', 'Gene', (59, 66))
23508	28918047	Previous studies have indicated that alternative factors are involved in CRC pathogenesis, including genetic alternations in oncogenes or tumor suppressor genes, as well as changes in the transforming growth factor beta (TGF-beta) and Wnt signaling pathways.	('tumor', 'Disease', (138, 143))	('alternations', 'Var', (109, 121))	('Wnt signaling pathways', 'Pathway', (235, 257))	('transforming growth factor beta', 'Gene', (188, 219))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('changes', 'Reg', (173, 180))	('si', 'Chemical', 'MESH:D012825', (239, 241))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('138', '154'))	('transforming growth factor beta', 'Gene', '7040', (188, 219))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('CRC', 'Disease', (73, 76))	('genetic alternations', 'Var', (101, 121))	('si', 'Chemical', 'MESH:D012825', (86, 88))	('TGF-beta', 'Gene', '7040', (221, 229))	('tumor suppressor', 'biological_process', 'GO:0051726', ('138', '154'))	('CRC', 'Phenotype', 'HP:0003003', (73, 76))	('signaling', 'biological_process', 'GO:0023052', ('239', '248'))	('oncogenes', 'Gene', (125, 134))	('transforming growth factor beta', 'molecular_function', 'GO:0005160', ('188', '219'))	('TGF-beta', 'Gene', (221, 229))	('pathogenesis', 'biological_process', 'GO:0009405', ('77', '89'))
23515	28918047	It has been documented that aberrant methylation of TIMP-3 occurs in primary cancers of the colon, lung, breast, kidney, and brain.	('lung', 'Disease', (99, 103))	('brain', 'Disease', (125, 130))	('cancers of the colon', 'Disease', 'MESH:D015179', (77, 97))	('kidney', 'Disease', (113, 119))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('TIMP-3', 'Gene', (52, 58))	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('aberrant', 'Var', (28, 36))	('TIMP-3', 'Gene', '7078', (52, 58))	('occurs', 'Reg', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('breast', 'Disease', (105, 111))	('cancers of the colon', 'Disease', (77, 97))	('methylation', 'MPA', (37, 48))
23516	28918047	Such tumor-specific methylation is associated with a lack of the TIMP-3 protein.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('TIMP-3', 'Gene', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('methylation', 'Var', (20, 31))	('tumor', 'Disease', (5, 10))	('lack', 'NegReg', (53, 57))	('TIMP-3', 'Gene', '7078', (65, 71))
23525	28918047	Here we demonstrate for the first time that lncRNA BC032913 suppresses CRC metastasis through upregulating TIMP3 expression, followed by inhibition of the nuclear translocation of beta-catenin, which inactivates the Wnt/beta-catenin pathway.	('expression', 'MPA', (113, 123))	('beta-catenin', 'Protein', (180, 192))	('CRC', 'Disease', (71, 74))	('suppresses', 'NegReg', (60, 70))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('nuclear translocation', 'MPA', (155, 176))	('BC032913', 'Chemical', '-', (51, 59))	('si', 'Chemical', 'MESH:D012825', (119, 121))	('inhibition', 'NegReg', (137, 147))	('CRC', 'Phenotype', 'HP:0003003', (71, 74))	('upregulating', 'PosReg', (94, 106))	('TIMP3', 'Gene', (107, 112))	('Wnt/beta-catenin', 'Pathway', (216, 232))	('lncRNA BC032913', 'Var', (44, 59))
23533	28918047	The results indicated that ENST00000502715 and ENST00000418454 were increased in CRC, whereas the levels of BC029135, NR_003191, and BC032913 were decreased (Figure 1B).	('ENST00000418454', 'Var', (47, 62))	('CRC', 'Disease', (81, 84))	('BC032913', 'Chemical', '-', (133, 141))	('CRC', 'Phenotype', 'HP:0003003', (81, 84))	('ENST00000502715', 'Var', (27, 42))	('increased', 'PosReg', (68, 77))
23541	28918047	Kaplan-Meier survival analysis showed that the low-level group was associated with poor OS in CRC patients (p = 0.028' Figure 1D).	('patients', 'Species', '9606', (98, 106))	('CRC', 'Phenotype', 'HP:0003003', (94, 97))	('poor OS', 'Disease', (83, 90))	('low-level', 'Var', (47, 56))	('CRC', 'Disease', (94, 97))	('si', 'Chemical', 'MESH:D012825', (27, 29))
23542	28918047	These clinical data suggested that BC032913 could affect CRC metastasis and serve as a novel prognostic marker for CRC.	('CRC', 'Phenotype', 'HP:0003003', (57, 60))	('BC032913', 'Chemical', '-', (35, 43))	('CRC', 'Disease', (115, 118))	('BC032913', 'Var', (35, 43))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('affect', 'Reg', (50, 56))	('CRC', 'Phenotype', 'HP:0003003', (115, 118))	('CRC', 'Disease', (57, 60))
23545	28918047	Thus, we conducted migration, invasion, and sphere-forming assays, and the results demonstrated that ectopic BC032913 expression caused significant suppression of cell migration in both HCT116 and DLD-1 cells compared with cells transfected with an empty vector (p < 0.05; Figure 2A).	('cell migration', 'biological_process', 'GO:0016477', ('163', '177'))	('ectopic', 'Var', (101, 108))	('BC032913', 'Gene', (109, 117))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('cell migration', 'CPA', (163, 177))	('suppression', 'NegReg', (148, 159))	('BC032913', 'Chemical', '-', (109, 117))	('HCT116', 'CellLine', 'CVCL:0291', (186, 192))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('si', 'Chemical', 'MESH:D012825', (124, 126))	('si', 'Chemical', 'MESH:D012825', (155, 157))
23547	28918047	Overexpression of BC032913 resulted in the formation of fewer and smaller spheres (p < 0.05; Figure 2C).	('BC032913', 'Chemical', '-', (18, 26))	('fewer', 'NegReg', (56, 61))	('smaller', 'NegReg', (66, 73))	('BC032913', 'Var', (18, 26))	('formation', 'biological_process', 'GO:0009058', ('43', '52'))	('si', 'Chemical', 'MESH:D012825', (10, 12))
23549	28918047	To explore the mechanism underlying the inhibition of an aggressive phenotype by BC032913, metastasis-related genes that were deregulated between HCT116 cells stably transfected with pLNCX2-BC032913 (HCT116-BC032913) or pLNCX2 (HCT116-control) were determined using a human tumor metastasis PCR array.	('pLNCX2-BC032913', 'Var', (183, 198))	('tumor metastasis', 'Disease', (274, 290))	('si', 'Chemical', 'MESH:D012825', (287, 289))	('human', 'Species', '9606', (268, 273))	('BC032913', 'Chemical', '-', (207, 215))	('BC032913', 'Gene', (81, 89))	('BC032913', 'Chemical', '-', (190, 198))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('HCT116', 'CellLine', 'CVCL:0291', (200, 206))	('BC032913', 'Chemical', '-', (81, 89))	('HCT116', 'CellLine', 'CVCL:0291', (146, 152))	('deregulated', 'PosReg', (126, 137))	('metastasis-related genes', 'Gene', (91, 115))	('HCT116', 'CellLine', 'CVCL:0291', (228, 234))	('tumor metastasis', 'Disease', 'MESH:D009362', (274, 290))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('si', 'Chemical', 'MESH:D012825', (261, 263))
23555	28918047	Western blot analyses showed that the protein levels of TIMP3 were elevated in both the HCT116-BC032913 and DLD-1-BC032913 cell lines compared with the corresponding control cell lines (Figure 3E).	('BC032913', 'Chemical', '-', (114, 122))	('elevated', 'PosReg', (67, 75))	('BC032913', 'Chemical', '-', (95, 103))	('protein levels', 'MPA', (38, 52))	('HCT116', 'CellLine', 'CVCL:0291', (88, 94))	('HCT116-BC032913', 'Var', (88, 103))
23558	28918047	The above data indicate that BC032913 could upregulate TIMP3 expression and inhibit the activity of the Wnt/beta-catenin pathway.	('TIMP3', 'Gene', (55, 60))	('inhibit', 'NegReg', (76, 83))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('BC032913', 'Chemical', '-', (29, 37))	('upregulate', 'PosReg', (44, 54))	('activity', 'MPA', (88, 96))	('BC032913', 'Var', (29, 37))	('Wnt/beta-catenin pathway', 'Pathway', (104, 128))	('expression', 'MPA', (61, 71))
23559	28918047	First, it was confirmed that overexpression of TIMP3 suppressed the invasion capability (p < 0.05; Figure 4A), whereas knockdown of TIMP3 promoted invasion (p < 0.05; Figure 4B) in HCT-116 and DLD-1 cells.	('TIMP3', 'Gene', (132, 137))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('si', 'Chemical', 'MESH:D012825', (151, 153))	('invasion', 'CPA', (147, 155))	('promoted', 'PosReg', (138, 146))	('knockdown', 'Var', (119, 128))	('invasion capability', 'CPA', (68, 87))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('HCT-116', 'CellLine', 'CVCL:0291', (181, 188))	('suppressed', 'NegReg', (53, 63))
23561	28918047	Compared with the negative control (HCT116-control/DLD1-control), stably expressed BC032913 (HCT116-BC032913/DLD1-BC032913) markedly reduced the number of invasive cells (p < 0.05; Figures 4C and 4D).	('si', 'Chemical', 'MESH:D012825', (159, 161))	('HCT116', 'CellLine', 'CVCL:0291', (36, 42))	('BC032913', 'Chemical', '-', (114, 122))	('HCT116-BC032913/DLD1-BC032913', 'Var', (93, 122))	('BC032913', 'Chemical', '-', (83, 91))	('HCT116', 'CellLine', 'CVCL:0291', (93, 99))	('reduced', 'NegReg', (133, 140))	('BC032913', 'Chemical', '-', (100, 108))
23564	28918047	The results showed a clear decrease in luciferase activity in the presence of BC032913 and partial rescue by TIMP3 knockdown.	('BC032913', 'Var', (78, 86))	('luciferase', 'Enzyme', (39, 49))	('decrease', 'NegReg', (27, 35))	('TIMP3', 'Gene', (109, 114))	('activity', 'MPA', (50, 58))	('BC032913', 'Chemical', '-', (78, 86))
23565	28918047	Moreover, the western blot analysis shown in Figure 4F revealed that BC032913 increased TIMP3 and E-cadherin expression levels and decreased nuclear beta-catenin and CD44 expression levels compared with the corresponding negative control.	('BC032913', 'Chemical', '-', (69, 77))	('CD44', 'Gene', (166, 170))	('cadherin', 'molecular_function', 'GO:0008014', ('100', '108'))	('si', 'Chemical', 'MESH:D012825', (115, 117))	('E-cadherin', 'Gene', (98, 108))	('si', 'Chemical', 'MESH:D012825', (177, 179))	('BC032913', 'Var', (69, 77))	('decreased', 'NegReg', (131, 140))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('nuclear beta-catenin', 'MPA', (141, 161))	('E-cadherin', 'Gene', '999', (98, 108))	('increased', 'PosReg', (78, 87))	('CD44', 'Gene', '960', (166, 170))
23569	28918047	Compared with the control, fewer and much smaller lung micrometastases were observed in the HCT116-BC032913 group (p < 0.01; Figure 5A).	('HCT116', 'CellLine', 'CVCL:0291', (92, 98))	('smaller', 'NegReg', (42, 49))	('metastases', 'Disease', (60, 70))	('smaller lung', 'Phenotype', 'HP:0002089', (42, 54))	('metastases', 'Disease', 'MESH:D009362', (60, 70))	('BC032913', 'Chemical', '-', (99, 107))	('HCT116-BC032913', 'Var', (92, 107))
23572	28918047	Furthermore, we assessed the expression of TIPM3 and beta-catenin by real-time qPCR in lung and liver metastases originating from mice in the HCT116-control and HCT116-BC032913 groups.	('mice', 'Species', '10090', (130, 134))	('liver metastases', 'Disease', (96, 112))	('HCT116-BC032913', 'Var', (161, 176))	('beta-catenin', 'Protein', (53, 65))	('TIPM3', 'Gene', (43, 48))	('liver metastases', 'Disease', 'MESH:D009362', (96, 112))	('HCT116', 'CellLine', 'CVCL:0291', (161, 167))	('HCT116', 'CellLine', 'CVCL:0291', (142, 148))	('si', 'Chemical', 'MESH:D012825', (35, 37))	('BC032913', 'Chemical', '-', (168, 176))
23573	28918047	The mRNA levels of TIMP3 and beta-catenin were increased and decreased, respectively, in mice in the HCT116-BC032913 group compared with mice in the HCT116-control group (p < 0.01; Figure 5C).	('mRNA levels', 'MPA', (4, 15))	('BC032913', 'Chemical', '-', (108, 116))	('mice', 'Species', '10090', (89, 93))	('HCT116', 'CellLine', 'CVCL:0291', (101, 107))	('increased', 'PosReg', (47, 56))	('HCT116-BC032913', 'Var', (101, 116))	('decreased', 'NegReg', (61, 70))	('HCT116', 'CellLine', 'CVCL:0291', (149, 155))	('TIMP3', 'MPA', (19, 24))	('beta-catenin', 'MPA', (29, 41))	('mice', 'Species', '10090', (137, 141))
23575	28918047	In conclusion, lncRNA BC032913 inhibited CRC metastasis through inactivation of the Wnt/beta-catenin pathway, which was followed by modulation of TIMP3, nuclear beta-catenin, E-cadherin, and CD44 expression.	('lncRNA BC032913', 'Var', (15, 30))	('CD44', 'Gene', '960', (191, 195))	('CD44', 'Gene', (191, 195))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('CRC', 'Disease', (41, 44))	('BC032913', 'Chemical', '-', (22, 30))	('inactivation', 'NegReg', (64, 76))	('modulation', 'Reg', (132, 142))	('CRC', 'Phenotype', 'HP:0003003', (41, 44))	('TIMP3', 'Protein', (146, 151))	('nuclear', 'Protein', (153, 160))	('E-cadherin', 'Gene', (175, 185))	('E-cadherin', 'Gene', '999', (175, 185))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('Wnt/beta-catenin pathway', 'Pathway', (84, 108))	('expression', 'MPA', (196, 206))	('si', 'Chemical', 'MESH:D012825', (202, 204))	('inhibited', 'NegReg', (31, 40))	('BC032913', 'Var', (22, 30))
23576	28918047	Emerging research has shown that lncRNAs play important roles in cancer carcinogenesis and progression, and aberrant lncRNA expression has been identified in CRC.	('CRC', 'Phenotype', 'HP:0003003', (158, 161))	('lncRNA expression', 'Protein', (117, 134))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('aberrant', 'Var', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('CRC', 'Disease', (158, 161))	('cancer carcinogenesis', 'Disease', (65, 86))	('si', 'Chemical', 'MESH:D012825', (83, 85))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('cancer carcinogenesis', 'Disease', 'MESH:D063646', (65, 86))	('identified', 'Reg', (144, 154))
23579	28918047	CCAT2 is elevated in microsatellite-stable CRC and promotes tumor growth, metastasis, and chromosomal instability.	('elevated', 'PosReg', (9, 17))	('CCAT2', 'Gene', (0, 5))	('microsatellite-stable', 'Var', (21, 42))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('metastasis', 'CPA', (74, 84))	('chromosomal instability', 'Phenotype', 'HP:0040012', (90, 113))	('promotes', 'PosReg', (51, 59))	('CCAT2', 'Gene', '101805488', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('CRC', 'Phenotype', 'HP:0003003', (43, 46))	('tumor', 'Disease', (60, 65))	('chromosomal instability', 'CPA', (90, 113))
23582	28918047	Five selected lncRNAs were further validated in an additional 20 pairs of CRC tissues via real-time qPCR (Figure 1), and we found that the novel lncRNA BC032913 was markedly downregulated in 115 CRC tissues.	('CRC', 'Phenotype', 'HP:0003003', (195, 198))	('BC032913', 'Chemical', '-', (152, 160))	('downregulated', 'NegReg', (174, 187))	('BC032913', 'Var', (152, 160))	('CRC', 'Disease', (195, 198))	('CRC', 'Phenotype', 'HP:0003003', (74, 77))
23584	28918047	Low BC032913 levels were positively correlated with an advanced TNM stage and a higher risk of lymph node and distant metastases, suggesting that the downregulation of BC032913 in CRC may facilitate the invasive/metastatic phenotype (Figure 1; Table 1).	('facilitate', 'PosReg', (188, 198))	('BC032913', 'Chemical', '-', (4, 12))	('BC032913', 'Var', (168, 176))	('si', 'Chemical', 'MESH:D012825', (207, 209))	('downregulation', 'NegReg', (150, 164))	('metastases', 'Disease', (118, 128))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('CRC', 'Phenotype', 'HP:0003003', (180, 183))	('invasive/metastatic phenotype', 'CPA', (203, 232))	('si', 'Chemical', 'MESH:D012825', (27, 29))	('BC032913', 'Chemical', '-', (168, 176))
23589	28918047	In humans, LOC389023 recruits polycomb 2 (PRC2) and other transcriptional repressors in cis, thereby inhibiting the expression of the sense transcript DPP10.	('LOC389023', 'Var', (11, 20))	('expression', 'MPA', (116, 126))	('PRC2', 'Gene', (42, 46))	('DPP10', 'Gene', (151, 156))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('DPP10', 'Gene', '57628', (151, 156))	('humans', 'Species', '9606', (3, 9))	('inhibiting', 'NegReg', (101, 111))
23590	28918047	This research suggests that BC032913 may also play a functional role in CRC through regulating DPP10 transcription.	('DPP10', 'Gene', '57628', (95, 100))	('CRC', 'Disease', (72, 75))	('BC032913', 'Chemical', '-', (28, 36))	('BC032913', 'Var', (28, 36))	('CRC', 'Phenotype', 'HP:0003003', (72, 75))	('transcription', 'biological_process', 'GO:0006351', ('101', '114'))	('transcription', 'MPA', (101, 114))	('DPP10', 'Gene', (95, 100))	('regulating', 'Reg', (84, 94))
23596	28918047	To explore the underlying mechanism, metastasis-related genes that were deregulated in HCT116-BC032913 versus HCT116-control cells were identified using a human tumor metastasis PCR array.	('tumor metastasis', 'Disease', 'MESH:D009362', (161, 177))	('si', 'Chemical', 'MESH:D012825', (148, 150))	('human', 'Species', '9606', (155, 160))	('tumor metastasis', 'Disease', (161, 177))	('BC032913', 'Chemical', '-', (94, 102))	('si', 'Chemical', 'MESH:D012825', (174, 176))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('HCT116-BC032913', 'Var', (87, 102))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('HCT116', 'CellLine', 'CVCL:0291', (87, 93))	('HCT116', 'CellLine', 'CVCL:0291', (110, 116))	('deregulated', 'PosReg', (72, 83))	('metastasis-related genes', 'Gene', (37, 61))
23597	28918047	BC032913 was verified to elevate TIMP3 at both the mRNA and protein levels.	('elevate', 'PosReg', (25, 32))	('TIMP3', 'Gene', (33, 38))	('BC032913', 'Chemical', '-', (0, 8))	('BC032913', 'Var', (0, 8))
23598	28918047	Subsequently, we demonstrated that BC032913 inactivated the Wnt/beta-catenin pathway by upregulating TIMP3 (Figures 3 and 4).	('BC032913', 'Chemical', '-', (35, 43))	('Wnt/beta-catenin pathway', 'Pathway', (60, 84))	('BC032913', 'Var', (35, 43))	('inactivated', 'NegReg', (44, 55))	('upregulating', 'PosReg', (88, 100))	('TIMP3', 'Gene', (101, 106))
23603	28918047	In mammary epithelial cells, extracellular TIMP3 functions to inactivate the Wnt-beta-catenin pathway, followed by increasing phosphorylated beta-catenin levels and decreasing nuclear beta-catenin levels.	('phosphorylated beta-catenin levels', 'MPA', (126, 160))	('nuclear beta-catenin levels', 'MPA', (176, 203))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('inactivate', 'NegReg', (62, 72))	('extracellular TIMP3', 'Var', (29, 48))	('decreasing', 'NegReg', (165, 175))	('si', 'Chemical', 'MESH:D012825', (171, 173))	('increasing', 'PosReg', (115, 125))	('Wnt-beta-catenin pathway', 'Pathway', (77, 101))	('extracellular', 'cellular_component', 'GO:0005576', ('29', '42'))
23604	28918047	In accord with the above studies, TIMP3, upregulated by BC032913, inhibits nuclear translocation of beta-catenin, followed by inactivating the Wnt/beta-catenin pathway in our research.	('inhibits', 'NegReg', (66, 74))	('BC032913', 'Chemical', '-', (56, 64))	('Wnt/beta-catenin pathway', 'Pathway', (143, 167))	('upregulated', 'PosReg', (41, 52))	('nuclear translocation of beta-catenin', 'MPA', (75, 112))	('inactivating', 'NegReg', (126, 138))	('BC032913', 'Var', (56, 64))	('TIMP3', 'Gene', (34, 39))
23605	28918047	A downstream target gene of the Wnt pathway, CD44, was also identified to be downregulated by BC032913 using a human tumor metastasis PCR array (Figure 3B).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('downregulated', 'NegReg', (77, 90))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('human', 'Species', '9606', (111, 116))	('CD44', 'Gene', '960', (45, 49))	('BC032913', 'Chemical', '-', (94, 102))	('tumor metastasis', 'Disease', 'MESH:D009362', (117, 133))	('CD44', 'Gene', (45, 49))	('BC032913', 'Var', (94, 102))	('tumor metastasis', 'Disease', (117, 133))	('Wnt pathway', 'Pathway', (32, 43))
23606	28918047	Hence, we hypothesized that the BC032913/TIMP3 axis may inhibit CRC metastasis by inactivating Wnt/beta-catenin signaling and subsequently blocking CD44 transcription.	('si', 'Chemical', 'MESH:D012825', (75, 77))	('inactivating', 'NegReg', (82, 94))	('BC032913', 'Chemical', '-', (32, 40))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('signaling', 'biological_process', 'GO:0023052', ('112', '121'))	('blocking', 'NegReg', (139, 147))	('CRC', 'Disease', (64, 67))	('CD44', 'Gene', (148, 152))	('BC032913/TIMP3', 'Var', (32, 46))	('CD44', 'Gene', '960', (148, 152))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('transcription', 'MPA', (153, 166))	('transcription', 'biological_process', 'GO:0006351', ('153', '166'))	('Wnt/beta-catenin signaling', 'MPA', (95, 121))	('CRC', 'Phenotype', 'HP:0003003', (64, 67))	('inhibit', 'NegReg', (56, 63))
23607	28918047	The data revealed that the BC032913/TIMP3 axis decreased the levels of nuclear beta-catenin and CD44, which are important molecules in the Wnt/beta-catenin pathway (Figure 4F).	('BC032913/TIMP3', 'Var', (27, 41))	('CD44', 'Gene', '960', (96, 100))	('levels of nuclear beta-catenin', 'MPA', (61, 91))	('CD44', 'Gene', (96, 100))	('BC032913', 'Chemical', '-', (27, 35))	('decreased', 'NegReg', (47, 56))
23611	28918047	As shown in Figure 4F, BC032913 promoted E-cadherin expression levels and suppressed CD44 expression levels compared with the corresponding negative control.	('promoted', 'PosReg', (32, 40))	('suppressed', 'NegReg', (74, 84))	('CD44', 'Gene', '960', (85, 89))	('cadherin', 'molecular_function', 'GO:0008014', ('43', '51'))	('CD44', 'Gene', (85, 89))	('BC032913', 'Chemical', '-', (23, 31))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('E-cadherin', 'Gene', (41, 51))	('E-cadherin', 'Gene', '999', (41, 51))	('BC032913', 'Var', (23, 31))	('si', 'Chemical', 'MESH:D012825', (96, 98))
23612	28918047	Moreover, TIMP3 knockdown reversed the effect of BC032913 on the expression of E-cadherin and CD44.	('CD44', 'Gene', (94, 98))	('BC032913', 'Chemical', '-', (49, 57))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('BC032913', 'Var', (49, 57))	('E-cadherin', 'Gene', (79, 89))	('CD44', 'Gene', '960', (94, 98))	('E-cadherin', 'Gene', '999', (79, 89))
23622	28918047	For example, TNFSF10 was downregulated by BC032913, indicating that BC032913 may influence CRC carcinogenesis and progression by modulating TNFSF10.	('modulating', 'Reg', (129, 139))	('TNFSF10', 'Gene', '8743', (13, 20))	('BC032913', 'Var', (68, 76))	('BC032913', 'Chemical', '-', (42, 50))	('carcinogenesis', 'Disease', 'MESH:D063646', (95, 109))	('CRC', 'Disease', (91, 94))	('influence', 'Reg', (81, 90))	('carcinogenesis', 'Disease', (95, 109))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('downregulated', 'NegReg', (25, 38))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('BC032913', 'Chemical', '-', (68, 76))	('CRC', 'Phenotype', 'HP:0003003', (91, 94))	('TNFSF10', 'Gene', (140, 147))	('progression', 'CPA', (114, 125))	('TNFSF10', 'Gene', (13, 20))	('TNFSF10', 'Gene', '8743', (140, 147))
23648	28918047	GP293 cells were transfected with pLNCX2-BC032913 or pLNCX2 and the package plasmids according to the manufacturer's instructions.	('pLNCX2', 'Var', (53, 59))	('BC032913', 'Chemical', '-', (41, 49))	('pLNCX2-BC032913', 'Var', (34, 49))	('GP293', 'CellLine', 'CVCL:E072', (0, 5))
23667	28918047	The primary antibodies used included anti-TIMP3 (sc-9906, Santa Cruz), anti-GAPDH (sc-32233), anti-Histone H3 (sc-8654), anti-beta-catenin (8480, Cell Signaling Technology), and anti-E-cadherin (3195, Cell Signaling Technology).	('anti-TIMP3', 'Var', (37, 47))	('Signaling', 'biological_process', 'GO:0023052', ('151', '160'))	('E-cadherin', 'Gene', '999', (183, 193))	('GAPDH', 'Gene', '2597', (76, 81))	('GAPDH', 'Gene', (76, 81))	('anti-Histone', 'Var', (94, 106))	('Signaling', 'biological_process', 'GO:0023052', ('206', '215'))	('sc-32233', 'Var', (83, 91))	('cadherin', 'molecular_function', 'GO:0008014', ('185', '193'))	('E-cadherin', 'Gene', (183, 193))
23676	28918047	For the hepatic metastasis model, tumor cell suspensions (HCT116-BC032913 or HCT116-control, 1 x 106 cells/mouse/100 muL) were injected into the distal tip of the spleen.	('HCT116', 'CellLine', 'CVCL:0291', (77, 83))	('hepatic metastasis', 'Disease', (8, 26))	('HCT116-BC032913', 'Var', (58, 73))	('tumor', 'Disease', (34, 39))	('hepatic metastasis', 'Disease', 'MESH:D009362', (8, 26))	('mouse', 'Species', '10090', (107, 112))	('HCT116', 'CellLine', 'CVCL:0291', (58, 64))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('BC032913', 'Chemical', '-', (65, 73))
23725	27027349	Furthermore, structural modifications of nimbolide to various amide derivatives have conferred improved cytotoxicity.	('amide', 'Chemical', 'MESH:D000577', (62, 67))	('cytotoxicity', 'Disease', 'MESH:D064420', (104, 116))	('nimbolide', 'Gene', (41, 50))	('structural modifications', 'Var', (13, 37))	('nimbolide', 'Chemical', 'MESH:C042198', (41, 50))	('improved', 'PosReg', (95, 103))	('cytotoxicity', 'Disease', (104, 116))
23764	27027349	For instance, chemopreventive agents hinder tumour initiation by preventing interaction between carcinogens or reactive free radicals and DNA, hence lowering the chance of DNA damage and mutations.	('tumour initiation', 'Disease', (44, 61))	('preventing', 'NegReg', (65, 75))	('lowering', 'NegReg', (149, 157))	('free radical', 'Chemical', 'MESH:D005609', (120, 132))	('DNA', 'cellular_component', 'GO:0005574', ('138', '141'))	('interaction', 'Interaction', (76, 87))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('mutations', 'Var', (187, 196))	('DNA', 'cellular_component', 'GO:0005574', ('172', '175'))	('hinder', 'NegReg', (37, 43))	('tumour initiation', 'Disease', 'MESH:D009369', (44, 61))	('DNA damage', 'MPA', (172, 182))
23773	27027349	Evidently, nimbolide was found to reduce cyclin A level, which is required for colon cancer cells to proceed through S phase, hence inducing cell cycle arrest and resulting ininhibition of cell growth.	('cell growth', 'CPA', (189, 200))	('colon cancer', 'Disease', (79, 91))	('nimbolide', 'Var', (11, 20))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (141, 158))	('reduce cyclin A level', 'Phenotype', 'HP:0500152', (34, 55))	('cyclin A', 'Gene', (41, 49))	('cell cycle arrest', 'CPA', (141, 158))	('reduce', 'NegReg', (34, 40))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('cyclin A', 'Gene', '890', (41, 49))	('inducing', 'Reg', (132, 140))	('nimbolide', 'Chemical', 'MESH:C042198', (11, 20))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
23776	27027349	Apart from G1/S phasearrest, nimbolidealso caused cell cycle arrest at both the G0/G1 and G2/M phases.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (50, 67))	('nimbolidealso', 'Chemical', '-', (29, 42))	('G2/M phases', 'CPA', (90, 101))	('nimbolidealso', 'Var', (29, 42))	('cell cycle arrest', 'CPA', (50, 67))
23795	27027349	ROS also induced lipid peroxidation of cellular membranes, generating toxic metabolites such as malondialdehyde (MDA) that can react with DNA to form adducts to induce apoptosis.	('ROS', 'Var', (0, 3))	('malondialdehyde', 'MPA', (96, 111))	('induced', 'Reg', (9, 16))	('induce', 'Reg', (161, 167))	('lipid', 'Chemical', 'MESH:D008055', (17, 22))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('malondialdehyde', 'Chemical', 'MESH:D008315', (96, 111))	('lipid peroxidation', 'MPA', (17, 35))	('MDA', 'Chemical', 'MESH:D008315', (113, 116))	('rat', 'Species', '10116', (63, 66))
23818	27027349	Hence, mutations in the Wnt pathway correlate to human birth defects and cancer.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('human', 'Species', '9606', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('birth defects', 'Disease', 'MESH:D000014', (55, 68))	('Wnt pathway', 'Pathway', (24, 35))	('birth defects', 'Disease', (55, 68))	('mutations', 'Var', (7, 16))
23821	27027349	This effect was found to be mediated via an increased production of reactive oxygen species due to GSH/GSSG imbalance.	('imbalance', 'Var', (108, 117))	('imbalance', 'Phenotype', 'HP:0002172', (108, 117))	('production of reactive oxygen species', 'MPA', (54, 91))	('GSSG', 'Chemical', 'MESH:D019803', (103, 107))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (68, 91))	('GSH', 'Chemical', '-', (99, 102))	('increased', 'PosReg', (44, 53))	('increased production of reactive oxygen', 'Phenotype', 'HP:0025464', (44, 83))
23841	27027349	In another in vivo study withnimbolide in the DMBA-painted buccal pouch of hamster, nimbolidetreatment increased the levels of various antioxidant enzymes (glutathione peroxidase, gamma-glutamyltranspeptidase, superoxide dismutase, and catalase) compared to control group.	('nimbolide', 'Chemical', 'MESH:C042198', (84, 93))	('DMBA', 'Chemical', 'MESH:D015127', (46, 50))	('increased', 'PosReg', (103, 112))	('hamster', 'Species', '10034', (75, 82))	('nimbolidetreatment', 'Var', (84, 102))	('gamma-glutamyltranspeptidase', 'MPA', (180, 208))	('superoxide dismutase', 'MPA', (210, 230))	('levels of', 'MPA', (117, 126))	('catalase', 'Gene', (236, 244))	('glutathione', 'Chemical', 'MESH:D005978', (156, 167))	('antioxidant enzymes', 'MPA', (135, 154))	('nimbolide', 'Chemical', 'MESH:C042198', (29, 38))	('catalase', 'Gene', '24248', (236, 244))
23898	24708595	Circulating cell-free methylated DNA and lactate dehydrogenase release in colorectal cancer Hypermethylation of DNA is an epigenetic alteration commonly found in colorectal cancer (CRC) and can also be detected in blood samples of cancer patients.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('CRC', 'Phenotype', 'HP:0003003', (181, 184))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (162, 179))	('cancer', 'Disease', (231, 237))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('DNA', 'Gene', (112, 115))	('Hypermethylation', 'Var', (92, 108))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('patients', 'Species', '9606', (238, 246))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('colorectal cancer', 'Disease', 'MESH:D015179', (162, 179))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('colorectal cancer', 'Disease', 'MESH:D015179', (74, 91))	('colorectal cancer', 'Disease', (162, 179))	('colorectal cancer', 'Disease', (74, 91))
23899	24708595	Methylation of the genes helicase-like transcription factor (HLTF) and hyperplastic polyposis 1 (HPP1) have been proposed as prognostic, and neurogenin 1 (NEUROG1) as diagnostic biomarker.	('HLTF', 'Gene', (61, 65))	('neurogenin 1', 'Gene', (141, 153))	('NEUROG1', 'Gene', '4762', (155, 162))	('hyperplastic polyposis', 'Phenotype', 'HP:0012183', (71, 93))	('Methylation', 'Var', (0, 11))	('hyperplastic polyposis', 'Disease', (71, 93))	('NEUROG1', 'Gene', (155, 162))	('hyperplastic polyposis', 'Disease', 'MESH:D011125', (71, 93))	('neurogenin 1', 'Gene', '4762', (141, 153))	('HLTF', 'Gene', '6596', (61, 65))
23903	24708595	Hypermethylation of HLTF and HPP1 was detected significantly more often in patients with elevated LDH levels (32% vs. 12% [p = 0.0005], and 68% vs. 11% [p < 0.0001], respectively).	('detected', 'Reg', (38, 46))	('HLTF', 'Gene', '6596', (20, 24))	('HLTF', 'Gene', (20, 24))	('Hypermethylation', 'Var', (0, 16))	('patients', 'Species', '9606', (75, 83))	('HPP1', 'Gene', (29, 33))	('LDH levels', 'MPA', (98, 108))
23906	24708595	Concerning the clinical characteristics, high levels of LDH as well as methylation of HLTF and HPP1 were significantly associated with larger and more advanced stages of CRC.	('methylation', 'Var', (71, 82))	('associated with', 'Reg', (119, 134))	('CRC', 'Disease', (170, 173))	('high', 'Var', (41, 45))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('HLTF', 'Gene', '6596', (86, 90))	('HLTF', 'Gene', (86, 90))	('LDH', 'Protein', (56, 59))	('CRC', 'Phenotype', 'HP:0003003', (170, 173))	('HPP1', 'Gene', (95, 99))
23908	24708595	We were able to provide evidence that methylation of HLTF and especially HPP1 detected in serum is strongly correlated with cell death in CRC using LDH as surrogate marker.	('HPP1', 'Gene', (73, 77))	('CRC', 'Disease', (138, 141))	('methylation', 'Var', (38, 49))	('CRC', 'Phenotype', 'HP:0003003', (138, 141))	('cell death', 'CPA', (124, 134))	('correlated with', 'Reg', (108, 123))	('HLTF', 'Gene', '6596', (53, 57))	('HLTF', 'Gene', (53, 57))
23914	24708595	In many human cancers aberrant hypermethylation of CpG islands is a common epigenetic DNA modification leading to transcriptional silencing of genes that is already detectable in early stages of carcinogenesis.	('cancers', 'Disease', (14, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('transcriptional', 'MPA', (114, 129))	('CpG islands', 'Gene', (51, 62))	('carcinogenesis', 'Disease', 'MESH:D063646', (195, 209))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('carcinogenesis', 'Disease', (195, 209))	('aberrant hypermethylation', 'Var', (22, 47))	('DNA modification', 'biological_process', 'GO:0006304', ('86', '102'))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('human', 'Species', '9606', (8, 13))	('cancers', 'Disease', 'MESH:D009369', (14, 21))
23915	24708595	Genes found hypermethylated in colorectal cancer have many functions, including mismatch repair, cell-cycle regulation and cell differentiation.	('colorectal cancer', 'Disease', 'MESH:D015179', (31, 48))	('hypermethylated', 'Var', (12, 27))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (31, 48))	('mismatch repair', 'CPA', (80, 95))	('cell-cycle regulation', 'CPA', (97, 118))	('colorectal cancer', 'Disease', (31, 48))	('cell differentiation', 'CPA', (123, 143))
23916	24708595	Methylated tumor DNA cannot only be found in primary colorectal cancer tissue, but can also be detected in remote media like serum or stool and potentially be used as biomarkers for various purposes.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('colorectal cancer', 'Disease', 'MESH:D015179', (53, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (53, 70))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('Methylated', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('colorectal cancer', 'Disease', (53, 70))
23917	24708595	We have previously described methylation of the genes neurogenin 1 (NEUROG1) in serum and HIC1 in stool as diagnostic markers and helicase-like transcription factor (HLTF) and hyperplastic polyposis 1 (HPP1), also known as transmembrane protein with EGF-like and two follistatin-like domains 2 (TMEFF2), as prognostic serum markers.	('transcription factor', 'molecular_function', 'GO:0000981', ('144', '164'))	('HIC1', 'Gene', (90, 94))	('TMEFF2', 'Gene', '23671', (295, 301))	('EGF', 'molecular_function', 'GO:0005154', ('250', '253'))	('hyperplastic polyposis', 'Phenotype', 'HP:0012183', (176, 198))	('methylation', 'biological_process', 'GO:0032259', ('29', '40'))	('transmembrane', 'cellular_component', 'GO:0016021', ('223', '236'))	('transcription', 'biological_process', 'GO:0006351', ('144', '157'))	('HLTF', 'Gene', '6596', (166, 170))	('HIC1', 'Gene', '3090', (90, 94))	('transmembrane', 'cellular_component', 'GO:0044214', ('223', '236'))	('NEUROG1', 'Gene', (68, 75))	('methylation', 'Var', (29, 40))	('protein', 'cellular_component', 'GO:0003675', ('237', '244'))	('neurogenin 1', 'Gene', '4762', (54, 66))	('TMEFF2', 'Gene', (295, 301))	('NEUROG1', 'Gene', '4762', (68, 75))	('HLTF', 'Gene', (166, 170))	('hyperplastic polyposis', 'Disease', (176, 198))	('transmembrane protein with EGF-like and two follistatin-like domains 2', 'Gene', '23671', (223, 293))	('neurogenin 1', 'Gene', (54, 66))	('hyperplastic polyposis', 'Disease', 'MESH:D011125', (176, 198))
23919	24708595	Moreover NEUROG1 has been described to be frequently hypermethylated in colorectal cancers and has been proposed as a marker to classify the CpG-island methylator phenotype in colorectal cancers.	('hypermethylated', 'Var', (53, 68))	('NEUROG1', 'Gene', '4762', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('colorectal cancer', 'Phenotype', 'HP:0003003', (176, 193))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('colorectal cancers', 'Disease', 'MESH:D015179', (72, 90))	('colorectal cancers', 'Disease', 'MESH:D015179', (176, 194))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('colorectal cancers', 'Disease', (72, 90))	('colorectal cancers', 'Disease', (176, 194))	('NEUROG1', 'Gene', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))
23923	24708595	Hypermethylation of HLTF can commonly be found in all stages of CRC as well as in adenomas and is associated with tumor size, stage and poor prognosis.	('found', 'Reg', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('HLTF', 'Gene', '6596', (20, 24))	('HLTF', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('Hypermethylation', 'Var', (0, 16))	('adenomas', 'Disease', 'MESH:D000236', (82, 90))	('tumor', 'Disease', (114, 119))	('adenomas', 'Disease', (82, 90))	('CRC', 'Disease', (64, 67))	('associated', 'Reg', (98, 108))	('CRC', 'Phenotype', 'HP:0003003', (64, 67))
23924	24708595	Besides its occurrence in serum, methylated HLTF has also been detected in stool samples of CRC patients.	('detected', 'Reg', (63, 71))	('CRC', 'Disease', (92, 95))	('patients', 'Species', '9606', (96, 104))	('HLTF', 'Gene', '6596', (44, 48))	('HLTF', 'Gene', (44, 48))	('methylated', 'Var', (33, 43))	('CRC', 'Phenotype', 'HP:0003003', (92, 95))
23925	24708595	While reported to function as a tumor suppressor related to the STAT1 pathway earlier, a recently published study failed to identify tumors in HPP1 mutant mice.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor suppressor', 'biological_process', 'GO:0051726', ('32', '48'))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('STAT1', 'Gene', '20846', (64, 69))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('32', '48'))	('mutant', 'Var', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('HPP1', 'Gene', (143, 147))	('tumor', 'Disease', (133, 138))	('mice', 'Species', '10090', (155, 159))	('tumor', 'Disease', (32, 37))	('STAT1', 'Gene', (64, 69))
23926	24708595	Hypermethylation of HPP1 can be detected already early in colorectal carcinogenesis.	('HPP1', 'Gene', (20, 24))	('colorectal carcinogenesis', 'Disease', (58, 83))	('Hypermethylation', 'Var', (0, 16))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (58, 83))
23927	24708595	Hyperplastic polyps and ulcerative colitis associated dysplasias as well as a several other tumor entities, including Barrett's-associated esophageal adenocarcinoma, gastric adenocarcinoma, bladder cancer, non-small cell lung cancer and others, frequently showed HPP1 methylation.	('methylation', 'biological_process', 'GO:0032259', ('268', '279'))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (206, 232))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (24, 42))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (166, 188))	('bladder cancer', 'Disease', 'MESH:D001749', (190, 204))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (210, 232))	('polyps', 'Disease', (13, 19))	('bladder cancer', 'Disease', (190, 204))	('HPP1', 'Gene', (263, 267))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('colitis', 'Phenotype', 'HP:0002583', (35, 42))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (206, 232))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('bladder cancer', 'Phenotype', 'HP:0009725', (190, 204))	('ulcerative colitis', 'Disease', (24, 42))	('dysplasias', 'Disease', 'MESH:D004476', (54, 64))	('methylation', 'Var', (268, 279))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (139, 164))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (139, 164))	('polyps', 'Disease', 'MESH:D011127', (13, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (221, 232))	('gastric adenocarcinoma', 'Disease', (166, 188))	('non-small cell lung cancer', 'Disease', (206, 232))	('showed', 'Reg', (256, 262))	('ulcerative colitis', 'Disease', 'MESH:D003093', (24, 42))	('esophageal adenocarcinoma', 'Disease', (139, 164))	('dysplasias', 'Disease', (54, 64))	('tumor', 'Disease', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
23949	24708595	Methylation of HLTF was detected in 41 cases (16%), methylation of HPP1 in 57 cases (22%) and methylation of NEUROG1 in 66 cases (25%).	('methylation', 'biological_process', 'GO:0032259', ('94', '105'))	('detected', 'Reg', (24, 32))	('Methylation', 'MPA', (0, 11))	('NEUROG1', 'Gene', '4762', (109, 116))	('methylation', 'MPA', (52, 63))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('HPP1', 'Gene', (67, 71))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('HLTF', 'Gene', '6596', (15, 19))	('HLTF', 'Gene', (15, 19))	('methylation', 'Var', (94, 105))	('NEUROG1', 'Gene', (109, 116))
23950	24708595	HLTF methylation in the serum was significantly correlated with metastatic diseases (p = 0.013) and advanced tumor stages (p = 0.0489) as well as T4 tumors (T1-3 vs. T4, p = 0.046).	('methylation', 'Var', (5, 16))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('HLTF', 'Gene', (0, 4))	('HLTF', 'Gene', '6596', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('metastatic diseases', 'CPA', (64, 83))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumor', 'Disease', (149, 154))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('correlated', 'Reg', (48, 58))	('methylation', 'biological_process', 'GO:0032259', ('5', '16'))	('tumor', 'Disease', (109, 114))
23951	24708595	HPP1 methylation in serum was significantly correlated with larger tumor size (p < 0.001), positive nodal status (p < 0.0001), metastatic disease (p < 0.0001), tumor stage (p < .0001) as well as higher tumor grades (p = 0.0002).	('methylation', 'Var', (5, 16))	('tumor', 'Disease', (202, 207))	('metastatic disease', 'CPA', (127, 145))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('correlated', 'Reg', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('positive nodal status', 'CPA', (91, 112))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', (160, 165))	('HPP1', 'Gene', (0, 4))
23957	24708595	In the 50 samples with elevated LDH levels, methylation of HLTF, HPP1, or NEUROG1 was detected in 16 (32%), 34 (68%), or 12 cases (24%), respectively, compared to 25 (12%), 23 (11%), or 54 (26%) in those 209 samples with normal LDH levels.	('HLTF', 'Gene', '6596', (59, 63))	('HPP1', 'Gene', (65, 69))	('NEUROG1', 'Gene', (74, 81))	('methylation', 'Var', (44, 55))	('HLTF', 'Gene', (59, 63))	('detected', 'Reg', (86, 94))	('NEUROG1', 'Gene', '4762', (74, 81))	('LDH levels', 'MPA', (32, 42))	('methylation', 'biological_process', 'GO:0032259', ('44', '55'))
23959	24708595	Methylation of HLTF was found significantly more often in HPP1 positive samples (51% vs. 17%, p < 0.0001).	('HPP1', 'Gene', (58, 62))	('Methylation', 'Var', (0, 11))	('positive', 'Reg', (63, 71))	('HLTF', 'Gene', '6596', (15, 19))	('HLTF', 'Gene', (15, 19))	('found', 'Reg', (24, 29))
23960	24708595	No significant difference in the frequency of either HLTF or HPP1 methylation was observed between NEUROG1 positive and NEUROG1 negative cases (32% vs. 24% and 26% vs. 25%, respectively).	('NEUROG1', 'Gene', (99, 106))	('NEUROG1', 'Gene', (120, 127))	('NEUROG1', 'Gene', '4762', (99, 106))	('NEUROG1', 'Gene', '4762', (120, 127))	('methylation', 'Var', (66, 77))	('HPP1', 'Gene', (61, 65))	('HLTF', 'Gene', '6596', (53, 57))	('HLTF', 'Gene', (53, 57))
23961	24708595	Patients with methylation of HLTF had slightly, but still significantly higher LDH levels (median 208 U/l vs. 180 U/l, p = 0.0050), while no difference was found in LDH levels between NEUROG1 positive and negative samples (median 187 U/L vs. 184 U/l, p = 0.95).	('NEUROG1', 'Gene', '4762', (184, 191))	('LDH levels', 'MPA', (79, 89))	('NEUROG1', 'Gene', (184, 191))	('Patients', 'Species', '9606', (0, 8))	('methylation', 'Var', (14, 25))	('HLTF', 'Gene', '6596', (29, 33))	('HLTF', 'Gene', (29, 33))	('higher', 'PosReg', (72, 78))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))
23966	24708595	We earlier reported methylation of HLTF and HPP1 to be independent prognostic markers in metastastatic colorectal cancer.	('metastastatic colorectal cancer', 'Disease', 'MESH:D015179', (89, 120))	('metastastatic colorectal cancer', 'Disease', (89, 120))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('HLTF', 'Gene', '6596', (35, 39))	('HLTF', 'Gene', (35, 39))	('HPP1', 'Gene', (44, 48))	('methylation', 'Var', (20, 31))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))
23968	24708595	As reported earlier methylation of HLTF and HPP1 was associated with a higher mortality.	('HLTF', 'Gene', '6596', (35, 39))	('HLTF', 'Gene', (35, 39))	('HPP1', 'Gene', (44, 48))	('methylation', 'Var', (20, 31))	('associated', 'Reg', (53, 63))
23969	24708595	In the current study, the median survival was 6.4 years (95% CI 4.9-9.0) and 8.0 years (95% CI 6.1-11.2) for HLTF- and HPP1-negative cases compared to 3.7 years (95% CI 1.1-5.2) and 1.2 years (95% CI 0.9-1.9) in case of positivity for HLTF or HPP1 methylation (p = 0.0008 and p < 0.0001), respectively (Figure 2A, 2B).	('HPP1', 'Gene', (243, 247))	('HLTF', 'Gene', '6596', (235, 239))	('HLTF', 'Gene', (235, 239))	('methylation', 'biological_process', 'GO:0032259', ('248', '259'))	('methylation', 'Var', (248, 259))	('HLTF', 'Gene', '6596', (109, 113))	('HLTF', 'Gene', (109, 113))
23972	24708595	However, in stage IV HLTF methylation positive patients showed a median survival of 0.86 years (95% CI 0.5-1.2) versus 1.6 years (95% CI 1.2-2.3) for HLTF negative cases (p = 0.0081; Figure 2D).	('HLTF', 'Gene', '6596', (21, 25))	('HLTF', 'Gene', (21, 25))	('HLTF', 'Gene', '6596', (150, 154))	('HLTF', 'Gene', (150, 154))	('patients', 'Species', '9606', (47, 55))	('positive', 'Var', (38, 46))	('methylation positive', 'Var', (26, 46))
23974	24708595	Our data confirm our previous findings that methylation of HLTF or HPP1 in serum is found more often in patients with advanced stages of colorectal cancer, especially in those with distant metastases, whereas no correlation between methylation of NEUROG1 and any clinicopathologic data was found.	('HLTF', 'Gene', '6596', (59, 63))	('metastases', 'Disease', (189, 199))	('NEUROG1', 'Gene', (247, 254))	('methylation', 'Var', (44, 55))	('metastases', 'Disease', 'MESH:D009362', (189, 199))	('colorectal cancer', 'Disease', (137, 154))	('HLTF', 'Gene', (59, 63))	('found', 'Reg', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('colorectal cancer', 'Disease', 'MESH:D015179', (137, 154))	('HPP1', 'Gene', (67, 71))	('NEUROG1', 'Gene', '4762', (247, 254))	('patients', 'Species', '9606', (104, 112))	('colorectal cancer', 'Phenotype', 'HP:0003003', (137, 154))
23975	24708595	While methylation of HLTF was only correlated with metastastatic disease, methylation of HPP1 was also associated with local tumor extent and nodal status as well as tumor grade with high statistic significance.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('methylation', 'Var', (74, 85))	('HLTF', 'Gene', '6596', (21, 25))	('metastastatic disease', 'Disease', (51, 72))	('HLTF', 'Gene', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('associated', 'Reg', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', (125, 130))	('methylation', 'Var', (6, 17))	('metastastatic disease', 'Disease', 'MESH:D004194', (51, 72))	('HPP1', 'Gene', (89, 93))
23980	24708595	In this study we found methylation of HLTF and, even to a higher degree, HPP1 to be correlated with elevated LDH levels.	('HPP1', 'Gene', (73, 77))	('HLTF', 'Gene', '6596', (38, 42))	('HLTF', 'Gene', (38, 42))	('methylation', 'Var', (23, 34))	('methylation', 'biological_process', 'GO:0032259', ('23', '34'))	('elevated', 'PosReg', (100, 108))	('LDH levels', 'MPA', (109, 119))
23989	24708595	In conclusion we were able to provide evidence that methylation of HLTF and especially HPP1 detected in serum is strongly correlated with cell death in colorectal cancer using LDH as surrogate marker.	('HPP1', 'Gene', (87, 91))	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('correlated with', 'Reg', (122, 137))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('cell death', 'CPA', (138, 148))	('methylation', 'Var', (52, 63))	('colorectal cancer', 'Disease', (152, 169))	('cell death', 'biological_process', 'GO:0008219', ('138', '148'))	('HLTF', 'Gene', '6596', (67, 71))	('HLTF', 'Gene', (67, 71))
23998	24317430	Collectively, this present study has shown that rice bran IP6 induces apoptosis, by regulating the pro- and anti-apoptotic markers; Bax and Bcl-xl and via the activation of caspase molecules (caspase-3 and -8).	('activation', 'PosReg', (159, 169))	('induces', 'PosReg', (62, 69))	('Bax', 'Gene', (132, 135))	('Bcl-xl', 'Gene', '598', (140, 146))	('caspase', 'Gene', '834;841;842', (192, 199))	('caspase', 'Gene', (192, 199))	('apoptosis', 'biological_process', 'GO:0097194', ('70', '79'))	('Bax', 'Gene', '581', (132, 135))	('Bcl-xl', 'Gene', (140, 146))	('apoptosis', 'biological_process', 'GO:0006915', ('70', '79'))	('caspase', 'Gene', '834;841;842', (173, 180))	('apoptosis', 'CPA', (70, 79))	('rice', 'Species', '4530', (48, 52))	('IP6', 'Var', (58, 61))	('IP6', 'Chemical', 'MESH:D010833', (58, 61))	('regulating', 'Reg', (84, 94))	('caspase', 'Gene', (173, 180))
24001	24317430	Cancer generally occurs through a multistep sequence of events where the genomes of new tumor cells inherit, alter and/or acquire mutant alleles of oncogenes, tumor suppressor genes, and other genes that control cell proliferation process and have abnormal regulation compared to normal cells.	('oncogenes', 'Gene', (148, 157))	('tumor suppressor', 'biological_process', 'GO:0051726', ('159', '175'))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('alter', 'Reg', (109, 114))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('159', '175'))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('cell proliferation', 'biological_process', 'GO:0008283', ('212', '230'))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('regulation', 'biological_process', 'GO:0065007', ('257', '267'))	('mutant', 'Var', (130, 136))	('tumor', 'Disease', (88, 93))	('regulation', 'MPA', (257, 267))
24019	24317430	IP6 has been shown to inhibit the growth of a wide variety of tumor cells in multiple experimental model systems.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('inhibit', 'NegReg', (22, 29))	('tumor', 'Disease', (62, 67))	('men', 'Species', '9606', (92, 95))	('IP6', 'Var', (0, 3))	('IP6', 'Chemical', 'MESH:D010833', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
24024	24317430	Initially, we proved strong evidence that IP6 showed an increase of early apoptosis in HT-29 cells using Annexin V assay.	('IP6', 'Var', (42, 45))	('IP6', 'Chemical', 'MESH:D010833', (42, 45))	('HT-29 cells', 'CellLine', 'CVCL:0320', (87, 98))	('increase', 'PosReg', (56, 64))	('early apoptosis', 'CPA', (68, 83))
24025	24317430	IP6 elicited its growth inhibitory effects by increasing the total number of apoptosis; 9%, 22% and 41% following 9.5, 12.0 or 14.5 mug/mL of IP6, respectively, relative to the control in a dose-dependent manner after 24 h of incubation.	('increasing', 'PosReg', (46, 56))	('IP6', 'Chemical', 'MESH:D010833', (142, 145))	('mug', 'molecular_function', 'GO:0043739', ('132', '135'))	('apoptosis', 'CPA', (77, 86))	('growth inhibitory effects', 'MPA', (17, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('IP6', 'Chemical', 'MESH:D010833', (0, 3))	('IP6', 'Var', (142, 145))
24028	24317430	We further examined the molecular mechanism by which IP6 induces apoptotic cell death in HT-29 cells at mRNA and protein levels.	('induces', 'Reg', (57, 64))	('IP6', 'Var', (53, 56))	('IP6', 'Chemical', 'MESH:D010833', (53, 56))	('apoptotic cell death', 'CPA', (65, 85))	('HT-29 cells', 'CellLine', 'CVCL:0320', (89, 100))
24035	24317430	Notably, IP6 upregulated the transcript of the pro-apoptotic gene, Bax and downregulated the transcription of the anti-apoptotic gene, Bcl-xl by several fold.	('Bcl-xl', 'Gene', (135, 141))	('transcript', 'MPA', (29, 39))	('downregulated', 'NegReg', (75, 88))	('IP6', 'Var', (9, 12))	('IP6', 'Chemical', 'MESH:D010833', (9, 12))	('upregulated', 'PosReg', (13, 24))	('transcription', 'MPA', (93, 106))	('Bcl-xl', 'Gene', '598', (135, 141))	('Bax', 'Gene', '581', (67, 70))	('Bax', 'Gene', (67, 70))
24041	24317430	It was clearly shown that IP6 upregulated the transcript of caspase-8 and -3 at mRNA level by several folds.	('transcript', 'MPA', (46, 56))	('upregulated', 'PosReg', (30, 41))	('caspase-8 and -3', 'Gene', '841;836', (60, 76))	('IP6', 'Var', (26, 29))	('IP6', 'Chemical', 'MESH:D010833', (26, 29))
24044	24317430	Together, these data suggest that IP6 caused a marked increase in apoptosis, which was accompanied by upregulation of caspase-8 and caspase-3 expression at mRNA level.	('caspase-3', 'Protein', (132, 141))	('caspase-8', 'Gene', (118, 127))	('apoptosis', 'CPA', (66, 75))	('upregulation', 'PosReg', (102, 114))	('expression', 'MPA', (142, 152))	('caspase-8', 'Gene', '841', (118, 127))	('IP6', 'Var', (34, 37))	('IP6', 'Chemical', 'MESH:D010833', (34, 37))
24046	24317430	Pro-apoptotic, Bax protein level, which was detected as a 23 kDa band, was significantly (p < 0.05) increased after IP6 treatment of HT-29 cells in a dose-dependent manner (Figure 3A).	('increased', 'PosReg', (100, 109))	('Bax', 'Gene', (15, 18))	('men', 'Species', '9606', (125, 128))	('Bax', 'Gene', '581', (15, 18))	('HT-29 cells', 'CellLine', 'CVCL:0320', (133, 144))	('IP6', 'Var', (116, 119))	('IP6', 'Chemical', 'MESH:D010833', (116, 119))
24048	24317430	Furthermore, Bcl-xl which was detected as a 30 kDa band was reduced by 0.21, 0.19 or 0.17 fold after incubation with 9.5, 12.0 or 14.5 mug/mL of IP6, respectively, relative to the control (Figure 3B).	('IP6', 'Var', (145, 148))	('IP6', 'Chemical', 'MESH:D010833', (145, 148))	('Bcl-xl', 'Gene', '598', (13, 19))	('reduced', 'NegReg', (60, 67))	('Bcl-xl', 'Gene', (13, 19))	('mug', 'molecular_function', 'GO:0043739', ('135', '138'))
24050	24317430	Interestingly, caspase-8 and -3 protein expression, detected as 55 and 32 kDa bands respectively, were markedly increased after IP6 treatment of HT-29 cells in a dose-dependent manner as compared to the control (Figure 4A,B).	('expression', 'MPA', (40, 50))	('IP6', 'Chemical', 'MESH:D010833', (128, 131))	('HT-29 cells', 'CellLine', 'CVCL:0320', (145, 156))	('caspase-8 and -3', 'Gene', '841;836', (15, 31))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('increased', 'PosReg', (112, 121))	('men', 'Species', '9606', (137, 140))	('IP6', 'Var', (128, 131))
24057	24317430	Notably, we observed a significant (p < 0.05) increase in the activities of both caspase-8 and -3 following the increment of the dose of IP6, demonstrating a dose-dependent manner (Figure 4C,D).	('increase', 'PosReg', (46, 54))	('activities', 'MPA', (62, 72))	('men', 'Species', '9606', (117, 120))	('IP6', 'Var', (137, 140))	('caspase-8 and -3', 'Gene', '841;836', (81, 97))	('IP6', 'Chemical', 'MESH:D010833', (137, 140))
24071	24317430	Therefore, additional studies are needed to define whether IP6-mediated alteration in Bax and Bcl-xl levels activate mitochondrial damage, leading to cytochrome c release and hence activate caspase in its overall apoptotic response in HT-29 cells.	('cytochrome c', 'Gene', '54205', (150, 162))	('Bcl-xl', 'Gene', (94, 100))	('Bax', 'Gene', '581', (86, 89))	('caspase', 'Gene', (190, 197))	('leading to', 'Reg', (139, 149))	('mitochondrial damage', 'MPA', (117, 137))	('activate', 'PosReg', (181, 189))	('apoptotic', 'CPA', (213, 222))	('HT-29 cells', 'CellLine', 'CVCL:0320', (235, 246))	('activate', 'PosReg', (108, 116))	('Bcl-xl', 'Gene', '598', (94, 100))	('alteration', 'Var', (72, 82))	('Bax', 'Gene', (86, 89))	('cytochrome c', 'Gene', (150, 162))	('caspase', 'Gene', '834;841;842', (190, 197))	('IP6', 'Chemical', 'MESH:D010833', (59, 62))
24076	24317430	This agrees with published data by Sharma et al., who found that IP6 has been shown to significantly increase caspase-3 activity in experimental mouse prostate cancer model.	('prostate cancer', 'Phenotype', 'HP:0012125', (151, 166))	('men', 'Species', '9606', (138, 141))	('caspase-3 activity', 'molecular_function', 'GO:0004208', ('110', '128'))	('mouse', 'Species', '10090', (145, 150))	('increase', 'PosReg', (101, 109))	('caspase-3 activity', 'molecular_function', 'GO:0030693', ('110', '128'))	('prostate cancer', 'Disease', (151, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('activity', 'MPA', (120, 128))	('IP6', 'Var', (65, 68))	('caspase-3', 'Enzyme', (110, 119))	('IP6', 'Chemical', 'MESH:D010833', (65, 68))	('prostate cancer', 'Disease', 'MESH:D011471', (151, 166))
24081	24317430	The activation of caspase-3 induced by IP6 in HT-29 cells also suggested that an alternative pathway of inducing apoptosis might have been activated.	('caspase-3', 'Protein', (18, 27))	('HT-29 cells', 'CellLine', 'CVCL:0320', (46, 57))	('IP6', 'Chemical', 'MESH:D010833', (39, 42))	('IP6', 'Var', (39, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('113', '122'))	('activation', 'PosReg', (4, 14))	('apoptosis', 'biological_process', 'GO:0006915', ('113', '122'))
24087	24317430	Another pathway is that caspase-8 cleaves procaspase-3 directly and activates it.	('caspase-8', 'Gene', (24, 33))	('cleaves', 'Var', (34, 41))	('caspase-8', 'Gene', '841', (24, 33))	('procaspase-3', 'Gene', (42, 54))	('activates', 'PosReg', (68, 77))	('procaspase-3', 'Gene', '836', (42, 54))
24088	24317430	However, further analyses are needed to determine which pathway triggers caspase-3 activation by IP6.	('IP6', 'Chemical', 'MESH:D010833', (97, 100))	('caspase-3', 'Protein', (73, 82))	('IP6', 'Var', (97, 100))
24089	24317430	Recently we showed IP6 reduced the tumor number by modulating the wnt/beta-catenin pathway during azoxymethane-induced colon cancer in rats.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('wnt', 'Gene', (66, 69))	('colon cancer', 'Phenotype', 'HP:0003003', (119, 131))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('azoxymethane', 'Chemical', 'MESH:D001397', (98, 110))	('beta-catenin', 'Gene', (70, 82))	('wnt', 'Gene', '114487', (66, 69))	('colon cancer', 'Disease', 'MESH:D015179', (119, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', (35, 40))	('modulating', 'Reg', (51, 61))	('colon cancer', 'Disease', (119, 131))	('IP6', 'Chemical', 'MESH:D010833', (19, 22))	('IP6', 'Var', (19, 22))	('beta-catenin', 'Gene', '84353', (70, 82))	('rats', 'Species', '10116', (135, 139))	('reduced', 'NegReg', (23, 30))
24107	24317430	10 muL of each sample was mixed with 1.0 muL of loading dye [10 mM Tris-HCl (pH 7.6), 0.03% bromophenol blue, 0.03% xylene cyanol, 60% glycerol, 60 mM EDTA].	('glycerol', 'Chemical', 'MESH:D005990', (135, 143))	('bromophenol blue', 'Chemical', 'MESH:D001978', (92, 108))	('xylene cyanol', 'Chemical', 'MESH:C048951', (116, 129))	('0.03%', 'Var', (86, 91))	('Tris-HCl', 'Chemical', '-', (67, 75))	('0.03', 'Var', (110, 114))	('EDTA', 'Chemical', 'MESH:D004492', (151, 155))
24125	24317430	These results provide molecular evidence for how IP6 may elicit the growth inhibition of colon cancer in vitro.	('IP6', 'Chemical', 'MESH:D010833', (49, 52))	('growth inhibition', 'CPA', (68, 85))	('colon cancer', 'Phenotype', 'HP:0003003', (89, 101))	('colon cancer', 'Disease', 'MESH:D015179', (89, 101))	('colon cancer', 'Disease', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('IP6', 'Var', (49, 52))
24129	23520519	Alterations in Protein kinase C (PKC) isozyme expression and aberrant regulation also comprise early events in intestinal carcinomas.	('aberrant', 'Var', (61, 69))	('regulation', 'MPA', (70, 80))	('Protein kinase C', 'Gene', '112476', (15, 31))	('intestinal carcinomas', 'Disease', 'MESH:D007414', (111, 132))	('Alterations', 'Var', (0, 11))	('Protein kinase C', 'Gene', (15, 31))	('PKC', 'Gene', (33, 36))	('intestinal carcinomas', 'Disease', (111, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('rat', 'Species', '10116', (4, 7))	('expression', 'MPA', (46, 56))	('PKC', 'Gene', '112476', (33, 36))
24131	23520519	Reciprocal co-immunoprecipitation and immunofluorescence studies revealed that PKCdelta interacts specifically with both full-length (from non-malignant cells) and truncated APC protein (from cancerous cells) at the cytoplasm and at the cell nucleus.	('truncated', 'Var', (164, 173))	('APC', 'Phenotype', 'HP:0005227', (174, 177))	('cancerous', 'Disease', 'MESH:D009369', (192, 201))	('interacts', 'Interaction', (88, 97))	('APC protein', 'Protein', (174, 185))	('PKCdelta', 'Enzyme', (79, 87))	('cancerous', 'Disease', (192, 201))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
24134	23520519	These negative effects were confirmed by siRNA-mediated knockdown of PKCdelta and by the expression of a dominant negative form of PKCdelta in RKO cells.	('RKO', 'CellLine', 'CVCL:0504', (143, 146))	('PKCdelta', 'Enzyme', (69, 77))	('knockdown', 'Var', (56, 65))	('negative', 'NegReg', (114, 122))
24143	23520519	Most of these dysplastic ACFs bear APC mutations, whereas nonmalignant hyperplastic ACFs may arise from activating mutations in K-RAS or complementary mutations in the upstream component B-RAF .	('B-RAF', 'Gene', (187, 192))	('dysplastic ACFs bear APC', 'Disease', 'MESH:D011125', (14, 38))	('mutations', 'Var', (115, 124))	('APC', 'Phenotype', 'HP:0005227', (35, 38))	('mutations', 'Var', (39, 48))	('K-RAS', 'Gene', '3845', (128, 133))	('arise from', 'Reg', (93, 103))	('K-RAS', 'Gene', (128, 133))	('dysplastic ACFs bear APC', 'Disease', (14, 38))	('B-RAF', 'Gene', '673', (187, 192))
24157	23520519	We have recently reported that atypical PKCzeta positively modulates canonical Wnt signaling by controlling nuclear beta-catenin localization.	('PKCzeta', 'molecular_function', 'GO:0004697', ('40', '47'))	('modulates', 'Reg', (59, 68))	('PKCzeta', 'Gene', '5590', (40, 47))	('canonical Wnt signaling', 'Pathway', (69, 92))	('PKCzeta', 'Gene', (40, 47))	('signaling', 'biological_process', 'GO:0023052', ('83', '92'))	('atypical', 'Var', (31, 39))	('localization', 'biological_process', 'GO:0051179', ('129', '141'))	('controlling', 'Reg', (96, 107))	('beta-catenin', 'Gene', (116, 128))	('beta-catenin', 'Gene', '1499', (116, 128))
24223	23520519	However, it has been reported that they have mutated the Wnt antagonist Naked cuticle 1 (NKD1) which negatively modulates Dvl levels.	('Dvl', 'Gene', (122, 125))	('Naked cuticle', 'Phenotype', 'HP:0030808', (72, 85))	('Dvl', 'Gene', '8215', (122, 125))	('NKD1', 'Gene', '85407', (89, 93))	('Naked cuticle 1', 'Gene', '85407', (72, 87))	('Naked cuticle 1', 'Gene', (72, 87))	('NKD1', 'Gene', (89, 93))	('mutated', 'Var', (45, 52))	('modulates', 'Reg', (112, 121))
24224	23520519	Contrariwise, HT-29 and SW480 human malignant cells express truncated versions of APC, thus altering Wnt signaling (Figure 1A).	('human', 'Species', '9606', (30, 35))	('APC', 'Gene', (82, 85))	('SW480', 'CellLine', 'CVCL:0546', (24, 29))	('Wnt signaling', 'MPA', (101, 114))	('APC', 'Phenotype', 'HP:0005227', (82, 85))	('HT-29', 'CellLine', 'CVCL:0320', (14, 19))	('altering', 'Reg', (92, 100))	('truncated', 'Var', (60, 69))
24240	23520519	Because canonical Wnt signaling activation promotes cell proliferation via the expression of target genes such as C-MYC and CYCLIN D1, we hypothesized that PKCdelta inhibition or its knockdown in Wnt3a-stimulated RKO cells might increase the expression of Wnt target genes and cell proliferation.	('cell proliferation', 'biological_process', 'GO:0008283', ('277', '295'))	('CYCLIN', 'molecular_function', 'GO:0016538', ('124', '130'))	('increase', 'PosReg', (229, 237))	('rat', 'Species', '10116', (64, 67))	('expression', 'MPA', (79, 89))	('RKO', 'CellLine', 'CVCL:0504', (213, 216))	('C-MYC', 'Gene', '4609', (114, 119))	('CYCLIN D1', 'Gene', (124, 133))	('C-MYC', 'Gene', (114, 119))	('cell proliferation', 'CPA', (277, 295))	('promotes', 'PosReg', (43, 51))	('PKCdelta', 'molecular_function', 'GO:0004697', ('156', '164'))	('rat', 'Species', '10116', (289, 292))	('PKCdelta', 'Enzyme', (156, 164))	('knockdown', 'Var', (183, 192))	('cell proliferation', 'biological_process', 'GO:0008283', ('52', '70'))	('cell proliferation', 'CPA', (52, 70))	('signaling', 'biological_process', 'GO:0023052', ('22', '31'))	('CYCLIN D1', 'Gene', '595', (124, 133))	('expression', 'MPA', (242, 252))
24246	23520519	As it can be observed in Figure 3, panel B, the PKCdelta inhibitor increased cell proliferation per se, in the absence of Wnt3a, in comparison with control cells incubated without both the ligand and rottlerin.	('rottlerin', 'Chemical', 'MESH:C085746', (200, 209))	('rat', 'Species', '10116', (89, 92))	('increased', 'PosReg', (67, 76))	('PKCdelta', 'Enzyme', (48, 56))	('cell proliferation', 'CPA', (77, 95))	('inhibitor', 'Var', (57, 66))
24248	23520519	Taken together, these results indicate that PKCdelta negatively affects tumor cell proliferation via negative regulation of Wnt signaling pathway.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('affects', 'Reg', (64, 71))	('Wnt signaling pathway', 'Pathway', (124, 145))	('negatively', 'NegReg', (53, 63))	('PKCdelta', 'Var', (44, 52))	('negative regulation', 'NegReg', (101, 120))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('rat', 'Species', '10116', (90, 93))
24253	23520519	Notably, in each engrafted mouse (n = 5), the weight of the tumor produced at the time of sacrifice by knockdown cells was clearly bigger than the weight of the tumor produced from control cells injected in the same animal (Figure 3C).	('mouse', 'Species', '10090', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('knockdown cells', 'Var', (103, 118))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (60, 65))	('bigger', 'PosReg', (131, 137))	('tumor', 'Disease', (161, 166))
24257	23520519	These cells express wild-type APC but also express a beta-catenin degradation-resistant mutant (S33Y); thus, like SW480 cells, they possess constitutively active beta-catenin transcriptional activity.	('APC', 'Phenotype', 'HP:0005227', (30, 33))	('S33Y', 'Mutation', 'rs121913400', (96, 100))	('beta-catenin', 'Gene', (162, 174))	('beta-catenin', 'Gene', (53, 65))	('beta-catenin', 'Gene', '1499', (162, 174))	('S33Y);', 'Var', (96, 102))	('SW480', 'CellLine', 'CVCL:0546', (114, 119))	('beta-catenin', 'Gene', '1499', (53, 65))
24260	23520519	As it can be observed, beta-catenin transcriptional activity was neither affected in SW480 nor in HCT116 cells expressing a dominant-negative form of PKCdelta or a wild-type PKCdelta, since the small differences observed were not statistically significant.	('SW480', 'CellLine', 'CVCL:0546', (85, 90))	('HCT116', 'CellLine', 'CVCL:0291', (98, 104))	('beta-catenin', 'Gene', (23, 35))	('PKCdelta', 'molecular_function', 'GO:0004697', ('150', '158'))	('SW480', 'Var', (85, 90))	('PKCdelta', 'molecular_function', 'GO:0004697', ('174', '182'))	('beta-catenin', 'Gene', '1499', (23, 35))
24273	23520519	The results presented in Figure 4C indicated that beta-catenin protein levels were increased because of Wnt3a treatment of cells, as expected, but interestingly, these levels were also slightly increased by rottlerin alone at the cytoplasm and at the nuclear fraction, suggesting that PKCdelta inhibition favors beta-catenin stabilization and its translocation to the nuclear compartment.	('protein', 'cellular_component', 'GO:0003675', ('63', '70'))	('increased', 'PosReg', (83, 92))	('beta-catenin', 'Gene', '1499', (50, 62))	('stabilization', 'MPA', (325, 338))	('favors', 'PosReg', (305, 311))	('inhibition', 'Var', (294, 304))	('cytoplasm', 'cellular_component', 'GO:0005737', ('230', '239'))	('beta-catenin', 'Gene', (50, 62))	('PKCdelta', 'molecular_function', 'GO:0004697', ('285', '293'))	('increased', 'PosReg', (194, 203))	('translocation', 'MPA', (347, 360))	('rottlerin', 'Chemical', 'MESH:C085746', (207, 216))	('beta-catenin', 'Gene', (312, 324))	('PKCdelta', 'Enzyme', (285, 293))	('beta-catenin', 'Gene', '1499', (312, 324))
24277	23520519	Taken together, these results suggest that PKCdelta negatively modulates the canonical Wnt pathway, probably acting at the beta-catenin degradation complex.	('negatively', 'NegReg', (52, 62))	('beta-catenin', 'Gene', '1499', (123, 135))	('canonical Wnt pathway', 'Pathway', (77, 98))	('modulates', 'Reg', (63, 72))	('beta-catenin degradation complex', 'cellular_component', 'GO:0030877', ('123', '155'))	('PKCdelta', 'Var', (43, 51))	('PKCdelta', 'molecular_function', 'GO:0004697', ('43', '51'))	('beta-catenin', 'Gene', (123, 135))	('degradation', 'biological_process', 'GO:0009056', ('136', '147'))
24306	23520519	Indeed, the analysis of the crystal structure of a complex between the armadillo repeats 1-5 of beta-catenin and a phosphorylated APC 20 amino acid repeat region revealed that phosphorylation enhances their interaction by 300- to 500-fold).	('phosphorylation', 'biological_process', 'GO:0016310', ('176', '191'))	('beta-catenin', 'Gene', '1499', (96, 108))	('APC', 'Phenotype', 'HP:0005227', (130, 133))	('APC', 'cellular_component', 'GO:0005680', ('130', '133'))	('phosphorylation', 'Var', (176, 191))	('enhances', 'PosReg', (192, 200))	('interaction', 'Interaction', (207, 218))	('complex', 'Interaction', (51, 58))	('beta-catenin', 'Gene', (96, 108))
24323	23520519	Thus, phosphorylation of APC by PKC would induce it to bind tightly to ss-catenin and to prevent the latter from binding to the destruction complex at the cytoplasm and/or to TCF4 at the cell nuclei.	('bind', 'Interaction', (55, 59))	('binding', 'molecular_function', 'GO:0005488', ('113', '120'))	('prevent', 'NegReg', (89, 96))	('PKC', 'molecular_function', 'GO:0004697', ('32', '35'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('155', '164'))	('APC', 'Phenotype', 'HP:0005227', (25, 28))	('induce', 'Reg', (42, 48))	('phosphorylation', 'biological_process', 'GO:0016310', ('6', '21'))	('PKC', 'Gene', (32, 35))	('ss-catenin', 'Chemical', '-', (71, 81))	('PKC', 'Gene', '112476', (32, 35))	('destruction', 'Protein', (128, 139))	('ss-catenin', 'Protein', (71, 81))	('phosphorylation', 'Var', (6, 21))	('APC', 'cellular_component', 'GO:0005680', ('25', '28'))	('binding', 'Interaction', (113, 120))	('TCF4', 'Gene', (175, 179))	('TCF4', 'Gene', '6925', (175, 179))
24325	29127628	KRAS and BRAF are two major oncogenic drivers of colorectal cancer (CRC) that have been frequently described as mutually exclusive, thus the BRAF V600E mutation is not expected to be present in the cases with KRAS mutation.	('BRAF', 'Gene', (141, 145))	('BRAF', 'Gene', (9, 13))	('V600E', 'Var', (146, 151))	('BRAF', 'Gene', '673', (9, 13))	('colorectal cancer', 'Phenotype', 'HP:0003003', (49, 66))	('KRAS', 'Gene', (0, 4))	('colorectal cancer', 'Disease', (49, 66))	('KRAS', 'Gene', '3845', (209, 213))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (49, 66))	('KRAS', 'Gene', (209, 213))	('V600E', 'Mutation', 'rs113488022', (146, 151))	('BRAF', 'Gene', '673', (141, 145))	('KRAS', 'Gene', '3845', (0, 4))
24327	29127628	One-hundred and twenty cases with/without KRAS or BRAF mutations were acquired.	('KRAS', 'Gene', (42, 46))	('BRAF', 'Gene', (50, 54))	('KRAS', 'Gene', '3845', (42, 46))	('mutations', 'Var', (55, 64))	('BRAF', 'Gene', '673', (50, 54))
24331	29127628	Out of 60 cases with KRAS mutation, 56 cases (93.3%) were negative for BRAF V600E mutation by IHC.	('V600E', 'Mutation', 'rs113488022', (76, 81))	('KRAS', 'Gene', '3845', (21, 25))	('BRAF', 'Gene', '673', (71, 75))	('V600E', 'Var', (76, 81))	('BRAF', 'Gene', (71, 75))	('KRAS', 'Gene', (21, 25))
24333	29127628	These cases were confirmed to be negative for BRAF V600E mutation by Sanger sequencing.	('V600E', 'Mutation', 'rs113488022', (51, 56))	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('V600E', 'Var', (51, 56))
24337	29127628	Approximately 35-45% of patients with colorectal tumors have mutation in KRAS gene, while BRAF V600E mutation is found in about 5-15% of colorectal adenocarcinomas.	('BRAF', 'Gene', (90, 94))	('colorectal tumors', 'Disease', 'MESH:D015179', (38, 55))	('KRAS', 'Gene', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('colorectal tumors', 'Disease', (38, 55))	('KRAS', 'Gene', '3845', (73, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('mutation', 'Var', (61, 69))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (137, 163))	('V600E', 'Mutation', 'rs113488022', (95, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('patients', 'Species', '9606', (24, 32))	('BRAF', 'Gene', '673', (90, 94))	('colorectal adenocarcinomas', 'Disease', (137, 163))
24338	29127628	Both these mutations are considered to be oncogenic driver mutations, since they are both responsible for the initiation and maintenance of the tumor.	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('mutations', 'Var', (11, 20))
24341	29127628	The oncogenic mutations in BRAF gene result in constitutive activation of the MAPK signaling pathway, leading to increased cell proliferation, resistance to apoptosis and tumor progression.	('cell proliferation', 'CPA', (123, 141))	('apoptosis', 'biological_process', 'GO:0006915', ('157', '166'))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('cell proliferation', 'biological_process', 'GO:0008283', ('123', '141'))	('MAPK', 'molecular_function', 'GO:0004707', ('78', '82'))	('BRAF', 'Gene', '673', (27, 31))	('signaling pathway', 'biological_process', 'GO:0007165', ('83', '100'))	('activation', 'PosReg', (60, 70))	('apoptosis', 'biological_process', 'GO:0097194', ('157', '166'))	('increased', 'PosReg', (113, 122))	('MAPK signaling pathway', 'Pathway', (78, 100))	('BRAF', 'Gene', (27, 31))	('tumor', 'Disease', (171, 176))	('resistance to apoptosis', 'CPA', (143, 166))	('mutations', 'Var', (14, 23))	('MAPK signaling', 'biological_process', 'GO:0000165', ('78', '92'))
24342	29127628	The most common of these mutations, the V600E mutation, occurs in exon 15 and results in a substitution from valine to glutamic acid at position 600 within the BRAF kinase domain.	('BRAF', 'Gene', (160, 164))	('BRAF', 'Gene', '673', (160, 164))	('V600E', 'Mutation', 'rs113488022', (40, 45))	('results in', 'Reg', (78, 88))	('valine to glutamic acid at position 600', 'Mutation', 'rs113488022', (109, 148))	('V600E', 'Var', (40, 45))
24352	29127628	The most common approach for the detection of BRAF mutation is sequencing of tumor DNA, for example Sanger sequencing, pyrosequencing and high resolution melting.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutation', 'Var', (51, 59))	('tumor', 'Disease', (77, 82))
24353	29127628	In contrast, immunohistochemistry allows direct visualization of the mutant protein in the tumor cells in tissue context.	('mutant', 'Var', (69, 75))	('protein', 'cellular_component', 'GO:0003675', ('76', '83'))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('protein', 'Protein', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
24355	29127628	This antibody is a mutation-specific mouse monoclonal antibody that was raised against a synthetic peptide representing the BRAF V600E mutated amino acid sequence from amino acids 596 to 606 (GLATEKSRWSG).	('V600E', 'Mutation', 'rs113488022', (129, 134))	('mutated', 'Var', (135, 142))	('BRAF', 'Gene', '673', (124, 128))	('mouse', 'Species', '10090', (37, 42))	('BRAF', 'Gene', (124, 128))
24357	29127628	Since concomitant KRAS and BRAF tumor mutations are considered mutually exclusive we wanted to confirm that the CRC cases carrying KRAS mutation show negative BRAF V600E staining by IHC with anti-BRAF V600E (VE1) antibody.	('BRAF tumor', 'Disease', (27, 37))	('BRAF tumor', 'Disease', 'MESH:D009369', (27, 37))	('KRAS', 'Gene', (18, 22))	('BRAF', 'Gene', (159, 163))	('V600E', 'Mutation', 'rs113488022', (201, 206))	('KRAS', 'Gene', (131, 135))	('negative', 'NegReg', (150, 158))	('mutation', 'Var', (136, 144))	('KRAS', 'Gene', '3845', (18, 22))	('BRAF', 'Gene', '673', (196, 200))	('BRAF', 'Gene', '673', (27, 31))	('V600E', 'Mutation', 'rs113488022', (164, 169))	('KRAS', 'Gene', '3845', (131, 135))	('BRAF', 'Gene', (196, 200))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('BRAF', 'Gene', (27, 31))	('BRAF', 'Gene', '673', (159, 163))
24360	29127628	The requested cases included 60 CRC cases with confirmed KRAS mutation, 30 CRC cases with confirmed BRAF V600E mutation and 30 CRC cases confirmed to be wild-type BRAF and wild-type KRAS.	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('CRC', 'Disease', (32, 35))	('KRAS', 'Gene', '3845', (182, 186))	('V600E', 'Mutation', 'rs113488022', (105, 110))	('V600E mutation', 'Var', (105, 119))	('BRAF', 'Gene', '673', (100, 104))	('KRAS', 'Gene', (57, 61))	('mutation', 'Var', (62, 70))	('KRAS', 'Gene', '3845', (57, 61))	('BRAF', 'Gene', (100, 104))	('KRAS', 'Gene', (182, 186))
24367	29127628	The absence/presence of the BRAF V600E mutation in the tissues was confirmed by Sanger sequencing.	('BRAF', 'Gene', (28, 32))	('BRAF', 'Gene', '673', (28, 32))	('V600E', 'Var', (33, 38))	('V600E', 'Mutation', 'rs113488022', (33, 38))
24375	29127628	The equivocal cases were sequenced by Sanger sequencing to confirm the presence/absence of BRAF V600E mutation.	('BRAF', 'Gene', '673', (91, 95))	('BRAF', 'Gene', (91, 95))	('V600E', 'Mutation', 'rs113488022', (96, 101))	('V600E', 'Var', (96, 101))
24382	29127628	These data are consistent with previous reports indicating that majority of tumor cells express mutated BRAF V600E protein, since this mutation is driving tumor proliferation.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('V600E', 'Mutation', 'rs113488022', (109, 114))	('tumor', 'Disease', (155, 160))	('protein', 'Protein', (115, 122))	('BRAF', 'Gene', '673', (104, 108))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))	('BRAF', 'Gene', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('V600E', 'Var', (109, 114))
24390	29127628	Since these four case exhibited ambiguous, non-uniform, heterogeneous and nuclear staining pattern, they were assigned as equivocal for BRAF V600E mutation.	('BRAF', 'Gene', (136, 140))	('BRAF', 'Gene', '673', (136, 140))	('V600E', 'Mutation', 'rs113488022', (141, 146))	('V600E', 'Var', (141, 146))
24397	29127628	These cases were also sequenced for BRAF V600E mutation.	('V600E', 'Var', (41, 46))	('BRAF', 'Gene', (36, 40))	('BRAF', 'Gene', '673', (36, 40))	('V600E', 'Mutation', 'rs113488022', (41, 46))
24398	29127628	All these cases were negative for BRAF V600E mutation by Sanger sequencing.	('BRAF', 'Gene', (34, 38))	('V600E', 'Mutation', 'rs113488022', (39, 44))	('V600E', 'Var', (39, 44))	('BRAF', 'Gene', '673', (34, 38))
24405	29127628	analyzed 52 colorectal carcinomas with known BRAF mutation status determined by pyrosequencing and found that IHC had a low sensitivity (71%) and specificity (74%) for detecting BRAF V600E mutation compared to pyrosequencing (Table 2).	('colorectal carcinomas', 'Disease', 'MESH:D015179', (12, 33))	('colorectal carcinomas', 'Disease', (12, 33))	('V600E', 'Mutation', 'rs113488022', (183, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('V600E', 'Var', (183, 188))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('BRAF', 'Gene', (178, 182))	('BRAF', 'Gene', '673', (178, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (23, 33))
24406	29127628	They concluded that IHC using anti-BRAF V600E (VE1) antibody is not a useful surrogate for detecting BRAF mutation in colorectal carcinoma.	('BRAF', 'Gene', (101, 105))	('BRAF', 'Gene', (35, 39))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (118, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('V600E', 'Mutation', 'rs113488022', (40, 45))	('BRAF', 'Gene', '673', (101, 105))	('V600E', 'Var', (40, 45))	('BRAF', 'Gene', '673', (35, 39))	('colorectal carcinoma', 'Disease', (118, 138))
24421	29127628	In our study all 30 cases with BRAF V600E mutation showed unequivocal positive cytoplasmic staining in 85-100% tumor cells; all 30 cases with wild-type KRAS and BRAF were negative; 6.7% (4/60) cases with KRAS mutation showed heterogeneous, cytoplasmic/nuclear staining at stain intensity 1.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('KRAS', 'Gene', (152, 156))	('V600E', 'Mutation', 'rs113488022', (36, 41))	('tumor', 'Disease', (111, 116))	('KRAS', 'Gene', (204, 208))	('BRAF', 'Gene', (161, 165))	('KRAS', 'Gene', '3845', (152, 156))	('KRAS', 'Gene', '3845', (204, 208))	('BRAF', 'Gene', '673', (161, 165))	('V600E', 'Var', (36, 41))	('BRAF', 'Gene', '673', (31, 35))	('BRAF', 'Gene', (31, 35))
24422	29127628	Therefore, these cases were assigned as equivocal for BRAF V600E mutation.	('BRAF', 'Gene', (54, 58))	('V600E', 'Mutation', 'rs113488022', (59, 64))	('BRAF', 'Gene', '673', (54, 58))	('V600E', 'Var', (59, 64))
24423	29127628	These cases were sequenced and confirmed to be negative for BRAF V600E mutation.	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('V600E', 'Var', (65, 70))	('V600E', 'Mutation', 'rs113488022', (65, 70))
24425	29127628	The results presented in this study are consistent with previous reports indicating that KRAS and BRAF V600E mutation are mutually exclusive.	('V600E', 'Var', (103, 108))	('BRAF', 'Gene', (98, 102))	('BRAF', 'Gene', '673', (98, 102))	('V600E', 'Mutation', 'rs113488022', (103, 108))	('KRAS', 'Gene', (89, 93))	('KRAS', 'Gene', '3845', (89, 93))
24427	29127628	We propose that in the minority of cases with an equivocal staining pattern, additional molecular testing should be done to assess BRAF mutational status.	('mutational', 'Var', (136, 146))	('BRAF', 'Gene', (131, 135))	('BRAF', 'Gene', '673', (131, 135))
24457	28684680	In particular, regarding colorectal cancer patients, V-KI-RAS2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status was considered to drive therapy: patients with a mutated status of KRAS were treated with folinic acid (leucovorin), 5-fluorouracil and oxaliplatin (FOLFOX) or folinic acid (leucovorin), 5-fluorouracil and irinotecan (FOLFIRI) schemes in combination with bevacizumab as up-front therapy.	('rat', 'Species', '10116', (71, 74))	('colorectal cancer', 'Disease', 'MESH:D015179', (25, 42))	('FOLFIRI', 'Chemical', '-', (347, 354))	('sarcoma', 'Disease', 'MESH:D012509', (75, 82))	('irinotecan', 'Chemical', 'MESH:D000077146', (335, 345))	('sarcoma', 'Disease', (75, 82))	('bevacizumab', 'Chemical', 'MESH:D000068258', (384, 395))	('colorectal cancer', 'Disease', (25, 42))	('folinic acid', 'Chemical', 'MESH:D002955', (219, 231))	('folinic acid', 'Chemical', 'MESH:D002955', (289, 301))	('mutated', 'Var', (178, 185))	('patients', 'Species', '9606', (162, 170))	('FOLFOX', 'Chemical', '-', (278, 284))	('leucovorin', 'Chemical', 'MESH:D002955', (233, 243))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (265, 276))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (246, 260))	('patients', 'Species', '9606', (43, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (75, 82))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (316, 330))	('colorectal cancer', 'Phenotype', 'HP:0003003', (25, 42))	('leucovorin', 'Chemical', 'MESH:D002955', (303, 313))	('KRAS', 'Gene', (196, 200))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
24458	28684680	Conversely, patients with KRAS wild type status, already treated with Epidermal Growth Factor Receptor (EGFR) inhibitors plus FOLFOX or FOLFIRI, were considered suitable for the second-line bevacizumab-based chemotherapy.	('patients', 'Species', '9606', (12, 20))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (70, 102))	('bevacizumab', 'Chemical', 'MESH:D000068258', (190, 201))	('EGFR', 'Gene', (104, 108))	('FOLFIRI', 'Chemical', '-', (136, 143))	('Epidermal Growth Factor Receptor', 'Gene', (70, 102))	('FOLFOX', 'Chemical', '-', (126, 132))	('inhibitors', 'Var', (110, 120))	('EGFR', 'Gene', '1956', (104, 108))
24473	28684680	Normalization also reduces intratumoral pressure, which improves the penetration of macromolecules such as chemotherapy.	('Normalization', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('rat', 'Species', '10116', (74, 77))	('rat', 'Species', '10116', (30, 33))	('reduces intratumoral pressure', 'Phenotype', 'HP:0012641', (19, 48))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('reduces', 'NegReg', (19, 26))	('improves', 'PosReg', (56, 64))	('penetration of macromolecules', 'MPA', (69, 98))
24549	28684680	In addition, the combination of bevacizumab and FOLFOX4 resulted in a statistically significant improvement in progression-free survival (PFS) compared with those treated with chemotherapy alone (7.3 vs. 4.7 months; hazard ratio for progression = 0.61; p < 0.0001).	('progression-free', 'MPA', (111, 127))	('bevacizumab', 'Chemical', 'MESH:D000068258', (32, 43))	('FOLFOX4', 'Chemical', '-', (48, 55))	('men', 'Species', '9606', (103, 106))	('FOLFOX4', 'Var', (48, 55))	('combination', 'Interaction', (17, 28))	('rat', 'Species', '10116', (223, 226))	('improvement', 'PosReg', (96, 107))
24562	28684680	The denaturation of membrane proteins alters the permeability of tumor cells and permits the easier entrance of chemotherapeutic agents, which have already arrived in greater tumor quantity due to HT-induced vasodilation, damaging them irreversibly and leading to necrosis or apoptosis.	('necrosis', 'biological_process', 'GO:0008220', ('264', '272'))	('necrosis', 'Disease', (264, 272))	('apoptosis', 'biological_process', 'GO:0097194', ('276', '285'))	('necrosis', 'biological_process', 'GO:0070265', ('264', '272'))	('necrosis', 'biological_process', 'GO:0019835', ('264', '272'))	('apoptosis', 'biological_process', 'GO:0006915', ('276', '285'))	('tumor', 'Disease', (65, 70))	('necrosis', 'biological_process', 'GO:0001906', ('264', '272'))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (175, 180))	('denaturation', 'Var', (4, 16))	('HT', 'Phenotype', 'HP:0001945', (197, 199))	('leading to', 'Reg', (253, 263))	('permeability', 'MPA', (49, 61))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('membrane', 'cellular_component', 'GO:0016020', ('20', '28'))	('necrosis', 'biological_process', 'GO:0008219', ('264', '272'))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('damaging', 'NegReg', (222, 230))	('alters', 'Reg', (38, 44))	('necrosis', 'Disease', 'MESH:D009336', (264, 272))	('vasodilation', 'biological_process', 'GO:0042311', ('208', '220'))	('rat', 'Species', '10116', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('apoptosis', 'CPA', (276, 285))
24643	27923268	In most studies, it has been reported that salt and salty foods can increase the incidence of this cancer, while the consumption of fruits, fresh vegetables, and fish can have a protective effect.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('salt', 'Var', (43, 47))	('increase', 'PosReg', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('salty foods', 'Phenotype', 'HP:0030083', (52, 63))
24670	27923268	Physical activity and maintaining an ideal weight can lead to a significant decrease in the incidence of colorectal cancer, as physically active people are 20 to 30% less affected by this cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('colorectal cancer', 'Disease', 'MESH:D015179', (105, 122))	('people', 'Species', '9606', (145, 151))	('Physical', 'Var', (0, 8))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('cancer', 'Disease', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('decrease', 'NegReg', (76, 84))	('colorectal cancer', 'Disease', (105, 122))
24702	27980680	The depletion of the Nup93 sub-complex significantly upregulated HOXA gene expression levels.	('Nup93', 'Gene', (21, 26))	('depletion', 'Var', (4, 13))	('HOXA', 'Gene', (65, 69))	('upregulated', 'PosReg', (53, 64))	('HOXA', 'Gene', '3197', (65, 69))
24705	27980680	Consistently, Nup93 knockdown increased active histone marks (H3K9ac), decreased repressive histone marks (H3K27me3) on the HOXA1 promoter and increased transcription elongation marks (H3K36me3) within the HOXA1 gene.	('HOXA1', 'Gene', (206, 211))	('increased', 'PosReg', (143, 152))	('repressive histone marks', 'MPA', (81, 105))	('HOXA1', 'Gene', (124, 129))	('H3', 'Chemical', 'MESH:C012616', (62, 64))	('Nup93', 'Gene', (14, 19))	('H3', 'Chemical', 'MESH:C012616', (185, 187))	('H3K36me3', 'Var', (185, 193))	('HOXA1', 'Gene', '3198', (206, 211))	('H3K9ac', 'Var', (62, 68))	('HOXA1', 'Gene', '3198', (124, 129))	('active histone marks', 'MPA', (40, 60))	('increased', 'PosReg', (30, 39))	('transcription', 'MPA', (153, 166))	('knockdown', 'Var', (20, 29))	('decreased', 'NegReg', (71, 80))	('H3', 'Chemical', 'MESH:C012616', (107, 109))
24706	27980680	Moreover, the combined depletion of Nup93 and CTCF (a known organizer of HOXA gene cluster) but not Nup93 alone, significantly increased GLCCI1 gene expression levels.	('CTCF', 'Gene', '10664', (46, 50))	('depletion', 'MPA', (23, 32))	('CTCF', 'Gene', (46, 50))	('HOXA', 'Gene', (73, 77))	('Nup93', 'Var', (36, 41))	('GLCCI1', 'Gene', (137, 143))	('GLCCI1', 'Gene', '113263', (137, 143))	('increased', 'PosReg', (127, 136))	('HOXA', 'Gene', '3197', (73, 77))
24727	27980680	Aberrant HOXA expression levels correlate with cancers and is dysregulated in breast carcinoma, human cutaneous melanoma and oral cancers.	('breast carcinoma', 'Disease', (78, 94))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('HOXA', 'Gene', (9, 13))	('expression levels', 'MPA', (14, 31))	('Aberrant', 'Var', (0, 8))	('human', 'Species', '9606', (96, 101))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('dysregulated', 'Reg', (62, 74))	('breast carcinoma', 'Disease', 'MESH:D001943', (78, 94))	('cutaneous melanoma and oral cancers', 'Disease', 'MESH:C562393', (102, 137))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('HOXA', 'Gene', '3197', (9, 13))	('breast carcinoma', 'Phenotype', 'HP:0003002', (78, 94))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
24729	27980680	These loops of the HOXA gene loci are disrupted by the combined action of retinoic acid treatment and depletion of CTCF or PRC2 that transcriptionally activate HOXA gene expression.	('HOXA', 'Gene', (19, 23))	('retinoic acid', 'Chemical', 'MESH:D014212', (74, 87))	('activate', 'PosReg', (151, 159))	('HOXA', 'Gene', '3197', (160, 164))	('depletion', 'Var', (102, 111))	('HOXA', 'Gene', '3197', (19, 23))	('CTCF', 'Gene', (115, 119))	('PRC2', 'Gene', (123, 127))	('CTCF', 'Gene', '10664', (115, 119))	('expression', 'MPA', (170, 180))	('HOXA', 'Gene', (160, 164))
24730	27980680	showed for the first time that Nup93 contacts chromatin and associates with the HOXA promoter.	('HOXA', 'Gene', '3197', (80, 84))	('Nup93', 'Var', (31, 36))	('chromatin', 'Protein', (46, 55))	('associates', 'Interaction', (60, 70))	('chromatin', 'cellular_component', 'GO:0000785', ('46', '55'))	('HOXA', 'Gene', (80, 84))
24731	27980680	We extended this study to address the consequences of depleting Nup93 on HOXA gene expression.	('HOXA', 'Gene', (73, 77))	('depleting', 'Var', (54, 63))	('HOXA', 'Gene', '3197', (73, 77))	('Nup93', 'Gene', (64, 69))
24732	27980680	We show that Nup93 associates with and represses HOXA gene expression in a manner dependent on its interacting partners:Nup188 and Nup205, in diploid colorectal cancer cells (DLD1).	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('colorectal cancer', 'Phenotype', 'HP:0003003', (150, 167))	('Nup205', 'Gene', '23165', (131, 137))	('Nup188', 'Var', (120, 126))	('Nup205', 'Gene', (131, 137))	('diploid colorectal cancer', 'Disease', (142, 167))	('expression', 'MPA', (59, 69))	('HOXA', 'Gene', (49, 53))	('associates', 'Interaction', (19, 29))	('represses', 'NegReg', (39, 48))	('diploid colorectal cancer', 'Disease', 'MESH:D015179', (142, 167))	('HOXA', 'Gene', '3197', (49, 53))	('Nup93', 'Gene', (13, 18))
24733	27980680	The depletion of Nup93 or its interacting partners:Nup188 and Nup205, derepresses the HOXA gene cluster since this showed a marked increase in HOXA gene expression, facilitated by enhanced levels of the active histone marks (H3K9ac) and decreased levels of repressive histone marks (H3K27me3) on the HOXA1 promoter.	('HOXA1', 'Gene', '3198', (300, 305))	('depletion', 'Var', (4, 13))	('expression', 'MPA', (153, 163))	('active', 'MPA', (203, 209))	('HOXA', 'Gene', '3197', (300, 304))	('Nup205', 'Gene', (62, 68))	('HOXA', 'Gene', '3197', (86, 90))	('H3K9ac', 'Protein', (225, 231))	('HOXA', 'Gene', (143, 147))	('H3', 'Chemical', 'MESH:C012616', (225, 227))	('repressive histone marks', 'MPA', (257, 281))	('HOXA1', 'Gene', (300, 305))	('levels', 'MPA', (189, 195))	('decreased', 'NegReg', (237, 246))	('increase', 'PosReg', (131, 139))	('gene expression', 'biological_process', 'GO:0010467', ('148', '163'))	('enhanced', 'PosReg', (180, 188))	('HOXA', 'Gene', (300, 304))	('HOXA', 'Gene', (86, 90))	('Nup205', 'Gene', '23165', (62, 68))	('H3', 'Chemical', 'MESH:C012616', (283, 285))	('HOXA', 'Gene', '3197', (143, 147))	('facilitated', 'PosReg', (165, 176))
24734	27980680	In addition, transcription elongation marks (H3K36me3) were enriched within the HOXA1 gene.	('HOXA1', 'Gene', (80, 85))	('transcription', 'biological_process', 'GO:0006351', ('13', '26'))	('H3K36me3', 'Var', (45, 53))	('HOXA1', 'Gene', '3198', (80, 85))	('H3', 'Chemical', 'MESH:C012616', (45, 47))
24736	27980680	Furthermore, Nup93 represses HOXA gene cluster independent of its key regulator, i.e., CTCF.	('Nup93', 'Var', (13, 18))	('CTCF', 'Gene', (87, 91))	('HOXA', 'Gene', '3197', (29, 33))	('CTCF', 'Gene', '10664', (87, 91))	('HOXA', 'Gene', (29, 33))
24737	27980680	Taken together, this study reveals that Nup93 along with its interacting partners:Nup188 and Nup205, represses HOXA gene expression.	('HOXA', 'Gene', '3197', (111, 115))	('gene expression', 'biological_process', 'GO:0010467', ('116', '131'))	('represses', 'NegReg', (101, 110))	('Nup205', 'Gene', '23165', (93, 99))	('Nup205', 'Gene', (93, 99))	('HOXA', 'Gene', (111, 115))	('Nup93', 'Var', (40, 45))
24740	27980680	The focus of our study was to examine the consequences of depleting Nup93 and its interactors on HOXA gene expression in diploid colorectal cancer cells (DLD1).	('gene expression', 'biological_process', 'GO:0010467', ('102', '117'))	('Nup93', 'Gene', (68, 73))	('HOXA', 'Gene', '3197', (97, 101))	('depleting', 'Var', (58, 67))	('diploid colorectal cancer', 'Disease', 'MESH:D015179', (121, 146))	('diploid colorectal cancer', 'Disease', (121, 146))	('colorectal cancer', 'Phenotype', 'HP:0003003', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('HOXA', 'Gene', (97, 101))
24748	27980680	ChIP-qPCR results showed a significantly reduced association of Nup93 with the HOXA1 promoter upon Nup93 knockdown (Fig.	('reduced', 'NegReg', (41, 48))	('HOXA1', 'Gene', '3198', (79, 84))	('knockdown', 'Var', (105, 114))	('association', 'Interaction', (49, 60))	('Nup93', 'Gene', (99, 104))	('HOXA1', 'Gene', (79, 84))	('Nup93', 'Gene', (64, 69))
24765	27980680	1d, e-i) showed that Nup188 and Nup205 depletion decreased the occupancy of Nup93 by ~70% on the HOXA1 promoter (Fig.	('depletion', 'Var', (39, 48))	('HOXA1', 'Gene', (97, 102))	('occupancy', 'MPA', (63, 72))	('decreased', 'NegReg', (49, 58))	('HOXA1', 'Gene', '3198', (97, 102))	('Nup205', 'Gene', '23165', (32, 38))	('Nup188', 'Var', (21, 27))	('Nup205', 'Gene', (32, 38))
24766	27980680	However, the occupancy of the core histone H3 (ChIP with anti-PanH3 antibody that detects core histone H3) was unaltered on either HOXA1 or GLCCI1 promoters upon Nup188 or Nup205 depletion (Additional file 1: Fig.	('antibody', 'molecular_function', 'GO:0003823', ('68', '76'))	('Nup205', 'Gene', '23165', (172, 178))	('GLCCI1', 'Gene', '113263', (140, 146))	('Nup205', 'Gene', (172, 178))	('Nup188', 'Var', (162, 168))	('occupancy', 'MPA', (13, 22))	('HOXA1', 'Gene', (131, 136))	('H3', 'Chemical', 'MESH:C012616', (43, 45))	('core', 'cellular_component', 'GO:0019013', ('30', '34'))	('antibody', 'cellular_component', 'GO:0042571', ('68', '76'))	('core', 'cellular_component', 'GO:0019013', ('90', '94'))	('antibody', 'cellular_component', 'GO:0019815', ('68', '76'))	('HOXA1', 'Gene', '3198', (131, 136))	('GLCCI1', 'Gene', (140, 146))	('antibody', 'cellular_component', 'GO:0019814', ('68', '76'))	('H3', 'Chemical', 'MESH:C012616', (103, 105))	('H3', 'Chemical', 'MESH:C012616', (65, 67))
24767	27980680	Although independent knockdowns of Nup93, Nup188 and Nup205 did not affect the transcript levels of one another (Additional file 1: Fig.	('Nup93', 'Gene', (35, 40))	('Nup188', 'Gene', (42, 48))	('knockdowns', 'Var', (21, 31))	('Nup205', 'Gene', '23165', (53, 59))	('Nup205', 'Gene', (53, 59))	('transcript levels', 'MPA', (79, 96))
24769	27980680	To account for the decrease in the levels of Nup93 upon Nup188 or Nup205 depletion, we overexpressed Nup93 in a background of Nup188 or Nup205 depletion (Fig.	('Nup205', 'Gene', (136, 142))	('Nup205', 'Gene', '23165', (66, 72))	('Nup205', 'Gene', (66, 72))	('Nup188', 'Var', (126, 132))	('Nup93', 'Gene', (101, 106))	('Nup205', 'Gene', '23165', (136, 142))
24775	27980680	We independently knocked down Nup93, Nup188 and Nup205 in DLD1 cells and assessed expression levels of all genes within the HOXA gene cluster (HOXA1-HOXA13) by qRT-PCR (Fig.	('HOXA', 'Gene', '3197', (124, 128))	('Nup205', 'Gene', (48, 54))	('HOXA', 'Gene', '3197', (149, 153))	('HOXA1', 'Gene', '3198', (143, 148))	('Nup205', 'Gene', '23165', (48, 54))	('HOXA1', 'Gene', (149, 154))	('HOXA', 'Gene', (143, 147))	('HOXA13', 'Gene', (149, 155))	('knocked', 'Var', (17, 24))	('HOXA13', 'Gene', '3209', (149, 155))	('HOXA', 'Gene', '3197', (143, 147))	('HOXA1', 'Gene', '3198', (149, 154))	('Nup188', 'Gene', (37, 43))	('HOXA', 'Gene', (124, 128))	('expression levels', 'MPA', (82, 99))	('HOXA1', 'Gene', (143, 148))	('Nup93', 'Gene', (30, 35))	('HOXA', 'Gene', (149, 153))
24776	27980680	Nup93, Nup188 and Nup205 knockdown showed a >80% reduction in their transcript levels (Fig.	('reduction', 'NegReg', (49, 58))	('Nup188', 'Gene', (7, 13))	('Nup205', 'Gene', '23165', (18, 24))	('Nup205', 'Gene', (18, 24))	('transcript levels', 'MPA', (68, 85))	('knockdown', 'Var', (25, 34))	('Nup93', 'Gene', (0, 5))
24777	27980680	Remarkably, the transcript levels of HOXA genes (HOXA1, HOXA3, HOXA5 and HOXA9) were strikingly upregulated (fold change >twofold) upon Nup93 Kd (Fig.	('HOXA', 'Gene', '3197', (56, 60))	('HOXA', 'Gene', (49, 53))	('HOXA', 'Gene', (73, 77))	('HOXA5', 'Gene', '3202', (63, 68))	('HOXA1', 'Gene', (49, 54))	('HOXA', 'Gene', '3197', (37, 41))	('HOXA', 'Gene', (63, 67))	('HOXA', 'Gene', (56, 60))	('HOXA5', 'Gene', (63, 68))	('Nup93 Kd', 'Var', (136, 144))	('HOXA3', 'Gene', '3200', (56, 61))	('upregulated', 'PosReg', (96, 107))	('HOXA', 'Gene', '3197', (49, 53))	('HOXA', 'Gene', '3197', (73, 77))	('HOXA3', 'Gene', (56, 61))	('HOXA', 'Gene', (37, 41))	('HOXA1', 'Gene', '3198', (49, 54))	('transcript levels', 'MPA', (16, 33))	('HOXA', 'Gene', '3197', (63, 67))
24778	27980680	HOXA1 showed an increase in transcript levels in all three nucleoporin knockdowns to ~four-sixfold, suggesting a significantly greater impact on HOXA1 expression levels upon Nup93, Nup188 and Nup205 knockdowns.	('Nup205', 'Gene', (192, 198))	('greater impact', 'PosReg', (127, 141))	('knockdowns', 'Var', (71, 81))	('HOXA1', 'Gene', (145, 150))	('HOXA1', 'Gene', '3198', (0, 5))	('increase', 'PosReg', (16, 24))	('knockdowns', 'Var', (199, 209))	('nucleoporin', 'Gene', '729857', (59, 70))	('HOXA1', 'Gene', '3198', (145, 150))	('HOXA1', 'Gene', (0, 5))	('transcript levels', 'MPA', (28, 45))	('Nup205', 'Gene', '23165', (192, 198))	('nucleoporin', 'Gene', (59, 70))	('expression levels', 'MPA', (151, 168))
24779	27980680	Furthermore, HOXA1, HOXA3, HOXA5 and HOXA9 were significantly upregulated in Nup188- and Nup205-depleted cells (Fig.	('Nup205', 'Gene', (89, 95))	('HOXA9', 'Gene', (37, 42))	('HOXA1', 'Gene', '3198', (13, 18))	('HOXA5', 'Gene', '3202', (27, 32))	('HOXA3', 'Gene', '3200', (20, 25))	('HOXA5', 'Gene', (27, 32))	('upregulated', 'PosReg', (62, 73))	('Nup188-', 'Var', (77, 84))	('HOXA3', 'Gene', (20, 25))	('HOXA1', 'Gene', (13, 18))	('Nup205', 'Gene', '23165', (89, 95))
24781	27980680	We also used two independent siRNA oligonucleotides to knockdown Nup93 (Additional file 2: Fig.	('Nup93', 'Gene', (65, 70))	('knockdown', 'Var', (55, 64))	('oligonucleotides', 'Chemical', 'MESH:D009841', (35, 51))
24783	27980680	Of note, the depletion of Nup98 did not alter gene expression levels of the HOXA gene cluster and GLCC1 (Additional file 2: Fig.	('gene expression', 'biological_process', 'GO:0010467', ('46', '61'))	('gene expression levels', 'MPA', (46, 68))	('HOXA', 'Gene', '3197', (76, 80))	('GLCC1', 'Gene', (98, 103))	('Nup98', 'Gene', (26, 31))	('depletion', 'Var', (13, 22))	('HOXA', 'Gene', (76, 80))
24790	27980680	We allowed cells to recover in culture for 8 days after 48 h of Nup93, Nup188 and Nup205 knockdown in DLD1 cells.	('knockdown', 'Var', (89, 98))	('Nup188', 'Gene', (71, 77))	('Nup205', 'Gene', '23165', (82, 88))	('Nup205', 'Gene', (82, 88))	('Nup93', 'Gene', (64, 69))
24794	27980680	The significant upregulation of HOXA genes upon Nup93, Nup188 and Nup205 depletion prompted us to determine the spatial localization of HOXA gene locus upon Nup93, Nup188 or Nup205 depletion in the interphase nucleus.	('Nup205', 'Gene', '23165', (66, 72))	('HOXA', 'Gene', '3197', (32, 36))	('HOXA', 'Gene', (136, 140))	('Nup93', 'Var', (48, 53))	('upregulation', 'PosReg', (16, 28))	('Nup205', 'Gene', (66, 72))	('depletion', 'Var', (73, 82))	('Nup188', 'Var', (164, 170))	('HOXA', 'Gene', '3197', (136, 140))	('Nup205', 'Gene', '23165', (174, 180))	('Nup93', 'Var', (157, 162))	('Nup205', 'Gene', (174, 180))	('Nup188', 'Var', (55, 61))	('HOXA', 'Gene', (32, 36))
24799	27980680	In contrast, Nup98 depletion did not affect the positioning of the HOXA loci with respect to the nuclear periphery (Fig.	('HOXA', 'Gene', '3197', (67, 71))	('HOXA', 'Gene', (67, 71))	('depletion', 'Var', (19, 28))
24801	27980680	We determined whether the observed derepression of the HOXA gene cluster upon Nup93 depletion is associated with an altered occupancy of active and inactive histone marks on the HOXA1 promoter region (Fig.	('HOXA1', 'Gene', '3198', (178, 183))	('depletion', 'Var', (84, 93))	('Nup93', 'Gene', (78, 83))	('histone', 'Protein', (157, 164))	('occupancy', 'MPA', (124, 133))	('HOXA', 'Gene', (178, 182))	('HOXA', 'Gene', (55, 59))	('derepression', 'PosReg', (35, 47))	('HOXA1', 'Gene', (178, 183))	('HOXA', 'Gene', '3197', (55, 59))	('HOXA', 'Gene', '3197', (178, 182))
24802	27980680	We performed ChIP with active (H3K9ac) and repressive (H3K27me3) histone marks on the HOXA1 promoter in Nup93-depleted cells (Fig.	('HOXA1', 'Gene', (86, 91))	('HOXA1', 'Gene', '3198', (86, 91))	('H3K9ac', 'Var', (31, 37))	('H3K27me3', 'Var', (55, 63))	('H3', 'Chemical', 'MESH:C012616', (31, 33))	('H3', 'Chemical', 'MESH:C012616', (55, 57))
24804	27980680	We performed ChIP with antibodies against active (H3K9ac) and repressive (H3K27me3) histone marks followed by ChIP-qPCR with overlapping primers ~1 Kb upstream of the HOXA1 transcription start site (Fig.	('H3K27me3', 'Var', (74, 82))	('H3', 'Chemical', 'MESH:C012616', (50, 52))	('H3', 'Chemical', 'MESH:C012616', (74, 76))	('HOXA1', 'Gene', (167, 172))	('transcription', 'biological_process', 'GO:0006351', ('173', '186'))	('H3K9ac', 'Var', (50, 56))	('HOXA1', 'Gene', '3198', (167, 172))
24805	27980680	We detected a significant enrichment of the active histone mark (H3K9ac), ~1 Kb upstream of the transcription start site of the HOXA1 gene (Fig.	('transcription', 'biological_process', 'GO:0006351', ('96', '109'))	('HOXA1', 'Gene', (128, 133))	('H3K9ac', 'Var', (65, 71))	('HOXA1', 'Gene', '3198', (128, 133))	('H3', 'Chemical', 'MESH:C012616', (65, 67))
24806	27980680	5b) and a marked decrease in the occupancy of the repressive histone mark (H3K27me3) upon Nup93 knockdown (Fig.	('knockdown', 'Var', (96, 105))	('H3K27me3', 'Protein', (75, 83))	('H3', 'Chemical', 'MESH:C012616', (75, 77))	('decrease', 'NegReg', (17, 25))	('Nup93', 'Gene', (90, 95))	('occupancy of the', 'MPA', (33, 49))
24807	27980680	Notably, the relative levels of active and repressive histone marks were unaltered upon Nup93 depletion on the promoters of control genes:GAPDH and GLCCI1 (Fig.	('GLCCI1', 'Gene', (148, 154))	('GAPDH', 'Gene', '2597', (138, 143))	('GAPDH', 'Gene', (138, 143))	('GLCCI1', 'Gene', '113263', (148, 154))	('Nup93', 'Gene', (88, 93))	('depletion', 'Var', (94, 103))
24808	27980680	Furthermore, the total levels of H3K9ac, H3K27me3 and PanH3 were unaffected upon Nup93 depletion in DLD1 cells (Fig.	('H3K9ac', 'Protein', (33, 39))	('H3', 'Chemical', 'MESH:C012616', (33, 35))	('H3', 'Chemical', 'MESH:C012616', (57, 59))	('depletion', 'Var', (87, 96))	('H3K27me3', 'Var', (41, 49))	('H3', 'Chemical', 'MESH:C012616', (41, 43))	('Nup93', 'Gene', (81, 86))
24809	27980680	Taken together, these results suggest a strong correlation between Nup93 depletion and the relative enrichment of the active histone mark and decreased occupancy of the inactive histone mark on the HOXA1 promoter.	('HOXA1', 'Gene', '3198', (198, 203))	('decreased', 'NegReg', (142, 151))	('occupancy of the', 'MPA', (152, 168))	('active', 'MPA', (118, 124))	('HOXA1', 'Gene', (198, 203))	('depletion', 'Var', (73, 82))	('Nup93', 'Gene', (67, 72))
24811	27980680	Since we detected a striking increase in the expression levels of the HOXA1 gene upon Nup93, Nup188 and Nup205 knockdown, we asked whether HOXA1 gene expression correlates with active transcriptional elongation, i.e., active transcription of the HOXA1 gene.	('active transcriptional elongation', 'CPA', (177, 210))	('HOXA1', 'Gene', (70, 75))	('knockdown', 'Var', (111, 120))	('expression levels', 'MPA', (45, 62))	('Nup205', 'Gene', '23165', (104, 110))	('Nup205', 'Gene', (104, 110))	('HOXA1', 'Gene', '3198', (70, 75))	('increase', 'PosReg', (29, 37))	('HOXA1', 'Gene', (139, 144))	('gene expression', 'biological_process', 'GO:0010467', ('145', '160'))	('HOXA1', 'Gene', (246, 251))	('transcription', 'biological_process', 'GO:0006351', ('225', '238'))	('HOXA1', 'Gene', '3198', (139, 144))	('HOXA1', 'Gene', '3198', (246, 251))
24813	27980680	Interestingly, Nup93 knockdown showed a specific enrichment of H3K36me3 on all three regions (Region 1-Region 3) within the HOXA1 gene (Fig.	('HOXA1', 'Gene', (124, 129))	('H3', 'Chemical', 'MESH:C012616', (63, 65))	('H3K36me3', 'Var', (63, 71))	('HOXA1', 'Gene', '3198', (124, 129))
24818	27980680	Nup93, Nup188 or Nup205 depletion showed a reduced nuclear import of the reporter GFP construct as compared to control cells after 30 min of dexamethasone addition (Fig.	('Nup205', 'Gene', (17, 23))	('dexamethasone', 'Chemical', 'MESH:D003907', (141, 154))	('Nup188', 'Var', (7, 13))	('reduced', 'NegReg', (43, 50))	('nuclear import', 'MPA', (51, 65))	('Nup205', 'Gene', '23165', (17, 23))
24832	27980680	We therefore investigated the effect of CTCF depletion on HOXA gene expression, by knocking down CTCF alone and in combination with Nup93 (Fig.	('investigated', 'Reg', (13, 25))	('knocking down', 'Var', (83, 96))	('CTCF', 'Gene', (97, 101))	('CTCF', 'Gene', (40, 44))	('HOXA', 'Gene', (58, 62))	('CTCF', 'Gene', '10664', (97, 101))	('HOXA', 'Gene', '3197', (58, 62))	('CTCF', 'Gene', '10664', (40, 44))
24837	27980680	Notably, the combined knockdown of both CTCF and Nup93 upregulated expression levels of HOXA genes, comparable to Nup93 knockdown alone (Fig.	('HOXA', 'Gene', (88, 92))	('Nup93', 'Gene', (49, 54))	('HOXA', 'Gene', '3197', (88, 92))	('knockdown', 'Var', (22, 31))	('CTCF', 'Gene', (40, 44))	('upregulated', 'PosReg', (55, 66))	('expression levels', 'MPA', (67, 84))	('CTCF', 'Gene', '10664', (40, 44))
24838	27980680	Of note, GLCCI1 showed an enhanced upregulation in Nup93 + CTCF Kd cells, suggesting an altered regulatory role for CTCF in cells subjected to a combined depletion of Nup93 and CTCF.	('enhanced upregulation', 'PosReg', (26, 47))	('CTCF', 'Gene', (59, 63))	('GLCCI1', 'Gene', (9, 15))	('CTCF', 'Gene', '10664', (116, 120))	('CTCF', 'Gene', '10664', (177, 181))	('CTCF', 'Gene', '10664', (59, 63))	('GLCCI1', 'Gene', '113263', (9, 15))	('regulatory', 'MPA', (96, 106))	('CTCF', 'Gene', (177, 181))	('altered', 'Reg', (88, 95))	('Nup93 +', 'Var', (51, 58))	('CTCF', 'Gene', (116, 120))
24846	27980680	In addition, the upregulation of HOXA genes upon Nup93 depletion was associated with an increase in active histone marks, reduced inactive marks and enrichment of a transcription elongation mark.	('HOXA', 'Gene', (33, 37))	('HOXA', 'Gene', '3197', (33, 37))	('Nup93', 'Gene', (49, 54))	('increase', 'PosReg', (88, 96))	('inactive marks', 'MPA', (130, 144))	('upregulation', 'PosReg', (17, 29))	('reduced', 'NegReg', (122, 129))	('depletion', 'Var', (55, 64))	('active histone marks', 'MPA', (100, 120))
24853	27980680	The active state of the HOXA gene cluster is marked by active histone marks such as H3K9ac and H3K4me3, while the inactive state shows an enrichment of inactive marks such as H3K9me3 and H3K27me3.	('H3K9ac', 'Var', (84, 90))	('H3K27me3', 'Var', (187, 195))	('H3K4me3', 'Var', (95, 102))	('H3', 'Chemical', 'MESH:C012616', (187, 189))	('H3', 'Chemical', 'MESH:C012616', (84, 86))	('H3', 'Chemical', 'MESH:C012616', (95, 97))	('H3K9me3', 'Var', (175, 182))	('HOXA', 'Gene', (24, 28))	('H3', 'Chemical', 'MESH:C012616', (175, 177))	('HOXA', 'Gene', '3197', (24, 28))
24856	27980680	We surmise that the depletion of Nup93, Nup188 or Nup205 and their reduced stability, enhances the accessibility of the HOXA gene cluster to transcriptional activators and epigenetic modulators that could facilitate their untimely expression of HOXA genes:the physiological ramifications of which remain unclear.	('HOXA', 'Gene', (245, 249))	('HOXA', 'Gene', (120, 124))	('HOXA', 'Gene', '3197', (245, 249))	('accessibility', 'MPA', (99, 112))	('Nup188', 'Var', (40, 46))	('HOXA', 'Gene', '3197', (120, 124))	('Nup205', 'Gene', '23165', (50, 56))	('Nup93', 'Var', (33, 38))	('Nup205', 'Gene', (50, 56))	('facilitate', 'PosReg', (205, 215))	('depletion', 'MPA', (20, 29))	('enhances', 'PosReg', (86, 94))	('stability', 'MPA', (75, 84))
24863	27980680	Interestingly, Nup98 depletion in DLD1 cells did not alter either the spatial localization or the expression levels of the HOXA gene (Fig.	('HOXA', 'Gene', (123, 127))	('HOXA', 'Gene', '3197', (123, 127))	('depletion', 'Var', (21, 30))	('localization', 'biological_process', 'GO:0051179', ('78', '90'))	('expression', 'MPA', (98, 108))
24865	27980680	However, in cells depleted of Nup93, Nup188 or Nup205, nuclear export was relatively unaffected although nuclear import was reduced (Fig.	('reduced', 'NegReg', (124, 131))	('Nup188', 'Var', (37, 43))	('nuclear import', 'biological_process', 'GO:0051170', ('105', '119'))	('nuclear export', 'biological_process', 'GO:0051168', ('55', '69'))	('nuclear export', 'MPA', (55, 69))	('nuclear import', 'MPA', (105, 119))	('Nup205', 'Gene', '23165', (47, 53))	('Nup205', 'Gene', (47, 53))	('Nup93', 'Var', (30, 35))
24877	27980680	Regulation of HOXA gene expression is essential during early development, since the aberrant expression of HOX genes leads to developmental defects.	('aberrant', 'Var', (84, 92))	('developmental defects', 'CPA', (126, 147))	('leads to', 'Reg', (117, 125))	('HOXA', 'Gene', (14, 18))	('gene expression', 'biological_process', 'GO:0010467', ('19', '34'))	('expression', 'MPA', (93, 103))	('HOX genes', 'Gene', (107, 116))	('HOXA', 'Gene', '3197', (14, 18))
24879	27980680	Similarly, HOXA gene regulation is also important in adult tissues since their aberrant expression is associated with various cancers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('HOXA', 'Gene', '3197', (11, 15))	('associated', 'Reg', (102, 112))	('aberrant', 'Var', (79, 87))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('HOXA', 'Gene', (11, 15))	('cancers', 'Disease', 'MESH:D009369', (126, 133))
24889	27980680	Depletion of Nup93, Nup188 or Nup205 significantly enhances HOXA gene expression.	('Nup205', 'Gene', (30, 36))	('Nup93', 'Var', (13, 18))	('HOXA', 'Gene', (60, 64))	('HOXA', 'Gene', '3197', (60, 64))	('gene expression', 'biological_process', 'GO:0010467', ('65', '80'))	('expression', 'MPA', (70, 80))	('Nup188', 'Var', (20, 26))	('Nup205', 'Gene', '23165', (30, 36))	('enhances', 'PosReg', (51, 59))
24890	27980680	The elevated levels of HOXA gene expression upon the depletion of Nup93 or its interactors:Nup188 and Nup205, is associated with an increase in the occupancy of active histone marks, and decreased levels of inactive histone marks with a concomitant increase in transcriptional elongation marks within the HOXA gene.	('Nup188', 'Var', (91, 97))	('HOXA', 'Gene', '3197', (23, 27))	('HOXA', 'Gene', (305, 309))	('expression', 'MPA', (33, 43))	('elevated', 'PosReg', (4, 12))	('active histone marks', 'MPA', (161, 181))	('transcriptional', 'MPA', (261, 276))	('increase', 'PosReg', (132, 140))	('levels', 'MPA', (197, 203))	('levels', 'MPA', (13, 19))	('Nup205', 'Gene', (102, 108))	('HOXA', 'Gene', (23, 27))	('increase', 'PosReg', (249, 257))	('HOXA', 'Gene', '3197', (305, 309))	('inactive histone marks', 'MPA', (207, 229))	('Nup93', 'Gene', (66, 71))	('occupancy', 'MPA', (148, 157))	('decreased', 'NegReg', (187, 196))	('Nup205', 'Gene', '23165', (102, 108))
24899	27980680	CTCF knockdown was performed using a single oligo (5'CAAGAAGCGGAGAGGACGA3') at a final concentration of 50 nM.	('knockdown', 'Var', (5, 14))	('CTCF', 'Gene', (0, 4))	('CTCF', 'Gene', '10664', (0, 4))
24902	27980680	After 48 h of Nup93-GPF transfection, cells were either fixed with 4% paraformaldehyde or harvested for RNA extraction using Trizol.	('paraformaldehyde', 'Chemical', 'MESH:C003043', (70, 86))	('Trizol', 'Chemical', 'MESH:C411644', (125, 131))	('RNA', 'cellular_component', 'GO:0005562', ('104', '107'))	('Nup93-GPF', 'Gene', (14, 23))	('transfection', 'Var', (24, 36))
24909	27980680	Rabbit anti-Nup93 (1:500, sc-292099, Lot-E0211, Santa Cruz Biotechnology, CA), rabbit anti-Nup188 (1:1000, Abcam, ab86601, Lot-GR43443-4), mouse anti-Nup98 (1:500, sc-74553, Lot-H0108, Santa Cruz Biotechnology, Santa Cruz, CA), rabbit anti-Nup205 antibody (1:500, HPA024574, Lot-R11937, Atlas Antibodies), rabbit anti-EED (1:500, ab4469, Lot-GR51357-1), rabbit anti-EZH2 (1:500, ab3748, Lot-GR252135-1), rabbit anti-Suz12 (1:500, ab12073, Lot-GR79631-1) and rabbit anti-CTCF antibody (1:500, 07-729, Lot-2375606, Millipore).	('rabbit', 'Species', '9986', (354, 360))	('Nup205', 'Gene', (240, 246))	('Suz12', 'Gene', (416, 421))	('EZH2', 'Gene', '2146', (366, 370))	('CTCF', 'Gene', (470, 474))	('EZH2', 'Gene', (366, 370))	('Lot-GR79631-1', 'Var', (439, 452))	('Lot-GR252135-1', 'Var', (387, 401))	('Rabbit', 'Species', '9986', (0, 6))	('Nup205', 'Gene', '23165', (240, 246))	('EED', 'Gene', (318, 321))	('mouse', 'Species', '10090', (139, 144))	('Lot-GR51357-1', 'Var', (338, 351))	('Suz12', 'Gene', '23512', (416, 421))	('rabbit', 'Species', '9986', (79, 85))	('rabbit', 'Species', '9986', (228, 234))	('rabbit', 'Species', '9986', (458, 464))	('CTCF', 'Gene', '10664', (470, 474))	('rabbit', 'Species', '9986', (404, 410))	('EED', 'Gene', '8726', (318, 321))	('rabbit', 'Species', '9986', (306, 312))
24916	27980680	Lysates were pre-cleared using protein A dynabeads (Invitrogen, 10002D), 1 h at 4  C. Pre-cleared extracts were incubated overnight at 4  C with anti-Nup93, anti-Nup205 and anti-Nup188 antibodies independently (2 mug/500 mug of total protein).	('anti-Nup188', 'Var', (173, 184))	('Nup205', 'Gene', '23165', (162, 168))	('Nup205', 'Gene', (162, 168))	('anti-Nup93', 'Var', (145, 155))
24928	27980680	After 48 h of Nup93 knockdown, the cells were washed with ice-cold 1x PBS and treated with cytoskeletal (CSK) digestion buffer (0.1 M NaCl, 0.3 M sucrose, 3 mM MgCl2, 10 mM PIPES (pH 7.4), 0.5% Triton X-100) for 5 min followed by fixation with 4% PFA in 1X PBS (pH 7.4) for 10 min at RT.	('Nup93', 'Gene', (14, 19))	('PFA', 'Chemical', 'MESH:D017245', (247, 250))	('NaCl', 'Chemical', 'MESH:D012965', (134, 138))	('PBS', 'Chemical', 'MESH:D007854', (70, 73))	('PBS', 'Chemical', 'MESH:D007854', (257, 260))	('sucrose', 'Chemical', 'MESH:D013395', (146, 153))	('knockdown', 'Var', (20, 29))	('MgCl2', 'Chemical', 'MESH:D015636', (160, 165))	('Triton X-100', 'Chemical', 'MESH:D017830', (194, 206))	('PIPES', 'Chemical', 'MESH:C008916', (173, 178))
24932	27980680	Cells were hybridized with 3 microl of human whole chromosome 7 paint (Applied Spectral Imaging (ASI), Israel, or MetaSystems, USA) and nick-translated BAC DNA probe (RP11-1132K14) for HOXA gene locus (3 microl).	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('chromosome', 'cellular_component', 'GO:0005694', ('51', '61'))	('RP11-1132K14', 'Var', (167, 179))	('HOXA', 'Gene', (185, 189))	('HOXA', 'Gene', '3197', (185, 189))	('human', 'Species', '9606', (39, 44))
24942	27980680	After 48 h of Nup93 knockdown, the cells were fixed with 4% PFA in 1x PBS (pH 7.4) for 15 min at RT.	('knockdown', 'Var', (20, 29))	('PFA', 'Chemical', 'MESH:D017245', (60, 63))	('PBS', 'Chemical', 'MESH:D007854', (70, 73))	('Nup93', 'Gene', (14, 19))
24948	27980680	Kd knockdown IP immunoprecipitation ChIP chromatin immunoprecipitation FISH fluorescence in situ hybridization HDAC histone deacetylase PRC Polycomb repressive complex qPCR quantitative polymerase chain reaction H3K9ac histone H3 lysine 9 acetylation H3K27me3 histone H3 lysine 27 tri-methylation H3K36me3 histone H3 lysine 36 tri-methylation ENCODE encyclopedia of DNA elements	('lysine', 'Chemical', 'MESH:D008239', (271, 277))	('H3', 'Chemical', 'MESH:C012616', (268, 270))	('lysine', 'Chemical', 'MESH:D008239', (317, 323))	('H3K27me3 histone', 'Var', (251, 267))	('H3', 'Chemical', 'MESH:C012616', (314, 316))	('H3', 'Chemical', 'MESH:C012616', (297, 299))	('H3K9ac', 'Var', (212, 218))	('encyclopedia of DNA', 'Disease', (350, 369))	('lysine', 'Chemical', 'MESH:D008239', (230, 236))	('H3', 'Chemical', 'MESH:C012616', (212, 214))	('H3', 'Chemical', 'MESH:C012616', (251, 253))	('H3', 'Chemical', 'MESH:C012616', (227, 229))	('H3K36me3', 'Var', (297, 305))
24961	27120793	Recently, dysregulation of miR-638 has been described in several different types of human tumors.	('miR-638', 'Gene', (27, 34))	('dysregulation', 'Var', (10, 23))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('human', 'Species', '9606', (84, 89))	('miR-638', 'Gene', '693223', (27, 34))	('described', 'Reg', (44, 53))
25003	27120793	Dysregulation of miR-638 has been described in several different types of human tumors, including human gastric cancer, basal cell carcinoma, breast cancer, nonsmall-cell lung cancer, colorectal carcinoma and chronic lymphocytic leukemia.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Dysregulation', 'Var', (0, 13))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('breast cancer', 'Disease', (142, 155))	('tumors', 'Disease', (80, 86))	('leukemia', 'Phenotype', 'HP:0001909', (229, 237))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('basal cell carcinoma', 'Disease', (120, 140))	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('nonsmall-cell lung cancer', 'Disease', (157, 182))	('described', 'Reg', (34, 43))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (209, 237))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (120, 140))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (209, 237))	('miR-638', 'Gene', (17, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('chronic lymphocytic leukemia', 'Disease', (209, 237))	('colorectal carcinoma', 'Disease', (184, 204))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('nonsmall-cell lung cancer', 'Disease', 'MESH:D002289', (157, 182))	('miR-638', 'Gene', '693223', (17, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (184, 204))	('human', 'Species', '9606', (74, 79))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (120, 140))	('human', 'Species', '9606', (98, 103))	('gastric cancer', 'Disease', (104, 118))
25021	27120793	Inhibiting VEGF has been shown to repress tumor angiogenesis and HCC growth under both in vitro and in vivo conditions.	('HCC', 'Phenotype', 'HP:0001402', (65, 68))	('VEGF', 'Gene', (11, 15))	('Inhibiting', 'Var', (0, 10))	('tumor', 'Disease', (42, 47))	('repress', 'NegReg', (34, 41))	('HCC', 'Gene', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('HCC', 'Gene', '619501', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
25038	27120793	Ectopic expression of miR-638 can repress tumor growth and inhibit angiogenesis by downregulating VEGF.	('downregulating', 'NegReg', (83, 97))	('tumor', 'Disease', (42, 47))	('repress', 'NegReg', (34, 41))	('VEGF', 'MPA', (98, 102))	('angiogenesis', 'CPA', (67, 79))	('Ectopic expression', 'Var', (0, 18))	('miR-638', 'Gene', '693223', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('miR-638', 'Gene', (22, 29))	('inhibit', 'NegReg', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
25054	27120793	For VEGF 3'-untranslated region (UTR) luciferase reporter assay, 100 ng of wild-type or mutant reporter constructs (pGL3 cm-VEGF-3'UTR-WT or pGL3 cm-VEGF-3'UTR-MUT) were co-transfected into HEK293 cells in 96-well plates with 100 nmol/L miR-638 or 100 nmol/L miR-NC expression vector and Renilla plasmid by using lipofectamine 2000 (Invitrogen).	('miR', 'Gene', '220972', (259, 262))	('miR', 'Gene', (259, 262))	('pGL3', 'Gene', (141, 145))	('miR', 'Gene', '220972', (237, 240))	('miR', 'Gene', (237, 240))	('pGL3', 'Gene', '6391', (141, 145))	('mutant', 'Var', (88, 94))	('miR-638', 'Gene', '693223', (237, 244))	('pGL3', 'Gene', (116, 120))	('HEK293', 'CellLine', 'CVCL:0045', (190, 196))	('miR-638', 'Gene', (237, 244))	('pGL3', 'Gene', '6391', (116, 120))
25090	23455466	Dysregulated expression of microRNAs in various tissues has been associated with a variety of diseases, including cancers (reviewed below), arthritis, neurodegenerative disorders, and cardiovascular diseases, and it has been shown that miRNA signatures can be used as novel biomarkers, potentially offering more sensitive and specific tests than those currently available for early diagnosis of cancer and other diseases.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('miR', 'Gene', (236, 239))	('cancers', 'Disease', (114, 121))	('microRNAs', 'Gene', (27, 36))	('associated', 'Reg', (65, 75))	('cancer', 'Disease', 'MESH:D009369', (395, 401))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (184, 207))	('arthritis', 'Phenotype', 'HP:0001369', (140, 149))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (151, 178))	('Dysregulated', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('neurodegenerative disorders', 'Disease', (151, 178))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cardiovascular diseases', 'Disease', (184, 207))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (184, 207))	('cancer', 'Disease', (395, 401))	('miR', 'Gene', '220972', (236, 239))	('arthritis', 'Disease', 'MESH:D001168', (140, 149))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (151, 178))	('cancer', 'Phenotype', 'HP:0002664', (395, 401))	('expression', 'MPA', (13, 23))	('arthritis', 'Disease', (140, 149))	('cancer', 'Disease', (114, 120))
25110	23455466	Single nucleotide polymorphisms (SNPs), which alter the expression of ANRIL, are associated with many diseases, including various cancers as well as coronary artery disease and diabetes.	('Single nucleotide polymorphisms', 'Var', (0, 31))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('ANRIL', 'Gene', (70, 75))	('cancers', 'Disease', (130, 137))	('ANRIL', 'Gene', '100048912', (70, 75))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('expression', 'MPA', (56, 66))	('coronary artery disease', 'Disease', 'MESH:D003324', (149, 172))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('diabetes', 'Disease', (177, 185))	('alter', 'Reg', (46, 51))	('associated', 'Reg', (81, 91))	('diabetes', 'Disease', 'MESH:D003920', (177, 185))	('coronary artery disease', 'Disease', (149, 172))
25123	23455466	Often, T-UCRs are found in fragile genomic regions that are usually associated with cancer.	('T-UCRs', 'Var', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('fragile', 'Disease', (27, 34))	('associated', 'Reg', (68, 78))	('cancer', 'Disease', (84, 90))	('fragile', 'Disease', 'MESH:D005600', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
25125	23455466	Deregulated T-UCR signatures are cancer-specific and have prognostic implications.	('T-UCR', 'Protein', (12, 17))	('Deregulated', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Disease', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
25228	23455466	Thus, plasma miR-141 may represent a novel biomarker that complements CEA in detecting colon cancer with distant metastasis, and high levels of miR-141 in plasma are associated with poor prognosis.	('colon cancer', 'Disease', (87, 99))	('miR-141', 'Gene', '406933', (144, 151))	('CEA', 'Gene', (70, 73))	('CEA', 'Gene', '1048', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('colon cancer', 'Phenotype', 'HP:0003003', (87, 99))	('miR-141', 'Gene', (144, 151))	('miR-141', 'Gene', (13, 20))	('men', 'Species', '9606', (64, 67))	('miR-141', 'Gene', '406933', (13, 20))	('colon cancer', 'Disease', 'MESH:D015179', (87, 99))	('high levels', 'Var', (129, 140))
25255	23455466	Recently, locked nucleic acids (LNA) have been used to increase melting temperature, probe affinity for its target, and mismatch discrimination.	('increase', 'PosReg', (55, 63))	('mismatch', 'Var', (120, 128))	('rat', 'Species', '10116', (77, 80))	('melting temperature', 'MPA', (64, 83))	('probe', 'MPA', (85, 90))
25280	23455466	This approach is very sensitive to mismatches and, since probes can be linked to different fluorophores, is also helpful to simultaneously detect different target miRNAs.	('miR', 'Gene', '220972', (163, 166))	('sensitive', 'Reg', (22, 31))	('miR', 'Gene', (163, 166))	('mismatches', 'Var', (35, 45))
25282	23455466	In this case, when the probes hybridize to pre-miRNA or pri-miRNA, its fluorescence is quenched by a guanine in the target sequence, while hybridization of the probe with mature miRNA, which has no complementary guanine, results in fluorescent signal emission.	('miR', 'Gene', '220972', (60, 63))	('miR', 'Gene', (60, 63))	('miR', 'Gene', '220972', (178, 181))	('miR', 'Gene', (178, 181))	('miR', 'Gene', (47, 50))	('miR', 'Gene', '220972', (47, 50))	('guanine', 'Chemical', 'MESH:D006147', (101, 108))	('fluorescent signal emission', 'MPA', (232, 259))	('men', 'Species', '9606', (204, 207))	('hybridize', 'Var', (30, 39))	('quenched', 'NegReg', (87, 95))	('guanine', 'Chemical', 'MESH:D006147', (212, 219))	('fluorescence', 'MPA', (71, 83))
25315	23455466	Furthermore, the technology may be useful for the development of tests for personalized-medicine applications by simultaneously querying multiple single-nucleotide polymorphisms and copy number variants, in addition to the development of biomarker panels for health status assessments with fingerprick-size blood or other patient samples.	('patient', 'Species', '9606', (322, 329))	('men', 'Species', '9606', (230, 233))	('copy number variants', 'Var', (182, 202))	('men', 'Species', '9606', (279, 282))	('variants', 'Var', (194, 202))	('men', 'Species', '9606', (57, 60))
25323	23455466	As discussed, deregulated expression of miRNAs has been extensively described in a variety of diseases, particularly in cancer.	('expression', 'MPA', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('deregulated', 'Var', (14, 25))	('described', 'Reg', (68, 77))
25334	33920665	However, the 5-year overall survival from stage I-IV colon and rectal carcinoma was worse in the high ACCI group compared to the low ACCI group.	('age', 'Gene', (44, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('high ACCI', 'Var', (97, 106))	('age', 'Gene', '5973', (44, 47))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (63, 79))	('colon and rectal carcinoma', 'Disease', 'MESH:D003110', (53, 79))	('worse', 'NegReg', (84, 89))
25386	33920665	The incidence of right-sided colon cancers, medical comorbidities and older age was most frequent in the high ACCI group.	('colon cancer', 'Phenotype', 'HP:0003003', (29, 41))	('colon cancers', 'Disease', (29, 42))	('age', 'Gene', '5973', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('high ACCI', 'Var', (105, 114))	('colon cancers', 'Phenotype', 'HP:0003003', (29, 42))	('colon cancers', 'Disease', 'MESH:D015179', (29, 42))	('age', 'Gene', (76, 79))	('medical', 'Disease', (44, 51))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))
25395	33920665	The administration of adjuvant chemotherapy for stages II-III colon carcinoma was less frequent in the high ACCI group.	('high ACCI', 'Var', (103, 112))	('age', 'Gene', (50, 53))	('II-III colon carcinoma', 'Disease', 'MESH:D003110', (55, 77))	('age', 'Gene', '5973', (50, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('II-III colon carcinoma', 'Disease', (55, 77))
25398	33920665	The incidence of metastatic disease, observed in some 30% of patients over time, was lower in the high ACCI group for colon cancer but not for rectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Disease', (124, 130))	('lower', 'NegReg', (85, 90))	('colon cancer', 'Disease', (118, 130))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('patients', 'Species', '9606', (61, 69))	('high ACCI', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('rectal cancer', 'Phenotype', 'HP:0100743', (143, 156))	('metastatic disease', 'Disease', (17, 35))	('cancer', 'Disease', (150, 156))	('colon cancer', 'Phenotype', 'HP:0003003', (118, 130))	('colon cancer', 'Disease', 'MESH:D015179', (118, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
25432	33920665	In our series the use metastasectomy was significantly reduced in the high ACCI group due to patient comorbidities, high age and multisite metastatic patterns.	('high ACCI', 'Var', (70, 79))	('use metastasectomy', 'CPA', (18, 36))	('reduced', 'NegReg', (55, 62))	('patient', 'Species', '9606', (93, 100))	('age', 'Gene', (121, 124))	('age', 'Gene', '5973', (121, 124))
25446	33920665	Tumors originating in the right colon are more frequently associated with female patients, the elderly, BRAF mutations, the enhanced CpG island methylator phenotype, high microsatellite instability, and high expression of consensus molecular subtypes 1 and 3 compared with left-side origin tumors.	('tumors', 'Disease', (290, 296))	('tumors', 'Disease', 'MESH:D009369', (290, 296))	('associated', 'Reg', (58, 68))	('patients', 'Species', '9606', (81, 89))	('enhanced', 'PosReg', (124, 132))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('BRAF', 'Gene', '673', (104, 108))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('microsatellite instability', 'MPA', (171, 197))	('CpG island methylator phenotype', 'MPA', (133, 164))	('mutations', 'Var', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('BRAF', 'Gene', (104, 108))	('tumors', 'Phenotype', 'HP:0002664', (290, 296))
25469	33065997	Chemically, terpenes are built from isoprene units (C5), the number of which decide on the type of terpene: monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), triterpenes (C30), tetraterpenes (C40), and polyterpenes.	('C10', 'Gene', (122, 125))	('C', 'Chemical', 'MESH:D002244', (52, 53))	('C', 'Chemical', 'MESH:D002244', (162, 163))	('C10', 'Gene', '3226', (122, 125))	('isoprene', 'Chemical', 'MESH:C005059', (36, 44))	('terpenes', 'Chemical', 'MESH:D013729', (12, 20))	('sesquiterpenes', 'Chemical', 'MESH:D012717', (128, 142))	('C', 'Chemical', 'MESH:D002244', (122, 123))	('monoterpenes', 'Chemical', 'MESH:D039821', (108, 120))	('terpenes', 'Chemical', 'MESH:D013729', (171, 179))	('terpene', 'Chemical', 'MESH:D013729', (192, 199))	('C', 'Chemical', 'MESH:D002244', (202, 203))	('terpene', 'Chemical', 'MESH:D013729', (216, 223))	('terpene', 'Chemical', 'MESH:D013729', (152, 159))	('polyterpenes', 'Chemical', '-', (212, 224))	('C', 'Chemical', 'MESH:D002244', (144, 145))	('C40', 'Gene', '55571', (202, 205))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('terpene', 'Chemical', 'MESH:D013729', (112, 119))	('terpenes', 'Chemical', 'MESH:D013729', (192, 200))	('terpene', 'Chemical', 'MESH:D013729', (134, 141))	('terpenes', 'Chemical', 'MESH:D013729', (216, 224))	('terpenes', 'Chemical', 'MESH:D013729', (152, 160))	('C40', 'Gene', (202, 205))	('C15', 'Gene', '51316', (144, 147))	('terpenes', 'Chemical', 'MESH:D013729', (112, 120))	('C', 'Chemical', 'MESH:D002244', (181, 182))	('diterpenes', 'Chemical', 'MESH:D004224', (150, 160))	('C15', 'Gene', (144, 147))	('triterpenes', 'Chemical', 'MESH:D014315', (168, 179))	('C30', 'Var', (181, 184))	('terpene', 'Chemical', 'MESH:D013729', (12, 19))	('terpene', 'Chemical', 'MESH:D013729', (99, 106))	('tetraterpenes', 'Chemical', 'MESH:D002338', (187, 200))	('terpene', 'Chemical', 'MESH:D013729', (171, 178))	('terpenes', 'Chemical', 'MESH:D013729', (134, 142))
25508	33065997	In the presence of beta-cyclocitral and TMPE, no changes in the cytotoxicity of doxorubicin against LoVo and HT29 cells were observed.	('cytotoxicity', 'Disease', (64, 76))	('beta-cyclocitral', 'Var', (19, 35))	('HT29 cells', 'CellLine', 'CVCL:0320', (109, 119))	('cytotoxicity', 'Disease', 'MESH:D064420', (64, 76))	('doxorubicin', 'Chemical', 'MESH:D004317', (80, 91))	('TMPE', 'Chemical', '-', (40, 44))	('beta-cyclocitral', 'Chemical', 'MESH:C516118', (19, 35))
25526	33065997	When the activity of TMPE was compared with verapamil, the known inhibitor of ABCB1 transporter, it was found that FIR values of TMPE were higher in case of LoVo/Dx cells and comparable to verapamil in HT29/Dx cells (Figure 5).	('TMPE', 'Chemical', '-', (129, 133))	('ABCB1', 'Gene', (78, 83))	('verapamil', 'Chemical', 'MESH:D014700', (44, 53))	('ABCB1', 'Gene', '5243', (78, 83))	('HT29/Dx', 'CellLine', 'CVCL:4T93', (202, 209))	('FIR', 'MPA', (115, 118))	('TMPE', 'Chemical', '-', (21, 25))	('verapamil', 'Chemical', 'MESH:D014700', (189, 198))	('LoVo/Dx', 'Var', (157, 164))	('higher', 'PosReg', (139, 145))
25564	33065997	During our studies we usually observed that doxorubicin-resistant cells tended to be less vulnerable to other chemicals than their sensitive counterparts; thus, the result was particularly important.	('doxorubicin', 'Chemical', 'MESH:D004317', (44, 55))	('doxorubicin-resistant', 'Var', (44, 65))	('vulnerable', 'MPA', (90, 100))
25572	33065997	It has been shown that TMPE was able to increase doxorubicin cytotoxicity in both LoVo/Dx and HT29/Dx cells, i.e., to reduce the resistance of cancer cells to the anticancer drug.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('TMPE', 'Chemical', '-', (23, 27))	('cytotoxicity', 'Disease', (61, 73))	('TMPE', 'Var', (23, 27))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('HT29/Dx', 'CellLine', 'CVCL:4T93', (94, 101))	('cancer', 'Disease', (167, 173))	('increase', 'PosReg', (40, 48))	('resistance', 'MPA', (129, 139))	('cytotoxicity', 'Disease', 'MESH:D064420', (61, 73))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('doxorubicin', 'Chemical', 'MESH:D004317', (49, 60))	('reduce', 'NegReg', (118, 124))
25575	33065997	Additionally, TMPE caused significant increase of accumulation of doxorubicin and ABCB1 substrate, rhodamine 123, inside the resistant colon cancer cells.	('ABCB1', 'Gene', '5243', (82, 87))	('increase', 'PosReg', (38, 46))	('rhodamine 123', 'MPA', (99, 112))	('rhodamine 123', 'Chemical', 'MESH:D020112', (99, 112))	('ABCB1', 'Gene', (82, 87))	('colon cancer', 'Disease', (135, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('colon cancer', 'Phenotype', 'HP:0003003', (135, 147))	('TMPE', 'Var', (14, 18))	('TMPE', 'Chemical', '-', (14, 18))	('doxorubicin', 'Chemical', 'MESH:D004317', (66, 77))	('accumulation', 'MPA', (50, 62))	('colon cancer', 'Disease', 'MESH:D015179', (135, 147))	('doxorubicin', 'MPA', (66, 77))
25594	33065997	The presence of longer side chain in TMPE molecule resulted in an elevated hydrophobicity of this derivative.	('hydrophobicity', 'MPA', (75, 89))	('presence', 'Var', (4, 12))	('TMPE', 'Chemical', '-', (37, 41))	('elevated', 'PosReg', (66, 74))
25664	31594750	We firstly investigated the role of gut microbiota in the progression of intestinal adenoma using the mouse model with adenomatous polyposis coli (Apc) gene mutation through fecal microbiota transplantation (FMT).	('adenomatous polyposis coli', 'Disease', (119, 145))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (119, 145))	('Apc', 'Phenotype', 'HP:0005227', (147, 150))	('mutation', 'Var', (157, 165))	('intestinal adenoma', 'Disease', (73, 91))	('intestinal adenoma', 'Disease', 'MESH:D000236', (73, 91))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (119, 145))	('Apc', 'cellular_component', 'GO:0005680', ('147', '150'))	('mouse', 'Species', '10090', (102, 107))
25684	31594750	Adenomatous polyposis coli (Apc) is a recognized key tumour suppressor gene in CRC, and its mutation is an early event of adenoma formation.	('Adenomatous polyposis coli', 'Disease', (0, 26))	('Adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (0, 26))	('mutation', 'Var', (92, 100))	('Adenomatous polyposis coli', 'Disease', 'MESH:D011125', (0, 26))	('adenoma', 'Disease', 'MESH:D000236', (122, 129))	('tumour', 'Disease', (53, 59))	('CRC', 'Phenotype', 'HP:0003003', (79, 82))	('CRC', 'Disease', 'MESH:D015179', (79, 82))	('Apc', 'Phenotype', 'HP:0005227', (28, 31))	('adenoma', 'Disease', (122, 129))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('CRC', 'Disease', (79, 82))	('tumour', 'Disease', 'MESH:D009369', (53, 59))
25711	31594750	Paraffin-embedded intestinal tissue cut into 5-mum slices by a microtome were also subjected to immunostaining for detecting the expressions of Ki-67 (Abcam Cat# ab16667, RRID: AB_302459), lysozyme (Abcam Cat# ab108508, RRID:AB_10861277), beta-catenin (Abcam Cat# ab32572, RRID:AB_725966), and cyclin D1 (Abcam Cat# ab16663, RRID:AB_443423).	('lysozyme', 'Protein', (189, 197))	('Paraffin', 'Chemical', 'MESH:D010232', (0, 8))	('Cat', 'molecular_function', 'GO:0004096', ('311', '314'))	('Cat', 'molecular_function', 'GO:0004096', ('157', '160'))	('cyclin', 'molecular_function', 'GO:0016538', ('294', '300'))	('beta-catenin', 'Protein', (239, 251))	('Cat', 'molecular_function', 'GO:0004096', ('205', '208'))	('Abcam', 'Var', (253, 258))	('Cat', 'molecular_function', 'GO:0004096', ('259', '262'))	('cyclin D1', 'Protein', (294, 303))	('Ki-67', 'Gene', (144, 149))
25754	31594750	PAS staining of colon tissues revealed that the average number of goblet cells in each crypt was lower in the FMT-AC group.	('FMT-AC', 'Var', (110, 116))	('PAS', 'Chemical', 'MESH:D010504', (0, 3))	('lower', 'NegReg', (97, 102))
25770	31594750	Although there was no difference in total beta-catenin protein expression, the protein level of active beta-catenin, cyclinD1, and c-myc was increased in FMT-AC group (Fig.	('protein level of active beta-catenin', 'MPA', (79, 115))	('FMT-AC', 'Var', (154, 160))	('cyclinD1', 'Gene', (117, 125))	('increased', 'PosReg', (141, 150))	('cyclinD1', 'Gene', '595', (117, 125))	('c-myc', 'Gene', '4609', (131, 136))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('c-myc', 'Gene', (131, 136))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))
25781	31594750	Accordingly, we detected the content of acetate, propionate, and butyrate in cecum, which were reduced in the FMT-AC group compared to the FMT-AH group (Fig.	('content', 'MPA', (29, 36))	('butyrate', 'Chemical', 'MESH:D002087', (65, 73))	('butyrate', 'MPA', (65, 73))	('acetate', 'Chemical', 'MESH:D000085', (40, 47))	('acetate', 'MPA', (40, 47))	('FMT-AC', 'Var', (110, 116))	('propionate', 'Chemical', 'MESH:D011422', (49, 59))	('reduced', 'NegReg', (95, 102))	('propionate', 'MPA', (49, 59))
25803	31594750	Recent studies have found that microRNA activated Wnt/beta-catenin signalling to promote CRC by inducing tumour cell proliferation, angiogenesis, invasion, and metastasis.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('promote', 'PosReg', (81, 88))	('tumour', 'Disease', (105, 111))	('metastasis', 'CPA', (160, 170))	('invasion', 'CPA', (146, 154))	('microRNA', 'Var', (31, 39))	('CRC', 'Disease', (89, 92))	('inducing', 'PosReg', (96, 104))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('CRC', 'Phenotype', 'HP:0003003', (89, 92))	('CRC', 'Disease', 'MESH:D015179', (89, 92))	('angiogenesis', 'CPA', (132, 144))
25814	30976068	Detection of KRAS mutation via ligation-initiated LAMP reaction KRAS mutations are abnormalities widely found in genomic DNA and circulating tumor DNA (ctDNA) of various types of cancers.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('mutations', 'Var', (69, 78))	('DNA', 'cellular_component', 'GO:0005574', ('121', '124'))	('found', 'Reg', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('DNA', 'cellular_component', 'GO:0005574', ('147', '150'))	('KRAS', 'Gene', (64, 68))	('tumor', 'Disease', (141, 146))	('KRAS', 'Gene', '3845', (64, 68))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('KRAS', 'Gene', (13, 17))	('cancers', 'Disease', (179, 186))	('KRAS', 'Gene', '3845', (13, 17))	('genomic DNA', 'Disease', (113, 124))
25815	30976068	Thus, highly sensitive detection of KRAS mutations in genomic DNA is of great significance in disease diagnosis and personalized medicine.	('mutations', 'Var', (41, 50))	('KRAS', 'Gene', '3845', (36, 40))	('KRAS', 'Gene', (36, 40))
25817	30976068	In the presence of mutant KRAS DNA (mutDNA), the dumbbell-shaped structure (DSS) is formed by the specific ligation of two substrates (SLS1 and SLS2), which act as a template to initiate the following LAMP amplification.	('DSS', 'Chemical', '-', (76, 79))	('mutant', 'Var', (19, 25))	('KRAS', 'Gene', (26, 30))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('KRAS', 'Gene', '3845', (26, 30))
25819	30976068	Furthermore, this strategy has been successfully applied for detection of a KRAS mutation from tissue samples of colorectal cancer patients.	('patients', 'Species', '9606', (131, 139))	('colorectal cancer', 'Disease', (113, 130))	('KRAS', 'Gene', (76, 80))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('mutation', 'Var', (81, 89))	('KRAS', 'Gene', '3845', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))
25821	30976068	Moreover, single nucleotide mutation often occurs in and near codons of the KRAS gene, causing normal cells to become cancerous state.	('cancerous', 'Disease', (118, 127))	('KRAS', 'Gene', (76, 80))	('causing', 'Reg', (87, 94))	('KRAS', 'Gene', '3845', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('single nucleotide mutation', 'Var', (10, 36))	('cancerous', 'Disease', 'MESH:D009369', (118, 127))
25822	30976068	Whole genome sequencing indicates that KRAS mutations are activated in various malignancies, such as colorectal cancer, non-small-cell lung cancer and pancreatic adenocarcinoma.	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('non-small-cell lung cancer', 'Disease', (120, 146))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (120, 146))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (151, 176))	('pancreatic adenocarcinoma', 'Disease', (151, 176))	('malignancies', 'Disease', 'MESH:D009369', (79, 91))	('malignancies', 'Disease', (79, 91))	('activated', 'PosReg', (58, 67))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (124, 146))	('KRAS', 'Gene', '3845', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('colorectal cancer', 'Disease', (101, 118))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (120, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (151, 176))	('mutations', 'Var', (44, 53))	('KRAS', 'Gene', (39, 43))
25823	30976068	Importantly, as a potential personalized biomarker, KRAS mutations can be used to not only predict the primary tumor but monitor minimal residual tumor during therapy.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('KRAS', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('KRAS', 'Gene', '3845', (52, 56))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', (111, 116))	('mutations', 'Var', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
25824	30976068	Therefore, accurate and ultrasensitive detection of KRAS mutations will provide a robust evidence for early diagnosis of mutant KRAS-related cancer.	('KRAS', 'Gene', (128, 132))	('mutant', 'Var', (121, 127))	('KRAS', 'Gene', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('KRAS', 'Gene', '3845', (52, 56))	('KRAS', 'Gene', '3845', (128, 132))	('mutations', 'Var', (57, 66))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
25825	30976068	Herein, making use of the remarkable specificity of ligation reaction and highly amplified efficiency of LAMP, we developed a label-free ligation-initiated LAMP strategy for specific and sensitive detection of KRAS mutation.	('mutation', 'Var', (215, 223))	('KRAS', 'Gene', '3845', (210, 214))	('KRAS', 'Gene', (210, 214))
25826	30976068	In the ligation reaction, two ligation substrates, stem-loop substrate 1 (SLS1) and stem-loop substrate 2 (SLS2), are designed for discriminating the single base between mutant KRAS DNA (mutDNA) and wild-type KRAS DNA (wtDNA) respectively.	('DNA', 'cellular_component', 'GO:0005574', ('214', '217'))	('KRAS', 'Gene', (177, 181))	('single base', 'MPA', (150, 161))	('KRAS', 'Gene', '3845', (177, 181))	('mutant', 'Var', (170, 176))	('DNA', 'cellular_component', 'GO:0005574', ('182', '185'))	('KRAS', 'Gene', (209, 213))	('KRAS', 'Gene', '3845', (209, 213))
25832	30976068	With high-efficiency strand displacement activity, the Bst DNA polymerase initiates the amplification reaction and creates more elongated structures along the DSS.	('more', 'PosReg', (123, 127))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('strand', 'Var', (21, 27))	('DSS', 'Chemical', '-', (159, 162))	('strand displacement', 'biological_process', 'GO:0000732', ('21', '40'))	('creates', 'Reg', (115, 122))	('elongated structures', 'MPA', (128, 148))	('amplification', 'MPA', (88, 101))
25835	30976068	The developed strategy kept a low background signal for the detection of KRAS mutation by adding a mismatch site.	('mismatch site', 'MPA', (99, 112))	('KRAS', 'Gene', (73, 77))	('mutation', 'Var', (78, 86))	('KRAS', 'Gene', '3845', (73, 77))
25836	30976068	Moreover, the developed strategy can also be successfully applied for the detection of KRAS mutation from tissue samples of colorectal cancer patients, presenting a promising application for ultrasensitive detection of mutation in clinical diagnosis.	('KRAS', 'Gene', (87, 91))	('mutation', 'Var', (92, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('KRAS', 'Gene', '3845', (87, 91))	('colorectal cancer', 'Disease', (124, 141))	('clinical', 'Species', '191496', (231, 239))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('patients', 'Species', '9606', (142, 150))	('colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))
25842	30976068	As a result, 7 of 10 samples harbored the KRAS mutation, whereas the other 3 samples were negative.	('KRAS', 'Gene', (42, 46))	('mutation', 'Var', (47, 55))	('harbored', 'Reg', (29, 37))	('KRAS', 'Gene', '3845', (42, 46))
25843	30976068	These results demonstrated the proposed strategy can be applied for the identification of KRAS mutation in genomic DNA from tissue samples, holding a great potential in the diagnosis of mutation-related human diseases.	('KRAS', 'Gene', (90, 94))	('human', 'Species', '9606', (203, 208))	('KRAS', 'Gene', '3845', (90, 94))	('mutation', 'Var', (95, 103))
25845	30976068	Moreover, the strategy has been successfully applied for the accurate detection of mutation from the tissue samples of colorectal cancer patients, and the results of our method are consistent with the that of RT-PCR.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('colorectal cancer', 'Disease', (119, 136))	('patients', 'Species', '9606', (137, 145))	('mutation', 'Var', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))
25867	30374420	For instance, Fusobacterium can activate the E-cadherin/beta-catenin signaling pathway and is associated with particular epigenetic phenotype, such as microsatellite instability (MSI) and hypermethylation, via its strong adhesive and invasive abilities resulting in malignant transformation of epithelial cells.	('MSI', 'Disease', 'None', (179, 182))	('microsatellite', 'MPA', (151, 165))	('Fusobacterium', 'Var', (14, 27))	('adhesive', 'CPA', (221, 229))	('invasive abilities', 'CPA', (234, 252))	('MSI', 'Disease', (179, 182))	('resulting in', 'Reg', (253, 265))	('activate', 'PosReg', (32, 40))	('E-cadherin/beta-catenin signaling pathway', 'Pathway', (45, 86))	('hypermethylation', 'Var', (188, 204))	('malignant transformation of epithelial cells', 'CPA', (266, 310))	('Fusobacterium', 'Species', '859', (14, 27))
25875	30374420	This finding denotes the importance of gut microbiota symbiosis and the dysfunctional proportion could exacerbate human diseases, since both normal and pathogenic flora are important in the regulation of homeostasis.	('dysfunctional', 'Var', (72, 85))	('human diseases', 'Disease', (114, 128))	('human', 'Species', '9606', (114, 119))	('exacerbate', 'PosReg', (103, 113))
25882	30374420	Although it is still unclear whether Fusobacterium is the passenger or driver of CRC, many studies have concluded that Fusobacterium is a novel risk factor for CRC development and progression, as well as a determinant affecting patient survival outcomes.	('Fusobacterium', 'Var', (119, 132))	('CRC', 'Disease', (160, 163))	('Fusobacterium', 'Species', '859', (37, 50))	('CRC', 'Phenotype', 'HP:0003003', (81, 84))	('CRC', 'Phenotype', 'HP:0003003', (160, 163))	('Fusobacterium', 'Species', '859', (119, 132))	('patient', 'Species', '9606', (228, 235))
25900	30374420	Consistently, the expression of oncogenes, inflammatory genes and Wnt genes are increased in CRC cells under modulation of purified FadA.	('FadA', 'Chemical', '-', (132, 136))	('Wnt genes', 'Gene', (66, 75))	('increased', 'PosReg', (80, 89))	('CRC', 'Phenotype', 'HP:0003003', (93, 96))	('oncogenes', 'Gene', (32, 41))	('expression', 'MPA', (18, 28))	('modulation', 'Var', (109, 119))	('inflammatory genes', 'Gene', (43, 61))
25901	30374420	Further experiments with purified FadA or F. nucleatum could only stimulated cell lines with APC or beta-catenin mutations but not non-cancerous HEK-293 cells, indicated that oncogenesis promoted by Fusobacterium was secondary to these significant mutation events.	('HEK-293', 'CellLine', 'CVCL:0045', (145, 152))	('cancerous', 'Disease', (135, 144))	('oncogenesis', 'CPA', (175, 186))	('Fusobacterium', 'Species', '859', (199, 212))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutations', 'Var', (113, 122))	('F. nucleatum', 'Species', '851', (42, 54))	('cancerous', 'Disease', 'MESH:D009369', (135, 144))	('APC', 'Disease', 'MESH:D011125', (93, 96))	('FadA', 'Chemical', '-', (34, 38))	('APC', 'Disease', (93, 96))
25907	30374420	Abnormalities on either side will disrupt this balance and brings about disease and malignancy.	('Abnormalities', 'Var', (0, 13))	('disrupt', 'NegReg', (34, 41))	('malignancy', 'Disease', 'MESH:D009369', (84, 94))	('balance', 'MPA', (47, 54))	('brings about', 'Reg', (59, 71))	('malignancy', 'Disease', (84, 94))	('disease', 'CPA', (72, 79))
25909	30374420	In APC gene deleted mouse models (CRC animal models), significant defective intestinal barrier function at tumor sites has been described and therefore concluded that changes in the local environment and a deficient barrier could provide favorable condition for Fusobacterium to reproduce and cause further mucosal injury.	('CRC', 'Phenotype', 'HP:0003003', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('mucosal injury', 'Disease', (307, 321))	('intestinal barrier function at', 'CPA', (76, 106))	('tumor', 'Disease', (107, 112))	('mucosal injury', 'Disease', 'MESH:D052016', (307, 321))	('APC', 'Disease', 'MESH:D011125', (3, 6))	('APC', 'Disease', (3, 6))	('changes', 'Var', (167, 174))	('defective', 'NegReg', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cause', 'Reg', (293, 298))	('Fusobacterium', 'Species', '859', (262, 275))	('mouse', 'Species', '10090', (20, 25))
25925	30374420	found that CD11b+ myeloid derived suppressive cells (MDSCs), including granulocytes/tumor associated neutrophils (TANs) and macrophages/tumor associated macrophages (TAMs), are more abundant in tumor tissues than normal tissue of Fusobacterium-fed APC Min mice.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('CD11b+', 'Var', (11, 17))	('mice', 'Species', '10090', (256, 260))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', (84, 89))	('APC', 'Disease', 'MESH:D011125', (248, 251))	('APC', 'cellular_component', 'GO:0005680', ('248', '251'))	('TAMs', 'Chemical', '-', (166, 170))	('tumor', 'Disease', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('APC', 'Disease', (248, 251))	('Fusobacterium', 'Species', '859', (230, 243))	('tumor', 'Disease', (136, 141))
25932	30374420	It is well documented that inflammatory oxidative stress can lead to p53 mutation, thus promoting oncogenesis.	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('lead', 'Reg', (61, 65))	('oncogenesis', 'CPA', (98, 109))	('promoting', 'PosReg', (88, 97))	('mutation', 'Var', (73, 81))	('oxidative stress', 'Phenotype', 'HP:0025464', (40, 56))
25933	30374420	Oxidative stress also contributes to aberrant hypermethylation, which in turn causes tumor-suppressive gene inactivation and carcinogenesis.	('tumor', 'Disease', (85, 90))	('hypermethylation', 'MPA', (46, 62))	('causes', 'Reg', (78, 84))	('inactivation', 'NegReg', (108, 120))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('carcinogenesis', 'Disease', 'MESH:D063646', (125, 139))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('carcinogenesis', 'Disease', (125, 139))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('aberrant', 'Var', (37, 45))
25934	30374420	Hypermethylation could also occur in promoter regions of mismatch repair protein (MLH1) gene and result in microsatellite instability (MSI), which was recognized as an early molecular phenomenon in CRC.	('MSI', 'Disease', (135, 138))	('result in', 'Reg', (97, 106))	('Hypermethylation', 'Var', (0, 16))	('microsatellite instability', 'MPA', (107, 133))	('MLH1', 'Gene', '4292', (82, 86))	('MLH1', 'Gene', (82, 86))	('MSI', 'Disease', 'None', (135, 138))	('CRC', 'Phenotype', 'HP:0003003', (198, 201))
25937	30374420	Mice treated with Fusobacterium were found to have more CD103+ DCs within tumors compared with control groups.	('Fusobacterium', 'Species', '859', (18, 31))	('CD103+ DCs', 'Var', (56, 66))	('Fusobacterium', 'Var', (18, 31))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('more', 'PosReg', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('Mice', 'Species', '10090', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('CD', 'Chemical', 'MESH:D002104', (56, 58))	('tumors', 'Disease', (74, 80))
25938	30374420	These cells regulate immune responses by promoting the activation of Foxp3+ regulatory T cells, a CD4+ T cell subset that inhibits cytotoxic and effector T cells, and results in restrained antitumor immunity.	('promoting', 'PosReg', (41, 50))	('immune responses', 'CPA', (21, 37))	('inhibits', 'NegReg', (122, 130))	('Foxp3+', 'Var', (69, 75))	('cytotoxic and', 'CPA', (131, 144))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('regulate', 'Reg', (12, 20))	('CD4', 'Species', '1151252', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', (193, 198))	('restrained', 'NegReg', (178, 188))	('activation', 'PosReg', (55, 65))
25944	30374420	Kaplan found that Fap2, together with adhesin RadD can cause lymphocyte death by direct contact with target lymphocytes.	('Fap2', 'Var', (18, 22))	('Fap2', 'Species', '1412835', (18, 22))	('death', 'Disease', 'MESH:D003643', (72, 77))	('death', 'Disease', (72, 77))	('cause', 'Reg', (55, 60))
25947	30374420	Recent findings support the claim that Fusobacterium could enhance the development from being in inflammatory state to malignancy.	('development', 'CPA', (71, 82))	('malignancy', 'Disease', (119, 129))	('enhance', 'PosReg', (59, 66))	('Fusobacterium', 'Species', '859', (39, 52))	('Fusobacterium', 'Var', (39, 52))	('malignancy', 'Disease', 'MESH:D009369', (119, 129))
25949	30374420	Higher level of inflammation and more colonic tumors were found in the F. nucleatum group compared to control.	('F. nucleatum', 'Species', '851', (71, 83))	('inflammation', 'Disease', 'MESH:D007249', (16, 28))	('colonic tumors', 'Disease', 'MESH:D015179', (38, 52))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('F. nucleatum', 'Var', (71, 83))	('inflammation', 'biological_process', 'GO:0006954', ('16', '28'))	('inflammation', 'Disease', (16, 28))	('colonic tumors', 'Disease', (38, 52))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('more', 'PosReg', (33, 37))
25951	30374420	This may suggest that Fusobacterium induce oncogenesis downstream of the APC pathway and the tumorigenesis does not depend on pre-existing colitis condition because the colitis mice did not develop colon tumors after F. nucleatum introduction.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('colitis', 'Disease', 'MESH:D003092', (169, 176))	('colitis', 'Disease', 'MESH:D003092', (139, 146))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('Fusobacterium', 'Species', '859', (22, 35))	('colon tumors', 'Disease', 'MESH:D015179', (198, 210))	('colitis', 'Phenotype', 'HP:0002583', (169, 176))	('colitis', 'Phenotype', 'HP:0002583', (139, 146))	('Fusobacterium', 'Var', (22, 35))	('oncogenesis', 'CPA', (43, 54))	('colon tumors', 'Phenotype', 'HP:0100273', (198, 210))	('F. nucleatum', 'Species', '851', (217, 229))	('mice', 'Species', '10090', (177, 181))	('colon tumors', 'Disease', (198, 210))	('colitis', 'Disease', (169, 176))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (204, 209))	('APC', 'Disease', 'MESH:D011125', (73, 76))	('colitis', 'Disease', (139, 146))	('APC', 'Disease', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
25959	30374420	Moreover, p53 overexpression also leads to TP53 mutation, which is a key event during CRC development.	('p53', 'Gene', '7157', (10, 13))	('leads to', 'Reg', (34, 42))	('CRC', 'Phenotype', 'HP:0003003', (86, 89))	('mutation', 'Var', (48, 56))	('TP53', 'Gene', (43, 47))	('p53', 'Gene', (10, 13))
25960	30374420	Additionally, chronic inflammation and ROS production cause many other mutations (such as CHD7 and CHD8, members of the chromodomain helicase/ATP-dependent chromatin remodeling family and genomic instability), all of which would accelerate CRC development.	('ROS', 'Chemical', 'MESH:D017382', (39, 42))	('CHD', 'Disease', (99, 102))	('cause', 'Reg', (54, 59))	('accelerate', 'PosReg', (229, 239))	('CRC development', 'CPA', (240, 255))	('CHD7', 'CellLine', 'CVCL:3472', (90, 94))	('CRC', 'Phenotype', 'HP:0003003', (240, 243))	('chromatin', 'cellular_component', 'GO:0000785', ('156', '165'))	('CHD', 'Disease', 'None', (90, 93))	('ATP', 'Chemical', 'MESH:D000255', (142, 145))	('mutations', 'Var', (71, 80))	('inflammation', 'Disease', 'MESH:D007249', (22, 34))	('CHD', 'Disease', (90, 93))	('inflammation', 'biological_process', 'GO:0006954', ('22', '34'))	('inflammation', 'Disease', (22, 34))	('ATP-dependent chromatin remodeling', 'biological_process', 'GO:0043044', ('142', '176'))	('CHD', 'Disease', 'None', (99, 102))
25962	30374420	Fusobacterium detected in colorectal cancer tissues was related to CpG island methylator phenotype (CIMP) status, high MSI and MLH1 hypermethylation and up-regulating expression of microRNA-21.	('high', 'Var', (114, 118))	('microRNA-21', 'Gene', (181, 192))	('MLH1', 'Gene', (127, 131))	('up-regulating', 'PosReg', (153, 166))	('MSI', 'Disease', (119, 122))	('colorectal cancer', 'Disease', (26, 43))	('MLH1', 'Gene', '4292', (127, 131))	('hypermethylation', 'Var', (132, 148))	('colorectal cancer', 'Disease', 'MESH:D015179', (26, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('colorectal cancer', 'Phenotype', 'HP:0003003', (26, 43))	('CIMP', 'Chemical', '-', (100, 104))	('expression', 'MPA', (167, 177))	('Fusobacterium', 'Species', '859', (0, 13))	('MSI', 'Disease', 'None', (119, 122))
25965	30374420	CIMP is characterized by simultaneous hypermethylation of numerous CpG islands surrounding the promoter regions of several genes.	('hypermethylation', 'Var', (38, 54))	('CIMP', 'Chemical', '-', (0, 4))	('CIMP', 'Disease', (0, 4))
25968	30374420	Inflammatory state and reactive oxygen stress produced by Fusobacterium may contribute to epigenetic silencing of the MMR protein MLH1 and reduction of its enzymatic activity, which leads to MSI CRC.	('epigenetic', 'Var', (90, 100))	('MSI', 'Disease', (191, 194))	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('Fusobacterium', 'Species', '859', (58, 71))	('MLH1', 'Gene', '4292', (130, 134))	('silencing', 'NegReg', (101, 110))	('CRC', 'Phenotype', 'HP:0003003', (195, 198))	('MLH1', 'Gene', (130, 134))	('reduction', 'NegReg', (139, 148))	('reactive oxygen stress', 'Phenotype', 'HP:0025464', (23, 45))	('leads to', 'Reg', (182, 190))	('MSI', 'Disease', 'None', (191, 194))	('enzymatic activity', 'MPA', (156, 174))	('MMR', 'biological_process', 'GO:0006298', ('118', '121'))	('oxygen', 'Chemical', 'MESH:D010100', (32, 38))
25971	30374420	microRNA-21 in turn increases the levels of IL-10 and PGE2 (prostaglandin E2), which inhibit antitumor immunity mediated by T cells in the TME, and therefore high level of microRNA-21 usually indicates worse clinical outcomes.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('IL-10', 'Gene', '16153', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('IL-10', 'Gene', (44, 49))	('inhibit', 'NegReg', (85, 92))	('high', 'Var', (158, 162))	('tumor', 'Disease', (97, 102))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (60, 76))	('levels', 'MPA', (34, 40))	('PGE2', 'Chemical', 'MESH:D015232', (54, 58))
25973	30374420	Numerous studies have found that enrichment of Fusobacterium is related to worse clinical outcome in CRC patients.	('patients', 'Species', '9606', (105, 113))	('enrichment', 'Var', (33, 43))	('CRC', 'Disease', (101, 104))	('related', 'Reg', (64, 71))	('CRC', 'Phenotype', 'HP:0003003', (101, 104))	('Fusobacterium', 'Species', '859', (47, 60))	('Fusobacterium', 'Var', (47, 60))
25978	30374420	In FadA-E cadherin pathway, FadA gene copy number has been found to have a direct correlation with either healthy, pre-cancerous or CRC states, suggesting that FadA may be a promising biomarker in CRC diagnosis.	('FadA', 'Chemical', '-', (28, 32))	('FadA', 'Chemical', '-', (3, 7))	('cancerous', 'Disease', 'MESH:D009369', (119, 128))	('FadA', 'Chemical', '-', (160, 164))	('FadA-E cadherin pathway', 'Pathway', (3, 26))	('CRC states', 'Disease', (132, 142))	('CRC', 'Phenotype', 'HP:0003003', (132, 135))	('FadA', 'Gene', (28, 32))	('correlation', 'Reg', (82, 93))	('cancerous', 'Disease', (119, 128))	('gene copy number', 'Var', (33, 49))	('CRC', 'Phenotype', 'HP:0003003', (197, 200))	('healthy', 'Disease', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
26010	30374420	It would be a possible explanation that CRC cells with frameshift mutations in the absence of normal mismatch repair function produce a mutation-associated neoantigen, which may activate anti-tumor immunity and enhance the effect of PD-L1 blockade.	('tumor', 'Disease', (192, 197))	('activate', 'PosReg', (178, 186))	('frameshift mutations', 'Var', (55, 75))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('mutation-associated', 'Reg', (136, 155))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('mismatch repair', 'biological_process', 'GO:0006298', ('101', '116'))	('CRC', 'Phenotype', 'HP:0003003', (40, 43))	('enhance', 'PosReg', (211, 218))	('neoantigen', 'MPA', (156, 166))
26012	30374420	Further studies are needed to clarify whether Fusobacterium influences mismatch repair signaling pathways and alters the patient's immune response.	('immune response', 'biological_process', 'GO:0006955', ('131', '146'))	('influences', 'Reg', (60, 70))	('signaling', 'biological_process', 'GO:0023052', ('87', '96'))	('mismatch repair signaling pathways', 'Pathway', (71, 105))	('Fusobacterium', 'Species', '859', (46, 59))	('mismatch repair', 'biological_process', 'GO:0006298', ('71', '86'))	('Fusobacterium', 'Var', (46, 59))	('alters', 'Reg', (110, 116))	('immune response', 'CPA', (131, 146))	('patient', 'Species', '9606', (121, 128))
26019	30374420	In another paper, Dejea and colleagues studied patchy biofilms in colonic mucosa of patients with an APC gene mutations.	('colonic mucosa', 'Disease', 'MESH:D015179', (66, 80))	('APC', 'Disease', (101, 104))	('colonic mucosa', 'Disease', (66, 80))	('mutations', 'Var', (110, 119))	('patients', 'Species', '9606', (84, 92))	('APC', 'cellular_component', 'GO:0005680', ('101', '104'))	('APC', 'Disease', 'MESH:D011125', (101, 104))
26022	30374420	In a cohort study of 137217 adults to explore the association between diets with CRC prevalence, a stronger relationship between diet and CRC was found in F. nucleatum enriched individuals than subgroups without F. nucleatum detection.	('CRC', 'Disease', (81, 84))	('F. nucleatum', 'Species', '851', (212, 224))	('F. nucleatum', 'Var', (155, 167))	('CRC', 'Phenotype', 'HP:0003003', (138, 141))	('F. nucleatum', 'Species', '851', (155, 167))	('CRC', 'Phenotype', 'HP:0003003', (81, 84))
26040	27463203	Isolates Efm106, Efm121 and Efm113 (p < .001 compared to Ef222) exhibited the higher translocation ability and were able to adhere 2-3 times higher than S. gallolyticus isolates.	('translocation', 'MPA', (85, 98))	('Efm113', 'Var', (28, 34))	('higher', 'PosReg', (78, 84))	('adhere', 'CPA', (124, 130))	('S. gallolyticus', 'Species', '315405', (153, 168))	('higher', 'PosReg', (141, 147))	('Efm121', 'Var', (17, 23))	('Efm106', 'Var', (9, 15))
26078	27463203	Indeed, the translocation ability of the four S. gallolyticus isolates was considered low (Sg74) or medium (Sg1, Sg6 and Sg78) whereas E. faecium isolates were classified as medium (Efm222) or high (Efm197, Efm217, Efm113, Efm121, Efm106).	('E. faecium', 'Species', '1352', (135, 145))	('Efm106', 'Var', (231, 237))	('Efm217', 'Var', (207, 213))	('S. gallolyticus', 'Species', '315405', (46, 61))	('Efm113', 'Var', (215, 221))	('Efm121', 'Var', (223, 229))	('Efm197', 'Var', (199, 205))	('translocation', 'MPA', (12, 25))
26085	27463203	In particular, strains Efm106, Efm113, Efm121 and Efm197, isolated from oncohaematological patients and harbouring the esp and acm genes, adhered two to six times more than S. gallolyticus strains.	('patients', 'Species', '9606', (91, 99))	('Efm113', 'Var', (31, 37))	('adhered', 'Interaction', (138, 145))	('esp', 'Gene', '148713', (119, 122))	('Efm121', 'Var', (39, 45))	('S. gallolyticus', 'Species', '315405', (173, 188))	('esp', 'Gene', (119, 122))	('Efm197', 'Var', (50, 56))	('Efm106', 'Var', (23, 29))	('more', 'PosReg', (163, 167))
26087	27463203	On the three surfaces tested, S. gallolyticus isolates formed biofilms more efficiently (weak or strong) than the enterococcal ones, independently of their origin.	('S. gallolyticus', 'Species', '315405', (30, 45))	('biofilms', 'CPA', (62, 70))	('S. gallolyticus', 'Var', (30, 45))
26089	27463203	Globally, the density of the biofilm produced by S. gallolyticus was, in all cases, significantly higher than that produced by the enterococcal species (Fig 3).	('higher', 'PosReg', (98, 104))	('S. gallolyticus', 'Species', '315405', (49, 64))	('S. gallolyticus', 'Var', (49, 64))	('density', 'MPA', (14, 21))
26104	27463203	In our model, E. faecium induced a decrease in TER values below that of the control cells (not exposed to bacteria) suggesting a destabilization of the epithelium.	('decrease', 'NegReg', (35, 43))	('TER values', 'MPA', (47, 57))	('E. faecium', 'Species', '1352', (14, 24))	('E. faecium', 'Var', (14, 24))
26119	27463203	Variations in the expression of these components might also modulate the translocation process and be responsible for the differences detected in each strain.	('translocation process', 'CPA', (73, 94))	('modulate', 'Reg', (60, 68))	('Variations', 'Var', (0, 10))	('expression', 'MPA', (18, 28))	('esp', 'Gene', '148713', (103, 106))	('esp', 'Gene', (103, 106))
26121	27463203	In E. faecium the presence of esp has been related with initial adherence to polystyrene and biofilm formation in urinary experimental infection models.	('presence', 'Var', (18, 26))	('esp', 'Gene', '148713', (30, 33))	('biofilm formation', 'CPA', (93, 110))	('esp', 'Gene', (30, 33))	('polystyrene', 'Chemical', 'MESH:D011137', (77, 88))	('related', 'Reg', (43, 50))	('biofilm formation', 'biological_process', 'GO:0042710', ('93', '110'))	('E. faecium', 'Species', '1352', (3, 13))
26125	27463203	This locus, encoding 2 LPXTG proteins (Gallo2178 and Gallo2179) and 1 sortase C (Gallo2177), was shown to be essential for adhesion to collagen I and contributed to colonization and establishment of infective endocarditis in rat models.	('infective endocarditis', 'Disease', 'MESH:D004696', (199, 221))	('rat', 'Species', '10116', (225, 228))	('colonization', 'CPA', (165, 177))	('Gallo2178', 'Var', (39, 48))	('infective endocarditis', 'Phenotype', 'HP:0006689', (199, 221))	('Gallo2179', 'Var', (53, 62))	('endocarditis', 'Phenotype', 'HP:0100584', (209, 221))	('infective endocarditis', 'Disease', (199, 221))	('contributed', 'Reg', (150, 161))	('adhesion', 'MPA', (123, 131))	('collagen', 'molecular_function', 'GO:0005202', ('135', '143'))
26143	25967390	In this review, we summarize a growing body of preclinical and clinical data that indicate that while NEDD9 is itself non-oncogenic, changes in expression of NEDD9 (most commonly elevation of expression) are common features of tumors, and directly impact tumor aggressiveness, metastasis, and response to at least some targeted agents inhibiting NEDD9-interacting proteins.	('response', 'CPA', (293, 301))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('expression', 'MPA', (144, 154))	('expression', 'MPA', (192, 202))	('elevation', 'PosReg', (179, 188))	('tumors', 'Disease', (227, 233))	('changes', 'Var', (133, 140))	('NEDD9', 'Gene', (102, 107))	('metastasis', 'CPA', (277, 287))	('impact tumor aggressiveness', 'Disease', (248, 275))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('impact tumor aggressiveness', 'Disease', 'MESH:D004834', (248, 275))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('NEDD9', 'Gene', (158, 163))	('aggressiveness', 'Phenotype', 'HP:0000718', (261, 275))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
26147	25967390	Because of its pleiotropic function, in many human cancers, altered expression of NEDD9 has emerged as predictive of poor outcome, metastatic potential, and resistance to chemotherapy, while altered NEDD9 function has more recently been linked to additional non-malignant pathological conditions, such as stroke and polycystic kidney disease.	('linked', 'Reg', (237, 243))	('stroke', 'Disease', (305, 311))	('expression', 'MPA', (68, 78))	('stroke', 'Disease', 'MESH:D020521', (305, 311))	('metastatic potential', 'CPA', (131, 151))	('NEDD9', 'Gene', (82, 87))	('altered', 'Var', (191, 198))	('polycystic kidney disease', 'Disease', (316, 341))	('human', 'Species', '9606', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('altered', 'Var', (60, 67))	('polycystic kidney', 'Phenotype', 'HP:0000113', (316, 333))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('polycystic kidney disease', 'Disease', 'MESH:D007690', (316, 341))	('kidney disease', 'Phenotype', 'HP:0000112', (327, 341))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('stroke', 'Phenotype', 'HP:0001297', (305, 311))
26148	25967390	Neither overexpression nor gene loss of NEDD9 induces tumorigenesis in the absence of other driver lesions.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('NEDD9', 'Gene', (40, 45))	('gene loss', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('induces', 'Reg', (46, 53))
26150	25967390	In this article, we summarize the current preclinical and clinical data describing the action of NEDD9 in cancer, placing this work in the context of specific mechanisms by which altered expression of NEDD9 supports the disease process.	('altered', 'Var', (179, 186))	('NEDD9', 'Gene', (201, 206))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('expression', 'MPA', (187, 197))	('supports', 'PosReg', (207, 215))	('disease', 'Disease', (220, 227))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
26153	25967390	It is possible that a SNP located in an intronic region of NEDD9 contributes to predisposition to late onset Alzheimer's disease, although this is not yet proven, as is discussed more fully in.	("Alzheimer's disease", 'Disease', (109, 128))	('contributes', 'Reg', (65, 76))	('predisposition', 'Reg', (80, 94))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (109, 128))	('NEDD9', 'Gene', (59, 64))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (109, 128))	('SNP located', 'Var', (22, 33))
26163	25967390	These activities are reflected in a growing number of studies that recognize elevation of NEDD9 as a factor contributing to aggressive tumor behavior.	('NEDD9', 'Gene', (90, 95))	('elevation', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('aggressive tumor', 'Disease', 'MESH:D001523', (124, 140))	('contributing', 'Reg', (108, 120))	('aggressive tumor', 'Disease', (124, 140))
26165	25967390	This may reflect underlying differences in the biology of distinct tumor types (for instance, solid versus liquid tumors), but alternatively or in addition may reflect dominant negative activity associated with loss of NEDD9, based on the disruption of signaling complexes for which it is an essential scaffold.	('negative', 'NegReg', (177, 185))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('activity', 'MPA', (186, 194))	('loss', 'Var', (211, 215))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (114, 119))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumor', 'Disease', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('NEDD9', 'Gene', (219, 224))
26169	25967390	Ligation of beta-integrin signaling causes NEDD9 tyrosine phosphorylation by FAK and by the FAK related kinase RAFTK, and subsequently phosphorylation by SRC kinases.	('FAK', 'Gene', '5747', (77, 80))	('tyrosine', 'Chemical', 'MESH:D014443', (49, 57))	('Ligation', 'Var', (0, 8))	('SRC', 'Gene', '6714', (154, 157))	('SRC', 'Gene', (154, 157))	('RAFTK', 'Gene', (111, 116))	('FAK', 'Gene', (92, 95))	('FAK', 'Gene', (77, 80))	('FAK', 'Gene', '5747', (92, 95))	('NEDD9', 'Gene', (43, 48))	('RAFTK', 'Gene', '2185', (111, 116))	('phosphorylation', 'MPA', (135, 150))
26173	25967390	Soon after the initial description of the protein, altered NEDD9 activity was associated with the pathogenesis of BCR/ABL-dependent tumors, such as the Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) and chronic myelogenous leukemia (CML).	('activity', 'MPA', (65, 73))	('CML', 'Phenotype', 'HP:0005506', (260, 263))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (230, 258))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (197, 219))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('ABL-dependent tumors', 'Disease', 'MESH:D000012', (118, 138))	('leukemia', 'Phenotype', 'HP:0001909', (211, 219))	('NEDD9', 'Gene', (59, 64))	('ALL', 'Phenotype', 'HP:0006721', (221, 224))	('CML', 'Disease', 'MESH:D015464', (260, 263))	('associated', 'Reg', (78, 88))	('altered', 'Var', (51, 58))	('CML', 'Disease', (260, 263))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('acute lymphoblastic leukemia', 'Disease', (191, 219))	('leukemia', 'Phenotype', 'HP:0001909', (250, 258))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (230, 258))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (191, 219))	('chronic myelogenous leukemia', 'Disease', (230, 258))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('pathogenesis', 'biological_process', 'GO:0009405', ('98', '110'))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (238, 258))	('chromosome', 'cellular_component', 'GO:0005694', ('165', '175'))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (191, 219))	('ABL-dependent tumors', 'Disease', (118, 138))
26174	25967390	showed that NEDD9 is hyperphosphorylated in P190BCR/ABL transgenic mice with pre-B cell ALL.	('ALL', 'Phenotype', 'HP:0006721', (88, 91))	('P190BCR/ABL', 'Var', (44, 55))	('NEDD9', 'Gene', (12, 17))	('transgenic mice', 'Species', '10090', (56, 71))
26175	25967390	In P190BCR/ABL transgenic mice, hyperphosphorylated NEDD9 was recovered from complexes with BCR/ABL and CRKL.	('complexes', 'Interaction', (77, 86))	('P190BCR/ABL', 'Var', (3, 14))	('transgenic mice', 'Species', '10090', (15, 30))
26179	25967390	ABL-mediated tyrosine phosphorylation of NEDD9 and binding of C3G leads to activation of Rap1 and migration/chemotaxis of lymphoid cells.	('Rap1', 'Gene', '5906', (89, 93))	('binding', 'molecular_function', 'GO:0005488', ('51', '58'))	('C3G', 'Gene', (62, 65))	('migration/chemotaxis of lymphoid cells', 'CPA', (98, 136))	('chemotaxis', 'biological_process', 'GO:0006935', ('108', '118'))	('binding', 'Interaction', (51, 58))	('activation', 'PosReg', (75, 85))	('C3G', 'Gene', '2889', (62, 65))	('Rap1', 'Gene', (89, 93))	('phosphorylation', 'biological_process', 'GO:0016310', ('22', '37'))	('tyrosine', 'Chemical', 'MESH:D014443', (13, 21))	('NEDD9', 'Gene', (41, 46))	('tyrosine', 'Var', (13, 21))
26182	25967390	analyzed the consequence of deleting NEDD9 in a transgenic model for BCR-ABL leukemogenesis, and surprisingly found that the disease was more aggressive in mice lacking NEDD9.	('NEDD9', 'Gene', (37, 42))	('lacking', 'NegReg', (161, 168))	('NEDD9', 'Gene', (169, 174))	('BCR-ABL', 'Gene', '25', (69, 76))	('deleting', 'Var', (28, 36))	('mice', 'Species', '10090', (156, 160))	('transgenic', 'Species', '10090', (48, 58))	('BCR-ABL', 'Gene', (69, 76))
26186	25967390	showed that, at the age of 1 year, 9 out of 11 Nedd9-/- mice and 8 out of 11 Nedd9+/- mice developed reactive lymphoid hyperplasia affecting solid tissues, in contrast to only 2 out of 11 of Nedd9+/+ animals.	('lymphoid hyperplasia', 'Disease', (110, 130))	('mice', 'Species', '10090', (86, 90))	('Nedd9-/-', 'Var', (47, 55))	('mice', 'Species', '10090', (56, 60))	('lymphoid hyperplasia', 'Disease', 'MESH:D006965', (110, 130))	('lymphoid hyperplasia', 'Phenotype', 'HP:0002716', (110, 130))
26187	25967390	Further, Nedd9 knockout resulted in a minor decrease in the concentration of B cells, but increased macrophages in the peripheral blood and spleen of Nedd9-/- in comparison to Nedd9+/+ mice.	('knockout', 'Var', (15, 23))	('decrease', 'NegReg', (44, 52))	('macrophages', 'CPA', (100, 111))	('increased', 'PosReg', (90, 99))	('mice', 'Species', '10090', (185, 189))	('Nedd9', 'Gene', (9, 14))	('concentration of B cells', 'MPA', (60, 84))
26205	25967390	MMTV-expressed PyVmT antigen induces mammary cancers due to its binding and activation of the proteins SHC, SRC, and PI3K, which are central effectors of HER2 signaling.	('binding', 'Interaction', (64, 71))	('PI3K', 'molecular_function', 'GO:0016303', ('117', '121'))	('binding', 'molecular_function', 'GO:0005488', ('64', '71'))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('PyVmT', 'Var', (15, 20))	('HER2', 'Gene', '2064', (154, 158))	('SHC', 'Gene', (103, 106))	('signaling', 'biological_process', 'GO:0023052', ('159', '168'))	('SHC', 'Gene', '6464', (103, 106))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('HER2', 'Gene', (154, 158))	('induces', 'PosReg', (29, 36))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('SRC', 'Gene', (108, 111))	('cancers', 'Disease', (45, 52))	('MMTV', 'Species', '11757', (0, 4))	('activation', 'PosReg', (76, 86))	('SRC', 'Gene', '6714', (108, 111))
26206	25967390	Lack of NEDD9 increased the latency until tumor appearance, and slowed the growth rate of mammary tumors.	('increased', 'PosReg', (14, 23))	('tumors', 'Disease', (98, 104))	('tumor', 'Disease', (42, 47))	('slowed', 'NegReg', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('NEDD9', 'Gene', (8, 13))	('Lack', 'Var', (0, 4))	('latency', 'MPA', (28, 35))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
26219	25967390	This was mediated in part by inactivation of MMP14, and confirmed the tumor-intrinsic effect of loss of NEDD9.	('NEDD9', 'Gene', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('loss', 'Var', (96, 100))	('tumor', 'Disease', (70, 75))	('MMP14', 'Gene', '4323', (45, 50))	('MMP14', 'Gene', (45, 50))	('inactivation', 'Var', (29, 41))	('MMP', 'molecular_function', 'GO:0004235', ('45', '48'))
26224	25967390	Subsequent studies showed that NEDD9 function is required not only for the trafficking of MMP14, but also for the trafficking of ligand-bound integrins, likely through the inactivation of tyrosine phosphorylated caveolin-1 (CAV1) (Fig.	('caveolin-1', 'Gene', (212, 222))	('MMP14', 'Gene', (90, 95))	('caveolin-1', 'Gene', '857', (212, 222))	('inactivation', 'Var', (172, 184))	('CAV1', 'Gene', (224, 228))	('MMP', 'molecular_function', 'GO:0004235', ('90', '93'))	('tyrosine', 'Chemical', 'MESH:D014443', (188, 196))	('ligand', 'molecular_function', 'GO:0005488', ('129', '135'))	('MMP14', 'Gene', '4323', (90, 95))	('CAV1', 'Gene', '857', (224, 228))
26244	25967390	Intriguingly, several studies of NEDD9 raise the possibility that under some conditions, loss of NEDD9 rather than its overexpression can induce features associated with tumor promotion in mammary tissue.	('loss', 'Var', (89, 93))	('NEDD9', 'Gene', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('induce', 'Reg', (138, 144))	('tumor', 'Disease', (170, 175))
26246	25967390	As previously discussed, Nedd9 knockout was associated with increased number of lung metastases following tail vein injection of the tumor cells in some mouse models.	('lung metastases', 'Disease', (80, 95))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('lung metastases', 'Disease', 'MESH:D009362', (80, 95))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Nedd9', 'Gene', (25, 30))	('mouse', 'Species', '10090', (153, 158))	('tumor', 'Disease', (133, 138))	('knockout', 'Var', (31, 39))
26249	25967390	Somatic mutations of the LKB1 tumor suppressor gene, or loss of the region of chromosome 19p containing LKB1, are present in about one third of lung adenocarcinomas.	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (144, 164))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (144, 164))	('LKB1', 'Gene', (25, 29))	('loss', 'NegReg', (56, 60))	('LKB1', 'Gene', (104, 108))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (144, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('mutations', 'Var', (8, 17))	('LKB1', 'Gene', '6794', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('LKB1', 'Gene', '6794', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('lung adenocarcinomas', 'Disease', (144, 164))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))	('tumor', 'Disease', (30, 35))
26253	25967390	Ectopic expression of either NEDD9 or CRTC1 partially reversed the inhibitory function of LKB1 on metastasis of lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('NEDD9', 'Gene', (29, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('CRTC1', 'Gene', (38, 43))	('CRTC1', 'Gene', '23373', (38, 43))	('LKB1', 'Gene', (90, 94))	('metastasis of lung cancer', 'Disease', 'MESH:D009362', (98, 123))	('Ectopic', 'Var', (0, 7))	('LKB1', 'Gene', '6794', (90, 94))	('metastasis of lung cancer', 'Disease', (98, 123))	('inhibitory function', 'MPA', (67, 86))
26254	25967390	In mouse models, RNAi-mediated silencing of Nedd9 inhibited tumor progression of Lkb1-deficient lung tumors, whereas ectopic NEDD9 expression accelerated tumor growth.	('silencing', 'Var', (31, 40))	('Lkb1-deficient lung tumors', 'Disease', (81, 107))	('Nedd9', 'Gene', (44, 49))	('mouse', 'Species', '10090', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('deficient lung', 'Phenotype', 'HP:0002089', (86, 100))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('lung tumors', 'Phenotype', 'HP:0100526', (96, 107))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Lkb1-deficient lung tumors', 'Disease', 'MESH:D008175', (81, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', (60, 65))	('inhibited', 'NegReg', (50, 59))	('tumor', 'Disease', (154, 159))
26264	25967390	Notably, the mean overall survival of NSCLC patients overexpressing NEDD9 (39.10 +/- 6.49 months) was markedly shorter than patients with normal NEDD9 expression (56.67 +/- 7.44 months; Log-Rank, P = 0.001).	('NSCLC', 'Disease', (38, 43))	('patients', 'Species', '9606', (44, 52))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('overexpressing', 'Var', (53, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('NEDD9', 'Gene', (68, 73))	('shorter', 'NegReg', (111, 118))	('patients', 'Species', '9606', (124, 132))
26270	25967390	NEDD9 knockdown reduced frequency of metastases in mouse xenografts, as well as reduced proliferation and inhibited invasion in melanoma cell lines.	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('metastases', 'Disease', (37, 47))	('inhibited', 'NegReg', (106, 115))	('invasion', 'CPA', (116, 124))	('reduced', 'NegReg', (80, 87))	('reduced', 'NegReg', (16, 23))	('mouse', 'Species', '10090', (51, 56))	('NEDD9', 'Gene', (0, 5))	('metastases', 'Disease', 'MESH:D009362', (37, 47))	('proliferation', 'CPA', (88, 101))	('knockdown', 'Var', (6, 15))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('melanoma', 'Disease', (128, 136))
26277	25967390	Germline mutations of LKB1 are implicated in Peutz-Jeghers syndrome, which includes aberrant mucocutaneous pigmentation.	('Germline mutations', 'Var', (0, 18))	('implicated', 'Reg', (31, 41))	('LKB1', 'Gene', '6794', (22, 26))	('Peutz-Jeghers syndrome', 'Disease', 'MESH:D010580', (45, 67))	('LKB1', 'Gene', (22, 26))	('Peutz-Jeghers syndrome', 'Disease', (45, 67))
26278	25967390	Somatic LKB1 mutations occur in 10% of cutaneous melanoma, explaining overexpression of NEDD9 in these tumors.	('LKB1', 'Gene', '6794', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('cutaneous melanoma', 'Disease', (39, 57))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (39, 57))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (39, 57))	('mutations', 'Var', (13, 22))	('LKB1', 'Gene', (8, 12))
26291	25967390	Misregulation of the canonical WNT/beta-catenin pathway and aberrant activation of WNT signaling target genes are common in colorectal cancer, and contribute to cancer progression.	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('Misregulation', 'Var', (0, 13))	('WNT', 'Gene', '89780', (83, 86))	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('WNT', 'Gene', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('contribute', 'Reg', (147, 157))	('colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))	('colorectal cancer', 'Disease', (124, 141))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('WNT', 'Gene', '89780', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('aberrant', 'Var', (60, 68))	('beta-catenin', 'Gene', (35, 47))	('WNT', 'Gene', (31, 34))	('beta-catenin', 'Gene', '1499', (35, 47))	('activation', 'PosReg', (69, 79))
26298	25967390	In murine models of spontaneously arising ovarian cancer (MISIR-TAg), MISIR-Tag;Nedd9-/- mice exhibited delayed tumor development, decreased tumor burden, and reduced number of lung metastases comparing to MISIR-Tag;Nedd9+/+ mice.	('decreased tumor', 'Disease', 'MESH:D009369', (131, 146))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('ovarian cancer', 'Disease', 'MESH:D010051', (42, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('decreased tumor', 'Disease', (131, 146))	('reduced', 'NegReg', (159, 166))	('lung metastases', 'Disease', 'MESH:D009362', (177, 192))	('delayed', 'NegReg', (104, 111))	('ovarian cancer', 'Disease', (42, 56))	('MISIR-Tag', 'Var', (70, 79))	('mice', 'Species', '10090', (225, 229))	('tumor', 'Disease', (112, 117))	('ovarian cancer', 'Phenotype', 'HP:0100615', (42, 56))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('lung metastases', 'Disease', (177, 192))	('murine', 'Species', '10090', (3, 9))	('mice', 'Species', '10090', (89, 93))	('tumor', 'Disease', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))
26302	25967390	Overexpression of NEDD9 significantly correlated with advanced-stage, high tumor grade, and suboptimal primary cytoreductive surgery.	('correlated', 'Reg', (38, 48))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('NEDD9', 'Gene', (18, 23))	('advanced-stage', 'CPA', (54, 68))	('tumor', 'Disease', (75, 80))
26308	25967390	Studies in prostate cancer, renal cell carcinoma (RCC) and glioblastoma have identified NEDD9 as a target of the micro-RNA miR-145, an important repressor of pluripotency of embryonic stem cells and a tumor suppressor in different cancers, and showed decreased level of miR-145 and reciprocal increase of NEDD9 expression in tumor samples compared to normal tissue (Fig.	('micro-RNA', 'Var', (113, 122))	('prostate cancer', 'Disease', 'MESH:D011471', (11, 26))	('increase', 'PosReg', (293, 301))	('prostate cancer', 'Phenotype', 'HP:0012125', (11, 26))	('miR-145', 'Gene', (270, 277))	('prostate cancer', 'Disease', (11, 26))	('glioblastoma', 'Disease', 'MESH:D005909', (59, 71))	('renal cell carcinoma', 'Disease', (28, 48))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (28, 48))	('expression', 'MPA', (311, 321))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('cancers', 'Disease', (231, 238))	('RCC', 'Disease', (50, 53))	('glioblastoma', 'Disease', (59, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('miR-145', 'Gene', '406937', (123, 130))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('201', '217'))	('tumor', 'Disease', (201, 206))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('NEDD9', 'Gene', (305, 310))	('pluripotency of embryonic', 'Disease', 'MESH:D009373', (158, 183))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('tumor suppressor', 'biological_process', 'GO:0051726', ('201', '217'))	('miR-145', 'Gene', (123, 130))	('tumor', 'Disease', (325, 330))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('NEDD9', 'Gene', (88, 93))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (28, 48))	('decreased', 'NegReg', (251, 260))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('level', 'MPA', (261, 266))	('pluripotency of embryonic', 'Disease', (158, 183))	('miR-145', 'Gene', '406937', (270, 277))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('RNA', 'cellular_component', 'GO:0005562', ('119', '122'))
26313	25967390	Regulation of NEDD9 may be an important means whereby all-trans retinoic acid promotes cell spreading and neurite outgrowth in SH-SY5Y human neuroblastoma cells.	('neuroblastoma', 'Disease', 'MESH:D009447', (141, 154))	('promotes', 'PosReg', (78, 86))	('neurite outgrowth', 'CPA', (106, 123))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (127, 134))	('neuroblastoma', 'Disease', (141, 154))	('Regulation', 'Var', (0, 10))	('retinoic acid', 'Chemical', 'MESH:D014212', (64, 77))	('neuroblastoma', 'Phenotype', 'HP:0003006', (141, 154))	('human', 'Species', '9606', (135, 140))	('NEDD9', 'Gene', (14, 19))	('cell spreading', 'CPA', (87, 101))
26316	25967390	In brief summary, the upregulation of NEDD9 by loss of VHL and by hypoxia detected in colon cancer and kidney tissue has implications for other conditions associated with hypoxia, including notable stroke.	('colon cancer', 'Disease', (86, 98))	('stroke', 'Disease', 'MESH:D020521', (198, 204))	('hypoxia', 'Disease', 'MESH:D000860', (171, 178))	('colon cancer', 'Phenotype', 'HP:0003003', (86, 98))	('hypoxia', 'Disease', (171, 178))	('hypoxia', 'Disease', (66, 73))	('VHL', 'Gene', (55, 58))	('hypoxia', 'Disease', 'MESH:D000860', (66, 73))	('NEDD9', 'Gene', (38, 43))	('loss', 'Var', (47, 51))	('upregulation', 'PosReg', (22, 34))	('stroke', 'Phenotype', 'HP:0001297', (198, 204))	('colon cancer', 'Disease', 'MESH:D015179', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('stroke', 'Disease', (198, 204))	('VHL', 'Gene', '7428', (55, 58))
26320	25967390	Although genetic ablation of Nedd9 does not independently influence cystogenesis, constitutive absence of Nedd9 strongly promotes cyst formation in a mouse model of ADPKD.	('cyst formation', 'CPA', (130, 144))	('Nedd9', 'Gene', (106, 111))	('absence', 'NegReg', (95, 102))	('ablation', 'Var', (17, 25))	('promotes', 'PosReg', (121, 129))	('mouse', 'Species', '10090', (150, 155))
26321	25967390	ADPKD arises from defective signaling by mutated forms of the ciliary proteins PKD1 and PKD2, resulting in defective intracellular calcium homeostasis, and other signaling defects.	('mutated', 'Var', (41, 48))	('defective intracellular calcium', 'Phenotype', 'HP:0003575', (107, 138))	('calcium', 'Chemical', 'MESH:D002118', (131, 138))	('ADPKD', 'Disease', (0, 5))	('PKD1', 'Gene', (79, 83))	('PKD2', 'Gene', '5311', (88, 92))	('intracellular calcium homeostasis', 'MPA', (117, 150))	('signaling defects', 'MPA', (162, 179))	('defective', 'NegReg', (18, 27))	('PKD1', 'Gene', '5310', (79, 83))	('defective', 'NegReg', (107, 116))	('PKD2', 'Gene', (88, 92))
26325	25967390	In brief summary, NEDD9 was independently discovered as a protein highly phosphorylated following ligation of the beta1 integrin receptor in T cells {Minegishi, 1996 #22}.	('beta1 integrin', 'Gene', '3688', (114, 128))	('phosphorylated', 'MPA', (73, 87))	('ligation', 'Var', (98, 106))	('beta1 integrin', 'Gene', (114, 128))	('NEDD9', 'Gene', (18, 23))
26334	25967390	In one study, deletion of Nedd9 in MMTV-neu mammary tumors increased their sensitivity to inhibitors of FAK and SRC.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('SRC', 'Gene', '6714', (112, 115))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('SRC', 'Gene', (112, 115))	('increased', 'PosReg', (59, 68))	('MMTV', 'Species', '11757', (35, 39))	('FAK', 'Gene', '5747', (104, 107))	('deletion', 'Var', (14, 22))	('FAK', 'Gene', (104, 107))	('Nedd9', 'Gene', (26, 31))
26336	25967390	NEDD9 depletion sensitizes breast tumor cell lines to the Aurora A inhibitor alisertib, decreasing its IC50 from 200 nmol/L to 20 nmol/L.	('IC50', 'MPA', (103, 107))	('Aurora A', 'Gene', '6790', (58, 66))	('breast tumor', 'Phenotype', 'HP:0100013', (27, 39))	('NEDD9', 'Gene', (0, 5))	('depletion', 'Var', (6, 15))	('alisertib', 'Chemical', 'MESH:C550258', (77, 86))	('Aurora A', 'Gene', (58, 66))	('breast tumor', 'Disease', 'MESH:D001943', (27, 39))	('breast tumor', 'Disease', (27, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('decreasing', 'NegReg', (88, 98))
26342	25967390	Silencing of NEDD9 with siRNA in resistant cells restored sensitivity to imatinib.	('imatinib', 'Chemical', 'MESH:D000068877', (73, 81))	('restored', 'PosReg', (49, 57))	('sensitivity to imatinib', 'MPA', (58, 81))	('NEDD9', 'Gene', (13, 18))	('Silencing', 'Var', (0, 9))
26344	25967390	The recent emergence of preclinical data linking NEDD9 expression to additional pathological conditions, including stroke, ADPKD, and potentially some neurodegenerative diseases open new areas for exploration.	('NEDD9', 'Gene', (49, 54))	('stroke', 'Disease', 'MESH:D020521', (115, 121))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (151, 177))	('ADPKD', 'Disease', (123, 128))	('neurodegenerative diseases', 'Disease', (151, 177))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (151, 177))	('stroke', 'Phenotype', 'HP:0001297', (115, 121))	('stroke', 'Disease', (115, 121))	('expression', 'Var', (55, 65))
26388	25366068	These altered arrangements yielded disorderliness scores of 0.4286, 0.5434 and 0.7177 respectively.	('disorderliness', 'Disease', (35, 49))	('disorderliness', 'Disease', 'None', (35, 49))	('0.5434', 'Var', (68, 74))
26425	25260785	Knocking down Kiss-1 resulted in increased invasion and migration of colorectal cancer cells.	('Kiss-1', 'Gene', '3814', (14, 20))	('Knocking down', 'Var', (0, 13))	('colorectal cancer', 'Phenotype', 'HP:0003003', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Kiss-1', 'Gene', (14, 20))	('colorectal cancer', 'Disease', (69, 86))	('increased', 'PosReg', (33, 42))	('rat', 'Species', '10116', (59, 62))	('colorectal cancer', 'Disease', 'MESH:D015179', (69, 86))
26441	25260785	On the basis of the data from these experiments, Kiss-1 may play a metastasis suppressor role in human colorectal cancer and be linked to the disease progression of patients, by way of aberrant expression and molecular and cellular mechanism (s) that are yet to be identified.	('Kiss-1', 'Gene', '3814', (49, 55))	('colorectal cancer', 'Disease', 'MESH:D015179', (103, 120))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('linked', 'Reg', (128, 134))	('aberrant', 'Var', (185, 193))	('metastasis suppressor', 'CPA', (67, 88))	('human', 'Species', '9606', (97, 102))	('Kiss-1', 'Gene', (49, 55))	('colorectal cancer', 'Disease', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('patients', 'Species', '9606', (165, 173))
26475	25260785	After an overnight incubation and 4 hours treatment with appropriate peptide receptor or inhibitor (300 nM Kisspeptin-10, 300 nM Kisspeptin-234 or 200 nM ERK inhibitor), the medium was collected.	('ERK', 'Gene', '5594', (154, 157))	('300 nM', 'Var', (100, 106))	('ERK', 'Gene', (154, 157))
26486	25260785	In contrast to Kiss-1, the expression pattern of Kiss-1R revealed that high levels of Kiss-1R transcript are associated with both a poor overall survival (Figure 2C, p = 0.0011) and poor disease free survival (Figure 2D, p = 0.0033).	('Kiss-1', 'Gene', '3814', (49, 55))	('Kiss-1', 'Gene', '3814', (86, 92))	('high', 'Var', (71, 75))	('Kiss-1', 'Gene', (49, 55))	('Kiss-1', 'Gene', (86, 92))	('poor', 'NegReg', (132, 136))	('Kiss-1', 'Gene', '3814', (15, 21))	('disease free survival', 'CPA', (187, 208))	('overall survival', 'CPA', (137, 153))	('Kiss-1', 'Gene', (15, 21))	('poor', 'NegReg', (182, 186))
26492	25260785	Analysis of the in vitro function assays revealed cells with Kiss-1 knockdown had significantly increased invasiveness (p = 0.015) and migration (p = 0.0094) compared HT115 pEF cells (Figure 3B and C), but knockdown of Kiss-1 and Kiss-1R did not demonstrate a significant change on cell growth and adhesion of HT115 and HRT18 cells (p > 0.05).	('rat', 'Species', '10116', (138, 141))	('Kiss-1', 'Gene', '3814', (230, 236))	('increased', 'PosReg', (96, 105))	('HT115 pEF', 'CellLine', 'CVCL:2520', (167, 176))	('Kiss-1', 'Gene', (219, 225))	('migration', 'CPA', (135, 144))	('Kiss-1', 'Gene', (230, 236))	('HT115', 'CellLine', 'CVCL:2520', (310, 315))	('rat', 'Species', '10116', (253, 256))	('Kiss-1', 'Gene', '3814', (61, 67))	('knockdown', 'Var', (68, 77))	('HT115', 'CellLine', 'CVCL:2520', (167, 172))	('Kiss-1', 'Gene', '3814', (219, 225))	('invasiveness', 'CPA', (106, 118))	('Kiss-1', 'Gene', (61, 67))
26493	25260785	HT115 Kiss-1 knockdown cells treated with Kisspeptin-10 had a significant decrease in motility compared to the control cells (Figure 4A), but no significant difference was observed between control and Kiss-1R knockdown cells.	('decrease', 'NegReg', (74, 82))	('Kiss-1', 'Gene', (6, 12))	('motility', 'CPA', (86, 94))	('Kiss-1', 'Gene', '3814', (201, 207))	('Kiss-1', 'Gene', (201, 207))	('Kisspeptin-10', 'Var', (42, 55))	('Kiss-1', 'Gene', '3814', (6, 12))	('HT115', 'CellLine', 'CVCL:2520', (0, 5))
26505	25260785	The enzyme activity of MMP-9 in HT115 pEF cells treated with ERK inhibitor was significantly inhibited compared with that of controls in all three groups.	('HT115 pEF', 'CellLine', 'CVCL:2520', (32, 41))	('inhibitor', 'Var', (65, 74))	('enzyme activity', 'molecular_function', 'GO:0003824', ('4', '19'))	('ERK', 'Gene', '5594', (61, 64))	('MMP-9', 'Gene', (23, 28))	('MMP-9', 'Gene', '4318', (23, 28))	('ERK', 'Gene', (61, 64))	('inhibited', 'NegReg', (93, 102))	('enzyme activity', 'MPA', (4, 19))	('MMP-9', 'molecular_function', 'GO:0004229', ('23', '28'))	('ERK', 'molecular_function', 'GO:0004707', ('61', '64'))
26507	25260785	Furthermore, the results show that both HT115 cells treated with Kisspeptin-10 exhibited a decreased expression of MMP-9 in comparison to the cells treated with serum free medium and Kisspeptin-234.	('MMP-9', 'Gene', '4318', (115, 120))	('MMP-9', 'Gene', (115, 120))	('expression', 'MPA', (101, 111))	('HT115', 'CellLine', 'CVCL:2520', (40, 45))	('Kisspeptin-10', 'Var', (65, 78))	('decreased', 'NegReg', (91, 100))	('MMP-9', 'molecular_function', 'GO:0004229', ('115', '120'))
26512	25260785	Aberrant Kiss-1 and Kiss-1R expression is definitely a point for consideration.	('rat', 'Species', '10116', (72, 75))	('Kiss-1', 'Gene', (20, 26))	('Aberrant', 'Var', (0, 8))	('Kiss-1', 'Gene', '3814', (9, 15))	('Kiss-1', 'Gene', (9, 15))	('Kiss-1', 'Gene', '3814', (20, 26))
26515	25260785	Kiss-1R knockdown has little effect on cell migration compared with the control cells which may support this hypothesis.	('knockdown', 'Var', (8, 17))	('cell migration', 'biological_process', 'GO:0016477', ('39', '53'))	('rat', 'Species', '10116', (47, 50))	('cell migration', 'CPA', (39, 53))	('Kiss-1R', 'Gene', (0, 7))
26519	25260785	Interestingly, no increase in cell migration of Kiss-1R knockdown cells compared with the controls was observed.	('knockdown', 'Var', (56, 65))	('rat', 'Species', '10116', (38, 41))	('cell migration', 'CPA', (30, 44))	('Kiss-1R', 'Gene', (48, 55))
26520	25260785	The motility of Kiss-1R knockdown cells would increase the same as the Kiss-1 knockdown cells did, if Kiss-1 indeed had the inhibitory influence on cell migration through Kiss-1R.	('Kiss-1', 'Gene', (171, 177))	('motility', 'CPA', (4, 12))	('rat', 'Species', '10116', (156, 159))	('Kiss-1', 'Gene', '3814', (102, 108))	('cell migration', 'biological_process', 'GO:0016477', ('148', '162'))	('increase', 'PosReg', (46, 54))	('Kiss-1', 'Gene', (102, 108))	('Kiss-1', 'Gene', '3814', (71, 77))	('Kiss-1', 'Gene', '3814', (16, 22))	('cell migration', 'CPA', (148, 162))	('Kiss-1', 'Gene', '3814', (171, 177))	('Kiss-1', 'Gene', (71, 77))	('knockdown', 'Var', (24, 33))	('Kiss-1', 'Gene', (16, 22))
26550	33937249	The second-generation BTKi acalabrutinib also binds Cys481 in the BTK active site, and it is FDA approved for the treatment of adults with CLL or SLL.	('acalabrutinib', 'Chemical', 'MESH:C000604908', (27, 40))	('Cys481', 'Var', (52, 58))	('Cys481', 'Chemical', '-', (52, 58))	('CLL', 'Disease', (139, 142))
26553	33937249	Overexpression of BTK in solid tumor cells was associated with elevated expression of genes with functions related to cell adhesion, cytoskeletal structure, and extracellular matrix as well as aggressiveness of the cancer.	('aggressiveness of the cancer', 'Disease', 'MESH:D009369', (193, 221))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('aggressiveness', 'Phenotype', 'HP:0000718', (193, 207))	('tumor', 'Disease', (31, 36))	('aggressiveness of the cancer', 'Disease', (193, 221))	('expression of genes', 'MPA', (72, 91))	('Overexpression', 'Var', (0, 14))	('elevated', 'PosReg', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('BTK', 'Gene', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
26556	33937249	Furthermore, BTKi ibrutinib inhibited the proliferation of human colorectal cancer cell lines in vitro and enhanced the chemosensitivity of drug-resistant colorectal cancer cells.	('ibrutinib', 'Chemical', 'MESH:C551803', (18, 27))	('BTKi', 'Var', (13, 17))	('human', 'Species', '9606', (59, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (65, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (155, 172))	('drug-resistant colorectal cancer', 'Disease', (140, 172))	('proliferation', 'CPA', (42, 55))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('colorectal cancer', 'Disease', 'MESH:D015179', (65, 82))	('enhanced', 'PosReg', (107, 115))	('colorectal cancer', 'Disease', (65, 82))	('drug-resistant colorectal cancer', 'Disease', 'MESH:D015179', (140, 172))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('inhibited', 'NegReg', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('chemosensitivity', 'CPA', (120, 136))
26557	33937249	Inhibition of BTK also reduced the clonogenicity of cancer stem cells and decreased their resistance to chemotherapy drugs.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('BTK', 'Gene', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('resistance to chemotherapy drugs', 'MPA', (90, 122))	('Inhibition', 'Var', (0, 10))	('decreased', 'NegReg', (74, 83))	('cancer', 'Disease', (52, 58))	('reduced', 'NegReg', (23, 30))
26560	33937249	p65BTK was also detected in non-small cell lung cancer (NSCLC) cell lines, including those with mutant KRAS, and treatment of these cell lines with BTKi resulted in loss of viability and inhibition of clonogenic growth.	('KRAS', 'Gene', (103, 107))	('mutant', 'Var', (96, 102))	('inhibition', 'NegReg', (187, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('p65BTK', 'Var', (0, 6))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (28, 54))	('NSCLC', 'Disease', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (32, 54))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (28, 54))	('detected', 'Reg', (16, 24))	('clonogenic growth', 'CPA', (201, 218))	('loss', 'NegReg', (165, 169))	('non-small cell lung cancer', 'Disease', (28, 54))	('KRAS', 'Gene', '16653', (103, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))
26562	33937249	reported that human glioblastoma (GBM) cells express p77BTK, and downregulation of BTK expression inhibits the antiapoptotic AKT/mTOR pathway, and BTKi ibrutinib exhibits in vivo antitumor activity in a mouse xenograft model of GBM.	('glioblastoma', 'Disease', 'MESH:D005909', (20, 32))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('mTOR', 'Gene', (129, 133))	('p77BTK', 'Var', (53, 59))	('ibrutinib', 'Chemical', 'MESH:C551803', (152, 161))	('glioblastoma', 'Disease', (20, 32))	('AKT', 'Gene', (125, 128))	('mTOR', 'Gene', '2475', (129, 133))	('glioblastoma', 'Phenotype', 'HP:0012174', (20, 32))	('mouse', 'Species', '10090', (203, 208))	('human', 'Species', '9606', (14, 19))	('GBM', 'Phenotype', 'HP:0012174', (34, 37))	('tumor', 'Disease', (183, 188))	('inhibits', 'NegReg', (98, 106))	('AKT', 'Gene', '207', (125, 128))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('downregulation', 'NegReg', (65, 79))	('BTK', 'Gene', (83, 86))	('GBM', 'Phenotype', 'HP:0012174', (228, 231))
26563	33937249	Recently, reported that p65BTK is expressed in patient-derived human glioma cells, and BTKi diminish their viability.	('glioma', 'Disease', (69, 75))	('patient', 'Species', '9606', (47, 54))	('human', 'Species', '9606', (63, 68))	('p65BTK', 'Var', (24, 30))	('viability', 'CPA', (107, 116))	('diminish', 'NegReg', (92, 100))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))
26564	33937249	Both BTK and the related TEC kinases ETK and BMX are abundantly expressed in prostate cancer cells, and knockdown of BTK expression in prostate cancer cells results in reduced proliferative activity.	('reduced', 'NegReg', (168, 175))	('prostate cancer', 'Disease', (135, 150))	('BMX', 'Gene', '660', (45, 48))	('ETK', 'Gene', '660', (37, 40))	('prostate cancer', 'Disease', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('BMX', 'Gene', (45, 48))	('prostate cancer', 'Disease', 'MESH:D011471', (135, 150))	('prostate cancer', 'Disease', 'MESH:D011471', (77, 92))	('ETK', 'Gene', (37, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (135, 150))	('prostate cancer', 'Phenotype', 'HP:0012125', (77, 92))	('proliferative activity', 'CPA', (176, 198))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('BTK', 'Gene', (117, 120))	('knockdown', 'Var', (104, 113))
26565	33937249	Inhibition of BTK and ETK with a small molecule inhibitor caused inhibition of proliferation, clonogenic growth, invasiveness of human prostate cancer cell lines both in in vitro and an in vivo SCID mouse xenograft model.	('SCID', 'Disease', 'MESH:D053632', (194, 198))	('inhibition', 'NegReg', (65, 75))	('proliferation', 'CPA', (79, 92))	('SCID', 'Disease', (194, 198))	('invasiveness of human prostate cancer', 'Disease', (113, 150))	('mouse', 'Species', '10090', (199, 204))	('invasiveness of human prostate cancer', 'Disease', 'MESH:D011471', (113, 150))	('prostate cancer', 'Phenotype', 'HP:0012125', (135, 150))	('ETK', 'Gene', (22, 25))	('Inhibition', 'Var', (0, 10))	('clonogenic growth', 'CPA', (94, 111))	('BTK', 'Gene', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('ETK', 'Gene', '660', (22, 25))
26568	33937249	Similarly, numerous studies have shown that BTK inhibition causes substantial cytotoxicity to HER2+ breast cancer cells, inhibits their proliferation and clonogenicity, and diminishes their resistance to chemotherapy both in vitro and in vivo.	('HER2+', 'Protein', (94, 99))	('clonogenicity', 'CPA', (154, 167))	('resistance to chemotherapy', 'CPA', (190, 216))	('cytotoxicity', 'Disease', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('BTK', 'Gene', (44, 47))	('inhibits', 'NegReg', (121, 129))	('inhibition', 'Var', (48, 58))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('diminishes', 'NegReg', (173, 183))	('cytotoxicity', 'Disease', 'MESH:D064420', (78, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('proliferation', 'CPA', (136, 149))
26570	33937249	Nonetheless, LFM-A13, a first-generation BTKi with no HER-2 or EGF-R inhibitory activity, also exhibited antitumor activity in the MMTV/neu transgenic mouse model of HER2-positive breast cancer.	('mouse', 'Species', '10090', (151, 156))	('MMTV', 'Species', '11757', (131, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('EGF-R', 'Gene', '1956', (63, 68))	('HER-2', 'Gene', (54, 59))	('HER-2', 'Gene', '2064', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Disease', (180, 193))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('LFM-A13', 'Var', (13, 20))	('EGF-R', 'Gene', (63, 68))	('tumor', 'Disease', (109, 114))
26572	33937249	In the DMBA breast cancer model, the BTKi LFM-A13 significantly delayed spontaneous tumor appearance as well as tumor progression, and it substantially improved tumor-free survival.	('breast cancer', 'Disease', (12, 25))	('delayed', 'NegReg', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (84, 89))	('improved', 'PosReg', (152, 160))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('tumor', 'Disease', (112, 117))	('BTKi LFM-A13', 'Var', (37, 49))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))	('tumor', 'Disease', (161, 166))
26574	33937249	Hence, BTK inhibition prevented the development of aggressive and rapidly progressive mammary gland tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('aggressive', 'CPA', (51, 61))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('inhibition', 'Var', (11, 21))	('BTK', 'Protein', (7, 10))	('prevented', 'NegReg', (22, 31))
26576	33937249	In view of the broad-spectrum anti-cancer activity exerted by BTKi in various non-clinical cancer models, BTK inhibition with ibrutinib and acalabrutinib has been evaluated in several proof-of-concept solid tumor trials (e.g., NCT02403271, NCT03525925, NCT03379428, NCT02599824, and NCT02562898) aimed at assessing its potential clinical benefit in patients with solid tumors, including ovarian cancer, breast cancer, lung cancer, prostate cancer, and pancreas cancer.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('NCT03525925', 'Var', (240, 251))	('acalabrutinib', 'Chemical', 'MESH:C000604908', (140, 153))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('cancer', 'Disease', 'MESH:D009369', (395, 401))	('tumor', 'Disease', (369, 374))	('ovarian cancer', 'Disease', (387, 401))	('cancer', 'Disease', (461, 467))	('prostate cancer', 'Disease', 'MESH:D011471', (431, 446))	('prostate cancer', 'Phenotype', 'HP:0012125', (431, 446))	('cancer', 'Disease', (423, 429))	('breast cancer', 'Phenotype', 'HP:0003002', (403, 416))	('prostate cancer', 'Disease', (431, 446))	('ovarian cancer', 'Phenotype', 'HP:0100615', (387, 401))	('tumor', 'Disease', 'MESH:D009369', (369, 374))	('lung cancer', 'Disease', (418, 429))	('cancer', 'Disease', 'MESH:D009369', (410, 416))	('NCT03379428', 'Var', (253, 264))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (423, 429))	('tumors', 'Phenotype', 'HP:0002664', (369, 375))	('breast cancer', 'Disease', 'MESH:D001943', (403, 416))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (440, 446))	('NCT02562898', 'Var', (283, 294))	('breast cancer', 'Disease', (403, 416))	('NCT02403271', 'Var', (227, 238))	('tumor', 'Phenotype', 'HP:0002664', (369, 374))	('tumors', 'Disease', (369, 375))	('pancreas cancer', 'Disease', 'MESH:D010190', (452, 467))	('cancer', 'Disease', 'MESH:D009369', (461, 467))	('cancer', 'Disease', (395, 401))	('tumor', 'Disease', (207, 212))	('ibrutinib', 'Chemical', 'MESH:C551803', (126, 135))	('lung cancer', 'Disease', 'MESH:D008175', (418, 429))	('pancreas cancer', 'Phenotype', 'HP:0002894', (452, 467))	('cancer', 'Disease', 'MESH:D009369', (423, 429))	('NCT02599824', 'Var', (266, 277))	('cancer', 'Phenotype', 'HP:0002664', (395, 401))	('patients', 'Species', '9606', (349, 357))	('lung cancer', 'Phenotype', 'HP:0100526', (418, 429))	('cancer', 'Disease', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('ovarian cancer', 'Disease', 'MESH:D010051', (387, 401))	('pancreas cancer', 'Disease', (452, 467))	('cancer', 'Disease', (410, 416))	('tumors', 'Disease', 'MESH:D009369', (369, 375))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (440, 446))	('cancer', 'Phenotype', 'HP:0002664', (410, 416))	('cancer', 'Disease', (35, 41))
26582	33937249	Furthermore, in a breast cancer mouse model, BTKi ibrutinib improved the efficacy of anti-PD-L1 treatment.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('PD-L1', 'Gene', '60533', (90, 95))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('ibrutinib', 'Chemical', 'MESH:C551803', (50, 59))	('BTKi', 'Var', (45, 49))	('breast cancer', 'Disease', (18, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('mouse', 'Species', '10090', (32, 37))	('improved', 'PosReg', (60, 68))	('efficacy', 'MPA', (73, 81))	('PD-L1', 'Gene', (90, 95))
26584	33937249	A recent study in which >500 lung adenocarcinoma cases were analyzed for possible contribution of BTK to an immune-dominant profile of the TME revealed that BTK expression in the TME was associated with a less aggressive disease and an improved survival outcome.	('BTK expression', 'Var', (157, 171))	('lung adenocarcinoma', 'Disease', (29, 48))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (29, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('aggressive disease', 'Disease', 'MESH:D001523', (210, 228))	('improved', 'PosReg', (236, 244))	('survival outcome', 'CPA', (245, 261))	('aggressive disease', 'Disease', (210, 228))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (29, 48))
26595	33937249	We discovered that the crystal structure of the BTK kinase domain reveals a distinct 7 A x 7 A rectangular binding pocket near the hinge region of the BTK kinase domain with Leu-460, Tyr-476, Arg-525, and Asp-539 residues occupying the corners of the rectangle.	('Leu', 'Chemical', 'MESH:D007930', (174, 177))	('Tyr', 'Chemical', 'MESH:D014443', (183, 186))	('Leu-460', 'Var', (174, 181))	('Asp', 'Chemical', 'MESH:D001224', (205, 208))	('Arg-525', 'Var', (192, 199))	('binding', 'Interaction', (107, 114))	('Asp-539 residues', 'Var', (205, 221))	('Tyr-476', 'Var', (183, 190))	('Arg', 'Chemical', 'MESH:D001120', (192, 195))
26735	33509261	This study is supported by grants from the European Commission FP7 project SYSCOL (UE7-SYSCOL-258236), the Novo Nordisk Foundation (NNF16OC0023182), the Danish National Advanced Technology Foundation (056-2010-1), the John and Birthe Meyer Foundation, the Danish Council for Independent Research (Medical Sciences) (DFF-0602-02128B, DFF-4183-00619, DFF-7016-00332B), the Danish Council for Strategic Research (1309-00006B), the Danish Cancer Society (R40-A1965_11_S2, R56-A3110-12-S2, R107-A7035, R133-A8520), the National Cancer Institute of the National Institutes of Health (R01 CA207467), the Aage and Johanne Louis-Hansen's Foundation (17-2-0457), Dansk Kraeftforskningsfond (DKF-2017-26-26), the Knud and Edith Eriksen's Memorial Foundation, the Neye Foundation, and the Manufacturer Einar Willumsen's Memorial Foundation (6000073).	('R40-A1965_11_S2', 'Var', (451, 466))	('Cancer', 'Disease', 'MESH:D009369', (523, 529))	('Cancer', 'Disease', 'MESH:D009369', (435, 441))	('Cancer', 'Disease', (435, 441))	('Cancer', 'Phenotype', 'HP:0002664', (435, 441))	("Manufacturer Einar Willumsen's Memorial", 'Disease', (777, 816))	('R107-A7035', 'Var', (485, 495))	('R107-A7035', 'Mutation', 'p.R107,7035A', (485, 495))	("Manufacturer Einar Willumsen's Memorial", 'Disease', 'MESH:D008569', (777, 816))	('R56-A3110-12-S2', 'Var', (468, 483))	('Cancer', 'Phenotype', 'HP:0002664', (523, 529))	('Cancer', 'Disease', (523, 529))	('DKF-2017-26-26', 'CellLine', 'CVCL:8806', (681, 695))
26737	30390498	Inducible Intestine-Specific Expression of krasV12 Triggers Intestinal Tumorigenesis In Transgenic Zebrafish1 KRAS mutations are a major risk factor in colorectal cancers.	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('Zebrafish', 'Species', '7955', (99, 108))	('mutations', 'Var', (115, 124))	('krasV12', 'Gene', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Triggers', 'Reg', (51, 59))	('risk factor', 'Reg', (137, 148))	('Intestinal Tumorigenesis', 'CPA', (60, 84))	('colorectal cancers', 'Disease', 'MESH:D015179', (152, 170))	('KRAS', 'Gene', (110, 114))	('colorectal cancers', 'Disease', (152, 170))
26739	30390498	These results provide in vivo evidence of Ras pathway activation via krasV12 overexpression.	('kras', 'Gene', '445289', (69, 73))	('kras', 'Gene', (69, 73))	('activation', 'PosReg', (54, 64))	('Ras pathway', 'Pathway', (42, 53))	('overexpression', 'Var', (77, 91))
26743	30390498	Our results demonstrate that krasV12 overexpression induces intestinal tumorigenesis in zebrafish, which mimics intestinal tumor formation in humans.	('intestinal tumor', 'Disease', 'MESH:D007414', (60, 76))	('kras', 'Gene', '445289', (29, 33))	('intestinal tumor', 'Disease', 'MESH:D007414', (112, 128))	('intestinal tumor', 'Disease', (60, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('intestinal tumor', 'Disease', (112, 128))	('kras', 'Gene', (29, 33))	('induces', 'Reg', (52, 59))	('overexpression', 'Var', (37, 51))	('zebrafish', 'Species', '7955', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('humans', 'Species', '9606', (142, 148))
26748	30390498	Single mutations in the tumor suppressor PTEN, which normally inhibits PI3K, have been shown to contribute to colorectal carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor suppressor', 'biological_process', 'GO:0051726', ('24', '40'))	('colorectal carcinogenesis', 'Disease', (110, 135))	('inhibits', 'NegReg', (62, 70))	('tumor', 'Disease', (24, 29))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('24', '40'))	('PTEN', 'Gene', '368415', (41, 45))	('contribute', 'Reg', (96, 106))	('PTEN', 'Gene', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('Single mutations', 'Var', (0, 16))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (110, 135))	('PI3K', 'molecular_function', 'GO:0016303', ('71', '75'))
26749	30390498	Finally, mutations in the tumor suppressor TP53 have been observed in 40%-50% of CRC patients.	('mutations', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('CRC', 'Disease', (81, 84))	('patients', 'Species', '9606', (85, 93))	('tumor suppressor', 'biological_process', 'GO:0051726', ('26', '42'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('26', '42'))	('CRC', 'Phenotype', 'HP:0003003', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('TP53', 'Gene', (43, 47))	('observed', 'Reg', (58, 66))
26750	30390498	Mutations in TP53 are believed to be a late event in colorectal carcinogenesis and are thought to have a possible role in the transition from adenoma to carcinoma.	('TP53', 'Gene', (13, 17))	('role', 'Reg', (114, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('colorectal carcinogenesis', 'Disease', (53, 78))	('adenoma to carcinoma', 'Disease', 'MESH:D000236', (142, 162))	('Mutations', 'Var', (0, 9))	('adenoma to carcinoma', 'Disease', (142, 162))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (53, 78))
26751	30390498	The KRAS oncogene plays an important role in tumor initiation of CRC; indeed, KRAS mutations have been reported in approximately 30% of colorectal adenomas and in 30% to 50% of CRC patients.	('mutations', 'Var', (83, 92))	('CRC', 'Disease', (177, 180))	('colorectal adenomas', 'Disease', 'MESH:D015179', (136, 155))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('reported', 'Reg', (103, 111))	('tumor', 'Disease', (45, 50))	('CRC', 'Phenotype', 'HP:0003003', (65, 68))	('KRAS', 'Gene', (78, 82))	('patients', 'Species', '9606', (181, 189))	('CRC', 'Phenotype', 'HP:0003003', (177, 180))	('colorectal adenomas', 'Disease', (136, 155))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
26754	30390498	Mutational activation of the KRAS gene reduces or abolishes intrinsic GTPase activity, thereby locking it in its GTP-bound conformation and leading to the constitutive activation of MAPK and PI3K/AKT signal transduction pathways.	('GTP', 'Chemical', 'MESH:D006160', (113, 116))	('abolishes', 'NegReg', (50, 59))	('Mutational', 'Var', (0, 10))	('KRAS', 'Gene', (29, 33))	('locking', 'Reg', (95, 102))	('leading to', 'Reg', (140, 150))	('GTP', 'Chemical', 'MESH:D006160', (70, 73))	('intrinsic', 'MPA', (60, 69))	('activation', 'PosReg', (168, 178))	('activity', 'MPA', (77, 85))	('activation', 'PosReg', (11, 21))	('GTPase', 'Protein', (70, 76))	('reduces', 'NegReg', (39, 46))
26778	30390498	For DSS treatment, kras+ transgenic fish and wild-type control fish were exposed with 0.0625% of DSS (Sigma) for 3 weeks.	('0.0625%', 'Var', (86, 93))	('kras', 'Gene', (19, 23))	('kras', 'Gene', '445289', (19, 23))
26810	30390498	Immunofluorescence staining for phosphorylated Erk (p-Erk) demonstrated a dramatic increase of p-Erk in the intestine of kras+ compared to that of wild-type control fish (Figure 2, E and F).	('increase', 'PosReg', (83, 91))	('p-Erk', 'Var', (95, 100))	('kras', 'Gene', (121, 125))	('kras', 'Gene', '445289', (121, 125))
26824	30390498	These results provide the first in vivo evidence that krasV12 overexpression in zebrafish facilitates intestinal carcinogenesis.	('overexpression', 'Var', (62, 76))	('facilitates', 'PosReg', (90, 101))	('kras', 'Gene', '445289', (54, 58))	('zebrafish', 'Species', '7955', (80, 89))	('kras', 'Gene', (54, 58))	('intestinal carcinogenesis', 'Disease', (102, 127))	('intestinal carcinogenesis', 'Disease', 'MESH:D063646', (102, 127))
26843	30390498	In humans, the classical genetic events related to disease initiation and progression are the activation of mutations in the KRAS oncogene and the inactivation of mutations/deletions in APC and TP53 tumor suppressor genes.	('tumor', 'Disease', (199, 204))	('inactivation', 'NegReg', (147, 159))	('APC', 'cellular_component', 'GO:0005680', ('186', '189'))	('mutations', 'Var', (108, 117))	('KRAS', 'Gene', (125, 129))	('tumor suppressor', 'biological_process', 'GO:0051726', ('199', '215'))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('humans', 'Species', '9606', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('APC', 'Gene', (186, 189))	('mutations/deletions', 'Var', (163, 182))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('199', '215'))	('activation', 'PosReg', (94, 104))
26844	30390498	In human CRC, the presence of the KRAS mutations is associated with an increase in invasive stages and liver metastasis.	('presence', 'Var', (18, 26))	('invasive stages', 'CPA', (83, 98))	('human', 'Species', '9606', (3, 8))	('liver metastasis', 'Disease', 'MESH:D009362', (103, 119))	('mutations', 'Var', (39, 48))	('liver metastasis', 'Disease', (103, 119))	('CRC', 'Phenotype', 'HP:0003003', (9, 12))	('increase', 'PosReg', (71, 79))	('KRAS', 'Gene', (34, 38))
26845	30390498	Lung metastases carrying the oncogenic KRAS mutation are common in CRC cases, indicating that oncogenic KRAS plays an important role in tumor progression.	('mutation', 'Var', (44, 52))	('CRC', 'Disease', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('CRC', 'Phenotype', 'HP:0003003', (67, 70))	('metastases', 'Disease', (5, 15))	('KRAS', 'Gene', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('metastases', 'Disease', 'MESH:D009362', (5, 15))	('tumor', 'Disease', (136, 141))
26855	30390498	In addition, krasV12 overexpression promotes Erk and Akt phosphorylation (Figures 2, E and F; 4, C and D; E and F) and leads to the downregulation of E-cadherin, a molecular marker signaling enhanced EMT (Figures 2, G and H; 4, G and H).	('cadherin', 'molecular_function', 'GO:0008014', ('152', '160'))	('downregulation', 'NegReg', (132, 146))	('Erk', 'molecular_function', 'GO:0004707', ('45', '48'))	('overexpression', 'Var', (21, 35))	('E-cadherin', 'Gene', (150, 160))	('signaling', 'biological_process', 'GO:0023052', ('181', '190'))	('EMT', 'CPA', (200, 203))	('phosphorylation', 'biological_process', 'GO:0016310', ('57', '72'))	('kras', 'Gene', '445289', (13, 17))	('Erk', 'Pathway', (45, 48))	('enhanced', 'PosReg', (191, 199))	('Akt', 'Pathway', (53, 56))	('E-cadherin', 'Gene', '114424', (150, 160))	('kras', 'Gene', (13, 17))	('promotes', 'PosReg', (36, 44))	('EMT', 'biological_process', 'GO:0001837', ('200', '203'))
26861	30390498	However, the KrasV12 point mutation was shown to accelerate intestinal carcinogenesis in Apc mutant mice as well as in tumors induced by treatment with 1,2-dimethylhydrazine.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('point mutation', 'Var', (21, 35))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('Kras', 'Gene', (13, 17))	('mice', 'Species', '10090', (100, 104))	('1,2-dimethylhydrazine', 'Chemical', 'MESH:D019813', (152, 173))	('accelerate', 'PosReg', (49, 59))	('mutant', 'Var', (93, 99))	('intestinal carcinogenesis', 'Disease', (60, 85))	('Apc', 'Gene', (89, 92))	('Apc', 'Gene', '11789', (89, 92))	('intestinal carcinogenesis', 'Disease', 'MESH:D063646', (60, 85))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Kras', 'Gene', '445289', (13, 17))
26862	30390498	Previously, it has been reported that intestinal-specific expression of CagA in transgenic zebrafish caused intestinal hyperplasia, but overexpression of CagA in p53 mutant zebrafish also caused hyperplasia and further led to the occurrence of small cell carcinoma and adenocarcinoma.	('p53', 'Gene', (162, 165))	('small cell carcinoma and adenocarcinoma', 'Disease', 'MESH:D018288', (244, 283))	('hyperplasia', 'Disease', (119, 130))	('hyperplasia', 'Disease', 'MESH:D006965', (119, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (244, 264))	('p53', 'Gene', '30590', (162, 165))	('overexpression', 'PosReg', (136, 150))	('mutant', 'Var', (166, 172))	('CagA', 'Gene', (72, 76))	('intestinal hyperplasia', 'Disease', 'MESH:D006965', (108, 130))	('hyperplasia', 'Disease', (195, 206))	('zebrafish', 'Species', '7955', (173, 182))	('led to', 'Reg', (219, 225))	('caused', 'Reg', (188, 194))	('hyperplasia', 'Disease', 'MESH:D006965', (195, 206))	('intestinal hyperplasia', 'Disease', (108, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('zebrafish', 'Species', '7955', (91, 100))
26865	30390498	Moreover, inflammation/inflammatory stimuli induced by treatment with 2% DSS after initiation with carcinogens is effective for rapid induction of colon tumors that possess B-catenin gene mutations.	('colon tumors', 'Disease', (147, 159))	('B-catenin', 'Gene', (173, 182))	('inflammation', 'Disease', 'MESH:D007249', (10, 22))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('inflammation', 'biological_process', 'GO:0006954', ('10', '22'))	('colon tumors', 'Phenotype', 'HP:0100273', (147, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('mutations', 'Var', (188, 197))	('colon tumors', 'Disease', 'MESH:D015179', (147, 159))	('inflammation', 'Disease', (10, 22))
26879	30302144	ROC curve analysis showed that the best cut-off values indicating an infectious process were: CRP 129 mg/l on POD3 (92% sensitivity/80% specificity), IL-6 of 78 pg/ml on POD2 (91% sensitivity/97% specificity) and PCT 0.24 ng/ml on POD3 (93% sensitivity/68% specificity).	('CRP', 'Gene', '1401', (94, 97))	('infectious', 'Disease', (69, 79))	('IL-6', 'Gene', (150, 154))	('CRP', 'Gene', (94, 97))	('PCT 0.24', 'Var', (213, 221))	('IL-6', 'Gene', '3569', (150, 154))	('IL-6', 'molecular_function', 'GO:0005138', ('150', '154'))
26960	30027065	The main risk factors are the following: age over 50 years; family history of colon and rectal cancer, including some hereditary conditions (family adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC)); high-fat content in diet, meat consumption, and low calcium content; physical inactivity and obesity; and inflammatory colon diseases such as chronic ulcerative colitis and Crohn's disease.	('rectal cancer', 'Phenotype', 'HP:0100743', (88, 101))	('rectal cancer', 'Phenotype', 'HP:0100743', (208, 221))	('colorectal cancer', 'Phenotype', 'HP:0003003', (204, 221))	('low calcium content', 'Phenotype', 'HP:0002901', (280, 299))	('inflammatory colon diseases', 'Disease', (338, 365))	("Crohn's disease", 'Phenotype', 'HP:0100280', (405, 420))	('colitis', 'Phenotype', 'HP:0002583', (393, 400))	('obesity', 'Phenotype', 'HP:0001513', (325, 332))	("Crohn's disease", 'Disease', (405, 420))	("Crohn's disease", 'Disease', 'MESH:D003424', (405, 420))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (382, 400))	('inflammatory colon diseases', 'Disease', 'MESH:D003108', (338, 365))	('hereditary nonpolyposis colorectal cancer', 'Disease', (180, 221))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('adenomatous polyposis', 'Disease', (148, 169))	('HNPCC', 'Disease', 'None', (223, 228))	('HNPCC', 'Disease', (223, 228))	('colon and rectal cancer', 'Disease', 'MESH:D012004', (78, 101))	('obesity', 'Disease', (325, 332))	('chronic ulcerative colitis', 'Disease', 'MESH:D003093', (374, 400))	('FAP', 'Disease', (171, 174))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (180, 221))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (148, 169))	('FAP', 'Disease', 'MESH:C567782', (171, 174))	('obesity', 'Disease', 'MESH:D009765', (325, 332))	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (180, 221))	('calcium', 'Chemical', 'MESH:D002118', (284, 291))	('adenomatous polyposis', 'Disease', 'MESH:D011125', (148, 169))	('chronic ulcerative colitis', 'Disease', (374, 400))	('high-fat', 'Var', (232, 240))
26969	30027065	Thenceforward, CRC critical genes have already been well established, 40% of the cases of CRC have a specific point mutation in KRAS, 60% have inactivating mutations or deletions of p53, and more than 60% have mutations in the APC (adenomatous polyposis coli) tumor suppressor gene.	('tumor', 'Disease', (260, 265))	('APC', 'cellular_component', 'GO:0005680', ('227', '230'))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('inactivating', 'NegReg', (143, 155))	('p53', 'Gene', '7157', (182, 185))	('mutations', 'Reg', (210, 219))	('CRC', 'Disease', (90, 93))	('point mutation', 'Var', (110, 124))	('KRAS', 'Gene', '3845', (128, 132))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (232, 253))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('deletions', 'Var', (169, 178))	('p53', 'Gene', (182, 185))	('KRAS', 'Gene', (128, 132))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('260', '276'))	('APC', 'Disease', 'MESH:D011125', (227, 230))	('APC', 'Disease', (227, 230))	('tumor suppressor', 'biological_process', 'GO:0051726', ('260', '276'))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (232, 258))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (232, 258))	('adenomatous polyposis coli', 'Disease', (232, 258))
26970	30027065	The inactivation of the APC gene appears to be a very early step in most CRC cases, since it can be detected already in small benign polyps at the same high frequency as in malignant tumors.	('CRC', 'Disease', (73, 76))	('inactivation', 'Var', (4, 16))	('malignant tumors', 'Disease', 'MESH:D018198', (173, 189))	('polyps', 'Disease', (133, 139))	('APC', 'cellular_component', 'GO:0005680', ('24', '27'))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('polyps', 'Disease', 'MESH:D011127', (133, 139))	('APC', 'Disease', 'MESH:D011125', (24, 27))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('APC', 'Disease', (24, 27))	('malignant tumors', 'Disease', (173, 189))
26972	30027065	Mutations involving the KRAS oncogene appear to take place later than those in APC as they are infrequent in small polyps but common in larger ones that present undifferentiated cells.	('KRAS', 'Gene', '3845', (24, 28))	('small polyps', 'Disease', (109, 121))	('APC', 'Disease', 'MESH:D011125', (79, 82))	('Mutations', 'Var', (0, 9))	('APC', 'Disease', (79, 82))	('small polyps', 'Disease', 'MESH:D011127', (109, 121))	('KRAS', 'Gene', (24, 28))
26973	30027065	Finally, mutations in p53 are rare in polyps but common in carcinomas, suggesting that they may often occur late in the sequence.	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('carcinomas', 'Disease', (59, 69))	('mutations', 'Var', (9, 18))	('polyps', 'Disease', (38, 44))	('p53', 'Gene', (22, 25))	('carcinomas', 'Disease', 'MESH:D002277', (59, 69))	('p53', 'Gene', '7157', (22, 25))	('polyps', 'Disease', 'MESH:D011127', (38, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))
26974	30027065	Loss of p53 function leads abnormal cells to avert apoptosis, divide, and promote the accumulation of additional mutations.	('p53', 'Gene', (8, 11))	('promote', 'PosReg', (74, 81))	('p53', 'Gene', '7157', (8, 11))	('divide', 'CPA', (62, 68))	('apoptosis', 'biological_process', 'GO:0097194', ('51', '60'))	('apoptosis', 'biological_process', 'GO:0006915', ('51', '60'))	('Loss', 'NegReg', (0, 4))	('mutations', 'Var', (113, 122))	('avert', 'NegReg', (45, 50))	('apoptosis', 'CPA', (51, 60))
26995	30027065	Through the aberrant modulation of HS biosynthetic enzymes, the specific HS fine structure enables cancer cells to spread by the breakdown of ECM, to receive nutrients through angiogenesis, to proliferate via disruption of signaling pathways, and to escape immune cells.	('modulation', 'Var', (21, 31))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('spread', 'CPA', (115, 121))	('signaling pathways', 'Pathway', (223, 241))	('cancer', 'Disease', (99, 105))	('proliferate', 'CPA', (193, 204))	('disruption', 'NegReg', (209, 219))	('HS', 'Chemical', 'MESH:D006497', (35, 37))	('HS', 'Chemical', 'MESH:D006497', (73, 75))	('aberrant modulation', 'Var', (12, 31))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
27009	30027065	In addition, HCT116 transfected with syndecan-2 presented increased cell migration, which was diminished by the knockdown of integrin alpha2 using a specific siRNA.	('cell migration', 'CPA', (68, 82))	('transfected', 'Var', (20, 31))	('increased', 'PosReg', (58, 67))	('integrin alpha2', 'Gene', '3673', (125, 140))	('HCT116', 'CellLine', 'CVCL:0291', (13, 19))	('syndecan-2', 'Gene', '6383', (37, 47))	('syndecan-2', 'Gene', (37, 47))	('integrin alpha2', 'Gene', (125, 140))
27013	30027065	Consistently, the overexpression of syndecan-2 in HT29 cells increased the expression and secretion of MMP-7 whereas siRNA-mediated knockdown of MMP-7 in these same cells significantly increased E-cadherin levels.	('secretion', 'biological_process', 'GO:0046903', ('90', '99'))	('E-cadherin', 'Gene', (195, 205))	('increased', 'PosReg', (61, 70))	('HT29 cells', 'CellLine', 'CVCL:0320', (50, 60))	('MMP-7', 'Gene', (145, 150))	('E-cadherin', 'Gene', '999', (195, 205))	('syndecan', 'molecular_function', 'GO:0015023', ('36', '44'))	('knockdown', 'Var', (132, 141))	('MMP-7', 'molecular_function', 'GO:0004235', ('145', '150'))	('cadherin', 'molecular_function', 'GO:0008014', ('197', '205'))	('MMP-7', 'Gene', (103, 108))	('increased', 'PosReg', (185, 194))	('MMP-7', 'Gene', '4316', (145, 150))	('MMP-7', 'Gene', '4316', (103, 108))	('overexpression', 'PosReg', (18, 32))	('syndecan-2', 'Gene', (36, 46))	('syndecan-2', 'Gene', '6383', (36, 46))	('MMP-7', 'molecular_function', 'GO:0004235', ('103', '108'))	('secretion', 'MPA', (90, 99))	('expression', 'MPA', (75, 85))
27019	30027065	In addition, it has already been demonstrated that the shed of syndecan-1 is associated with chemotherapy resistance in castration-resistant prostate cancer.	('chemotherapy', 'MPA', (93, 105))	('syndecan-1', 'Gene', '6382', (63, 73))	('syndecan', 'molecular_function', 'GO:0015023', ('63', '71'))	('prostate cancer', 'Disease', 'MESH:D011471', (141, 156))	('prostate cancer', 'Phenotype', 'HP:0012125', (141, 156))	('syndecan-1', 'Gene', (63, 73))	('shed', 'Var', (55, 59))	('prostate cancer', 'Disease', (141, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('associated', 'Reg', (77, 87))
27036	30027065	Several independent studies using antisense RNA strategies in various tumor cells have confirmed the central role of perlecan in angiogenesis, with both in vitro and in vivo models.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('angiogenesis', 'CPA', (129, 141))	('antisense', 'Var', (34, 43))	('perlecan', 'Protein', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
27042	30027065	Subsequently, the chain undergoes a series of reactions of polymer modifications: N-deacetylation/N-sulfation, epimerization of beta-D-glucuronic acid residue to alpha-L-iduronic acid, and O-sulfation in different positions.	('beta-D-glucuronic acid', 'Chemical', '-', (128, 150))	('N-deacetylation/N-sulfation', 'MPA', (82, 109))	('O-sulfation', 'Var', (189, 200))	('polymer', 'Chemical', 'MESH:D011108', (59, 66))	('alpha-L-iduronic acid', 'Chemical', '-', (162, 183))	('epimerization', 'MPA', (111, 124))
27051	30027065	These effects were reversed by shRNA-mediated knockdown of SULF1 or SULF2 and by the addition of unfractionated heparin to the cell medium.	('SULF1', 'Gene', '23213', (59, 64))	('SULF1', 'Gene', (59, 64))	('SULF2', 'Gene', (68, 73))	('knockdown', 'Var', (46, 55))	('heparin', 'Chemical', 'MESH:D006493', (112, 119))	('SULF2', 'Gene', '55959', (68, 73))
27056	30027065	Dysregulated expression of HSPGs, as well as of enzymes involved in their biosynthesis and degradation, has been reported to affect all stages of tumorigenesis.	('HSPG', 'Gene', '6383', (27, 31))	('affect', 'Reg', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('expression', 'MPA', (13, 23))	('tumor', 'Disease', (146, 151))	('Dysregulated', 'Var', (0, 12))	('HSPG', 'Gene', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
27065	30027065	Moreover, the inhibition of syndecan-2 could reduce tumor cell migration, protecting CRC patients from metastasis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('syndecan-2', 'Gene', (28, 38))	('patients', 'Species', '9606', (89, 97))	('reduce', 'NegReg', (45, 51))	('syndecan-2', 'Gene', '6383', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('inhibition', 'Var', (14, 24))	('metastasis', 'CPA', (103, 113))
27131	28035578	Genetic mutations leading to the activation of protooncogenes and/or loss of functioning of tumor suppressor genes may lead to the deregulation of various cellular pathways, including autophagy, and thus to cancer formation.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('protooncogenes', 'Protein', (47, 61))	('deregulation', 'MPA', (131, 143))	('activation', 'PosReg', (33, 43))	('cancer', 'Disease', (207, 213))	('mutations', 'Var', (8, 17))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('autophagy', 'biological_process', 'GO:0016236', ('184', '193'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('92', '108'))	('loss of functioning', 'NegReg', (69, 88))	('cellular', 'Pathway', (155, 163))	('tumor suppressor', 'biological_process', 'GO:0051726', ('92', '108'))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('autophagy', 'biological_process', 'GO:0006914', ('184', '193'))	('lead', 'Reg', (119, 123))	('formation', 'biological_process', 'GO:0009058', ('214', '223'))	('autophagy', 'CPA', (184, 193))	('tumor', 'Disease', (92, 97))
27140	28035578	Therefore, we may conclude that during the early stages of CRC carcinogenesis apoptosis is more prone to occur than autophagy, while during tumor progression an accumulation of genetic alterations may disturb the process of apoptosis and thus contribute to tumor progression and promotion.	('genetic alterations', 'Var', (177, 196))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('autophagy', 'biological_process', 'GO:0016236', ('116', '125'))	('tumor', 'Disease', (257, 262))	('apoptosis', 'biological_process', 'GO:0097194', ('224', '233'))	('promotion', 'PosReg', (279, 288))	('CRC', 'Phenotype', 'HP:0003003', (59, 62))	('contribute', 'Reg', (243, 253))	('CRC carcinogenesis apoptosis', 'Disease', 'MESH:D015179', (59, 87))	('apoptosis', 'biological_process', 'GO:0006915', ('224', '233'))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('autophagy', 'biological_process', 'GO:0006914', ('116', '125'))	('CRC carcinogenesis apoptosis', 'Disease', (59, 87))	('apoptosis', 'CPA', (224, 233))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))	('process', 'CPA', (213, 220))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('disturb', 'Reg', (201, 208))	('tumor', 'Disease', (140, 145))
27147	28035578	The influence of the underexpression of UVRAG on anticancer therapy has been studied in experiments in which UVRAG expression has been inhibited by specific short hairpin RNAs (sshRNAs) transfection.	('UVRAG', 'Gene', '7405', (40, 45))	('cancer', 'Disease', (53, 59))	('UVRAG', 'Gene', '7405', (109, 114))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('UVRAG', 'Gene', (109, 114))	('UVRAG', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('expression', 'MPA', (115, 125))	('transfection', 'Var', (186, 198))	('inhibited', 'NegReg', (135, 144))
27158	28035578	It has been proven that the loss of Bif-1 inhibits the following: (1) BAX/Bak conformational activation, (2) release of cytochrome c and (3) caspase activation in response to intrinsic signals of death.	('release of cytochrome c', 'MPA', (109, 132))	('Bif-1', 'Gene', '51100', (36, 41))	('loss', 'Var', (28, 32))	('inhibits', 'NegReg', (42, 50))	('Bif-1', 'Gene', (36, 41))	('Bak', 'Gene', (74, 77))	('Bak', 'Gene', '578', (74, 77))	('response to intrinsic signals of death', 'MPA', (163, 201))	('BAX', 'Gene', (70, 73))	('BAX', 'Gene', '581', (70, 73))	('activation', 'PosReg', (149, 159))	('caspase', 'Pathway', (141, 148))
27171	28035578	It has been hypothesized that BECN1 acts as tumor suppressor gene, because of its frequent deletion in a variety of tumors such as breast, ovarian and prostate.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('deletion', 'Var', (91, 99))	('BECN1', 'Gene', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('BECN1', 'Gene', '8678', (30, 35))	('breast, ovarian and prostate', 'Disease', 'MESH:D010051', (131, 159))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', (44, 49))
27323	24782655	The dose-limiting toxicities of L-OHP were shown to be cumulative sensory neurotoxicity and neutropenia, whereas hypersensitivity reactions have been recognized as problematic with the increasing use of L-OHP in clinical practice.	('L-OHP', 'Chemical', 'MESH:D000077150', (203, 208))	('sensory neurotoxicity', 'Disease', 'MESH:D015417', (66, 87))	('neutropenia', 'Phenotype', 'HP:0001875', (92, 103))	('hypersensitivity reactions', 'Disease', (113, 139))	('toxicities', 'Disease', (18, 28))	('hypersensitivity reactions', 'Disease', 'MESH:D004342', (113, 139))	('sensory neurotoxicity', 'Disease', (66, 87))	('L-OHP', 'Chemical', 'MESH:D000077150', (32, 37))	('neutropenia', 'Disease', (92, 103))	('neutropenia', 'Disease', 'MESH:D009503', (92, 103))	('toxicities', 'Disease', 'MESH:D064420', (18, 28))	('L-OHP', 'Var', (32, 37))
27349	24782655	Pyruvate is further transformed to acetyl-CoA under normoxic conditions; however, suboptimal oxygen availability switches the metabolic pathway, resulting in the transformation to lactate via LDH-5, one of the 5 isoenzymes of LDH.	('Pyruvate', 'Chemical', 'MESH:D019289', (0, 8))	('transformation to lactate', 'MPA', (162, 187))	('lactate', 'Chemical', 'MESH:D019344', (180, 187))	('LDH-5', 'Gene', (192, 197))	('suboptimal', 'Var', (82, 92))	('oxygen', 'Chemical', 'MESH:D010100', (93, 99))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (35, 45))	('switches', 'Reg', (113, 121))
27353	24782655	In this study, we analyzed laboratory test data from the first to last cycle of the treatment, and serum LDH levels were shown to be maintained at lower levels in patients with grade 1/2 reactions than those with no reactions (Tables 2 and 3).	('serum LDH levels', 'MPA', (99, 115))	('grade 1/2', 'Var', (177, 186))	('patients', 'Species', '9606', (163, 171))
27362	24782655	Regarding L-OHP, most reactions are thought to be of type I, while reports of hemolysis and thrombocytopenia suggest a type II reaction, and chronic urticaria, joint pain, and proteinuria can be attributed to a type III reaction.	('thrombocytopenia', 'Disease', (92, 108))	('joint pain', 'Phenotype', 'HP:0002829', (160, 170))	('pain', 'Phenotype', 'HP:0012531', (166, 170))	('proteinuria', 'Disease', (176, 187))	('joint pain', 'Disease', (160, 170))	('joint pain', 'Disease', 'MESH:D018771', (160, 170))	('hemolysis', 'Disease', (78, 87))	('thrombocytopenia', 'Disease', 'MESH:D013921', (92, 108))	('L-OHP', 'Var', (10, 15))	('proteinuria', 'Disease', 'MESH:D011507', (176, 187))	('hemolysis', 'Disease', 'MESH:D006461', (78, 87))	('urticaria', 'Phenotype', 'HP:0001025', (149, 158))	('proteinuria', 'Phenotype', 'HP:0000093', (176, 187))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (92, 108))	('chronic urticaria', 'Phenotype', 'HP:0410133', (141, 158))	('urticaria', 'Disease', (149, 158))	('urticaria', 'Disease', 'MESH:D014581', (149, 158))	('L-OHP', 'Chemical', 'MESH:D000077150', (10, 15))
27427	32850691	Among those, GO:0048568 Embryonic organ development, GO:0061458 Reproductive system development, GO:0007389 Pattern specification process, GO:0043062 Extracellular structure organization, GO:0002009 Morphogenesis of an epithelium, and GO:0048732 Gland development were related to tissue or organ morphogenesis.	('Embryonic organ', 'Disease', (24, 39))	('GO:0048732', 'Var', (235, 245))	('GO:0002009', 'Var', (188, 198))	('GO:0043062', 'Var', (139, 149))	('GO:0048568', 'Var', (13, 23))	('GO:0061458', 'Var', (53, 63))	('GO:0007389', 'Var', (97, 107))	('Reproductive system development', 'CPA', (64, 95))	('Gland development', 'CPA', (246, 263))	('Embryonic organ', 'Disease', 'MESH:D019965', (24, 39))	('Pattern specification', 'CPA', (108, 129))
27444	32850691	Additionally, the deregulated expression of KLKs has been utilized in designing novel therapeutic targets for prostate cancer.	('KLKs', 'Gene', (44, 48))	('expression', 'MPA', (30, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (110, 125))	('prostate cancer', 'Phenotype', 'HP:0012125', (110, 125))	('prostate cancer', 'Disease', (110, 125))	('deregulated', 'Var', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
27469	28165529	Alterations of a number of critical genes in CRC development and progression such as dMMR andBRAF activating mutations have been shown to affect prognosis, as measured by several metrics of tumor progression or survival.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('prognosis', 'CPA', (145, 154))	('activating', 'Gene', (98, 108))	('affect', 'Reg', (138, 144))	('Alterations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('dMMR', 'Gene', (85, 89))	('tumor', 'Disease', (190, 195))	('mutations', 'Var', (109, 118))	('CRC', 'Disease', (45, 48))	('andBRAF activating', 'Gene', (90, 108))
27477	28165529	Laboratory data and test performance characteristics included percent mutation, concordance of testing methods, sensitivity of testing methods, specificity of testing methods, concordance of detected mutations between primary and metastatic mutations (number [%] of cases with mutations vs number of cases with no mutations in the gene of interest), and concordance of mutations (synchronous primary vs metastatic, metachronous primary vs metastatic, between synchronous metastases, between metachronous metastases).	('metastases', 'Disease', 'MESH:D009362', (471, 481))	('mutations', 'Var', (200, 209))	('synchronous metastases', 'Disease', 'MESH:D009362', (459, 481))	('metastases', 'Disease', (504, 514))	('mutations', 'Var', (277, 286))	('synchronous metastases', 'Disease', (459, 481))	('metastases', 'Disease', 'MESH:D009362', (504, 514))	('metastases', 'Disease', (471, 481))	('metachronous primary', 'Disease', (415, 435))
27480	28165529	Aberrant activation of EGFR signaling pathways in CRC is primarily associated with activating mutations of genes in the mitogen-activated protein kinase and phosphatidylinositol-3-kinase (PI3K) pathways.	('PI3K', 'molecular_function', 'GO:0016303', ('188', '192'))	('activation', 'PosReg', (9, 19))	('EGFR signaling pathways', 'Pathway', (23, 46))	('mutations', 'Var', (94, 103))	('CRC', 'Disease', (50, 53))	('EGFR', 'molecular_function', 'GO:0005006', ('23', '27'))	('phosphatidylinositol-3-kinase', 'Gene', (157, 186))	('phosphatidylinositol-3-kinase', 'Gene', '5290', (157, 186))	('signaling', 'biological_process', 'GO:0023052', ('28', '37'))	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))
27481	28165529	Together,KRAS, NRAS, andBRAF mutations have been reported to occur in more than half of all CRC cases, andKRAS orNRAS andBRAF mutations are inversely associated, with a small proportion of individual CRCs showing co-occurrence ofRAS andRAF mutations.	('andKRAS orNRAS andBRAF', 'Disease', (103, 125))	('andKRAS orNRAS andBRAF', 'Disease', 'None', (103, 125))	('mutations', 'Var', (29, 38))	('CRC', 'Disease', (92, 95))	('ofRAS andRAF', 'Disease', (227, 239))	('ofRAS andRAF', 'Disease', 'None', (227, 239))
27484	28165529	A few studies reported anti-EGFR antibody treatment outcomes for the following comparisons:KRAS G13D vs codon 12 mutations,KRAS codon 13 mutations vs other mutations, and G13D vs other exon 2 mutations.	('G13D', 'Mutation', 'rs112445441', (96, 100))	('G13D', 'Var', (171, 175))	('G13D', 'SUBSTITUTION', 'None', (171, 175))	('G13D', 'Var', (96, 100))	('G13D', 'Mutation', 'rs112445441', (171, 175))	('G13D', 'SUBSTITUTION', 'None', (96, 100))	('KRAS codon', 'Var', (123, 133))
27485	28165529	Survival advantages (OS and PFS, ORR) for G13D mutations over codon 12 and G13D over other mutations were reported in two studies and codon 13 over otherKRAS mutations.	('advantages', 'PosReg', (9, 19))	('G13D', 'Var', (75, 79))	('G13D', 'SUBSTITUTION', 'None', (75, 79))	('G13D', 'SUBSTITUTION', 'None', (42, 46))	('G13D', 'Var', (42, 46))
27486	28165529	Douillard et al published a reanalysis of the Panitumumab Randomized Control Trial in Combination with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) trial, reporting that patients with anyRAS mutations were associated with inferior PFS and OS with panitumumab-FOLFOX4 treatment, which was consistent with the findings previously reported for patients withKRAS mutations in exon 2.	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (131, 148))	('inferior', 'NegReg', (253, 261))	('Metastatic Colorectal Cancer', 'Disease', (120, 148))	('PFS', 'CPA', (262, 265))	('Panitumumab', 'Chemical', 'MESH:D000077544', (46, 57))	('mutations', 'Var', (222, 231))	('FOLFOX4', 'Chemical', '-', (290, 297))	('anyRAS', 'Disease', (215, 221))	('Metastatic Colorectal Cancer', 'Disease', 'MESH:D015179', (120, 148))	('Cancer', 'Phenotype', 'HP:0002664', (142, 148))	('anyRAS', 'Disease', 'None', (215, 221))
27487	28165529	Recommendation: BRAF p.V600 (BRAF c.1799 [p.V600]) position mutational analysis should be performed in CRC tissue in selected patients with colorectal carcinoma for prognostic stratification.	('colorectal carcinoma', 'Disease', (140, 160))	('p.V600', 'Var', (21, 27))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (140, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
27491	28165529	A recent publication of the PETACC-8 (oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer randomised phase 3) trial reported that trials in the adjuvant setting should consider mismatch repair,BRAF, andKRAS status for stratification, sinceBRAF p.V600 andKRAS mutations were associated with shorter DFS and OS in patients with microsatellite-stable colon cancer but not in those with tumors with MSI.	('colon cancer', 'Disease', (142, 154))	('DFS', 'MPA', (363, 366))	('cancer', 'Phenotype', 'HP:0002664', (419, 425))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('microsatellite-stable colon cancer', 'Disease', (391, 425))	('p.V600', 'Var', (309, 315))	('tumor', 'Phenotype', 'HP:0002664', (448, 453))	('shorter', 'NegReg', (355, 362))	('colon cancer', 'Phenotype', 'HP:0003003', (413, 425))	('colon cancer', 'Phenotype', 'HP:0003003', (142, 154))	('colon cancer', 'Disease', 'MESH:D015179', (142, 154))	('microsatellite-stable colon cancer', 'Disease', 'MESH:D015179', (391, 425))	('colon cancer', 'Disease', 'MESH:D015179', (413, 425))	('tumors', 'Phenotype', 'HP:0002664', (448, 454))
27492	28165529	In Lynch syndrome CRC, the underlying mechanism is usually a germline mutation of one of the four (MLH1,MSH2,MSH6, andPMS2) mismatch repair genes and, in rare patients, a deletion involvingEPCAM (epithelial cell adhesion molecule), a gene adjacent toMSH2, that leads to epigenetic inactivation of theMSH2 gene.	('MSH2', 'Gene', '4436', (250, 254))	('MSH6', 'Gene', (109, 113))	('MSH2', 'Gene', '4436', (104, 108))	('PMS2', 'Gene', (118, 122))	('Lynch syndrome CRC', 'Disease', 'MESH:D015179', (3, 21))	('MSH6', 'Gene', '2956', (109, 113))	('epigenetic inactivation', 'MPA', (270, 293))	('MSH2', 'Gene', (300, 304))	('involvingEPCAM', 'Gene', (180, 194))	('mismatch repair', 'biological_process', 'GO:0006298', ('124', '139'))	('epithelial cell adhesion molecule', 'Gene', (196, 229))	('epithelial cell adhesion molecule', 'Gene', '4072', (196, 229))	('MLH1', 'Gene', (99, 103))	('deletion', 'Var', (171, 179))	('MSH2', 'Gene', '4436', (300, 304))	('Lynch syndrome CRC', 'Disease', (3, 21))	('PMS2', 'Gene', '5395', (118, 122))	('MSH2', 'Gene', (250, 254))	('MSH2', 'Gene', (104, 108))	('cell adhesion', 'biological_process', 'GO:0007155', ('207', '220'))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('207', '229'))
27493	28165529	The molecular pathology underlying most MSI tumors is somatically acquired CpG methylation of the promoter of the gene,MLH1.	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('MLH1', 'Gene', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('MSI tumors', 'Disease', 'MESH:D009369', (40, 50))	('CpG methylation', 'Var', (75, 90))	('MSI tumors', 'Disease', (40, 50))
27495	28165529	Individuals with germline mutations in the MMR genes are said to have Lynch syndrome, an autosomal dominant disorder that confers dramatically increased risks for colorectal and endometrial cancers and moderately increases risks for a variety of other tumors.	('autosomal dominant disorder', 'Disease', (89, 116))	('colorectal and endometrial cancers', 'Disease', 'MESH:D015179', (163, 197))	('increased', 'PosReg', (143, 152))	('Lynch syndrome', 'Disease', (70, 84))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('MMR', 'biological_process', 'GO:0006298', ('43', '46'))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (89, 116))	('MMR', 'Gene', (43, 46))	('germline mutations', 'Var', (17, 35))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))
27498	28165529	Note: Retrospective studies have suggested improved survival with postoperative aspirin use in patients whose colorectal carcinoma harbors aPIK3CA mutation.	('colorectal carcinoma', 'Disease', (110, 130))	('aPIK3CA', 'Gene', (139, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('survival', 'MPA', (52, 60))	('mutation', 'Var', (147, 155))	('improved', 'PosReg', (43, 51))	('aspirin', 'Chemical', 'MESH:D001241', (80, 87))
27500	28165529	PTEN functions as a tumor suppressor gene, and loss of PTEN results in upregulation of the PI3K/AKT pathway.PTEN mutations occur in approximately 5% to 14% of colorectal cancers, and loss ofPTEN expression can be observed in tumors withKRAS,BRAF, andPIK3CA mutations.	('rectal cancer', 'Phenotype', 'HP:0100743', (163, 176))	('tumors withKRAS,BRAF', 'Disease', 'MESH:D009369', (225, 245))	('AKT', 'Gene', (96, 99))	('loss ofPTEN', 'Disease', (183, 194))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('loss ofPTEN', 'Disease', 'MESH:D014786', (183, 194))	('colorectal cancer', 'Phenotype', 'HP:0003003', (159, 176))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('pathway.PTEN', 'Gene', (100, 112))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('AKT', 'Gene', '207', (96, 99))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('colorectal cancers', 'Disease', (159, 177))
27508	28165529	With NGS and highly sensitive PCR technologies, mutations should be identifiable in specimens with as little as 10% tumor (mutant allele frequency of 5% assuming heterozygosity and diploidy).	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutations', 'Var', (48, 57))	('diploidy', 'Disease', 'None', (181, 189))	('diploidy', 'Disease', (181, 189))
27516	28165529	Understanding that the number of mutated alleles for a particular gene may represent as few as half of the alleles in diploid tumor cells, a tumor cell focus with a nominal proportion of 50% tumor cells would have a mutant allele fraction of 25%, a value approaching the analytical sensitivity of some molecular assays.	('diploid tumor', 'Disease', (118, 131))	('mutant', 'Var', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('diploid tumor', 'Disease', 'MESH:C548012', (118, 131))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
27519	28165529	Hence, if a particular assay has a lower limit of mutant allele detection of 5%, then the minimum tumor cell content in samples analyzed by this assay should be at least 10% to reliably detect heterozygous mutations in those neoplasms.	('neoplasms', 'Phenotype', 'HP:0002664', (225, 234))	('detect', 'Reg', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('neoplasms', 'Disease', 'MESH:D009369', (225, 234))	('neoplasms', 'Disease', (225, 234))	('mutant', 'Var', (50, 56))
27520	28165529	The presence of deficient MMR orBRAF p.V600E mutation in proficient MMR CRCs has important prognostic significance.	('deficient MMR orBRAF', 'Disease', (16, 36))	('deficient MMR orBRAF', 'Disease', 'MESH:C536928', (16, 36))	('p.V600E', 'Mutation', 'rs113488022', (37, 44))	('p.V600E', 'Var', (37, 44))
27523	28165529	While earlier testing approaches were focused on one or a few testing targets (eg,BRAF p.V600 mutations), currently, new approaches are using gene panels such as targeted NGS cancer panels, which can range from a few to hundreds of genes and amplicons with known mutational hotspots in cancer.	('NGS cancer', 'Disease', 'MESH:D009369', (171, 181))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('NGS cancer', 'Disease', (171, 181))	('p.V600 mutations', 'Var', (87, 103))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
27543	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))
27580	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))
27601	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))
27602	32014012	Hypoxia-induced overexpression of circDENND2A promotes the migration and invasion of glioma cells by sponging miR-625-5p.	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('circDENND2A', 'Var', (34, 45))	('Hypoxia', 'Disease', (0, 7))	('glioma', 'Disease', (85, 91))	('migration', 'CPA', (59, 68))	('promotes', 'PosReg', (46, 54))	('miR', 'Gene', (110, 113))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('miR', 'Gene', '220972', (110, 113))
27603	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))
27620	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))
27622	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))
27634	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))	('snail family zinc finger 1', 'Gene', (31, 57))	('PKM2', 'Gene', (317, 321))	('cancer', 'Phenotype', 'HP:0002664', (383, 389))	('modulates', 'Var', (93, 102))	('PKM2', 'Gene', '5315', (317, 321))	('SNAIL', 'Gene', '6615', (59, 64))	('SNAIL', 'Gene', (59, 64))	('p70S6K', 'Gene', '6198', (189, 195))	('RPS6KB1', 'Gene', '6198', (165, 172))	('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))	('expression', 'MPA', (323, 333))
27636	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))
27681	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))	('miR', 'Gene', '220972', (90, 93))	('human', 'Species', '9606', (3, 8))	('reducing', 'NegReg', (199, 207))	('destabilize', 'NegReg', (164, 175))	('miR', 'Gene', '220972', (141, 144))	('miR', 'Gene', (141, 144))	('HIF-1alpha', 'Var', (122, 132))	('activity', 'MPA', (212, 220))	('miR', 'Gene', (90, 93))
27692	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))	('H19', 'Gene', '283120', (76, 79))	('miR-215', 'Gene', '406997', (84, 91))	('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))
27694	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))
27701	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))
27750	31835465	Deletion of MMP-1 leads to decreased vascular permeability and reduced transendothelial migration.	('reduced', 'NegReg', (63, 70))	('vascular permeability', 'MPA', (37, 58))	('decreased', 'NegReg', (27, 36))	('transendothelial migration', 'CPA', (71, 97))	('MMP-1', 'Gene', '4312', (12, 17))	('MMP-1', 'Gene', (12, 17))	('Deletion', 'Var', (0, 8))
27756	31835465	Genetic and pharmaceutical deletion of pericyte results in increased vascular leakage and intratumoral hypoxia, leading to EMT-driven metastasis.	('vascular leakage', 'CPA', (69, 85))	('EMT-driven metastasis', 'CPA', (123, 144))	('EMT', 'biological_process', 'GO:0001837', ('123', '126'))	('intratumoral hypoxia', 'Disease', 'MESH:D000860', (90, 110))	('deletion', 'Var', (27, 35))	('pericyte', 'Gene', (39, 47))	('intratumoral hypoxia', 'Disease', (90, 110))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('increased', 'PosReg', (59, 68))
27769	31835465	Inhibition of neutrophil infiltration by interleukin 8 (IL-8) neutralization leads to diminished tumor angiogenesis and intravasation.	('interleukin 8', 'Gene', '3576', (41, 54))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('intravasation', 'MPA', (120, 133))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('diminished', 'NegReg', (86, 96))	('IL-8', 'Gene', '3576', (56, 60))	('angiogenesis', 'biological_process', 'GO:0001525', ('103', '115'))	('neutralization', 'Var', (62, 76))	('interleukin 8', 'Gene', (41, 54))	('IL-8', 'Gene', (56, 60))	('IL-8', 'molecular_function', 'GO:0005153', ('56', '60'))
27832	31835465	Ang2 neutralization inhibits the recruitment of CCR2+Tie2- MAMs via blocking C-C motif chemokine ligand 2 (CCL2) and ICAM-1, leading to reduced metastases.	('ICAM-1', 'Gene', '3383', (117, 123))	('neutralization', 'Var', (5, 19))	('reduced', 'NegReg', (136, 143))	('metastases', 'Disease', 'MESH:D009362', (144, 154))	('CCL2', 'Gene', (107, 111))	('Ang2', 'Gene', (0, 4))	('metastases', 'Disease', (144, 154))	('inhibits', 'NegReg', (20, 28))	('ICAM-1', 'Gene', (117, 123))	('Tie2', 'Gene', (53, 57))	('CCR2', 'Gene', (48, 52))	('CCL2', 'Gene', '6347', (107, 111))	('recruitment', 'MPA', (33, 44))	('C-C motif chemokine ligand 2', 'Gene', (77, 105))	('CCR2', 'Gene', '729230', (48, 52))	('C-C motif chemokine ligand 2', 'Gene', '6347', (77, 105))	('Tie2', 'Gene', '7010', (53, 57))	('blocking', 'NegReg', (68, 76))	('Ang2', 'Gene', '285', (0, 4))
27838	31835465	Tie1 deficiency leads to reduced angiogenesis and increased mural cell coverage with improved vessel perfusion via activating the Ang1/Tie2 signaling pathway.	('reduced', 'NegReg', (25, 32))	('improved', 'PosReg', (85, 93))	('deficiency', 'Var', (5, 15))	('vessel perfusion', 'CPA', (94, 110))	('signaling pathway', 'biological_process', 'GO:0007165', ('140', '157'))	('angiogenesis', 'CPA', (33, 45))	('Tie2', 'Gene', (135, 139))	('increased', 'PosReg', (50, 59))	('Tie1', 'Gene', '7075', (0, 4))	('activating', 'Reg', (115, 125))	('Ang1', 'Gene', '284', (130, 134))	('Tie2', 'Gene', '7010', (135, 139))	('Ang1', 'Gene', (130, 134))	('angiogenesis', 'biological_process', 'GO:0001525', ('33', '45'))	('Tie1', 'Gene', (0, 4))	('mural cell coverage', 'CPA', (60, 79))
27842	31835465	The genetic inhibition of the glycolytic activator PFKFB3 improves vessel perfusion and tightens the endothelial cell barrier.	('tightens', 'PosReg', (88, 96))	('genetic inhibition', 'Var', (4, 22))	('vessel perfusion', 'CPA', (67, 83))	('improves', 'PosReg', (58, 66))	('PFKFB3', 'Gene', (51, 57))	('endothelial cell barrier', 'CPA', (101, 125))	('PFKFB3', 'Gene', '5209', (51, 57))
27853	31835465	Anti-angiogenic agents, including DC101 (antibody against VEGFR-2) and sunitinib, promote local invasiveness and increase distant metastasis in the mouse models of pancreatic neuroendocrine cancer and glioblastoma multiforme.	('promote', 'PosReg', (82, 89))	('neuroendocrine cancer', 'Phenotype', 'HP:0100634', (175, 196))	('pancreatic neuroendocrine cancer', 'Disease', (164, 196))	('antibody', 'molecular_function', 'GO:0003823', ('41', '49'))	('sunitinib', 'Chemical', 'MESH:C473478', (71, 80))	('antibody', 'cellular_component', 'GO:0042571', ('41', '49'))	('mouse', 'Species', '10090', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('DC101', 'Var', (34, 39))	('glioblastoma', 'Phenotype', 'HP:0012174', (201, 213))	('VEGFR-2', 'Gene', (58, 65))	('increase', 'PosReg', (113, 121))	('antibody', 'cellular_component', 'GO:0019815', ('41', '49'))	('glioblastoma multiforme', 'Disease', (201, 224))	('pancreatic neuroendocrine cancer', 'Disease', 'MESH:D010190', (164, 196))	('pancreatic neuroendocrine cancer', 'Phenotype', 'HP:0030405', (164, 196))	('distant metastasis', 'CPA', (122, 140))	('local invasiveness', 'CPA', (90, 108))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (201, 224))	('antibody', 'cellular_component', 'GO:0019814', ('41', '49'))
27854	31835465	Mice treated with DC101 or sunitinib show severe hypoxia, especially in the micrometastases of distant organs, indicating the crucial role of hypoxia in promoting metastasis after anti-angiogenic therapy.	('metastasis', 'CPA', (163, 173))	('metastases', 'Disease', (81, 91))	('hypoxia', 'Disease', 'MESH:D000860', (49, 56))	('promoting', 'PosReg', (153, 162))	('hypoxia', 'Disease', 'MESH:D000860', (142, 149))	('Mice', 'Species', '10090', (0, 4))	('hypoxia', 'Disease', (49, 56))	('sunitinib', 'Chemical', 'MESH:C473478', (27, 36))	('hypoxia', 'Disease', (142, 149))	('metastases', 'Disease', 'MESH:D009362', (81, 91))	('DC101', 'Var', (18, 23))
27872	31835465	Fatty acid synthase (FASN) is a critical enzyme in lipogenesis, and blocking FASN inhibits tumor regrowth and metastasis after the withdrawal of sunitinib treatment.	('blocking', 'Var', (68, 76))	('FASN', 'Gene', (77, 81))	('sunitinib', 'Chemical', 'MESH:C473478', (145, 154))	('FASN', 'Gene', '2194', (77, 81))	('FASN', 'Gene', (21, 25))	('FASN', 'Gene', '2194', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('inhibits', 'NegReg', (82, 90))	('Fatty acid synthase', 'Gene', '2194', (0, 19))	('Fatty acid synthase', 'Gene', (0, 19))
27882	31835465	High TAM infiltration and variations in genes regulating TAM-related functions such as TBK1, CCL2, CCL18 and IRF3 predict poor outcome in metastatic patients treated with bevacizumab.	('TAM', 'Chemical', 'MESH:C419191', (57, 60))	('CCL2', 'Gene', '6347', (93, 97))	('patients', 'Species', '9606', (149, 157))	('predict', 'Reg', (114, 121))	('TBK1', 'Gene', (87, 91))	('CCL', 'molecular_function', 'GO:0044101', ('99', '102'))	('CCL2', 'Gene', (93, 97))	('CCL18', 'Gene', '6362', (99, 104))	('IRF3', 'Gene', (109, 113))	('IRF3', 'Gene', '3661', (109, 113))	('CCL', 'molecular_function', 'GO:0044101', ('93', '96'))	('TBK1', 'molecular_function', 'GO:0008384', ('87', '91'))	('CCL18', 'Gene', (99, 104))	('metastatic', 'Disease', (138, 148))	('TAM', 'Chemical', 'MESH:C419191', (5, 8))	('variations', 'Var', (26, 36))	('TBK1', 'Gene', '29110', (87, 91))
27900	31835465	Moreover, the combination of VEGFR-2 and PD-L1 antibodies induces high endothelial venules (HEVs) to facilitate IFNgamma+ CD4+ and IFNgamma+ CD8+ lymphocyte infiltration in breast cancer and pancreatic neuroendocrine tumors, finally leading to tumor cell apoptosis and necrosis.	('combination', 'Var', (14, 25))	('facilitate', 'PosReg', (101, 111))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (191, 223))	('CD8', 'Gene', '925', (141, 144))	('PD-L1', 'Gene', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('tumor', 'Disease', (217, 222))	('PD-L1', 'Gene', '29126', (41, 46))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (202, 223))	('pancreatic neuroendocrine tumors', 'Disease', (191, 223))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('necrosis', 'Disease', 'MESH:D009336', (269, 277))	('VEGFR-2', 'Gene', (29, 36))	('breast cancer', 'Disease', (173, 186))	('antibodies', 'Var', (47, 57))	('IFNgamma', 'Gene', '3458', (131, 139))	('IFNgamma', 'Gene', (131, 139))	('CD4', 'Gene', '920', (122, 125))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('necrosis', 'Disease', (269, 277))	('CD8', 'Gene', (141, 144))	('CD4', 'Gene', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (244, 249))	('IFNgamma', 'Gene', (112, 120))	('IFNgamma', 'Gene', '3458', (112, 120))	('leading to', 'Reg', (233, 243))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
27914	31137841	Moreover, using cell lines and patient-derived xenograft models, we showed that inhibition of YAP1 enhances the efficacy of conventional therapies by attenuating CSC stemness features.	('CSC', 'Disease', (162, 165))	('efficacy', 'MPA', (112, 120))	('attenuating', 'NegReg', (150, 161))	('YAP1', 'Gene', (94, 98))	('YAP1', 'Gene', '10413', (94, 98))	('patient', 'Species', '9606', (31, 38))	('enhances', 'PosReg', (99, 107))	('inhibition', 'Var', (80, 90))
27945	31137841	Recently, treatment of breast CSCs with interferon-beta in vitro has been reported to limit stemness, migration, sphere-forming properties, and re-expression of CD24, and promote an epithelial-like morphology.	('stemness', 'CPA', (92, 100))	('promote', 'PosReg', (171, 178))	('limit', 'NegReg', (86, 91))	('re-expression', 'Var', (144, 157))	('CD24', 'Gene', (161, 165))	('CD24', 'Gene', '100133941', (161, 165))	('sphere-forming properties', 'CPA', (113, 138))	('interferon-beta', 'Gene', (40, 55))	('interferon-beta', 'Gene', '3456', (40, 55))	('migration', 'CPA', (102, 111))	('epithelial-like morphology', 'CPA', (182, 208))
27956	31137841	Moreover, CD133+ colorectal cancer cells have also been shown to be resistant to radiotherapy and chemotherapy, consistent with a CSC phenotype.	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('colorectal cancer', 'Disease', (17, 34))	('CD133+', 'Var', (10, 16))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))
27971	31137841	CD133 has also been identified as a lung CSC marker; notably, CD133+ cells have sphere-forming and tumorigenic capabilities, are chemoresistant, and are a biomarker of poor prognosis in lung cancer patients.	('tumor', 'Disease', (99, 104))	('sphere-forming', 'CPA', (80, 94))	('patients', 'Species', '9606', (198, 206))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('CD133+', 'Var', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', (186, 197))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))
27978	31137841	Among the CSC-targeting strategies explored in lung cancer to date, genetic knockdown or pharmacological inhibition of ALDH1 has been shown to attenuate the proliferative and migratory capabilities of NSCLC cells.	('NSCLC', 'Phenotype', 'HP:0030358', (201, 206))	('attenuate', 'NegReg', (143, 152))	('genetic knockdown', 'Var', (68, 85))	('lung cancer', 'Disease', (47, 58))	('pharmacological', 'Var', (89, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('NSCLC', 'Disease', (201, 206))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('ALDH1', 'Gene', (119, 124))	('NSCLC', 'Disease', 'MESH:D002289', (201, 206))	('ALDH1', 'Gene', '216', (119, 124))
27989	31137841	CD133+ ovarian cancer cells have been shown to have a more proliferative phenotype than do CD133- cells.	('ovarian cancer', 'Phenotype', 'HP:0100615', (7, 21))	('CD133+', 'Var', (0, 6))	('ovarian cancer', 'Disease', 'MESH:D010051', (7, 21))	('ovarian cancer', 'Disease', (7, 21))	('proliferative', 'CPA', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
27990	31137841	A recent study showed that CD133+ CSCs induced CD133- cells to undergo the EMT and to display enhanced metastatic capacity via secretion of CCL5 and activation of NF-kappaB signaling.	('CCL5', 'Gene', '6352', (140, 144))	('secretion', 'MPA', (127, 136))	('CD133+ CSCs', 'Var', (27, 38))	('EMT', 'CPA', (75, 78))	('enhanced', 'PosReg', (94, 102))	('metastatic capacity', 'CPA', (103, 122))	('CCL5', 'Gene', (140, 144))	('activation', 'PosReg', (149, 159))	('NF-kappaB signaling', 'Pathway', (163, 182))
27992	31137841	CD44 knockdown in CSCs suppressed their proliferation, migration/invasion, and sphere-forming abilities and increased their drug sensitivity.	('suppressed', 'NegReg', (23, 33))	('migration/invasion', 'CPA', (55, 73))	('knockdown', 'Var', (5, 14))	('increased', 'PosReg', (108, 117))	('CD44', 'Gene', '960', (0, 4))	('sphere-forming abilities', 'CPA', (79, 103))	('drug sensitivity', 'CPA', (124, 140))	('CD44', 'Gene', (0, 4))	('drug sensitivity', 'Phenotype', 'HP:0020174', (124, 140))	('proliferation', 'CPA', (40, 53))
27997	31137841	The authors proposed that high ALDH1 alone may be insufficient to drive the ovarian CSC phenotype, but that ALDH1 and CD44 co-expression may trigger chemoresistance and poor clinical outcome.	('chemoresistance', 'CPA', (149, 164))	('CD44', 'Gene', '960', (118, 122))	('ovarian CSC', 'Disease', (76, 87))	('CD44', 'Gene', (118, 122))	('ALDH1', 'Gene', (31, 36))	('ovarian CSC', 'Disease', 'MESH:D010051', (76, 87))	('ALDH1', 'Gene', (108, 113))	('co-expression', 'Var', (123, 136))	('ALDH1', 'Gene', '216', (31, 36))	('ALDH1', 'Gene', '216', (108, 113))	('trigger', 'Reg', (141, 148))	('insufficient', 'Disease', 'MESH:D000309', (50, 62))	('insufficient', 'Disease', (50, 62))
27999	31137841	For example, miR-199a decreased CD44 expression, resulting in reduced tumorigenicity and increased chemotherapeutic sensitivity.	('chemotherapeutic sensitivity', 'CPA', (99, 127))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CD44', 'Gene', (32, 36))	('tumor', 'Disease', (70, 75))	('increased', 'PosReg', (89, 98))	('miR-199a', 'Var', (13, 21))	('expression', 'MPA', (37, 47))	('CD44', 'Gene', '960', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('reduced', 'NegReg', (62, 69))	('decreased', 'NegReg', (22, 31))
28000	31137841	In this study, other stemness factors, such as NANOG, OCT4 and CD133, were also reduced by miR-199a overexpression.	('CD133', 'CPA', (63, 68))	('miR-199a', 'Var', (91, 99))	('NANOG', 'Gene', (47, 52))	('reduced', 'NegReg', (80, 87))	('stemness factors', 'CPA', (21, 37))	('OCT4', 'Gene', '5460', (54, 58))	('OCT4', 'Gene', (54, 58))	('overexpression', 'PosReg', (100, 114))	('NANOG', 'Gene', '79923', (47, 52))
28001	31137841	Targeting of CD133+ cells with an anti-CD133 antibody-toxin conjugate was shown to inhibit the progression of ovarian cancer.	('progression', 'CPA', (95, 106))	('ovarian cancer', 'Disease', 'MESH:D010051', (110, 124))	('ovarian cancer', 'Disease', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ovarian cancer', 'Phenotype', 'HP:0100615', (110, 124))	('anti-CD133', 'Var', (34, 44))	('inhibit', 'NegReg', (83, 90))	('anti-CD133', 'Gene', (34, 44))
28002	31137841	ALDH1 overexpression in ovarian CSCs increased taxane and platinum resistance, and conversely, ALDH1 knockdown overcomes the resistance, enhancing growth inhibition in the presence of chemotherapeutic agents.	('enhancing', 'PosReg', (137, 146))	('ALDH1', 'Gene', '216', (0, 5))	('taxane', 'MPA', (47, 53))	('ALDH', 'molecular_function', 'GO:0004030', ('95', '99'))	('platinum', 'Chemical', 'MESH:D010984', (58, 66))	('ALDH', 'molecular_function', 'GO:0004030', ('0', '4'))	('growth inhibition', 'CPA', (147, 164))	('increased', 'PosReg', (37, 46))	('ALDH1', 'Gene', (0, 5))	('ALDH1', 'Gene', (95, 100))	('overexpression', 'PosReg', (6, 20))	('taxane', 'Chemical', 'MESH:C080625', (47, 53))	('ALDH1', 'Gene', '216', (95, 100))	('ovarian CSC', 'Disease', 'MESH:D010051', (24, 35))	('ovarian CSC', 'Disease', (24, 35))	('knockdown', 'Var', (101, 110))
28015	31137841	reported that motesanib decreased the expression of survival-related genes in the PI3K/AKT pathway, and combination treatment with motesanib synergistically enhanced the anticancer effect of cisplatin.	('decreased', 'NegReg', (24, 33))	('motesanib', 'Chemical', 'MESH:C000625785', (14, 23))	('expression', 'MPA', (38, 48))	('AKT', 'Gene', (87, 90))	('enhanced', 'PosReg', (157, 165))	('motesanib', 'Chemical', 'MESH:C000625785', (131, 140))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('cancer', 'Disease', (174, 180))	('cisplatin', 'Chemical', 'MESH:D002945', (191, 200))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('survival-related genes', 'Gene', (52, 74))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('AKT', 'Gene', '207', (87, 90))	('motesanib', 'Var', (131, 140))
28017	31137841	Among bladder cancer patients, 20 single nucleotide polymorphisms in 40 genes in the Wnt/beta-catenin pathway were associated with an increased risk of cancer.	('cancer', 'Disease', (14, 20))	('single nucleotide polymorphisms', 'Var', (34, 65))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('bladder cancer', 'Phenotype', 'HP:0009725', (6, 20))	('patients', 'Species', '9606', (21, 29))	('Wnt/beta-catenin pathway', 'Pathway', (85, 109))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('bladder cancer', 'Disease', 'MESH:D001749', (6, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('associated with', 'Reg', (115, 130))	('bladder cancer', 'Disease', (6, 20))
28027	31137841	CD133 has also been investigated as a CSC marker in HNSCC; consistent with this, CD133+ cells showed reduced sensitivity to paclitaxel.	('sensitivity to paclitaxel', 'MPA', (109, 134))	('reduced', 'NegReg', (101, 108))	('CD133+', 'Var', (81, 87))	('paclitaxel', 'Chemical', 'MESH:D017239', (124, 134))
28035	31137841	Examination of specimens from patients with oral lichen planus showed that high BMI1 levels were associated with a higher risk of progressing to oral squamous cell carcinoma.	('BMI1', 'Gene', (80, 84))	('high', 'Var', (75, 79))	('BMI1', 'Gene', '648', (80, 84))	('patients', 'Species', '9606', (30, 38))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (145, 173))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('levels', 'MPA', (85, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('oral squamous cell carcinoma', 'Disease', (145, 173))
28036	31137841	In another study, the expression of BMI1 or ALDH1 was associated with the transformation from oral erythroplakia to cancer.	('BMI1', 'Gene', (36, 40))	('ALDH', 'molecular_function', 'GO:0004030', ('44', '48'))	('expression', 'Var', (22, 32))	('oral erythroplakia', 'Phenotype', 'HP:0030934', (94, 112))	('oral erythroplakia to cancer', 'Disease', (94, 122))	('ALDH1', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('BMI1', 'Gene', '648', (36, 40))	('ALDH1', 'Gene', '216', (44, 49))	('associated with', 'Reg', (54, 69))	('oral erythroplakia to cancer', 'Disease', 'MESH:D009062', (94, 122))
28037	31137841	Indeed, in several studies, BMI1 expression was associated with a lack of response to chemoradiotherapy.	('associated', 'Reg', (48, 58))	('BMI1', 'Gene', '648', (28, 32))	('BMI1', 'Gene', (28, 32))	('expression', 'Var', (33, 43))
28047	31137841	In addition, YAP1 signaling is activated by long noncoding RNAs in liver cancer, leading to the induction of self-renewal by CSCs.	('liver cancer', 'Disease', (67, 79))	('self-renewal', 'CPA', (109, 121))	('YAP1', 'Gene', (13, 17))	('long noncoding RNAs', 'Var', (44, 63))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('signaling', 'biological_process', 'GO:0023052', ('18', '27'))	('liver cancer', 'Phenotype', 'HP:0002896', (67, 79))	('liver cancer', 'Disease', 'MESH:D006528', (67, 79))	('YAP1', 'Gene', '10413', (13, 17))
28062	31137841	In this study, high YAP1 expression was associated with increased levels of mesenchymal markers, and YAP1 induced CSC properties, such as sphere-forming and self-renewal abilities, invasiveness and drug resistance via induction of SOX2.	('drug resistance', 'Phenotype', 'HP:0020174', (198, 213))	('induced', 'PosReg', (106, 113))	('drug resistance', 'biological_process', 'GO:0009315', ('198', '213'))	('invasiveness', 'Disease', (181, 193))	('drug resistance', 'biological_process', 'GO:0042493', ('198', '213'))	('high', 'Var', (15, 19))	('CSC properties', 'CPA', (114, 128))	('expression', 'MPA', (25, 35))	('SOX2', 'Gene', '6657', (231, 235))	('YAP1', 'Gene', '10413', (101, 105))	('SOX2', 'Gene', (231, 235))	('levels of mesenchymal markers', 'MPA', (66, 95))	('drug resistance', 'CPA', (198, 213))	('sphere-forming', 'CPA', (138, 152))	('invasiveness', 'Disease', 'MESH:D009362', (181, 193))	('YAP1', 'Gene', '10413', (20, 24))	('YAP1', 'Gene', (101, 105))	('increased', 'PosReg', (56, 65))	('YAP1', 'Gene', (20, 24))
28069	31137841	Using patient-derived xenograft mice models in which the heterogeneity of the primary human tumor was preserved, we found that simultaneous blockade of YAP1 and STAT3 by verteporfin suppressed CSC activity and tumor growth when combined with chemotherapy.	('verteporfin', 'Chemical', 'MESH:D000077362', (170, 181))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('CSC activity', 'MPA', (193, 205))	('suppressed', 'NegReg', (182, 192))	('blockade', 'Var', (140, 148))	('tumor', 'Disease', (210, 215))	('patient', 'Species', '9606', (6, 13))	('human', 'Species', '9606', (86, 91))	('YAP1', 'Gene', (152, 156))	('YAP1', 'Gene', '10413', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mice', 'Species', '10090', (32, 36))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
28083	30880326	A large number of studies have identified smoking, obesity, epigenetic and genetic factors as risk factors for colorectal cancer.	('obesity', 'Phenotype', 'HP:0001513', (51, 58))	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('epigenetic', 'Var', (60, 70))	('genetic factors', 'Var', (75, 90))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('obesity', 'Disease', 'MESH:D009765', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal cancer', 'Disease', (111, 128))	('obesity', 'Disease', (51, 58))
28098	30880326	Expression levels of mRNAs and lncRNAs were statistically significantly expression between SW480 cells under hypoxia (SW480_H) and SW480 cells under normoxia (SW480_N) (P<0.05; fold-change >2).	('SW480', 'CellLine', 'CVCL:0546', (91, 96))	('hypoxia', 'Disease', (109, 116))	('Expression', 'MPA', (0, 10))	('SW480_H', 'Var', (118, 125))	('hypoxia', 'Disease', 'MESH:D000860', (109, 116))	('SW480', 'CellLine', 'CVCL:0546', (131, 136))	('SW480', 'CellLine', 'CVCL:0546', (159, 164))	('SW480', 'CellLine', 'CVCL:0546', (118, 123))
28103	30880326	We found that in the upregulated mRNAs from SW480_H (Figure 3A), the highest enriched GO terms were the cellular macromolecule metabolic process (biological process), the nucleus (cellular component),and the DNA binding (molecular function).	('DNA binding', 'molecular_function', 'GO:0003677', ('208', '219'))	('SW480', 'CellLine', 'CVCL:0546', (44, 49))	('cellular component', 'cellular_component', 'GO:0005575', ('180', '198'))	('biological process', 'biological_process', 'GO:0008150', ('146', '164'))	('nucleus', 'cellular_component', 'GO:0005634', ('171', '178'))	('upregulated', 'PosReg', (21, 32))	('SW480_H', 'Var', (44, 51))	('cellular macromolecule metabolic process', 'biological_process', 'GO:0044260', ('104', '144'))	('DNA binding', 'Interaction', (208, 219))	('DNA', 'cellular_component', 'GO:0005574', ('208', '211'))	('molecular function', 'molecular_function', 'GO:0003674', ('221', '239'))	('cellular macromolecule metabolic process', 'MPA', (104, 144))
28106	30880326	Among the enrichment pathways, many pathways were linked to cancer, such as "TNF signaling pathway" (associated with 8 genes), "Focal adhesion" (associated with 5 genes), "Viral carcinogenesis" (associated with 23 genes), "Colorectal cancer" (associated with 4 genes), "Transcriptional misregulation in cancer" (associated with 15 genes) and "Alcoholism" (associated with 40 genes).	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('linked', 'Reg', (50, 56))	('Viral carcinogenesis', 'Disease', (172, 192))	('Colorectal cancer', 'Disease', 'MESH:D015179', (223, 240))	('cancer', 'Disease', (303, 309))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('Transcriptional misregulation', 'Var', (270, 299))	('Alcoholism', 'Phenotype', 'HP:0030955', (343, 353))	('Alcoholism', 'Disease', (343, 353))	('Colorectal cancer', 'Disease', (223, 240))	('Viral carcinogenesis', 'Disease', 'MESH:D063646', (172, 192))	('Focal adhesion', 'Disease', (128, 142))	('cancer', 'Disease', 'MESH:D009369', (303, 309))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', (234, 240))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (223, 240))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
28127	28423643	POLE and POLD1 screening in 155 patients with multiple polyps and early-onset colorectal cancer Germline mutations in POLE and POLD1 have been shown to cause predisposition to colorectal multiple polyposis and a wide range of neoplasms, early-onset colorectal cancer being the most prevalent.	('colorectal cancer', 'Disease', (249, 266))	('neoplasms', 'Phenotype', 'HP:0002664', (226, 235))	('mutations', 'Var', (105, 114))	('POLD1', 'Gene', '5424', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('colorectal multiple polyposis', 'Disease', (176, 205))	('POLD1', 'Gene', (9, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('colorectal cancer', 'Phenotype', 'HP:0003003', (249, 266))	('colorectal cancer', 'Disease', (78, 95))	('neoplasms', 'Disease', 'MESH:D009369', (226, 235))	('neoplasms', 'Disease', (226, 235))	('POLD1', 'Gene', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('patients', 'Species', '9606', (32, 40))	('multiple polyps', 'Disease', (46, 61))	('POLD1', 'Gene', '5424', (9, 14))	('multiple polyps', 'Disease', 'MESH:D011127', (46, 61))	('colorectal cancer', 'Disease', 'MESH:D015179', (249, 266))	('POLE', 'Gene', (118, 122))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('colorectal multiple polyposis', 'Disease', 'MESH:D011125', (176, 205))	('cause predisposition', 'Reg', (152, 172))
28128	28423643	In order to find additional mutations affecting the proofreading activity of these polymerases, we sequenced its exonuclease domain in 155 patients with multiple polyps or an early-onset colorectal cancer phenotype without alterations in the known hereditary colorectal cancer genes.	('colorectal cancer', 'Disease', (187, 204))	('multiple polyps', 'Disease', 'MESH:D011127', (153, 168))	('patients', 'Species', '9606', (139, 147))	('colorectal cancer', 'Disease', 'MESH:D015179', (259, 276))	('hereditary colorectal cancer', 'Disease', (248, 276))	('colorectal cancer', 'Disease', 'MESH:D015179', (187, 204))	('hereditary colorectal cancer', 'Disease', 'MESH:D015179', (248, 276))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (259, 276))	('colorectal cancer', 'Phenotype', 'HP:0003003', (187, 204))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('multiple polyps', 'Disease', (153, 168))	('mutations', 'Var', (28, 37))
28130	28423643	On the other hand, among the genetic variants detected, only two of them stood out as putative pathogenic in the POLE gene, c.1359 + 46del71 and c.1420G > A (p.Val474Ile).	('46del71', 'Var', (133, 140))	('c.1420G > A', 'Mutation', 'rs890665991', (145, 156))	('c.1420G > A', 'Var', (145, 156))	('pathogenic', 'Reg', (95, 105))	('46del71', 'DELETION', 'None', (133, 140))	('p.Val474Ile', 'Mutation', 'rs890665991', (158, 169))
28131	28423643	Contrarily, c.1420G > A (p.Val474Ile) was detected in one early-onset colorectal cancer patient and located right next to the exonuclease domain.	('patient', 'Species', '9606', (88, 95))	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('p.Val474Ile', 'Mutation', 'rs890665991', (25, 36))	('c.1420G > A', 'Mutation', 'rs890665991', (12, 23))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('c.1420G > A', 'Var', (12, 23))	('colorectal cancer', 'Disease', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
28133	28423643	This is the first study to functionally analyze a POLE genetic variant outside the exonuclease domain and widens the spectrum of genetic changes in this DNA polymerase that could lead to colorectal cancer predisposition.	('variant', 'Var', (63, 70))	('colorectal cancer', 'Disease', (187, 204))	('colorectal cancer', 'Disease', 'MESH:D015179', (187, 204))	('lead to', 'Reg', (179, 186))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (187, 204))
28136	28423643	They account for ~5% of all cases, and are due to germline mutations in APC, MUTYH and the mismatch repair (MMR) genes, which confer a high risk of developing this disease.	('MUTYH', 'Gene', (77, 82))	('MUTYH', 'Gene', '4595', (77, 82))	('germline mutations', 'Var', (50, 68))	('due', 'Reg', (43, 46))	('APC', 'Disease', 'MESH:D011125', (72, 75))	('APC', 'Disease', (72, 75))
28140	28423643	By doing so, p.Leu424Val and p.Ser478Asn mutations in POLE and POLD1 DNA polymerases, respectively, were established as a new high-penetrance cause of germline CRC predisposition with an autosomal dominant pattern of inheritance.	('CRC', 'Phenotype', 'HP:0003003', (160, 163))	('p.Leu424Val', 'Var', (13, 24))	('p.Leu424Val', 'Mutation', 'rs1315928771', (13, 24))	('p.Ser478Asn', 'Var', (29, 40))	('cause', 'Reg', (142, 147))	('POLD1', 'Gene', '5424', (63, 68))	('p.Ser478Asn', 'Mutation', 'rs397514632', (29, 40))	('POLD1', 'Gene', (63, 68))
28141	28423643	POLD1 p.Ser478Asn was also found to be involved in germline predisposition to endometrial cancer.	('involved', 'Reg', (39, 47))	('p.Ser478Asn', 'Var', (6, 17))	('endometrial cancer', 'Disease', 'MESH:D016889', (78, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('p.Ser478Asn', 'Mutation', 'rs397514632', (6, 17))	('POLD1', 'Gene', '5424', (0, 5))	('POLD1', 'Gene', (0, 5))	('endometrial cancer', 'Disease', (78, 96))	('endometrial cancer', 'Phenotype', 'HP:0012114', (78, 96))
28142	28423643	Therefore, mutations in this protein domain will disrupt the fidelity of DNA replication, which will lead to a mutator phenotype, resulting in tumorigenesis.	('mutations', 'Var', (11, 20))	('disrupt', 'NegReg', (49, 56))	('resulting in', 'Reg', (130, 142))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('DNA replication', 'biological_process', 'GO:0006260', ('73', '88'))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('fidelity', 'MPA', (61, 69))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('lead', 'Reg', (101, 105))
28144	28423643	Regarding somatic studies, tumors from POLE and POLD1 mutation carriers showed a hypermutated phenotype with an excess of G > T/C > A and C > T/G > A transversions, especially in the context TCT > TAT and TCG > TTG.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutation', 'Var', (54, 62))	('C > T/G > A', 'Var', (138, 149))	('TAT', 'Disease', 'None', (197, 200))	('TTG', 'Chemical', '-', (211, 214))	('TCG', 'Chemical', '-', (205, 208))	('tumors', 'Disease', (27, 33))	('G > T/C > A', 'Var', (122, 133))	('TAT', 'Disease', (197, 200))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('POLD1', 'Gene', '5424', (48, 53))	('POLD1', 'Gene', (48, 53))
28146	28423643	To this date, POLE mutations have been found to be the germline predisposition factor in families with multiple adenomas and early-onset CRC, as well as in other neoplasms such as endometrial, ovarian, brain, pancreas, small intestine and cutaneous melanoma.	('small intestine', 'Disease', (219, 234))	('cutaneous melanoma', 'Disease', (239, 257))	('neoplasms', 'Phenotype', 'HP:0002664', (162, 171))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (239, 257))	('early-onset CRC', 'Disease', (125, 140))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (239, 257))	('ovarian', 'Disease', (193, 200))	('CRC', 'Phenotype', 'HP:0003003', (137, 140))	('pancreas', 'Disease', (209, 217))	('multiple adenomas', 'Disease', (103, 120))	('neoplasms', 'Disease', 'MESH:D009369', (162, 171))	('endometrial', 'Disease', 'MESH:D014591', (180, 191))	('endometrial', 'Disease', (180, 191))	('neoplasms', 'Disease', (162, 171))	('melanoma', 'Phenotype', 'HP:0002861', (249, 257))	('mutations', 'Var', (19, 28))	('pancreas', 'Disease', 'MESH:D010190', (209, 217))	('brain', 'Disease', (202, 207))	('multiple adenomas', 'Disease', 'MESH:D000236', (103, 120))
28147	28423643	On the other hand, POLD1 mutations have been found to predispose carriers to multiple adenomas, CRC, endometrial and breast cancer.	('mutations', 'Var', (25, 34))	('endometrial', 'Disease', (101, 112))	('CRC', 'Phenotype', 'HP:0003003', (96, 99))	('POLD1', 'Gene', (19, 24))	('POLD1', 'Gene', '5424', (19, 24))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('multiple adenomas', 'Disease', 'MESH:D000236', (77, 94))	('breast cancer', 'Disease', (117, 130))	('predispose', 'Reg', (54, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('endometrial', 'Disease', 'MESH:D014591', (101, 112))	('CRC', 'Disease', (96, 99))	('multiple adenomas', 'Disease', (77, 94))
28148	28423643	Recently, some CRC patients with deficient MMR system caused by tumor biallelic inactivation were reported to also carry germline mutations in POLE, these MMR somatic mutations being the consequence of the POLE hypermutator tumor phenotype.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('patients', 'Species', '9606', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('CRC', 'Disease', (15, 18))	('biallelic inactivation', 'Var', (70, 92))	('MMR', 'biological_process', 'GO:0006298', ('43', '46'))	('deficient MMR system', 'Disease', (33, 53))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('MMR', 'biological_process', 'GO:0006298', ('155', '158'))	('CRC', 'Phenotype', 'HP:0003003', (15, 18))	('POLE', 'Gene', (143, 147))	('deficient MMR system', 'Disease', 'MESH:C536143', (33, 53))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
28149	28423643	Regarding the prevalent mutations reported up to now, POLE p.L424V has been detected in 24 independent families, whereas POLD1 p.S478N has been found in 4 independent families.	('POLD1', 'Gene', (121, 126))	('POLD1', 'Gene', '5424', (121, 126))	('p.L424V', 'Mutation', 'rs1315928771', (59, 66))	('p.S478N', 'Mutation', 'rs397514632', (127, 134))	('p.L424V', 'Var', (59, 66))	('p.S478N', 'Var', (127, 134))
28151	28423643	A functional validation of the exonuclease activity was previously available for POLE p.D368V, p.Y458F, and POLD1 p.D316H, p.D316G, p.P327L and p.L474P, or it was specifically produced for POLE p.W347C.	('p.Y458F', 'Var', (95, 102))	('POLD1', 'Gene', (108, 113))	('POLD1', 'Gene', '5424', (108, 113))	('p.D316G', 'Mutation', 'p.D316G', (123, 130))	('p.D316H', 'Mutation', 'rs746087148', (114, 121))	('p.L474P', 'Mutation', 'rs587777627', (144, 151))	('p.L474P', 'Var', (144, 151))	('p.D368V', 'Var', (86, 93))	('p.W347C', 'SUBSTITUTION', 'None', (194, 201))	('activity', 'MPA', (43, 51))	('p.Y458F', 'Mutation', 'p.Y458F', (95, 102))	('p.D316H', 'Var', (114, 121))	('p.D368V', 'Mutation', 'p.D368V', (86, 93))	('p.P327L', 'Mutation', 'rs397514633', (132, 139))	('p.P327L', 'Var', (132, 139))	('p.W347C', 'Var', (194, 201))	('p.D316G', 'Var', (123, 130))
28153	28423643	Accordingly, the aim of our study was to screen the exonuclease domain of POLE and POLD1 in 155 patients with multiple polyps and early-onset CRC in order to find mutations affecting the replication fidelity of these proteins and shed light on this matter.	('multiple polyps', 'Disease', 'MESH:D011127', (110, 125))	('mutations', 'Var', (163, 172))	('CRC', 'Phenotype', 'HP:0003003', (142, 145))	('patients', 'Species', '9606', (96, 104))	('multiple polyps', 'Disease', (110, 125))	('replication', 'MPA', (187, 198))	('POLD1', 'Gene', (83, 88))	('POLD1', 'Gene', '5424', (83, 88))	('affecting', 'Reg', (173, 182))
28165	28423643	After screening the exonuclease domain of POLE and POLD1 in our cohort of patients, we detected several genetic variants that are listed in Table 2.	('POLD1', 'Gene', '5424', (51, 56))	('patients', 'Species', '9606', (74, 82))	('POLD1', 'Gene', (51, 56))	('variants', 'Var', (112, 120))
28166	28423643	Firstly, it is important to highlight that none of the two previously described recurrent mutations in POLE (p.Leu424Val) and POLD1 (p.Ser478Asn) were present in our cohort.	('p.Leu424Val', 'Var', (109, 120))	('p.Leu424Val', 'Mutation', 'rs1315928771', (109, 120))	('p.Ser478Asn', 'Mutation', 'rs397514632', (133, 144))	('POLE', 'Gene', (103, 107))	('POLD1', 'Gene', (126, 131))	('POLD1', 'Gene', '5424', (126, 131))	('Ser', 'cellular_component', 'GO:0005790', ('135', '138'))	('p.Ser478Asn', 'Var', (133, 144))
28170	28423643	Instead of the previously described variants, we detected an interesting POLE missense variant in an early-onset CRC patient that corresponded to c.1420G > A (p.Val474Ile) (Table 2).	('c.1420G > A', 'Mutation', 'rs890665991', (146, 157))	('p.Val474Ile', 'Mutation', 'rs890665991', (159, 170))	('early-onset', 'Disease', (101, 112))	('c.1420G > A', 'Var', (146, 157))	('patient', 'Species', '9606', (117, 124))	('CRC', 'Phenotype', 'HP:0003003', (113, 116))
28181	28423643	Furthermore, besides the structural analysis, additional bioinformatics assessment of this variant (using PolyPhen and CADD) predicted a deleterious effect for this amino acid change and most protein stability predictions were also in favor of a damaging effect (Eris, PoPMuSiC, I-Mutant).	('protein', 'MPA', (192, 199))	('variant', 'Var', (91, 98))	('Eris', 'Gene', '340061', (263, 267))	('Eris', 'Gene', (263, 267))
28187	28423643	Regarding Pol2 p.V475I, the mutation rate was 17 times higher when compared to the wild-type strain (P-value = 0.0040).	('p.V475I', 'Mutation', 'p.V475I', (15, 22))	('Pol2', 'Gene', (10, 14))	('higher', 'PosReg', (55, 61))	('p.V475I', 'Var', (15, 22))
28188	28423643	Paired-tumor tissue was only available from the patient carrying the POLE p.Val474Ile variant.	('tumor', 'Disease', (7, 12))	('p.Val474Ile', 'Var', (74, 85))	('patient', 'Species', '9606', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('p.Val474Ile', 'Mutation', 'rs890665991', (74, 85))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
28190	28423643	Whole-exome sequencing (WES) was also performed in the tumor DNA of the patient carrying the POLE p.Val474Ile variant to study the number and spectrum of somatic mutations.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('patient', 'Species', '9606', (72, 79))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('p.Val474Ile', 'Var', (98, 109))	('p.Val474Ile', 'Mutation', 'rs890665991', (98, 109))
28191	28423643	We had available WES data obtained from four other MMR proficient CRC tumors that did not present germline or tumor alterations in POLE or POLD1 to compare their number of substitutions and mutational spectrum with our POLE mutant.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('substitutions', 'Var', (172, 185))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('CRC', 'Phenotype', 'HP:0003003', (66, 69))	('POLD1', 'Gene', (139, 144))	('tumor', 'Disease', (70, 75))	('POLD1', 'Gene', '5424', (139, 144))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('MMR', 'biological_process', 'GO:0006298', ('51', '54'))	('CRC tumors', 'Disease', (66, 76))	('CRC tumors', 'Disease', 'MESH:D015179', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
28193	28423643	First, a tumor profile for each sample was generated by eliminating variants present in a germline exome dataset.	('variants', 'Var', (68, 76))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))
28196	28423643	By doing so, a slight increase of the total number of substitutions in the tumor DNA from the p.Val474Ile germline carrier was detected when compared with the POLE wild-type MMR proficient tumors (Supplementary Table 2).	('p.Val474Ile', 'Var', (94, 105))	('tumor', 'Disease', (189, 194))	('p.Val474Ile', 'Mutation', 'rs890665991', (94, 105))	('substitutions', 'Var', (54, 67))	('tumors', 'Disease', (189, 195))	('increase', 'PosReg', (22, 30))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (75, 80))
28197	28423643	However, when mutation spectrum was analyzed, the tumor DNA from the p.Val474Ile germline carrier did not show an increase in G > T/C > A or C > T/G > A transversions as suggested by previous studies.	('p.Val474Ile', 'Var', (69, 80))	('p.Val474Ile', 'Mutation', 'rs890665991', (69, 80))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('G > T/C > A', 'Var', (126, 137))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('carrier', 'molecular_function', 'GO:0005215', ('90', '97'))	('C > T/G > A', 'Var', (141, 152))	('tumor', 'Disease', (50, 55))
28198	28423643	Our molecular screening of the POLE and POLD1 exonuclease domains in a cohort of 155 patients with multiple polyps or early-onset CRC identified a novel POLE mutation in one family.	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('multiple polyps', 'Disease', (99, 114))	('POLD1', 'Gene', '5424', (40, 45))	('mutation', 'Var', (158, 166))	('patients', 'Species', '9606', (85, 93))	('POLD1', 'Gene', (40, 45))	('multiple polyps', 'Disease', 'MESH:D011127', (99, 114))
28199	28423643	Importantly, we did not find any of the previously described mutations for POLE (p.Leu424Val) and POLD1 (p.Ser478Asn) in our cohort.	('p.Leu424Val', 'Var', (81, 92))	('p.Leu424Val', 'Mutation', 'rs1315928771', (81, 92))	('POLD1', 'Gene', '5424', (98, 103))	('POLD1', 'Gene', (98, 103))	('Ser', 'cellular_component', 'GO:0005790', ('107', '110'))	('p.Ser478Asn', 'Var', (105, 116))	('p.Ser478Asn', 'Mutation', 'rs397514632', (105, 116))
28200	28423643	As reported by previous studies, the POLE p.Leu424Val mutation frequency in multiple colorectal adenomas or familial CRC cohorts seems to be typically <= 0.3%, whereas the POLD1 p.Ser478Asn mutation seems to be even less frequent (< 0.1%).	('p.Ser478Asn', 'Mutation', 'rs397514632', (178, 189))	('multiple colorectal adenomas', 'Disease', (76, 104))	('CRC', 'Phenotype', 'HP:0003003', (117, 120))	('p.Leu424Val', 'Var', (42, 53))	('p.Leu424Val', 'Mutation', 'rs1315928771', (42, 53))	('multiple colorectal adenomas', 'Disease', 'MESH:C563924', (76, 104))	('familial CRC', 'Disease', (108, 120))	('POLD1', 'Gene', (172, 177))	('POLD1', 'Gene', '5424', (172, 177))
28201	28423643	Additionally, it could be also possible that the frequency of these mutations may be even lower in the Spanish population since only one carrier for the POLE p.Leu424Val mutation and no POLD1 p.Ser478Asn mutation carriers have been reported so far.	('POLD1', 'Gene', '5424', (186, 191))	('p.Ser478Asn', 'Mutation', 'rs397514632', (192, 203))	('p.Leu424Val', 'Var', (158, 169))	('p.Leu424Val', 'Mutation', 'rs1315928771', (158, 169))	('POLD1', 'Gene', (186, 191))
28202	28423643	Leaving aside these potentially recurrent mutations, other different variants have already been reported in POLE and POLD1.	('mutations', 'Var', (42, 51))	('POLD1', 'Gene', (117, 122))	('POLD1', 'Gene', '5424', (117, 122))
28203	28423643	Most of them are located in the protein exonuclease domain and include p.Trp347Cys, p.Asn363Lys, p.Asp386Val, p.Lys425Arg, p.Pro436Ser, p.Tyr458Phe in POLE, and p.Asp316His, p.Asp316Gly, p.Pro327Leu, p.Arg409Trp, p.Leu474Pro for POLD1.	('POLD1', 'Gene', '5424', (229, 234))	('p.Pro436Ser', 'Var', (123, 134))	('p.Asp316His', 'Var', (161, 172))	('p.Lys425Arg', 'Var', (110, 121))	('p.Pro436Ser', 'Mutation', 'p.P436S', (123, 134))	('p.Leu474Pro', 'Mutation', 'rs587777627', (213, 224))	('p.Tyr458Phe', 'Mutation', 'p.Y458F', (136, 147))	('p.Leu474Pro', 'Var', (213, 224))	('Ser', 'cellular_component', 'GO:0005790', ('131', '134'))	('p.Asp386Val', 'Mutation', 'p.D386V', (97, 108))	('p.Asp316Gly', 'Var', (174, 185))	('p.Pro327Leu', 'Mutation', 'rs397514633', (187, 198))	('p.Trp347Cys', 'Var', (71, 82))	('p.Arg409Trp', 'Mutation', 'rs778135510', (200, 211))	('p.Pro327Leu', 'Var', (187, 198))	('p.Asn363Lys', 'Mutation', 'p.N363K', (84, 95))	('p.Asp386Val', 'Var', (97, 108))	('POLD1', 'Gene', (229, 234))	('protein', 'cellular_component', 'GO:0003675', ('32', '39'))	('p.Lys425Arg', 'Mutation', 'p.K425R', (110, 121))	('p.Arg409Trp', 'Var', (200, 211))	('p.Asp316Gly', 'Mutation', 'p.D316G', (174, 185))	('p.Tyr458Phe', 'Var', (136, 147))	('p.Asn363Lys', 'Var', (84, 95))	('p.Trp347Cys', 'SUBSTITUTION', 'None', (71, 82))	('p.Asp316His', 'Mutation', 'rs746087148', (161, 172))
28204	28423643	These previously reported variants and our newly identified variant are indicative that the entire coding region for POLE and POLD1 should be screened instead of focusing only in a few variants.	('POLD1', 'Gene', (126, 131))	('POLD1', 'Gene', '5424', (126, 131))	('POLE', 'Gene', (117, 121))	('variants', 'Var', (26, 34))
28207	28423643	Considering previously reported known POLE or POLD1 mutation carriers, the phenotypic spectrum included multiple polyps and early-onset CRC, as well as family history and would reinforce therefore the phenotype selection criteria used in our cohort.	('POLD1', 'Gene', '5424', (46, 51))	('CRC', 'Phenotype', 'HP:0003003', (136, 139))	('POLD1', 'Gene', (46, 51))	('included', 'Reg', (95, 103))	('multiple polyps', 'Disease', (104, 119))	('mutation', 'Var', (52, 60))	('early-onset CRC', 'Disease', (124, 139))	('multiple polyps', 'Disease', 'MESH:D011127', (104, 119))
28208	28423643	This approach is not biased to detect only POLE p.Leu424Val and POLD1 p.Ser478Asn mutations as it was the case for some previous studies and permitted to detect additional mutations located in this region.	('p.Ser478Asn', 'Var', (70, 81))	('p.Ser478Asn', 'Mutation', 'rs397514632', (70, 81))	('p.Leu424Val', 'Var', (48, 59))	('p.Leu424Val', 'Mutation', 'rs1315928771', (48, 59))	('POLD1', 'Gene', (64, 69))	('POLD1', 'Gene', '5424', (64, 69))	('Ser', 'cellular_component', 'GO:0005790', ('72', '75'))
28210	28423643	Our results in yeast suggest that the human POLE p.L424V and POLE p.V474I variants will cause an increased mutation rate due to faulty proofreading activity of this protein, although POLE p.V474I with an attenuated phenotype when compared to POLE p.L424V.	('p.L424V', 'Mutation', 'rs1315928771', (49, 56))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('yeast', 'Species', '4932', (15, 20))	('increased', 'PosReg', (97, 106))	('human', 'Species', '9606', (38, 43))	('p.V474I', 'Var', (66, 73))	('p.V474I', 'Mutation', 'rs890665991', (188, 195))	('p.L424V', 'Var', (49, 56))	('faulty', 'NegReg', (128, 134))	('proofreading activity', 'MPA', (135, 156))	('p.V474I', 'Mutation', 'rs890665991', (66, 73))	('p.L424V', 'Mutation', 'rs1315928771', (247, 254))	('mutation rate', 'MPA', (107, 120))
28211	28423643	However, since POLE Val474Ile is having a smaller effect on proof reading, other additional genetic variants also contributing to CRC predisposition cannot be disregarded.	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('Val474Ile', 'SUBSTITUTION', 'None', (20, 29))	('Val474Ile', 'Var', (20, 29))	('CRC', 'Disease', (130, 133))
28212	28423643	Exome sequencing of the tumor corresponding to the p.V474I variant carrier revealed a slightly higher number of substitutions compared with four POLE wild-type tumors, although the increment was not as high as could be expected taking into account previously reported data.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('carrier', 'molecular_function', 'GO:0005215', ('67', '74'))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('p.V474I', 'Var', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('substitutions', 'Var', (112, 125))	('tumors', 'Disease', (160, 166))	('tumor', 'Disease', (160, 165))	('p.V474I', 'Mutation', 'rs890665991', (51, 58))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
28214	28423643	TCGA-CA-6718-01, P286R, 5,946 substitutions; and TCGA-A6-6141-01, p.S297F, 1,981 substitutions), a hypermutated profile was not evident.	('p.S297F', 'Mutation', 'p.S297F', (66, 73))	('P286R', 'Var', (17, 22))	('TCG', 'Chemical', '-', (0, 3))	('p.S297F', 'Var', (66, 73))	('P286R', 'Mutation', 'p.P286R', (17, 22))	('TCG', 'Chemical', '-', (49, 52))
28216	28423643	Besides, the percentage of G > T/C > A transversions was not increased compared with the other POLE wild-type tumors.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', (110, 116))	('G > T/C > A', 'Var', (27, 38))	('tumors', 'Disease', 'MESH:D009369', (110, 116))
28218	28423643	This gastric tumor presented, as defined by the authors, "an ultramutated profile", with 11,375 substitutions, and a mutation rate of approximately 283 mutations per Megabase.	('gastric tumor', 'Disease', (5, 18))	('substitutions', 'Var', (96, 109))	('gastric tumor', 'Phenotype', 'HP:0006753', (5, 18))	('gastric tumor', 'Disease', 'MESH:D013274', (5, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
28219	28423643	Notably, this ultramutated tumor presented three other somatic missense variants in POLE located far away from the exonuclease domain (p.R1111Q, p.S681R and Y1889C) that could be promoting even a stronger effect.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('p.S681R', 'Var', (145, 152))	('tumor', 'Disease', (27, 32))	('p.S681R', 'Mutation', 'p.S681R', (145, 152))	('Y1889C', 'Mutation', 'p.Y1889C', (157, 163))	('p.R1111Q', 'Mutation', 'p.R1111Q', (135, 143))	('Y1889C', 'Var', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('p.R1111Q', 'Var', (135, 143))
28221	28423643	We can hypothesize that our tumor profiling may have failed to show a clear distinctive profile for our novel POLE mutation due to a suboptimal filtering of germline variants and a limited sequencing coverage, as well as a milder mutator effect as shown by the functional assays in yeast.	('tumor', 'Disease', (28, 33))	('yeast', 'Species', '4932', (282, 287))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('mutation', 'Var', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
28222	28423643	In conclusion, we detected a new plausible POLE mutation, p.V474I, in an early-onset CRC patient.	('patient', 'Species', '9606', (89, 96))	('early-onset', 'Disease', (73, 84))	('p.V474I', 'Var', (58, 65))	('p.V474I', 'Mutation', 'rs890665991', (58, 65))	('CRC', 'Phenotype', 'HP:0003003', (85, 88))
28223	28423643	This variant is located right next to the exonuclease domain and affects protein function, leading to a proofreading activity defect as shown by yeast studies.	('defect', 'NegReg', (126, 132))	('protein', 'Protein', (73, 80))	('variant', 'Var', (5, 12))	('proofreading activity', 'MPA', (104, 125))	('affects', 'Reg', (65, 72))	('yeast', 'Species', '4932', (145, 150))
28224	28423643	When checking its tumor profile, it showed an increase in the number of variants but not as strong as in the p.L424V POLE mutation in agreement with the yeast functional results.	('yeast', 'Species', '4932', (153, 158))	('p.L424V', 'Var', (109, 116))	('tumor', 'Disease', (18, 23))	('p.L424V', 'Mutation', 'rs1315928771', (109, 116))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
28230	28423643	The entire exonuclease domain of POLE and POLD1 was screened for mutations by PCR amplification using custom primers designed with Primer3Plus (Supplementary Table 3) and subsequent Sanger sequencing (GATC Biotech, Germany).	('POLD1', 'Gene', '5424', (42, 47))	('POLD1', 'Gene', (42, 47))	('mutations', 'Var', (65, 74))
28240	28423643	Both pol2-L425V and pol2-V475I S. pombe mutant strains (encoding variants equivalent to human POLE L424V and V474I respectively) were constructed by cloning the wild type pol2 gene fragment into the pFA6a-kanMX6 vector, followed by point mutation and insertion into an ade6-485 strain by recombination.	('S. pombe', 'Species', '4896', (31, 39))	('L425V', 'Mutation', 'p.L425V', (10, 15))	('V474I', 'Mutation', 'rs890665991', (109, 114))	('human', 'Species', '9606', (88, 93))	('pol2', 'Gene', (171, 175))	('L424V', 'Mutation', 'rs1315928771', (99, 104))	('ade6', 'Chemical', '-', (269, 273))	('point mutation', 'Var', (232, 246))	('V475I', 'Mutation', 'p.V475I', (25, 30))
28241	28423643	Point mutations were performed with Quikchange lightning site-directed mutagenesis kit (Agilent, Santa Clara, CA, USA) using primers Pol2-L425V fw + Pol2-L425V rev for pol2-L425V and Pol2-V475I fw + Pol2-V475I rev for pol2-V475I (Supplementary Table 3).	('V475I', 'Mutation', 'p.V475I', (204, 209))	('L425V', 'Mutation', 'p.L425V', (138, 143))	('L425V', 'Mutation', 'p.L425V', (173, 178))	('V475I', 'Mutation', 'p.V475I', (188, 193))	('pol2-L425V', 'Var', (168, 178))	('V475I', 'Mutation', 'p.V475I', (223, 228))	('Pol2-L425V fw +', 'Var', (133, 148))	('L425V', 'Mutation', 'p.L425V', (154, 159))	('Pol2-V475I fw +', 'Var', (183, 198))
28242	28423643	The created pFA6a-kanMX6 plasmids carrying wild-type pol2 version, pol2-L425V or pol2-V475I mutants were integrated into pol2 locus of the ade6-485 strain after linearization with BamHI and selecting for G418/Geneticin resistance.	('L425V', 'Mutation', 'p.L425V', (72, 77))	('pol2', 'Gene', (53, 57))	('pol2-L425V', 'Gene', (67, 77))	('pol2-V475I', 'Gene', (81, 91))	('mutants', 'Var', (92, 99))	('V475I', 'Mutation', 'p.V475I', (86, 91))	('ade6', 'Chemical', '-', (139, 143))
28244	28423643	LOH was studied in FFPE tumor DNA comparing to the germline DNA of a patient carrying a missense variant in POLE by PCR amplification using specific primers in the region surrounding the variant designed (Supplementary Table 3) and subsequent Sanger sequencing (GATC Biotech, Germany).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('patient', 'Species', '9606', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('missense variant', 'Var', (88, 104))
28245	28423643	WES was performed in the tumour DNA of a patient carrying a missense variant detected in POLE and four other MMR proficient CRC tumors that did not present germline or tumor alterations in POLE or POLD1 in order to study the number and spectrum of somatic mutations.	('CRC tumors', 'Disease', (124, 134))	('CRC tumors', 'Disease', 'MESH:D015179', (124, 134))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', (168, 173))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('CRC', 'Phenotype', 'HP:0003003', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('POLD1', 'Gene', (197, 202))	('patient', 'Species', '9606', (41, 48))	('POLD1', 'Gene', '5424', (197, 202))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumour', 'Disease', (25, 31))	('missense variant', 'Var', (60, 76))
28259	27070449	One of the diagnostic criteria critical for the evaluation of trial eligibility was the high-expression of NY-ESO-1 based on immunohistochemical analysis.	('NY-ESO-1', 'Gene', '246100', (107, 115))	('NY-ESO-1', 'Gene', (107, 115))	('high-expression', 'Var', (88, 103))
28305	27070449	In summary, the expression patterns of MAGE-A and NY-ESO-1 in metastatic lesions are similar to the staining patterns seen in primary lesions with MAGE-A expression being significantly higher than NY-ESO-1 in multiple primary and metastatic malignancies (Table 1, 2, and 3).	('MAGE-A', 'Var', (147, 153))	('MAGE-A', 'Chemical', '-', (147, 153))	('NY-ESO-1', 'Gene', (197, 205))	('malignancies', 'Disease', 'MESH:D009369', (241, 253))	('NY-ESO-1', 'Gene', '246100', (197, 205))	('NY-ESO-1', 'Gene', '246100', (50, 58))	('MAGE-A', 'Chemical', '-', (39, 45))	('NY-ESO-1', 'Gene', (50, 58))	('higher', 'PosReg', (185, 191))	('malignancies', 'Disease', (241, 253))	('expression', 'MPA', (154, 164))
28340	25666195	The clinical relevance of our findings is illustrated by the fact that high CC1 expression in patients with CRC combined with some inflammation-regulated and STAT3-regulated genes correlate with improved 10-year survival.	('patients', 'Species', '9606', (94, 102))	('inflammation', 'Disease', 'MESH:D007249', (131, 143))	('high', 'Var', (71, 75))	('improved', 'PosReg', (195, 203))	('inflammation', 'Disease', (131, 143))	('CC1', 'Gene', (76, 79))	('CC1', 'Gene', '26365', (76, 79))	('CRC', 'Phenotype', 'HP:0003003', (108, 111))	('expression', 'MPA', (80, 90))	('inflammation', 'biological_process', 'GO:0006954', ('131', '143'))	('CRC', 'Disease', (108, 111))
28356	25666195	Investigation of the CC1-L-associated regulatory network in MC38 liver metastatic inhibition revealed that CC1-L expression impairs STAT3 activity, thus decreasing the synthesis and secretion of its CCL2 target that controls metastatic immune infiltration.	('CC1', 'Gene', '26365', (21, 24))	('decreasing', 'NegReg', (153, 163))	('CCL2 target', 'MPA', (199, 210))	('synthesis', 'MPA', (168, 177))	('CC1', 'Gene', (107, 110))	('CC1', 'Gene', '26365', (107, 110))	('expression', 'Var', (113, 123))	('secretion', 'MPA', (182, 191))	('STAT3 activity', 'MPA', (132, 146))	('impairs', 'NegReg', (124, 131))	('metastatic immune', 'CPA', (225, 242))	('CC1', 'Gene', (21, 24))
28358	25666195	Metastatic mouse MC38 colon cancer cells were separated through fluorescent activated cell sorting for CC1-negative expression and retrovirally infected with virions expressing the CC1-L WT and CC1-FF mutant constructs.	('CC1', 'Gene', (181, 184))	('CC1', 'Gene', '26365', (181, 184))	('mouse', 'Species', '10090', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('CC1', 'Gene', (103, 106))	('CC1', 'Gene', '26365', (103, 106))	('colon cancer', 'Phenotype', 'HP:0003003', (22, 34))	('colon cancer', 'Disease', 'MESH:D015179', (22, 34))	('mutant', 'Var', (201, 207))	('CC1', 'Gene', (194, 197))	('CC1', 'Gene', '26365', (194, 197))	('colon cancer', 'Disease', (22, 34))
28371	25666195	Cox proportional hazards analysis was performed to estimate the effect of each gene or signature on survival time and also to estimate whether there was evidence for interaction between high CEACAM1 expression and expression of other signature genes on survival.	('CEACAM1', 'Gene', (191, 198))	('Cox', 'Gene', (0, 3))	('high', 'Var', (186, 190))	('Cox', 'Gene', '12857', (0, 3))
28380	25666195	Therefore, CC1-L expression modifies intrinsic MC38 signalling events through its two Tyr residues, leading to inhibition of liver metastatic development.	('Tyr', 'Chemical', 'MESH:D014443', (86, 89))	('CC1', 'Gene', (11, 14))	('signalling', 'biological_process', 'GO:0023052', ('52', '62'))	('liver metastatic development', 'CPA', (125, 153))	('intrinsic MC38 signalling events', 'MPA', (37, 69))	('expression', 'Var', (17, 27))	('modifies', 'Reg', (28, 36))	('CC1', 'Gene', '26365', (11, 14))	('inhibition', 'NegReg', (111, 121))
28384	25666195	CCL2 plays a key role in infiltration of CD11b+Gr1mid myeloid cells into the CRC hepatic metastatic microenvironment, and CCL2 expression in human stage 4 CRC correlates with higher metastatic burden, lower patient survival and recruitment of CCR2+Ly6C+ monocytes to lung metastases.	('CCL2', 'Gene', (122, 126))	('CRC', 'Phenotype', 'HP:0003003', (77, 80))	('CRC', 'Phenotype', 'HP:0003003', (155, 158))	('higher', 'PosReg', (175, 181))	('CCL', 'molecular_function', 'GO:0044101', ('122', '125'))	('CCR', 'molecular_function', 'GO:0043880', ('243', '246'))	('patient survival', 'CPA', (207, 223))	('human', 'Species', '9606', (141, 146))	('patient', 'Species', '9606', (207, 214))	('lung metastases', 'Disease', (267, 282))	('Gr1', 'Gene', (47, 50))	('metastatic burden', 'CPA', (182, 199))	('expression', 'Var', (127, 137))	('recruitment', 'CPA', (228, 239))	('lung metastases', 'Disease', 'MESH:D009362', (267, 282))	('CCL', 'molecular_function', 'GO:0044101', ('0', '3'))	('lower', 'NegReg', (201, 206))	('Gr1', 'Gene', '546644', (47, 50))
28386	25666195	The CCL2-KD cells produced 3.4-fold less metastases in vivo than the CT-KD cells, the former exhibiting similar levels to those of MC38-CC1-L cells (figure 2D).	('CC1', 'Gene', (136, 139))	('metastases', 'Disease', 'MESH:D009362', (41, 51))	('less', 'NegReg', (36, 40))	('CCL2-KD', 'Var', (4, 11))	('metastases', 'Disease', (41, 51))	('CC1', 'Gene', '26365', (136, 139))
28396	25666195	No apparent differences were noted between MC38-CC1-L cells in mice of either genetic background, whereas CCL2 silencing caused lower metastatic development in Ccr2-null animals (figure 2F).	('Ccr2', 'Gene', '12772', (160, 164))	('CC1', 'Gene', (48, 51))	('CCL2', 'Gene', (106, 110))	('CC1', 'Gene', '26365', (48, 51))	('silencing', 'Var', (111, 120))	('metastatic development', 'CPA', (134, 156))	('mice', 'Species', '10090', (63, 67))	('lower', 'NegReg', (128, 133))	('Ccr', 'molecular_function', 'GO:0043880', ('160', '163'))	('Ccr2', 'Gene', (160, 164))	('CCL', 'molecular_function', 'GO:0044101', ('106', '109'))
28397	25666195	Hence, our results confirm that MC38-expressed CC1-L decreases CCL2 signalling, which contributes, in part, to lowered metastatic development.	('metastatic development', 'CPA', (119, 141))	('MC38-expressed', 'Var', (32, 46))	('CC1', 'Gene', '26365', (47, 50))	('decreases', 'NegReg', (53, 62))	('lowered', 'NegReg', (111, 118))	('CC1', 'Gene', (47, 50))	('CCL2 signalling', 'MPA', (63, 78))
28398	25666195	Pan and Shively demonstrated that CC1 deletion in neutrophils altered STAT3 activity and hampered granulopoiesis.	('hampered', 'NegReg', (89, 97))	('altered', 'Reg', (62, 69))	('CC1', 'Gene', (34, 37))	('CC1', 'Gene', '26365', (34, 37))	('STAT3 activity', 'MPA', (70, 84))	('deletion', 'Var', (38, 46))	('granulopoiesis', 'CPA', (98, 112))
28406	25666195	At these time points, pSTAT3 activity was completely abrogated in MC38-CT cells, as compared with vehicle-treated MC38-CC1-L cells (figure 3D, top panel).	('MC38-CT', 'CellLine', 'CVCL:B288', (66, 73))	('abrogated', 'NegReg', (53, 62))	('pSTAT3 activity', 'MPA', (22, 37))	('MC38-CT', 'Var', (66, 73))	('CC1', 'Gene', '26365', (119, 122))	('CC1', 'Gene', (119, 122))
28408	25666195	To confirm that inhibition of STAT3 activity led to reduced CRC liver metastasis in vivo, MC38-CT cells were then treated with two potent and selective, direct-binding STAT3 derivatives of the BP-1-102 compound (SH-0454 and SH-08100, chemically modified for better potency) shown to inhibit human breast and lung cancer xenograft growth in vivo.	('lung cancer', 'Phenotype', 'HP:0100526', (308, 319))	('reduced', 'NegReg', (52, 59))	('inhibit', 'NegReg', (283, 290))	('MC38-CT', 'CellLine', 'CVCL:B288', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('CRC liver metastasis', 'Disease', 'MESH:D015179', (60, 80))	('inhibition', 'Var', (16, 26))	('SH-0454', 'Chemical', '-', (212, 219))	('breast and lung cancer', 'Disease', 'MESH:D001943', (297, 319))	('CRC', 'Phenotype', 'HP:0003003', (60, 63))	('human', 'Species', '9606', (291, 296))	('CRC liver metastasis', 'Disease', (60, 80))
28409	25666195	Treatment of MC38-CT cells in vitro with either the SH-0454 or SH-08100 inhibitors (5 muM) led to dramatic reduction of STAT3 activity and CCL2/CCL5 chemokine secretion (figure 3D, bottom panel, and E) as well as decreases in cell migration in vitro (see online supplementary figure S3D), although lower concentrations did not modify MC38-CT cell proliferation or migration over several days (see online supplementary figure S3A, B), due to moderate or no reduction of pSTAT3 levels (figure 3D, bottom panel).	('STAT3 activity', 'MPA', (120, 134))	('SH-0454', 'Chemical', '-', (52, 59))	('reduction', 'NegReg', (107, 116))	('pSTAT3 levels', 'MPA', (469, 482))	('cell migration in vitro', 'CPA', (226, 249))	('CCL5', 'Gene', '20304', (144, 148))	('decreases', 'NegReg', (213, 222))	('MC38-CT', 'CellLine', 'CVCL:B288', (334, 341))	('MC38-CT', 'CellLine', 'CVCL:B288', (13, 20))	('CCL', 'molecular_function', 'GO:0044101', ('139', '142'))	('SH-0454', 'Var', (52, 59))	('cell migration', 'biological_process', 'GO:0016477', ('226', '240'))	('CCL', 'molecular_function', 'GO:0044101', ('144', '147'))	('cell proliferation', 'biological_process', 'GO:0008283', ('342', '360'))	('inhibitors', 'Var', (72, 82))	('SH-08100', 'Gene', (63, 71))	('CCL5', 'Gene', (144, 148))	('chemokine secretion', 'biological_process', 'GO:0090195', ('149', '168'))
28411	25666195	MC38-CT cells treated for 2 h with either STAT3 inhibitors, then intrasplenically injected into C57Bl/6 mice, showed considerably reduced metastatic load (66% inhibition for SH-0454 and 45% inhibition for SH-08100) compared with mice bearing vehicle-treated MC38-CT cells (figure 3F).	('MC38-CT', 'CellLine', 'CVCL:B288', (258, 265))	('inhibition', 'NegReg', (190, 200))	('metastatic load', 'CPA', (138, 153))	('mice', 'Species', '10090', (104, 108))	('MC38-CT', 'CellLine', 'CVCL:B288', (0, 7))	('SH-0454', 'Chemical', '-', (174, 181))	('reduced', 'NegReg', (130, 137))	('SH-0454', 'Var', (174, 181))	('mice', 'Species', '10090', (229, 233))	('SH-08100', 'Var', (205, 213))	('inhibition', 'NegReg', (159, 169))
28412	25666195	Additional thrice weekly injections (IP) of the SH-0454 inhibitor did not result in further decreases in in vivo metastasis (data not shown), most likely due to low blood concentrations of the inhibitor (313+-8 nM, 30 min post-injection of 10 mg/kg).	('SH-0454', 'Chemical', '-', (48, 55))	('blood concentrations', 'MPA', (165, 185))	('313+-8 nM', 'Var', (204, 213))	('SH-0454', 'Gene', (48, 55))	('decreases', 'NegReg', (92, 101))
28413	25666195	Hence, in vivo liver metastasis induced by MC38-CT cells is significantly reduced via decreased STAT3 activity, leading to attenuated CCL2/CCL5 expression.	('CCL', 'molecular_function', 'GO:0044101', ('139', '142'))	('liver metastasis', 'CPA', (15, 31))	('CCL5', 'Gene', (139, 143))	('STAT3 activity', 'MPA', (96, 110))	('attenuated', 'NegReg', (123, 133))	('CCL5', 'Gene', '20304', (139, 143))	('decreased', 'NegReg', (86, 95))	('CCL', 'molecular_function', 'GO:0044101', ('134', '137'))	('reduced', 'NegReg', (74, 81))	('MC38-CT', 'CellLine', 'CVCL:B288', (43, 50))	('MC38-CT cells', 'Var', (43, 56))
28418	25666195	As STAT3 activation depends on Tyr750 phosphorylation of the protein and dimerisation resulting in nuclear translocation to activate transcription of target genes, we relied on STAT3 gene signatures to measure STAT3 activity in patient samples, (see online supplementary table S1).	('Tyr750', 'Chemical', '-', (31, 37))	('patient', 'Species', '9606', (228, 235))	('transcription', 'biological_process', 'GO:0006351', ('133', '146'))	('activate', 'PosReg', (124, 132))	('dimerisation', 'MPA', (73, 85))	('phosphorylation', 'biological_process', 'GO:0016310', ('38', '53'))	('transcription', 'MPA', (133, 146))	('Tyr750', 'Var', (31, 37))	('nuclear translocation', 'MPA', (99, 120))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
28422	25666195	We then queried whether the CC1, CCL2 and CCR2 gene expressions were predictive of overall survival; Kaplan-Meier survival analyses for high/low CC1, CCL2 and CCR2 expression did not reveal significant overall 10-year survival differences for patients with T3-T4 CRCs, although those with higher CCR2 expression exhibited a trend towards longer survival (P=0.08).	('CC1', 'Gene', (28, 31))	('CC1', 'Gene', '26365', (28, 31))	('T3-T4', 'Var', (257, 262))	('CC1', 'Gene', '26365', (145, 148))	('CCL', 'molecular_function', 'GO:0044101', ('150', '153'))	('patients', 'Species', '9606', (243, 251))	('CC1', 'Gene', (145, 148))	('CCR', 'molecular_function', 'GO:0043880', ('296', '299'))	('CCR', 'molecular_function', 'GO:0043880', ('159', '162'))	('CCR', 'molecular_function', 'GO:0043880', ('42', '45'))	('CRC', 'Phenotype', 'HP:0003003', (263, 266))	('CCL', 'molecular_function', 'GO:0044101', ('33', '36'))
28430	25666195	Nevertheless, patient cohorts with advanced CRC tumours exhibiting high CC1 expression significantly correlate with some inflammation-regulated and STAT3-regulated genes and the results are suggestive of longer survival.	('CRC tumours', 'Disease', 'MESH:D015179', (44, 55))	('inflammation', 'Disease', 'MESH:D007249', (121, 133))	('high', 'Var', (67, 71))	('correlate', 'Reg', (101, 110))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('CC1', 'Gene', '26365', (72, 75))	('inflammation', 'Disease', (121, 133))	('CC1', 'Gene', (72, 75))	('inflammation', 'biological_process', 'GO:0006954', ('121', '133'))	('patient', 'Species', '9606', (14, 21))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('longer', 'PosReg', (204, 210))	('CRC', 'Phenotype', 'HP:0003003', (44, 47))	('CRC tumours', 'Disease', (44, 55))
28438	25666195	Similarly, ablation of the CCL2-CCR2 axis in Ccr2-/- mice only partially protected mice against liver metastasis, as described.	('mice', 'Species', '10090', (53, 57))	('Ccr', 'molecular_function', 'GO:0043880', ('45', '48'))	('Ccr2', 'Gene', (45, 49))	('CCL', 'molecular_function', 'GO:0044101', ('27', '30'))	('mice', 'Species', '10090', (83, 87))	('Ccr2', 'Gene', '12772', (45, 49))	('CCR', 'molecular_function', 'GO:0043880', ('32', '35'))	('liver metastasis', 'CPA', (96, 112))	('ablation', 'Var', (11, 19))
28442	25666195	In fact, discontinuation of an anti-CCL2 treatment in breast cancer models leads to accelerated metastasis through angiogenesis stimulation.	('anti-CCL2', 'Gene', (31, 40))	('breast cancer', 'Disease', (54, 67))	('metastasis', 'CPA', (96, 106))	('discontinuation', 'Var', (9, 24))	('angiogenesis', 'CPA', (115, 127))	('accelerated', 'PosReg', (84, 95))	('stimulation', 'PosReg', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
28443	25666195	Although high or low CC1 expression is not predictive of 10-year overall survival in patients with stages 3 and 4 CRC, as predicted by Kaplan-Meier survival curves, patients with low CCL2 or high CCR2 expression have a marginally better survival.	('CC1', 'Gene', '26365', (21, 24))	('CCR', 'molecular_function', 'GO:0043880', ('196', '199'))	('CCR2', 'Gene', (196, 200))	('better', 'PosReg', (230, 236))	('CCL2', 'Gene', (183, 187))	('CCL', 'molecular_function', 'GO:0044101', ('183', '186'))	('patients', 'Species', '9606', (85, 93))	('CRC', 'Phenotype', 'HP:0003003', (114, 117))	('patients', 'Species', '9606', (165, 173))	('high', 'Var', (191, 195))	('CC1', 'Gene', (21, 24))
28451	25666195	In this analysis of TCGA CRC samples, we demonstrate that high CC1 expression combined with four of the STAT3 signature genes expressed during inflammation were predictive of longer survival times (table 2).	('CC1', 'Gene', '26365', (63, 66))	('longer', 'PosReg', (175, 181))	('CRC', 'Phenotype', 'HP:0003003', (25, 28))	('CC1', 'Gene', (63, 66))	('inflammation', 'Disease', 'MESH:D007249', (143, 155))	('high', 'Var', (58, 62))	('inflammation', 'Disease', (143, 155))	('expression', 'MPA', (67, 77))	('inflammation', 'biological_process', 'GO:0006954', ('143', '155'))
28460	25666195	Patients with stages 1-4 CRC expressing low levels of CCL2 or high CCR2 exhibit a better 10-year survival.	('CCL2', 'MPA', (54, 58))	('CRC', 'Phenotype', 'HP:0003003', (25, 28))	('better', 'PosReg', (82, 88))	('CCR2', 'Gene', (67, 71))	('Patients', 'Species', '9606', (0, 8))	('high', 'Var', (62, 66))	('low levels', 'Var', (40, 50))
28532	26043032	The unadjusted and calibrated DFE values were highest among the mulatto/black race, followed by the white and Asian races.	('DFE', 'MPA', (30, 33))	('mulatto/black', 'Var', (64, 77))	('DFE', 'Chemical', '-', (30, 33))
28536	26043032	DFE supplement intake was significantly higher among women (1750.00 mug) compared to men (440.00 mug).	('men', 'Species', '9606', (10, 13))	('men', 'Species', '9606', (55, 58))	('DFE', 'Chemical', '-', (0, 3))	('higher', 'PosReg', (40, 46))	('women', 'Species', '9606', (53, 58))	('DFE supplement intake', 'MPA', (0, 21))	('1750.00 mug', 'Var', (60, 71))	('men', 'Species', '9606', (85, 88))	('mug', 'molecular_function', 'GO:0043739', ('97', '100'))	('mug', 'molecular_function', 'GO:0043739', ('68', '71'))
28557	26043032	assessed the relationship between folate, methionine and alcohol and a genetic polymorphism and found a mean folate intake similar to the unadjusted data found in this study, 634 mug day-1 (SD = 307) for patients with colon cancer and 638 mug day-1 (SD = 334) for rectal tumors.	('patients', 'Species', '9606', (204, 212))	('colon cancer', 'Phenotype', 'HP:0003003', (218, 230))	('folate', 'Chemical', 'MESH:D005492', (34, 40))	('rectal tumors', 'Disease', 'MESH:D012004', (264, 277))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('colon cancer', 'Disease', 'MESH:D015179', (218, 230))	('alcohol', 'Chemical', 'MESH:D000438', (57, 64))	('634 mug', 'Var', (175, 182))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('methionine', 'Chemical', 'MESH:D008715', (42, 52))	('rectal tumors', 'Disease', (264, 277))	('colon cancer', 'Disease', (218, 230))	('rectal tumors', 'Phenotype', 'HP:0100743', (264, 277))	('rectal tumor', 'Phenotype', 'HP:0100743', (264, 276))	('folate', 'Chemical', 'MESH:D005492', (109, 115))
28570	26043032	However, the errors present in the measurements of the questionnaire may attenuate the estimates of the relative risks that are found, and thus diminish the statistical power of studies evaluating the relationship between diet and disease.	('men', 'Species', '9606', (42, 45))	('attenuate', 'NegReg', (73, 82))	('relationship', 'Interaction', (201, 213))	('diminish', 'NegReg', (144, 152))	('errors', 'Var', (13, 19))
28586	26043032	In addition, Asian participants ingested less folate, both unadjusted and calibrated, than the participants of any other race.	('participants', 'Species', '9606', (95, 107))	('participants', 'Species', '9606', (19, 31))	('folate', 'MPA', (46, 52))	('Asian', 'Var', (13, 18))	('less', 'NegReg', (41, 45))	('folate', 'Chemical', 'MESH:D005492', (46, 52))
28593	26043032	One of the mechanisms by which folate deficiency can lead to CRC is related to the synthesis of purines and thymidylate.	('folate deficiency', 'Phenotype', 'HP:0100507', (31, 48))	('lead to', 'Reg', (53, 60))	('deficiency', 'Var', (38, 48))	('folate', 'Chemical', 'MESH:D005492', (31, 37))	('CRC', 'Disease', (61, 64))	('purines', 'Chemical', 'MESH:D011687', (96, 103))	('CRC', 'Phenotype', 'HP:0003003', (61, 64))	('folate', 'Protein', (31, 37))
28600	26043032	It is known that vitamin B6 deficiency can lead to hyperhomocysteinemia, weakness, nervous disorders, irritability, insomnia and difficulty walking.	('weakness', 'Disease', 'MESH:D018908', (73, 81))	('vitamin B6', 'Gene', (17, 27))	('difficulty walking', 'Disease', (129, 147))	('weakness', 'Disease', (73, 81))	('difficulty walking', 'Phenotype', 'HP:0002355', (129, 147))	('deficiency', 'Var', (28, 38))	('insomnia', 'Phenotype', 'HP:0100785', (116, 124))	('irritability', 'Disease', (102, 114))	('nervous disorders', 'Disease', (83, 100))	('irritability', 'Disease', 'MESH:D001523', (102, 114))	('hyperhomocysteinemia', 'Disease', 'MESH:D020138', (51, 71))	('lead to', 'Reg', (43, 50))	('nervous disorders', 'Disease', 'MESH:D009421', (83, 100))	('vitamin B6', 'Chemical', 'MESH:D025101', (17, 27))	('insomnia', 'Disease', 'MESH:D007319', (116, 124))	('hyperhomocysteinemia', 'Disease', (51, 71))	('irritability', 'Phenotype', 'HP:0000737', (102, 114))	('vitamin B6 deficiency', 'Phenotype', 'HP:0008326', (17, 38))	('insomnia', 'Disease', (116, 124))
28629	26043032	The mechanisms by which this occurs include the provision of precursors for DNA synthesis and hypermethylation of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('hypermethylation', 'Var', (94, 110))	('tumor', 'Disease', (114, 119))	('DNA synthesis', 'MPA', (76, 89))
28633	26043032	Recent studies have shown that folate deficiency in normal intestinal mucosa can lead to the instability and incorporation of uracil in the DNA molecule.	('folate deficiency', 'Phenotype', 'HP:0100507', (31, 48))	('uracil', 'Chemical', 'MESH:D014498', (126, 132))	('incorporation of uracil in the DNA molecule', 'MPA', (109, 152))	('lead to', 'Reg', (81, 88))	('instability', 'MPA', (93, 104))	('deficiency', 'Var', (38, 48))	('folate', 'Chemical', 'MESH:D005492', (31, 37))	('folate', 'Gene', (31, 37))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))
28635	26043032	However, in preneoplastic lesions, with intense cell division, folate deficiency appears to disrupt this process, thus inhibiting tumor growth and even tumor regression.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('folate', 'Protein', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('inhibiting', 'NegReg', (119, 129))	('preneoplastic lesions', 'Disease', (12, 33))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', (152, 157))	('folate', 'Chemical', 'MESH:D005492', (63, 69))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (15, 33))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('deficiency', 'Var', (70, 80))	('preneoplastic lesions', 'Disease', 'MESH:D011230', (12, 33))	('disrupt', 'NegReg', (92, 99))	('tumor', 'Disease', (130, 135))	('folate deficiency', 'Phenotype', 'HP:0100507', (63, 80))
28642	26043032	Sauer et al., notes that fortification or supplementation with folic acid can interfere negatively in the carbon-1 cycle and thus becomes an important issue for extrapolation.	('carbon', 'Chemical', 'MESH:D002244', (106, 112))	('men', 'Species', '9606', (48, 51))	('folic acid', 'Chemical', 'MESH:D005492', (63, 73))	('interfere negatively', 'NegReg', (78, 98))	('supplementation', 'Var', (42, 57))	('carbon-1 cycle', 'MPA', (106, 120))
28653	26043032	We also suggest further studies to identify potential polymorphisms in the MTHFR enzyme, which is involved in the metabolic pathways that degrade homocysteine, in order to determine whether changes in this enzyme can effectively interfere with folate metabolism.	('polymorphisms', 'Var', (54, 67))	('changes', 'Var', (190, 197))	('MTHFR', 'Gene', (75, 80))	('folate', 'Chemical', 'MESH:D005492', (244, 250))	('folate metabolism', 'MPA', (244, 261))	('interfere', 'Reg', (229, 238))	('MTHFR', 'Gene', '4524', (75, 80))	('folate metabolism', 'biological_process', 'GO:0046655', ('244', '261'))	('homocysteine', 'Chemical', 'MESH:D006710', (146, 158))
28658	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))
28681	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.	('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))	('initiating', 'Reg', (35, 45))	('damage', 'Var', (97, 103))	('abnormal chromosomal segregation', 'Phenotype', 'HP:0002916', (130, 162))	('lead to', 'Reg', (108, 115))	('abnormal chromosomal segregation', 'CPA', (130, 162))	('death', 'CPA', (116, 121))
28683	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))	('p53', 'Gene', (15, 18))	('p53', 'Gene', '7157', (15, 18))	('rapid apoptotic death', 'MPA', (68, 89))	('premature entry', 'MPA', (135, 150))
28733	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))
28737	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))
28738	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))	('invasiveness', 'Disease', (197, 209))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('primary tumors', 'Disease', (238, 252))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('invasiveness', 'Disease', 'MESH:D009362', (197, 209))	('VEGF-A', 'Gene', (162, 168))	('primary tumors', 'Disease', 'MESH:D009369', (238, 252))	('inhibitors', 'Var', (169, 179))
28740	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))	('VEGF', 'Gene', (84, 88))	('VEGF', 'Gene', (119, 123))	('VEGF', 'Gene', '7422', (84, 88))
28743	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))
28751	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))
28762	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.	('ceramide', 'Chemical', 'MESH:D002518', (143, 151))	('mice', 'Species', '10090', (119, 123))	('anti-VEGF-A antibody', 'Var', (17, 37))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('antibody', 'Var', (29, 37))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('mice', 'Species', '10090', (87, 91))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
28929	33842408	Dr. Liby's talk "Targeting the Immune System for the Prevention of KRAS-Driven Cancers", described the role of combinations of rexinoids, selective agonists for retinoid X receptors, and the synthetic oleanane triterpenoid bardoxolone methyl, an activator of the cytoprotective Nuclear factor E2-related factor 2 (Nrf2) pathway, as attractive drugs for preventing lung and pancreatic cancer because they are active in preclinical models of lung and pancreatic cancer driven by Kras mutations.	('driven by', 'Reg', (467, 476))	('Cancers', 'Disease', (79, 86))	('Cancers', 'Phenotype', 'HP:0002664', (79, 86))	('pancreatic cancer', 'Disease', 'MESH:D010190', (449, 466))	('Kras', 'Gene', '3845', (477, 481))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (373, 390))	('pancreatic cancer', 'Disease', (449, 466))	('rexinoids', 'Chemical', '-', (127, 136))	('Kras', 'Gene', (477, 481))	('lung', 'Disease', (364, 368))	('cancer', 'Phenotype', 'HP:0002664', (460, 466))	('mutations', 'Var', (482, 491))	('bardoxolone', 'Chemical', 'MESH:C116817', (223, 234))	('Nuclear factor E2-related factor 2', 'Gene', (278, 312))	('Cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Cancers', 'Disease', 'MESH:D009369', (79, 86))	('pancreatic cancer', 'Disease', 'MESH:D010190', (373, 390))	('Nuclear factor E2-related factor 2', 'Gene', '4780', (278, 312))	('lung', 'Disease', (440, 444))	('triterpenoid', 'Chemical', 'MESH:D014315', (210, 222))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (449, 466))	('oleanane', 'Chemical', 'MESH:C413246', (201, 209))	('P', 'Chemical', 'MESH:D010758', (53, 54))	('pancreatic cancer', 'Disease', (373, 390))	('cancer', 'Phenotype', 'HP:0002664', (384, 390))
28932	33842408	Surprisingly, they found a higher tumor burden and a novel immune signature in the lungs and tumors of Nrf2 knockout (KO) mice compared to wildtype mice with lung cancer.	('lung cancer', 'Disease', (158, 169))	('mice', 'Species', '10090', (148, 152))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('mice', 'Species', '10090', (122, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('immune signature', 'MPA', (59, 75))	('higher', 'PosReg', (27, 33))	('Nrf2', 'Gene', (103, 107))	('tumors', 'Disease', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('knockout', 'Var', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
28951	33842408	Thus, interventions with broccoli sprout-based preparations enhance the detoxication of some airborne pollutants and may provide a frugal means to attenuate their associated long-term health risks.	('rat', 'Species', '10116', (52, 55))	('attenuate', 'NegReg', (147, 156))	('enhance', 'PosReg', (60, 67))	('detoxication of', 'MPA', (72, 87))	('interventions', 'Var', (6, 19))
28959	33842408	CS3D also reduced both incidence and size of lung tumors that arose over time, and induced apoptosis in the airways, while showing no discernable toxicity.	('lung tumors', 'Disease', 'MESH:D008175', (45, 56))	('reduced', 'NegReg', (10, 17))	('apoptosis', 'CPA', (91, 100))	('lung tumor', 'Phenotype', 'HP:0100526', (45, 55))	('toxicity', 'Disease', 'MESH:D064420', (146, 154))	('CS3D', 'Var', (0, 4))	('toxicity', 'Disease', (146, 154))	('lung tumors', 'Phenotype', 'HP:0100526', (45, 56))	('lung tumors', 'Disease', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('induced', 'Reg', (83, 90))
28962	33842408	Other pathways downregulated by CS3D were NF-kappaB, COX-2, IL-6, and VEGF.	('VEGF', 'Gene', (70, 74))	('CS3D', 'Var', (32, 36))	('COX-2', 'Gene', '4513', (53, 58))	('IL-6', 'Gene', (60, 64))	('COX-2', 'Gene', (53, 58))	('IL-6', 'molecular_function', 'GO:0005138', ('60', '64'))	('IL-6', 'Gene', '3569', (60, 64))	('VEGF', 'Gene', '7422', (70, 74))	('NF-kappaB', 'Protein', (42, 51))	('downregulated', 'NegReg', (15, 28))
28963	33842408	CS3D also produced a less immunosuppressive microenvironment in the lungs, with fewer M2 macrophages and MDSC cells.	('CS3D', 'Var', (0, 4))	('men', 'Species', '9606', (56, 59))	('fewer', 'NegReg', (80, 85))
28965	33842408	These results suggest that blocking STAT3 may be a useful strategy for lung cancer prevention and may involve both inhibition of oncogenic signaling and enhanced anti-tumor immunity.	('inhibition', 'NegReg', (115, 125))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('lung cancer', 'Disease', (71, 82))	('blocking', 'Var', (27, 35))	('rat', 'Species', '10116', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('STAT3', 'Gene', (36, 41))	('oncogenic', 'CPA', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('enhanced', 'PosReg', (153, 161))	('tumor', 'Disease', (167, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
28978	33842408	Importantly, the immunoprevention was a bona fide feature of SA-4-1BBL as agonistic Abs to CD137 receptor had no impact on the tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('Abs', 'Var', (84, 87))	('CD137', 'Gene', (91, 96))	('CD137', 'Gene', '3604', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('SA-4-1BBL', 'Chemical', '-', (61, 70))
28979	33842408	The cancer immunoprevention effect of SA-4-1BBL operated through an innate immune surveillance mechanism that evolved within three weeks of treatment, lasted for months, and did not involve CD8+ T cells.	('CD8', 'Gene', '925', (190, 193))	('SA-4-1BBL', 'Chemical', '-', (38, 47))	('men', 'Species', '9606', (145, 148))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('SA-4-1BBL', 'Var', (38, 47))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('CD8', 'Gene', (190, 193))	('rat', 'Species', '10116', (51, 54))
29024	33842408	Thus, topical application of PHT-427 can deliver active drug to skin and tumor, inhibiting AKT and PDPK1, both of which drive the PI3K pathway important in UVB induced SCC, breast CMD, and AKT in immunocompromised subjects, with significant inhibition of tumor growth without adverse effects on normal skin.	('SCC', 'Phenotype', 'HP:0002860', (168, 171))	('PHT-427', 'Var', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('P', 'Chemical', 'MESH:D010758', (130, 131))	('P', 'Chemical', 'MESH:D010758', (99, 100))	('AKT', 'Gene', (189, 192))	('drive', 'PosReg', (120, 125))	('SCC', 'Disease', (168, 171))	('breast CMD', 'Disease', 'MESH:D001943', (173, 183))	('AKT', 'Gene', (91, 94))	('PDPK1', 'Gene', (99, 104))	('breast CMD', 'Disease', (173, 183))	('tumor', 'Disease', (255, 260))	('tumor', 'Disease', (73, 78))	('PI3K pathway', 'Pathway', (130, 142))	('inhibiting', 'NegReg', (80, 90))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('AKT', 'Gene', '207', (189, 192))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('AKT', 'Gene', '207', (91, 94))	('P', 'Chemical', 'MESH:D010758', (29, 30))	('P', 'Chemical', 'MESH:D010758', (101, 102))	('PDPK1', 'Gene', '5170', (99, 104))
29032	33842408	Dr. Lipkin's talk "Frameshift neoantigen vaccination prevent Lynch syndrome mouse model intestinal cancer", focused on microsatellite-unstable (MSI) cancers occurring in the context of Lynch syndrome.	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('Frameshift', 'Var', (19, 29))	('intestinal cancer', 'Disease', 'MESH:D007414', (88, 105))	('mouse', 'Species', '10090', (76, 81))	('cancers', 'Disease', 'MESH:D009369', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('Lynch syndrome', 'Disease', (61, 75))	('intestinal cancer', 'Disease', (88, 105))	('Lynch syndrome', 'Disease', (185, 199))	('Lynch syndrome', 'Disease', 'MESH:D003123', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Lynch syndrome', 'Disease', 'MESH:D003123', (185, 199))
29033	33842408	These tumors elicit pronounced tumor-specific immune responses directed against frameshift peptide (FSP) neoantigens, which result from mismatch repair (MMR) deficiency-induced insertion/deletion mutations in coding microsatellites (cMS).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('P', 'Chemical', 'MESH:D010758', (102, 103))	('elicit', 'Reg', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumor', 'Disease', (31, 36))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('insertion/deletion mutations', 'Var', (177, 205))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Disease', (6, 11))
29037	33842408	Subsequently, intestinal tumors obtained from Lynch syndrome mice (Msh2flox/flox VpC+/+) were evaluated for mutations affecting these candidate microsatellites.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mice', 'Species', '10090', (61, 65))	('mutations', 'Var', (108, 117))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('Lynch syndrome', 'Disease', (46, 60))	('intestinal tumors', 'Disease', (14, 31))	('Lynch syndrome', 'Disease', 'MESH:D003123', (46, 60))	('intestinal tumors', 'Disease', 'MESH:D007414', (14, 31))
29040	33842408	Four FSP neoantigens derived from cMS mutations in the genes Nacad, Maz, Xirp1, and Senp6 elicited strong antigen-specific cellular immune responses.	('Senp6', 'Gene', '26054', (84, 89))	('Nacad', 'Gene', (61, 66))	('antigen-specific cellular immune responses', 'CPA', (106, 148))	('Senp6', 'Gene', (84, 89))	('Maz', 'Gene', '4150', (68, 71))	('Xirp1', 'Gene', (73, 78))	('Maz', 'Gene', (68, 71))	('elicited', 'Reg', (90, 98))	('P', 'Chemical', 'MESH:D010758', (7, 8))	('Xirp1', 'Gene', '165904', (73, 78))	('mutations', 'Var', (38, 47))	('Nacad', 'Gene', '23148', (61, 66))
29043	33842408	Additionally, NSAIDs, which have chemopreventive efficacy for Lynch syndrome, increase T cell immunity against neoantigens, thus supporting the further development of vaccination strategies for preventing cancers associated with Lynch syndrome.	('Lynch syndrome', 'Disease', (62, 76))	('NSAIDs', 'Var', (14, 20))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('men', 'Species', '9606', (159, 162))	('cancers', 'Disease', (205, 212))	('increase T', 'Disease', 'MESH:D006973', (78, 88))	('Lynch syndrome', 'Disease', 'MESH:D003123', (62, 76))	('increase T cell', 'Phenotype', 'HP:0100828', (78, 93))	('Lynch syndrome', 'Disease', (229, 243))	('Lynch syndrome', 'Disease', 'MESH:D003123', (229, 243))	('rat', 'Species', '10116', (181, 184))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('increase T', 'Disease', (78, 88))
29060	33842408	Fusion with calreticulin (CRT) profoundly enhances the potency of DNA vaccines in generating HPV antigen-specific CD8+ T cell mediated immune responses even in CD4-depleted animals.	('Fusion', 'Var', (0, 6))	('calreticulin', 'Gene', '811', (12, 24))	('enhances', 'PosReg', (42, 50))	('CD8', 'Gene', '925', (114, 117))	('CD8', 'Gene', (114, 117))	('potency', 'MPA', (55, 62))	('calreticulin', 'Gene', (12, 24))	('P', 'Chemical', 'MESH:D010758', (94, 95))	('CRT', 'Gene', (26, 29))	('rat', 'Species', '10116', (86, 89))
29061	33842408	In addition, vaccination with the CRTE6E7L2 DNA vaccine induces both L2-specific neutralizing antibodies and protection from experimental vaginal challenge.	('men', 'Species', '9606', (131, 134))	('L2-specific', 'Protein', (69, 80))	('induces', 'PosReg', (56, 63))	('CRTE6E7L2', 'Var', (34, 43))	('protection', 'CPA', (109, 119))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))
29064	33842408	His group has previously shown that electroporation is a much more effective DNA vaccine administration method to generate HPV-specific CD8+ T cell immune responses as compared to conventional intramuscular injection or epidermal delivery via gene gun.	('rat', 'Species', '10116', (97, 100))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('rat', 'Species', '10116', (118, 121))	('CD8', 'Gene', (136, 139))	('electroporation', 'Var', (36, 51))	('CD8', 'Gene', '925', (136, 139))	('P', 'Chemical', 'MESH:D010758', (124, 125))	('rat', 'Species', '10116', (45, 48))
29068	33842408	KRAS mutations can occur in up to one third of lung adenocarcinomas.	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (47, 67))	('KRAS', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('mutations', 'Var', (5, 14))	('lung adenocarcinomas', 'Disease', (47, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('occur', 'Reg', (19, 24))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (47, 67))
29069	33842408	Through a collaborative effort, his group is examining whether vaccines can be used to target mutant KRAS by mobilizing the immune system.	('KRAS', 'Gene', (101, 105))	('mutant', 'Var', (94, 100))	('rat', 'Species', '10116', (17, 20))
29073	33842408	Using an inducible KRAS mouse model, they demonstrated that the multi-peptide vaccine was able to significantly reduce tumor burden when administered prior to induction of mutant KRAS expression.	('mutant', 'Var', (172, 178))	('tumor', 'Disease', (119, 124))	('mouse', 'Species', '10090', (24, 29))	('reduce', 'NegReg', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('KRAS', 'Gene', (179, 183))	('rat', 'Species', '10116', (49, 52))
29111	33842408	With respect to immunomodulatory agents, NSAIDs inhibit COX-2 and the downstream production of pro-tumorigenic prostaglandins that promote local inflammation.	('tumor', 'Disease', (99, 104))	('inflammation', 'Disease', 'MESH:D007249', (145, 157))	('inflammation', 'Disease', (145, 157))	('prostaglandins', 'Chemical', 'MESH:D011453', (111, 125))	('COX-2', 'Gene', (56, 61))	('inhibit', 'NegReg', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('inflammation', 'biological_process', 'GO:0006954', ('145', '157'))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('NSAIDs', 'Var', (41, 47))	('COX-2', 'Gene', '4513', (56, 61))	('promote', 'PosReg', (131, 138))
29128	33842408	Surprisingly, aspirin was associated with increased all-cause mortality that was driven primarily by cancer deaths that was not accompanied by an increase in cancer incidence over 4.7 years.	('increased', 'PosReg', (42, 51))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('mortality', 'Disease', 'MESH:D003643', (62, 71))	('aspirin', 'Var', (14, 21))	('cancer', 'Disease', (158, 164))	('aspirin', 'Chemical', 'MESH:D001241', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mortality', 'Disease', (62, 71))	('cancer deaths', 'Disease', 'MESH:D009369', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer deaths', 'Disease', (101, 114))
29185	33683579	The proposed mechanisms of action associated with polyphenols are largely related to their antioxidant activity, directly leading to a reduction in reactive oxygen species (ROS).	('reduction', 'NegReg', (135, 144))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (148, 171))	('polyphenols', 'Var', (50, 61))	('antioxidant activity', 'MPA', (91, 111))	('ROS', 'Chemical', 'MESH:D017382', (173, 176))	('reactive oxygen species', 'MPA', (148, 171))	('polyphenols', 'Chemical', 'MESH:D059808', (50, 61))
29253	33683579	Work on the liver cancer cell line HepG2 demonstrated that exposure to luteolin 7-glucoside and apigenin 7-glucoside reduced cell viability, with an IC50 of 21 mug/mL and 17 mug/mL, respectively.	('HepG2', 'CellLine', 'CVCL:0027', (35, 40))	('luteolin 7-glucoside', 'Chemical', 'MESH:C066408', (71, 91))	('reduced', 'NegReg', (117, 124))	('cell viability', 'CPA', (125, 139))	('mug', 'molecular_function', 'GO:0043739', ('160', '163'))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('liver cancer', 'Phenotype', 'HP:0002896', (12, 24))	('liver cancer', 'Disease', 'MESH:D006528', (12, 24))	('mug', 'molecular_function', 'GO:0043739', ('174', '177'))	('apigenin', 'Var', (96, 104))	('liver cancer', 'Disease', (12, 24))	('apigenin 7-glucoside', 'Chemical', 'MESH:C057792', (96, 116))
29256	33683579	Inhibition of cyclin D1 is core to hydroxytyrosol efficacy, resulting in cell cycle arrest at G1/S phase in the MCF-7 cell line.	('cyclin', 'molecular_function', 'GO:0016538', ('14', '20'))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('73', '90'))	('arrest', 'Disease', 'MESH:D006323', (84, 90))	('S phase', 'biological_process', 'GO:0051320', ('97', '104'))	('hydroxytyrosol', 'Chemical', 'MESH:C005975', (35, 49))	('core', 'cellular_component', 'GO:0019013', ('27', '31'))	('arrest', 'Disease', (84, 90))	('Inhibition', 'Var', (0, 10))	('cyclin D1', 'Gene', '595', (14, 23))	('MCF-7', 'CellLine', 'CVCL:0031', (112, 117))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (73, 90))	('cyclin D1', 'Gene', (14, 23))
29260	33683579	Moreover, evidence suggests that hydroxytyrosol can cause superoxide and hydrogen peroxide generation leading to induction of apoptosis in prostate cancer PC3 cells.	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (73, 90))	('hydroxytyrosol', 'Chemical', 'MESH:C005975', (33, 47))	('hydroxytyrosol', 'Var', (33, 47))	('prostate cancer', 'Disease', (139, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cause', 'Reg', (52, 57))	('PC3', 'CellLine', 'CVCL:0035', (155, 158))	('prostate cancer', 'Disease', 'MESH:D011471', (139, 154))	('hydrogen peroxide generation', 'MPA', (73, 101))	('superoxide', 'Chemical', 'MESH:D013481', (58, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (139, 154))	('superoxide', 'MPA', (58, 68))
29262	33683579	The study revealed hydroxytyrosol inhibited cyclins D1/E and cyclin-dependent kinases cdk2/4 and induced the cell cycle inhibitors p21/p27, resulting in G1/S cell cycle arrest.	('cell', 'MPA', (109, 113))	('cdk', 'molecular_function', 'GO:0004693', ('86', '89'))	('hydroxytyrosol', 'Var', (19, 33))	('cyclins D1/E', 'Enzyme', (44, 56))	('cyclin-dependent kinases cdk2/4', 'Enzyme', (61, 92))	('inhibited', 'NegReg', (34, 43))	('hydroxytyrosol', 'Chemical', 'MESH:C005975', (19, 33))	('arrest', 'Disease', 'MESH:D006323', (169, 175))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('158', '175'))	('p21/p27', 'MPA', (131, 138))	('induced', 'PosReg', (97, 104))	('arrest', 'Disease', (169, 175))	('cell cycle', 'biological_process', 'GO:0007049', ('109', '119'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (158, 175))	('cyclin', 'molecular_function', 'GO:0016538', ('61', '67'))
29263	33683579	Hydroxytyrosol induced apoptosis, as demonstrated through caspase activation, PARP cleavage, and BAX/Bcl-2 ratio.	('BAX/Bcl-2 ratio', 'MPA', (97, 112))	('PARP cleavage', 'CPA', (78, 91))	('Bcl-2', 'molecular_function', 'GO:0015283', ('101', '106'))	('apoptosis', 'CPA', (23, 32))	('caspase activation', 'biological_process', 'GO:0006919', ('58', '76'))	('apoptosis', 'biological_process', 'GO:0097194', ('23', '32'))	('Hydroxytyrosol', 'Var', (0, 14))	('apoptosis', 'biological_process', 'GO:0006915', ('23', '32'))	('caspase', 'CPA', (58, 65))	('Hydroxytyrosol', 'Chemical', 'MESH:C005975', (0, 14))	('activation', 'PosReg', (66, 76))
29274	33683579	highlighted that verbascoside can bind directly to the c-Met protein, and that verbascoside causes c-Met protein degradation through the ubiquitination-proteasome pathway.	('verbascoside', 'Chemical', 'MESH:C058956', (17, 29))	('verbascoside', 'Chemical', 'MESH:C058956', (79, 91))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('proteasome pathway', 'biological_process', 'GO:0043161', ('152', '170'))	('ubiquitination-proteasome pathway', 'Pathway', (137, 170))	('protein degradation', 'biological_process', 'GO:0030163', ('105', '124'))	('c-Met protein degradation', 'MPA', (99, 124))	('proteasome', 'molecular_function', 'GO:0004299', ('152', '162'))	('proteasome', 'cellular_component', 'GO:0000502', ('152', '162'))	('bind', 'Interaction', (34, 38))	('verbascoside', 'Var', (79, 91))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
29315	33339271	CIN includes changes in the chromosome number and structure, such as deletions, gains, translocations, and other chromosomal rearrangements.	('CIN', 'Disease', (0, 3))	('gains', 'CPA', (80, 85))	('translocations', 'CPA', (87, 101))	('changes', 'Reg', (13, 20))	('deletions', 'Var', (69, 78))	('CIN', 'Disease', 'MESH:D007674', (0, 3))	('men', 'Species', '9606', (134, 137))
29316	33339271	For example, Lynch syndrome or hereditary nonpolyposis colorectal cancer syndrome is caused by inherited mutations in one of the mismatch repair (MMR) genes (predominantly MLH1 and MSH2).	('MSH2', 'Gene', (181, 185))	('MMR', 'Gene', (146, 149))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('MSH2', 'Gene', '4436', (181, 185))	('Lynch syndrome', 'Disease', 'MESH:D003123', (13, 27))	('hereditary nonpolyposis colorectal cancer syndrome', 'Disease', 'MESH:D003123', (31, 81))	('colorectal cancer', 'Phenotype', 'HP:0003003', (55, 72))	('MLH1', 'Gene', '4292', (172, 176))	('mutations', 'Var', (105, 114))	('caused by', 'Reg', (85, 94))	('MLH1', 'Gene', (172, 176))	('hereditary nonpolyposis colorectal cancer syndrome', 'Disease', (31, 81))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (31, 72))	('Lynch syndrome', 'Disease', (13, 27))
29318	33339271	The first pathway involves genomic instability due to CIN, MSI, and aberrant DNA methylation.	('aberrant DNA methylation', 'Var', (68, 92))	('CIN', 'Disease', (54, 57))	('CIN', 'Disease', 'MESH:D007674', (54, 57))	('MSI', 'Var', (59, 62))
29319	33339271	The second pathway involves mutational inactivation of tumor-suppressor genes, such as APC, TP53, and TGF-beta.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('TGF-beta', 'Gene', '7039', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('APC', 'Phenotype', 'HP:0005227', (87, 90))	('tumor', 'Disease', (55, 60))	('APC', 'Disease', 'MESH:D011125', (87, 90))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('APC', 'Disease', (87, 90))	('mutational inactivation', 'Var', (28, 51))	('TGF-beta', 'Gene', (102, 110))
29322	33339271	Methylation leads to transcriptional silencing and plays a crucial role in the loss of expression of tumor suppressor or DNA repair genes.	('loss of', 'NegReg', (79, 86))	('Methylation', 'Var', (0, 11))	('silencing', 'NegReg', (37, 46))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('expression', 'MPA', (87, 97))	('DNA repair genes', 'Gene', (121, 137))	('transcriptional', 'MPA', (21, 36))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
29324	33339271	However, in up to 20% of CRC tumors, APC mutation is not present and gene inactivation via transcriptional silencing due to promoter hypermethylation led to the loss of APC function.	('APC', 'cellular_component', 'GO:0005680', ('37', '40'))	('promoter hypermethylation', 'Var', (124, 149))	('CRC', 'Phenotype', 'HP:0003003', (25, 28))	('inactivation', 'NegReg', (74, 86))	('APC', 'Disease', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('APC', 'Disease', 'MESH:D011125', (37, 40))	('transcriptional', 'MPA', (91, 106))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('APC', 'Phenotype', 'HP:0005227', (169, 172))	('APC', 'cellular_component', 'GO:0005680', ('169', '172'))	('APC', 'Disease', 'MESH:D011125', (169, 172))	('loss of APC function', 'Disease', 'MESH:D011125', (161, 181))	('CRC tumors', 'Disease', 'MESH:D015179', (25, 35))	('loss of APC function', 'Disease', (161, 181))	('APC', 'Phenotype', 'HP:0005227', (37, 40))	('APC', 'Disease', (169, 172))	('CRC tumors', 'Disease', (25, 35))
29326	33339271	Currently used tests in clinics related to prognosis and treatment in CRCs include MSI testing, mutations in RAS, and EGFR immunohistochemical test for anti-EGFR therapy.	('men', 'Species', '9606', (62, 65))	('EGFR', 'Gene', (157, 161))	('EGFR', 'Gene', '1956', (157, 161))	('CRC', 'Phenotype', 'HP:0003003', (70, 73))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('RAS', 'Gene', (109, 112))	('mutations', 'Var', (96, 105))
29333	33339271	The human single stranded DNA binding protein 2 (SSBP2) gene was first identified in primary leukemic blasts and was found to be translocated and deleted in myelodysplasia and acute myelogenous leukemia (AML).	('AML', 'Disease', 'MESH:D015470', (204, 207))	('SSBP2', 'Gene', (49, 54))	('single stranded DNA binding protein 2', 'Gene', (10, 47))	('human', 'Species', '9606', (4, 9))	('AML', 'Disease', (204, 207))	('SSBP2', 'Gene', '23635', (49, 54))	('AML', 'Phenotype', 'HP:0004808', (204, 207))	('deleted', 'Var', (146, 153))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (176, 202))	('leukemia', 'Phenotype', 'HP:0001909', (194, 202))	('leukemic blasts', 'Disease', 'MESH:D001753', (93, 108))	('single stranded DNA binding protein 2', 'Gene', '23635', (10, 47))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (182, 202))	('leukemic blasts', 'Disease', (93, 108))	('myelodysplasia and acute myelogenous leukemia', 'Disease', 'MESH:D015470', (157, 202))	('myelodysplasia', 'Phenotype', 'HP:0002863', (157, 171))
29335	33339271	The loss of SSBP2 expression is associated with various types of malignancies, such as esophageal squamous cell carcinoma, prostate cancer, gallbladder cancer, and acute myeloid leukemia.	('prostate cancer', 'Phenotype', 'HP:0012125', (123, 138))	('malignancies', 'Disease', 'MESH:D009369', (65, 77))	('prostate cancer', 'Disease', (123, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('malignancies', 'Disease', (65, 77))	('associated', 'Reg', (32, 42))	('SSBP2', 'Gene', (12, 17))	('esophageal squamous cell carcinoma', 'Disease', (87, 121))	('acute myeloid leukemia', 'Disease', (164, 186))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('gallbladder cancer', 'Disease', 'MESH:D005706', (140, 158))	('leukemia', 'Phenotype', 'HP:0001909', (178, 186))	('loss', 'Var', (4, 8))	('SSBP2', 'Gene', '23635', (12, 17))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (170, 186))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (164, 186))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (87, 121))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (164, 186))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('prostate cancer', 'Disease', 'MESH:D011471', (123, 138))	('gallbladder cancer', 'Disease', (140, 158))
29338	33339271	described that the candidate myeloid leukemia suppressor gene encoding sequence-SSBP2 from chromosome 5q13.3 was frequently deleted in AML.	('myeloid leukemia', 'Disease', 'MESH:D007951', (29, 45))	('AML', 'Disease', 'MESH:D015470', (135, 138))	('SSBP2', 'Gene', (80, 85))	('AML', 'Phenotype', 'HP:0004808', (135, 138))	('AML', 'Disease', (135, 138))	('deleted', 'Var', (124, 131))	('myeloid leukemia', 'Disease', (29, 45))	('SSBP2', 'Gene', '23635', (80, 85))	('leukemia', 'Phenotype', 'HP:0001909', (37, 45))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (29, 45))
29344	33339271	Meanwhile, several studies on promoter methylation of SSBP2 in tumors have shown that SSBP2 is one of the genes that are downregulated by methylation.	('SSBP2', 'Gene', '23635', (54, 59))	('SSBP2', 'Gene', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('methylation', 'biological_process', 'GO:0032259', ('138', '149'))	('SSBP2', 'Gene', '23635', (86, 91))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('downregulated', 'NegReg', (121, 134))	('methylation', 'Var', (138, 149))	('SSBP2', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
29392	33339271	compared SSBP2 methylation in normal and tumor tissues in 20 pairs of esophageal squamous cell carcinoma and matched normal esophageal tissues using TaqMan-MSP analysis, and a higher degree of SSBP2 methylation in paired tumors than in paired normal tissues was observed in 15 of 20 esophageal squamous cell carcinoma patients.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (70, 104))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (294, 317))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (283, 317))	('methylation', 'Var', (199, 210))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('methylation', 'Var', (15, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('tumors', 'Disease', (221, 227))	('SSBP2', 'Gene', (9, 14))	('tumor', 'Disease', (41, 46))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('tumor', 'Disease', (221, 226))	('SSBP2', 'Gene', (193, 198))	('methylation', 'biological_process', 'GO:0032259', ('199', '210'))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('esophageal squamous cell carcinoma', 'Disease', (70, 104))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('esophageal squamous cell carcinoma', 'Disease', (283, 317))	('patients', 'Species', '9606', (318, 326))	('SSBP2', 'Gene', '23635', (9, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('SSBP2', 'Gene', '23635', (193, 198))
29393	33339271	reported that the SSBP2 promoter region was hypermethylated in 61.4% (54 of 88) of prostate cancer cases, whereas none of the 23 benign prostatic hyperplasia cases showed hypermethylation.	('hypermethylated', 'Var', (44, 59))	('SSBP2', 'Gene', '23635', (18, 23))	('prostate cancer', 'Disease', 'MESH:D011471', (83, 98))	('prostate cancer', 'Phenotype', 'HP:0012125', (83, 98))	('benign prostatic hyperplasia', 'Phenotype', 'HP:0008711', (129, 157))	('prostatic hyperplasia', 'Disease', (136, 157))	('prostate cancer', 'Disease', (83, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('SSBP2', 'Gene', (18, 23))	('prostatic hyperplasia', 'Disease', 'MESH:D011470', (136, 157))
29395	33339271	In addition, another study was conducted to identify a panel of epigenetic biomarkers that can distinguish cholecystitis from gallbladder cancer patients.	('patients', 'Species', '9606', (145, 153))	('cholecystitis', 'Disease', 'MESH:D002764', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('epigenetic', 'Var', (64, 74))	('gallbladder cancer', 'Disease', (126, 144))	('cholecystitis', 'Disease', (107, 120))	('cholecystitis', 'Phenotype', 'HP:0001082', (107, 120))	('gallbladder cancer', 'Disease', 'MESH:D005706', (126, 144))
29397	33339271	Furthermore, in ovarian cancer, SSBP2 methylation was found in 9% of tumor cases, whereas no cases showed methylation of the SSBP2 promoter in normal tissues.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('SSBP2', 'Gene', (125, 130))	('ovarian cancer', 'Disease', (16, 30))	('methylation', 'Var', (38, 49))	('tumor', 'Disease', (69, 74))	('SSBP2', 'Gene', (32, 37))	('found', 'Reg', (54, 59))	('SSBP2', 'Gene', '23635', (125, 130))	('ovarian cancer', 'Phenotype', 'HP:0100615', (16, 30))	('SSBP2', 'Gene', '23635', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('ovarian cancer', 'Disease', 'MESH:D010051', (16, 30))
29429	33061521	Non-expression of TLR3 in CRC cells was associated with lymph node metastasis and was an independent risk factor for recurrence.	('C', 'Chemical', 'MESH:D002244', (28, 29))	('lymph node metastasis', 'CPA', (56, 77))	('TLR3', 'Gene', (18, 22))	('TLR3', 'Gene', '7098', (18, 22))	('C', 'Chemical', 'MESH:D002244', (26, 27))	('CRC', 'Phenotype', 'HP:0003003', (26, 29))	('associated', 'Reg', (40, 50))	('Non-expression', 'Var', (0, 14))
29448	33061521	Eiro et al suggested a possible protective role of TLR9 expression against malignant transformation in CRC.	('TLR9', 'Gene', '54106', (51, 55))	('C', 'Chemical', 'MESH:D002244', (103, 104))	('CRC', 'Phenotype', 'HP:0003003', (103, 106))	('malignant transformation', 'CPA', (75, 99))	('TLR9', 'Gene', (51, 55))	('C', 'Chemical', 'MESH:D002244', (105, 106))	('expression', 'Var', (56, 66))	('CRC', 'Disease', (103, 106))
29470	33061521	Non-silencing negative control small-interfering RNA (siRNA) (1027281) and siRNA against TLR3 (SI02655156) were purchased from Qiagen (Hilden, Germany).	('TLR3', 'Gene', '7098', (89, 93))	('TLR3', 'Gene', (89, 93))	('SI02655156', 'Var', (95, 105))	('1027281', 'Var', (62, 69))
29486	33061521	These membranes were blocked and then incubated with anti-TLR3 (1:500) and anti-actin (1:5000) antibodies, followed by incubation with horseradish peroxidase-conjugated secondary antibody.	('TLR3', 'Gene', (58, 62))	('antibody', 'cellular_component', 'GO:0019815', ('179', '187'))	('horseradish', 'Species', '3704', (135, 146))	('TLR3', 'Gene', '7098', (58, 62))	('antibody', 'cellular_component', 'GO:0019814', ('179', '187'))	('antibody', 'molecular_function', 'GO:0003823', ('179', '187'))	('1:5000', 'Var', (87, 93))	('antibody', 'cellular_component', 'GO:0042571', ('179', '187'))
29509	33061521	Upon treatment of the cells with poly I:C, mRNA levels for CCL2, CCL5, and IL-8 increased, peaked within 4 hours, and then decreased (Figure 4A-C).	('decreased', 'NegReg', (123, 132))	('IL-8', 'Gene', (75, 79))	('poly I:C', 'Var', (33, 41))	('CCL5', 'Gene', '6352', (65, 69))	('mRNA levels', 'MPA', (43, 54))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('CCL', 'molecular_function', 'GO:0044101', ('65', '68'))	('CCL2', 'Gene', (59, 63))	('C', 'Chemical', 'MESH:D002244', (66, 67))	('C', 'Chemical', 'MESH:D002244', (144, 145))	('CCL5', 'Gene', (65, 69))	('IL-8', 'Gene', '3576', (75, 79))	('C', 'Chemical', 'MESH:D002244', (65, 66))	('C', 'Chemical', 'MESH:D002244', (40, 41))	('IL-8', 'molecular_function', 'GO:0005153', ('75', '79'))	('CCL2', 'Gene', '6347', (59, 63))	('increased', 'PosReg', (80, 89))	('CCL', 'molecular_function', 'GO:0044101', ('59', '62'))	('poly I:C', 'Chemical', 'MESH:D011070', (33, 41))	('C', 'Chemical', 'MESH:D002244', (59, 60))
29510	33061521	Poly I:C also induced mRNA and protein expression of these chemokines in a concentration-dependent manner (Figure 4D-I).	('C', 'Chemical', 'MESH:D002244', (7, 8))	('Poly I', 'Chemical', 'MESH:D011069', (0, 6))	('Poly I:C', 'Var', (0, 8))	('induced', 'Reg', (14, 21))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))
29523	33061521	Nojiri et al found that poly I:C transfection of SW480 cells activated TLR3 and induced apoptosis in CRC, whereas Niedzielska et al showed that TLR3 mRNA expression tended to decrease in adenocarcinoma than in a polyp.	('poly I:C', 'Chemical', 'MESH:D011070', (24, 32))	('activated', 'PosReg', (61, 70))	('CRC', 'Phenotype', 'HP:0003003', (101, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('polyp', 'Disease', 'MESH:D011127', (212, 217))	('adenocarcinoma', 'Disease', (187, 201))	('induced', 'Reg', (80, 87))	('polyp', 'Disease', (212, 217))	('C', 'Chemical', 'MESH:D002244', (103, 104))	('TLR3', 'Gene', '7098', (144, 148))	('TLR3', 'Gene', '7098', (71, 75))	('TLR3', 'Gene', (144, 148))	('apoptosis', 'CPA', (88, 97))	('C', 'Chemical', 'MESH:D002244', (31, 32))	('adenocarcinoma', 'Disease', 'MESH:D000230', (187, 201))	('C', 'Chemical', 'MESH:D002244', (101, 102))	('poly', 'Var', (24, 28))	('decrease', 'NegReg', (175, 183))	('SW480', 'CellLine', 'CVCL:0546', (49, 54))	('TLR3', 'Gene', (71, 75))
29524	33061521	In the present study, positive TLR3 expression also reduced the lymph node metastasis rate and the recurrence rate, supporting the results of previous reports on various carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('positive', 'Var', (22, 30))	('reduced', 'NegReg', (52, 59))	('recurrence rate', 'CPA', (99, 114))	('TLR3', 'Gene', (31, 35))	('lymph node metastasis rate', 'CPA', (64, 90))	('carcinomas', 'Disease', 'MESH:D009369', (170, 180))	('TLR3', 'Gene', '7098', (31, 35))	('reduced the lymph node metastasis rate', 'Phenotype', 'HP:0002732', (52, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (170, 180))	('carcinomas', 'Disease', (170, 180))
29539	33061521	The present study indicated that the non-expression of TLR3 in CRC cells was associated with lymph node metastasis, and was an independent risk factor for recurrence.	('TLR3', 'Gene', (55, 59))	('C', 'Chemical', 'MESH:D002244', (65, 66))	('CRC', 'Phenotype', 'HP:0003003', (63, 66))	('TLR3', 'Gene', '7098', (55, 59))	('non-expression', 'Var', (37, 51))	('lymph node metastasis', 'CPA', (93, 114))	('C', 'Chemical', 'MESH:D002244', (63, 64))	('associated', 'Reg', (77, 87))
29542	33061521	In summary, the non-expression of TLR3 in CRC cells was associated with lymph node metastasis and was an independent risk factor for recurrence.	('C', 'Chemical', 'MESH:D002244', (42, 43))	('TLR3', 'Gene', (34, 38))	('TLR3', 'Gene', '7098', (34, 38))	('CRC', 'Phenotype', 'HP:0003003', (42, 45))	('associated', 'Reg', (56, 66))	('non-expression', 'Var', (16, 30))	('C', 'Chemical', 'MESH:D002244', (44, 45))	('lymph node metastasis', 'CPA', (72, 93))
29581	31547641	Notably, only for the male patients, sedentary behavior represents a potential risk for colorectal adenoma recurrence (OR, 1.47; 95% CI, 1.03 to 2.11; p=0.03).	('patients', 'Species', '9606', (27, 35))	('colorectal adenoma', 'Disease', (88, 106))	('sedentary behavior', 'Var', (37, 55))	('colorectal adenoma', 'Disease', 'MESH:D015179', (88, 106))
29586	31547641	For example, with aging, patients' muscle tissue undergo atrophy and can show a false-negative predisposition, especially with BMI >=30 kg/m (OR, 1.17; 95% CI, 0.92 to 1.48; p=0.04).	('false', 'biological_process', 'GO:0071878', ('80', '85'))	('BMI >=30 kg/m', 'Var', (127, 140))	('atrophy', 'Disease', 'MESH:D001284', (57, 64))	('atrophy', 'Disease', (57, 64))	('patients', 'Species', '9606', (25, 33))	('false', 'biological_process', 'GO:0071877', ('80', '85'))	('aging', 'biological_process', 'GO:0007568', ('18', '23'))
29587	31547641	Visceral fat deposition can induce some dysregulation of the body processes, including insulin resistance and hyperinsulinemia.	('insulin', 'Gene', '3630', (87, 94))	('insulin', 'Gene', (115, 122))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (110, 126))	('induce', 'Reg', (28, 34))	('insulin', 'Gene', '3630', (115, 122))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (110, 126))	('dysregulation', 'MPA', (40, 53))	('body processes', 'CPA', (61, 75))	('hyperinsulinemia', 'Disease', (110, 126))	('insulin', 'molecular_function', 'GO:0016088', ('87', '94'))	('Visceral', 'Var', (0, 8))	('insulin', 'Gene', (87, 94))	('insulin resistance', 'Phenotype', 'HP:0000855', (87, 105))
29589	31547641	Cigarettes have a substantial number of components, such as polycyclic aromatic hydrocarbons, heterocyclic amines and nitrosamines, with carcinogenic action.	('nitrosamines', 'Chemical', 'MESH:D009602', (118, 130))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (60, 92))	('carcinogenic', 'Disease', 'MESH:D063646', (137, 149))	('carcinogenic', 'Disease', (137, 149))	('polycyclic', 'Var', (60, 70))	('heterocyclic amines', 'MPA', (94, 113))	('heterocyclic amines', 'Chemical', '-', (94, 113))
29598	31547641	An increasing number of new drugs are produced on the basis of the mechanism that NSAIDs can inhibit cyclooxygenase (COX), producing an anti-inflammatory action and decreasing the recurrence rate of the polyps (OR, 0.77; 95% CI, 0.63 to 0.95; p=0.02).	('inhibit', 'NegReg', (93, 100))	('anti-inflammatory action', 'MPA', (136, 160))	('polyps', 'Disease', (203, 209))	('NSAIDs', 'Var', (82, 88))	('decreasing', 'NegReg', (165, 175))	('polyps', 'Disease', 'MESH:D011127', (203, 209))	('recurrence rate', 'CPA', (180, 195))
29603	31547641	Gene variation may confer a potential risk for colorectal adenoma recurrence, manifesting as gene polymorphism.	('colorectal adenoma', 'Disease', 'MESH:D015179', (47, 65))	('colorectal adenoma', 'Disease', (47, 65))	('Gene variation', 'Var', (0, 14))
29604	31547641	IL single-nucleotide polymorphisms (SNPs) may be associated with the risk of colorectal adenoma recurrence.	('colorectal adenoma', 'Disease', (77, 95))	('single-nucleotide polymorphisms', 'Var', (3, 34))	('associated', 'Reg', (49, 59))	('colorectal adenoma', 'Disease', 'MESH:D015179', (77, 95))
29612	31547641	The D2 dopamine receptor (DRD2) gene polymorphism might be associated with a lower recurrence rate of colorectal adenoma.	('DRD2', 'Gene', (26, 30))	('lower', 'NegReg', (77, 82))	('colorectal adenoma', 'Disease', 'MESH:D015179', (102, 120))	('D2 dopamine receptor', 'Gene', (4, 24))	('DRD2', 'Gene', '1813', (26, 30))	('D2 dopamine receptor', 'Gene', '1813', (4, 24))	('colorectal adenoma', 'Disease', (102, 120))	('polymorphism', 'Var', (37, 49))
29613	31547641	Two kinds of variants, the rs1799732 CT (OR, 1.30; 95% CI, 1.01 to 1.69; p=0.03) and rs1800497 TT (OR, 2.40; 95% CI, 1.11 to 5.20; p=0.02), are significantly associated with the recurrence of advanced adenomas.	('rs1800497', 'Mutation', 'rs1800497', (85, 94))	('associated with', 'Reg', (158, 173))	('adenomas', 'Disease', (201, 209))	('rs1800497 TT', 'Var', (85, 97))	('rs1799732 CT', 'Var', (27, 39))	('adenomas', 'Disease', 'MESH:D000236', (201, 209))	('rs1799732', 'Mutation', 'rs1799732', (27, 36))
29614	31547641	Alcohol addiction may play a role in differing results between DRD2 rs1799732 and rs6277 genotypes.	('rs1799732', 'Var', (68, 77))	('Alcohol addiction', 'Disease', (0, 17))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('Alcohol addiction', 'Phenotype', 'HP:0030955', (0, 17))	('DRD2', 'Gene', (63, 67))	('rs6277', 'Mutation', 'rs6277', (82, 88))	('rs1799732', 'Mutation', 'rs1799732', (68, 77))	('DRD2', 'Gene', '1813', (63, 67))	('rs6277', 'Var', (82, 88))
29615	31547641	The DRD2 polymorphism can decrease the number of dopamine receptors in the colonic mucosa, contributing to the reduction of the cyclic AMP inside the cells, thereby inhibiting proliferation.	('reduction', 'NegReg', (111, 120))	('colonic mucosa', 'Disease', 'MESH:D003110', (75, 89))	('number of dopamine receptors', 'MPA', (39, 67))	('cyclic AMP inside the cells', 'MPA', (128, 155))	('dopamine', 'Chemical', 'MESH:D004298', (49, 57))	('DRD2', 'Gene', (4, 8))	('decrease', 'NegReg', (26, 34))	('cyclic AMP', 'Chemical', 'MESH:D000242', (128, 138))	('proliferation', 'CPA', (176, 189))	('DRD2', 'Gene', '1813', (4, 8))	('polymorphism', 'Var', (9, 21))	('colonic mucosa', 'Disease', (75, 89))	('inhibiting', 'NegReg', (165, 175))
29619	31547641	More copies of the T allele in CYP24A1 rs927650 contribute to high recurrence of any colorectal adenomas, for heterozygotes (OR, 1.30; 95% CI, 0.99 to 1.70; p=0.04) and homozygotes (OR, 1.38; 95% CI, 1.01 to 1.89; p=0.04), respectively.	('CYP24A1', 'Gene', (31, 38))	('colorectal adenomas', 'Disease', 'MESH:D015179', (85, 104))	('CYP24A1', 'Gene', '1591', (31, 38))	('rectal adenomas', 'Phenotype', 'HP:0100896', (89, 104))	('rs927650', 'Var', (39, 47))	('colorectal adenomas', 'Disease', (85, 104))	('rs927650', 'Mutation', 'rs927650', (39, 47))
29620	31547641	When the gene polymorphisms cooperate with vitamin D metabolites, the effect can be enhanced.	('enhanced', 'PosReg', (84, 92))	('polymorphisms', 'Var', (14, 27))	('vitamin D', 'Chemical', 'MESH:D014807', (43, 52))
29621	31547641	Other polymorphism, namely CYP24A1 rs35051736, has been reported that has positively statistical significance with advanced colorectal adenoma (p<0.001).	('rs35051736', 'Mutation', 'rs35051736', (35, 45))	('rs35051736', 'Var', (35, 45))	('colorectal adenoma', 'Disease', (124, 142))	('significance', 'Reg', (97, 109))	('colorectal adenoma', 'Disease', 'MESH:D015179', (124, 142))	('CYP24A1', 'Gene', (27, 34))	('CYP24A1', 'Gene', '1591', (27, 34))
29622	31547641	In addition, CYP2C9 genotype has positive association with recurrent adenoma of 29% (OR, 1.29; 95% CI, 1.09 to 1.51; p=0.04) for rs1799853 and 47% (OR, 1.47; 95% CI, 1.19 to 1.83; p=0.04) for rs1057910 allele.	('rs1057910', 'Mutation', 'rs1057910', (192, 201))	('adenoma', 'Disease', 'MESH:D000236', (69, 76))	('CYP2C9', 'Gene', (13, 19))	('rs1799853', 'Var', (129, 138))	('rs1799853', 'Mutation', 'rs1799853', (129, 138))	('adenoma', 'Disease', (69, 76))	('rs1057910', 'Var', (192, 201))	('CYP2C9', 'Gene', '1559', (13, 19))
29625	31547641	The rs5277 which exhibits homozygous genotype of the minor C allele can increase 51% recurrent risk (OR, 1.51; 95% CI, 1.01 to 2.25; p=0.02), and the rs4648310 as a heterozygote of the minor G allele can increase 37% risk of recurrent adenoma compared with AA genotype (OR, 1.37; 95% CI, 1.05 to 1.79; p=0.03).	('increase', 'PosReg', (72, 80))	('rs5277', 'Var', (4, 10))	('rs5277', 'Mutation', 'rs5277', (4, 10))	('adenoma', 'Disease', (235, 242))	('recurrent risk', 'MPA', (85, 99))	('rs4648310', 'Var', (150, 159))	('adenoma', 'Disease', 'MESH:D000236', (235, 242))	('rs4648310', 'Mutation', 'rs4648310', (150, 159))
29637	31547641	More recently, lesion occupying >=75% of the luminal circumference has been conducted as an independent risk factor of recurrent adenoma (OR, 5.6; 95% CI, 2.4 to 12.9; p<0.001).	('adenoma', 'Disease', (129, 136))	('lesion', 'Var', (15, 21))	('adenoma', 'Disease', 'MESH:D000236', (129, 136))	('luminal', 'Chemical', 'MESH:D010634', (45, 52))
29680	31547641	In particular, ingesting less folate might mediate the carcinogenesis by abnormal gene expression and genetic instability.	('folate', 'Chemical', 'MESH:D005492', (30, 36))	('gene expression', 'MPA', (82, 97))	('folate', 'MPA', (30, 36))	('less', 'NegReg', (25, 29))	('abnormal', 'Reg', (73, 81))	('ingesting', 'Var', (15, 24))	('genetic instability', 'CPA', (102, 121))	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('carcinogenesis', 'Disease', (55, 69))
29691	31547641	Significantly high recurrence of advanced polyps was contributed by overeating either pan-fried red meat (OR, 1.85; 95% CI, 1.10 to 3.13; p=0.02) or well-done red meat (OR, 1.71; 95% CI, 1.02 to 2.86; p=0.03).	('overeating', 'Var', (68, 78))	('polyps', 'Disease', 'MESH:D011127', (42, 48))	('polyps', 'Disease', (42, 48))
29694	31547641	This mutagen can trigger the covalent modification of the DNA/DNA adduct generation process in guanine site, leading to the mutation.	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('leading to', 'Reg', (109, 119))	('mutation', 'Var', (124, 132))	('guanine', 'Chemical', 'MESH:D006147', (95, 102))
29700	31547641	The possible mechanism is that the SNPs in the promotor site of the genes encoding IL-1beta, IL-6, IL-8, and IL-10 are effective at reducing the expression of these ILs, leading to the proliferation and carcinogenesis of mucosa cells.	('IL-6', 'Gene', '3569', (93, 97))	('leading to', 'Reg', (170, 180))	('expression', 'MPA', (145, 155))	('IL-8', 'Gene', (99, 103))	('carcinogenesis', 'Disease', (203, 217))	('IL-8', 'molecular_function', 'GO:0005153', ('99', '103'))	('IL-6', 'Gene', (93, 97))	('carcinogenesis', 'Disease', 'MESH:D063646', (203, 217))	('IL-1beta', 'Gene', (83, 91))	('IL-10', 'Gene', '3586', (109, 114))	('IL-8', 'Gene', '3576', (99, 103))	('SNPs in', 'Var', (35, 42))	('IL-10', 'Gene', (109, 114))	('IL-10', 'molecular_function', 'GO:0005141', ('109', '114'))	('IL-1', 'molecular_function', 'GO:0005149', ('83', '87'))	('reducing', 'NegReg', (132, 140))	('proliferation', 'CPA', (185, 198))	('IL-1beta', 'Gene', '3552', (83, 91))	('IL-6', 'molecular_function', 'GO:0005138', ('93', '97'))
29706	31547641	The preventive effect of high calcium consumption can only be observed among patients with high circulating concentrations of vitamin D. With intake of a dairy product, the vitamin D plus calcium can inverse the high recurrence rate for adenoma.	('vitamin', 'Var', (173, 180))	('high circulating concentrations of vitamin D.', 'Phenotype', 'HP:0100512', (91, 136))	('adenoma', 'Disease', 'MESH:D000236', (237, 244))	('calcium', 'Chemical', 'MESH:D002118', (30, 37))	('adenoma', 'Disease', (237, 244))	('calcium', 'Chemical', 'MESH:D002118', (188, 195))	('vitamin D', 'Chemical', 'MESH:D014807', (173, 182))	('patients', 'Species', '9606', (77, 85))	('high calcium consumption', 'Phenotype', 'HP:0003072', (25, 49))	('vitamin D', 'Chemical', 'MESH:D014807', (126, 135))
29708	31547641	A sex-specific analyses indicated that high lignin consumption of lignin can increase the risk of any adenoma recurrence only in female patients (OR, 2.07; 95% CI, 1.22 to 3.52; p=0.004).	('adenoma', 'Disease', 'MESH:D000236', (102, 109))	('lignin', 'Chemical', 'MESH:D008031', (44, 50))	('adenoma', 'Disease', (102, 109))	('patients', 'Species', '9606', (136, 144))	('high lignin', 'Var', (39, 50))	('lignin', 'Chemical', 'MESH:D008031', (66, 72))
29740	31547641	Third, uncomplete polypectomy could delay follow-up surveillance and missed diagnosis would substantially increase the recurrence rate of colorectal polyps.	('colorectal polyps', 'Phenotype', 'HP:0200063', (138, 155))	('colorectal polyps', 'Disease', 'MESH:D003111', (138, 155))	('colorectal polyps', 'Disease', (138, 155))	('uncomplete', 'Var', (7, 17))	('colorectal polyp', 'Phenotype', 'HP:0200063', (138, 154))	('increase', 'PosReg', (106, 114))	('recurrence', 'MPA', (119, 129))
29788	31662828	For lymph vascular invasion, 3 studies (545 patients) were qualified for the meta-analysis and there was statistically significant association between high-grade tumor budding and lymph vascular invasion (OR = 7.85, 95%CI: 5.04-12.21, P < 0.01) (Figure 4).	('high-grade', 'Var', (151, 161))	('lymph vascular invasion', 'CPA', (180, 203))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('patients', 'Species', '9606', (44, 52))	('tumor', 'Disease', (162, 167))	('budding', 'biological_process', 'GO:0007114', ('168', '175'))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
29789	31662828	For lymph node metastasis, 5 studies (966 patients) were qualified for the meta-analysis and there was statistically significant association between high-grade tumor budding and lymph node metastasis (OR = 5.75, 95%CI: 3.20-10.32, P < 0.01) (Figure 5).	('high-grade', 'Var', (149, 159))	('significant association', 'Reg', (117, 140))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('lymph node metastasis', 'CPA', (178, 199))	('budding', 'biological_process', 'GO:0007114', ('166', '173'))	('patients', 'Species', '9606', (42, 50))	('tumor', 'Disease', (160, 165))
29791	31662828	The 5-year OS was extracted from 5 studies (1833 patients) and analysis of the synthesized data with the fixed-effects model (I2 = 0.0%, Rho =0.549) (Figure 6) revealed that high-grade tumor budding was associated with a poor 5-year OS (HR = 1.79, 95%CI: 1.53-2.05, P < 0.01) (Figure 6).	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('patients', 'Species', '9606', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('high-grade', 'Var', (174, 184))
29792	31662828	Subsequently, 2 studies (572 patients) on intestinal-type GC also revealed that high-grade tumor budding was associated with an adverse 5-year OS (HR = 1.93, 95%CI: 1.45-2.42, P < 0.01) (Figure 7) and no significant heterogeneity was detected (I2 = 0.0%, Rho = 0.929) (Figure 7).	('patients', 'Species', '9606', (29, 37))	('intestinal-type GC', 'Disease', 'MESH:D013274', (42, 60))	('intestinal-type GC', 'Disease', (42, 60))	('GC', 'Phenotype', 'HP:0012126', (58, 60))	('high-grade', 'Var', (80, 90))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('budding', 'biological_process', 'GO:0007114', ('97', '104'))	('tumor', 'Disease', (91, 96))
29799	31662828	In addition, high-grade tumor budding was a statistically significant predictor of poor OS in patients with GC.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('GC', 'Disease', 'MESH:D013274', (108, 110))	('patients', 'Species', '9606', (94, 102))	('budding', 'biological_process', 'GO:0007114', ('30', '37'))	('tumor', 'Disease', (24, 29))	('GC', 'Phenotype', 'HP:0012126', (108, 110))	('poor OS', 'Disease', (83, 90))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('high-grade', 'Var', (13, 23))
29827	31662828	The results of this study showed that high-grade tumor budding was related to a poor 5-year OS and aggressive clinicopathological features in patients with GC.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('poor', 'NegReg', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('GC', 'Disease', 'MESH:D013274', (156, 158))	('tumor', 'Disease', (49, 54))	('budding', 'biological_process', 'GO:0007114', ('55', '62'))	('GC', 'Phenotype', 'HP:0012126', (156, 158))	('patients', 'Species', '9606', (142, 150))	('high-grade', 'Var', (38, 48))
29830	31662828	Our results demonstrated that high-grade tumor budding was related to poor 5-year overall survival (OS) in patients with gastric cancer (GC).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('poor', 'NegReg', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('budding', 'biological_process', 'GO:0007114', ('47', '54'))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('tumor', 'Disease', (41, 46))	('overall survival', 'MPA', (82, 98))	('GC', 'Disease', 'MESH:D013274', (137, 139))	('GC', 'Phenotype', 'HP:0012126', (137, 139))	('high-grade', 'Var', (30, 40))	('gastric cancer', 'Disease', (121, 135))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('patients', 'Species', '9606', (107, 115))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))
29836	31662828	This research is the first to demonstrate that high-grade tumor budding is related to poor 5-year OS and aggressive clinicopathological features in patients with GC.	('patients', 'Species', '9606', (148, 156))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('GC', 'Disease', 'MESH:D013274', (162, 164))	('GC', 'Phenotype', 'HP:0012126', (162, 164))	('high-grade', 'Var', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('budding', 'biological_process', 'GO:0007114', ('64', '71'))
29858	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))	('STK11', 'Gene', '6794', (30, 35))	('Inactivating mutations', 'Var', (0, 22))	('PJS', 'Gene', '6794', (126, 129))	('LKB1', 'Gene', (36, 40))	('PJS', 'Gene', (126, 129))	('LKB1', 'Gene', '6794', (36, 40))
29861	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))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('STK11', 'Gene', (72, 77))	('mutation', 'Var', (83, 91))	('cancer', 'Disease', (121, 127))	('PJS', 'Gene', '6794', (59, 62))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('STK11', 'molecular_function', 'GO:0033868', ('72', '77'))	('STK11', 'Gene', '6794', (72, 77))	('LKB1', 'Gene', (78, 82))	('PJS', 'Gene', (59, 62))
29862	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', 'Gene', (95, 100))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (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))
29863	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'))
29867	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))
29870	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))
29873	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))
29874	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))
29875	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))
29880	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))	('G1/G2 cell cycle arrest', 'CPA', (48, 71))	('p16', 'Gene', '1029', (34, 37))	('inducing', 'Reg', (39, 47))
29882	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))
29883	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))
29885	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))
29892	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))	('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))
29894	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))	('neoplasms', 'Disease', (123, 132))	('malignancies', 'Disease', (160, 172))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('PC', 'Phenotype', 'HP:0002894', (92, 94))	('mutation', 'Var', (63, 71))	('endometrial', 'Disease', (181, 192))	('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))	('MMR gene', 'Gene', (54, 62))	('neoplasm', 'Phenotype', 'HP:0002664', (123, 131))
29896	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))
29898	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))
29899	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))
29902	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))
29903	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', (74, 79))	('BRCA1', 'Gene', '672', (74, 79))	('BRCA2', 'Gene', (6, 11))	('mutation', 'Var', (12, 20))
29904	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))
29905	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))
29912	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))	('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))
29913	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))
29914	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))
29915	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))	('BRCA1', 'Gene', '672', (104, 109))	('6174delT', 'Var', (67, 75))	('5382insC', 'INSERTION', 'None', (122, 130))	('185delAG', 'Var', (110, 118))	('BRCA2', 'Gene', (61, 66))	('BRCA1', 'Gene', (104, 109))	('6174delT', 'Mutation', 'rs786204278', (67, 75))	('BRCA2', 'Gene', '675', (61, 66))
29917	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))
29918	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'))
29919	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))
29920	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))
29921	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))	('c.170G>A', 'Var', (59, 67))	('mutations', 'Var', (167, 176))	('8266A>T', 'Var', (50, 57))	('ATM', 'Gene', (24, 27))	('ATM', 'Gene', (163, 166))
29927	30699894	detected 1100delC variant of CHEK2 in 2.9% of German FPC families, and Lener et al.	('PC', 'Phenotype', 'HP:0002894', (54, 56))	('CHEK2', 'Gene', '11200', (29, 34))	('CHEK2', 'Gene', (29, 34))	('1100delC', 'Var', (9, 17))	('1100delC', 'Mutation', 'rs555607708', (9, 17))
29928	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))
29931	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))
29934	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.	('FPC', 'Disease', (198, 201))	('PC', 'Phenotype', 'HP:0002894', (101, 103))	('Familial Pancreatic Cancer', 'Disease', (130, 156))	('PC', 'Phenotype', 'HP:0002894', (75, 77))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('PC', 'Phenotype', 'HP:0002894', (229, 231))	('Pancreatic Cancer', 'Phenotype', 'HP:0002894', (139, 156))	('Cancer', 'Phenotype', 'HP:0002664', (150, 156))	('patients', 'Species', '9606', (78, 86))	('PC', 'Phenotype', 'HP:0002894', (199, 201))	('mutations', 'Var', (252, 261))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('harbored', 'Reg', (238, 246))	('Mayo', 'Species', '162683', (118, 122))	('Familial Pancreatic Cancer', 'Disease', 'MESH:D010190', (130, 156))
29937	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.	('PALB2', 'Gene', (121, 126))	('ATM', 'Gene', (146, 149))	('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))
29938	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))
29939	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))
29940	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))
29941	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))
29942	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))
29943	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))	('hereditary cancer syndrome', 'Disease', (110, 136))	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (110, 136))	('PC', 'Phenotype', 'HP:0002894', (141, 143))	('mutated', 'Var', (31, 38))
29944	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))
29947	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))
29948	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))
29952	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))
29954	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))	('fluorouracil', 'Chemical', 'MESH:D005472', (99, 111))	('MSH2', 'Gene', '4436', (257, 261))	('BRCA2', 'Gene', (243, 248))	('BRCA1', 'Gene', '672', (236, 241))
29961	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'))
29963	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))
29964	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))
29967	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))
29969	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))	('BRCA1', 'Gene', (90, 95))	('PALB2', 'Gene', (106, 111))	('platinum', 'Chemical', 'MESH:D010984', (292, 300))	('rucaparib', 'Chemical', 'MESH:C531549', (29, 38))
29970	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))	('olaparib', 'Chemical', 'MESH:C531550', (217, 225))	('mutation', 'Var', (96, 104))	('metastatic PC', 'Disease', (47, 60))	('BRCA1', 'Gene', '672', (84, 89))	('BRCA2', 'Gene', '675', (90, 95))	('BRCA1', 'Gene', (84, 89))	('PC', 'Phenotype', 'HP:0002894', (58, 60))	('platinum', 'Chemical', 'MESH:D010984', (155, 163))
29972	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))
29985	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))	('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))
30008	30684960	Vast majority of CRCs are thought to evolve from conventional adenomas through as a result of several dozens of mutations; this process is referred to as the adenoma-to-carcinoma sequence.	('CRCs', 'Disease', (17, 21))	('adenomas', 'Disease', (62, 70))	('CRC', 'Phenotype', 'HP:0003003', (17, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('mutations', 'Var', (112, 121))	('adenoma-to-carcinoma', 'Disease', (158, 178))	('adenoma-to-carcinoma', 'Disease', 'MESH:D000236', (158, 178))	('adenomas', 'Disease', 'MESH:D000236', (62, 70))
30010	30684960	A progressive accumulation of multiple genetic mutations contributes to transition from normal mucosa to benign adenoma, severe dysplasia, and eventually, a frank carcinoma.	('adenoma', 'Disease', 'MESH:D000236', (112, 119))	('frank carcinoma', 'Disease', (157, 172))	('frank carcinoma', 'Disease', 'MESH:D001946', (157, 172))	('adenoma', 'Disease', (112, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('dysplasia', 'Disease', (128, 137))	('mutations', 'Var', (47, 56))	('dysplasia', 'Disease', 'MESH:D004476', (128, 137))
30011	30684960	It is estimated that approximately 15% of sporadic colon cancers are a consequence of malfunction in mismatch repair genes, whereas other 80-85% are associated with mutations in adenomatous polyposis coli (APC) gene.	('malfunction', 'Var', (86, 97))	('APC', 'cellular_component', 'GO:0005680', ('206', '209'))	('colon cancers', 'Disease', (51, 64))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (178, 204))	('APC', 'Phenotype', 'HP:0005227', (206, 209))	('APC', 'Disease', 'MESH:D011125', (206, 209))	('adenomatous polyposis coli', 'Disease', (178, 204))	('colon cancers', 'Disease', 'MESH:D015179', (51, 64))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('colon cancers', 'Phenotype', 'HP:0003003', (51, 64))	('associated', 'Reg', (149, 159))	('APC', 'Disease', (206, 209))	('mismatch repair genes', 'Gene', (101, 122))	('colon cancer', 'Phenotype', 'HP:0003003', (51, 63))	('mutations', 'Var', (165, 174))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (178, 204))	('mismatch repair', 'biological_process', 'GO:0006298', ('101', '116'))
30013	30684960	Less than 50% of colon cancers harbor mutated KRAS, a protein that is involved in intracellular signal transduction.	('mutated', 'Var', (38, 45))	('colon cancers', 'Phenotype', 'HP:0003003', (17, 30))	('colon cancers', 'Disease', 'MESH:D015179', (17, 30))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('intracellular', 'cellular_component', 'GO:0005622', ('82', '95'))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('KRAS', 'Gene', (46, 50))	('colon cancer', 'Phenotype', 'HP:0003003', (17, 29))	('KRAS', 'Gene', '3845', (46, 50))	('intracellular signal transduction', 'biological_process', 'GO:0035556', ('82', '115'))	('colon cancers', 'Disease', (17, 30))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
30014	30684960	Approximately 50% of colonic lesions with high-grade dysplasia and about 75% of frank cancers may carry p53 mutations.	('p53', 'Gene', (104, 107))	('mutations', 'Var', (108, 117))	('colonic lesions', 'Disease', (21, 36))	('p53', 'Gene', '7157', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('frank cancers', 'Disease', 'MESH:D009369', (80, 93))	('dysplasia', 'Disease', (53, 62))	('colonic lesions', 'Disease', 'MESH:D003108', (21, 36))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('frank cancers', 'Disease', (80, 93))	('dysplasia', 'Disease', 'MESH:D004476', (53, 62))
30016	30684960	Two main genetic defects found in CRC, KRAS and p53 mutations, are both associated with enhanced proliferation.	('mutations', 'Var', (52, 61))	('p53', 'Gene', (48, 51))	('CRC', 'Phenotype', 'HP:0003003', (34, 37))	('p53', 'Gene', '7157', (48, 51))	('KRAS', 'Gene', (39, 43))	('KRAS', 'Gene', '3845', (39, 43))	('enhanced', 'PosReg', (88, 96))	('CRC', 'Gene', (34, 37))
30022	30684960	Many oncogenic mutations seem to affect glutamine metabolism, which may open new therapeutic perspectives.	('glutamine', 'Chemical', 'MESH:D005973', (40, 49))	('affect', 'Reg', (33, 39))	('mutations', 'Var', (15, 24))	('glutamine metabolism', 'MPA', (40, 60))
30063	30684960	Also position of the double bond within the PUFA molecule is vital from the functional perspective, since n-6 PUFA metabolites are generally proinflammatory whereas n-3 PUFAs act as anti-inflammatory compounds.	('PUFA', 'Gene', (44, 48))	('FAs', 'Chemical', 'MESH:D005227', (171, 174))	('PUFA', 'Gene', '9933', (110, 114))	('PUFA', 'Gene', '9933', (44, 48))	('PUFA', 'Gene', (110, 114))	('proinflammatory', 'MPA', (141, 156))	('PUFA', 'Gene', '9933', (169, 173))	('n-6', 'Var', (106, 109))	('PUFA', 'Gene', (169, 173))
30073	30684960	demonstrated that FASN knockdown results in downregulation of cancer invasion and spread in cell lines.	('spread in cell lines', 'CPA', (82, 102))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('downregulation', 'NegReg', (44, 58))	('knockdown', 'Var', (23, 32))	('FASN', 'Gene', (18, 22))	('FASN', 'Gene', '2194', (18, 22))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
30080	30684960	Substitution of cis-PUFAs and MUFAs with an equivalent amount of energy from dietary SFAs contributed to an increase in serum levels of total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides, although this effect was statistically significant only in the case of PUFA replacement.	('triglycerides', 'Chemical', 'MESH:D014280', (192, 205))	('PUFA', 'Gene', '9933', (278, 282))	('PUFA', 'Gene', (20, 24))	('FAs', 'Chemical', 'MESH:D005227', (32, 35))	('cholesterol', 'Chemical', 'MESH:D002784', (176, 187))	('cholesterol', 'Chemical', 'MESH:D002784', (159, 170))	('increase', 'PosReg', (108, 116))	('LDL', 'molecular_function', 'GO:0005322', ('172', '175'))	('FAs', 'Chemical', 'MESH:D005227', (86, 89))	('HDL', 'molecular_function', 'GO:0005321', ('155', '158'))	('triglycerides', 'MPA', (192, 205))	('FAs', 'Chemical', 'MESH:D005227', (22, 25))	('cholesterol', 'Chemical', 'MESH:D002784', (142, 153))	('HDL-cholesterol', 'MPA', (155, 170))	('Substitution', 'Var', (0, 12))	('PUFA', 'Gene', '9933', (20, 24))	('SFA', 'Chemical', 'MESH:D005227', (85, 88))	('LDL-cholesterol', 'MPA', (172, 187))	('PUFA', 'Gene', (278, 282))	('serum levels of total cholesterol', 'MPA', (120, 153))	('men', 'Species', '9606', (290, 293))
30089	30684960	Moreover, we found 26:0 cerotic acid exclusively in the sera of CRC patients, and hence, proposed it as a serum biomarker of this malignancy.	('malignancy', 'Disease', (130, 140))	('cerotic acid', 'Chemical', 'MESH:C017364', (24, 36))	('26:0', 'Var', (19, 23))	('patients', 'Species', '9606', (68, 76))	('found', 'Reg', (13, 18))	('malignancy', 'Disease', 'MESH:D009369', (130, 140))	('sera', 'molecular_function', 'GO:0004617', ('56', '60'))	('CRC', 'Phenotype', 'HP:0003003', (64, 67))
30100	30684960	Moreover, oleic acid was shown to decrease mRNA levels for some FA transporters and receptors and to reduce lipid droplet content in colonic adenocarcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('reduce', 'NegReg', (101, 107))	('lipid droplet content', 'MPA', (108, 129))	('colonic adenocarcinoma', 'Disease', (133, 155))	('decrease', 'NegReg', (34, 42))	('lipid', 'Chemical', 'MESH:D008055', (108, 113))	('mRNA levels', 'MPA', (43, 54))	('oleic acid', 'Var', (10, 20))	('colonic adenocarcinoma', 'Disease', 'MESH:D003110', (133, 155))	('oleic acid', 'Chemical', 'MESH:D019301', (10, 20))
30106	30684960	The relation between cancer mortality and activity of SCD-1, estimated on the basis of serum cholesteryl ester ratio of 16:1 n-7 and 16:0, and presence of a single nucleotide polymorphism in its gene, suggests that endogenous synthesis of MUFAs may exert an effect on cancer outcome.	('cancer', 'Disease', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('single nucleotide polymorphism', 'Var', (157, 187))	('activity', 'MPA', (42, 50))	('FAs', 'Chemical', 'MESH:D005227', (241, 244))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cholesteryl ester', 'Chemical', 'MESH:D002788', (93, 110))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('presence', 'Var', (143, 151))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('effect', 'Reg', (258, 264))
30109	30684960	Further, silencing of SCD-1 with siRNAs was shown to activate apoptosis in HCT116 cells.	('apoptosis', 'biological_process', 'GO:0097194', ('62', '71'))	('HCT116', 'CellLine', 'CVCL:0291', (75, 81))	('siRNAs', 'Gene', (33, 39))	('silencing', 'Var', (9, 18))	('apoptosis', 'biological_process', 'GO:0006915', ('62', '71'))	('SCD-1', 'Gene', (22, 27))	('apoptosis', 'CPA', (62, 71))	('activate', 'PosReg', (53, 61))
30138	30684960	Certain proportion of dietary 18:2 n-6 and 18:3 n-3 are converted to long-chain PUFAs by elongation and desaturation.	('PUFA', 'Gene', (80, 84))	('FAs', 'Chemical', 'MESH:D005227', (82, 85))	('PUFA', 'Gene', '9933', (80, 84))	('elongation', 'Var', (89, 99))
30145	30684960	In turn, commercially available supplements are racemates of cis-9, trans-11, trans-10 and cis-12 CLAs.	('men', 'Species', '9606', (38, 41))	('trans-11', 'Var', (68, 76))	('cis-9, trans-11, trans-10', 'Chemical', '-', (61, 86))	('cis-12 CLAs', 'Chemical', '-', (91, 102))	('cis-9', 'Var', (61, 66))	('cis-12', 'Var', (91, 97))	('trans-10', 'Var', (78, 86))
30160	30684960	However, 4-HNE may also exert an anticancerogenic effect, as it was shown to inhibit the activity of telomerase in Caco-2 and HT-29 cell lines.	('4-HNE', 'Var', (9, 14))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('Caco-2', 'CellLine', 'CVCL:0025', (115, 121))	('telomerase', 'Enzyme', (101, 111))	('inhibit', 'NegReg', (77, 84))	('cancer', 'Disease', (37, 43))	('HT-29', 'CellLine', 'CVCL:0320', (126, 131))	('4-HNE', 'Chemical', '-', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('activity', 'MPA', (89, 97))
30170	30684960	Previous studies demonstrated that concentration of prostaglandin PGE2 correlated positively with cancer stem cell (CSC) markers in human colorectal tumor samples; furthermore, PGE2 was shown to promote CSC expansion in a murine model.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('murine', 'Species', '10090', (222, 228))	('PGE2', 'Var', (177, 181))	('colorectal tumor', 'Disease', 'MESH:D015179', (138, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('prostaglandin', 'Chemical', 'MESH:D011453', (52, 65))	('PGE2', 'Chemical', 'MESH:D015232', (66, 70))	('promote', 'PosReg', (195, 202))	('cancer', 'Disease', (98, 104))	('human', 'Species', '9606', (132, 137))	('CSC expansion', 'CPA', (203, 216))	('PGE2', 'Chemical', 'MESH:D015232', (177, 181))	('colorectal tumor', 'Disease', (138, 154))
30185	30684960	Further studies demonstrated that a moiety with molecular mass of 446 (C28H46O4), referred to as GTA-446, may be a marker of CRC risk in healthy persons and is more sensitive than blood gFOBT.	('CRC', 'Disease', (125, 128))	('GTA', 'Chemical', '-', (97, 100))	('gFOBT', 'Chemical', '-', (186, 191))	('CRC', 'Phenotype', 'HP:0003003', (125, 128))	('C28H46O4', 'Chemical', '-', (71, 79))	('C28H46O4', 'Var', (71, 79))	('persons', 'Species', '9606', (145, 152))
30188	30684960	Thus, the structure of PLs determines physical properties of membrane bilayer; a change in the degree of saturation of FAs that build PLs may affect membrane fluidity and consequently, also its permeability.	('permeability', 'MPA', (194, 206))	('change', 'Var', (81, 87))	('PLs', 'Chemical', '-', (134, 137))	('membrane', 'cellular_component', 'GO:0016020', ('61', '69'))	('affect', 'Reg', (142, 148))	('membrane', 'cellular_component', 'GO:0016020', ('149', '157'))	('PLs', 'Chemical', '-', (23, 26))	('FAs', 'Chemical', 'MESH:D005227', (119, 122))	('membrane fluidity', 'MPA', (149, 166))
30194	30684960	Another signature of CRC seems to be a significant upregulation of PC-16:0/16:1, lysophosphatidylcholines LPC-16:0, LPC-18:1 and PC-16:0/18:1.	('upregulation', 'PosReg', (51, 63))	('PC-16:0/18:1', 'Var', (129, 141))	('LPC', 'Gene', '9159', (106, 109))	('CRC', 'Phenotype', 'HP:0003003', (21, 24))	('PC-16', 'CellLine', 'CVCL:7099', (107, 112))	('PC-16:0/16:1', 'Var', (67, 79))	('LPC', 'Gene', (116, 119))	('LPC', 'Gene', (106, 109))	('PC-16', 'CellLine', 'CVCL:7099', (129, 134))	('PC-16', 'CellLine', 'CVCL:7099', (67, 72))	('LPC', 'Gene', '9159', (116, 119))	('lysophosphatidylcholines', 'Chemical', 'MESH:D008244', (81, 105))
30195	30684960	The authors of one lipidomic study demonstrated considerable alterations of several complex plasma lipids in CRC patients, and based on the analysis of receiver operating characteristic (ROC) curve proposed phosphatidylglycerol PG-18:0/16:0, sphingomyelin SM-d18:1/24:1 (42:2), ceramide Cer-d18:1/26:4 (elevated), LPC-18:3, LPC-18:2, phosphorylethanolamines PE-18:2/18:1, PE-18:1/20:2 and SM-38:8 (decreased) as biomarkers of this malignancy.	('SM-38:8', 'Var', (389, 396))	('LPC', 'Gene', (314, 317))	('decreased', 'NegReg', (398, 407))	('lipid', 'Chemical', 'MESH:D008055', (99, 104))	('LPC', 'Gene', '9159', (324, 327))	('patients', 'Species', '9606', (113, 121))	('PE', 'Chemical', 'MESH:C005448', (358, 360))	('PE', 'Chemical', 'MESH:C005448', (372, 374))	('alterations', 'Reg', (61, 72))	('malignancy', 'Disease', (431, 441))	('amide', 'Chemical', 'MESH:D000577', (281, 286))	('LPC', 'Gene', '9159', (314, 317))	('malignancy', 'Disease', 'MESH:D009369', (431, 441))	('lipids', 'Chemical', 'MESH:D008055', (99, 105))	('lipid', 'Chemical', 'MESH:D008055', (19, 24))	('LPC', 'Gene', (324, 327))	('CRC', 'Phenotype', 'HP:0003003', (109, 112))
30200	30684960	In one study, cancer tissue contained elevated levels of PA-36:2 and less PA-38:3, PA-40:5, PE-38:4, sphingomyelins SM-22:0 and SM-22:4.	('cancer', 'Disease', (14, 20))	('PA', 'Chemical', 'MESH:D011478', (83, 85))	('sphingomyelins', 'MPA', (101, 115))	('PE-38:4', 'Var', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('PA', 'Chemical', 'MESH:D011478', (57, 59))	('PA-36:2', 'Var', (57, 64))	('PE', 'Chemical', 'MESH:C005448', (92, 94))	('PA', 'Chemical', 'MESH:D011478', (74, 76))	('elevated', 'PosReg', (38, 46))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('PA-40:5', 'Var', (83, 90))	('sphingomyelins', 'Chemical', 'MESH:D013109', (101, 115))
30203	30684960	CRC patients may present with elevated plasma levels of some glycosphingolipids containing glucose (Glu) or lactose (Lac), namely GluCer-42:3, GluCer-42:2, GluCer-36:4, GluCer-34:1, GluCer-33:2, LacCer-42:4, LacCer-40:1, LacCer-40:2, LacCer-40:4, LacCer-38:1 and LacCer-35:1.	('LacCer', 'Chemical', 'MESH:C009744', (221, 227))	('Lac', 'Chemical', 'MESH:D007785', (208, 211))	('LacCer-38:1', 'Var', (247, 258))	('plasma levels', 'MPA', (39, 52))	('Lac', 'Chemical', 'MESH:D007785', (263, 266))	('lactose', 'Chemical', 'MESH:D007785', (108, 115))	('LacCer', 'Chemical', 'MESH:C009744', (195, 201))	('elevated', 'PosReg', (30, 38))	('Glu', 'Chemical', 'MESH:D005947', (169, 172))	('GluCer', 'Chemical', '-', (182, 188))	('GluCer', 'Chemical', '-', (143, 149))	('Glu', 'Chemical', 'MESH:D005947', (130, 133))	('Lac', 'Chemical', 'MESH:D007785', (221, 224))	('glucose', 'Chemical', 'MESH:D005947', (91, 98))	('patients', 'Species', '9606', (4, 12))	('LacCer-40:4', 'Var', (234, 245))	('LacCer', 'Chemical', 'MESH:C009744', (234, 240))	('Lac', 'Chemical', 'MESH:D007785', (117, 120))	('GluCer-42:2', 'Var', (143, 154))	('LacCer', 'Chemical', 'MESH:C009744', (208, 214))	('Glu', 'Chemical', 'MESH:D005947', (182, 185))	('GluCer-36:4', 'Var', (156, 167))	('LacCer', 'Chemical', 'MESH:C009744', (263, 269))	('Glu', 'Chemical', 'MESH:D005947', (143, 146))	('GluCer', 'Chemical', '-', (156, 162))	('GluCer-34:1', 'Var', (169, 180))	('GluCer', 'Chemical', '-', (130, 136))	('LacCer', 'Chemical', 'MESH:C009744', (247, 253))	('CRC', 'Disease', (0, 3))	('Lac', 'Chemical', 'MESH:D007785', (195, 198))	('Lac', 'Chemical', 'MESH:D007785', (234, 237))	('GluCer-33:2', 'Var', (182, 193))	('CRC', 'Phenotype', 'HP:0003003', (0, 3))	('LacCer-40:1', 'Var', (208, 219))	('glycosphingolipids', 'Chemical', 'MESH:D006028', (61, 79))	('GluCer', 'Chemical', '-', (169, 175))	('LacCer-35:1', 'Var', (263, 274))	('Glu', 'Chemical', 'MESH:D005947', (100, 103))	('Lac', 'Chemical', 'MESH:D007785', (247, 250))	('GluCer-42:3', 'Var', (130, 141))	('Glu', 'Chemical', 'MESH:D005947', (156, 159))
30204	30684960	CRC tissues were shown to contain more Cer-16:0, Cer-24:0 and Cer-24:1, and less Cer-18:0 and Cer-22:0, as well as elevated mRNA levels for ceramidase synthases, CerS1, CerS2, CerS5 and CerS6.	('CerS5', 'Gene', (176, 181))	('elevated', 'PosReg', (115, 123))	('CRC', 'Phenotype', 'HP:0003003', (0, 3))	('Cer-16:0', 'Var', (39, 47))	('CerS2', 'Gene', '29956', (169, 174))	('CerS5', 'Gene', '91012', (176, 181))	('mRNA levels', 'MPA', (124, 135))	('Cer-24:1', 'Var', (62, 70))	('CerS6', 'Gene', '253782', (186, 191))	('CerS6', 'Gene', (186, 191))	('CerS2', 'Gene', (169, 174))	('Cer-22:0', 'Var', (94, 102))	('Cer-24:0', 'Var', (49, 57))	('CerS1', 'Gene', (162, 167))	('CerS1', 'Gene', '10715', (162, 167))	('ceramidase synthases', 'Enzyme', (140, 160))
30208	30684960	In CerS2-overexpressing cells, supplementation with nervonyl- or lignoceryl-CoA resulted in upregulation of very long chain-containing Cer species, Cer-24:0 and Cer-24:1, and enhanced proliferation.	('very long chain-containing Cer species', 'MPA', (108, 146))	('enhanced', 'PosReg', (175, 183))	('CerS2', 'Gene', (3, 8))	('proliferation', 'CPA', (184, 197))	('upregulation', 'PosReg', (92, 104))	('Cer-24:1', 'Var', (161, 169))	('Cer-24:0', 'MPA', (148, 156))	('men', 'Species', '9606', (37, 40))	('CerS2', 'Gene', '29956', (3, 8))
30213	30684960	The inhibition of SCD-1 in human adenocarcinoma LOVO cells was shown to be associated with a significant decrease in proliferation rate and accumulation of saturated endoceramides, Cer-16:0 to Cer-24:0.	('SCD-1', 'Gene', (18, 23))	('adenocarcinoma', 'Disease', 'MESH:D000230', (33, 47))	('proliferation rate', 'CPA', (117, 135))	('accumulation', 'PosReg', (140, 152))	('human', 'Species', '9606', (27, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('Cer-16:0', 'Var', (181, 189))	('adenocarcinoma', 'Disease', (33, 47))	('inhibition', 'NegReg', (4, 14))	('endoceramides', 'Chemical', '-', (166, 179))	('decrease', 'NegReg', (105, 113))
30219	30684960	SphK1 expression knockdown in colorectal adenocarcinoma cell lines was associated with a decrease in tumor cell migration and invasiveness, probably due to interference with epithelial-mesenchymal transition (EMT), a process observed during cancer progression and spread.	('epithelial-mesenchymal transition', 'CPA', (174, 207))	('interference', 'NegReg', (156, 168))	('colorectal adenocarcinoma', 'Disease', (30, 55))	('SphK1', 'Gene', '8877', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('SphK1', 'Gene', (0, 5))	('tumor', 'Disease', (101, 106))	('decrease', 'NegReg', (89, 97))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (30, 55))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('cancer', 'Disease', (241, 247))	('knockdown', 'Var', (17, 26))	('invasiveness', 'CPA', (126, 138))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
30261	30684960	Some of those alterations, such as accumulation of PC-16:0/16:1, may be considered as cancer biomarkers.	('accumulation', 'PosReg', (35, 47))	('PC-16', 'CellLine', 'CVCL:7099', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('PC-16:0/16:1', 'Var', (51, 63))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
30268	30098223	ABCA1 overexpression worsens colorectal cancer prognosis by facilitating tumour growth and caveolin-1-dependent invasiveness, and these effects can be ameliorated using the BET inhibitor apabetalone At the time of diagnosis, 20% of patients with colorectal cancer present metastasis.	('rectal cancer', 'Phenotype', 'HP:0100743', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('overexpression', 'Var', (6, 20))	('facilitating', 'PosReg', (60, 72))	('worsens', 'NegReg', (21, 28))	('colorectal cancer', 'Phenotype', 'HP:0003003', (29, 46))	('apabetalone', 'Chemical', 'MESH:C000628794', (187, 198))	('ABCA1', 'Gene', '19', (0, 5))	('BET', 'Gene', '92737', (173, 176))	('colorectal cancer', 'Disease', 'MESH:D015179', (246, 263))	('caveolin-1', 'Gene', (91, 101))	('tumour growth', 'Disease', 'MESH:D006130', (73, 86))	('caveolin-1', 'Gene', '857', (91, 101))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('colorectal cancer', 'Disease', (246, 263))	('colorectal cancer', 'Disease', 'MESH:D015179', (29, 46))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('colorectal cancer', 'Disease', (29, 46))	('metastasis', 'CPA', (272, 282))	('BET', 'Gene', (173, 176))	('patients', 'Species', '9606', (232, 240))	('rectal cancer', 'Phenotype', 'HP:0100743', (250, 263))	('tumour growth', 'Disease', (73, 86))	('ABCA1', 'Gene', (0, 5))	('colorectal cancer', 'Phenotype', 'HP:0003003', (246, 263))
30274	30098223	Thus, intracellular cholesterol imbalances mediated by ABCA1 overexpression may contribute to primary tumour growth and dissemination to distant locations.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('intracellular', 'cellular_component', 'GO:0005622', ('6', '19'))	('tumour growth', 'Disease', 'MESH:D006130', (102, 115))	('dissemination', 'CPA', (120, 133))	('imbalance', 'Phenotype', 'HP:0002172', (32, 41))	('imbalances', 'Phenotype', 'HP:0002172', (32, 42))	('ABCA1', 'Gene', '19', (55, 60))	('cholesterol', 'Chemical', 'MESH:D002784', (20, 31))	('cholesterol imbalances', 'Phenotype', 'HP:0003107', (20, 42))	('overexpression', 'Var', (61, 75))	('ABCA1', 'Gene', (55, 60))	('intracellular cholesterol imbalances', 'MPA', (6, 42))	('contribute', 'Reg', (80, 90))	('tumour growth', 'Disease', (102, 115))
30313	30098223	ab18180; Abcam); anti-apolipoprotein AI antibody (EP1368Y; Abcam.	('apolipoprotein AI', 'Gene', '335', (22, 39))	('antibody', 'cellular_component', 'GO:0042571', ('40', '48'))	('EP1368Y;', 'Var', (50, 58))	('apolipoprotein', 'molecular_function', 'GO:0005320', ('22', '36'))	('antibody', 'cellular_component', 'GO:0019814', ('40', '48'))	('antibody', 'cellular_component', 'GO:0019815', ('40', '48'))	('apolipoprotein AI', 'Gene', (22, 39))	('apolipoprotein', 'molecular_function', 'GO:0005319', ('22', '36'))	('antibody', 'molecular_function', 'GO:0003823', ('40', '48'))
30330	30098223	Notably, ABCA1 expression had a risk effect on overall survival, and the pooled Hazard ratio (HR) was 1.29 [95% confidence interval (CI) 0.99-1.69].	('expression', 'Var', (15, 25))	('ABCA1', 'Gene', '19', (9, 14))	('overall survival', 'MPA', (47, 63))	('ABCA1', 'Gene', (9, 14))
30331	30098223	In the same direction, expression of the cholesterol transporter increased risk of recurrence in patients from stages I to III [HR = 1.86 (95% CI 1.37-2.53) (Fernandez et al., 2017)].	('recurrence', 'Disease', (83, 93))	('patients', 'Species', '9606', (97, 105))	('cholesterol', 'Chemical', 'MESH:D002784', (41, 52))	('expression', 'Var', (23, 33))
30339	30098223	High levels of the transporter led to a significant increase in APOA1-dependent cholesterol efflux, demonstrating the functionality of exogenous ABCA1 (Fig.	('APOA1', 'Gene', (64, 69))	('cholesterol efflux', 'biological_process', 'GO:0033344', ('80', '98'))	('increase', 'PosReg', (52, 60))	('High levels', 'Var', (0, 11))	('ABCA1', 'Gene', '19', (145, 150))	('APOA1', 'Gene', '335', (64, 69))	('cholesterol', 'Chemical', 'MESH:D002784', (80, 91))	('ABCA1', 'Gene', (145, 150))
30340	30098223	Overexpression of ABCA1 resulted in a significant increase in cell proliferation (Fig.	('cell proliferation', 'biological_process', 'GO:0008283', ('62', '80'))	('ABCA1', 'Gene', '19', (18, 23))	('cell proliferation', 'CPA', (62, 80))	('increase', 'PosReg', (50, 58))	('ABCA1', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))
30362	30098223	We confirmed that CAV-1 protein levels were higher in cells overexpressing the cholesterol transporter, whereas mRNA levels were comparable to control cells (Figs 5A and S3A).	('cholesterol transporter', 'Var', (79, 102))	('higher', 'PosReg', (44, 50))	('CAV-1', 'Gene', (18, 23))	('cholesterol', 'Chemical', 'MESH:D002784', (79, 90))	('overexpressing', 'PosReg', (60, 74))	('CAV-1', 'Gene', '857', (18, 23))
30381	30098223	Together with these phenotypes, inhibition of CAV-1 provoked a highly significant decrease in the size of focal adhesions (Fig.	('decrease', 'NegReg', (82, 90))	('CAV-1', 'Gene', '857', (46, 51))	('inhibition', 'Var', (32, 42))	('CAV-1', 'Gene', (46, 51))
30394	30098223	APOA1 overexpression has been associated with the inhibition of COX-2 expression in hepatocytes (Mao et al., 2014); as COX-2 inhibition is known to be able to downregulate both ABCA1 mRNA and protein (Chan et al., 2007), we analyzed the levels of the COX-2 in our model.	('COX-2', 'Gene', '5743', (251, 256))	('APOA1', 'Gene', (0, 5))	('ABCA1', 'Gene', (177, 182))	('protein', 'Protein', (192, 199))	('APOA1', 'Gene', '335', (0, 5))	('ABCA1', 'Gene', '19', (177, 182))	('mRNA and', 'MPA', (183, 191))	('COX-2', 'Gene', (119, 124))	('downregulate', 'NegReg', (159, 171))	('COX-2', 'Gene', (64, 69))	('COX-2', 'Gene', '5743', (64, 69))	('inhibition', 'Var', (125, 135))	('COX-2', 'Gene', '5743', (119, 124))	('COX-2', 'Gene', (251, 256))
30399	30098223	While this manuscript was in preparation, apabetalone was entered in a Phase 3 clinical trial for high-risk cardiovascular disease (CVD) patients with type 2 diabetes mellitus and low HDL (BETonMACE).	('HDL', 'MPA', (184, 187))	('low HDL', 'Phenotype', 'HP:0003233', (180, 187))	('BETonMACE', 'Gene', (189, 198))	('low', 'Var', (180, 183))	('type 2 diabetes mellitus', 'Disease', 'MESH:D003924', (151, 175))	('BETonMACE', 'Gene', '92737', (189, 198))	('cardiovascular disease', 'Disease', (108, 130))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (158, 175))	('apabetalone', 'Chemical', 'MESH:C000628794', (42, 53))	('patients', 'Species', '9606', (137, 145))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (108, 130))	('CVD', 'Disease', 'None', (132, 135))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (151, 166))	('cardiovascular disease', 'Disease', 'MESH:D002318', (108, 130))	('CVD', 'Disease', (132, 135))	('type 2 diabetes mellitus', 'Disease', (151, 175))
30403	30098223	Thus, RVX-208 could revert the EMT phenotype present in cells overexpressing the cholesterol transporter.	('EMT phenotype', 'CPA', (31, 44))	('cholesterol', 'Chemical', 'MESH:D002784', (81, 92))	('RVX-208', 'Var', (6, 13))	('RVX-208', 'Chemical', 'MESH:C000628794', (6, 13))
30406	30098223	Moreover, RVX-208 compromised the stability of CAV-1, causing a reduction in its total protein levels (Fig.	('stability', 'MPA', (34, 43))	('RVX-208', 'Var', (10, 17))	('compromised', 'NegReg', (18, 29))	('total protein levels', 'MPA', (81, 101))	('reduction', 'NegReg', (64, 73))	('CAV-1', 'Gene', '857', (47, 52))	('RVX-208', 'Chemical', 'MESH:C000628794', (10, 17))	('CAV-1', 'Gene', (47, 52))
30424	30098223	The increased amount of cholesterol in the membrane derived from ABCA1 overexpression could affect the size of raft domains and the composition of the membrane, its fluidity and flexibility, with consequential implications for cell mobility and cell signalling (Guerra et al., 2016).	('flexibility', 'MPA', (178, 189))	('composition of the membrane', 'MPA', (132, 159))	('ABCA1', 'Gene', '19', (65, 70))	('membrane', 'cellular_component', 'GO:0016020', ('151', '159'))	('size of raft domains', 'MPA', (103, 123))	('cholesterol', 'Chemical', 'MESH:D002784', (24, 35))	('affect', 'Reg', (92, 98))	('ABCA1', 'Gene', (65, 70))	('membrane', 'cellular_component', 'GO:0016020', ('43', '51'))	('fluidity', 'MPA', (165, 173))	('overexpression', 'Var', (71, 85))	('signalling', 'biological_process', 'GO:0023052', ('250', '260'))	('increased', 'PosReg', (4, 13))	('implications', 'Reg', (210, 222))
30436	30098223	2011, 2006, 2012, 2003Lower serum APOA1 levels were also associated with higher risk of breast cancer as well as breast cancer recurrence (Chang et al., 2007) (Lane et al., 1995).	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('APOA1', 'Gene', (34, 39))	('serum', 'MPA', (28, 33))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('APOA1', 'Gene', '335', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('2003Lower', 'Var', (18, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
30439	30098223	Consistent with our results demonstrating that hAPOA1 treatment attenuates ABCA1-driven phenotypes, we also showed that, through APOA1 up-regulation, RVX-208 diminishes cell malignancy in CRC-derived cells.	('malignancy', 'Disease', 'MESH:D009369', (174, 184))	('diminishes', 'NegReg', (158, 168))	('RVX-208', 'Chemical', 'MESH:C000628794', (150, 157))	('ABCA1', 'Gene', '19', (75, 80))	('malignancy', 'Disease', (174, 184))	('ABCA1', 'Gene', (75, 80))	('APOA1', 'Gene', (48, 53))	('APOA1', 'Gene', '335', (129, 134))	('up-regulation', 'PosReg', (135, 148))	('hAPOA1', 'Gene', '335', (47, 53))	('RVX-208', 'Var', (150, 157))	('hAPOA1', 'Gene', (47, 53))	('APOA1', 'Gene', '335', (48, 53))	('APOA1', 'Gene', (129, 134))	('attenuates', 'NegReg', (64, 74))
30456	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))	('integration', 'MPA', (211, 222))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('integrity', 'MPA', (170, 179))	('mutated', 'Var', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
30457	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'))
30465	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))	('cancer', 'Disease', (151, 157))	('promoted', 'PosReg', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('uptake', 'MPA', (141, 147))
30478	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))
30484	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))	('expression', 'MPA', (45, 55))	('cancer', 'Disease', (150, 156))	('uptake', 'MPA', (140, 146))	('promoted', 'PosReg', (24, 32))	('increased', 'PosReg', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
30556	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.	('mutations', 'Var', (66, 75))	('cancer', 'Disease', (145, 151))	('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))	('oncosuppressor gene', 'Gene', (46, 65))	('cargo', 'MPA', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('allow', 'Reg', (139, 144))	('deliver', 'MPA', (180, 187))
30560	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))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('interact', 'Interaction', (91, 99))	('BRCA1', 'Gene', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
30562	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))	('cancer', 'Disease', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('increased', 'PosReg', (212, 221))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
30600	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))
30601	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.	('EPCAM', 'Gene', '4072', (210, 215))	('aggressiveness', 'Disease', (154, 168))	('dynamin', 'Protein', (177, 184))	('integrins', 'Protein', (186, 195))	('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))
30603	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))	('metastatic event', 'CPA', (207, 223))	('malignant transformation at distance', 'CPA', (152, 188))	('active uptake', 'MPA', (69, 82))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('enable', 'PosReg', (58, 64))	('cancer', 'Disease', (86, 92))
30606	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.	('mutations', 'Var', (100, 109))	('dysplastic', 'Disease', (195, 205))	('dysplastic', 'Disease', 'MESH:D004416', (195, 205))	('carcinogenesis', 'Disease', 'MESH:D063646', (21, 35))	('carcinogenesis', 'Disease', (21, 35))
30609	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))
30659	27074564	The pooled overall OR for NEO was 0.94 (95% CI: 0.89-0.96; p = 0.03; I2 = 62.3%, p = 0.01), indicating that neoadjuvant chemotherapy increased the incidence of post-operative complication rate after hepatic resection, as compared to SG (Supplementary Figure 4).	('NEO', 'Chemical', '-', (26, 29))	('hepatic', 'Disease', (199, 206))	('increased', 'PosReg', (133, 142))	('neoadjuvant', 'Var', (108, 119))	('post-operative complication', 'MPA', (160, 187))
30683	27074564	KRAS mutation status is a prognostic factor in patients undergoing resection of CRLM, irrespective of chemotherapy regimen.	('KRAS', 'Gene', (0, 4))	('patients', 'Species', '9606', (47, 55))	('mutation', 'Var', (5, 13))	('KRAS', 'Gene', '3845', (0, 4))
30693	26867160	Long-term use of lithium and risk of colorectal adenocarcinoma: a nationwide case-control study Lithium accumulates in the colon and inhibits the enzyme GSK-3beta that possesses anti-carcinogenic effects.	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (37, 62))	('Lithium', 'Chemical', 'MESH:D008094', (96, 103))	('GSK-3beta', 'Gene', '2932', (153, 162))	('GSK-3beta', 'Gene', (153, 162))	('carcinogenic', 'Disease', 'MESH:D063646', (183, 195))	('lithium', 'Chemical', 'MESH:D008094', (17, 24))	('carcinogenic', 'Disease', (183, 195))	('Lithium', 'Var', (96, 103))	('colorectal adenocarcinoma', 'Disease', (37, 62))	('inhibits', 'NegReg', (133, 141))	('accumulates', 'PosReg', (104, 115))
30703	26867160	Tumour cells from mice with adenomatous polyposis coli mutant-multiple intestinal neoplasia (Min) express increased ENaC activity, and when treated with lithium these mice develop larger tumours.	('tumours', 'Disease', 'MESH:D009369', (187, 194))	('lithium', 'Chemical', 'MESH:D008094', (153, 160))	('activity', 'MPA', (121, 129))	('intestinal neoplasia', 'Disease', 'MESH:D009369', (71, 91))	('neoplasia', 'Phenotype', 'HP:0002664', (82, 91))	('ENaC', 'Enzyme', (116, 120))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('mutant-multiple', 'Var', (55, 70))	('increased', 'PosReg', (106, 115))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (28, 54))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (28, 54))	('adenomatous polyposis coli', 'Disease', (28, 54))	('mice', 'Species', '10090', (18, 22))	('mice', 'Species', '10090', (167, 171))	('multiple intestinal neoplasia', 'Phenotype', 'HP:0200008', (62, 91))	('intestinal neoplasia', 'Disease', (71, 91))	('tumours', 'Disease', (187, 194))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (28, 49))	('tumours', 'Phenotype', 'HP:0002664', (187, 194))
30786	25897964	Recently, it was reported that MDSCs suppressed antitumour immune responses and promoted cancer cell proliferation and metastasis by inducing epithelial to mesenchymal transition.	('promoted', 'PosReg', (80, 88))	('inducing', 'PosReg', (133, 141))	('antitumour immune responses', 'CPA', (48, 75))	('MDSCs', 'Var', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('metastasis', 'CPA', (119, 129))	('cancer', 'Disease', (89, 95))	('epithelial to mesenchymal transition', 'CPA', (142, 178))	('suppressed', 'NegReg', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
30814	25897964	Spleen and tumors were collected and cut into small pieces before incubation for 15 min at 37 C with the following enzymes dissolved in HBSS: collagenase Type I (0.05 mg/ml), collagenase Type IV (0.05 mg/ml), hyaluronidase (0.025 mg/ml), and DNase I (0.01 mg/ml) and soybean trypsin inhibitor (0.2 trypsin inhibitor unit/ml).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (11, 17))	('0.025', 'Var', (224, 229))	('0.05', 'Var', (196, 200))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('soybean', 'Species', '3847', (267, 274))	('0.05', 'Var', (162, 166))
30853	25897964	Intense nuclear staining for p53 (CM5 clone: detects both mutant and wild-type forms) was detected in the neoplastic epithelium and in nondysplastic crypts; an observation that is highly suggestive of p53 mutations.	('mutant', 'Var', (58, 64))	('ser', 'Chemical', 'MESH:D012694', (162, 165))	('p53', 'Gene', (201, 204))	('mutations', 'Var', (205, 214))	('neoplastic epithelium', 'Phenotype', 'HP:0031492', (106, 127))
30858	25897964	AT1, but not GRc, significantly decreased cell viability in a time-and dose-dependent manner.	('cell viability', 'CPA', (42, 56))	('GRc', 'Chemical', 'MESH:C044462', (13, 16))	('AT1', 'Chemical', '-', (0, 3))	('AT1', 'Var', (0, 3))	('decreased', 'NegReg', (32, 41))
30867	25897964	Furthermore, the other three EMT markers, N-cad, Fibronectin and Vimentin were strongly expressed in model group and were decreased by SBS significantly (Figure 6A, Table 2).	('SBS', 'Chemical', '-', (135, 138))	('Vimentin', 'Gene', (65, 73))	('EMT', 'biological_process', 'GO:0001837', ('29', '32'))	('Vimentin', 'Gene', '7431', (65, 73))	('N-cad', 'Gene', (42, 47))	('Fibronectin', 'Gene', '2335', (49, 60))	('Vimentin', 'cellular_component', 'GO:0045098', ('65', '73'))	('N-cad', 'Gene', '1000', (42, 47))	('Fibronectin', 'Gene', (49, 60))	('SBS', 'Var', (135, 138))	('Vimentin', 'cellular_component', 'GO:0045099', ('65', '73'))	('decreased', 'NegReg', (122, 131))
30869	25897964	We also found that upregulation of Snail, a transcription factor that plays a pivotal role in the formation of EMT, was decreased by SBS (Figure 6B, Table 3).	('decreased', 'NegReg', (120, 129))	('SBS', 'Var', (133, 136))	('SBS', 'Chemical', '-', (133, 136))	('upregulation', 'PosReg', (19, 31))	('Snail', 'Gene', '6615', (35, 40))	('Snail', 'Gene', (35, 40))
30892	25897964	AOM is known to induce mutations in exon 3 of Ctnnb, which causes constitutive activation of the Wnt pathway by stabilizing beta-catenin.	('Wnt pathway', 'Pathway', (97, 108))	('AOM', 'Disease', (0, 3))	('mutations in', 'Var', (23, 35))	('AOM', 'Disease', 'MESH:C537492', (0, 3))	('stabilizing', 'NegReg', (112, 123))	('beta-catenin', 'MPA', (124, 136))	('activation', 'PosReg', (79, 89))	('Ctnnb', 'Gene', '1499', (46, 51))	('Ctnnb', 'Gene', (46, 51))
30893	25897964	So, various mutations around the GSK-3beta phosphorylation sites on beta-catenin combined with the upregulation of TGF-beta might be causative to beta-catenin accumulation in our study.	('TGF-beta', 'Gene', '7040', (115, 123))	('phosphorylation', 'biological_process', 'GO:0016310', ('43', '58'))	('mutations', 'Var', (12, 21))	('GSK-3beta', 'Gene', (33, 42))	('upregulation', 'PosReg', (99, 111))	('TGF-beta', 'Gene', (115, 123))	('GSK-3beta', 'Gene', '2932', (33, 42))	('beta-catenin', 'Protein', (68, 80))	('GSK', 'molecular_function', 'GO:0050321', ('33', '36'))
31033	24370906	There was a trend toward shorter progression-free survival in patients with subcentimeter pulmonary nodules compared with those without.	('progression-free survival', 'CPA', (33, 58))	('shorter', 'NegReg', (25, 32))	('subcentimeter pulmonary nodules', 'Var', (76, 107))	('patients', 'Species', '9606', (62, 70))
31236	31558870	CRT induces the necrosis of neoplastic tissue as well as reductions in cellular density and metabolism, increases in the extracellular space and the suppression of neoangiogenesis (Figure 4); these phenomena can be investigated via PA of tomographic images.	('necrosis', 'Disease', 'MESH:D009336', (16, 24))	('men', 'Species', '9606', (203, 206))	('suppression', 'NegReg', (149, 160))	('neoangiogenesis', 'CPA', (164, 179))	('increases', 'PosReg', (104, 113))	('reductions', 'NegReg', (57, 67))	('extracellular space', 'MPA', (121, 140))	('cellular density', 'CPA', (71, 87))	('metabolism', 'CPA', (92, 102))	('necrosis', 'Disease', (16, 24))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (28, 45))	('CRT', 'Var', (0, 3))
31306	31558870	Muralidharan et al reported that high MTV and TLG values for CRLMs before surgical resection were significantly associated with poorer recurrence-free survival (RFS) and OS, while the SUVmax and SUVmean did not show any significant predictive ability.	('recurrence-free survival', 'CPA', (135, 159))	('high', 'Var', (33, 37))	('CRLMs', 'Disease', (61, 66))	('CRLMs', 'Disease', 'MESH:D009362', (61, 66))	('poorer', 'NegReg', (128, 134))	('TLG', 'MPA', (46, 49))	('MTV', 'MPA', (38, 41))
31343	31558870	Liu et al reported that entropy values calculated by using ADC maps were significantly higher in pN1-2 than in pN0 RC.	('RC', 'Phenotype', 'HP:0100743', (115, 117))	('pN1-2', 'Var', (97, 102))	('entropy values', 'MPA', (24, 38))	('RC', 'Disease', 'MESH:D012004', (115, 117))	('higher', 'PosReg', (87, 93))
31344	31558870	Similarly, Zhu et al reported significantly higher kurtosis values calculated by using DWI in pN1-2 compared to pN0 RC.	('RC', 'Phenotype', 'HP:0100743', (116, 118))	('higher', 'PosReg', (44, 50))	('DWI', 'Var', (87, 90))	('kurtosis values', 'MPA', (51, 66))	('RC', 'Disease', 'MESH:D012004', (116, 118))
31400	31558870	The K-ras gene mutation is an independent prognostic factor for survival and a negative predictive marker of tumor responses to drugs that target anti-epidermal growth factor receptors (EGFRs).	('mutation', 'Var', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('anti-epidermal', 'Protein', (146, 160))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('K-ras', 'Gene', (4, 9))	('tumor', 'Disease', (109, 114))
31401	31558870	Shin et al reported that the frequency of K-ras mutations was higher in polypoid tumors with a larger axial to longitudinal dimension ratio.	('K-ras', 'Protein', (42, 47))	('men', 'Species', '9606', (126, 129))	('mutations', 'Var', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('polypoid tumors', 'Disease', 'MESH:D009369', (72, 87))	('polypoid tumors', 'Disease', (72, 87))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('higher', 'Reg', (62, 68))
31402	31558870	Using an animal model, Miles et al reported that the combined multiparametric assessment of 18F-FDG uptake (expressed as SUVmax), CT texture (expressed as the mean value of tumor pixels with positive values) and perfusion (expressed as BF) has excellent accuracy (90.1%) in the identification of CRCs with K-ras mutations.	('K-ras', 'Gene', (306, 311))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('CRC', 'Phenotype', 'HP:0003003', (296, 299))	('RC', 'Phenotype', 'HP:0100743', (297, 299))	('CRC', 'Disease', 'MESH:D015179', (296, 299))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('men', 'Species', '9606', (84, 87))	('FDG', 'Gene', '23583', (96, 99))	('mutations', 'Var', (312, 321))	('FDG', 'Gene', (96, 99))	('CRC', 'Disease', (296, 299))
31425	28296564	AZD1775 induces toxicity through double-stranded DNA breaks independently of chemotherapeutic agents in p53-mutated colorectal cancer cells AZD1775 is a small molecule WEE1 inhibitor used in combination with DNA-damaging agents to cause premature mitosis and cell death in p53-mutated cancer cells.	('p53', 'Gene', '7157', (104, 107))	('DNA', 'cellular_component', 'GO:0005574', ('49', '52'))	('p53', 'Gene', (273, 276))	('premature mitosis', 'Disease', (237, 254))	('DNA', 'cellular_component', 'GO:0005574', ('208', '211'))	('WEE1', 'Gene', '7465', (168, 172))	('colorectal cancer', 'Phenotype', 'HP:0003003', (116, 133))	('toxicity', 'Disease', 'MESH:D064420', (16, 24))	('p53', 'Gene', (104, 107))	('AZD1775', 'Chemical', 'MESH:C549567', (140, 147))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', (285, 291))	('AZD1775', 'Var', (140, 147))	('toxicity', 'Disease', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('colorectal cancer', 'Disease', 'MESH:D015179', (116, 133))	('premature mitosis', 'Disease', 'MESH:C536271', (237, 254))	('cell death', 'CPA', (259, 269))	('WEE1', 'Gene', (168, 172))	('cell death', 'biological_process', 'GO:0008219', ('259', '269'))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('colorectal cancer', 'Disease', (116, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('p53', 'Gene', '7157', (273, 276))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('mitosis', 'biological_process', 'GO:0000278', ('247', '254'))
31426	28296564	Here we sought to determine the mechanism of action of AZD1775 in combination with chemotherapeutic agents in light of recent findings that AZD1775 can cause double-stranded DNA (DS-DNA) breaks.	('AZD1775', 'Var', (140, 147))	('AZD1775', 'Chemical', 'MESH:C549567', (140, 147))	('AZD1775', 'Chemical', 'MESH:C549567', (55, 62))	('DNA', 'cellular_component', 'GO:0005574', ('174', '177'))	('cause', 'Reg', (152, 157))	('DNA', 'cellular_component', 'GO:0005574', ('182', '185'))
31427	28296564	AZD1775 significantly improved the cytotoxicity of 5-FU in a p53-mutated colorectal cancer cell line (HT29 cells), decreasing the IC50 from 9.3 muM to 3.5 muM.	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('AZD1775', 'Var', (0, 7))	('5-FU', 'Chemical', 'MESH:D005472', (51, 55))	('colorectal cancer', 'Disease', (73, 90))	('IC50', 'MPA', (130, 134))	('decreasing', 'NegReg', (115, 125))	('muM', 'Gene', '56925', (144, 147))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('muM', 'Gene', (144, 147))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('HT29 cells', 'CellLine', 'CVCL:0320', (102, 112))	('improved', 'PosReg', (22, 30))	('p53', 'Gene', '7157', (61, 64))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('muM', 'Gene', '56925', (155, 158))	('muM', 'Gene', (155, 158))	('cytotoxicity', 'Disease', (35, 47))	('p53', 'Gene', (61, 64))	('cytotoxicity', 'Disease', 'MESH:D064420', (35, 47))
31431	28296564	In conclusion, AZD1775 enhances 5-FU cytotoxicity through increased DS-DNA breaks, not premature mitosis, in p53-mutated colorectal cancer cells.	('cytotoxicity', 'Disease', (37, 49))	('DS-DNA breaks', 'MPA', (68, 81))	('increased', 'PosReg', (58, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('enhances', 'PosReg', (23, 31))	('cytotoxicity', 'Disease', 'MESH:D064420', (37, 49))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('p53', 'Gene', (109, 112))	('colorectal cancer', 'Disease', (121, 138))	('AZD1775', 'Var', (15, 22))	('premature mitosis', 'Disease', (87, 104))	('p53', 'Gene', '7157', (109, 112))	('premature mitosis', 'Disease', 'MESH:C536271', (87, 104))	('5-FU', 'Chemical', 'MESH:D005472', (32, 36))	('AZD1775', 'Chemical', 'MESH:C549567', (15, 22))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))
31441	28296564	This is thought to be particularly effective in cancers with non-functioning p53 (a key component of the G1 checkpoint) as these cells are more reliant on the G2/M checkpoint for DNA repair.	('cancers', 'Disease', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('DNA repair', 'biological_process', 'GO:0006281', ('179', '189'))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('DNA', 'cellular_component', 'GO:0005574', ('179', '182'))	('non-functioning', 'Var', (61, 76))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('G2/M checkpoint', 'biological_process', 'GO:0000075', ('159', '174'))
31443	28296564	Currently there are over 25 clinical trials assessing AZD1775 (a small molecule WEE1 inhibitor) in combination with DNA-damaging agents in a range of cancers (Clinical Trails.gov Accessed August 2016).	('range of cancers', 'Disease', (141, 157))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('WEE1', 'Gene', (80, 84))	('WEE1', 'Gene', '7465', (80, 84))	('AZD1775', 'Var', (54, 61))	('range of cancers', 'Disease', 'MESH:D009369', (141, 157))	('AZD1775', 'Chemical', 'MESH:C549567', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
31444	28296564	Interestingly, several studies have demonstrated that AZD1775 has anti-cancer activity independent of p53 function.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('AZD1775', 'Var', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('p53', 'Gene', (102, 105))	('p53', 'Gene', '7157', (102, 105))	('AZD1775', 'Chemical', 'MESH:C549567', (54, 61))
31449	28296564	Whether or not AZD1775 increases the sensitivity of p53-mutated and wild type cancer cells to DNA-damaging therapies and the mechanism by which it achieves this sensitization are unanswered questions.	('AZD1775', 'Chemical', 'MESH:C549567', (15, 22))	('type cancer', 'Disease', (73, 84))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('AZD1775', 'Var', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('type cancer', 'Disease', 'MESH:D009369', (73, 84))	('increases', 'PosReg', (23, 32))	('sensitivity', 'MPA', (37, 48))
31451	28296564	In the majority of current clinical trials AZD1775 is administered following DNA-damaging treatment to cause mitotic catastrophe and cancer cell death.	('AZD1775', 'Chemical', 'MESH:C549567', (43, 50))	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('mitotic catastrophe and cancer cell death', 'Disease', 'MESH:D002388', (109, 150))	('mitotic catastrophe', 'biological_process', 'GO:0070270', ('109', '128'))	('cell death', 'biological_process', 'GO:0008219', ('140', '150'))	('cause', 'PosReg', (103, 108))	('AZD1775', 'Var', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
31455	28296564	Combination treatment showed an enhancing effect of AZD1775 at low doses of 5-FU, slightly increased maximum response to 5-FU and reduction in the 5-FU IC50 from 9.3 muM to 3.5 muM (Fig.	('enhancing', 'PosReg', (32, 41))	('muM', 'Gene', (166, 169))	('maximum response to 5-FU', 'MPA', (101, 125))	('5-FU', 'Chemical', 'MESH:D005472', (147, 151))	('5-FU IC50', 'MPA', (147, 156))	('AZD1775', 'Var', (52, 59))	('muM', 'Gene', '56925', (177, 180))	('reduction', 'NegReg', (130, 139))	('AZD1775', 'Chemical', 'MESH:C549567', (52, 59))	('5-FU', 'Chemical', 'MESH:D005472', (76, 80))	('5-FU', 'Chemical', 'MESH:D005472', (121, 125))	('muM', 'Gene', '56925', (166, 169))	('increased', 'PosReg', (91, 100))	('muM', 'Gene', (177, 180))
31456	28296564	When used in combination with oxaliplatin, AZD1775 decreased cell viability at low doses of oxaliplatin, but not higher doses (Fig.	('AZD1775', 'Chemical', 'MESH:C549567', (43, 50))	('cell viability', 'CPA', (61, 75))	('decreased', 'NegReg', (51, 60))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (30, 41))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (92, 103))	('AZD1775', 'Var', (43, 50))
31458	28296564	Similarly, with irinotecan and AZD1775 combination therapy, cell viability was decreased at lower doses of irinotecan but not higher doses (Fig.	('cell viability', 'CPA', (60, 74))	('irinotecan', 'Chemical', 'MESH:D000077146', (16, 26))	('decreased', 'NegReg', (79, 88))	('AZD1775', 'Chemical', 'MESH:C549567', (31, 38))	('irinotecan', 'Chemical', 'MESH:D000077146', (107, 117))	('AZD1775 combination', 'Var', (31, 50))	('combination', 'Var', (39, 50))
31459	28296564	Overall, the data suggest that 5-FU cytotoxicity is improved with AZD1775 addition, but both oxaliplatin and irinotecan treatments are only improved at low concentrations.	('AZD1775', 'Var', (66, 73))	('AZD1775', 'Chemical', 'MESH:C549567', (66, 73))	('cytotoxicity', 'Disease', 'MESH:D064420', (36, 48))	('improved', 'PosReg', (52, 60))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (93, 104))	('irinotecan', 'Chemical', 'MESH:D000077146', (109, 119))	('5-FU', 'Chemical', 'MESH:D005472', (31, 35))	('cytotoxicity', 'Disease', (36, 48))
31461	28296564	To further investigate the mechanism by which AZD1775 addition enhances chemotherapy cytotoxicity, we focused on concentrations of 1 muM 5-FU and 300 nM AZD1775 as this resulted in a 31% reduction in HT29 viability compared with 1 muM 5-FU alone (Fig.	('muM', 'Gene', (133, 136))	('HT29', 'CellLine', 'CVCL:0320', (200, 204))	('AZD1775', 'Chemical', 'MESH:C549567', (46, 53))	('reduction', 'NegReg', (187, 196))	('AZD1775', 'Var', (153, 160))	('cytotoxicity', 'Disease', (85, 97))	('muM', 'Gene', '56925', (231, 234))	('HT29 viability', 'CPA', (200, 214))	('enhances', 'PosReg', (63, 71))	('AZD1775', 'Var', (46, 53))	('AZD1775', 'Chemical', 'MESH:C549567', (153, 160))	('muM', 'Gene', '56925', (133, 136))	('cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))	('5-FU', 'Chemical', 'MESH:D005472', (235, 239))	('muM', 'Gene', (231, 234))	('5-FU', 'Chemical', 'MESH:D005472', (137, 141))
31463	28296564	With AZD1775 addition, pCDK1-Y15 was significantly reduced as WEE1 was prevented from phosphorylating CDK1 (Fig.	('WEE1', 'Gene', '7465', (62, 66))	('reduced', 'NegReg', (51, 58))	('CDK1', 'Gene', '983', (102, 106))	('CDK1', 'Gene', (102, 106))	('CDK1', 'Gene', '983', (24, 28))	('CDK1', 'Gene', (24, 28))	('AZD1775', 'Var', (5, 12))	('WEE1', 'Gene', (62, 66))	('AZD1775', 'Chemical', 'MESH:C549567', (5, 12))
31468	28296564	The data suggest that AZD1775 alters CDK1 activity and is able to increase the number of 5-FU treated HT29 cells in S Phase and G2/M Phase.	('increase', 'PosReg', (66, 74))	('CDK', 'molecular_function', 'GO:0004693', ('37', '40'))	('CDK1', 'Gene', (37, 41))	('activity', 'MPA', (42, 50))	('alters', 'Reg', (30, 36))	('G2/M Phase', 'Gene', (128, 138))	('CDK1', 'Gene', '983', (37, 41))	('5-FU', 'Chemical', 'MESH:D005472', (89, 93))	('S Phase', 'CPA', (116, 123))	('S Phase', 'biological_process', 'GO:0051320', ('116', '123'))	('M Phase', 'biological_process', 'GO:0000279', ('131', '138'))	('HT29 cells', 'CellLine', 'CVCL:0320', (102, 112))	('G2/M Phase', 'Gene', '200575', (128, 138))	('AZD1775', 'Var', (22, 29))	('AZD1775', 'Chemical', 'MESH:C549567', (22, 29))
31472	28296564	In contrast, levels of mitosis peaked 8 hrs after AZD1775 addition at 56.2% compared with 3.4% in 5-FU alone.	('mitosis', 'Disease', (23, 30))	('mitosis', 'Disease', 'None', (23, 30))	('AZD1775', 'Var', (50, 57))	('AZD1775', 'Chemical', 'MESH:C549567', (50, 57))	('5-FU', 'Chemical', 'MESH:D005472', (98, 102))
31475	28296564	The data suggest that AZD1775 can induce both mitosis and DS-DNA breaks in cells pre-treated with 5-FU.	('AZD1775', 'Chemical', 'MESH:C549567', (22, 29))	('induce', 'PosReg', (34, 40))	('mitosis', 'biological_process', 'GO:0000278', ('46', '53'))	('mitosis', 'Disease', (46, 53))	('mitosis', 'Disease', 'None', (46, 53))	('pre', 'molecular_function', 'GO:0003904', ('81', '84'))	('DNA', 'cellular_component', 'GO:0005574', ('61', '64'))	('AZD1775', 'Var', (22, 29))	('DS-DNA breaks', 'CPA', (58, 71))	('5-FU', 'Chemical', 'MESH:D005472', (98, 102))
31490	28296564	This study shows that when AZD1775 is used in combination with 5-FU against a p53-mutated colorectal cancer cell line the enhanced cytotoxicity is due to AZD1775 causing increased DS-DNA breaks, not premature mitosis.	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('enhanced', 'PosReg', (122, 130))	('cytotoxicity', 'Disease', 'MESH:D064420', (131, 143))	('colorectal cancer', 'Disease', (90, 107))	('AZD1775', 'Chemical', 'MESH:C549567', (154, 161))	('AZD1775', 'Chemical', 'MESH:C549567', (27, 34))	('increased', 'PosReg', (170, 179))	('premature mitosis', 'Disease', 'MESH:C536271', (199, 216))	('DNA', 'cellular_component', 'GO:0005574', ('183', '186'))	('AZD1775', 'Var', (154, 161))	('p53', 'Gene', '7157', (78, 81))	('5-FU', 'Chemical', 'MESH:D005472', (63, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('p53', 'Gene', (78, 81))	('mitosis', 'biological_process', 'GO:0000278', ('209', '216'))	('premature mitosis', 'Disease', (199, 216))	('DS-DNA breaks', 'MPA', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cytotoxicity', 'Disease', (131, 143))
31491	28296564	AZD1775 exerts its own cytotoxic effects independent of chemotherapeutic agents.	('cytotoxic effects', 'CPA', (23, 40))	('AZD1775', 'Var', (0, 7))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))
31494	28296564	To address this we took advantage of the HT29 colorectal cancer cell line as this has a mutated non-functional p53 (Arg-273 to His) and therefore both DS-DNA breaks and premature mitosis are possible mechanisms of AZD1775 action.	('DNA', 'cellular_component', 'GO:0005574', ('154', '157'))	('premature mitosis', 'Disease', 'MESH:C536271', (169, 186))	('premature mitosis', 'Disease', (169, 186))	('HT29 colorectal cancer', 'Disease', (41, 63))	('Arg-273 to His', 'Mutation', 'rs28934576', (116, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (46, 63))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))	('HT29 colorectal cancer', 'Disease', 'MESH:D015179', (41, 63))	('mutated', 'Var', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Arg-273 to His', 'Var', (116, 130))	('mitosis', 'biological_process', 'GO:0000278', ('179', '186'))	('non-functional', 'MPA', (96, 110))	('AZD1775', 'Chemical', 'MESH:C549567', (214, 221))
31499	28296564	Despite acting independently of chemotherapeutic agents, AZD1775 did improve the IC50 of 5-FU in viability assays.	('AZD1775', 'Chemical', 'MESH:C549567', (57, 64))	('5-FU', 'Chemical', 'MESH:D005472', (89, 93))	('IC50 of 5-FU', 'MPA', (81, 93))	('improve', 'PosReg', (69, 76))	('AZD1775', 'Var', (57, 64))
31501	28296564	AZD1775 has potent monotherapeutic action against HT29 cells and has been found to have more potent effects on cell viability than some DNA-damaging agents in other cancer cell lines.	('AZD1775', 'Var', (0, 7))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cell viability', 'CPA', (111, 125))	('HT29 cells', 'CellLine', 'CVCL:0320', (50, 60))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('monotherapeutic action', 'MPA', (19, 41))
31506	28296564	As our data suggest that AZD1775 causes DS-DNA breaks rather than premature mitosis, giving AZD1775 immediately after DNA-damaging treatments of short periods may not be the optimal dosing strategy.	('AZD1775', 'Chemical', 'MESH:C549567', (92, 99))	('AZD1775', 'Var', (25, 32))	('AZD1775', 'Chemical', 'MESH:C549567', (25, 32))	('DS-DNA breaks', 'Disease', (40, 53))	('premature mitosis', 'Disease', (66, 83))	('AZD1775', 'Var', (92, 99))	('premature mitosis', 'Disease', 'MESH:C536271', (66, 83))	('causes', 'Reg', (33, 39))
31508	28296564	In conclusion, the data suggest that AZD1775 has independent cytotoxic effects from chemotherapeutic agents in p53-mutated colorectal cancer cells.	('AZD1775', 'Chemical', 'MESH:C549567', (37, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (123, 140))	('p53', 'Gene', (111, 114))	('colorectal cancer', 'Disease', (123, 140))	('p53', 'Gene', '7157', (111, 114))	('cytotoxic effects', 'CPA', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('AZD1775', 'Var', (37, 44))	('colorectal cancer', 'Disease', 'MESH:D015179', (123, 140))
31512	28296564	These cells have a mutated p53 (Arg-273 to His).	('Arg-273 to His', 'Mutation', 'rs28934576', (32, 46))	('p53', 'Gene', '7157', (27, 30))	('p53', 'Gene', (27, 30))	('Arg-273 to His', 'Var', (32, 46))
31540	29158795	The effect of hMLH1 overexpression in LoVo cells resulted in a similar increase in apoptosis that was greatly stimulated by estradiol.	('apoptosis', 'biological_process', 'GO:0097194', ('83', '92'))	('overexpression', 'Var', (20, 34))	('hMLH1', 'Gene', (14, 19))	('apoptosis', 'biological_process', 'GO:0006915', ('83', '92'))	('estradiol', 'Chemical', 'MESH:D004958', (124, 133))	('hMLH1', 'Gene', '4292', (14, 19))	('apoptosis', 'CPA', (83, 92))	('LoVo', 'CellLine', 'CVCL:0399', (38, 42))
31542	29158795	Re-expression of hMSH2 or overexpression of ERbeta in HCT116 cells also enhanced apoptosis; however, the effects were independent of estradiol.	('ERbeta', 'Gene', '2100', (44, 50))	('HCT116', 'CellLine', 'CVCL:0291', (54, 60))	('overexpression', 'PosReg', (26, 40))	('apoptosis', 'CPA', (81, 90))	('Re-expression', 'Var', (0, 13))	('hMSH2', 'Gene', '4436', (17, 22))	('enhanced', 'PosReg', (72, 80))	('ERbeta', 'Gene', (44, 50))	('hMSH2', 'Gene', (17, 22))	('estradiol', 'Chemical', 'MESH:D004958', (133, 142))
31553	29158795	Two MMR-deficient human colon carcinoma cell lines were used: the hMLH1 deficient HCT116 cells containing a homozygous nonsense mutation at codon 252 (stop codon) in exon 9, and the hMSH2 deficient LoVo cells containing a homozygous deletion in the hMSH2 gene from exon 3 to exon 8.	('hMSH', 'molecular_function', 'GO:0018775', ('182', '186'))	('hMSH2', 'Gene', (249, 254))	('colon carcinoma', 'Disease', 'MESH:D015179', (24, 39))	('hMLH1', 'Gene', (66, 71))	('HCT116', 'CellLine', 'CVCL:0291', (82, 88))	('deficient', 'NegReg', (72, 81))	('colon carcinoma', 'Disease', (24, 39))	('human', 'Species', '9606', (18, 23))	('hMSH2', 'Gene', '4436', (182, 187))	('LoVo', 'CellLine', 'CVCL:0399', (198, 202))	('hMSH', 'molecular_function', 'GO:0018775', ('249', '253'))	('MMR', 'biological_process', 'GO:0006298', ('4', '7'))	('hMSH2', 'Gene', (182, 187))	('deletion', 'Var', (233, 241))	('hMLH1', 'Gene', '4292', (66, 71))	('mutation', 'Var', (128, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('hMSH2', 'Gene', '4436', (249, 254))
31585	29158795	Clearly, deficiency of MSH2 in LoVo cells did not affect the E2-mediated enhancement of apoptosis, as E2 potently activated caspase -3 and -9 and increased the expression of P53 and Bax.	('expression', 'MPA', (160, 170))	('Bax', 'Gene', '581', (182, 185))	('LoVo', 'CellLine', 'CVCL:0399', (31, 35))	('MSH2', 'Gene', (23, 27))	('activated', 'PosReg', (114, 123))	('MSH2', 'Gene', '4436', (23, 27))	('P53', 'Gene', (174, 177))	('increased', 'PosReg', (146, 155))	('Bax', 'Gene', (182, 185))	('caspase', 'Enzyme', (124, 131))	('P53', 'Gene', '7157', (174, 177))	('deficiency', 'Var', (9, 19))
31598	29158795	MMR protein-dependent pro-death signaling in response to various DNA-damaging agents have been well characterized, including 5-fluorouracil, cisplatin, and methylation agents.	('5-fluorouracil', 'MPA', (125, 139))	('cisplatin', 'Chemical', 'MESH:D002945', (141, 150))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (125, 139))	('methylation', 'Var', (156, 167))
31623	28079806	NAFLD and MetS were significantly correlated with colorectal neoplasm and colorectal cancer (CRC), respectively.	('MetS', 'Var', (10, 14))	('CRC', 'Phenotype', 'HP:0003003', (93, 96))	('NAFLD', 'Gene', (0, 5))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('colorectal neoplasm and colorectal cancer', 'Disease', 'MESH:D015179', (50, 91))	('correlated', 'Reg', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('neoplasm', 'Phenotype', 'HP:0002664', (61, 69))
31625	28079806	NAFLD and MetS are risk factors for colorectal neoplasm and CRC, respectively.	('colorectal neoplasm', 'Disease', 'MESH:D015179', (36, 55))	('MetS', 'Var', (10, 14))	('CRC', 'Disease', (60, 63))	('colorectal neoplasm', 'Disease', (36, 55))	('NAFLD', 'Var', (0, 5))	('CRC', 'Phenotype', 'HP:0003003', (60, 63))	('neoplasm', 'Phenotype', 'HP:0002664', (47, 55))
31633	28079806	In addition, MetS has also been proved to increase the risk of developing colorectal neoplasm.	('colorectal neoplasm', 'Disease', 'MESH:D015179', (74, 93))	('colorectal neoplasm', 'Disease', (74, 93))	('MetS', 'Var', (13, 17))	('neoplasm', 'Phenotype', 'HP:0002664', (85, 93))
31650	28079806	The MetS was defined as presence of equal or more than 3 of the following components: BMI >= 25 kg/m2, antihypertensive drug administration and (or) systolic blood pressure (SBP) >=140 mm Hg or diastolic blood pressure (DBP) >=90 mm Hg, triglyceride >= 1.7 mmol/L and (or) HDL < 0.9 mmol/L (male), <1.0 mmol/L (female), and fasting plasma glucose >=6.1 mmol/L or 2-hour postprandial glucose >=7.8 mmol/L.	('HDL', 'molecular_function', 'GO:0005321', ('273', '276'))	('HDL', 'MPA', (273, 276))	('glucose', 'Chemical', 'MESH:D005947', (383, 390))	('>=90', 'Var', (225, 229))	('DBP', 'Chemical', 'MESH:D004145', (220, 223))	('triglyceride', 'MPA', (237, 249))	('>=140', 'Var', (179, 184))	('glucose', 'Chemical', 'MESH:D005947', (339, 346))	('>= 25', 'Var', (90, 95))
31659	28079806	The result showed that NAFLD and MetS were still risk factors for colorectal neoplasm (95% CI, 1.352-2.871; OR, 2.113; P = 0.001 and 95% CI, 1.262-2.227; OR, 1.781; P = 0.001).	('NAFLD', 'Var', (23, 28))	('colorectal neoplasm', 'Disease', 'MESH:D015179', (66, 85))	('MetS', 'Var', (33, 37))	('colorectal neoplasm', 'Disease', (66, 85))	('neoplasm', 'Phenotype', 'HP:0002664', (77, 85))
31661	28079806	The patients were divided into 4 groups basing on the status of NAFLD and MetS in Table 3, including NAFLD (-) MetS (-), NAFLD (-) MetS (+), NAFLD (+) MetS (-), and NAFLD (+) MetS (+) groups.	('NAFLD', 'Var', (101, 106))	('patients', 'Species', '9606', (4, 12))	('NAFLD (-', 'Var', (121, 129))
31662	28079806	The result showed that the probabilities of colorectal neoplasm in NAFLD (-) MetS (+), NAFLD (+) MetS (-), and NAFLD (+) MetS (+) groups were greater than that in NAFLD (-) MetS (-) group after adjusting for age and sex.	('colorectal neoplasm', 'Disease', 'MESH:D015179', (44, 63))	('NAFLD (-) MetS (+', 'Var', (67, 84))	('neoplasm', 'Phenotype', 'HP:0002664', (55, 63))	('colorectal neoplasm', 'Disease', (44, 63))	('greater', 'PosReg', (142, 149))
31663	28079806	However, the incidence of colorectal neoplasm had no difference among NAFLD (-) MetS (+), NAFLD (+) MetS (-), and NAFLD (+) MetS (+) groups (P = 0.796, 0.336, and 0.667).	('colorectal neoplasm', 'Disease', 'MESH:D015179', (26, 45))	('NAFLD', 'Var', (114, 119))	('colorectal neoplasm', 'Disease', (26, 45))	('neoplasm', 'Phenotype', 'HP:0002664', (37, 45))	('NAFLD', 'Var', (70, 75))
31672	28079806	Ahmed et al investigated a large size of participants including 14,109 individuals and found that MetS had a positive association with incidence of CRC.	('CRC', 'Phenotype', 'HP:0003003', (148, 151))	('MetS', 'Var', (98, 102))	('participants', 'Species', '9606', (41, 53))	('CRC', 'Disease', (148, 151))
31678	28079806	The present study primarily found that NAFLD and MetS were independently associated with an increased frequency of both colorectal neoplasm and CRC with adjustment for confounders.	('men', 'Species', '9606', (159, 162))	('CRC', 'Phenotype', 'HP:0003003', (144, 147))	('MetS', 'Var', (49, 53))	('NAFLD', 'Var', (39, 44))	('associated', 'Reg', (73, 83))	('colorectal neoplasm', 'Disease', 'MESH:D015179', (120, 139))	('neoplasm', 'Phenotype', 'HP:0002664', (131, 139))	('colorectal neoplasm', 'Disease', (120, 139))	('CRC', 'Disease', (144, 147))
31679	28079806	Then the result showed that patients with NAFLD and MetS had the highest incidence of CRC with the greatest value of OR compared to other groups.	('CRC', 'Phenotype', 'HP:0003003', (86, 89))	('MetS', 'Var', (52, 56))	('NAFLD', 'Var', (42, 47))	('patients', 'Species', '9606', (28, 36))	('CRC', 'Disease', (86, 89))
31680	28079806	The patients with NAFLD and MetS were associated with a 3.313 times higher increased risk of CRC compared with those who had no NAFLD or MetS.	('CRC', 'Disease', (93, 96))	('CRC', 'Phenotype', 'HP:0003003', (93, 96))	('MetS', 'Var', (28, 32))	('patients', 'Species', '9606', (4, 12))	('NAFLD', 'Var', (18, 23))
31682	28079806	Hwang et al suggested that NAFLD (+) MetS (+) group had a greater risk of colorectal adenomatous polyps than other groups because of the little higher OR value compared with other groups, but they did not research the CRC patients.	('NAFLD (+) MetS (+', 'Var', (27, 44))	('patients', 'Species', '9606', (222, 230))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (85, 103))	('colorectal adenomatous polyps', 'Disease', 'MESH:D018256', (74, 103))	('colorectal adenomatous polyps', 'Disease', (74, 103))	('CRC', 'Phenotype', 'HP:0003003', (218, 221))
31683	28079806	Currently, the mechanisms between the individual factor of NAFLD or MetS and colorectal neoplasms have not been clearly understood.	('neoplasms', 'Phenotype', 'HP:0002664', (88, 97))	('colorectal neoplasms', 'Disease', (77, 97))	('NAFLD', 'Var', (59, 64))	('colorectal neoplasms', 'Disease', 'MESH:D015179', (77, 97))	('neoplasm', 'Phenotype', 'HP:0002664', (88, 96))
31686	28079806	In addition, inflammatory cytokines may also play a critical role in the NAFLD inducing colorectal neoplasm.	('neoplasm', 'Phenotype', 'HP:0002664', (99, 107))	('colorectal neoplasm', 'Disease', 'MESH:D015179', (88, 107))	('inducing', 'Reg', (79, 87))	('NAFLD', 'Var', (73, 78))	('colorectal neoplasm', 'Disease', (88, 107))
31687	28079806	When it comes to the relationship between MetS and colorectal neoplasm, the reasonable explanation is that dysregulation of growth signals, inflammation cytokines, and vascular integrity factors may mediate the relationship and finally prompt tumorigenesis.	('prompt', 'Reg', (236, 242))	('tumorigenesis', 'CPA', (243, 256))	('neoplasm', 'Phenotype', 'HP:0002664', (62, 70))	('colorectal neoplasm', 'Disease', 'MESH:D015179', (51, 70))	('inflammation', 'Disease', 'MESH:D007249', (140, 152))	('dysregulation', 'Var', (107, 120))	('inflammation', 'Disease', (140, 152))	('colorectal neoplasm', 'Disease', (51, 70))
31691	28079806	Consequently, the presence of NAFLD and MetS in meantime may increase the risk of development of CRC.	('presence', 'Var', (18, 26))	('CRC', 'Disease', (97, 100))	('NAFLD', 'Gene', (30, 35))	('CRC', 'Phenotype', 'HP:0003003', (97, 100))	('increase', 'PosReg', (61, 69))	('men', 'Species', '9606', (89, 92))
31692	28079806	However, the mechanism by which the NAFLD and MetS cause local inflammation in colorectum needs to be further studied.	('NAFLD', 'Var', (36, 41))	('inflammation', 'Disease', 'MESH:D007249', (63, 75))	('cause', 'Reg', (51, 56))	('inflammation', 'Disease', (63, 75))
31694	28079806	The present study suggests that NAFLD and MetS are risk factors for increasing the risk of colorectal neoplasm and CRC, respectively.	('CRC', 'Disease', (115, 118))	('NAFLD', 'Var', (32, 37))	('colorectal neoplasm', 'Disease', (91, 110))	('MetS', 'Var', (42, 46))	('CRC', 'Phenotype', 'HP:0003003', (115, 118))	('neoplasm', 'Phenotype', 'HP:0002664', (102, 110))	('colorectal neoplasm', 'Disease', 'MESH:D015179', (91, 110))
31695	28079806	In addition, MetS may increase the risk of CRC in patients with NAFLD.	('patients', 'Species', '9606', (50, 58))	('MetS', 'Var', (13, 17))	('CRC', 'Disease', (43, 46))	('CRC', 'Phenotype', 'HP:0003003', (43, 46))
31698	26307678	LS174T, HT-29 and Caco-2 cells have high Ascl2 expression, while Lovo and SW480 cells have low Ascl2 expression.	('SW480', 'CellLine', 'CVCL:0546', (74, 79))	('HT-29', 'CellLine', 'CVCL:0320', (8, 13))	('LS174T', 'Var', (0, 6))	('Caco-2', 'CellLine', 'CVCL:0025', (18, 24))	('LS174T', 'CellLine', 'CVCL:1384', (0, 6))	('Ascl2', 'Gene', (41, 46))	('expression', 'MPA', (47, 57))
31700	26307678	Ascl2 knockdown promoted differentiation of CRC cells into a goblet cell phenotype, as determined by increased expression of MUC2, TFF3, and CDX2.	('differentiation', 'CPA', (25, 40))	('CDX2', 'Gene', '1045', (141, 145))	('TFF3', 'Gene', '7033', (131, 135))	('increased', 'PosReg', (101, 110))	('promoted', 'PosReg', (16, 24))	('expression', 'MPA', (111, 121))	('MUC2', 'Gene', (125, 129))	('MUC2', 'Gene', '4583', (125, 129))	('TFF3', 'Gene', (131, 135))	('knockdown', 'Var', (6, 15))	('CRC', 'Phenotype', 'HP:0003003', (44, 47))	('CDX2', 'Gene', (141, 145))
31714	26307678	To determine whether Ascl2 deficiency in CRC cells can lead to their differentiation, we used qRT-PCR to quantify expression levels of cell-type specific genes in shRNA-Ascl2/HT-29 and shRNA-Ascl2/LS174T cells.	('LS174T', 'CellLine', 'CVCL:1384', (197, 203))	('CRC', 'Phenotype', 'HP:0003003', (41, 44))	('HT-29', 'CellLine', 'CVCL:0320', (175, 180))	('deficiency', 'Var', (27, 37))	('lead to', 'Reg', (55, 62))
31721	26307678	Because Ascl2 deficiency in CRC cells led to their differentiation into a goblet cell phenotype and induced MUC2 expression, we hypothesized that it did so via increasing CDX2 expression.	('expression', 'MPA', (113, 123))	('increasing', 'PosReg', (160, 170))	('Ascl2', 'Gene', (8, 13))	('differentiation', 'CPA', (51, 66))	('MUC2', 'Gene', '4583', (108, 112))	('CRC', 'Phenotype', 'HP:0003003', (28, 31))	('CDX2', 'Gene', (171, 175))	('MUC2', 'Gene', (108, 112))	('expression', 'MPA', (176, 186))	('deficiency', 'Var', (14, 24))	('induced', 'Reg', (100, 107))	('CDX2', 'Gene', '1045', (171, 175))
31723	26307678	When compared with control cells, Ascl2 expression was significantly decreased in shRNA-Ascl2/HT-29 and shRNA-Ascl2/LS174T cells, while CDX2 expression was significantly increased (Figure 2A-2B).	('expression', 'MPA', (40, 50))	('LS174T', 'CellLine', 'CVCL:1384', (116, 122))	('CDX2', 'Gene', (136, 140))	('decreased', 'NegReg', (69, 78))	('increased', 'PosReg', (170, 179))	('Ascl2', 'Gene', (34, 39))	('expression', 'MPA', (141, 151))	('CDX2', 'Gene', '1045', (136, 140))	('shRNA-Ascl2/LS174T', 'Var', (104, 122))	('HT-29', 'CellLine', 'CVCL:0320', (94, 99))
31729	26307678	The full-length human CDX2 promoter (-2167/+417) generated a significantly higher level of luciferase activity in both shRNA-Ascl2/LS174T and shRNA-Ascl2/HT-29 cells than in control cells (p < 0.05 or p < 0.01; Figure 3B-3C).	('luciferase', 'Enzyme', (91, 101))	('higher', 'PosReg', (75, 81))	('CDX2', 'Gene', (22, 26))	('HT-29 cells', 'CellLine', 'CVCL:0320', (154, 165))	('CDX2', 'Gene', '1045', (22, 26))	('activity', 'MPA', (102, 110))	('LS174T', 'CellLine', 'CVCL:1384', (131, 137))	('-2167/+417', 'Var', (37, 47))	('human', 'Species', '9606', (16, 21))
31731	26307678	Interestingly, the pGL3-CDX2 promoter encompassing -272/+417 relative to the putative TSS also had increased luciferase activity (p < 0.01) even with no potential E-box present.	('encompassing -272/+417', 'Var', (38, 60))	('pGL3', 'Gene', (19, 23))	('luciferase', 'Enzyme', (109, 119))	('increased', 'PosReg', (99, 108))	('CDX2', 'Gene', (24, 28))	('activity', 'MPA', (120, 128))	('pGL3', 'Gene', '6391', (19, 23))	('CDX2', 'Gene', '1045', (24, 28))
31734	26307678	We performed chromatin immunoprecipitation assay (ChIP) assays to determine whether Ascl2 binds directly to the CDX2 promoter and whether this binding decreased with Ascl2 knockdown in LS174T cells.	('binding', 'Interaction', (143, 150))	('binds', 'Interaction', (90, 95))	('CDX2', 'Gene', (112, 116))	('decreased', 'NegReg', (151, 160))	('LS174T', 'CellLine', 'CVCL:1384', (185, 191))	('CDX2', 'Gene', '1045', (112, 116))	('knockdown', 'Var', (172, 181))
31736	26307678	ChIP experiments 3 and 5 indicated that Ascl2 binding to the CDX2 promoter was reduced in shRNA-Ascl2/LS174T cells compared to that in shRNA-Ctr/LS174T cells at promoter positions -841/-646 and -291/-134.	('Ctr', 'Gene', '799', (141, 144))	('reduced', 'NegReg', (79, 86))	('Ctr', 'Gene', (141, 144))	('LS174T', 'CellLine', 'CVCL:1384', (102, 108))	('CDX2', 'Gene', (61, 65))	('LS174T', 'CellLine', 'CVCL:1384', (145, 151))	('Ascl2', 'MPA', (40, 45))	('CDX2', 'Gene', '1045', (61, 65))	('shRNA-Ascl2/LS174T', 'Var', (90, 108))
31738	26307678	To determine whether Ascl2 transcriptionally suppressed CDX2 expression via binding to the E-boxes in the proximal promoter, we used the CDX2 promoter-Luc construct (-427/+417), in which only one E-box is present, to produce an E-box mutant (Figure 5A).	('CDX2', 'Gene', (56, 60))	('mutant', 'Var', (234, 240))	('CDX2', 'Gene', '1045', (56, 60))	('CDX2', 'Gene', (137, 141))	('suppressed', 'NegReg', (45, 55))	('binding', 'molecular_function', 'GO:0005488', ('76', '83'))	('CDX2', 'Gene', '1045', (137, 141))	('binding', 'Interaction', (76, 83))	('expression', 'MPA', (61, 71))
31739	26307678	shRNA-Ascl2/HT-29 cells or shRNA-Ctr/HT-29 cells were transfected with either the wild-type CDX2 promoter-Luc construct (-427/+417) or with the mutant construct.	('HT-29 cells', 'CellLine', 'CVCL:0320', (12, 23))	('CDX2', 'Gene', (92, 96))	('HT-29 cells', 'CellLine', 'CVCL:0320', (37, 48))	('-427/+417', 'Var', (121, 130))	('Ctr', 'Gene', '799', (33, 36))	('Ctr', 'Gene', (33, 36))	('CDX2', 'Gene', '1045', (92, 96))
31740	26307678	Both the wild-type and mutant CDX2 promoter-Luc constructs (-427/+417) showed significantly higher level of luciferase activity in shRNA-Ascl2/HT-29 cells compared to shRNA-Ctr/HT-29 cells (p < 0.05; Figure 5B).	('higher', 'PosReg', (92, 98))	('-427/+417', 'Var', (60, 69))	('HT-29 cells', 'CellLine', 'CVCL:0320', (177, 188))	('Ctr', 'Gene', '799', (173, 176))	('Ctr', 'Gene', (173, 176))	('CDX2', 'Gene', (30, 34))	('activity', 'MPA', (119, 127))	('HT-29 cells', 'CellLine', 'CVCL:0320', (143, 154))	('luciferase', 'Enzyme', (108, 118))	('mutant', 'Var', (23, 29))	('CDX2', 'Gene', '1045', (30, 34))
31743	26307678	However, possible Ascl2 binding sites residing -272/+417 relative to the putative TSS of CDX2, which, when bound with Ascl2 still functioned as transcriptional repressors, remain unidentified.	('residing -272/+417', 'Var', (38, 56))	('CDX2', 'Gene', (89, 93))	('binding', 'molecular_function', 'GO:0005488', ('24', '31'))	('transcriptional', 'MPA', (144, 159))	('CDX2', 'Gene', '1045', (89, 93))
31764	26307678	Ascl2 knockdown in CRC cells led to significant increases in the levels of goblet cell differentiation markers, including MUC2 and TFF3, and to marked increases in CDX2 mRNA and protein expression.	('TFF3', 'Gene', '7033', (131, 135))	('MUC2', 'Gene', (122, 126))	('increases', 'PosReg', (151, 160))	('increases', 'PosReg', (48, 57))	('cell differentiation', 'biological_process', 'GO:0030154', ('82', '102'))	('Ascl2', 'Gene', (0, 5))	('goblet cell differentiation', 'CPA', (75, 102))	('levels of', 'MPA', (65, 74))	('CDX2', 'Gene', (164, 168))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('TFF3', 'Gene', (131, 135))	('knockdown', 'Var', (6, 15))	('CRC', 'Phenotype', 'HP:0003003', (19, 22))	('CDX2', 'Gene', '1045', (164, 168))	('MUC2', 'Gene', '4583', (122, 126))
31767	26307678	Conversely, inhibition of Ascl2 expression in HT-29 and LS174T cell lines increased expression of two goblet cell-specific genes, MUC2 and TFF3, along with CDX2.	('CDX2', 'Gene', (156, 160))	('HT-29', 'CellLine', 'CVCL:0320', (46, 51))	('TFF3', 'Gene', '7033', (139, 143))	('MUC2', 'Gene', (130, 134))	('inhibition', 'Var', (12, 22))	('CDX2', 'Gene', '1045', (156, 160))	('Ascl2', 'Gene', (26, 31))	('increased', 'PosReg', (74, 83))	('LS174T', 'CellLine', 'CVCL:1384', (56, 62))	('expression', 'MPA', (84, 94))	('TFF3', 'Gene', (139, 143))	('MUC2', 'Gene', '4583', (130, 134))
31771	26307678	Moreover, intestinal Lgr5(+) cryptic stem cells are depleted in Ascl2 knockout mice, while Cdx2 knockout results in a reduction in the differentiated cells in intestinal mucosa.	('Cdx2', 'Gene', '12591', (91, 95))	('reduction', 'NegReg', (118, 127))	('mice', 'Species', '10090', (79, 83))	('Ascl2', 'Gene', (64, 69))	('knockout', 'Var', (96, 104))	('Cdx2', 'Gene', (91, 95))	('differentiated cells in intestinal mucosa', 'CPA', (135, 176))
31792	26307678	The pGL3-Basic vector containing the CDX2 promoter (-427/+417) and one E-Box site (CACCTG) served as a wild-type construct for the generation of the CDX2-Luc construct, which harbors a mutation in the E-BOX site (CACCGG) via PCR-based site-directed mutagenesis.	('CDX2', 'Gene', (149, 153))	('CDX2', 'Gene', (37, 41))	('CDX2', 'Gene', '1045', (149, 153))	('pGL3', 'Gene', '6391', (4, 8))	('-427/+417', 'Var', (52, 61))	('mutation', 'Var', (185, 193))	('CDX2', 'Gene', '1045', (37, 41))	('pGL3', 'Gene', (4, 8))
31811	26357473	Further, DendGDP had improved anticancer activity when compared with doxorubicin or DendDP in an in vivo CT26 tumor xenograft model, ie, the volume of the CT26 tumor xenograft was significantly inhibited when compared with xenografts treated with doxorubicin or DendDP nanoparticles.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('doxorubicin', 'Chemical', 'MESH:D004317', (247, 258))	('DendDP', 'Chemical', '-', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('CT26', 'CellLine', 'CVCL:7254', (155, 159))	('CT26', 'CellLine', 'CVCL:7254', (105, 109))	('DendGDP', 'Var', (9, 16))	('inhibited', 'NegReg', (194, 203))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('DendGDP', 'Chemical', '-', (9, 16))	('improved', 'PosReg', (21, 29))	('tumor', 'Disease', (160, 165))	('doxorubicin', 'Chemical', 'MESH:D004317', (69, 80))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', (110, 115))	('volume', 'CPA', (141, 147))	('cancer', 'Disease', (34, 40))	('DendDP', 'Chemical', '-', (262, 268))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
31819	26357473	Enhanced tumor targeting by nanoparticles is based on the enhanced permeation and retention (EPR) effect in tumor tissues.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('enhanced', 'PosReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', (9, 14))	('nanoparticles', 'Var', (28, 41))	('permeation', 'MPA', (67, 77))	('Enhanced', 'PosReg', (0, 8))
31824	26357473	Due to their structural peculiarity, dendrimers have better physicochemical behavior than linear or branched polymers.	('physicochemical behavior', 'MPA', (60, 84))	('polymers', 'Chemical', 'MESH:D011108', (109, 117))	('dendrimers', 'Var', (37, 47))
31825	26357473	For example, dendrimers tend to have lower viscosity, unique molecular behavior, and a lower hydrated radius when compared with linear polymers.	('lower', 'NegReg', (87, 92))	('viscosity', 'MPA', (43, 52))	('dendrimers', 'Var', (13, 23))	('polymers', 'Chemical', 'MESH:D011108', (135, 143))	('lower', 'NegReg', (37, 42))	('hydrated radius', 'MPA', (93, 108))
31903	26357473	CT26 cells treated with DendDP showed a relatively lower potential for growth inhibition (Figure 4A) even though observation of fluorescence intensity indicated higher uptake efficiency by tumor cells when compared with uptake of doxorubicin alone (Figure 4B).	('tumor', 'Disease', (189, 194))	('DendDP', 'Var', (24, 30))	('growth inhibition', 'CPA', (71, 88))	('DendDP', 'Chemical', '-', (24, 30))	('CT26', 'CellLine', 'CVCL:7254', (0, 4))	('lower', 'NegReg', (51, 56))	('uptake', 'MPA', (168, 174))	('doxorubicin', 'Chemical', 'MESH:D004317', (230, 241))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('higher', 'PosReg', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
31906	26357473	Otherwise, growth of CT26 cells in response to treatment with DendGDP was significantly inhibited to a greater extent than with doxorubicin alone or with the DendDP nanoparticles (Figure 4A).	('inhibited', 'NegReg', (88, 97))	('growth', 'CPA', (11, 17))	('CT26', 'CellLine', 'CVCL:7254', (21, 25))	('DendDP', 'Chemical', '-', (158, 164))	('DendGDP', 'Chemical', '-', (62, 69))	('DendGDP', 'Var', (62, 69))	('doxorubicin', 'Chemical', 'MESH:D004317', (128, 139))
31936	26357473	DendGDP has the highest fluorescence intensity in the tumor tissue rather than in the body organs, while doxorubicin alone and DendDP showed strong fluorescence in the organs, indicating that DendGDP has potential for use as a diagnostic tool for cancer.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('DendGDP', 'Chemical', '-', (192, 199))	('doxorubicin', 'Chemical', 'MESH:D004317', (105, 116))	('DendGDP', 'Chemical', '-', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('fluorescence intensity', 'MPA', (24, 46))	('DendDP', 'Chemical', '-', (127, 133))	('cancer', 'Disease', (247, 253))	('fluorescence', 'MPA', (148, 160))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('DendGDP', 'Var', (0, 7))	('tumor', 'Disease', (54, 59))
31943	26357473	Further, DendGDP had improved anticancer activity when compared with doxorubicin or DendDP in an vivo mouse CT26 tumor xenograft model.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Disease', (113, 118))	('DendGDP', 'Var', (9, 16))	('improved', 'PosReg', (21, 29))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('CT26', 'CellLine', 'CVCL:7254', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('cancer', 'Disease', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('DendGDP', 'Chemical', '-', (9, 16))	('doxorubicin', 'Chemical', 'MESH:D004317', (69, 80))	('mouse', 'Species', '10090', (102, 107))	('DendDP', 'Chemical', '-', (84, 90))
31944	26357473	DendGDP became relatively concentrated in the tumor tissue and had stronger fluorescence intensity compared with doxorubicin alone or DendDP nanoparticles.	('stronger', 'PosReg', (67, 75))	('DendDP', 'Chemical', '-', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('DendGDP', 'Chemical', '-', (0, 7))	('tumor', 'Disease', (46, 51))	('doxorubicin', 'Chemical', 'MESH:D004317', (113, 124))	('fluorescence intensity', 'MPA', (76, 98))	('DendGDP', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
31955	26355327	LELC generally comprises undifferentiated carcinoma or medullary carcinoma with lymphoid stroma, which are typically associated with Epstein - Barr virus (EBV) infection and/or microsatellite instability-high colorectal cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (209, 226))	('undifferentiated carcinoma', 'Disease', (25, 51))	('Epstein - Barr virus (EBV) infection', 'Disease', 'MESH:D020031', (133, 169))	('carcinoma', 'Disease', (42, 51))	('associated', 'Reg', (117, 127))	('carcinoma', 'Disease', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('colorectal cancer', 'Disease', (209, 226))	('carcinoma', 'Disease', 'MESH:D002277', (65, 74))	('lymphoid stroma', 'Disease', (80, 95))	('undifferentiated carcinoma', 'Disease', 'MESH:D002277', (25, 51))	('colorectal cancer', 'Disease', 'MESH:D015179', (209, 226))	('microsatellite instability-high', 'Var', (177, 208))	('carcinoma', 'Disease', 'MESH:D002277', (42, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('lymphoid stroma', 'Disease', 'MESH:D008223', (80, 95))
31991	26355327	Generally, LELC is an undifferentiated carcinoma or medullary carcinoma with lymphoid stroma that is typically associated with EBV infection and/or microsatellite instability-high colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (180, 197))	('associated', 'Reg', (111, 121))	('LELC', 'Disease', (11, 15))	('microsatellite instability-high', 'Var', (148, 179))	('undifferentiated carcinoma', 'Disease', 'MESH:D002277', (22, 48))	('EBV infection', 'Disease', 'MESH:D020031', (127, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('carcinoma', 'Disease', (39, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('lymphoid stroma', 'Disease', (77, 92))	('lymphoid stroma', 'Disease', 'MESH:D008223', (77, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (180, 197))	('carcinoma', 'Disease', (62, 71))	('EBV infection', 'Disease', (127, 140))	('colorectal cancer', 'Disease', (180, 197))	('undifferentiated carcinoma', 'Disease', (22, 48))	('carcinoma', 'Disease', 'MESH:D002277', (39, 48))	('carcinoma', 'Disease', 'MESH:D002277', (62, 71))
32003	26355327	Although LELC and dome-like carcinoma are rare and are not distinguishable by the current classification system, they are identified based on morphology (i. e. on the differentiation of the tumor), EBV infection status, and microsatellite instability.	('microsatellite instability', 'Var', (224, 250))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('carcinoma', 'Disease', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (190, 195))	('carcinoma', 'Disease', 'MESH:D002277', (28, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('EBV infection', 'Disease', (198, 211))	('EBV infection', 'Disease', 'MESH:D020031', (198, 211))	('LELC', 'Disease', (9, 13))
32033	25683114	This resulted in a total of 27 SNPs: rs16892766, rs6983267, rs10795668, rs3802842, rs4444235, rs4779584, rs9929218, rs4939827, rs10411210, rs961253, rs6687758, rs10936599, rs1321311, rs719725, rs3824999, rs7136702, rs1957636, rs4813802, rs4925386, rs10911251, rs11903757, rs3217810, rs3217901, rs59336, rs647161, rs10774214, rs2423279.	('rs647161', 'Var', (303, 311))	('rs647161', 'Mutation', 'rs647161', (303, 311))	('rs4779584', 'Mutation', 'rs4779584', (94, 103))	('rs10774214', 'Var', (313, 323))	('rs4779584', 'Var', (94, 103))	('rs2423279', 'Mutation', 'rs2423279', (325, 334))	('rs10936599', 'Mutation', 'rs10936599', (160, 170))	('rs3824999', 'Mutation', 'rs3824999', (193, 202))	('rs1957636', 'Mutation', 'rs1957636', (215, 224))	('rs719725', 'Var', (183, 191))	('rs7136702', 'Mutation', 'rs7136702', (204, 213))	('rs3217810', 'Mutation', 'rs3217810', (272, 281))	('rs6983267', 'Mutation', 'rs6983267', (49, 58))	('rs3217901', 'Var', (283, 292))	('rs11903757', 'Mutation', 'rs11903757', (260, 270))	('rs1957636', 'Var', (215, 224))	('rs4444235', 'Mutation', 'rs4444235', (83, 92))	('rs10911251', 'Mutation', 'rs10911251', (248, 258))	('rs10411210', 'Mutation', 'rs10411210', (127, 137))	('rs4444235', 'Var', (83, 92))	('rs10795668', 'Var', (60, 70))	('rs4939827', 'Var', (116, 125))	('rs4813802', 'Var', (226, 235))	('rs4925386', 'Var', (237, 246))	('rs9929218', 'Mutation', 'rs9929218', (105, 114))	('rs59336', 'Var', (294, 301))	('rs16892766', 'Var', (37, 47))	('rs7136702', 'Var', (204, 213))	('rs3824999', 'Var', (193, 202))	('rs6687758', 'Var', (149, 158))	('rs3802842', 'Mutation', 'rs3802842', (72, 81))	('rs1321311', 'Mutation', 'rs1321311', (172, 181))	('rs3802842', 'Var', (72, 81))	('rs10411210', 'Var', (127, 137))	('rs961253', 'Var', (139, 147))	('rs4925386', 'Mutation', 'rs4925386', (237, 246))	('rs16892766', 'Mutation', 'rs16892766', (37, 47))	('rs1321311', 'Var', (172, 181))	('rs10774214', 'Mutation', 'rs10774214', (313, 323))	('rs3217901', 'Mutation', 'rs3217901', (283, 292))	('rs3217810', 'Var', (272, 281))	('rs4813802', 'Mutation', 'rs4813802', (226, 235))	('rs961253', 'Mutation', 'rs961253', (139, 147))	('rs11903757', 'Var', (260, 270))	('rs6983267', 'Var', (49, 58))	('rs9929218', 'Var', (105, 114))	('rs2423279', 'Var', (325, 334))	('rs4939827', 'Mutation', 'rs4939827', (116, 125))	('rs10795668', 'Mutation', 'rs10795668', (60, 70))	('rs10911251', 'Var', (248, 258))	('rs10936599', 'Var', (160, 170))	('rs719725', 'Mutation', 'rs719725', (183, 191))	('rs6687758', 'Mutation', 'rs6687758', (149, 158))	('rs59336', 'Mutation', 'rs59336', (294, 301))
32048	25683114	Similarly, the genetic risk score was statistically significantly associated with increased risk of CRC at all tumor sites in both men and women.	('women', 'Species', '9606', (139, 144))	('men', 'Species', '9606', (141, 144))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('CRC', 'Phenotype', 'HP:0003003', (100, 103))	('CRC at', 'Disease', (100, 106))	('men', 'Species', '9606', (131, 134))	('associated', 'Reg', (66, 76))	('tumor', 'Disease', (111, 116))	('genetic risk score', 'Var', (15, 33))
32050	25683114	We also performed a sensitivity analysis excluding the two SNPs, rs59336 (p-value = 3.7x10-7) and rs3217901 (p-value = 5.9x10-8), that did not reach the genome-wide significance and the results were essentially unchanged (Supplemental Table S8 and S9).	('rs59336', 'Var', (65, 72))	('rs59336', 'Mutation', 'rs59336', (65, 72))	('men', 'Species', '9606', (228, 231))	('rs3217901', 'Var', (98, 107))	('rs3217901', 'Mutation', 'rs3217901', (98, 107))
32094	25683114	AUC area under the receiver-operating characteristic curve AR attributable risk CI confidence intervals CORECT Colorectal Transdisciplinary Study CRC colorectal cancer D' normalized linkage disequilibrium DACHS Darmkrebs: Chancen der Verhutung durch Screening DALS Diet, Activity and Lifestyle Study GECCO Genetics and Epidemiology of Colorectal Cancer Consortium GWAS genome-wide association studies HPFS Health Professionals Follow-up Study NHS Nurses' Health Study OR odds ratio PLCO the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial SEER Surveillance, Epidemiology and End Results registry SNPs single nucleotide polymorphisms VITAL Vitamins And Lifestyle Study WHI Women's Health Initiative	('Colorectal Cancer', 'Disease', 'MESH:D015179', (335, 352))	('Colorectal Cancer', 'Disease', (335, 352))	('colorectal cancer', 'Disease', (150, 167))	('single nucleotide polymorphisms', 'Var', (615, 646))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('Colorectal and Ovarian Cancer', 'Disease', 'MESH:D015179', (507, 536))	('colorectal cancer', 'Phenotype', 'HP:0003003', (150, 167))	('Cancer', 'Phenotype', 'HP:0002664', (346, 352))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (335, 352))	('Colorectal Transdisciplinary', 'Disease', 'MESH:D015179', (111, 139))	('NHS', 'Chemical', '-', (443, 446))	('colorectal cancer', 'Disease', 'MESH:D015179', (150, 167))	('CRC', 'Phenotype', 'HP:0003003', (146, 149))	('Colorectal Transdisciplinary', 'Disease', (111, 139))	('Cancer', 'Phenotype', 'HP:0002664', (530, 536))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (522, 536))	('Women', 'Species', '9606', (686, 691))
32100	25474488	By overexpressing miR-143/145 in Caco2, HT29 and SW480 colorectal cancer cells, we experimentally validated that miR-143/145 directly recognizes the 3'-UTR of the IGF1R transcript and regulates IGF1R expression.	('IGF1R', 'Gene', (194, 199))	('miR-143/145', 'Var', (113, 124))	('colorectal cancer', 'Disease', 'MESH:D015179', (55, 72))	('HT29', 'CellLine', 'CVCL:0320', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (55, 72))	('SW480', 'CellLine', 'CVCL:0546', (49, 54))	('expression', 'MPA', (200, 210))	('colorectal cancer', 'Disease', (55, 72))	('regulates', 'Reg', (184, 193))	('IGF1R', 'Gene', (163, 168))
32101	25474488	Taken together, our findings provide evidence for a role of the miR-143/145 cluster as a tumor suppressor in colorectal cancer through the inhibition of IGF1R translation.	('colorectal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('IGF1R', 'Gene', (153, 158))	('miR-143/145', 'Var', (64, 75))	('inhibition', 'NegReg', (139, 149))	('tumor suppressor', 'biological_process', 'GO:0051726', ('89', '105'))	('translation', 'biological_process', 'GO:0006412', ('159', '170'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('89', '105'))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('translation', 'MPA', (159, 170))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
32104	25474488	At the molecular level, colorectal cancer arises from a series of genetic and epigenetic alterations that inactivate tumor suppressor genes and activate oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('oncogenes', 'Gene', (153, 162))	('colorectal cancer', 'Phenotype', 'HP:0003003', (24, 41))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('117', '133'))	('tumor suppressor', 'Gene', '7248', (117, 133))	('inactivate', 'Var', (106, 116))	('activate', 'PosReg', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor suppressor', 'biological_process', 'GO:0051726', ('117', '133'))	('colorectal cancer', 'Disease', (24, 41))	('colorectal cancer', 'Disease', 'MESH:D015179', (24, 41))	('alterations', 'Var', (89, 100))	('tumor suppressor', 'Gene', (117, 133))
32107	25474488	IGF1R activation leads to autophosphorylation on tyrosines 1131, 1135 and 1136 in the kinase domain, followed by phosphorylation of juxtamembrane tyrosines and carboxy-terminal serines.	('autophosphorylation', 'MPA', (26, 45))	('serines', 'Chemical', 'MESH:D012694', (177, 184))	('phosphorylation', 'MPA', (113, 128))	('tyrosines', 'Chemical', 'MESH:D014443', (146, 155))	('IGF1R', 'Gene', (0, 5))	('tyrosines', 'Chemical', 'MESH:D014443', (49, 58))	('tyrosines 1131', 'Var', (49, 63))	('activation', 'PosReg', (6, 16))
32113	25474488	Importantly, recent studies indicate that the dysregulation of miRNAs is associated with human malignancies and suggest a causal role of miRNAs in cancer etiology.	('human', 'Species', '9606', (89, 94))	('malignancies', 'Disease', 'MESH:D009369', (95, 107))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('malignancies', 'Disease', (95, 107))	('associated', 'Reg', (73, 83))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('dysregulation', 'Var', (46, 59))	('cancer', 'Disease', (147, 153))	('miRNAs', 'Gene', (63, 69))
32114	25474488	miRNAs presumably play a role in cancer because they can affect the translation and stability of targeted oncogenes or tumor suppressors, which ultimately influence cellular physiology.	('tumor', 'Disease', (119, 124))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('translation', 'biological_process', 'GO:0006412', ('68', '79'))	('cellular physiology', 'MPA', (165, 184))	('oncogenes', 'Gene', (106, 115))	('translation', 'MPA', (68, 79))	('affect', 'Reg', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('miRNAs', 'Var', (0, 6))	('stability', 'MPA', (84, 93))	('influence', 'Reg', (155, 164))
32117	25474488	Although dysregulation of IGF1R and miRNAs is associated with tumorigenesis in human colorectal cancer, little is known about miRNAs that act on IGF1R.	('human', 'Species', '9606', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal cancer', 'Disease', (85, 102))	('IGF1R', 'Gene', (26, 31))	('tumor', 'Disease', (62, 67))	('associated', 'Reg', (46, 56))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('dysregulation', 'Var', (9, 22))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
32119	25474488	Furthermore, we showed that miR-143/145 can inhibit IGF1R expression to suppress the proliferation of colorectal cancer cells.	('colorectal cancer', 'Disease', (102, 119))	('suppress', 'NegReg', (72, 80))	('expression', 'MPA', (58, 68))	('inhibit', 'NegReg', (44, 51))	('miR-143/145', 'Var', (28, 39))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('IGF1R', 'Gene', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('proliferation', 'CPA', (85, 98))
32141	25474488	To test the binding specificity, the sequences that interact with the seed sequence of miR-143 and miR-145 were mutated (from UUGGGAG to AACCCUC for the miR-143 binding site and from UUGGGAG to AACCCUC for the miR-145 binding site), and the mutant IGF1R 3'-UTR was inserted into an equivalent luciferase reporter plasmid.	('miR-143', 'Gene', (87, 94))	('mutant', 'Var', (241, 247))	('miR-145', 'Gene', (99, 106))	('miR-145', 'Gene', '406937', (99, 106))	('IGF1R', 'Gene', (248, 253))	('miR-143', 'Gene', '406935', (87, 94))	('mutated', 'Var', (112, 119))	('miR-145', 'Gene', (210, 217))	('miR-143', 'Gene', '406935', (153, 160))	('miR-145', 'Gene', '406937', (210, 217))	('miR-143', 'Gene', (153, 160))
32169	25474488	In support of the notion that miR-143/145 function as key cancer suppressed miRNAs, Caco2, HT29 and SW480 cells transfected with pre-miR-143/145 showed suppressed proliferation (Figure 3A, 3E and 3I).	('suppressed', 'NegReg', (152, 162))	('pre-miR-143/145', 'Var', (129, 144))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('pre', 'molecular_function', 'GO:0003904', ('129', '132'))	('proliferation', 'CPA', (163, 176))	('SW480', 'CellLine', 'CVCL:0546', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('HT29', 'CellLine', 'CVCL:0320', (91, 95))	('cancer', 'Disease', (58, 64))
32174	25474488	Consistent with the results from the CCK-8 assay, the percentage of EdU-positive cells was significantly lower in cells transfected with pre-miR-143/145 (Figure 4A and 4B).	('lower', 'NegReg', (105, 110))	('EdU-positive cells', 'CPA', (68, 86))	('EdU', 'Chemical', 'MESH:C031086', (68, 71))	('pre-miR-143/145', 'Var', (137, 152))	('pre', 'molecular_function', 'GO:0003904', ('137', '140'))
32175	25474488	Similarly, significantly more EdU-positive cells were observed in the cells with IGF1R overexpression, whereas IGF1R-siRNA transfected cells showed the opposite effect on cell proliferation (Figure 4C and 4D).	('EdU-positive cells', 'CPA', (30, 48))	('overexpression', 'Var', (87, 101))	('EdU', 'Chemical', 'MESH:C031086', (30, 33))	('cell proliferation', 'biological_process', 'GO:0008283', ('171', '189'))	('IGF1R', 'Gene', (81, 86))	('more', 'PosReg', (25, 29))
32183	25474488	Finally, we showed that miR-143/145 inhibited IGF1R expression and consequently suppressed the proliferation of colorectal cancer cells in vitro.	('colorectal cancer', 'Disease', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('inhibited', 'NegReg', (36, 45))	('miR-143/145', 'Var', (24, 35))	('expression', 'MPA', (52, 62))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('proliferation', 'CPA', (95, 108))	('suppressed', 'NegReg', (80, 90))	('IGF1R', 'Gene', (46, 51))
32188	25474488	Nevertheless, the findings of ours and others highlight that miR-143/145 may act as tumor-suppressive miRNAs, and that the targeting of IGF1R may be one mechanism by which the miR-143/145 cluster exerts its tumor suppressive function.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('IGF1R', 'Gene', (136, 141))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('miR-143/145', 'Var', (176, 187))	('tumor', 'Disease', (207, 212))
32189	25474488	Therefore, the modulation of IGF1R by miR-143/145 may explain why the downregulation of miR-143/145 during colorectal carcinogenesis can promote cancer progression.	('cancer', 'Disease', (145, 151))	('miR-143/145', 'Var', (88, 99))	('IGF1R', 'Gene', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('promote', 'PosReg', (137, 144))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (107, 132))	('downregulation', 'NegReg', (70, 84))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('colorectal carcinogenesis', 'Disease', (107, 132))
32198	25474488	Conversely, attempts to reduce miRNA levels using biologically stable antisense oligonucleotides, such as antagomirs, have also proven capable of altering intracellular transcript profiles.	('antisense oligonucleotides', 'Var', (70, 96))	('miRNA levels', 'MPA', (31, 43))	('intracellular transcript profiles', 'MPA', (155, 188))	('altering', 'Reg', (146, 154))	('oligonucleotides', 'Chemical', 'MESH:D009841', (80, 96))
32246	32638384	Tumor location was categorized as right-sided colon (C18.0, C18.1, C18.2, C18.3 or C18.4), left-sided colon (C18.5, 18.6, 18.7), rectum (C19.9, C20.9) or unknown (C18.8 or C18.9).	('C18.4', 'Var', (83, 88))	('left-sided', 'Disease', (91, 101))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('C20.9', 'Var', (144, 149))	('C18.0', 'Var', (53, 58))	('C18.5', 'Var', (109, 114))	('C19.9', 'Var', (137, 142))	('C18.3 or C18.4', 'Var', (74, 88))	('C20.9', 'CellLine', 'CVCL:W178', (144, 149))
32381	33335899	Similarly, CDR1as was found to promote the progression of cholangiocarcinoma and osteoarthritis by sponging miR-641.	('osteoarthritis', 'Disease', 'MESH:D010003', (81, 95))	('CDR1as', 'Gene', '103611090', (11, 17))	('miR-641', 'Gene', (108, 115))	('cholangiocarcinoma', 'Disease', (58, 76))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('promote', 'PosReg', (31, 38))	('osteoarthritis', 'Phenotype', 'HP:0002758', (81, 95))	('osteoarthritis', 'Disease', (81, 95))	('miR-641', 'Gene', '693226', (108, 115))	('CDR1as', 'Gene', (11, 17))	('sponging', 'Var', (99, 107))
32382	33335899	Moreover, CDR1as was reported to sponge miR-135b-5p, miR-219a, miR-1299, and miR-876-5p in ovarian cancer, non-small-cell lung cancer and esophageal squamous cell carcinoma, respectively.	('ovarian cancer', 'Disease', 'MESH:D010051', (91, 105))	('miR-876', 'Gene', '100126310', (77, 84))	('miR-1299', 'Gene', (63, 71))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (138, 172))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (149, 172))	('miR-135b-5p', 'Var', (40, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('ovarian cancer', 'Disease', (91, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (91, 105))	('miR-219a', 'Var', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('miR-876', 'Gene', (77, 84))	('CDR1as', 'Gene', (10, 16))	('miR-1299', 'Gene', '100302167', (63, 71))	('CDR1as', 'Gene', '103611090', (10, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('non-small-cell lung cancer', 'Disease', (107, 133))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (107, 133))	('esophageal squamous cell carcinoma', 'Disease', (138, 172))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
32398	33335899	Furthermore, CDR1as knockdown inhibited tumor growth, invasion and metastasis by regulating the miR-219a-5p/SOX5 axis in non-small-cell lung cancer.	('regulating', 'Reg', (81, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('non-small-cell lung cancer', 'Disease', (121, 147))	('inhibited', 'NegReg', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (121, 147))	('SOX5', 'Gene', '6660', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('CDR1as', 'Gene', (13, 19))	('SOX5', 'Gene', (108, 112))	('knockdown', 'Var', (20, 29))	('tumor', 'Disease', (40, 45))	('CDR1as', 'Gene', '103611090', (13, 19))
32399	33335899	Similarly, the knockdown of CDR1as could inhibit tumor growth via miR-135p in ovarian cancer.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('knockdown', 'Var', (15, 24))	('ovarian cancer', 'Disease', 'MESH:D010051', (78, 92))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', (49, 54))	('miR-135p', 'Var', (66, 74))	('CDR1as', 'Gene', (28, 34))	('inhibit', 'NegReg', (41, 48))	('ovarian cancer', 'Disease', (78, 92))	('miR-135p', 'Chemical', '-', (66, 74))	('CDR1as', 'Gene', '103611090', (28, 34))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))
32406	33335899	However, CDR1as was found to sponge miR-135b-5p and upregulate the expression of HIF1AN to inhibit the growth, invasion and metastasis of ovarian cancer, which shows that the roles of CDR1as in tumor metastasis vary in different cacer types (Figure 2).	('metastasis of ovarian cancer', 'Disease', (124, 152))	('CDR1as', 'Gene', (9, 15))	('HIF1AN', 'Gene', '55662', (81, 87))	('expression', 'Var', (67, 77))	('growth', 'CPA', (103, 109))	('inhibit', 'NegReg', (91, 98))	('HIF1AN', 'Gene', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('CDR1as', 'Gene', '103611090', (184, 190))	('CDR1as', 'Gene', '103611090', (9, 15))	('metastasis of ovarian cancer', 'Disease', 'MESH:D009362', (124, 152))	('ovarian cancer', 'Phenotype', 'HP:0100615', (138, 152))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('upregulate', 'PosReg', (52, 62))	('CDR1as', 'Gene', (184, 190))
32408	33335899	A number of studies have demonstrated that the dysregulated expression of CDR1as is related to cancer chemoresistance.	('expression', 'MPA', (60, 70))	('related', 'Reg', (84, 91))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('CDR1as', 'Gene', (74, 80))	('cancer', 'Disease', (95, 101))	('CDR1as', 'Gene', '103611090', (74, 80))	('dysregulated', 'Var', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
32409	33335899	Two studies showed that the knockdown of CDR1as could increase the chemosensitivity of 5-fluorouracyl- and cisplatin-resistant breast cancer cells by sponging miR-7.	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('increase', 'PosReg', (54, 62))	('breast cancer', 'Disease', (127, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('knockdown', 'Var', (28, 37))	('CDR1as', 'Gene', (41, 47))	('5-fluorouracyl', 'Chemical', '-', (87, 101))	('CDR1as', 'Gene', '103611090', (41, 47))
32418	33335899	In detail, high CDR1as expression was associated with worse clinicopathological characteristics, including the T status, N status, histological grade, TNM stage and distant metastasis in solid tumors, such as esophageal squamous cell carcinoma (ESCC), non-small cell lung cancer (NSCLC), colorectal cancer (CC), and hepatocellular carcinoma.	('lung cancer', 'Phenotype', 'HP:0100526', (267, 278))	('colorectal cancer', 'Disease', (288, 305))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (316, 340))	('esophageal squamous cell carcinoma', 'Disease', (209, 243))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (252, 278))	('hepatocellular carcinoma', 'Disease', (316, 340))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (256, 278))	('colorectal cancer', 'Phenotype', 'HP:0003003', (288, 305))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (209, 243))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (220, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (331, 340))	('lung cancer', 'Disease', (267, 278))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('distant metastasis', 'CPA', (165, 183))	('NSCLC', 'Disease', 'MESH:D002289', (280, 285))	('expression', 'MPA', (23, 33))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (316, 340))	('CDR1as', 'Gene', (16, 22))	('tumors', 'Disease', (193, 199))	('CDR1as', 'Gene', '103611090', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('lung cancer', 'Disease', 'MESH:D008175', (267, 278))	('colorectal cancer', 'Disease', 'MESH:D015179', (288, 305))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('high', 'Var', (11, 15))	('NSCLC', 'Disease', (280, 285))
32420	33335899	In addition, the expression of CDR1as was found to be associated with poor prognosis in cancer patients.	('CDR1as', 'Gene', '103611090', (31, 37))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('patients', 'Species', '9606', (95, 103))	('expression', 'Var', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('CDR1as', 'Gene', (31, 37))	('associated', 'Reg', (54, 64))
32432	32021241	Real-time PCR assay was used to verify the aberrantly expressed genes expression in CRC samples.	('CRC', 'Phenotype', 'HP:0003003', (84, 87))	('aberrantly expressed genes', 'Var', (43, 69))	('CRC', 'Disease', (84, 87))	('CRC', 'Disease', 'MESH:D015179', (84, 87))
32452	32021241	A total of 738 CRC samples and 93 non-cancer samples were selected from four gene expression datasets (25 normal samples and 123 cancer samples in GSE21510 from Japan, 32 pairs in GSE8671 from Switzerland, 17 pairs in GSE32323 from Japan and 19 normal samples and 566 cancer samples plus clinical information in GSE39582 from France).	('cancer', 'Disease', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('gene expression', 'biological_process', 'GO:0010467', ('77', '92'))	('CRC', 'Disease', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('GSE8671', 'Var', (180, 187))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('CRC', 'Disease', 'MESH:D015179', (15, 18))	('cancer', 'Disease', (38, 44))	('CRC', 'Phenotype', 'HP:0003003', (15, 18))	('GSE21510', 'Var', (147, 155))	('cancer', 'Disease', 'MESH:D009369', (268, 274))
32455	32021241	The DEG analysis between tumor and non-tumor samples of the GSE8671, GSE21510, GSE32323, and GSE39582 datasets and the DELs between tumor and non-tumor of TCGA dataset were performed with the Limma package of Bioconductor R (http://www.bioconductor.org/packages/release/bioc/html/limma.html).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('non-tumor', 'Disease', (142, 151))	('tumor', 'Disease', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (132, 137))	('GSE8671', 'Var', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('non-tumor', 'Disease', 'MESH:C580335', (35, 44))	('GSE39582', 'Var', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('GSE21510', 'Var', (69, 77))	('GSE32323', 'Var', (79, 87))	('tumor', 'Disease', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('non-tumor', 'Disease', 'MESH:C580335', (142, 151))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('non-tumor', 'Disease', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (39, 44))
32466	32021241	By applying bioinformatics analysis, we investigated DEGs between CRC and non-cancer samples of the GEO dataset (GSE8671, GSE21510, GSE32323 and GSE39582).	('GSE39582', 'Var', (145, 153))	('CRC', 'Phenotype', 'HP:0003003', (66, 69))	('CRC', 'Disease', 'MESH:D015179', (66, 69))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('GSE32323', 'Var', (132, 140))	('GSE8671', 'Var', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('GSE21510', 'Var', (122, 130))	('CRC', 'Disease', (66, 69))
32478	32021241	As shown in Figure 6, in CRC samples of GSE39582, patients with CDC6, CDC45 or ORC6 low expression in the tumor samples had significantly worse relapse-free survival (RFS) (P<0.001, hazard ratio 2.555, 95% CI: 1.775-3.678 for CDC6, Figure 6A; P <0.001, hazard ratio: 1.916, 95% CI: 1.380-2.659 for CDC45, Figure 6B; P =0.0168, hazard ratio: 1.490, 95% CI: 1.074-2.067 for ORC6, Figure 6C) and overall survival (OS) (P=0.0033, hazard ratio 1.543, 95% CI: 1.155-2.061 for CDC6, Figure 6D; P = 0.0459, hazard ratio: 1.341, 95% CI: 1.005-1.788 for CDC45, Figure 6E) based on a 250 days follow-up.	('ORC6', 'Gene', '23594', (372, 376))	('worse', 'PosReg', (138, 143))	('CDC6', 'Gene', '990', (64, 68))	('GSE39582', 'Var', (40, 48))	('CDC6', 'Gene', (226, 230))	('relapse-free survival', 'CPA', (144, 165))	('tumor', 'Disease', (106, 111))	('overall survival', 'CPA', (393, 409))	('CDC45', 'Gene', '8318', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('CRC', 'Disease', (25, 28))	('CDC45', 'Gene', (70, 75))	('CDC6', 'Gene', (470, 474))	('CRC', 'Phenotype', 'HP:0003003', (25, 28))	('patients', 'Species', '9606', (50, 58))	('CDC6', 'Gene', (64, 68))	('CDC45', 'Gene', '8318', (544, 549))	('CDC6', 'Gene', '990', (226, 230))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('CDC45', 'Gene', '8318', (298, 303))	('CDC45', 'Gene', (544, 549))	('low', 'NegReg', (84, 87))	('CRC', 'Disease', 'MESH:D015179', (25, 28))	('CDC6', 'Gene', '990', (470, 474))	('ORC6', 'Gene', (79, 83))	('CDC45', 'Gene', (298, 303))	('ORC6', 'Gene', (372, 376))	('ORC6', 'Gene', '23594', (79, 83))
32494	32021241	In the present study, we identified the significantly differentially expressed mRNAs and lncRNAs in CRC by using GSE8671, GSE21510, GSE32323, GSE39582 and TCGA database.	('CRC', 'Phenotype', 'HP:0003003', (100, 103))	('CRC', 'Disease', 'MESH:D015179', (100, 103))	('GSE8671', 'Var', (113, 120))	('GSE21510', 'Var', (122, 130))	('CRC', 'Disease', (100, 103))
32495	32021241	GO and KEGG pathway analyses showed that DEGs were associated with CRC progression.	('CRC', 'Disease', (67, 70))	('associated', 'Reg', (51, 61))	('CRC', 'Phenotype', 'HP:0003003', (67, 70))	('DEGs', 'Var', (41, 45))	('CRC', 'Disease', 'MESH:D015179', (67, 70))
32499	32021241	Cancer is characterized by deregulated proliferative signaling resulting from aberrant cell cycle activity.	('aberrant', 'Var', (78, 86))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('deregulated proliferative signaling', 'MPA', (27, 62))	('cell cycle', 'biological_process', 'GO:0007049', ('87', '97'))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('aberrant cell cycle', 'Phenotype', 'HP:0011018', (78, 97))	('cell cycle activity', 'CPA', (87, 106))
32504	32021241	CDC6 dysregulated is associated with many types of human malignancies including breast cancer, prostate cancer, ovarian cancer as well as lung cancer and osteosarcoma.	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('osteosarcoma', 'Phenotype', 'HP:0002669', (154, 166))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('dysregulated', 'Var', (5, 17))	('human', 'Species', '9606', (51, 56))	('CDC6', 'Gene', '990', (0, 4))	('breast cancer', 'Disease', (80, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('malignancies', 'Disease', 'MESH:D009369', (57, 69))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('ovarian cancer', 'Disease', 'MESH:D010051', (112, 126))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('malignancies', 'Disease', (57, 69))	('prostate cancer', 'Disease', 'MESH:D011471', (95, 110))	('prostate cancer', 'Phenotype', 'HP:0012125', (95, 110))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('osteosarcoma', 'Disease', (154, 166))	('prostate cancer', 'Disease', (95, 110))	('ovarian cancer', 'Disease', (112, 126))	('associated', 'Reg', (21, 31))	('osteosarcoma', 'Disease', 'MESH:D012516', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Disease', (138, 149))	('ovarian cancer', 'Phenotype', 'HP:0100615', (112, 126))	('CDC6', 'Gene', (0, 4))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))
32540	31897139	Kaplan-Meier analysis revealed that patients with high expression levels of BMP-9 exhibited shorter overall survival rate than those with low levels of expression (54.7 vs. 41.3 months; log-rank test, P<0.05).	('BMP-9', 'Gene', (76, 81))	('high expression levels', 'Var', (50, 72))	('patients', 'Species', '9606', (36, 44))	('overall', 'MPA', (100, 107))	('shorter', 'NegReg', (92, 99))
32591	31897139	Additionally, the Kurashina (GSE11417) and Gaedcke (GSE20842) dataset from the Oncomine database , which is a cancer microarray database and web-based data-mining platform for genome-wide expression analyses, was downloaded.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('GSE11417', 'Var', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))
32595	31897139	A Kaplan-Meier analysis was performed in order to estimate the 5-year overall survival (OS) rate for patients with CRC with low- or high- BMP-9 expression levels.	('patients', 'Species', '9606', (101, 109))	('low-', 'NegReg', (124, 128))	('CRC', 'Disease', (115, 118))	('expression', 'MPA', (144, 154))	('high- BMP-9', 'Var', (132, 143))	('CRC', 'Disease', 'MESH:D015179', (115, 118))
32606	31897139	In normal mucosa, cells positive for nuclear Ki-67 were localized primarily at the bottom of the glands, whereas, in adenoma and carcinoma samples, such cells were distributed randomly (Fig.	('Ki-67', 'Var', (45, 50))	('adenoma and carcinoma', 'Disease', 'MESH:D000236', (117, 138))	('nuclear Ki-67', 'Var', (37, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))
32623	31897139	Furthermore, BMP-9 expression was independently associated with poor prognosis in CRC (P=0.044) as determined by multivariate analyses, which indicated the prognostic significance of BMP-9 expression in CRC [hazard ratio (HR), 3.14; 95% CI, 1.03-9.57; Table VII].	('CRC', 'Disease', 'MESH:D015179', (82, 85))	('BMP-9', 'Gene', (183, 188))	('CRC', 'Disease', 'MESH:D015179', (203, 206))	('expression', 'Var', (19, 29))	('CRC', 'Disease', (82, 85))	('BMP-9', 'Gene', (13, 18))	('CRC', 'Disease', (203, 206))
32624	31897139	Bioinformatics analysis using the available datasets confirmed the observations that patients with CRC and high BMP-9 mRNA expression exhibited decreased OS time compared with those with low expression (Fig.	('CRC', 'Disease', 'MESH:D015179', (99, 102))	('decreased', 'NegReg', (144, 153))	('mRNA', 'MPA', (118, 122))	('BMP-9', 'Gene', (112, 117))	('CRC', 'Disease', (99, 102))	('patients', 'Species', '9606', (85, 93))	('high', 'Var', (107, 111))	('OS time', 'MPA', (154, 161))
32630	31897139	In addition, it was revealed that BMP-9 may serve as an independent prognostic factor for patients with CRC, and that high BMP-9 expression was significantly associated with poor prognosis and decreased survival rate.	('high', 'Var', (118, 122))	('CRC', 'Disease', (104, 107))	('expression', 'MPA', (129, 139))	('survival rate', 'CPA', (203, 216))	('CRC', 'Disease', 'MESH:D015179', (104, 107))	('BMP-9', 'Gene', (34, 39))	('BMP-9', 'Gene', (123, 128))	('decreased', 'NegReg', (193, 202))	('patients', 'Species', '9606', (90, 98))
32640	31897139	Although research has been performed following the detection of a germline mutation of bone morphogenetic protein receptor type 1A in patients with juvenile polyposis syndrome, the precise role of BMP signaling in CRC remains unclear.	('BMP', 'Gene', '649', (197, 200))	('bone morphogenetic protein receptor type 1A', 'Gene', '657', (87, 130))	('juvenile polyposis', 'Phenotype', 'HP:0004784', (148, 166))	('bone morphogenetic protein receptor type 1A', 'Gene', (87, 130))	('patients', 'Species', '9606', (134, 142))	('juvenile polyposis syndrome', 'Disease', 'MESH:C537702', (148, 175))	('CRC', 'Disease', (214, 217))	('BMP', 'Gene', (197, 200))	('germline mutation', 'Var', (66, 83))	('CRC', 'Disease', 'MESH:D015179', (214, 217))	('juvenile polyposis syndrome', 'Disease', (148, 175))
32642	31897139	However, Yokoyama et al reported that the expression levels of BMP-4 in human CRC cells and tissues were upregulated when compared with those in normal epithelium or adenoma, while inhibition of BMP-4 promoted the apoptosis of CRC cells in vitro and in vivo.	('upregulated', 'PosReg', (105, 116))	('CRC', 'Disease', (227, 230))	('apoptosis', 'CPA', (214, 223))	('expression levels', 'MPA', (42, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('214', '223'))	('apoptosis', 'biological_process', 'GO:0006915', ('214', '223'))	('human', 'Species', '9606', (72, 77))	('BMP-4', 'Gene', (63, 68))	('inhibition', 'Var', (181, 191))	('CRC', 'Disease', 'MESH:D015179', (227, 230))	('BMP-4', 'Gene', (195, 200))	('CRC', 'Disease', (78, 81))	('BMP-4', 'Gene', '652', (195, 200))	('adenoma', 'Disease', 'MESH:D000236', (166, 173))	('BMP-4', 'Gene', '652', (63, 68))	('promoted', 'PosReg', (201, 209))	('adenoma', 'Disease', (166, 173))	('CRC', 'Disease', 'MESH:D015179', (78, 81))
32651	31897139	In order to evaluate the prognostic value of BMP-9 expression in patients with CRC, a Kaplan-Meier univariate survival analysis was performed in the present study, which revealed an association between high BMP-9 expression levels and poor prognosis in patients with this disease.	('patients', 'Species', '9606', (253, 261))	('CRC', 'Disease', 'MESH:D015179', (79, 82))	('high', 'Var', (202, 206))	('patients', 'Species', '9606', (65, 73))	('CRC', 'Disease', (79, 82))	('BMP-9 expression levels', 'MPA', (207, 230))
32660	31897139	Thus, modulating BMP-9 activity may be considered as a novel therapeutic strategy in the treatment of CRC; however, further investigation is warranted to elucidate the mechanism underlying the protumorigenic effects of BMP-9 in the disease.	('CRC', 'Disease', 'MESH:D015179', (102, 105))	('tumor', 'Disease', (196, 201))	('men', 'Species', '9606', (94, 97))	('CRC', 'Disease', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('modulating', 'Var', (6, 16))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
32662	31545917	Proteomics analysis of the matrisome from MC38 experimental mouse liver metastases Dissemination of primary tumors to distant anatomical sites has a substantial negative impact on patient prognosis.	('metastases', 'Disease', (72, 82))	('matrisome', 'cellular_component', 'GO:0031012', ('27', '36'))	('metastases', 'Disease', 'MESH:D009362', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('negative', 'NegReg', (161, 169))	('mouse', 'Species', '10090', (60, 65))	('tumors', 'Disease', (108, 114))	('MC38', 'Var', (42, 46))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('patient', 'Species', '9606', (180, 187))
32675	31545917	Alterations in the matrisome (i.e., the ensemble of ECM proteins) enable tumor cells to invade surrounding tissues and intravasate into capillaries through multiple mechanisms, including promotion of cell proliferation, invasion, and triggering of the epithelial-to-mesenchymal transition.	('cell proliferation', 'biological_process', 'GO:0008283', ('200', '218'))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Alterations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('252', '288'))	('invasion', 'CPA', (220, 228))	('promotion', 'PosReg', (187, 196))	('cell proliferation', 'CPA', (200, 218))	('tumor', 'Disease', (73, 78))	('epithelial-to-mesenchymal', 'CPA', (252, 277))	('matrisome', 'cellular_component', 'GO:0031012', ('19', '28'))
32696	31545917	Samples were then solubilized in a mixture of 8M urea (9U5378; Sigma), 100 mM ammonium bicarbonate (09830; Sigma), and 10 mM DTT (43817; Sigma), pH 7.8, and incubated at 37 C for 30 min.	('09830', 'Var', (100, 105))	('ammonium bicarbonate', 'Chemical', 'MESH:C027043', (78, 98))	('9U5378', 'Var', (55, 61))	('urea', 'Chemical', 'MESH:D014508', (49, 53))
32705	31545917	The MS proteomics data have been deposited to the ProteomeXchange consortium via the Proteomics Identifications (or PRIDE) partner repository with the data set identifiers PXD013350 and 10.6019/PXD013350.	('PXD013350', 'Var', (172, 181))	('PXD013350', 'Chemical', 'MESH:C487081', (172, 181))	('PXD013350', 'Chemical', 'MESH:C487081', (194, 203))	('10.6019/PXD013350', 'Var', (186, 203))
32708	31545917	For immunostaining, the sections were briefly fixed in acetone, washed with PBS, blocked with 20% goat/donkey serum, and incubated overnight with the following primary antibodies: annexin A1 (AF3770; R&D Systems), S100-A11 (10237-1-AP; Proteintech), collagen IV (ab6586; Abcam), collagen V (ab7046; Abcam), fibronectin (ab2413; Abcam), laminin (ab30320; Abcam), CD11b (ab62817; Abcam), Ly6G (551459; BD Biosciences), and CD3 (ab33429; Abcam).	('CD3', 'Gene', '12501', (421, 424))	('fibronectin', 'Gene', '14268', (307, 318))	('CD11b', 'Gene', '16409', (362, 367))	('collagen', 'molecular_function', 'GO:0005202', ('279', '287'))	('Ly6G', 'Gene', (386, 390))	('goat', 'Species', '9925', (98, 102))	('fibronectin', 'Gene', (307, 318))	('Ly6G', 'Gene', '546644', (386, 390))	('collagen', 'molecular_function', 'GO:0005202', ('250', '258'))	('CD11b', 'Gene', (362, 367))	('acetone', 'Chemical', 'MESH:D000096', (55, 62))	('CD3', 'Gene', (421, 424))	('AF3770', 'Var', (192, 198))	('donkey', 'Species', '9793', (103, 109))
32712	31545917	Blots were incubated for 18 h at 4 C with one of the following primary antibodies: annexin A1 (AF3770; R&D Systems), actin (sc-47778; Santa Cruz Biotechnology), or GAPDH (D16H11; Cell Signaling Technology).	('GAPDH', 'Gene', '14433', (164, 169))	('GAPDH', 'Gene', (164, 169))	('Signaling', 'biological_process', 'GO:0023052', ('184', '193'))	('AF3770;', 'Var', (95, 102))	('annexin A1', 'Protein', (83, 93))
32723	31545917	The Broad Institute's Cancer Cell Line Encyclopedia (https://portals.broadinstitute.org/ccle) was used to analyze coexpression of annexin A1 and S100-A11 in 1,072 cancer cell lines.	('Cancer', 'Phenotype', 'HP:0002664', (22, 28))	('Cancer', 'Disease', (22, 28))	('Cancer', 'Disease', 'MESH:D009369', (22, 28))	('annexin A1', 'Protein', (130, 140))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('S100-A11', 'Var', (145, 153))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
32766	31545917	Furthermore, mRNA levels of annexin A1 and S100-A11 positively correlated in 1,072 comprehensively characterized human cancer cell lines (Fig.	('correlated', 'Reg', (63, 73))	('S100-A11', 'Var', (43, 51))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('annexin A1', 'Protein', (28, 38))	('mRNA levels', 'MPA', (13, 24))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('human', 'Species', '9606', (113, 118))
32771	31545917	We then questioned if S100-A11 gene expression can be altered upon Anxa1 knockdown but found no alteration of mRNA levels compared with vector control cells (Fig.	('Anxa1', 'Gene', '16952', (67, 72))	('Anxa1', 'Gene', (67, 72))	('S100-A11', 'Gene', (22, 30))	('altered', 'Reg', (54, 61))	('gene expression', 'biological_process', 'GO:0010467', ('31', '46'))	('expression', 'MPA', (36, 46))	('knockdown', 'Var', (73, 82))
32773	31545917	To investigate whether Anxa1 knockdown impacts on tumor cell proliferation in vivo, we injected them subcutaneously into flanks of C57BL/6 mice (n = 5 mice per group).	('mice', 'Species', '10090', (151, 155))	('knockdown', 'Var', (29, 38))	('Anxa1', 'Gene', (23, 28))	('impacts', 'Reg', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mice', 'Species', '10090', (139, 143))	('Anxa1', 'Gene', '16952', (23, 28))	('tumor', 'Disease', (50, 55))
32779	31545917	Proteomics analysis of the matrisome from human colorectal cancer liver metastases revealed a strong over-representation of the TGF-beta pathway, whereas inhibition of TGF-beta signaling substantially diminished murine experimental hepatic metastases from colon cancer.	('signaling', 'biological_process', 'GO:0023052', ('177', '186'))	('human', 'Species', '9606', (42, 47))	('inhibition', 'Var', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('TGF-beta', 'Gene', '21803', (168, 176))	('diminished', 'NegReg', (201, 211))	('colon cancer', 'Phenotype', 'HP:0003003', (256, 268))	('murine', 'Species', '10090', (212, 218))	('colorectal cancer liver metastases', 'Disease', 'MESH:D015179', (48, 82))	('TGF-beta', 'Gene', (128, 136))	('over-representation', 'PosReg', (101, 120))	('hepatic metastases', 'Disease', 'MESH:D009362', (232, 250))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('colon cancer', 'Disease', 'MESH:D015179', (256, 268))	('hepatic metastases', 'Disease', (232, 250))	('TGF-beta', 'Gene', (168, 176))	('colorectal cancer', 'Phenotype', 'HP:0003003', (48, 65))	('colorectal cancer liver metastases', 'Disease', (48, 82))	('matrisome', 'cellular_component', 'GO:0031012', ('27', '36'))	('colon cancer', 'Disease', (256, 268))	('TGF-beta', 'Gene', '21803', (128, 136))
32780	31545917	Thus, the matrisome and its alterations are involved in important aspects of colorectal metastatic disease, yet the topic remains insufficiently studied.	('involved', 'Reg', (44, 52))	('colorectal metastatic disease', 'Disease', (77, 106))	('colorectal metastatic disease', 'Disease', 'MESH:D015179', (77, 106))	('alterations', 'Var', (28, 39))
32781	31545917	In this study, we have found 27 proteins differentially expressed between MC38 hepatic metastases and normal mouse liver.	('hepatic metastases', 'Disease', 'MESH:D009362', (79, 97))	('MC38', 'Var', (74, 78))	('hepatic metastases', 'Disease', (79, 97))	('mouse', 'Species', '10090', (109, 114))
32795	31545917	For example, disruption of the annexin A1/S100-A11 complex enhanced the migration and clonogenic growth of ovarian cancer cells by modulating epithelial growth factor signaling.	('growth of ovarian cancer', 'Disease', (97, 121))	('signaling', 'biological_process', 'GO:0023052', ('167', '176'))	('growth of ovarian cancer', 'Disease', 'MESH:D010051', (97, 121))	('disruption', 'Var', (13, 23))	('enhanced', 'PosReg', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ovarian cancer', 'Phenotype', 'HP:0100615', (107, 121))	('modulating', 'Reg', (131, 141))	('annexin A1/S100-A11 complex', 'Protein', (31, 58))	('epithelial growth factor signaling', 'MPA', (142, 176))
32797	31545917	To conclude, here, we quantitatively characterized the matrisome of MC38 murine hepatic metastases.	('murine', 'Species', '10090', (73, 79))	('MC38', 'Var', (68, 72))	('hepatic metastases', 'Disease', 'MESH:D009362', (80, 98))	('hepatic metastases', 'Disease', (80, 98))
32800	31545917	Support for this study has been provided by CRUK funding to the Oxford Institute for Radiation Oncology (C5255/A15935) and CRUK/EPSRC Oxford Cancer Imaging Centre (C5255/A16466).	('Oncology', 'Phenotype', 'HP:0002664', (95, 103))	('Su', 'Chemical', 'MESH:C035067', (0, 2))	('C5255', 'Chemical', 'MESH:C021943', (105, 110))	('C5255/A16466', 'Var', (164, 176))	('Cancer', 'Disease', (141, 147))	('Rad', 'Gene', (85, 88))	('Cancer', 'Phenotype', 'HP:0002664', (141, 147))	('C5255', 'Chemical', 'MESH:C021943', (164, 169))	('C5255/A15935', 'Var', (105, 117))	('Cancer', 'Disease', 'MESH:D009369', (141, 147))	('Rad', 'Gene', '56437', (85, 88))
32803	31316143	The sensitivity of using mSEPT9 methylation status for diagnosing CRC was significantly higher than using elevated CEA levels (73.2% vs 48.2%; p value < 0.001).	('higher', 'PosReg', (88, 94))	('mSEPT9', 'Gene', '53860', (25, 31))	('CRC', 'Phenotype', 'HP:0003003', (66, 69))	('CEA', 'Gene', (115, 118))	('mSEPT9', 'Gene', (25, 31))	('CEA', 'Gene', '1084', (115, 118))	('methylation status', 'Var', (32, 50))	('elevated CEA', 'Phenotype', 'HP:0031029', (106, 118))	('CRC', 'Disease', (66, 69))
32816	31316143	Aberrant methylation is a regulatory mechanism of gene expressions which is commonly found in tumor suppressor genes in many cancers, including CRC.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('CRC', 'Phenotype', 'HP:0003003', (144, 147))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', (94, 99))	('Aberrant methylation', 'Var', (0, 20))	('CRC', 'Disease', (144, 147))
32913	25670906	S + V was observed in four of 11 patients (36.4%), as well as V in two (18.2%), S + V + C in one (9.1%), E + S + V in one (9.1%), E + C in one (9.1%), E in one (9.1%), and C in one (9.1%).	('V', 'Chemical', 'MESH:D014639', (84, 85))	('C', 'Chemical', 'MESH:D002244', (134, 135))	('E + S + V', 'Chemical', '-', (105, 114))	('patients', 'Species', '9606', (33, 41))	('S +', 'Disease', (0, 3))	('V', 'Chemical', 'MESH:D014639', (113, 114))	('S', 'Chemical', 'MESH:D013455', (80, 81))	('S + V + C', 'Var', (80, 89))	('V', 'Chemical', 'MESH:D014639', (4, 5))	('E + C', 'Var', (130, 135))	('C', 'Chemical', 'MESH:D002244', (88, 89))	('V + C', 'Chemical', 'MESH:D014752', (84, 89))	('V', 'Chemical', 'MESH:D014639', (62, 63))	('C', 'Chemical', 'MESH:D002244', (172, 173))	('S', 'Chemical', 'MESH:D013455', (109, 110))	('E + C', 'Chemical', '-', (130, 135))	('E + S + V', 'Var', (105, 114))	('S', 'Chemical', 'MESH:D013455', (0, 1))
32981	25670906	In a prospective trial, the incidence of thrombosis was investigated in two groups assigned to receive LMWH or placebo for 6 weeks, with no significant difference being found (14.1% versus 18%).	('thrombosis', 'Disease', 'MESH:D013927', (41, 51))	('LMWH', 'Chemical', 'MESH:D006495', (103, 107))	('thrombosis', 'Disease', (41, 51))	('LMWH', 'Var', (103, 107))
33037	33271860	The antimetabolite 5-FU, commonly used in the treatment of colorectal cancer, exerts its anticancer activity through inhibition of thymidylate synthase and misincorporation of its metabolites into RNA and DNA.	('cancer', 'Disease', (93, 99))	('thymidylate synthase', 'Gene', (131, 151))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('colorectal cancer', 'Disease', (59, 76))	('misincorporation', 'Var', (156, 172))	('thymidylate synthase', 'Gene', '7298', (131, 151))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('DNA', 'cellular_component', 'GO:0005574', ('205', '208'))	('inhibition', 'NegReg', (117, 127))	('RNA', 'cellular_component', 'GO:0005562', ('197', '200'))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('colorectal cancer', 'Disease', 'MESH:D015179', (59, 76))	('5-FU', 'Chemical', 'MESH:D005472', (19, 23))
33046	33271860	In addition tRNA modification by incorporation of 2'-O-methylcytidine were previously described in 5-FU-treated Escherichia coli.	('5-FU', 'Chemical', 'MESH:D005472', (99, 103))	('Escherichia coli', 'Species', '562', (112, 128))	("2'-O-methylcytidine", 'Chemical', 'MESH:C052203', (50, 69))	('tRNA modification', 'MPA', (12, 29))	('incorporation', 'Var', (33, 46))
33047	33271860	Furthermore, we found an impact on lipid metabolism with decreased levels of AC 4:0, PC 30:0 and PC 32:2.	('lipid metabolism', 'biological_process', 'GO:0006629', ('35', '51'))	('PC 32:2', 'Var', (97, 104))	('lipid', 'Chemical', 'MESH:D008055', (35, 40))	('AC 4', 'Gene', '196883', (77, 81))	('AC 4', 'Gene', (77, 81))	('lipid metabolism', 'MPA', (35, 51))	('decreased', 'NegReg', (57, 66))
33080	33271860	Unless specifically stated otherwise, H+, Na+ and NH4+ adducts were selected for positive mode data while the deprotonated molecular ions and CH3COO- and HCOO- adducts were expected for negative mode data.	('NH4+', 'Var', (50, 54))	('CH3COO', 'Chemical', '-', (142, 148))	('HCOO', 'Chemical', '-', (154, 158))	('Na+', 'Var', (42, 45))	('NH4+', 'Chemical', '-', (50, 54))
33229	31673236	The HCT116-RFP tumors were also imaged by histology after one month.	('tumors', 'Disease', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('HCT116-RFP', 'Var', (4, 14))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
33240	31673236	Over a 48-hour period, strong cellular signals likely indicative of autophagy were observed in the rapamycin-treatment group, but not in the control group.	('rapamycin-treatment', 'Var', (99, 118))	('autophagy', 'biological_process', 'GO:0006914', ('68', '77'))	('men', 'Species', '9606', (114, 117))	('rapamycin', 'Chemical', 'MESH:D020123', (99, 108))	('autophagy', 'biological_process', 'GO:0016236', ('68', '77'))	('autophagy', 'CPA', (68, 77))
33249	31673236	Tumorigenesis is demonstrated with 3T3-GFP and HCT116-RFP cells in mural models, and real-time side-view endoscopy is used to demonstrate early identification of neoplasm.	('3T3-GFP', 'Var', (35, 42))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('HCT116-RFP', 'Var', (47, 57))	('neoplasm', 'Disease', (162, 170))	('Tumorigenesis', 'CPA', (0, 13))	('neoplasm', 'Disease', 'MESH:D009369', (162, 170))	('neoplasm', 'Phenotype', 'HP:0002664', (162, 170))
33256	30988064	Materials and methods: The aim of the present study was to analyze the association of TIMP2-418G/C and TIMP3-1296T/C promoter SNPs with colorectal cancer (CRC) susceptibility and development risk and also to evaluate the modifying effects of possible TIMP2-418G/C and TIMP3-1296T/C SNPs' genotypes on different risk factors of CRC or the reciprocal effect in ethnic population of Kashmir, India through a case-control setup.	('thr', 'Chemical', 'MESH:D013912', (395, 398))	('colorectal cancer', 'Phenotype', 'HP:0003003', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('CRC', 'Phenotype', 'HP:0003003', (155, 158))	('CRC', 'Disease', (327, 330))	('colorectal cancer', 'Disease', (136, 153))	('men', 'Species', '9606', (186, 189))	('colorectal cancer', 'Disease', 'MESH:D015179', (136, 153))	('CRC', 'Phenotype', 'HP:0003003', (327, 330))	('TIMP3-1296T/C', 'Var', (103, 116))
33257	30988064	The genotype frequencies of TIMP2-418G/C and TIMP3-1296T/C promoter SNPs were compared between 142 CRC patients and 184 individually matched healthy controls by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.	('CRC', 'Disease', (99, 102))	('TIMP2-418G/C', 'Var', (28, 40))	('men', 'Species', '9606', (209, 212))	('patients', 'Species', '9606', (103, 111))	('CRC', 'Phenotype', 'HP:0003003', (99, 102))	('TIMP3-1296T/C', 'Var', (45, 58))
33258	30988064	The associations between the TIMP2-418G/C and TIMP3-1296T/C SNPs and CRC risk were examined through conditional logistic regression models adjusted for multiple possible confounding (third) variables.	('TIMP2-418G/C', 'Var', (29, 41))	('TIMP3-1296T/C', 'Var', (46, 59))	('CRC', 'Phenotype', 'HP:0003003', (69, 72))	('thr', 'Chemical', 'MESH:D013912', (92, 95))	('CRC', 'Disease', (69, 72))	('associations', 'Interaction', (4, 16))
33261	30988064	The heterozygous genotype (GC) of TIMP2-418G/C was significantly associated with an increased risk of colorectal cancer [OR, 1.87 (95%CI, 1.07-3.27); P=0.027] whereas the heterozygous genotype (TC) of TIMP3-1296T/C SNP was significantly associated with a decreased risk of colorectal cancer [OR, 0.53 (95%CI, 0.32-0.86); P=0.011].	('colorectal cancer', 'Disease', (102, 119))	('TC', 'Chemical', 'MESH:D013667', (194, 196))	('colorectal cancer', 'Disease', (273, 290))	('decreased', 'NegReg', (255, 264))	('colorectal cancer', 'Disease', 'MESH:D015179', (273, 290))	('TIMP2-418G/C', 'Var', (34, 46))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (273, 290))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('TIMP3-1296T/C', 'Var', (201, 214))
33292	30988064	Several functional single nucleotide polymorphisms (SNPs) within the promoter regions of human TIMP genes have been reported to affect the production of the TIMPs in question through their effect on transcriptional activity that in turn leads to altered gene expression, secretion, and activity of these TIMPs and confer differences in susceptibility between different individuals to several diseases including various cancers.	('gene expression', 'biological_process', 'GO:0010467', ('254', '269'))	('secretion', 'MPA', (271, 280))	('altered', 'Reg', (246, 253))	('gene expression', 'MPA', (254, 269))	('cancers', 'Disease', 'MESH:D009369', (419, 426))	('human', 'Species', '9606', (89, 94))	('activity', 'MPA', (286, 294))	('TIMP', 'Gene', '7076', (95, 99))	('TIMP', 'Gene', '7076', (157, 161))	('TIMP', 'Gene', (304, 308))	('single nucleotide polymorphisms', 'Var', (19, 50))	('secretion', 'biological_process', 'GO:0046903', ('271', '280'))	('cancers', 'Phenotype', 'HP:0002664', (419, 426))	('production', 'MPA', (139, 149))	('thr', 'Chemical', 'MESH:D013912', (175, 178))	('cancers', 'Disease', (419, 426))	('differences', 'Reg', (321, 332))	('TIMP', 'Gene', '7076', (304, 308))	('transcriptional activity', 'MPA', (199, 223))	('affect', 'Reg', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (419, 425))	('TIMP', 'Gene', (95, 99))	('TIMP', 'Gene', (157, 161))
33293	30988064	Among these polymorphisms, the two functional SNPs located in the promoter region which have pivotal allele-specific effects on the regulation of TIMP2 and TIMP3 gene transcription and consequently the TIMP2 and TIMP3 protein activity occur at positions -418 and -1296 nucleotides (nt) relative to the transcription start site respectively representing a G to C transition and designated as TIMP2-418G/C SNP (rs8179090) and representing a T to C transition and designated as TIMP3-1296T/C SNP (rs9619311) are the most significant.	('TIMP2', 'Gene', '7077', (146, 151))	('TIMP3', 'Gene', (156, 161))	('TIMP3', 'Gene', '7078', (156, 161))	('rs8179090', 'Var', (409, 418))	('TIMP2', 'Gene', '7077', (391, 396))	('TIMP2', 'Gene', '7077', (202, 207))	('rs9619311', 'Var', (494, 503))	('effects', 'Reg', (117, 124))	('rs8179090', 'Mutation', 'rs8179090', (409, 418))	('TIMP2', 'Gene', (146, 151))	('TIMP3', 'Gene', (212, 217))	('TIMP3', 'Gene', '7078', (212, 217))	('TIMP3', 'Gene', (475, 480))	('TIMP3', 'Gene', '7078', (475, 480))	('TIMP2', 'Gene', (391, 396))	('TIMP2', 'Gene', (202, 207))	('rs9619311', 'Mutation', 'rs9619311', (494, 503))	('protein', 'cellular_component', 'GO:0003675', ('218', '225'))	('transcription', 'biological_process', 'GO:0006351', ('167', '180'))	('regulation', 'biological_process', 'GO:0065007', ('132', '142'))	('transcription', 'biological_process', 'GO:0006351', ('302', '315'))
33294	30988064	The TIMP2-418G/C SNP has been previously reported to be associated with risk modulation in colorectal cancer and other cancers including breast cancer, gastric cancer; oral cancer, prostate cancer, ovarian cancer, head and neck cancer, and non-Hodgkin's lymphoma.	('colorectal cancer', 'Disease', (91, 108))	('gastric cancer', 'Disease', (152, 166))	("non-Hodgkin's lymphoma", 'Disease', (240, 262))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('gastric cancer', 'Disease', 'MESH:D013274', (152, 166))	('TIMP2-418G/C SNP', 'Var', (4, 20))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (244, 262))	('head and neck cancer', 'Disease', 'MESH:D006258', (214, 234))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))	('lymphoma', 'Phenotype', 'HP:0002665', (254, 262))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('ovarian cancer', 'Disease', 'MESH:D010051', (198, 212))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('oral cancer', 'Disease', 'MESH:D009062', (168, 179))	('oral cancer', 'Disease', (168, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('gastric cancer', 'Phenotype', 'HP:0012126', (152, 166))	('neck', 'cellular_component', 'GO:0044326', ('223', '227'))	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (240, 262))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('prostate cancer', 'Disease', 'MESH:D011471', (181, 196))	('breast cancer', 'Disease', (137, 150))	('prostate cancer', 'Phenotype', 'HP:0012125', (181, 196))	('ovarian cancer', 'Disease', (198, 212))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (240, 262))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('head and neck cancer', 'Phenotype', 'HP:0012288', (214, 234))	('prostate cancer', 'Disease', (181, 196))	('ovarian cancer', 'Phenotype', 'HP:0100615', (198, 212))
33295	30988064	The association of TIMP3-1296T/C SNP has been reported in breast cancer gastroesophageal adenocarcinoma and hepatocellular carcinoma (HCC).	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (108, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('association', 'Interaction', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('HCC', 'Phenotype', 'HP:0001402', (134, 137))	('TIMP3-1296T/C SNP', 'Var', (19, 36))	('breast cancer gastroesophageal adenocarcinoma and hepatocellular carcinoma', 'Disease', 'MESH:D006528', (58, 132))
33297	30988064	In the present study, we systematically evaluated the possible association between TIMP2-418G/C and TIMP3-1296T/C SNPs and susceptibility to colorectal cancer in Kashmiri population through a case-control setup.	('TIMP3-1296T/C', 'Var', (100, 113))	('colorectal cancer', 'Disease', 'MESH:D015179', (141, 158))	('colorectal cancer', 'Phenotype', 'HP:0003003', (141, 158))	('TIMP2-418G/C', 'Var', (83, 95))	('colorectal cancer', 'Disease', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('thr', 'Chemical', 'MESH:D013912', (182, 185))
33318	30988064	The TIMP2-418G/C (rs8179090) and TIMP3-1296T/C (rs9619311) SNPs were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay.	('rs9619311', 'Var', (48, 57))	('rs8179090', 'Mutation', 'rs8179090', (18, 27))	('rs8179090', 'Var', (18, 27))	('rs9619311', 'Mutation', 'rs9619311', (48, 57))	('men', 'Species', '9606', (127, 130))
33322	30988064	The digestion products of TIMP2-418G/C and TIMP3-1296T/C SNPs were separated on 4% agarose gels stained with ethidium bromide (HiMedia, India) to a final concentration of 0.5 microg/ml.	('TIMP2-418G/C', 'Var', (26, 38))	('ethidium bromide', 'Chemical', 'MESH:D004996', (109, 125))	('TIMP3-1296T/C', 'Var', (43, 56))	('digestion', 'biological_process', 'GO:0007586', ('4', '13'))	('agarose', 'Chemical', 'MESH:D012685', (83, 90))
33331	30988064	The statistical power of 80% is widely used in genetic association studies to avoid Type II errors and to determine a cost-effective sample size under the assumption of 10-25% variant allele frequency, 1:1 case-to-control ratio, and 5% Type I error rate (alpha).	('variant', 'Var', (176, 183))	('Type II errors', 'Disease', (84, 98))	('Type II errors', 'Disease', 'MESH:D005776', (84, 98))
33337	30988064	The overall association between the TIMP2-418G/CSNP and the modulation of colorectal cancer risk was found to be significant (P=0.019) (Table 3).	('colorectal cancer', 'Disease', 'MESH:D015179', (74, 91))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('colorectal cancer', 'Disease', (74, 91))	('TIMP2-418G/CSNP', 'Var', (36, 51))
33338	30988064	The heterozygous genotype (GC) was significantly associated with an increased risk of colorectal cancer [OR, 1.87 (95%CI, 1.07-3.27); P=0.027].	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('heterozygous', 'Var', (4, 16))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('colorectal cancer', 'Disease', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))
33343	30988064	age, gender, dwelling, smoking status, tumor location, tumor grade, and lymph node status for TIMP2-418G/C SNP are listed in Table 5.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('TIMP2-418G/C SNP', 'Var', (94, 110))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))
33347	30988064	The overall association between the TIMP3-1296T/C SNP and the modulation of colorectal cancer risk was found to be highly significant (P=0.000) (Table 6).	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('TIMP3-1296T/C SNP', 'Var', (36, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('colorectal cancer', 'Disease', (76, 93))
33348	30988064	The heterozygous genotype (TC) was significantly associated with a decreased risk of colorectal cancer [OR, 0.53 (95%CI, 0.32-0.86); P=0.011].	('heterozygous', 'Var', (4, 16))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal cancer', 'Disease', (85, 102))	('TC', 'Chemical', 'MESH:D013667', (27, 29))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('decreased', 'NegReg', (67, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
33349	30988064	The variant genotype (CC) was also significantly associated with a decreased risk of colorectal cancer [OR, 0.18 (95%CI, 0.05-0.65); P=0.009].	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal cancer', 'Disease', (85, 102))	('variant', 'Var', (4, 11))	('decreased', 'NegReg', (67, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
33359	30988064	age, gender, dwelling, smoking status, tumor location, tumor grade, and lymph node status for TIMP3-1296T/C SNP are listed in Table 8.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('TIMP3-1296T/C SNP', 'Var', (94, 111))	('tumor', 'Disease', (39, 44))
33360	30988064	Further, the male subjects who carried the variant genotype (CC) were at an increased risk of developing colorectal cancer in comparison with females [OR, 8.18 (95%CI, 1.62-41.28); P=0.0066].	('colorectal cancer', 'Disease', 'MESH:D015179', (105, 122))	('variant', 'Var', (43, 50))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('colorectal cancer', 'Disease', (105, 122))
33361	30988064	Further, the subjects who carried the heterozygous genotype (TC) of TIMP3-1296T/C SNP were at a reduced risk of lymph node involvement [OR, 0.44 (95%CI, 0.22-0.89); P=0.0334].	('TIMP3-1296T/C SNP', 'Var', (68, 85))	('reduced risk of lymph node', 'Phenotype', 'HP:0002732', (96, 122))	('TC', 'Chemical', 'MESH:D013667', (61, 63))	('lymph node involvement', 'CPA', (112, 134))	('men', 'Species', '9606', (130, 133))	('reduced', 'NegReg', (96, 103))
33367	30988064	The functional significance of TIMP3-1296T/C SNP involving T to C substitution at -1296 position is not known yet experimentally but through in silico analysis using TESS (URL: http://www.cbil.upenn.edu/tess), TRANSFAC (URL: http://thr.cit.nih.gov/molbio/signal/), and other online resources, it has been predicted to alter the transcription factor binding site.	('cit', 'biological_process', 'GO:0106106', ('236', '239'))	('alter', 'Reg', (318, 323))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('328', '356'))	('transcription factor', 'MPA', (328, 348))	('transcription', 'biological_process', 'GO:0006351', ('328', '341'))	('thr', 'Chemical', 'MESH:D013912', (232, 235))	('thr', 'Chemical', 'MESH:D013912', (133, 136))	('T to C', 'Gene', (59, 65))	('TIMP3-1296T/C', 'Var', (31, 44))	('cbil', 'molecular_function', 'GO:0043781', ('188', '192'))	('men', 'Species', '9606', (120, 123))
33368	30988064	Based on the in silico analysis, it is reasonable to postulate that the SNP induced alteration possibly influences the binding affinities of various transactivating nuclear proteins such that these proteins bind with higher affinity to the C allele resulting in higher TIMP3 gene expression in comparison with that of the expression in case of the T allele.	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('TIMP3', 'Gene', (269, 274))	('expression', 'MPA', (280, 290))	('TIMP3', 'Gene', '7078', (269, 274))	('bind', 'Interaction', (207, 211))	('gene expression', 'biological_process', 'GO:0010467', ('275', '290'))	('higher', 'PosReg', (217, 223))	('binding', 'Interaction', (119, 126))	('influences', 'Reg', (104, 114))	('alteration', 'Var', (84, 94))	('higher', 'PosReg', (262, 268))
33369	30988064	Alternatively, the T to C transition represented by this SNP may be associated with decreased affinity of a putative transcription repressor protein to bind to its site on the TIMP3 promoter resulting again in a higher TIMP3 gene expression in case of the C allele in comparison with that of the expression in case of the T allele.	('affinity', 'MPA', (94, 102))	('gene expression', 'biological_process', 'GO:0010467', ('225', '240'))	('transcription', 'biological_process', 'GO:0006351', ('117', '130'))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('C allele', 'Var', (256, 264))	('expression', 'MPA', (230, 240))	('higher', 'PosReg', (212, 218))	('TIMP3', 'Gene', '7078', (219, 224))	('decreased', 'NegReg', (84, 93))	('TIMP3', 'Gene', (219, 224))	('TIMP3', 'Gene', '7078', (176, 181))	('TIMP3', 'Gene', (176, 181))
33412	30988064	In addition, the carriers of the heterozygous genotype (TC) of TIMP3-1296T/C SNP were at a reduced risk of lymph node infiltration.	('TIMP3-1296T/C SNP', 'Var', (63, 80))	('reduced risk of lymph node', 'Phenotype', 'HP:0002732', (91, 117))	('lymph node infiltration', 'CPA', (107, 130))	('reduced', 'NegReg', (91, 98))	('TC', 'Chemical', 'MESH:D013667', (56, 58))
33420	30988064	We have demonstrated through the present study that the TIMP2-418G/C and TIMP3-1296T/C promoter SNPs modulate the CRC risk in ethnic Kashmiri population in a strong and highly significant manner.	('modulate', 'Reg', (101, 109))	('TIMP3-1296T/C', 'Var', (73, 86))	('CRC', 'Phenotype', 'HP:0003003', (114, 117))	('TIMP2-418G/C', 'Var', (56, 68))	('CRC', 'Disease', (114, 117))	('thr', 'Chemical', 'MESH:D013912', (21, 24))
33422	30988064	CI confidence interval CRC colorectal cancer HWE Hardy-Weinberg equilibrium MMP matrix metalloproteinase OR odds ratio PCR-RFLP polymerase chain reaction-restriction fragment length polymorphism SNP single nucleotide polymorphism TIMP tissue inhibitors of metalloproteinase	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (27, 44))	('MMP', 'molecular_function', 'GO:0004235', ('76', '79'))	('single nucleotide polymorphism', 'Var', (199, 229))	('TIMP', 'Gene', '7076', (230, 234))	('colorectal cancer', 'Disease', (27, 44))	('men', 'Species', '9606', (170, 173))	('CRC', 'Phenotype', 'HP:0003003', (23, 26))	('TIMP', 'Gene', (230, 234))	('colorectal cancer', 'Disease', 'MESH:D015179', (27, 44))
33468	28753429	The five-year recurrence survival was substantially shorter in the F. nucleatum-high group than the F. nucleatum-low group.	('F. nucleatum', 'Species', '851', (67, 79))	('F. nucleatum', 'Species', '851', (100, 112))	('shorter', 'NegReg', (52, 59))	('F. nucleatum-high', 'Var', (67, 84))	('recurrence survival', 'CPA', (14, 33))
33503	28753429	As expected, Oxaliplatin (Figure 3A) and 5-FU (Figure 3B) induced HCT116 cell apoptosis.	('5-FU', 'Var', (41, 45))	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (13, 24))	('5-FU', 'Chemical', 'MESH:D005472', (41, 45))	('HCT116', 'CellLine', 'CVCL:0291', (66, 72))	('HCT116 cell apoptosis', 'CPA', (66, 87))
33519	28753429	Moreover, western blotting showed that Oxaliplatin and 5-FU induced the cleavage of caspase 9, caspase 3, caspase 6, caspase 7, PARP, and p-H2AX, and these effects were blocked by F. nucleatum co-culture in HCT116 cells (Figure 3E) and HT29 cells (Figure 3F).	('F. nucleatum', 'Species', '851', (180, 192))	('Oxaliplatin', 'Var', (39, 50))	('5-FU', 'Var', (55, 59))	('HT29 cells', 'CellLine', 'CVCL:0320', (236, 246))	('caspase', 'Protein', (106, 113))	('PARP', 'MPA', (128, 132))	('caspase', 'Protein', (117, 124))	('p-H2AX', 'Var', (138, 144))	('5-FU', 'Chemical', 'MESH:D005472', (55, 59))	('caspase 9', 'Protein', (84, 93))	('cleavage', 'MPA', (72, 80))	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (39, 50))	('HCT116', 'CellLine', 'CVCL:0291', (207, 213))	('caspase 3', 'Protein', (95, 104))
33532	28753429	We hypothesized that dysregulated miRNAs may contribute to F. nucleatum-increased ULK1 and ATG7 expression.	('ATG7', 'Gene', '10533', (91, 95))	('expression', 'MPA', (96, 106))	('F. nucleatum', 'Species', '851', (59, 71))	('miR', 'Gene', '220972', (34, 37))	('miR', 'Gene', (34, 37))	('ULK1', 'Gene', (82, 86))	('ATG7', 'Gene', (91, 95))	('ULK1', 'Gene', '8408', (82, 86))	('dysregulated', 'Var', (21, 33))
33534	28753429	Sixty-eight miRNAs were significantly downregulated in the CRC tissues with a high amount of F. nucleatum as compared to that with a low amount of F. nucleatum (Figure S4C, right; Table S6).	('high amount', 'Var', (78, 89))	('F. nucleatum', 'Species', '851', (147, 159))	('downregulated', 'NegReg', (38, 51))	('F. nucleatum', 'Species', '851', (93, 105))	('miR', 'Gene', '220972', (12, 15))	('miR', 'Gene', (12, 15))
33541	28753429	Real-time PCR showed that miR-18a* and miR-4802 decreased ULK1 and ATG7 mRNA levels, and the mRNA expression levels of ULK1 and ATG7 were rescued by miR-18a* and miR-4802 inhibitors in HCT116 cells (Figures 4D and 4E) and HT29 cells (Figures S4H and S4I).	('miR-4802', 'Gene', (39, 47))	('ATG7', 'Gene', (67, 71))	('miR-18a', 'Gene', '406953', (149, 156))	('miR-4802', 'Gene', '100616274', (39, 47))	('ATG7', 'Gene', (128, 132))	('decreased', 'NegReg', (48, 57))	('HT29 cells', 'CellLine', 'CVCL:0320', (222, 232))	('HCT116', 'CellLine', 'CVCL:0291', (185, 191))	('miR-4802', 'Gene', (162, 170))	('miR-18a', 'Gene', (26, 33))	('mRNA expression levels', 'MPA', (93, 115))	('ULK1', 'Gene', '8408', (58, 62))	('inhibitors', 'Var', (171, 181))	('miR-4802', 'Gene', '100616274', (162, 170))	('ULK1', 'Gene', '8408', (119, 123))	('ATG7', 'Gene', '10533', (67, 71))	('ULK1', 'Gene', (58, 62))	('miR-18a', 'Gene', (149, 156))	('miR-18a', 'Gene', '406953', (26, 33))	('ATG7', 'Gene', '10533', (128, 132))	('ULK1', 'Gene', (119, 123))
33549	28753429	Western blotting showed that the inhibitory effects of F. nucleatum on the chemotherapy-induced caspase and PARP cleavage and p-H2AX were abolished by miR-18a* and miR-4802 mimics transfection in HCT116 cells (Figure 5E) and HT29 cells (Figure S5F).	('miR-18a', 'Gene', (151, 158))	('p-H2AX', 'Var', (126, 132))	('abolished', 'NegReg', (138, 147))	('HT29 cells', 'CellLine', 'CVCL:0320', (225, 235))	('HCT116', 'CellLine', 'CVCL:0291', (196, 202))	('miR-4802', 'Gene', (164, 172))	('miR-4802', 'Gene', '100616274', (164, 172))	('F. nucleatum', 'Species', '851', (55, 67))	('caspase', 'Enzyme', (96, 103))	('miR-18a', 'Gene', '406953', (151, 158))	('transfection', 'Var', (180, 192))
33552	28753429	Interestingly, tumor growth was significantly decreased by Oxaliplatin (Figures S5J-S5L) and 5-FU treatment (Figures S5M-S5O), and these decreases were blocked by F. nucleatum treatment in vivo.	('Oxaliplatin', 'MPA', (59, 70))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (59, 70))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('5-FU', 'Chemical', 'MESH:D005472', (93, 97))	('decreased', 'NegReg', (46, 55))	('F. nucleatum', 'Species', '851', (163, 175))	('5-FU treatment', 'Var', (93, 107))
33564	28753429	Furthermore, F. nucleatum-induced CRC chemoresistance was rescued by knocking down TLR4 or MYD88 in the CRC xenograft mouse model, as shown by reduced tumor weight (Figures 6M and 6N, Figures S7E and S7F) and tumor volume (Figure 6O, Figure S7G).	('knocking down', 'Var', (69, 82))	('tumor', 'Disease', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('TLR4', 'Gene', '21898', (83, 87))	('TLR4', 'Gene', (83, 87))	('F. nucleatum', 'Species', '851', (13, 25))	('tumor', 'Disease', (151, 156))	('mouse', 'Species', '10090', (118, 123))	('MYD88', 'Gene', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('reduced', 'NegReg', (143, 150))
33576	28753429	Cancer genetic and epigenetic alterations in CRC chemotherapeutic response have been extensively reported.	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('epigenetic alterations', 'Var', (19, 41))
33647	28753429	When the cells were treated with Doxorubicin, we performed FVS510 and Annexin V-FITC double staining to avoid the fluorescent signal of the drug.	('Doxorubicin', 'Chemical', 'MESH:D004317', (33, 44))	('fluorescent', 'MPA', (114, 125))	('avoid', 'NegReg', (104, 109))	('FVS510', 'Var', (59, 65))
33666	28567967	Evaluation of genetic variants in association with colorectal cancer risk and survival in Asians Genome-wide association studies (GWAS) have identified over 40 genetic loci associated with colorectal cancer (CRC) risk.	('colorectal cancer', 'Phenotype', 'HP:0003003', (189, 206))	('colorectal cancer', 'Disease', 'MESH:D015179', (51, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('colorectal cancer', 'Disease', (189, 206))	('colorectal cancer', 'Phenotype', 'HP:0003003', (51, 68))	('colorectal cancer', 'Disease', (51, 68))	('associated', 'Reg', (173, 183))	('CRC', 'Phenotype', 'HP:0003003', (208, 211))	('colorectal cancer', 'Disease', 'MESH:D015179', (189, 206))	('variants', 'Var', (22, 30))
33668	28567967	Furthermore, the minor alleles of rs6983267 and rs1957636 were associated with worse CRC-specific and overall survival.	('rs1957636', 'Mutation', 'rs1957636', (48, 57))	('worse', 'NegReg', (79, 84))	('rs6983267', 'Var', (34, 43))	('rs6983267', 'Mutation', 'rs6983267', (34, 43))	('rs1957636', 'Var', (48, 57))	('CRC-specific', 'Disease', (85, 97))	('CRC', 'Phenotype', 'HP:0003003', (85, 88))	('overall survival', 'CPA', (102, 118))
33683	28567967	For the analysis of genetic variants with CRC risk, however, all cases from the SWHS, SMHS, and those recruited through Shanghai Cancer Registry were included, along with their controls.	('Shanghai Cancer', 'Disease', 'MESH:D009369', (120, 135))	('CRC', 'Phenotype', 'HP:0003003', (42, 45))	('variants', 'Var', (28, 36))	('Cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Shanghai Cancer', 'Disease', (120, 135))	('CRC', 'Disease', (42, 45))
33685	28567967	We compiled a list of all the loci reported to be associated with colorectal cancer risk at P < 5x10-8 through literature review, which identified 57 SNPs at 42 loci associated with CRC (Table 1).	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('SNPs', 'Var', (150, 154))	('CRC', 'Disease', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal cancer', 'Disease', (66, 83))	('associated', 'Reg', (166, 176))	('CRC', 'Phenotype', 'HP:0003003', (182, 185))	('colorectal cancer', 'Disease', 'MESH:D015179', (66, 83))
33690	28567967	In addition, we conducted analyses of the GRSs in relation to survival stratified by age at diagnosis, sex, BMI (< 25.0, 25.0-29.9, or > 30.0 kg/m2), tumor location (colon/rectum), and stage at diagnosis.	('< 25.0', 'Var', (113, 119))	('colon', 'Disease', 'MESH:D015179', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('colon', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
33701	28567967	We also constructed an Asian-specific GRS utilizing SNPs that have previously shown to be associated with survival among Asians (i.e., rs1321311, rs6983267, rs4939827, rs10411210, rs961253) and found a statistically significant linear trend with both CRC-specific and all-cause mortality (Table 3).	('rs10411210', 'Mutation', 'rs10411210', (168, 178))	('rs6983267', 'Var', (146, 155))	('rs961253', 'Var', (180, 188))	('CRC', 'Phenotype', 'HP:0003003', (251, 254))	('rs4939827', 'Mutation', 'rs4939827', (157, 166))	('associated', 'Reg', (90, 100))	('rs4939827', 'Var', (157, 166))	('rs10411210', 'Var', (168, 178))	('rs6983267', 'Mutation', 'rs6983267', (146, 155))	('rs1321311', 'Mutation', 'rs1321311', (135, 144))	('rs961253', 'Mutation', 'rs961253', (180, 188))	('rs1321311', 'Var', (135, 144))
33704	28567967	We also investigated whether any individual SNP may be associated with CRC survival and found two SNPs (rs6983267 near gene MYC and rs1957636 near gene BMP4) showing suggestive associations.	('rs6983267', 'Var', (104, 113))	('BMP4', 'Gene', (152, 156))	('CRC', 'Disease', (71, 74))	('BMP4', 'Gene', '652', (152, 156))	('MYC', 'Gene', '4609', (124, 127))	('MYC', 'Gene', (124, 127))	('associated', 'Reg', (55, 65))	('rs1957636', 'Mutation', 'rs1957636', (132, 141))	('CRC', 'Phenotype', 'HP:0003003', (71, 74))	('rs6983267', 'Mutation', 'rs6983267', (104, 113))	('associations', 'Interaction', (177, 189))	('rs1957636', 'Var', (132, 141))
33705	28567967	In Kaplan-Meier curves showing survival probability according to the genotypes of rs6983267 and rs1957636, the minor alleles of both SNPs (GG for rs6983267; CC for rs1957636) were associated with higher risk of CRC-specific death (rs6983267: log-rank P = 0.06; rs1957636: log-rank P = 0.04) and death due to any cause (rs6983267: log-rank P = 0.01; rs1957636: log-rank P = 0.07) (Figure 2).	('rs1957636', 'Mutation', 'rs1957636', (96, 105))	('death', 'Disease', (295, 300))	('rs1957636', 'Var', (96, 105))	('rs6983267', 'Mutation', 'rs6983267', (319, 328))	('CRC', 'Phenotype', 'HP:0003003', (211, 214))	('death', 'Disease', (224, 229))	('rs1957636', 'Mutation', 'rs1957636', (349, 358))	('rs1957636', 'Mutation', 'rs1957636', (261, 270))	('rs1957636', 'Var', (349, 358))	('rs1957636', 'Var', (261, 270))	('rs6983267', 'Var', (82, 91))	('rs1957636', 'Mutation', 'rs1957636', (164, 173))	('CRC-specific', 'Disease', (211, 223))	('death', 'Disease', 'MESH:D003643', (295, 300))	('rs6983267', 'Var', (231, 240))	('rs6983267', 'Mutation', 'rs6983267', (146, 155))	('death', 'Disease', 'MESH:D003643', (224, 229))	('rs6983267', 'Var', (319, 328))	('rs6983267', 'Mutation', 'rs6983267', (82, 91))	('rs6983267', 'Mutation', 'rs6983267', (231, 240))
33707	28567967	There was a dose-response relationship between the number of minor alleles of these two SNPs and risk of death due to CRC (P for trend = 0.01) or any cause (P for trend = 0.003) (Table 4).	('death', 'Disease', 'MESH:D003643', (105, 110))	('death', 'Disease', (105, 110))	('CRC', 'Disease', (118, 121))	('minor', 'Var', (61, 66))	('CRC', 'Phenotype', 'HP:0003003', (118, 121))
33709	28567967	Two SNPs, rs6983267 on chromosome 8q24.21 and rs1957636 on 14q22.2, were significantly associated with CRC survival, providing some evidence that certain genetic variants identified for CRC risk may also be related to CRC survival.	('CRC survival', 'Disease', (103, 115))	('rs1957636', 'Mutation', 'rs1957636', (46, 55))	('chromosome', 'cellular_component', 'GO:0005694', ('23', '33'))	('CRC', 'Disease', (218, 221))	('rs6983267', 'Mutation', 'rs6983267', (10, 19))	('CRC', 'Phenotype', 'HP:0003003', (103, 106))	('rs1957636', 'Var', (46, 55))	('associated with', 'Reg', (87, 102))	('CRC', 'Phenotype', 'HP:0003003', (218, 221))	('CRC', 'Phenotype', 'HP:0003003', (186, 189))	('rs6983267', 'Var', (10, 19))	('related', 'Reg', (207, 214))
33712	28567967	found the minor allele in rs4939827 (SMAD7) was associated with reduced overall and CRC-specific survival.	('SMAD7', 'Gene', '4092', (37, 42))	('rs4939827', 'Mutation', 'rs4939827', (26, 35))	('rs4939827', 'Var', (26, 35))	('reduced', 'NegReg', (64, 71))	('CRC', 'Phenotype', 'HP:0003003', (84, 87))	('SMAD7', 'Gene', (37, 42))	('CRC-specific survival', 'CPA', (84, 105))
33713	28567967	reported five SNPs (rs961253, rs355527, rs4464148, rs6983267 and rs10505477) were associated with survival for patients with stage III disease.	('rs6983267', 'Var', (51, 60))	('associated', 'Reg', (82, 92))	('stage III disease', 'Disease', (125, 142))	('rs10505477', 'Mutation', 'rs10505477', (65, 75))	('patients', 'Species', '9606', (111, 119))	('rs961253', 'Mutation', 'rs961253', (20, 28))	('rs6983267', 'Mutation', 'rs6983267', (51, 60))	('rs10505477', 'Var', (65, 75))	('rs4464148', 'Var', (40, 49))	('rs355527', 'Var', (30, 38))	('rs961253', 'Var', (20, 28))	('rs4464148', 'Mutation', 'rs4464148', (40, 49))	('rs355527', 'Mutation', 'rs355527', (30, 38))
33714	28567967	reported that rs4444235 was significantly associated with survival in CRC patients.	('rs4444235', 'Var', (14, 23))	('associated with', 'Reg', (42, 57))	('patients', 'Species', '9606', (74, 82))	('CRC', 'Phenotype', 'HP:0003003', (70, 73))	('rs4444235', 'Mutation', 'rs4444235', (14, 23))	('CRC', 'Disease', (70, 73))
33715	28567967	evaluated the influence of 20 GWAS-identified CRC risk SNPs in 7,635 cases, and found that patients who were homozygous for the minor allele (AA genotype) of rs9929218 had a poorer overall survival rate.	('poorer', 'NegReg', (174, 180))	('rs9929218', 'Mutation', 'rs9929218', (158, 167))	('patients', 'Species', '9606', (91, 99))	('rs9929218', 'Var', (158, 167))	('overall survival rate', 'CPA', (181, 202))	('CRC', 'Phenotype', 'HP:0003003', (46, 49))
33716	28567967	found an association between rs4779584 and a reduced risk of CRC mortality in 380 Chinese CRC patients.	('reduced', 'NegReg', (45, 52))	('patients', 'Species', '9606', (94, 102))	('rs4779584', 'Mutation', 'rs4779584', (29, 38))	('CRC', 'Phenotype', 'HP:0003003', (90, 93))	('CRC mortality', 'Disease', (61, 74))	('rs4779584', 'Var', (29, 38))	('CRC', 'Phenotype', 'HP:0003003', (61, 64))
33717	28567967	reported that rs1321311 (CDKN1A) and rs10411210 (RHPN2) were associated with survival for Korean patients with surgically resected CRC.	('rs1321311', 'Mutation', 'rs1321311', (14, 23))	('rs1321311', 'Var', (14, 23))	('rs10411210', 'Mutation', 'rs10411210', (37, 47))	('CRC', 'Phenotype', 'HP:0003003', (131, 134))	('CDKN1A', 'Gene', (25, 31))	('RHPN2', 'Gene', '85415', (49, 54))	('CDKN1A', 'Gene', '1026', (25, 31))	('survival', 'MPA', (77, 85))	('associated', 'Reg', (61, 71))	('RHPN2', 'Gene', (49, 54))	('rs10411210', 'Var', (37, 47))	('patients', 'Species', '9606', (97, 105))
33718	28567967	In our study, we found that the GG genotype of rs6983267 and the CC genotype of rs1957636 were significantly associated with poorer survival outcomes.	('rs6983267', 'Mutation', 'rs6983267', (47, 56))	('survival outcomes', 'CPA', (132, 149))	('poorer', 'NegReg', (125, 131))	('rs1957636', 'Mutation', 'rs1957636', (80, 89))	('rs6983267', 'Var', (47, 56))	('rs1957636', 'Var', (80, 89))
33719	28567967	The SNP rs6983267 was first identified in GWAS as a CRC susceptibility loci mapping to 8q24.1 in European descendants, and was later replicated in East Asians.	('CRC', 'Disease', (52, 55))	('rs6983267', 'Mutation', 'rs6983267', (8, 17))	('rs6983267', 'Var', (8, 17))	('CRC', 'Phenotype', 'HP:0003003', (52, 55))
33721	28567967	The G allele of rs6983267 confers an increased CRC risk through the mechanism of Wnt signaling by disrupting an enhancer element and interacting with the promoter of the MYC oncogene.	('rs6983267', 'Mutation', 'rs6983267', (16, 25))	('MYC', 'Gene', '4609', (170, 173))	('CRC', 'Phenotype', 'HP:0003003', (47, 50))	('Wnt', 'Gene', (81, 84))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('enhancer element', 'MPA', (112, 128))	('men', 'Species', '9606', (124, 127))	('CRC', 'Disease', (47, 50))	('interacting', 'Reg', (133, 144))	('rs6983267', 'Var', (16, 25))	('MYC', 'Gene', (170, 173))	('Wnt', 'Gene', '54361', (81, 84))	('disrupting', 'NegReg', (98, 108))
33723	28567967	It lies 116 kb telomeric to rs6983267, and some reports have shown that rs6983267 has a long-range physical interaction with MYC in CRC cell lines.	('rs6983267', 'Var', (72, 81))	('MYC', 'Gene', '4609', (125, 128))	('MYC', 'Gene', (125, 128))	('rs6983267', 'Mutation', 'rs6983267', (28, 37))	('physical interaction', 'Interaction', (99, 119))	('CRC', 'Phenotype', 'HP:0003003', (132, 135))	('rs6983267', 'Mutation', 'rs6983267', (72, 81))
33724	28567967	The variant rs6983267 that is associated with increased risk of colorectal adenomas  could also be associated with increased risk of CRC recurrence and initiation.	('colorectal adenomas', 'Disease', 'MESH:D015179', (64, 83))	('rs6983267', 'Var', (12, 21))	('CRC recurrence', 'Disease', (133, 147))	('rs6983267', 'Mutation', 'rs6983267', (12, 21))	('CRC', 'Phenotype', 'HP:0003003', (133, 136))	('colorectal adenomas', 'Disease', (64, 83))	('associated', 'Reg', (99, 109))
33725	28567967	Thus, it is possible that SNPs in MYC involved in CRC risk could also be related to CRC pathological severity and prognosis.	('MYC', 'Gene', (34, 37))	('CRC', 'Disease', (50, 53))	('CRC', 'Disease', (84, 87))	('SNPs', 'Var', (26, 30))	('MYC', 'Gene', '4609', (34, 37))	('CRC', 'Phenotype', 'HP:0003003', (50, 53))	('CRC', 'Phenotype', 'HP:0003003', (84, 87))	('related', 'Reg', (73, 80))
33726	28567967	SNP rs1957636 was reported to be associated with increased risk of colorectal adenoma suggesting that this SNP might play a role in the initiation of CRC.	('colorectal adenoma', 'Disease', 'MESH:D015179', (67, 85))	('CRC', 'Phenotype', 'HP:0003003', (150, 153))	('rs1957636', 'Var', (4, 13))	('colorectal adenoma', 'Disease', (67, 85))	('rs1957636', 'Mutation', 'rs1957636', (4, 13))	('SNP', 'Var', (0, 3))
33727	28567967	However, we observed a significant association of the C allele in rs1957636 with poorer survival after CRC diagnosis.	('CRC', 'Phenotype', 'HP:0003003', (103, 106))	('rs1957636', 'Mutation', 'rs1957636', (66, 75))	('poorer', 'NegReg', (81, 87))	('rs1957636', 'Var', (66, 75))
33729	28567967	SNP rs1957636 is upstream of the transcriptional start site of BMP4 (136 kb upstream) and 150 kb downstream to CRC susceptibility SNP rs4444235; however, rs1957636 and rs4444235 are not in strong LD.	('rs4444235', 'Mutation', 'rs4444235', (168, 177))	('BMP4', 'Gene', '652', (63, 67))	('rs1957636', 'Var', (154, 163))	('rs4444235', 'Var', (168, 177))	('rs1957636', 'Var', (4, 13))	('CRC', 'Phenotype', 'HP:0003003', (111, 114))	('BMP4', 'Gene', (63, 67))	('rs4444235', 'Mutation', 'rs4444235', (134, 143))	('rs1957636', 'Mutation', 'rs1957636', (154, 163))	('rs1957636', 'Mutation', 'rs1957636', (4, 13))	('rs4444235', 'Var', (134, 143))
33731	28567967	The interaction between BMP4 and TGF-beta and the pleiotropic functions of the TGF-beta pathway may explain the seemingly opposite association of rs1957636 with null association for CRC but poor survival after CRC diagnosis.	('TGF-beta', 'Gene', (79, 87))	('rs1957636', 'Mutation', 'rs1957636', (146, 155))	('interaction', 'Interaction', (4, 15))	('CRC', 'Phenotype', 'HP:0003003', (210, 213))	('BMP4', 'Gene', (24, 28))	('rs1957636', 'Var', (146, 155))	('TGF-beta', 'Gene', '7040', (33, 41))	('CRC', 'Disease', (182, 185))	('TGF-beta', 'Gene', (33, 41))	('BMP4', 'Gene', '652', (24, 28))	('TGF-beta', 'Gene', '7040', (79, 87))	('CRC', 'Phenotype', 'HP:0003003', (182, 185))
33733	28567967	The significant association observed in this study for SNPs rs6983267 and rs1957636 was no longer statistically significant after taking into consideration multiple comparisons.	('rs6983267', 'Var', (60, 69))	('rs1957636', 'Var', (74, 83))	('rs6983267', 'Mutation', 'rs6983267', (60, 69))	('rs1957636', 'Mutation', 'rs1957636', (74, 83))
33735	28567967	Furthermore, the current analysis includes data from Shanghai that was not included in the Asia Colorectal Cancer Consortium study that identified these risk variants.	('variants', 'Var', (158, 166))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Asia Colorectal Cancer', 'Disease', 'MESH:D015179', (91, 113))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (96, 113))	('Asia Colorectal Cancer', 'Disease', (91, 113))
33736	28567967	However, common germline variants in GWAS-identified loci near the MYC and BMP4 genes may be associated with CRC survival.	('variants', 'Var', (25, 33))	('MYC', 'Gene', '4609', (67, 70))	('BMP4', 'Gene', (75, 79))	('MYC', 'Gene', (67, 70))	('associated', 'Reg', (93, 103))	('CRC survival', 'Disease', (109, 121))	('BMP4', 'Gene', '652', (75, 79))	('CRC', 'Phenotype', 'HP:0003003', (109, 112))
33738	28567967	We also provided evidence for a suggestive association of two risk variants (rs6983267 and rs1957636) in relation to CRC survival.	('rs6983267', 'Mutation', 'rs6983267', (77, 86))	('rs1957636', 'Var', (91, 100))	('CRC survival', 'Disease', (117, 129))	('association', 'Reg', (43, 54))	('CRC', 'Phenotype', 'HP:0003003', (117, 120))	('rs6983267', 'Var', (77, 86))	('rs1957636', 'Mutation', 'rs1957636', (91, 100))
33846	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))
33847	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))
33881	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))
33910	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))	('mismatch repair enzyme', 'Enzyme', (453, 475))	('lymphoid reaction', 'Disease', (352, 369))	('colorectal cancer', 'Disease', 'MESH:D015179', (47, 64))	('tumor', 'Disease', 'MESH:D009369', (377, 382))	('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))
33966	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))
33973	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))
33990	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))
34001	25940441	Finally, in vivo studies demonstrated that induction of miR-137 can decrease growth of human colon cancer xenografts.	('colon cancer', 'Disease', (93, 105))	('miR-137', 'Gene', (56, 63))	('decrease', 'NegReg', (68, 76))	('human', 'Species', '9606', (87, 92))	('decrease growth', 'Phenotype', 'HP:0001510', (68, 83))	('growth of human', 'CPA', (77, 92))	('colon cancer', 'Phenotype', 'HP:0003003', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('colon cancer', 'Disease', 'MESH:D015179', (93, 105))	('induction', 'Var', (43, 52))
34002	25940441	Our results demonstrate that miR-137 acts as a tumor-suppressive miRNA in colorectal cancers and negatively regulates oncogenic MSI1.	('colorectal cancers', 'Disease', 'MESH:D015179', (74, 92))	('rectal cancer', 'Phenotype', 'HP:0100743', (78, 91))	('colorectal cancers', 'Disease', (74, 92))	('miR-137', 'Var', (29, 36))	('oncogenic MSI1', 'MPA', (118, 132))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('negatively', 'NegReg', (97, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('regulates', 'Reg', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Disease', (47, 52))
34011	25940441	Knocking down MSI1 in human colon cancer cell lines reduces growth, enhances apoptosis after radiation treatment and reduces colon cancer proliferation, migration and invasion in vitro.	('colon cancer', 'Disease', 'MESH:D015179', (125, 137))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('reduces', 'NegReg', (52, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('77', '86'))	('colon cancer', 'Disease', 'MESH:D015179', (28, 40))	('apoptosis', 'biological_process', 'GO:0006915', ('77', '86'))	('MSI1', 'Gene', (14, 18))	('colon cancer', 'Disease', (125, 137))	('apoptosis', 'CPA', (77, 86))	('colon cancer', 'Disease', (28, 40))	('invasion', 'CPA', (167, 175))	('colon cancer', 'Phenotype', 'HP:0003003', (125, 137))	('human', 'Species', '9606', (22, 27))	('Knocking down', 'Var', (0, 13))	('men', 'Species', '9606', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('enhances', 'PosReg', (68, 76))	('reduces', 'NegReg', (117, 124))	('colon cancer', 'Phenotype', 'HP:0003003', (28, 40))	('growth', 'CPA', (60, 66))
34028	25940441	Among the three prediction programs, five overlapping miRNAs contained conserved, potential binding sites within MSI1 3'UTR; miR-125b, miR-137, miR-144, miR-185, and miR-342-3p (Figure 1B, Supplemental Table 1).	('binding', 'Interaction', (92, 99))	('miR-342-3p', 'Var', (166, 176))	('miR-185', 'Var', (153, 160))	('miR-137', 'Var', (135, 142))	('binding', 'molecular_function', 'GO:0005488', ('92', '99'))	('MSI1', 'Gene', (113, 117))	('miR-144', 'Var', (144, 151))	('miR-125b', 'Var', (125, 133))	('men', 'Species', '9606', (195, 198))
34031	25940441	Interestingly, miR-125b and miR-342-3p mimics increased the expression of MSI1 in HCT-116 and DLD-1 respectively, suggesting an alternative mechanism of MSI1 regulation.	('miR-125b', 'Var', (15, 23))	('expression', 'MPA', (60, 70))	('increased', 'PosReg', (46, 55))	('MSI1', 'Gene', (74, 78))	('HCT-116', 'CellLine', 'CVCL:0291', (82, 89))	('HCT-116', 'Gene', (82, 89))	('miR-342-3p mimics', 'Var', (28, 45))	('expression', 'Species', '29278', (60, 70))	('DLD-1', 'Gene', (94, 99))
34038	25940441	Since miR-137 significantly decreased MSI1 protein expression in both HCT-116 and DLD-1 compared to the other mimics; we focused this study on understanding the miR-137-mediated regulation of MSI1.	('decreased', 'NegReg', (28, 37))	('expression', 'Species', '29278', (51, 61))	('MSI1 protein', 'Protein', (38, 50))	('miR-137', 'Var', (6, 13))	('HCT-116', 'CellLine', 'CVCL:0291', (70, 77))
34042	25940441	As expected, miR-137 inhibited the luciferase expression of the MSI1 WT 3'UTR construct (P < .0001), which was de-repressed by mutating the miR-137 seed sequence within the MSI1 3'UTR (Figure 2E).	('luciferase', 'Enzyme', (35, 45))	('expression', 'Species', '29278', (46, 56))	('inhibited', 'NegReg', (21, 30))	('expression', 'MPA', (46, 56))	('mutating', 'Var', (127, 135))	('miR-137', 'Gene', (140, 147))
34043	25940441	If miR-137 successfully knocks down MSI1 levels, we would expect an increase in MSI1 target genes, p21 and mNumb.	('increase', 'PosReg', (68, 76))	('miR-137', 'Var', (3, 10))	('p21', 'Gene', (99, 102))	('knocks down', 'NegReg', (24, 35))	('p21', 'Gene', '644914', (99, 102))	('MSI1 levels', 'MPA', (36, 47))
34044	25940441	As expected, in miR-137-transfected HCT-116 cells, mNumb and p21 protein expression is increased compared to cells transfected with NC mimic (Figure 3A).	('increased', 'PosReg', (87, 96))	('p21', 'Gene', '644914', (61, 64))	('miR-137-transfected', 'Var', (16, 35))	('expression', 'Species', '29278', (73, 83))	('HCT-116', 'CellLine', 'CVCL:0291', (36, 43))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('mNumb', 'Gene', (51, 56))	('p21', 'Gene', (61, 64))
34056	25940441	Based on our preliminary data, we hypothesized that miR-137 acts as a tumor suppressor miRNA by negatively regulating MSI1.	('miR-137', 'Var', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('negatively', 'NegReg', (96, 106))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('tumor', 'Disease', (70, 75))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('MSI1', 'MPA', (118, 122))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
34068	25940441	In summary, miR-137 inhibits clonogenic growth, supporting its predicted role as a tumor suppressor miRNA that reduces colon cancer stem cell properties, in part by directly down-regulating MSI1.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('miR-137', 'Var', (12, 19))	('colon cancer', 'Phenotype', 'HP:0003003', (119, 131))	('inhibits', 'NegReg', (20, 28))	('tumor', 'Disease', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colon cancer', 'Disease', 'MESH:D015179', (119, 131))	('MSI1', 'Gene', (190, 194))	('colon cancer', 'Disease', (119, 131))	('down-regulating', 'NegReg', (174, 189))	('reduces', 'NegReg', (111, 118))	('clonogenic growth', 'CPA', (29, 46))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
34078	25940441	The protein expression of MSI1 was decreased in the miR-137-treated tumors as compared to NC tumors (P = .0124) (Figure 5C and 5D).	('protein expression', 'MPA', (4, 22))	('tumors', 'Disease', (68, 74))	('NC tumors', 'Disease', (90, 99))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('NC tumors', 'Disease', 'OMIM:617025', (90, 99))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('decreased', 'NegReg', (35, 44))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('expression', 'Species', '29278', (12, 22))	('MSI1', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Disease', (93, 99))	('miR-137-treated', 'Var', (52, 67))
34079	25940441	Additionally, miR-137 expression was significantly increased in the Tet-on miR-137 tumors compared to NC xenografts (P < .0001) (Figure 5D).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('increased', 'PosReg', (51, 60))	('miR-137', 'Gene', (14, 21))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('Tet-on', 'Var', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('miR-137', 'Gene', (75, 82))	('expression', 'Species', '29278', (22, 32))	('Tet', 'Chemical', 'MESH:C010349', (68, 71))	('expression', 'MPA', (22, 32))
34081	25940441	Collectively the data supports our hypothesis that miR-137 acts as a tumor suppressor miRNA by down-regulating the oncogenic MSI1 that subsequently leads to tumor growth inhibition.	('tumor', 'Disease', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('oncogenic', 'Protein', (115, 124))	('tumor', 'Disease', (69, 74))	('down-regulating', 'NegReg', (95, 110))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('miR-137', 'Var', (51, 58))
34083	25940441	Patients with high MSI1 expression was significantly correlated with an increased hazards risk for poor overall survival in patients with bladder cancer (n = 165, P = 0.0150), AML (n = 34, P = 0.0002), colorectal cancer (n = 55, P = 0.0151) and ovarian cancer (n = 133, P = 0.0019) (Figures 6A).	('bladder cancer', 'Disease', 'MESH:D001749', (138, 152))	('bladder cancer', 'Disease', (138, 152))	('bladder cancer', 'Phenotype', 'HP:0009725', (138, 152))	('colorectal cancer', 'Disease', (202, 219))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('AML', 'Disease', 'MESH:D015470', (176, 179))	('patients', 'Species', '9606', (124, 132))	('expression', 'MPA', (24, 34))	('AML', 'Disease', (176, 179))	('poor', 'NegReg', (99, 103))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('rectal cancer', 'Phenotype', 'HP:0100743', (206, 219))	('ovarian cancer', 'Disease', 'MESH:D010051', (245, 259))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('colorectal cancer', 'Phenotype', 'HP:0003003', (202, 219))	('MSI1', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('expression', 'Species', '29278', (24, 34))	('ovarian cancer', 'Disease', (245, 259))	('ovarian cancer', 'Phenotype', 'HP:0100615', (245, 259))	('colorectal cancer', 'Disease', 'MESH:D015179', (202, 219))	('overall survival', 'MPA', (104, 120))
34093	25940441	In conclusion, our results show that miR-137 expression is decreased in colon cancer cell lines and rectal cancer tissues, and supports our overall hypothesis that loss of miR-137 promotes the overexpression of MSI1 in colorectal cancer.	('colon cancer', 'Disease', (72, 84))	('overexpression', 'MPA', (193, 207))	('rectal cancer', 'Disease', 'MESH:D012004', (100, 113))	('expression', 'Species', '29278', (197, 207))	('rectal cancer', 'Phenotype', 'HP:0100743', (223, 236))	('promotes', 'PosReg', (180, 188))	('MSI1', 'Protein', (211, 215))	('miR-137', 'Gene', (172, 179))	('colorectal cancer', 'Phenotype', 'HP:0003003', (219, 236))	('expression', 'Species', '29278', (45, 55))	('miR-137', 'Gene', (37, 44))	('colon cancer', 'Phenotype', 'HP:0003003', (72, 84))	('loss', 'Var', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('rectal cancer', 'Disease', 'MESH:D012004', (223, 236))	('rectal cancer', 'Disease', (100, 113))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colon cancer', 'Disease', 'MESH:D015179', (72, 84))	('rectal cancer', 'Phenotype', 'HP:0100743', (100, 113))	('colorectal cancer', 'Disease', 'MESH:D015179', (219, 236))	('decreased', 'NegReg', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Disease', (219, 236))	('expression', 'MPA', (45, 55))
34097	25940441	Furthermore, expressing miR-137 in HCT-116 significantly reduces xenografts tumor growth.	('HCT-116', 'Gene', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('miR-137', 'Var', (24, 31))	('reduces', 'NegReg', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('HCT-116', 'CellLine', 'CVCL:0291', (35, 42))
34098	25940441	In conclusion, our data suggest that miR-137 acts as a tumor suppressive miRNA and when down-regulated promotes tumorigenesis through the up regulation of MSI1.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('up regulation', 'PosReg', (138, 151))	('regulation', 'biological_process', 'GO:0065007', ('141', '151'))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('MSI1', 'Gene', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('miR-137', 'Var', (37, 44))	('promotes', 'PosReg', (103, 111))	('tumor', 'Disease', (112, 117))
34104	25940441	Previous studies have found that MSI1 knockdown sensitizes colon cancer cells to radiation therapy.	('colon cancer', 'Disease', (59, 71))	('radiation therapy', 'CPA', (81, 98))	('sensitizes', 'Reg', (48, 58))	('colon cancer', 'Phenotype', 'HP:0003003', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('MSI1', 'Gene', (33, 37))	('colon cancer', 'Disease', 'MESH:D015179', (59, 71))	('knockdown', 'Var', (38, 47))
34111	25940441	Our findings are consistent with a previous study that discovered miR-137 as a negative regulator of MSI1 in a glioblastoma cell model.	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('MSI1', 'Gene', (101, 105))	('negative regulator', 'NegReg', (79, 97))	('miR-137', 'Var', (66, 73))	('glioblastoma', 'Disease', (111, 123))	('glioblastoma', 'Disease', 'MESH:D005909', (111, 123))
34116	25940441	Our data is consistent with previous studies that discovered loss of miR-137 occurs early in the progression of colon cancer due to hypermethylation of the promoter region, which prevents binding of the transcription factor, high-mobility group AT-hook (HMGA)1.	('binding', 'Interaction', (188, 195))	('miR-137', 'Gene', (69, 76))	('colon cancer', 'Disease', 'MESH:D015179', (112, 124))	('colon cancer', 'Phenotype', 'HP:0003003', (112, 124))	('hypermethylation', 'Var', (132, 148))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('prevents', 'NegReg', (179, 187))	('colon cancer', 'Disease', (112, 124))	('loss', 'NegReg', (61, 65))
34117	25940441	This observation strongly supports our results and overall hypothesis that in colon cancer, miR-137 expression is silenced during differentiation due to hyper-methylation, resulting in MSI1 over-expression.	('MSI1', 'Gene', (185, 189))	('hyper-methylation', 'Var', (153, 170))	('colon cancer', 'Phenotype', 'HP:0003003', (78, 90))	('colon cancer', 'Disease', 'MESH:D015179', (78, 90))	('expression', 'Species', '29278', (100, 110))	('methylation', 'biological_process', 'GO:0032259', ('159', '170'))	('colon cancer', 'Disease', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('over-expression', 'PosReg', (190, 205))	('miR-137', 'Gene', (92, 99))	('expression', 'Species', '29278', (195, 205))
34167	25940441	HCT-116 stable clones with inducible miR-137 and NC miRNA were injected (0.5 x 106) into sub-cutaneous regions 5-6 week old, female athymic nude mice (Hsd:Athymic Nude-Foxn1nu, Harlan).	('sub-cutaneous regions', 'Phenotype', 'HP:0001482', (89, 110))	('miR-137', 'Var', (37, 44))	('nude mice', 'Species', '10090', (140, 149))	('HCT-116', 'Gene', (0, 7))	('HCT-116', 'CellLine', 'CVCL:0291', (0, 7))
34169	25940441	In the tumor progression experiment, after the tumors reached approximately 50 mm3 in size, mice were fed 1 mg/ml Doxycycline Hyclate (Sigma) in the drinking water to induce the expression of miR-137 or NC miRNA.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('expression', 'Species', '29278', (178, 188))	('men', 'Species', '9606', (31, 34))	('tumor', 'Disease', (7, 12))	('expression', 'MPA', (178, 188))	('NC miRNA', 'Var', (203, 211))	('mice', 'Species', '10090', (92, 96))	('Doxycycline Hyclate', 'Chemical', 'MESH:D004318', (114, 133))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('drinking water', 'Chemical', 'MESH:D060766', (149, 163))	('miR-137', 'Var', (192, 199))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('induce', 'PosReg', (167, 173))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
34176	25220207	Tumor budding in colorectal carcinoma assessed by cytokeratin immunostaining and budding areas: Possible involvement of c-Met Tumor budding/sprouting has been shown to be an independent adverse prognostic factor in T1 and T3N0 colorectal carcinomas, however, its assessment could be improved by more accurate identification of budding carcinoma cells and consideration of budding areas.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('T3N0', 'Var', (222, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (335, 344))	('carcinoma', 'Disease', 'MESH:D002277', (28, 37))	('Tumor', 'Phenotype', 'HP:0002664', (126, 131))	('carcinoma', 'Disease', (335, 344))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('carcinomas', 'Phenotype', 'HP:0030731', (238, 248))	('carcinoma', 'Disease', (238, 247))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (227, 248))	('colorectal carcinomas', 'Disease', (227, 248))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (227, 247))	('colorectal carcinoma', 'Disease', (17, 37))	('carcinoma', 'Disease', 'MESH:D002277', (335, 344))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (17, 37))	('carcinoma', 'Disease', 'MESH:D002277', (238, 247))	('carcinoma', 'Disease', (28, 37))	('c-Met', 'Var', (120, 125))
34200	25220207	Moreover, c-Met activity is deregulated in many human cancers, including colorectal carcinoma, as a result of genetic mutations, gene amplification, protein overexpression, or production of HGF-dependent autocrine circuits.	('genetic mutations', 'Var', (110, 127))	('c-Met', 'Gene', '4233', (10, 15))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('overexpression', 'PosReg', (157, 171))	('human', 'Species', '9606', (48, 53))	('protein', 'Protein', (149, 156))	('activity', 'MPA', (16, 24))	('deregulated', 'PosReg', (28, 39))	('c-Met', 'Gene', (10, 15))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('HGF', 'Gene', '3082', (190, 193))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('cancers', 'Disease', (54, 61))	('mutations', 'Var', (118, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('HGF', 'Gene', (190, 193))	('colorectal carcinoma', 'Disease', (73, 93))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (73, 93))	('gene amplification', 'Var', (129, 147))
34241	25220207	Disease-free survival was significantly shorter in patients with high budding scores or grades compared with that in patients with low budding scores or grades, respectively (P < 0.001 for budding scores and P = 0.002 for budding grade) (Fig.	('Disease-free survival', 'CPA', (0, 21))	('high', 'Var', (65, 69))	('patients', 'Species', '9606', (51, 59))	('shorter', 'NegReg', (40, 47))	('patients', 'Species', '9606', (117, 125))
34247	25220207	Moreover, c-Met scores at the invasive front were significantly higher in tumors with high budding scores than those in tumors with low budding scores (P < 0.05).	('c-Met', 'Gene', (10, 15))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('c-Met', 'Gene', '4233', (10, 15))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('budding', 'biological_process', 'GO:0007114', ('91', '98'))	('higher', 'PosReg', (64, 70))	('budding', 'biological_process', 'GO:0007114', ('136', '143'))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('high budding scores', 'Var', (86, 105))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
34249	25220207	Immunohistochemistry for p-c-Met showed similar results as staining for c-Met, except that p-c-Met scores were not significantly different between the invasive front and superficial portions of tumors with low-score budding (Fig.	('c-Met', 'Gene', (27, 32))	('low-score', 'Var', (206, 215))	('c-Met', 'Gene', '4233', (27, 32))	('c-Met', 'Gene', (93, 98))	('c-Met', 'Gene', (72, 77))	('c-Met', 'Gene', '4233', (93, 98))	('c-Met', 'Gene', '4233', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('tumors', 'Disease', (194, 200))
34256	25220207	Among 114 tumors, univariate analysis identified significant associations between shorter DFS and budding score (high score), budding grades (high grades), lymphatic invasion (positive), venous invasion (positive), LN metastasis (positive), tumor size (>=5 cm), pathologic wall penetration (T3 and T4), p-c-Met score (high score), and MET gene copy number per cell (>=2.4) (Table 4).	('budding', 'biological_process', 'GO:0007114', ('98', '105'))	('tumors', 'Disease', (10, 16))	('lymphatic invasion', 'CPA', (156, 174))	('budding score', 'CPA', (98, 111))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', (241, 246))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('c-Met', 'Gene', (305, 310))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('LN metastasis', 'CPA', (215, 228))	('shorter', 'NegReg', (82, 89))	('pathologic wall penetration', 'CPA', (262, 289))	('MET gene copy number', 'Var', (335, 355))	('budding', 'biological_process', 'GO:0007114', ('126', '133'))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('venous invasion', 'CPA', (187, 202))	('budding grades', 'CPA', (126, 140))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('c-Met', 'Gene', '4233', (305, 310))	('DFS', 'Gene', (90, 93))
34274	25220207	Previous studies have shown positive staining for c-Met by IHC in 60-79% of colorectal carcinomas and MET gene amplification by FISH in 2.6% of carcinomas.	('carcinomas', 'Disease', (144, 154))	('carcinomas', 'Disease', 'MESH:D002277', (144, 154))	('MET gene amplification', 'Var', (102, 124))	('carcinomas', 'Disease', 'MESH:D002277', (87, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('carcinomas', 'Disease', (87, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('c-Met', 'Gene', (50, 55))	('c-Met', 'Gene', '4233', (50, 55))	('colorectal carcinomas', 'Disease', (76, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (76, 97))
34332	24009633	Adenocarcinoma cells were positive for mixed CK, CK20, and EMA, but focal positive for vimentin (Fig.	('Adenocarcinoma', 'Disease', (0, 14))	('positive', 'Reg', (26, 34))	('CK20', 'Gene', (49, 53))	('CK20', 'Gene', '54474', (49, 53))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (0, 14))	('vimentin', 'Gene', '7431', (87, 95))	('vimentin', 'Gene', (87, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('EMA', 'CPA', (59, 62))	('mixed', 'Var', (39, 44))
34345	24009633	Adenocarcinoma cells were positive for mixed CK, CK20, and EMA, but focal positive for vimentin.	('Adenocarcinoma', 'Disease', (0, 14))	('vimentin', 'cellular_component', 'GO:0045098', ('87', '95'))	('positive', 'Reg', (26, 34))	('CK20', 'Gene', (49, 53))	('CK20', 'Gene', '54474', (49, 53))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (0, 14))	('vimentin', 'Gene', '7431', (87, 95))	('vimentin', 'Gene', (87, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('EMA', 'CPA', (59, 62))	('vimentin', 'cellular_component', 'GO:0045099', ('87', '95'))	('mixed', 'Var', (39, 44))
34360	24009633	Microsatellite instability (MSI) and p53 gene mutation are two major genetic abnormalities in colorectal cancers.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('MSI', 'Disease', 'None', (28, 31))	('rectal cancer', 'Phenotype', 'HP:0100743', (98, 111))	('genetic abnormalities', 'Disease', 'MESH:D030342', (69, 90))	('Microsatellite instability', 'Disease', (0, 26))	('genetic abnormalities', 'Disease', (69, 90))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('MSI', 'Disease', (28, 31))	('colorectal cancers', 'Disease', 'MESH:D015179', (94, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancers', 'Disease', (94, 112))	('mutation', 'Var', (46, 54))
34368	24009633	The overexpression of the p53 protein, suggesting mutation of the p53 gene, was noted in four out of the 10 reported cases.	('p53', 'Gene', '7157', (66, 69))	('p53', 'Gene', (26, 29))	('mutation', 'Var', (50, 58))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('p53', 'Gene', '7157', (26, 29))	('overexpression', 'PosReg', (4, 18))	('protein', 'Protein', (30, 37))	('p53', 'Gene', (66, 69))
34370	24009633	suggested a very restricted role of p53 mutations in the rhabdoid dedifferentiation of adenocarcinoma cells, because p53 protein was not observed in any of the adenocarcinoma cells and was noted in only a small subset of the rhabdoid tumor cells.	('adenocarcinoma cells', 'Disease', 'MESH:C538614', (160, 180))	('dedifferentiation', 'biological_process', 'GO:0043696', ('66', '83'))	('p53', 'Gene', (117, 120))	('rhabdoid tumor', 'Disease', (225, 239))	('p53', 'Gene', '7157', (117, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('mutations', 'Var', (40, 49))	('adenocarcinoma cells', 'Disease', 'MESH:C538614', (87, 107))	('adenocarcinoma cells', 'Disease', (87, 107))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (225, 239))	('adenocarcinoma cells', 'Disease', (160, 180))
34375	24009633	However, p53 protein overexpression in a small subset of the rhabdoid cells suggested a role of p53 mutation in the rhabdoid dedifferentiation of adenocarcinoma cells.	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('overexpression', 'PosReg', (21, 35))	('mutation', 'Var', (100, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('adenocarcinoma cells', 'Disease', (146, 166))	('adenocarcinoma cells', 'Disease', 'MESH:C538614', (146, 166))	('protein', 'Protein', (13, 20))
34436	30793813	This yielded an adjusted OR of 0.89 (95%CI: 0.81-0.96) for the association between high ortho-phthalate exposure and the risk of colorectal adenocarcinoma (Table 2).	('colorectal adenocarcinoma', 'Disease', (129, 154))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (129, 154))	('ortho-phthalate', 'Chemical', '-', (88, 103))	('high', 'Var', (83, 87))
34491	31892852	Dimer galectin-1 was found to be associated with the activation of JNK and downstream apoptosis or autophagy.	('JNK', 'Gene', (67, 70))	('activation', 'PosReg', (53, 63))	('JNK', 'Gene', '5599', (67, 70))	('galectin-1', 'Gene', (6, 16))	('apoptosis', 'CPA', (86, 95))	('Dimer', 'Var', (0, 5))	('autophagy', 'CPA', (99, 108))	('galectin-1', 'Gene', '3956', (6, 16))
34492	31892852	Moreover, through functional in vitro studies, we showed that differences in galectin-1 level affected tumor cell proliferation, migration, and invasion.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('differences', 'Var', (62, 73))	('tumor', 'Disease', (103, 108))	('galectin-1', 'Gene', (77, 87))	('invasion', 'CPA', (144, 152))	('migration', 'CPA', (129, 138))	('galectin-1', 'Gene', '3956', (77, 87))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('affected', 'Reg', (94, 102))
34575	31892852	After incubated with 400muM, 800muM and 1200muM shikonin, the degradation of galectin-1 decreased, which suggested shikonin displayed significant protection for galectin-1 in resisting degradation in a dose-dependent manner (Figure 3E).	('degradation', 'MPA', (62, 73))	('degradation', 'biological_process', 'GO:0009056', ('62', '73'))	('shikonin', 'Chemical', 'MESH:C016101', (48, 56))	('galectin-1', 'Gene', (77, 87))	('galectin-1 decreased', 'Phenotype', 'HP:0032205', (77, 97))	('galectin', 'molecular_function', 'GO:0001577', ('77', '85'))	('shikonin', 'Chemical', 'MESH:C016101', (115, 123))	('galectin-1', 'Gene', '3956', (77, 87))	('galectin-1', 'Gene', (161, 171))	('degradation', 'biological_process', 'GO:0009056', ('185', '196'))	('galectin', 'molecular_function', 'GO:0001577', ('161', '169'))	('decreased', 'NegReg', (88, 97))	('800muM', 'Var', (29, 35))	('galectin-1', 'Gene', '3956', (161, 171))
34603	31892852	Matrix metalloproteinases (MMPs) are proteolytic enzymes that can cleave or degrade almost all kinds of proteins in the ECM and destroy histologic barriers for tumor invasion and metastasis, enhance migration and invasion of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('histologic barriers', 'CPA', (136, 155))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('kinds', 'Protein', (95, 100))	('destroy', 'NegReg', (128, 135))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('degrade', 'MPA', (76, 83))	('cleave', 'Var', (66, 72))	('tumor', 'Disease', (225, 230))	('MMPs', 'Gene', (27, 31))	('MMPs', 'Gene', '4313;4318', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('enhance', 'PosReg', (191, 198))	('tumor', 'Disease', (160, 165))	('migration', 'CPA', (199, 208))
34607	31892852	In order to identify whether MAPKs, such as JNK, could contribute to galectin-1-induced apoptosis, we employed the chemical inhibitor of JNK and treated SW620 and HCT116 cells with SP600125 (a JNK inhibitor) in the concentration of 20muM 3h earlier before shikonin.	('shikonin', 'Chemical', 'MESH:C016101', (256, 264))	('JNK', 'Gene', (193, 196))	('contribute', 'Reg', (55, 65))	('galectin-1', 'Gene', '3956', (69, 79))	('JNK', 'Gene', (44, 47))	('JNK', 'Gene', '5599', (193, 196))	('3h', 'Chemical', 'MESH:D014316', (238, 240))	('JNK', 'Gene', (137, 140))	('JNK', 'Gene', '5599', (44, 47))	('SP600125', 'Chemical', 'MESH:C432165', (181, 189))	('galectin-1', 'Gene', (69, 79))	('HCT116', 'CellLine', 'CVCL:0291', (163, 169))	('SP600125', 'Var', (181, 189))	('JNK', 'Gene', '5599', (137, 140))	('SW620', 'CellLine', 'CVCL:0547', (153, 158))
34608	31892852	Western blot analysis showed that the protein levels of JNK were curbed by SP600125.	('JNK', 'Gene', (56, 59))	('JNK', 'Gene', '5599', (56, 59))	('SP600125', 'Chemical', 'MESH:C432165', (75, 83))	('curbed', 'NegReg', (65, 71))	('SP600125', 'Var', (75, 83))	('protein levels', 'MPA', (38, 52))	('protein', 'cellular_component', 'GO:0003675', ('38', '45'))	('JNK', 'molecular_function', 'GO:0004705', ('56', '59'))
34609	31892852	Our results indicated the SP600125 upregulated the expression of dimer galectin-1 and enhanced shikonin-induced cell death (Figure 7A-B).	('shikonin-induced', 'MPA', (95, 111))	('galectin-1', 'Gene', (71, 81))	('galectin-1', 'Gene', '3956', (71, 81))	('enhanced', 'PosReg', (86, 94))	('SP600125', 'Chemical', 'MESH:C432165', (26, 34))	('expression', 'MPA', (51, 61))	('upregulated', 'PosReg', (35, 46))	('death', 'Disease', (117, 122))	('shikonin', 'Chemical', 'MESH:C016101', (95, 103))	('death', 'Disease', 'MESH:D003643', (117, 122))	('SP600125', 'Var', (26, 34))
34610	31892852	Colorectal cancer cells (SW620 and HCT116) treated with SP600125 and shikonin at the same time promoted the degradation of caspase and PARP when compared with shikonin treatment alone (Figure 7B).	('SP600125', 'Var', (56, 64))	('degradation', 'MPA', (108, 119))	('promoted', 'PosReg', (95, 103))	('shikonin', 'Chemical', 'MESH:C016101', (69, 77))	('shikonin', 'Chemical', 'MESH:C016101', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('caspase', 'Gene', (123, 130))	('SW620', 'CellLine', 'CVCL:0547', (25, 30))	('HCT116', 'CellLine', 'CVCL:0291', (35, 41))	('rectal cancer', 'Phenotype', 'HP:0100743', (4, 17))	('PARP', 'Gene', '1302', (135, 139))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('Colorectal cancer', 'Disease', (0, 17))	('PARP', 'Gene', (135, 139))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('SP600125', 'Chemical', 'MESH:C432165', (56, 64))	('caspase', 'Gene', '841;842', (123, 130))
34623	31892852	Shikonin is one of the main active ingredient of traditional chinese medicines Recently, some studies indicate that shikonin has potential anti-tumor effects by inducing programmed cell death, inhibition of cancer cell proliferation, anti-angiogenesis, and shikonin also circumvents cancer drug resistance by inducing necroptotic death.	('shikonin', 'Gene', (116, 124))	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('programmed cell death', 'biological_process', 'GO:0012501', ('170', '191'))	('shikonin', 'Var', (257, 265))	('drug resistance', 'biological_process', 'GO:0009315', ('290', '305'))	('death', 'Disease', 'MESH:D003643', (330, 335))	('inducing', 'PosReg', (161, 169))	('death', 'Disease', 'MESH:D003643', (186, 191))	('drug resistance', 'Phenotype', 'HP:0020174', (290, 305))	('drug resistance', 'biological_process', 'GO:0042493', ('290', '305'))	('cancer', 'Disease', (207, 213))	('anti-angiogenesis', 'CPA', (234, 251))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cell proliferation', 'biological_process', 'GO:0008283', ('214', '232'))	('inducing', 'PosReg', (309, 317))	('tumor', 'Disease', (144, 149))	('cancer', 'Disease', (283, 289))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('death', 'Disease', (330, 335))	('angiogenesis', 'biological_process', 'GO:0001525', ('239', '251'))	('death', 'Disease', (186, 191))	('circumvents', 'NegReg', (271, 282))	('shikonin', 'Chemical', 'MESH:C016101', (116, 124))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('Shikonin', 'Chemical', 'MESH:C016101', (0, 8))	('shikonin', 'Chemical', 'MESH:C016101', (257, 265))	('inhibition', 'NegReg', (193, 203))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
34653	31892852	Also decreasing the amount of dimer galectin-1 in SW620 and HCT116 could reduce the level of cytochrome c and hinder the cleavage of LC3, which resulting in weaken the antitumor effects of shikonin (Figure 6G-I).	('cytochrome c', 'Gene', (93, 105))	('HCT116', 'CellLine', 'CVCL:0291', (60, 66))	('tumor', 'Disease', (172, 177))	('galectin-1', 'Gene', '3956', (36, 46))	('HCT116', 'Var', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('LC3', 'Gene', (133, 136))	('galectin', 'molecular_function', 'GO:0001577', ('36', '44'))	('SW620', 'CellLine', 'CVCL:0547', (50, 55))	('-I', 'Chemical', 'MESH:D007455', (208, 210))	('galectin-1', 'Gene', (36, 46))	('decreasing', 'NegReg', (5, 15))	('weaken', 'NegReg', (157, 163))	('cleavage', 'MPA', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cytochrome c', 'molecular_function', 'GO:0045155', ('93', '105'))	('shikonin', 'Chemical', 'MESH:C016101', (189, 197))	('cytochrome c', 'Gene', '54205', (93, 105))	('LC3', 'Gene', '84557', (133, 136))	('cytochrome c', 'molecular_function', 'GO:0009461', ('93', '105'))	('hinder', 'NegReg', (110, 116))	('reduce', 'NegReg', (73, 79))
34661	31892852	In our research, we also treated CRC cells with JNK inhibitor SP600125 and found that the shikonin-induced dimerization of galectin-1 increased and the shikonin-induced apoptosis and autophagy of SW620 and HCT116 were influenced.	('dimerization', 'MPA', (107, 119))	('JNK', 'Gene', (48, 51))	('apoptosis', 'CPA', (169, 178))	('JNK', 'Gene', '5599', (48, 51))	('galectin-1 increased', 'Phenotype', 'HP:0032205', (123, 143))	('influenced', 'Reg', (218, 228))	('galectin-1', 'Gene', (123, 133))	('SW620', 'CellLine', 'CVCL:0547', (196, 201))	('shikonin', 'Chemical', 'MESH:C016101', (90, 98))	('shikonin-induced', 'MPA', (90, 106))	('autophagy', 'CPA', (183, 192))	('shikonin', 'Chemical', 'MESH:C016101', (152, 160))	('HCT116', 'CellLine', 'CVCL:0291', (206, 212))	('CRC', 'Phenotype', 'HP:0030731', (33, 36))	('SP600125', 'Chemical', 'MESH:C432165', (62, 70))	('galectin-1', 'Gene', '3956', (123, 133))	('increased', 'PosReg', (134, 143))	('SP600125', 'Var', (62, 70))
34662	31892852	In both the two cell lines, shikonin-induced LC3 conversion was enhanced and the degradation of p62 was promoted, suggesting the inhibition of JNK accelerates the progress of autophagy (Figure 7A).	('enhanced', 'PosReg', (64, 72))	('degradation', 'biological_process', 'GO:0009056', ('81', '92'))	('shikonin', 'Chemical', 'MESH:C016101', (28, 36))	('LC3', 'Gene', '84557', (45, 48))	('inhibition', 'Var', (129, 139))	('p62', 'Gene', '8878', (96, 99))	('LC3', 'Gene', (45, 48))	('autophagy', 'biological_process', 'GO:0016236', ('175', '184'))	('p62', 'Gene', (96, 99))	('autophagy', 'biological_process', 'GO:0006914', ('175', '184'))	('JNK', 'molecular_function', 'GO:0004705', ('143', '146'))	('accelerates', 'PosReg', (147, 158))	('JNK', 'Gene', (143, 146))	('JNK', 'Gene', '5599', (143, 146))	('promoted', 'PosReg', (104, 112))	('autophagy', 'CPA', (175, 184))
34664	31892852	In SW620 cell, cleaved PARP was decrease with the combined treatment of SP600125 and shikonin, but the HCT116 cell show an upregulation of cleaved PARP under the same treatment.	('SP600125', 'Var', (72, 80))	('SP600125', 'Chemical', 'MESH:C432165', (72, 80))	('PARP', 'Gene', (23, 27))	('PARP', 'Gene', '1302', (147, 151))	('shikonin', 'Chemical', 'MESH:C016101', (85, 93))	('PARP', 'Gene', (147, 151))	('SW620', 'CellLine', 'CVCL:0547', (3, 8))	('HCT116', 'CellLine', 'CVCL:0291', (103, 109))	('upregulation', 'PosReg', (123, 135))	('PARP', 'Gene', '1302', (23, 27))	('decrease', 'NegReg', (32, 40))
34674	31581675	Glycemic Index, Glycemic Load and Cancer Risk: An Updated Meta-Analysis Diets high in glycemic index (GI) and glycemic load (GL) have been related to an increased risk of selected cancers, but additional quantification is required.	('Diets', 'Var', (72, 77))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('Cancer', 'Disease', (34, 40))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('related to', 'Reg', (139, 149))	('Cancer', 'Disease', 'MESH:D009369', (34, 40))	('glycemic', 'MPA', (86, 94))
34679	31581675	High GI was associated with small increased risks of colorectal (summary RR for GI: 1.20, 95% CI, 1.07-1.34:GL: 1.09, 95% CI, 0.97-1.22, 19 studies), bladder (GI: 1.25, 95% CI, 1.11-1.41:GL: 1.10, 95% CI, 0.85-1.42, four studies) and kidney cancers (GI: 1.16, 95% CI, 1.02-1.32:GL: 1.14, 95% CI, 0.81-1.60, five studies).	('kidney cancer', 'Phenotype', 'HP:0009726', (234, 247))	('kidney cancers', 'Disease', 'MESH:D007680', (234, 248))	('colorectal', 'Disease', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('kidney cancers', 'Disease', (234, 248))	('kidney cancers', 'Phenotype', 'HP:0009726', (234, 248))	('bladder', 'Disease', (150, 157))	('High GI', 'Var', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (241, 248))
34682	31581675	The present analysis, based on an updated comprehensive evaluation of the epidemiological literature, indicates moderate unfavorable effects of high versus low GI on colorectal, and possibly bladder and kidney cancers, and a possible moderate positive association between GL and endometrial cancer.	('bladder and kidney cancers', 'Disease', 'MESH:D001749', (191, 217))	('kidney cancer', 'Phenotype', 'HP:0009726', (203, 216))	('colorectal', 'Disease', (166, 176))	('endometrial cancer', 'Disease', (279, 297))	('kidney cancers', 'Phenotype', 'HP:0009726', (203, 217))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('endometrial cancer', 'Phenotype', 'HP:0012114', (279, 297))	('high', 'Var', (144, 148))	('endometrial cancer', 'Disease', 'MESH:D016889', (279, 297))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))
34696	31581675	A significantly increased colorectal cancer risk emerged for high GI (summary RR = 1.16, 95% CI, 1.07-1.25).	('colorectal cancer', 'Disease', (26, 43))	('high GI', 'Var', (61, 68))	('increased', 'PosReg', (16, 25))	('colorectal cancer', 'Disease', 'MESH:D015179', (26, 43))	('rectal cancer', 'Phenotype', 'HP:0100743', (30, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('colorectal cancer', 'Phenotype', 'HP:0003003', (26, 43))
34714	31581675	We updated subgroup analyses for breast cancer according to menopausal status and body mass index (BMI) (<25 kg/m2 and BMI >= 25 kg/m2).	('menopausal status', 'Phenotype', 'HP:0008209', (60, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('men', 'Species', '9606', (60, 63))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('<25', 'Var', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))
34728	31581675	High GI was associated with an increased risk of colon (HR for the fifth versus first quintile: 1.48, 95% CI, 1.09-2.01) and bladder cancer (HR: 1.51, 95% CI, 1.01-2.25), and high GL with an increased risk of colon (HR: 1.80, 95% CI, 1.18-2.74) and diabetes-related cancers (HR: 1.23, 95% CI, 1.03-1.48), but a decreased risk of rectal cancer (HR: 0.42, 95% CI, 0.18-0.98).	('high GL', 'Var', (175, 182))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('rectal cancer', 'Disease', 'MESH:D012004', (329, 342))	('cancers', 'Disease', (266, 273))	('rectal cancer', 'Disease', (329, 342))	('colon', 'Disease', (209, 214))	('cancers', 'Disease', 'MESH:D009369', (266, 273))	('bladder cancer', 'Phenotype', 'HP:0009725', (125, 139))	('rectal cancer', 'Phenotype', 'HP:0100743', (329, 342))	('colon', 'Disease', (49, 54))	('High GI', 'Var', (0, 7))	('diabetes', 'Disease', (249, 257))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('diabetes', 'Disease', 'MESH:D003920', (249, 257))	('bladder cancer', 'Disease', 'MESH:D001749', (125, 139))	('bladder cancer', 'Disease', (125, 139))
34746	31581675	High GL was not associated with colorectal (OR for the fourth versus first quartile: 1.14, 95% CI, 0.94-1.35), colon or rectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('High', 'Var', (0, 4))	('colon or rectal cancer', 'Disease', 'MESH:D015179', (111, 133))	('rectal cancer', 'Phenotype', 'HP:0100743', (120, 133))	('colon or rectal cancer', 'Disease', (111, 133))
34769	31581675	There was a positive significant association between high GI intake and colorectal cancer risk.	('colorectal cancer', 'Disease', 'MESH:D015179', (72, 89))	('high GI intake', 'Var', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('colorectal cancer', 'Disease', (72, 89))	('rectal cancer', 'Phenotype', 'HP:0100743', (76, 89))
34772	31581675	In a sensitivity analysis, the summary RR of colorectal cancer according to high GI remained statistically significant with the exclusion of each study in turn.	('colorectal cancer', 'Phenotype', 'HP:0003003', (45, 62))	('high GI', 'Var', (76, 83))	('colorectal cancer', 'Disease', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('rectal cancer', 'Phenotype', 'HP:0100743', (49, 62))	('colorectal cancer', 'Disease', 'MESH:D015179', (45, 62))
34774	31581675	A significant positive association was found between high GI and bladder cancer, with a summary RR of 1.25 (95% CI, 1.11-1.41; four studies, 3339 cases); the corresponding summary RR for GL was 1.10 (95% CI, 0.85-1.41; four studies, 3339 cases).	('bladder cancer', 'Disease', (65, 79))	('high GI', 'Var', (53, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('bladder cancer', 'Disease', 'MESH:D001749', (65, 79))
34792	31581675	According to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR), high dietary GL (but not GI) is probably a cause of endometrial cancer, while evidence on other cancer sites, including colorectal, pancreatic, liver and breast cancers, is inconclusive.	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Cancer', 'Disease', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', (192, 198))	('colorectal, pancreatic, liver and breast cancers', 'Disease', 'MESH:D001943', (216, 264))	('Cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('high dietary', 'Var', (96, 108))	('cancer', 'Disease', (160, 166))	('Cancer', 'Disease', 'MESH:D009369', (23, 29))	('endometrial cancer', 'Phenotype', 'HP:0012114', (148, 166))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancers', 'Phenotype', 'HP:0003002', (250, 264))	('Cancer', 'Disease', 'MESH:D009369', (67, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (250, 263))	('endometrial cancer', 'Disease', (148, 166))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('endometrial cancer', 'Disease', 'MESH:D016889', (148, 166))	('cause', 'Reg', (139, 144))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('cancer', 'Disease', (257, 263))
34796	31581675	In that report, high GI was associated with a marginally significant 10% increased risk of colorectal cancer (summary RR 1.10, 95% CI, 0.99-1.22), and each 10 units/day of GI to a 5% increased risk of borderline significance (summary RR 1.05, 95% CI, 1.00-1.10), while no association was reported for GL.	('colorectal cancer', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('high GI', 'Var', (16, 23))	('rectal cancer', 'Phenotype', 'HP:0100743', (95, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))
34804	31581675	We found a significant 25% increased risk of bladder cancer for high versus low GI intake, and the association remained significant when excluding each study in turn; no relation was observed for GL.	('low', 'Var', (76, 79))	('high', 'Var', (64, 68))	('bladder cancer', 'Phenotype', 'HP:0009725', (45, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('bladder cancer', 'Disease', 'MESH:D001749', (45, 59))	('bladder cancer', 'Disease', (45, 59))
34815	31581675	In epidemiologic studies, high dietary GI and GL were consistently associated with greater risks of diabetes and CHD.	('CHD', 'Disease', (113, 116))	('CHD', 'Phenotype', 'HP:0001677', (113, 116))	('diabetes', 'Disease', (100, 108))	('diabetes', 'Disease', 'MESH:D003920', (100, 108))	('associated', 'Reg', (67, 77))	('high dietary GI', 'Var', (26, 41))	('CHD', 'Disease', 'None', (113, 116))
34825	31581675	It indicates moderate unfavorable effects of high versus low GI on colorectal, and possibly, bladder and kidney cancers, and a possible modest positive association between GL and endometrial cancer.	('endometrial cancer', 'Phenotype', 'HP:0012114', (179, 197))	('endometrial cancer', 'Disease', 'MESH:D016889', (179, 197))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('colorectal', 'Disease', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('high', 'Var', (45, 49))	('kidney cancer', 'Phenotype', 'HP:0009726', (105, 118))	('endometrial cancer', 'Disease', (179, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('bladder and kidney cancers', 'Disease', 'MESH:D001749', (93, 119))	('kidney cancers', 'Phenotype', 'HP:0009726', (105, 119))
34830	31608277	In this article, we summarize the potential clinical utility of epigenetic signatures like DNA methylation, histone modifications, and microRNA dysregulation, which play important role in ovarian carcinogenesis and discuss its application in development of diagnostic, prognostic, and predictive biomarkers.	('ovarian carcinogenesis', 'Disease', 'MESH:D010049', (188, 210))	('microRNA', 'MPA', (135, 143))	('histone', 'MPA', (108, 115))	('ovarian carcinogenesis', 'Disease', (188, 210))	('DNA methylation', 'Var', (91, 106))
34831	31608277	Molecular characterization of epigenetic modification (methylation) in circulating cell free tumor DNA in body fluids offers novel, non-invasive approach for identification of potential promising cancer biomarkers, which can be performed at multiple time points and probably better reflects the prevailing molecular profile of cancer.	('epigenetic modification', 'Var', (30, 53))	('cancer', 'Disease', (327, 333))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
34843	31608277	More than one-fifth of ovarian carcinomas (about 23%) have hereditary susceptibility and germline mutations of BRCA1 and BRCA2 tumor suppressor genes; in particular contribute to 65-85% of these cases (Ramus et al.,).	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (23, 41))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor suppressor', 'biological_process', 'GO:0051726', ('127', '143'))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (23, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('tumor', 'Disease', (127, 132))	('BRCA2', 'Gene', '675', (121, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('127', '143'))	('BRCA1', 'Gene', '672', (111, 116))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (23, 40))	('mutations', 'Var', (98, 107))	('contribute', 'Reg', (165, 175))	('BRCA1', 'Gene', (111, 116))	('ovarian carcinomas', 'Disease', (23, 41))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('BRCA2', 'Gene', (121, 126))
34845	31608277	In addition, parity, pregnancy, lactation, tubal ligation, and oral contraceptive use are associated with reduced risk and have been found to be protective factors against disease development.	('lactation', 'Disease', (32, 41))	('lactation', 'Disease', 'MESH:D007775', (32, 41))	('reduced', 'NegReg', (106, 113))	('parity', 'Var', (13, 19))
34857	31608277	They are thought to arise from a low malignant potential precursor, are characterized as slow growing with low levels of chromosomal instability, intact DNA repair machinery and harbor mutations in KRAS, BRAF, and ERBB2 at a high frequency.	('ERBB2', 'Gene', '2064', (214, 219))	('mal', 'Gene', '4118', (37, 40))	('mal', 'Gene', '4118', (129, 132))	('ERBB2', 'Gene', (214, 219))	('BRAF', 'Gene', (204, 208))	('mal', 'Gene', (37, 40))	('KRAS', 'Gene', (198, 202))	('mal', 'Gene', (129, 132))	('chromosomal instability', 'Phenotype', 'HP:0040012', (121, 144))	('KRAS', 'Gene', '3845', (198, 202))	('mutations', 'Var', (185, 194))	('BRAF', 'Gene', '673', (204, 208))
34859	31608277	These aggressive tumors also include malignant mixed mesodermal and undifferentiated carcinomas, are characterized by rapid growth with no identified precursor lesions, high levels of chromosomal aberrations along with high frequency of TP53, BRCA1/2 mutations.	('mal', 'Gene', '4118', (192, 195))	('TP53', 'Gene', (237, 241))	('aggressive tumors', 'Disease', 'MESH:D001523', (6, 23))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (184, 207))	('mal', 'Gene', (192, 195))	('undifferentiated carcinomas', 'Disease', 'MESH:D002277', (68, 95))	('BRCA1', 'Gene', '672', (243, 248))	('BRCA1', 'Gene', (243, 248))	('TP53', 'Gene', '7157', (237, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('mal', 'Gene', '4118', (37, 40))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mutations', 'Var', (251, 260))	('mal', 'Gene', '4118', (60, 63))	('high levels of chromosomal aberrations', 'Phenotype', 'HP:0040012', (169, 207))	('mal', 'Gene', (37, 40))	('mal', 'Gene', (60, 63))	('undifferentiated carcinomas', 'Disease', (68, 95))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('aggressive tumors', 'Disease', (6, 23))
34863	31608277	On contrary, tubal precursor lesions, genetic evidence of BRCA1/2 mutation carriers and recent studies strongly implicate a non-ovarian origin and form the basis of the later model.	('implicate', 'Reg', (112, 121))	('BRCA1', 'Gene', (58, 63))	('ovarian', 'Disease', (128, 135))	('ovarian', 'Disease', 'MESH:D010049', (128, 135))	('mutation', 'Var', (66, 74))	('BRCA1', 'Gene', '672', (58, 63))
34865	31608277	It has also been postulated that aberrantly methylated Mullerian duct cells migrate into ovarian stroma where they are supported by the epigenetically/ genetically altered stromal environment, facilitating a cascade of events which culminate in ovarian carcinogenesis.	('mal', 'Gene', (176, 179))	('aberrantly methylated', 'Var', (33, 54))	('ovarian carcinogenesis', 'Disease', 'MESH:D010049', (245, 267))	('ovarian stroma', 'Disease', 'MESH:D010049', (89, 103))	('ovarian stroma', 'Disease', (89, 103))	('mal', 'Gene', '4118', (176, 179))	('ovarian carcinogenesis', 'Disease', (245, 267))
34866	31608277	Epigenetic profiling of endocervical glandular cells would facilitate in prediction of risk or early detection of ovarian cancer (Jones et al.,).	('ovarian cancer', 'Disease', (114, 128))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('Epigenetic', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('ovarian cancer', 'Disease', 'MESH:D010051', (114, 128))
34869	31608277	Additionally, aberrantly elevated serum CA125 have been reported in several benign conditions of endometriosis, pregnancy, peritonitis, pelvic inflammatory disease, uterine fibroids, menstrual cycle, liver cirrhosis.	('liver cirrhosis', 'Disease', 'MESH:D008103', (200, 215))	('pelvic inflammatory disease', 'Disease', (136, 163))	('aberrantly', 'Var', (14, 24))	('peritonitis', 'Disease', 'MESH:D010534', (123, 134))	('elevated serum CA125', 'Phenotype', 'HP:0031030', (25, 45))	('CA125', 'Gene', '94025', (40, 45))	('pregnancy', 'Disease', (112, 121))	('elevated', 'PosReg', (25, 33))	('uterine fibroids', 'Phenotype', 'HP:0000131', (165, 181))	('liver cirrhosis', 'Disease', (200, 215))	('menstrual cycle', 'Disease', (183, 198))	('peritonitis', 'Disease', (123, 134))	('reported', 'Reg', (56, 64))	('uterine fibroids', 'Disease', (165, 181))	('endometriosis', 'Disease', 'MESH:D004715', (97, 110))	('endometriosis', 'Disease', (97, 110))	('liver cirrhosis', 'Phenotype', 'HP:0001394', (200, 215))	('pelvic inflammatory disease', 'Disease', 'MESH:D000292', (136, 163))	('CA125', 'Gene', (40, 45))	('endometriosis', 'Phenotype', 'HP:0030127', (97, 110))	('peritonitis', 'Phenotype', 'HP:0002586', (123, 134))
34897	31608277	The cumulative lifetime risk of EOC for a woman with BRCA1 and BRCA2 mutation is 39-46% and 12-20%, respectively (Ramus et al.,).	('OC', 'Phenotype', 'HP:0100615', (33, 35))	('EOC', 'Disease', (32, 35))	('BRCA2', 'Gene', '675', (63, 68))	('mutation', 'Var', (69, 77))	('woman', 'Species', '9606', (42, 47))	('BRCA1', 'Gene', '672', (53, 58))	('BRCA2', 'Gene', (63, 68))	('BRCA1', 'Gene', (53, 58))
34898	31608277	Lifetime risk to develop breast cancer and ovarian cancer is enhanced up to 85% and up to 54% respectively in the carriers of BRCA1 and BRCA2 mutations.	('mutations', 'Var', (142, 151))	('carriers', 'Reg', (114, 122))	('BRCA1', 'Gene', (126, 131))	('enhanced', 'PosReg', (61, 69))	('ovarian cancer', 'Disease', 'MESH:D010051', (43, 57))	('ovarian cancer', 'Disease', (43, 57))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('ovarian cancer', 'Phenotype', 'HP:0100615', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('breast cancer', 'Disease', (25, 38))	('BRCA2', 'Gene', (136, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('BRCA1', 'Gene', '672', (126, 131))	('BRCA2', 'Gene', '675', (136, 141))
34901	31608277	DNA methylation, modification of histone proteins and miRNAs are the key modulator in regulating several cellular processes such as cell differentiation, embryogenesis, inactivation of X chromosome, genome imprinting, and many others (Jones,; Reik and Lewis,; Kacem and Feil,; Portela and Esteller,).	('miR', 'Gene', '220972', (54, 57))	('miR', 'Gene', (54, 57))	('cell differentiation', 'CPA', (132, 152))	('X chromosome', 'Gene', (185, 197))	('inactivation', 'Var', (169, 181))
34902	31608277	The epigenetic alternations involve interplay between DNA methylation, histone modification and micro RNA expression to modulate gene expression during development and cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('histone', 'Protein', (71, 78))	('gene expression', 'MPA', (129, 144))	('interplay', 'Interaction', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('modulate', 'Reg', (120, 128))	('epigenetic alternations', 'Var', (4, 27))	('cancer', 'Disease', (168, 174))
34906	31608277	Promoter methylation mediated epigenetic silencing of gene is regulated by the recruitment of MBD (methyl CpG binding proteins such as MeCP2, MBD1, MBD2, and MBD4) which in turn regulates chromatin state by recruiting histone modifying and chromatin-remodeling complexes (repressors) at the site of methylation, which subsequently generates condensed chromatin structure and results in transcriptional repression (Esteller,; Lopez-Serra and Esteller,).	('results in', 'Reg', (375, 385))	('condensed chromatin structure', 'MPA', (341, 370))	('MBD1', 'Gene', (142, 146))	('MBD2', 'Gene', (148, 152))	('MBD1', 'Gene', '4152', (142, 146))	('generates', 'Reg', (331, 340))	('regulates', 'Reg', (178, 187))	('transcriptional', 'MPA', (386, 401))	('MBD2', 'Gene', '8932', (148, 152))	('MBD4', 'Gene', (158, 162))	('MBD4', 'Gene', '8930', (158, 162))	('methylation', 'Var', (299, 310))	('MeCP2', 'Gene', '4204', (135, 140))	('MeCP2', 'Gene', (135, 140))	('recruiting', 'PosReg', (207, 217))	('Lopez-Serra', 'Disease', (425, 436))
34909	31608277	Apparently, it is quite evident now that DNA methylation plays an equal or possibly even greater role than the genetic lesion such as mutations, deletion and translocations which have been associated for long, with malignant transformations and carcinogenesis (Chan T. A. et al.,).	('mal', 'Gene', '4118', (215, 218))	('carcinogenesis', 'Disease', (245, 259))	('mal', 'Gene', (215, 218))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('mutations', 'Var', (134, 143))	('translocations', 'Var', (158, 172))	('carcinogenesis', 'Disease', 'MESH:D063646', (245, 259))	('DNA methylation', 'biological_process', 'GO:0006306', ('41', '56'))	('deletion', 'Var', (145, 153))
34910	31608277	For instance, though the familial breast cancer susceptibility gene 1 (BRCA1) mutations contributes to 5-10% of EOC, promoter hypermethylation of non-mutated BRCA1 allele is the second disruptive event to the development of this cancer (Barton et al.,).	('familial breast cancer', 'Disease', (25, 47))	('BRCA1', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('OC', 'Phenotype', 'HP:0100615', (113, 115))	('cancer', 'Disease', (229, 235))	('BRCA1', 'Gene', (158, 163))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('BRCA1', 'Gene', '672', (158, 163))	('hyper', 'Disease', 'MESH:D053306', (126, 131))	('EOC', 'Disease', (112, 115))	('mutations', 'Var', (78, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('BRCA1', 'Gene', '672', (71, 76))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('familial breast cancer', 'Disease', 'MESH:D001943', (25, 47))	('hyper', 'Disease', (126, 131))
34915	31608277	Methylation induced silencing of PTEN has also been frequently observed in primary epithelial ovarian carcinomas (Kurose et al.,).	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (94, 111))	('primary epithelial ovarian carcinomas', 'Disease', 'MESH:D010051', (75, 112))	('primary epithelial ovarian carcinomas', 'Disease', (75, 112))	('Methylation', 'Var', (0, 11))	('PTEN', 'Gene', (33, 37))	('PTEN', 'Gene', '5728', (33, 37))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (94, 112))	('silencing', 'NegReg', (20, 29))	('observed', 'Reg', (63, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))
34917	31608277	Several studies have identified the association of tumor-specific gene methylation with molecular, clinical, and pathological characteristics of epithelial ovarian carcinomas.	('methylation', 'Var', (71, 82))	('epithelial ovarian carcinomas', 'Disease', 'MESH:D010051', (145, 174))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (156, 173))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (156, 174))	('tumor', 'Disease', (51, 56))	('epithelial ovarian carcinomas', 'Disease', (145, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('association', 'Interaction', (36, 47))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
34920	31608277	Hypermethylation of FOXD3 correlated with tumor suppressive role (inhibition of proliferation, migration and promotion of apoptosis) in ovarian cancer cells and thus could serve as a potential therapeutic target for diagnosis of ovarian cancer (Luo et al.,).	('ovarian cancer', 'Disease', 'MESH:D010051', (229, 243))	('tumor', 'Disease', (42, 47))	('ovarian cancer', 'Disease', 'MESH:D010051', (136, 150))	('FOXD3', 'Gene', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('Hypermethylation', 'Var', (0, 16))	('proliferation', 'CPA', (80, 93))	('ovarian cancer', 'Disease', (136, 150))	('ovarian cancer', 'Disease', (229, 243))	('ovarian cancer', 'Phenotype', 'HP:0100615', (136, 150))	('FOXD3', 'Gene', '27022', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('promotion', 'PosReg', (109, 118))	('ovarian cancer', 'Phenotype', 'HP:0100615', (229, 243))	('migration', 'CPA', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('inhibition', 'NegReg', (66, 76))
34926	31608277	Furthermore, none of the normal non-neoplastic tissue showed methylation, revealing a specificity of 100%.	('mal', 'Gene', '4118', (28, 31))	('mal', 'Gene', (28, 31))	('methylation', 'Var', (61, 72))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (36, 53))
34930	31608277	investigated methylation in 126 primary ovarian tumors, 75 benign ovarian tumors and 14 borderline ovarian tumors and in 26 OC serum samples.	('ovarian tumor', 'Phenotype', 'HP:0100615', (40, 53))	('ovarian tumors', 'Disease', (99, 113))	('ovarian tumors', 'Phenotype', 'HP:0100615', (40, 54))	('OC', 'Phenotype', 'HP:0100615', (124, 126))	('ovarian tumors', 'Disease', 'MESH:D010051', (99, 113))	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('benign ovarian tumors', 'Disease', 'MESH:D010051', (59, 80))	('ovarian tumors', 'Disease', 'MESH:D010051', (66, 80))	('methylation', 'Var', (13, 24))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('benign ovarian tumors', 'Disease', (59, 80))	('ovarian tumors', 'Disease', (40, 54))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('ovarian tumors', 'Phenotype', 'HP:0100615', (99, 113))	('ovarian tumors', 'Disease', 'MESH:D010051', (40, 54))	('ovarian tumor', 'Phenotype', 'HP:0100615', (99, 112))	('ovarian tumor', 'Phenotype', 'HP:0100615', (66, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('ovarian tumors', 'Phenotype', 'HP:0100615', (66, 80))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
34934	31608277	Hypomethylation induced abnormal expression of several oncogenes such as CLDN4 (encodes an integral component of tight junctions) (Honda et al.,; Litkouhi et al.,), MAL (mal, T-cell differentiation protein) (Lee et al.,), BORIS (a cancer testis antigen family candidate oncogenes) (Woloszynska-Read et al.,), and IGF2 (an imprinted gene involved in other malignancies) (Murphy et al.,) has been demonstrated in ovarian carcinomas.	('mal', 'Gene', '4118', (170, 173))	('cancer testis', 'Phenotype', 'HP:0010788', (231, 244))	('T-cell differentiation', 'biological_process', 'GO:0030217', ('175', '197'))	('mal', 'Gene', (170, 173))	('protein', 'cellular_component', 'GO:0003675', ('198', '205'))	('CLDN4', 'Gene', (73, 78))	('MAL', 'Gene', '4118', (165, 168))	('IGF2', 'Gene', (313, 317))	('cancer testis', 'Disease', 'MESH:D013736', (231, 244))	('Hypomethylation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (419, 428))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (411, 429))	('malignancies', 'Disease', 'MESH:D009369', (355, 367))	('BORIS', 'Gene', '140690', (222, 227))	('IGF2', 'Gene', '3481', (313, 317))	('cancer testis', 'Disease', (231, 244))	('malignancies', 'Disease', (355, 367))	('mal', 'Gene', '4118', (355, 358))	('ovarian carcinomas', 'Disease', (411, 429))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (411, 429))	('mal', 'Gene', '4118', (29, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (419, 429))	('mal', 'Gene', (355, 358))	('mal', 'Gene', (29, 32))	('MAL', 'Gene', (165, 168))	('CLDN4', 'Gene', '1364', (73, 78))	('BORIS', 'Gene', (222, 227))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (411, 428))
34935	31608277	Promoter hypomethylation induced upregulation of other cancer-associated genes in ovarian cancer includes maspin (SERPINB5) (Rose et al.,), MCJ (Strathdee et al.,), and SNCG (synucelin-gamma) (Gupta et al.,; Czekierdowski et al.,), which encodes an activator of the MAPK and Elk-1 signaling cascades.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('maspin', 'Gene', '5268', (106, 112))	('Promoter hypomethylation', 'Var', (0, 24))	('upregulation', 'PosReg', (33, 45))	('SERPINB5', 'Gene', '5268', (114, 122))	('maspin', 'Gene', (106, 112))	('ovarian cancer', 'Disease', 'MESH:D010051', (82, 96))	('SNCG', 'Gene', (169, 173))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('MCJ', 'Gene', (140, 143))	('Elk-1', 'Gene', (275, 280))	('ovarian cancer', 'Disease', (82, 96))	('MCJ', 'Gene', '29103', (140, 143))	('SERPINB5', 'Gene', (114, 122))	('ovarian cancer', 'Phenotype', 'HP:0100615', (82, 96))	('SNCG', 'Gene', '6623', (169, 173))	('Elk-1', 'Gene', '2002', (275, 280))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (90, 96))
34936	31608277	Hypomethylation of SNCG, MASPIN, and CLDN4 correlates with advanced-stage and metastasis while that of BORIS is linked with disease presence.	('CLDN4', 'Gene', (37, 42))	('BORIS', 'Gene', (103, 108))	('advanced-stage', 'CPA', (59, 73))	('BORIS', 'Gene', '140690', (103, 108))	('Hypomethylation', 'Var', (0, 15))	('SNCG', 'Gene', '6623', (19, 23))	('MASPIN', 'Gene', '5268', (25, 31))	('MASPIN', 'Gene', (25, 31))	('CLDN4', 'Gene', '1364', (37, 42))	('SNCG', 'Gene', (19, 23))
34937	31608277	Hypomethylation of Sat2 (satellite 2) DNA in the juxtacentromeric region of chromosome 1 and 16 has been reported in ovarian cancer (Qu et al.,).	('Sat2', 'Gene', (19, 23))	('Hypomethylation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (117, 131))	('ovarian cancer', 'Disease', 'MESH:D010051', (117, 131))	('chromosome', 'cellular_component', 'GO:0005694', ('76', '86'))	('Sat2', 'molecular_function', 'GO:0003828', ('19', '23'))	('reported', 'Reg', (105, 113))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('ovarian cancer', 'Disease', (117, 131))
34940	31608277	Moreover, extensive hypomethylation was prevalent in high grade or advanced stage tumors (Widschwendter M. et al.,).	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('prevalent', 'Reg', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('extensive hypomethylation', 'Var', (10, 35))	('high', 'Disease', (53, 57))
34944	31608277	Methylation of >=1 gene of SFRP1, SFRP2, and SOX1 correlated with short disease free survival while SOX1, LMX1A, and SFRP1 methylation was associated with recurrence and short overall survival (Su et al.,).	('recurrence', 'CPA', (155, 165))	('SFRP1', 'Gene', '6422', (27, 32))	('associated with', 'Reg', (139, 154))	('SOX1', 'Gene', (45, 49))	('methylation', 'biological_process', 'GO:0032259', ('123', '134'))	('SFRP2', 'Gene', '6423', (34, 39))	('SOX1', 'Gene', (100, 104))	('Methylation', 'Var', (0, 11))	('overall', 'MPA', (176, 183))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('SFRP1', 'Gene', (117, 122))	('LMX1A', 'Gene', (106, 111))	('short disease', 'Disease', 'MESH:C537327', (66, 79))	('SFRP2', 'Gene', (34, 39))	('LMX1A', 'Gene', '4009', (106, 111))	('methylation', 'Var', (123, 134))	('short disease', 'Disease', (66, 79))	('SOX1', 'Gene', '6656', (45, 49))	('SOX1', 'Gene', '6656', (100, 104))	('SFRP1', 'Gene', '6422', (117, 122))	('SFRP1', 'Gene', (27, 32))
34946	31608277	Methylation of hMLH1, analyzed in 138 plasma samples predicted poor survival (hazard ratio: 1.99) (Gifford,) while CDH1, CDH13, and APC (out of a 15 gene panel) analyzed in peritoneal fluid from 57 ovarian cancer patients could predict overall survival (Suehiro et al.,).	('hMLH1', 'Gene', '4292', (15, 20))	('patients', 'Species', '9606', (213, 221))	('CDH13', 'Gene', (121, 126))	('Methylation', 'Var', (0, 11))	('CDH1', 'Gene', '999', (115, 119))	('APC', 'Disease', 'MESH:D011125', (132, 135))	('APC', 'Disease', (132, 135))	('ovarian cancer', 'Disease', 'MESH:D010051', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('CDH1', 'Gene', (115, 119))	('CDH1', 'Gene', '999', (121, 125))	('overall survival', 'MPA', (236, 252))	('poor', 'NegReg', (63, 67))	('CDH1', 'Gene', (121, 125))	('ovarian cancer', 'Disease', (198, 212))	('CDH13', 'Gene', '1012', (121, 126))	('peritoneal fluid', 'Phenotype', 'HP:0030995', (173, 189))	('predict', 'Reg', (228, 235))	('hMLH1', 'Gene', (15, 20))	('ovarian cancer', 'Phenotype', 'HP:0100615', (198, 212))
34947	31608277	recently reported that the epigenetic loss of heparin sulfate 3-O-sulfation makes ovarian cancer cells sensitive to oncogenic signals and could predict prognosis, thereby reflecting the utility of HS3ST2 for targeted therapy (Huang et al.,).	('predict', 'Reg', (144, 151))	('heparin sulfate', 'Protein', (46, 61))	('ovarian cancer', 'Phenotype', 'HP:0100615', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('HS3ST2', 'Gene', (197, 203))	('ovarian cancer', 'Disease', 'MESH:D010051', (82, 96))	('heparin sulfate', 'Chemical', 'MESH:D006497', (46, 61))	('ovarian cancer', 'Disease', (82, 96))	('sensitive', 'MPA', (103, 112))	('epigenetic', 'Var', (27, 37))	('HS3ST2', 'Gene', '9956', (197, 203))
34950	31608277	Promoter methylation of BRCA1 has been reported to be associated significantly with increased PFS of patients with OC undergoing adjuvant platinum-taxane-based chemotherapy (P = 0.008) as well for the patients with disease recurrence (PFS = 18.5 months over 12.8 months for patients without BRCA1 promoter methylation), thereby reflecting that promoter methylation of BRCA1 could be a better predictive marker of response to platinum-taxane-based chemotherapy in sporadic Epithelial ovarian carcinoma (Ignatov et al.,).	('BRCA1', 'Gene', (291, 296))	('BRCA1', 'Gene', '672', (368, 373))	('response to platinum', 'biological_process', 'GO:0070541', ('413', '433'))	('BRCA1', 'Gene', (368, 373))	('Promoter methylation', 'Var', (0, 20))	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (274, 282))	('sporadic Epithelial ovarian carcinoma', 'Disease', (463, 500))	('OC', 'Phenotype', 'HP:0100615', (115, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (491, 500))	('sporadic Epithelial ovarian carcinoma', 'Disease', 'MESH:D010051', (463, 500))	('patients', 'Species', '9606', (201, 209))	('BRCA1', 'Gene', '672', (24, 29))	('platinum-taxane', 'Chemical', '-', (425, 440))	('platinum-taxane', 'Chemical', '-', (138, 153))	('BRCA1', 'Gene', (24, 29))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('methylation', 'biological_process', 'GO:0032259', ('306', '317'))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (483, 500))	('PFS', 'MPA', (94, 97))	('BRCA1', 'Gene', '672', (291, 296))	('methylation', 'biological_process', 'GO:0032259', ('353', '364'))
34952	31608277	Presence of two or more methylated genes in patients significantly correlated with disease recurrence (hazard ratio: 1.91; p = 0.002) and shorter overall survival and disease free survival (hazard ratio: 1.96; p = 0.006) (Lin et al.,).	('patients', 'Species', '9606', (44, 52))	('overall survival', 'CPA', (146, 162))	('disease recurrence', 'CPA', (83, 101))	('shorter', 'NegReg', (138, 145))	('disease free survival', 'CPA', (167, 188))	('Presence', 'Var', (0, 8))
34959	31608277	Oncomorphic TP53 mutation correlated with worse progression free survival, higher risk of recurrence and higher rate of platinum resistance (Brachova et al.,).	('platinum', 'Chemical', 'MESH:D010984', (120, 128))	('worse', 'NegReg', (42, 47))	('mutation', 'Var', (17, 25))	('progression free survival', 'CPA', (48, 73))	('TP53', 'Gene', '7157', (12, 16))	('platinum resistance', 'CPA', (120, 139))	('TP53', 'Gene', (12, 16))
34962	31608277	Further validation using independent TCGA data set revealed the significant association of VEGFA, VEGFB, and VEGFC promoter methylation with progression free survival (Dai et al.,).	('VEGFC', 'Gene', (109, 114))	('VEGFB', 'Gene', '7423', (98, 103))	('VEGFA', 'Gene', '7422', (91, 96))	('methylation', 'biological_process', 'GO:0032259', ('124', '135'))	('VEGFB', 'Gene', (98, 103))	('promoter methylation', 'Var', (115, 135))	('association', 'Interaction', (76, 87))	('progression free survival', 'CPA', (141, 166))	('VEGFA', 'Gene', (91, 96))	('VEGFC', 'Gene', '7424', (109, 114))
34963	31608277	Promoter hypomethylation and expression of PRAME correlates with increased survival in high grade serous ovarian carcinoma (Zhang et al.,).	('increased', 'PosReg', (65, 74))	('serous ovarian carcinoma', 'Disease', (98, 122))	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (98, 122))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (105, 122))	('Promoter hypomethylation', 'Var', (0, 24))	('survival', 'MPA', (75, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('PRAME', 'Gene', '23532', (43, 48))	('PRAME', 'Gene', (43, 48))
34964	31608277	Promoter hypomethylation and increased expression of proto-oncogenes is predictive for more aggressiveness and metastasis of disease and thereby lower survival, which is evident from recent studies on GABRP, SLC6A12, MGAT3, CT45, CA9, MUC13, and AGR2 (Sung et al.,; Zhang et al.,; Kohler et al.,).	('MUC13', 'Gene', '56667', (235, 240))	('AGR2', 'Gene', (246, 250))	('survival', 'CPA', (151, 159))	('GABRP', 'Gene', '2568', (201, 206))	('increased', 'PosReg', (29, 38))	('Promoter hypomethylation', 'Var', (0, 24))	('GABRP', 'Gene', (201, 206))	('CT45', 'Gene', '2577', (224, 228))	('AGR2', 'Gene', '10551', (246, 250))	('CA9', 'Gene', (230, 233))	('CT45', 'Gene', (224, 228))	('SLC6A12', 'Gene', '6539', (208, 215))	('metastasis of disease', 'Disease', (111, 132))	('more', 'PosReg', (87, 91))	('MGAT3', 'Gene', '4248', (217, 222))	('lower', 'NegReg', (145, 150))	('expression', 'MPA', (39, 49))	('metastasis of disease', 'Disease', 'MESH:D009362', (111, 132))	('CA9', 'Gene', '768', (230, 233))	('aggressiveness', 'Disease', (92, 106))	('aggressiveness', 'Phenotype', 'HP:0000718', (92, 106))	('MUC13', 'Gene', (235, 240))	('aggressiveness', 'Disease', 'MESH:D001523', (92, 106))	('SLC6A12', 'Gene', (208, 215))	('MGAT3', 'Gene', (217, 222))
34967	31608277	Further, methylation induced silencing of KCNH2 (HERG, a potassium channel) could be a better prognostic factor for poor survival provided increased proliferation was mediated by overexpression of Eag family members.	('methylation', 'Var', (9, 20))	('KCNH2', 'Gene', '3757', (42, 47))	('HERG', 'Gene', (49, 53))	('silencing', 'NegReg', (29, 38))	('KCNH2', 'Gene', (42, 47))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('HERG', 'Gene', '3757', (49, 53))
34968	31608277	Further, epigenetic silencing of regulators of hedgehog signaling pathway ZIC1 and ZIC4 was associated with increased proliferation, migration, and invasion.	('ZIC1', 'Gene', '7545', (74, 78))	('ZIC1', 'Gene', (74, 78))	('ZIC4', 'Gene', (83, 87))	('increased', 'PosReg', (108, 117))	('proliferation', 'CPA', (118, 131))	('migration', 'CPA', (133, 142))	('ZIC4', 'Gene', '84107', (83, 87))	('epigenetic silencing', 'Var', (9, 29))	('invasion', 'CPA', (148, 156))
34972	31608277	Low CSK methylation significantly correlated with improved PFS and OS in HGSOC patients (Tomar et al.,).	('CSK', 'Gene', (4, 7))	('HGSOC', 'Disease', (73, 78))	('PFS', 'Disease', (59, 62))	('improved', 'PosReg', (50, 58))	('patients', 'Species', '9606', (79, 87))	('OC', 'Phenotype', 'HP:0100615', (76, 78))	('CSK', 'Gene', '1445', (4, 7))	('Low', 'NegReg', (0, 3))	('methylation', 'Var', (8, 19))
34975	31608277	Epigenetic silencing of POTE gene was functionally verified by experiments involving treatment with Decitabine and DNMT knockout cell lines.	('POTE', 'Gene', (24, 28))	('DNMT', 'Gene', '1786', (115, 119))	('POTE', 'Gene', '317754', (24, 28))	('DNMT', 'Gene', (115, 119))	('Decitabine', 'Chemical', 'MESH:D000077209', (100, 110))	('Epigenetic silencing', 'Var', (0, 20))
34977	31608277	Furthermore, several epigenetic alternations (pericentromeric activation, global and locus-specific L1 hypomethylation, and locus-specific 5' CpG hypomethylation) served as a determinant for regulation of epigenetic activation of POTE gene (Sharma et al.,).	('epigenetic', 'Var', (205, 215))	('POTE', 'Gene', '317754', (230, 234))	('POTE', 'Gene', (230, 234))
34979	31608277	Methylation mediated transcriptional repression of specific drug-response genes results in acquisition of drug resistance and significantly extends its impact on different facets of chemotherapeutic actions: membrane entry/exit, drug metabolism, response to cellular injury, DNA repair, apoptosis etc., in cancer cells.	('membrane entry/exit', 'MPA', (208, 227))	('results in', 'Reg', (80, 90))	('apoptosis', 'CPA', (287, 296))	('repression', 'NegReg', (37, 47))	('response to cellular injury', 'MPA', (246, 273))	('drug resistance', 'Phenotype', 'HP:0020174', (106, 121))	('acquisition', 'PosReg', (91, 102))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('drug metabolism', 'MPA', (229, 244))	('drug resistance', 'MPA', (106, 121))	('DNA repair', 'MPA', (275, 285))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('cancer', 'Disease', (306, 312))
34981	31608277	Three studies well defined in ovarian cancer includes: Methylation of either BRCA1, GSTP1, or MGMT significantly correlates with improved response to chemotherapy (p = 0.013) (Teodoridis et al.,).	('response to chemotherapy', 'MPA', (138, 162))	('BRCA1', 'Gene', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('ovarian cancer', 'Disease', 'MESH:D010051', (30, 44))	('MGMT', 'Gene', '4255', (94, 98))	('GSTP1', 'Gene', '2950', (84, 89))	('MGMT', 'Gene', (94, 98))	('ovarian cancer', 'Disease', (30, 44))	('Methylation', 'Var', (55, 66))	('BRCA1', 'Gene', '672', (77, 82))	('GSTP1', 'Gene', (84, 89))	('improved', 'PosReg', (129, 137))	('ovarian cancer', 'Phenotype', 'HP:0100615', (30, 44))
34982	31608277	Hypermethylation of RASSF1A and CABIN1 have been reported to correlate with response to adjuvant therapy.	('correlate', 'Reg', (61, 70))	('RASSF1A', 'Gene', (20, 27))	('Hypermethylation', 'Var', (0, 16))	('CABIN1', 'Gene', (32, 38))	('RASSF1A', 'Gene', '11186', (20, 27))
34984	31608277	demonstrated that high levels of MCJ methylation significantly correlated with poor response to therapy (p = 0.027) and poor overall survival (p = 0.023; HR = 2.9) (Strathdee et al.,).	('MCJ', 'Gene', (33, 36))	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('methylation', 'Var', (37, 48))	('overall survival', 'CPA', (125, 141))	('MCJ', 'Gene', '29103', (33, 36))	('poor', 'NegReg', (120, 124))	('high', 'Var', (18, 22))	('poor', 'NegReg', (79, 83))
34991	31608277	Promoter methylation of OPCML was significantly associated with poor overall survival of OC patients and thus could be of use in predicting disease prognosis (Zhou et al.,).	('overall', 'MPA', (69, 76))	('OC', 'Phenotype', 'HP:0100615', (89, 91))	('associated', 'Reg', (48, 58))	('poor', 'NegReg', (64, 68))	('patients', 'Species', '9606', (92, 100))	('Promoter methylation', 'Var', (0, 20))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('OPCML', 'Gene', (24, 29))	('OPCML', 'Gene', '4978', (24, 29))
34993	31608277	Hypomethylation of developmental genes MSX1 and TMEM88 correlated with platinum resistance in patients with ovarian cancer (Bonito et al.,; de Leon et al.,).	('ovarian cancer', 'Disease', (108, 122))	('MSX1', 'Gene', (39, 43))	('platinum resistance', 'CPA', (71, 90))	('patients', 'Species', '9606', (94, 102))	('MSX1', 'Gene', '4487', (39, 43))	('Hypomethylation', 'Var', (0, 15))	('TMEM88', 'Gene', (48, 54))	('correlated with', 'Reg', (55, 70))	('ovarian cancer', 'Phenotype', 'HP:0100615', (108, 122))	('platinum', 'Chemical', 'MESH:D010984', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ovarian cancer', 'Disease', 'MESH:D010051', (108, 122))	('Bonito', 'Species', '8226', (124, 130))	('TMEM88', 'Gene', '92162', (48, 54))
34994	31608277	Stimulation of EMT by non-coding RNA HOTAIR has been reported to be regulated by DNA methylation and is indicative of resistance to carboplatin (Teschendorff et al.,).	('HOTAIR', 'Gene', (37, 43))	('EMT', 'CPA', (15, 18))	('HOTAIR', 'Gene', '100124700', (37, 43))	('non-coding', 'Var', (22, 32))	('carboplatin', 'Chemical', 'MESH:D016190', (132, 143))
34996	31608277	Induction of EMT by TET is mediated by demethylation of Vimentin promoter in ovarian carcinoma (Han et al.,).	('Vimentin', 'Gene', (56, 64))	('demethylation', 'Var', (39, 52))	('TET', 'Chemical', 'MESH:C010349', (20, 23))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (77, 94))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (77, 94))	('Vimentin', 'Gene', '7431', (56, 64))	('ovarian carcinoma', 'Disease', (77, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))
34997	31608277	A recent study has described how methylome-targeting strategies could bring forth anti-tumor effect.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('methylome-targeting strategies', 'Var', (33, 63))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
35000	31608277	Another recent study has highlighted the tumor suppressor role of ZNF671 and its methylation could act as a predictor for early recurrence of serous ovarian carcinoma (Mase et al.,).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('41', '57'))	('methylation', 'biological_process', 'GO:0032259', ('81', '92'))	('methylation', 'Var', (81, 92))	('tumor', 'Disease', (41, 46))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (149, 166))	('ZNF671', 'Gene', (66, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('serous ovarian carcinoma', 'Disease', (142, 166))	('tumor suppressor', 'biological_process', 'GO:0051726', ('41', '57'))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (142, 166))	('ZNF671', 'Gene', '79891', (66, 72))
35001	31608277	has for the first time reported the exclusive association of massive DNA hypomethylation with poorly differentiated tumors, which correlates with disease aggressiveness and progression.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('aggressiveness', 'Disease', (154, 168))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('69', '88'))	('aggressiveness', 'Phenotype', 'HP:0000718', (154, 168))	('massive DNA hypomethylation', 'Var', (61, 88))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('association', 'Interaction', (46, 57))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('aggressiveness', 'Disease', 'MESH:D001523', (154, 168))
35002	31608277	In conclusion, it is speculated that the combinatorial therapies utilizing epigenetic inhibitors holds promise and would be most effective for chemo-resensitization of resistant tumors, possibly by restoration of pathways associated with drug response, and thus would subsequently implicate improved survival outcomes as well as personalized treatment for this devastating disease.	('epigenetic inhibitors', 'Var', (75, 96))	('tumors', 'Disease', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('improved', 'PosReg', (291, 299))
35005	31608277	Association of histone modifications with aberrant class III beta tubulin protein expression (Izutsu et al.,), reduction of PACE3 expression (Fu et al.,) and silencing of survivin (Mirza et al.,) has been reported in ovarian tumorigenesis.	('reduction', 'NegReg', (111, 120))	('ovarian tumor', 'Disease', 'MESH:D010051', (217, 230))	('class III beta tubulin', 'Gene', '10381', (51, 73))	('expression', 'MPA', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('histone', 'Protein', (15, 22))	('class III beta tubulin', 'Gene', (51, 73))	('ovarian tumor', 'Disease', (217, 230))	('aberrant', 'Var', (42, 50))	('PACE3', 'Protein', (124, 129))	('modifications', 'Var', (23, 36))	('ovarian tumor', 'Phenotype', 'HP:0100615', (217, 230))	('silencing', 'Var', (158, 167))	('survivin', 'Protein', (171, 179))
35017	31608277	identified genome-wide bivalent domains (H3K27me3 and H3K4me3) at gene promoter in tumor samples which were collected pre and post platinum resistance acquisition, and showed that these representative poised gene sets are pre-disposed to hypermethylation induced epigenetic silencing during acquisition of drug resistance, thus provides novel insights to prevent emergence of drug resistance (Curry et al.,).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('H3K4me3', 'Var', (54, 61))	('platinum', 'Chemical', 'MESH:D010984', (131, 139))	('epigenetic', 'Var', (263, 273))	('tumor', 'Disease', (83, 88))	('drug resistance', 'Phenotype', 'HP:0020174', (306, 321))	('hyper', 'Disease', (238, 243))	('H3K27me3', 'Var', (41, 49))	('hyper', 'Disease', 'MESH:D053306', (238, 243))	('drug resistance', 'Phenotype', 'HP:0020174', (376, 391))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
35018	31608277	reported that Enhancer of zeste homolog 2 (EZH2) mediates repression of tissue inhibitor of metalloproteinases 2(TIMP2) by H3K27me3 and DNA methylation thereby facilitating ovarian cancer metastasis (Yi et al.,).	('EZH2', 'Gene', (43, 47))	('H3K27me3', 'Protein', (123, 131))	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('TIMP2', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('Enhancer of zeste homolog 2', 'Gene', '2146', (14, 41))	('DNA methylation', 'biological_process', 'GO:0006306', ('136', '151'))	('tissue inhibitor of metalloproteinases 2', 'Gene', '7077', (72, 112))	('facilitating', 'Reg', (160, 172))	('TIMP2', 'Gene', '7077', (113, 118))	('DNA methylation', 'Var', (136, 151))	('ovarian cancer metastasis', 'Disease', (173, 198))	('tissue inhibitor of metalloproteinases 2', 'Gene', (72, 112))	('ovarian cancer metastasis', 'Disease', 'MESH:D010051', (173, 198))	('ovarian cancer', 'Phenotype', 'HP:0100615', (173, 187))	('EZH2', 'Gene', '2146', (43, 47))	('Enhancer of zeste homolog 2', 'Gene', (14, 41))
35019	31608277	In similar context, another study highlighted silencing of ARHI in ovarian cancer which was synergistically mediated by Enhancer of zeste homolog 2 (EZH2) induced H3K27me3 and DNA methylation.	('ovarian cancer', 'Disease', 'MESH:D010051', (67, 81))	('H3K27me3', 'Var', (163, 171))	('ovarian cancer', 'Phenotype', 'HP:0100615', (67, 81))	('ovarian cancer', 'Disease', (67, 81))	('silencing', 'Var', (46, 55))	('Enhancer of zeste homolog 2', 'Gene', (120, 147))	('ARHI', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('EZH2', 'Gene', '2146', (149, 153))	('Enhancer of zeste homolog 2', 'Gene', '2146', (120, 147))	('ARHI', 'Gene', '9077', (59, 63))	('EZH2', 'Gene', (149, 153))	('DNA methylation', 'MPA', (176, 191))
35025	31608277	Further, numerous subsequent studies confirmed that the tumor-specific pattern of alterations, such as chromosomal abnormality, somatic mutations, resistance mutation, aberrant methylation and copy number variations could be found in cfDNA, which can serve as potential target for diagnosis of cancer through non-invasive approach (Leon et al.,; Polivka et al.,; Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('copy number variations', 'Var', (193, 215))	('tumor', 'Disease', (56, 61))	('cfDNA', 'Disease', (234, 239))	('chromosomal abnormality', 'Disease', (103, 126))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancer', 'Disease', (294, 300))	('resistance mutation', 'Var', (147, 166))	('chromosomal abnormality', 'Disease', 'MESH:D002869', (103, 126))	('mutations', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('aberrant methylation', 'Var', (168, 188))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
35032	31608277	Numerous studies have demonstrated that tumor specific aberrant methylation can also be detected in cfDNA of patients with different tumor types such as lung, prostate, breast and colorectal cancer and further confirmed altered methylation as an independent diagnostic/ prognostic marker (Board et al.,; Brock et al.,; Lofton-Day et al.,; Vlassov et al.,).	('altered', 'Var', (220, 227))	('breast and colorectal cancer', 'Disease', 'MESH:D001943', (169, 197))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('patients', 'Species', '9606', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('colorectal cancer', 'Phenotype', 'HP:0003003', (180, 197))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('detected', 'Reg', (88, 96))	('cfDNA', 'Disease', (100, 105))	('tumor', 'Disease', (133, 138))	('lung', 'Disease', (153, 157))	('prostate', 'Disease', (159, 167))	('aberrant methylation', 'Var', (55, 75))	('tumor', 'Disease', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
35033	31608277	developed a highly sensitive non-invasive test for screening of colorectal cancer based on methylation of SEPT9 in plasma which could specifically detect all stages and locations of colorectal cancers (Warren et al.,).	('detect', 'Reg', (147, 153))	('methylation', 'Var', (91, 102))	('SEPT9', 'Gene', '10801', (106, 111))	('colorectal cancers', 'Disease', 'MESH:D015179', (182, 200))	('colorectal cancer', 'Disease', (64, 81))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('colorectal cancer', 'Phenotype', 'HP:0003003', (182, 199))	('SEPT9', 'Gene', (106, 111))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('colorectal cancers', 'Disease', (182, 200))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('colorectal cancer', 'Disease', 'MESH:D015179', (182, 199))
35034	31608277	Hypermethylation of Vim gene is strongly correlated with the occurrence of colorectal cancer.	('colorectal cancer', 'Disease', (75, 92))	('Vim', 'Gene', '7431', (20, 23))	('correlated with', 'Reg', (41, 56))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))	('Vim', 'Gene', (20, 23))
35036	31608277	Gstp1 methylation status in urine is strongly correlated with early onset of prostate cancer (Belinsky,).	('Gstp1', 'Gene', (0, 5))	('prostate cancer', 'Disease', (77, 92))	('Gstp1', 'Gene', '2950', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('methylation', 'biological_process', 'GO:0032259', ('6', '17'))	('prostate cancer', 'Disease', 'MESH:D011471', (77, 92))	('prostate cancer', 'Phenotype', 'HP:0012125', (77, 92))	('correlated with', 'Reg', (46, 61))	('methylation status', 'Var', (6, 24))
35039	31608277	explored the potential of eight gene panel for non-invasive detection of lung cancer using qMSP and revealed that the promoter methylation of any of the eight gene could detect the disease with a sensitivity of 72% with 91% specificity, reflecting the utility of plasma DNA methylation as a novel approach for detection of lung cancer at early stage (Yang et al.,).	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('lung cancer', 'Disease', 'MESH:D008175', (323, 334))	('promoter methylation', 'Var', (118, 138))	('detect', 'Reg', (170, 176))	('DNA methylation', 'biological_process', 'GO:0006306', ('270', '285'))	('methylation', 'biological_process', 'GO:0032259', ('127', '138'))	('DNA', 'cellular_component', 'GO:0005574', ('270', '273'))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (323, 334))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('lung cancer', 'Disease', (323, 334))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))
35042	31608277	analyzed the methylation of ADAMTS1 and BNC1 in cfDNA using qMSP, which exhibited a sensitivity of 94.8% and specificity of 91.6% with a AUC of 0.95 reflecting diagnostic potential of this blood based two-gene panel in detection of pancreatic cancer at an early stage (Eissa et al.,).	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('ADAMTS1', 'Gene', '9510', (28, 35))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (232, 249))	('methylation', 'Var', (13, 24))	('BNC1', 'Gene', (40, 44))	('pancreatic cancer', 'Disease', 'MESH:D010190', (232, 249))	('ADAMTS1', 'Gene', (28, 35))	('pancreatic cancer', 'Disease', (232, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('BNC1', 'Gene', '646', (40, 44))
35043	31608277	Methylation of APC, FOXA1, and RASSF1A in cell free DNA served as a best performing cassette in terms of diagnostic and prognostic value, revealing a sensitivity, specificity and accuracy over 70% suggesting its putative utility in management of breast cancer (Salta et al.,).	('breast cancer', 'Disease', (246, 259))	('FOXA1', 'Gene', (20, 25))	('APC', 'Disease', (15, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('Methylation', 'Var', (0, 11))	('RASSF1A', 'Gene', (31, 38))	('APC', 'cellular_component', 'GO:0005680', ('15', '18'))	('FOXA1', 'Gene', '3169', (20, 25))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('RASSF1A', 'Gene', '11186', (31, 38))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('APC', 'Disease', 'MESH:D011125', (15, 18))	('breast cancer', 'Disease', 'MESH:D001943', (246, 259))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
35044	31608277	using MeDIP-seq approach reported 10 significant differentially methylated genes as potent biomarker for lung cancer clinical application (Xu et al.,).	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('differentially methylated genes', 'Var', (49, 80))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('lung cancer', 'Disease', (105, 116))
35056	31608277	Aberrant expression of microRNAs has been confirmed in ovarian carcinogenesis.	('Aberrant expression', 'Var', (0, 19))	('ovarian carcinogenesis', 'Disease', (55, 77))	('ovarian carcinogenesis', 'Disease', 'MESH:D010049', (55, 77))	('microRNAs', 'Protein', (23, 32))
35061	31608277	A list of aberrantly expressed miRs which could serve as a promising biomarker for detection of ovarian cancer has been summarized in Table 11.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ovarian cancer', 'Phenotype', 'HP:0100615', (96, 110))	('miR', 'Gene', '220972', (31, 34))	('ovarian cancer', 'Disease', 'MESH:D010051', (96, 110))	('miR', 'Gene', (31, 34))	('aberrantly expressed', 'Var', (10, 30))	('ovarian cancer', 'Disease', (96, 110))
35084	31608277	Overexpression of miR-96-5p was correlated with increased proliferation and migration by suppressing Caveolae1 (CAV1) and inhibiting AKT signaling pathway and its downstream proteins (Cyclin D1 and P70), thus implying that miR-96-5p could serve as a promising therapeutic target for ovarian cancer (Liu et al.,, p. 1).	('Cyclin D1', 'Gene', (184, 193))	('CAV1', 'Gene', (112, 116))	('ovarian cancer', 'Disease', (283, 297))	('AKT', 'Gene', (133, 136))	('ovarian cancer', 'Phenotype', 'HP:0100615', (283, 297))	('miR-96-5p', 'Var', (18, 27))	('inhibiting', 'NegReg', (122, 132))	('Caveolae1', 'Gene', '857', (101, 110))	('P70', 'Gene', '84959', (198, 201))	('migration', 'CPA', (76, 85))	('suppressing', 'NegReg', (89, 100))	('AKT', 'Gene', '207', (133, 136))	('miR-96-5p', 'Chemical', '-', (18, 27))	('CAV1', 'Gene', '857', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('ovarian cancer', 'Disease', 'MESH:D010051', (283, 297))	('increased', 'PosReg', (48, 57))	('proliferation', 'CPA', (58, 71))	('Caveolae1', 'Gene', (101, 110))	('miR-96-5p', 'Chemical', '-', (223, 232))	('P70', 'Gene', (198, 201))	('Cyclin D1', 'Gene', '595', (184, 193))
35104	31608277	Furthermore, high serum miR-200c correlated with higher survival rate.	('higher', 'PosReg', (49, 55))	('high', 'Var', (13, 17))	('survival rate', 'CPA', (56, 69))	('miR-200c', 'Gene', (24, 32))	('miR-200c', 'Gene', '406985', (24, 32))
35114	31608277	Another limitation is the absence of standardized reference value for methylation analysis when trying to analyze if a particular locus is hyper or hypomethylated.	('hypomethylated', 'Var', (148, 162))	('hyper', 'Disease', 'MESH:D053306', (139, 144))	('methylation', 'biological_process', 'GO:0032259', ('70', '81'))	('hyper', 'Disease', (139, 144))
35115	31608277	Molecular analysis of epigenetic modification (methylation) in circulating cell free tumor DNA in fluids serves as a novel, non-invasive approach for identification of potential promising cancer biomarkers, which can be performed at multiple time points and probably better reflects the prevailing molecular profile of cancer.	('tumor', 'Disease', (85, 90))	('epigenetic modification', 'Var', (22, 45))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', (319, 325))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Disease', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))
35125	31275454	SOX9 expression was associated with lower risk of relapse in Cox univariable analysis (HR = 0.58; 95% CI = 0.35-0.97; P = 0.04).	('Cox', 'Gene', '1351', (61, 64))	('lower', 'NegReg', (36, 41))	('SOX9', 'Gene', (0, 4))	('Cox', 'Gene', (61, 64))	('relapse', 'CPA', (50, 57))	('expression', 'Var', (5, 15))
35135	31275454	Germline SOX9 heterozygous inactivating mutations result in campomelic dysplasia, a syndrome characterized by skeletal malformations and central nervous system dysfunction together with abnormalities in other organs, which is frequently associated with XY sex reversal.	('skeletal malformations', 'Phenotype', 'HP:0000924', (110, 132))	('result in', 'Reg', (50, 59))	('heterozygous inactivating mutations', 'Var', (14, 49))	('skeletal malformations and central nervous system dysfunction', 'Disease', 'MESH:D009421', (110, 171))	('sex reversal', 'Phenotype', 'HP:0012245', (256, 268))	('campomelic dysplasia', 'Disease', 'MESH:D055036', (60, 80))	('campomelic dysplasia', 'Disease', (60, 80))
35140	31275454	SOX9 overexpression in colorectal cancer cells is sufficient to inhibit cell proliferation whereas SOX9 knockdown increases the proliferation of the human colorectal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('colorectal cancer', 'Disease', (23, 40))	('SOX9', 'Gene', (99, 103))	('colorectal cancer', 'Disease', 'MESH:D015179', (155, 172))	('SOX9', 'Gene', (0, 4))	('colorectal cancer', 'Disease', 'MESH:D015179', (23, 40))	('cell proliferation', 'biological_process', 'GO:0008283', ('72', '90'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (155, 172))	('overexpression', 'PosReg', (5, 19))	('increases', 'PosReg', (114, 123))	('cell proliferation', 'CPA', (72, 90))	('proliferation', 'CPA', (128, 141))	('inhibit', 'NegReg', (64, 71))	('human', 'Species', '9606', (149, 154))	('colorectal cancer', 'Disease', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('colorectal cancer', 'Phenotype', 'HP:0003003', (23, 40))	('knockdown', 'Var', (104, 113))
35144	31275454	SOX9 knockdown resulted in decrease of proliferation and tumour growth capacity of colorectal cancer cells subcutaneously grafted or injected in the peritoneum of nude mice.	('colorectal cancer', 'Disease', 'MESH:D015179', (83, 100))	('tumour', 'Disease', (57, 63))	('nude mice', 'Species', '10090', (163, 172))	('SOX9', 'Gene', (0, 4))	('colorectal cancer', 'Phenotype', 'HP:0003003', (83, 100))	('knockdown', 'Var', (5, 14))	('decrease', 'NegReg', (27, 35))	('colorectal cancer', 'Disease', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('proliferation', 'CPA', (39, 52))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
35146	31275454	Regarding clinical value, there are reports correlating high levels of SOX9 with poor prognosis in colorectal cancer and one study enrolling a large number of patients that shows no association with prognosis.	('colorectal cancer', 'Disease', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('high levels', 'Var', (56, 67))	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('patients', 'Species', '9606', (159, 167))	('SOX9', 'Gene', (71, 75))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))
35149	31275454	One study reported a significant association between high SOX9 expression, advanced TNM stages, and lower overall survival, further reviewed in.	('TNM', 'Gene', (84, 87))	('high', 'Var', (53, 57))	('expression', 'MPA', (63, 73))	('lower', 'NegReg', (100, 105))	('SOX9', 'Protein', (58, 62))	('TNM', 'Gene', '10178', (84, 87))	('overall survival', 'CPA', (106, 122))
35196	31275454	On the contrary, the analysis we performed in both the ACRG and the TCGA databases reinforced the worse prognosis associated with low SOX9 expression in gastric cancer.	('gastric cancer', 'Disease', (153, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('gastric cancer', 'Disease', 'MESH:D013274', (153, 167))	('SOX9', 'Protein', (134, 138))	('gastric cancer', 'Phenotype', 'HP:0012126', (153, 167))	('low', 'Var', (130, 133))	('expression', 'MPA', (139, 149))
35203	31275454	On the other hand, SOX9 might have a dose-dependent effect, which has already been suggested for colorectal cancer, where the same apparently contradictory observations have been reported.	('colorectal cancer', 'Disease', 'MESH:D015179', (97, 114))	('SOX9', 'Var', (19, 23))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colorectal cancer', 'Disease', (97, 114))
35215	27929437	Treatment of the murine colon carcinoma cell line (CT26) with DBT-PD inhibits growth, whereas treatment with comparable amounts of purified astragaloside IV and ferulic acid showed no significant effect.	('DBT-PD', 'Var', (62, 68))	('colon carcinoma', 'Disease', 'MESH:D015179', (24, 39))	('growth', 'MPA', (78, 84))	('inhibits', 'NegReg', (69, 77))	('colon carcinoma', 'Disease', (24, 39))	('DBT-PD', 'Chemical', '-', (62, 68))	('CT26', 'CellLine', 'CVCL:7254', (51, 55))	('astragaloside IV', 'Chemical', 'MESH:C052064', (140, 156))	('murine', 'Species', '10090', (17, 23))	('men', 'Species', '9606', (99, 102))	('ferulic acid', 'Chemical', 'MESH:C004999', (161, 173))	('men', 'Species', '9606', (5, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))
35260	27929437	This implies that DBT-PD also inhibited cell growth in human colorectal adenocarcinoma.	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (61, 86))	('cell growth', 'CPA', (40, 51))	('inhibited', 'NegReg', (30, 39))	('DBT-PD', 'Var', (18, 24))	('human', 'Species', '9606', (55, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('cell growth', 'biological_process', 'GO:0016049', ('40', '51'))	('DBT-PD', 'Chemical', '-', (18, 24))	('colorectal adenocarcinoma', 'Disease', (61, 86))
35268	27929437	Marked swelling of mitochondria with vacuolization was observed in DBT-PD-treated cells, and autolysosomes were observed.	('mitochondria', 'MPA', (19, 31))	('mitochondria', 'cellular_component', 'GO:0005739', ('19', '31'))	('swelling', 'Disease', 'MESH:D004487', (7, 15))	('DBT-PD-treated', 'Var', (67, 81))	('swelling', 'Disease', (7, 15))	('vacuolization', 'MPA', (37, 50))	('DBT-PD', 'Chemical', '-', (67, 73))
35269	27929437	Concurrent treatment of CT26 cells with DBT-PD and low concentrations of 5-fluorouracil (5-FU) markedly inhibited cell growth compared to that with DBT-PD or 5-FU alone (Table 4).	('DBT-PD', 'Chemical', '-', (40, 46))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (73, 87))	('cell growth', 'CPA', (114, 125))	('5-FU', 'Chemical', 'MESH:D005472', (158, 162))	('5-FU', 'Chemical', 'MESH:D005472', (89, 93))	('CT26', 'CellLine', 'CVCL:7254', (24, 28))	('men', 'Species', '9606', (16, 19))	('DBT-PD', 'Chemical', '-', (148, 154))	('inhibited', 'NegReg', (104, 113))	('DBT-PD', 'Var', (40, 46))
35270	27929437	It is noteworthy that DBT-PD markedly enhanced the growth inhibitory effect of 0.1 and 0.5 microM 5-FU than that of 1.0 microM 5-FU alone.	('growth inhibitory effect', 'MPA', (51, 75))	('5-FU', 'Chemical', 'MESH:D005472', (127, 131))	('enhanced', 'PosReg', (38, 46))	('DBT-PD', 'Var', (22, 28))	('0.5 microM', 'Var', (87, 97))	('DBT-PD', 'Chemical', '-', (22, 28))	('5-FU', 'Chemical', 'MESH:D005472', (98, 102))
35290	27929437	In apparent correspondence with this observation, DBT-PD inhibited growth with greater potency than did DBT and DBT-PE.	('growth', 'MPA', (67, 73))	('inhibited', 'NegReg', (57, 66))	('DBT-PD', 'Var', (50, 56))	('DBT-PE', 'Chemical', '-', (112, 118))	('DBT-PD', 'Chemical', '-', (50, 56))
35294	27929437	On the basis of morphology changes in CT26 cells treated with DBT-PD, a form of autophagic cell death was induced.	('DBT-PD', 'Var', (62, 68))	('DBT-PD', 'Chemical', '-', (62, 68))	('CT26', 'CellLine', 'CVCL:7254', (38, 42))	('autophagic cell death', 'CPA', (80, 101))	('autophagic cell death', 'biological_process', 'GO:0048102', ('80', '101'))
35299	27929437	Thus, inhibition of autophagy should support radiation treatment and increase its efficacy.	('radiation treatment', 'CPA', (45, 64))	('autophagy', 'CPA', (20, 29))	('increase', 'PosReg', (69, 77))	('efficacy', 'MPA', (82, 90))	('inhibition', 'Var', (6, 16))	('men', 'Species', '9606', (60, 63))
35300	27929437	In this study, DBT-PD seems to act as a radiosensitizer, possibly by inducing autophagy.	('DBT-PD', 'Var', (15, 21))	('DBT-PD', 'Chemical', '-', (15, 21))	('autophagy', 'CPA', (78, 87))	('inducing', 'PosReg', (69, 77))
35350	30412600	Lithocholic and deoxycholic acid, for example, are enriched in the fecal contents of CRC patients and known to activate the NF-kB signaling pathway, which can promote resistance to chemotherapy in colonic epithelial cells.	('deoxycholic acid', 'Chemical', 'MESH:D003840', (16, 32))	('deoxycholic acid', 'Var', (16, 32))	('NF-kB signaling pathway', 'Pathway', (124, 147))	('resistance to chemotherapy', 'CPA', (167, 193))	('signaling pathway', 'biological_process', 'GO:0007165', ('130', '147'))	('activate', 'PosReg', (111, 119))	('Lithocholic', 'Chemical', '-', (0, 11))	('patients', 'Species', '9606', (89, 97))	('promote', 'PosReg', (159, 166))
35418	30412600	P. micra, the only species described in the genus, is known to cause bacteremia, abdominal abscesses, endocarditis, and other infections.	('bacteremia', 'Phenotype', 'HP:0031864', (69, 79))	('abdominal abscesses', 'Phenotype', 'HP:0025181', (81, 100))	('endocarditis', 'Disease', (102, 114))	('endocarditis', 'Disease', 'MESH:D004696', (102, 114))	('P. micra', 'Species', '33033', (0, 8))	('cause', 'Reg', (63, 68))	('P. micra', 'Var', (0, 8))	('endocarditis', 'Phenotype', 'HP:0100584', (102, 114))	('bacteremia', 'Disease', 'MESH:D016470', (69, 79))	('infections', 'Disease', (126, 136))	('bacteremia', 'Disease', (69, 79))	('abdominal abscesses', 'Disease', (81, 100))	('abscesses', 'Phenotype', 'HP:0025615', (91, 100))
35423	30412600	This effect was abolished by knocking down beta-catenin, hinting at an effect measure modifier role for the pathogen.	('beta-catenin', 'Gene', (43, 55))	('knocking down', 'Var', (29, 42))	('beta-catenin', 'Gene', '1499', (43, 55))
35454	29695839	Finally, we showed that modulation of let-7a expression regulated the epithelial-mesenchymal transition in colorectal cancer cell lines, and inhibited their capacity to metastasize in vivo.	('modulation', 'Var', (24, 34))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('70', '103'))	('let-7a', 'Gene', (38, 44))	('let-7a', 'Gene', '387244', (38, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('epithelial-mesenchymal transition', 'CPA', (70, 103))	('colorectal cancer', 'Disease', (107, 124))	('regulated', 'Reg', (56, 65))	('inhibited', 'NegReg', (141, 150))	('colorectal cancer', 'Disease', 'MESH:D015179', (107, 124))
35484	29695839	Liver metastases were found in eight mice in the IFNGR1 knockdown group and three mice in the control group (80% vs. 30%, P = 0.072).	('mice', 'Species', '10090', (82, 86))	('metastases', 'Disease', 'MESH:D009362', (6, 16))	('IFNGR1', 'Gene', (49, 55))	('metastases', 'Disease', (6, 16))	('knockdown', 'Var', (56, 65))	('mice', 'Species', '10090', (37, 41))
35485	29695839	Furthermore, more powerful fluorescence (P < 0.01), more metastatic foci (P < 0.01), and larger maximum metastatic tumor diameters (P < 0.01) were also detected in the IFNGR1 knockdown group.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('fluorescence', 'MPA', (27, 39))	('more', 'PosReg', (13, 17))	('tumor', 'Disease', (115, 120))	('IFNGR1', 'Gene', (168, 174))	('more', 'PosReg', (52, 56))	('knockdown', 'Var', (175, 184))	('metastatic foci', 'CPA', (57, 72))	('larger', 'PosReg', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
35497	29695839	We found that IFN-gamma-mediated repression of the let-7a cluster was significantly reduced in the cells in which IRF-1 had been knocked down (P < 0.01) (Fig.	('knocked down', 'Var', (129, 141))	('repression', 'NegReg', (33, 43))	('let-7a', 'Gene', (51, 57))	('IRF-1', 'Gene', (114, 119))	('let-7a', 'Gene', '387244', (51, 57))	('reduced', 'NegReg', (84, 91))
35506	29695839	The constructs upstream of the let-7a cluster TSS (879 bp), the PBS (chr9: 96,931,077-96,931,229), and the spot of the deletion mutation at position 718-721 (AATC) are shown in Fig.	('let-7a', 'Gene', (31, 37))	('deletion mutation', 'Var', (119, 136))	('let-7a', 'Gene', '387244', (31, 37))	('PBS', 'Chemical', '-', (64, 67))
35512	29695839	When compared with mice in the control group, mice in the let-7a-1-5p depletion group had a lower incidence of CRLM (16.7% vs. 66.7%, P = 0.242), less powerful fluorescence (P = 0.05) during imaging (Fig.	('let-7a-1-5p', 'Var', (58, 69))	('mice', 'Species', '10090', (46, 50))	('CRLM', 'CPA', (111, 115))	('lower', 'NegReg', (92, 97))	('mice', 'Species', '10090', (19, 23))	('less', 'NegReg', (146, 150))
35516	29695839	Splenic injection of these constructed CT26 cells transfected with shRNA-let-7a-1-5p or LV-let-7a-1-5p was also performed in mice with hepatitis (n = 10) (Supplementary Figs.	('hepatitis', 'Disease', 'MESH:D056486', (135, 144))	('hepatitis', 'Disease', (135, 144))	('mice', 'Species', '10090', (125, 129))	('hepatitis', 'Phenotype', 'HP:0012115', (135, 144))	('LV-let-7a-1-5p', 'Var', (88, 102))	('CT26', 'Gene', '168400', (39, 43))	('shRNA-let-7a-1-5p', 'Var', (67, 84))	('CT26', 'Gene', (39, 43))
35522	29695839	Our data from qRT-PCR studies showed that in HT29 cells, expression of N-cadherin, a known marker of the mesenchymal phenotype, was dramatically increased by >100-fold after stimulation with IFN-gamma (P < 0.01), and by >7-fold after depletion of let-7a-1-5p in HT29 (P < 0.01); however, the other two markers showed no significant differential expression trend (Fig.	('HT29 cells', 'CellLine', 'CVCL:0320', (45, 55))	('expression', 'MPA', (57, 67))	('let-7a-1-5p', 'Var', (247, 258))	('N-cadherin', 'Gene', '1000', (71, 81))	('cadherin', 'molecular_function', 'GO:0008014', ('73', '81'))	('increased', 'PosReg', (145, 154))	('N-cadherin', 'Gene', (71, 81))
35523	29695839	Our IHC studies of liver specimens revealed that N-cadherin levels were markedly increased in both the inflammation group and the let-7a-1-5p downregulated group, when compared with their respective control groups (Fig.	('let-7a-1-5p', 'Var', (130, 141))	('inflammation', 'Disease', (103, 115))	('N-cadherin', 'Gene', (49, 59))	('downregulated', 'NegReg', (142, 155))	('N-cadherin', 'Gene', '1000', (49, 59))	('increased', 'PosReg', (81, 90))	('inflammation', 'Disease', 'MESH:D007249', (103, 115))
35544	29695839	CT26 cell lines with either stable overexpression or knockdown of let-7a-1-5p were used to test this hypothesis in normal BALB/c mice.	('CT26', 'Gene', '168400', (0, 4))	('knockdown', 'Var', (53, 62))	('CT26', 'Gene', (0, 4))	('let-7a-1-5p', 'Gene', (66, 77))	('mice', 'Species', '10090', (129, 133))
35558	29695839	Understanding details of the mechanism by which depletion of let-7a cluster maintains the mesenchymal phenotype of CRC cells is worthy of further study.	('maintains', 'PosReg', (76, 85))	('CRC', 'Phenotype', 'HP:0003003', (115, 118))	('mesenchymal phenotype of CRC cells', 'CPA', (90, 124))	('depletion', 'Var', (48, 57))	('let-7a', 'Gene', (61, 67))	('let-7a', 'Gene', '387244', (61, 67))
35571	29695839	HT29 and CT26.WT were cultured in a six-well plate for 48 h; total protein was extracted using RIPA buffer (Servicebio, G2002, China) containing protease inhibitors (Servicebio, G2006, China) and quantified using BCA kit (Thermo Fisher Scientific, USA).	('RIPA buffer', 'Chemical', '-', (95, 106))	('G2006', 'Var', (178, 183))	('CT26', 'Gene', (9, 13))	('CT26', 'Gene', '168400', (9, 13))
35587	26787105	The prognostic effect of PTEN expression status in colorectal cancer development and evaluation of factors affecting it: miR-21 and promoter methylation PTEN is a tumor suppressor gene which is involved in cellular proliferation, differentiation, and apoptosis.	('colorectal cancer', 'Disease', 'MESH:D015179', (51, 68))	('tumor suppressor', 'biological_process', 'GO:0051726', ('163', '179'))	('colorectal cancer', 'Disease', (51, 68))	('tumor', 'Disease', (163, 168))	('miR-21', 'Gene', '406991', (121, 127))	('promoter methylation', 'Var', (132, 152))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('PTEN', 'Gene', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('miR-21', 'Gene', (121, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (51, 68))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('PTEN', 'Gene', (153, 157))	('methylation', 'biological_process', 'GO:0032259', ('141', '152'))	('PTEN', 'Gene', '5728', (25, 29))	('PTEN', 'Gene', '5728', (153, 157))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('163', '179'))	('apoptosis', 'biological_process', 'GO:0097194', ('251', '260'))	('apoptosis', 'biological_process', 'GO:0006915', ('251', '260'))
35596	26787105	This study suggests a high frequency of miR-21 overexpression and aberrant promoter methylation in down-regulation of PTEN expression in colorectal carcinoma.	('expression', 'MPA', (123, 133))	('overexpression', 'PosReg', (47, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('methylation', 'biological_process', 'GO:0032259', ('84', '95'))	('PTEN', 'Gene', (118, 122))	('colorectal carcinoma', 'Disease', (137, 157))	('down-regulation', 'NegReg', (99, 114))	('aberrant', 'Var', (66, 74))	('miR-21', 'Gene', '406991', (40, 46))	('regulation', 'biological_process', 'GO:0065007', ('104', '114'))	('miR-21', 'Gene', (40, 46))	('promoter', 'MPA', (75, 83))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (137, 157))
35599	26787105	The development of CRC from normal endothelium to advanced carcinomas involves a multiple process with accumulation of genetics and epigenetics changes, leading to a high activity of oncogenes and low activity or dysfunction of tumor suppressor genes.	('low', 'NegReg', (197, 200))	('dysfunction', 'MPA', (213, 224))	('activity', 'MPA', (201, 209))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('carcinomas', 'Disease', (59, 69))	('carcinomas', 'Disease', 'MESH:D002277', (59, 69))	('oncogenes', 'Protein', (183, 192))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('changes', 'Var', (144, 151))	('tumor', 'Disease', (228, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('tumor suppressor', 'biological_process', 'GO:0051726', ('228', '244'))	('activity', 'MPA', (171, 179))	('CRC', 'Phenotype', 'HP:0003003', (19, 22))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('228', '244'))
35604	26787105	Nuclear PTEN induce arrest in the G0-G1 phase of cell cycle by down-regulation of cyclin D1 and ERK/MAPK pathway.	('MAPK', 'Gene', '5594', (100, 104))	('G1 phase', 'biological_process', 'GO:0051318', ('37', '45'))	('ERK', 'molecular_function', 'GO:0004707', ('96', '99'))	('MAPK', 'Gene', (100, 104))	('cyclin D1', 'Gene', '595', (82, 91))	('regulation', 'biological_process', 'GO:0065007', ('68', '78'))	('MAPK', 'molecular_function', 'GO:0004707', ('100', '104'))	('PTEN', 'Gene', (8, 12))	('cyclin D1', 'Gene', (82, 91))	('Nuclear', 'Var', (0, 7))	('cell cycle', 'biological_process', 'GO:0007049', ('49', '59'))	('ERK', 'Gene', '5594', (96, 99))	('ERK', 'Gene', (96, 99))	('down-regulation', 'NegReg', (63, 78))	('cyclin', 'molecular_function', 'GO:0016538', ('82', '88'))
35605	26787105	In many tumor types, genetic alterations of PTEN gene enhance tumorigenesis and may determine aggressive clinicopathological behavior of a tumor.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('determine', 'Reg', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Disease', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('PTEN', 'Gene', (44, 48))	('aggressive clinicopathological behavior', 'CPA', (94, 133))	('tumor', 'Disease', (8, 13))	('enhance', 'PosReg', (54, 61))	('genetic alterations', 'Var', (21, 40))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
35612	26787105	Hyper-methylation of some tumor suppressor genes has been related to the initiation and development of various human cancers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Hyper-methylation', 'Var', (0, 17))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('human', 'Species', '9606', (111, 116))	('related', 'Reg', (58, 65))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
35648	26787105	Among these factors, Down-regulation of PTEN gene by promoter methylation and microRNA targeting has been reported in many types of human cancers.	('methylation', 'biological_process', 'GO:0032259', ('62', '73'))	('microRNA', 'Var', (78, 86))	('Down-regulation', 'NegReg', (21, 36))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('PTEN gene', 'Gene', (40, 49))	('promoter methylation', 'Var', (53, 73))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('human', 'Species', '9606', (132, 137))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))	('regulation', 'biological_process', 'GO:0065007', ('26', '36'))
35650	26787105	In the present study, we measured the expression of PTEN mRNA and protein in CRC tissues and analyzed the effect of miR-21 level and aberrant promoter methylation on reduction or loss of PTEN expression.	('aberrant', 'Var', (133, 141))	('expression', 'MPA', (38, 48))	('PTEN', 'Gene', (187, 191))	('expression', 'MPA', (192, 202))	('miR-21', 'Gene', '406991', (116, 122))	('loss', 'NegReg', (179, 183))	('CRC', 'Phenotype', 'HP:0003003', (77, 80))	('miR-21', 'Gene', (116, 122))
35658	26787105	Epigenetic silencing of PTEN gene by promoter methylation was initially proposed in prostate cancer cell lines and identified as an effective mechanism in melanoma development.	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('prostate cancer', 'Disease', (84, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('promoter methylation', 'Var', (37, 57))	('Epigenetic silencing', 'Var', (0, 20))	('prostate cancer', 'Disease', 'MESH:D011471', (84, 99))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))	('melanoma', 'Disease', (155, 163))	('PTEN', 'Gene', (24, 28))
35659	26787105	Moreover, we found that 85 % of the methylated CRC samples showed reduced or lost PTEN protein (Table 3), suggests high frequency of PTEN aberrant promoter methylation in colorectal carcinoma.	('lost', 'NegReg', (77, 81))	('reduced', 'NegReg', (66, 73))	('CRC', 'Phenotype', 'HP:0003003', (47, 50))	('aberrant', 'Var', (138, 146))	('PTEN protein', 'Protein', (82, 94))	('PTEN', 'Gene', (133, 137))	('colorectal carcinoma', 'Disease', (171, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (171, 191))
35660	26787105	These findings along with other results, suggest that the PTEN promoter methylation might be cancer specific and plays a role in the development of these neoplasms.	('promoter methylation', 'Var', (63, 83))	('cancer', 'Disease', (93, 99))	('neoplasms', 'Disease', (154, 163))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('neoplasms', 'Disease', 'MESH:D009369', (154, 163))	('role', 'Reg', (121, 125))	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('neoplasms', 'Phenotype', 'HP:0002664', (154, 163))	('plays', 'Reg', (113, 118))	('PTEN', 'Gene', (58, 62))
35762	33923028	Likewise, melatonin mediates the anti-angiogenic property in hypoxic PC-3 Prostate Cancer cells by upregulation of microRNA3195 and microRNA374b.	('hypoxic PC-3 Prostate Cancer', 'Disease', (61, 89))	('upregulation', 'PosReg', (99, 111))	('PC', 'Phenotype', 'HP:0012125', (69, 71))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('melatonin', 'Chemical', 'MESH:D008550', (10, 19))	('microRNA374b', 'Var', (132, 144))	('microRNA3195', 'Var', (115, 127))	('Prostate Cancer', 'Phenotype', 'HP:0012125', (74, 89))	('hypoxic PC-3 Prostate Cancer', 'Disease', 'MESH:D011471', (61, 89))	('anti-angiogenic property', 'CPA', (33, 57))
35888	33923028	However, an increase in the survival rate in poor prognosis group has been demonstrated in melatonin-treated patients as compared to untreated patients.	('survival', 'MPA', (28, 36))	('patients', 'Species', '9606', (109, 117))	('melatonin-treated', 'Var', (91, 108))	('melatonin', 'Chemical', 'MESH:D008550', (91, 100))	('increase', 'PosReg', (12, 20))	('patients', 'Species', '9606', (143, 151))
35905	33923028	The results showed that co-administration of melatonin with gefitinib reduced the viability of H1975 cells with harbored T790M somatic mutation, as compared to HCC827 cells with an active epidermal growth factor receptor (EGFR) mutation.	('gefitinib', 'Chemical', 'MESH:D000077156', (60, 69))	('epidermal growth factor receptor', 'Gene', (188, 220))	('T790M', 'Var', (121, 126))	('reduced', 'NegReg', (70, 77))	('EGFR', 'molecular_function', 'GO:0005006', ('222', '226'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('188', '211'))	('HCC', 'Phenotype', 'HP:0001402', (160, 163))	('epidermal growth factor receptor', 'Gene', '1956', (188, 220))	('EGFR', 'Gene', '1956', (222, 226))	('T790M', 'Mutation', 'rs121434569', (121, 126))	('melatonin', 'Chemical', 'MESH:D008550', (45, 54))	('viability', 'CPA', (82, 91))	('H1975', 'CellLine', 'CVCL:1511', (95, 100))	('EGFR', 'Gene', (222, 226))	('HCC827', 'CellLine', 'CVCL:2063', (160, 166))
36024	33923028	In studies combining melatonin with chemotherapy, adjuvant melatonin decreased one-year mortality (RR = 0.60; 95% CI = 0.54-0.67) and improved outcomes of stable disease, partial response, and complete response; statistically significant pooled RRs were 1.15, 1.70, and 2.53, respectively.	('improved', 'PosReg', (134, 142))	('mortality', 'Disease', 'MESH:D003643', (88, 97))	('complete', 'Disease', (193, 201))	('mortality', 'Disease', (88, 97))	('decreased', 'NegReg', (69, 78))	('melatonin', 'Chemical', 'MESH:D008550', (59, 68))	('one-year', 'CPA', (79, 87))	('adjuvant', 'Var', (50, 58))	('melatonin', 'Chemical', 'MESH:D008550', (21, 30))	('stable disease', 'Disease', (155, 169))	('partial', 'Disease', (171, 178))
36059	33923028	In those individuals taking melatonin, the overall tumor regression rate and the 5-year survival were elevated, together with an improved clinical tolerance to the pharmaceutical agents.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('5-year survival', 'CPA', (81, 96))	('elevated', 'PosReg', (102, 110))	('tumor', 'Disease', (51, 56))	('melatonin', 'Chemical', 'MESH:D008550', (28, 37))	('clinical', 'MPA', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('improved', 'PosReg', (129, 137))	('melatonin', 'Var', (28, 37))
36072	33923028	In a double-blind placebo-controlled randomized study, a reduced likelihood of presenting with symptoms suggestive of an affective disorder was reported in individuals administered 6 mg oral melatonin compared with those given a placebo.	('reduced', 'NegReg', (57, 64))	('6 mg', 'Var', (181, 185))	('affective disorder', 'Disease', (121, 139))	('melatonin', 'Chemical', 'MESH:D008550', (191, 200))
36149	33923028	An alkylating drug administered orally, TMZ is able to cross the blood-brain barrier and gain access to the cerebrospinal fluid.	('TMZ', 'Var', (40, 43))	('TMZ', 'Chemical', 'MESH:D000077204', (40, 43))	('gain', 'PosReg', (89, 93))
36268	31950578	Single-molecule detection of cancer mutations using a novel PCR-LDR-qPCR assay Detection of low-abundance mutations in cell-free DNA (cfDNA) is being used to identify early cancer and early cancer recurrence.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('DNA', 'cellular_component', 'GO:0005574', ('129', '132'))	('mutations', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('mutations', 'Var', (106, 115))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
36269	31950578	Major features of the assay include selective amplification and detection of mutant DNA employing multiple nested primer-binding regions as well as wild-type sequence blocking oligonucleotides, prevention of carryover contamination, spatial sample dilution, and detection of multiple mutations in the same position.	('oligonucleotides', 'Chemical', 'MESH:D009841', (176, 192))	('mutant', 'Var', (77, 83))	('DNA', 'Gene', (84, 87))
36270	31950578	Our method was tested to interrogate the following common cancer somatic mutations: BRAF:c.1799T>A (p.Val600Glu), TP53:c.743G>A (p.Arg248Gln), KRAS:c.35G>C (p.Gly12Ala), KRAS:c.35G>T (p.Gly12Val), KRAS:c.35G>A (p.Gly12Asp), KRAS:c.34G>T (p.Gly12Cys), and KRAS:c.34G>A (p.Gly12Ser).	('KRAS:c.35G>A', 'SUBSTITUTION', 'None', (197, 209))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('KRAS:c.34G>T', 'Var', (224, 236))	('TP53:c.743G>A', 'Var', (114, 127))	('p.Gly12Ala', 'Mutation', 'rs121913529', (157, 167))	('KRAS:c.35G>C', 'Var', (143, 155))	('p.Gly12Cys', 'Mutation', 'rs121913530', (238, 248))	('p.Gly12Asp', 'Mutation', 'rs121913529', (211, 221))	('p.Val600Glu', 'Mutation', 'rs113488022', (100, 111))	('p.Gly12Ser', 'Mutation', 'rs121913530', (269, 279))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('KRAS:c.35G>C', 'SUBSTITUTION', 'None', (143, 155))	('KRAS:c.35G>T', 'Var', (170, 182))	('TP53:c.743G>A', 'SUBSTITUTION', 'None', (114, 127))	('KRAS:c.34G>A', 'SUBSTITUTION', 'None', (255, 267))	('KRAS:c.34G>T', 'SUBSTITUTION', 'None', (224, 236))	('KRAS:c.35G>T', 'SUBSTITUTION', 'None', (170, 182))	('p.Arg248Gln', 'Mutation', 'rs11540652', (129, 140))	('p.Gly12Val', 'Mutation', 'rs121913529', (184, 194))	('BRAF:c.1799T>A', 'SUBSTITUTION', 'None', (84, 98))	('BRAF:c.1799T>A', 'Var', (84, 98))	('KRAS:c.34G>A', 'Var', (255, 267))	('KRAS:c.35G>A', 'Var', (197, 209))	('cancer', 'Disease', (58, 64))
36272	31950578	A 12-well (pixel) version of the assay was capable of single-molecule detection of the aforementioned mutations at TP53, BRAF, and KRAS (specifically p.Gly12Val and p.Gly12Cys), mixed with 1,000-2,250 GE of wild-type hgDNA from plasma or buffy coat.	('BRAF', 'Gene', (121, 125))	('p.Gly12Val', 'Mutation', 'rs121913529', (150, 160))	('KRAS', 'Gene', (131, 135))	('TP53', 'Gene', '7157', (115, 119))	('p.Gly12Cys', 'Mutation', 'rs121913530', (165, 175))	('TP53', 'Gene', (115, 119))	('KRAS', 'Gene', '3845', (131, 135))	('BRAF', 'Gene', '673', (121, 125))	('p.Gly12Cys', 'Var', (165, 175))	('p.Gly12Val', 'Var', (150, 160))
36273	31950578	Cancers arise, in part, due to the accumulation of unique function-altering somatic mutations in genes, and the detection of such genetic lesions is crucial for early diagnosis and characterizing the cancer genome (; 2012; 2008, 2011).	('Cancers', 'Disease', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('function-altering', 'Reg', (58, 75))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (84, 93))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('genes', 'Gene', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))
36276	31950578	Detection of mutations from tumor biopsies and more recently from circulating tumor DNA (ctDNA) has proved to be of great importance in clinical oncology and cancer research settings.	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancer', 'Disease', (158, 164))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', (78, 83))	('oncology', 'Phenotype', 'HP:0002664', (145, 153))	('mutations', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
36277	31950578	In recent years, several methods have been developed for the detection of low-abundance mutations in tumors, including quantitative real-time PCR, co-amplification at lower denaturation temperature-PCR (COLD-PCR), digital PCR, and pyrosequencing.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('mutations', 'Var', (88, 97))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
36278	31950578	Despite recent advances in diagnostic technology, several challenges still exist to accurately identify mutations in cancers, particularly in the presence of high backgrounds of wild-type DNA, as is typical in early-stage cancers or liquid biopsies.	('mutations', 'Var', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('DNA', 'cellular_component', 'GO:0005574', ('188', '191'))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('cancers', 'Disease', (222, 229))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
36279	31950578	Contingent upon the tumor type, the frequency of somatic mutations in the genome varies from 0.1 to 100 mutations per megabase (Mb) of DNA, thus making it difficult to detect such mutations (; 2012; 2008, 2011).	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mutations', 'Var', (104, 113))	('tumor', 'Disease', (20, 25))
36281	31950578	Developing a reliable method to detect such mutations is further compounded by intratumor heterogeneity driven by cancer genome evolution, copy-number variation, and high levels of wild-type DNA originating from normal cells.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('DNA', 'cellular_component', 'GO:0005574', ('191', '194'))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (44, 53))	('cancer', 'Disease', (114, 120))
36285	31950578	Cancer-associated point mutations may be identified through traditional PCR methods, and digital methods have substantially improved sensitivity.	('Cancer', 'Disease', (0, 6))	('point mutations', 'Var', (18, 33))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
36287	31950578	Screening for point mutations in a population with no prior indication of cancer, nor knowledge of the type of cancer, nor the specific mutations present, demands an affordable and scalable technique to identify several biomarkers from a single sample.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (74, 80))	('point mutations', 'Var', (14, 29))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
36288	31950578	One advantage of using PCR-LDR-qPCR is the ability to perform proportional PCR amplification of multiple fragments to enrich for low copy targets and subsequently use LDR followed by qPCR detection of the ligation products to identify cancer-specific mutations.	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('mutations', 'Var', (251, 260))
36289	31950578	Overall, we have demonstrated how the orthogonal nature and flexible design of this assay enable the detection of BRAF, TP53 and KRAS cancer-specific mutations with high sensitivity and specificity.	('BRAF', 'Gene', (114, 118))	('BRAF', 'Gene', '673', (114, 118))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('KRAS', 'Gene', (129, 133))	('mutations', 'Var', (150, 159))	('KRAS', 'Gene', '3845', (129, 133))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
36291	31950578	We used the colon adenocarcinoma cell lines HT-29, SW1116, SW480, LS123, and SW1463, which respectively harbor the mutations BRAF:c.1799T>A (p.Val600Glu) (NM_004333.4:c.1799T>A; COSV56056643), KRAS:c.35G>C (p.Gly12Ala) (NM_033360.3:c.35G>C; COSV55497479), KRAS:c.35G>T (p.Gly12Val) (NM_033360.3:c.35G>T; COSV55497419), KRAS:c.34G>A (p.Gly12Ser) (NM_033360.3:c.34G>A; COSV55497461), and KRAS:c.34G>T (p.Gly12Cys) (NM_033360.3:c.34G>T; COSV55497469).	('KRAS:c.35G>T', 'SUBSTITUTION', 'None', (256, 268))	('COSV55497469', 'Chemical', '-', (434, 446))	('NM_033360.3:c.34G>T', 'Var', (413, 432))	('KRAS:c.35G>C', 'SUBSTITUTION', 'None', (193, 205))	('HT-29', 'CellLine', 'CVCL:0320', (44, 49))	('c.35G>T', 'Var', (295, 302))	('LS123', 'CellLine', 'CVCL:1383', (66, 71))	('p.Val600Glu', 'Mutation', 'rs113488022', (141, 152))	('COSV56056643', 'Chemical', '-', (178, 190))	('SW1463', 'CellLine', 'CVCL:1718', (77, 83))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (12, 32))	('NM_033360.3:c.35G>C', 'SUBSTITUTION', 'None', (220, 239))	('KRAS:c.34G>T', 'SUBSTITUTION', 'None', (386, 398))	('p.Gly12Ser', 'Mutation', 'rs121913530', (333, 343))	('COSV55497461', 'Chemical', '-', (367, 379))	('SW480', 'CellLine', 'CVCL:0546', (59, 64))	('SW1116', 'CellLine', 'CVCL:0544', (51, 57))	('NM_033360.3:c.34G>A', 'Var', (346, 365))	('NM_033360.3:c.34G>T', 'SUBSTITUTION', 'None', (413, 432))	('NM_033360.3:c.35G>C', 'Var', (220, 239))	('colon adenocarcinoma', 'Disease', (12, 32))	('KRAS:c.34G>T', 'Var', (386, 398))	('BRAF:c.1799T>A', 'SUBSTITUTION', 'None', (125, 139))	('KRAS:c.35G>T', 'Var', (256, 268))	('BRAF:c.1799T>A', 'Var', (125, 139))	('p.Gly12Ala', 'Mutation', 'rs121913529', (207, 217))	('NM_033360.3:c.34G>A', 'SUBSTITUTION', 'None', (346, 365))	('KRAS:c.35G>C', 'Var', (193, 205))	('COSV55497479', 'Chemical', '-', (241, 253))	('KRAS:c.34G>A', 'SUBSTITUTION', 'None', (319, 331))	('NM_004333.4:c.1799T>A', 'Mutation', 'rs113488022', (155, 176))	('p.Gly12Cys', 'Mutation', 'rs121913530', (400, 410))	('NM_033360.3:c.35G>T', 'Mutation', 'rs121913529', (283, 302))	('p.Gly12Val', 'Mutation', 'rs121913529', (270, 280))	('KRAS:c.34G>A', 'Var', (319, 331))
36293	31950578	We also used as source of gDNA the HEC-1-A endometrial adenocarcinoma cell line with the following genotypes: homozygous TP53:c.743G>A (p.Arg248Gln) (NM_000546.5:c.743G>A; COSV52661580) and heterozygous KRAS:c.35G>A (p.Gly12Asp) (NM_033360.3:c.35G>A; COSV55497369).	('TP53:c.743G>A', 'Var', (121, 134))	('COSV55497369', 'Chemical', '-', (251, 263))	('KRAS:c.35G>A', 'Var', (203, 215))	('KRAS:c.35G>A', 'SUBSTITUTION', 'None', (203, 215))	('NM_000546.5:c.743G>A', 'SUBSTITUTION', 'None', (150, 170))	('p.Arg248Gln', 'Mutation', 'rs11540652', (136, 147))	('NM_000546.5:c.743G>A', 'Var', (150, 170))	('TP53:c.743G>A', 'SUBSTITUTION', 'None', (121, 134))	('p.Gly12Asp', 'Mutation', 'rs121913529', (217, 227))	('HEC-1-A endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (35, 69))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (43, 69))	('COSV52661580', 'Chemical', '-', (172, 184))	('NM_033360.3:c.35G>A', 'Mutation', 'rs121913529', (230, 249))	('HEC-1-A endometrial adenocarcinoma', 'Disease', (35, 69))
36301	31950578	The one mismatch in the fourth position after the rRNA base design was selected to detect BRAF and TP53 mutations, and the mismatch in the third and fourth position after the rRNA base was selected to detect KRAS mutations, based on the better results obtained with that additional mismatch in the KRAS detection experiments.	('BRAF', 'Gene', (90, 94))	('TP53', 'Gene', (99, 103))	('mutations', 'Var', (104, 113))	('BRAF', 'Gene', '673', (90, 94))	('detect', 'Reg', (83, 89))	('KRAS', 'Gene', (208, 212))	('KRAS', 'Gene', (298, 302))	('KRAS', 'Gene', '3845', (208, 212))	('TP53', 'Gene', '7157', (99, 103))	('KRAS', 'Gene', '3845', (298, 302))
36302	31950578	For the upstream LDR oligonucleotide probe, an additional mismatch (preferably either G-T or A-C mismatch) was utilized at the third position on the 5' side of the discriminating base.	('A-C mismatch', 'Var', (93, 105))	('G-T', 'Var', (86, 89))	('oligonucleotide', 'Chemical', 'MESH:D009841', (21, 36))
36311	31950578	For the PNA primers, a perfectly matched to wild-type PNA oligo was designed to include 4-6 bases on each side of the discriminating base, and to have a Tm of 70-76 C. Detection of BRAF:c.1799T>A (p.Val600Glu), TP53:c.743G>A (p.Arg248Gln), KRAS:c.34G>A (p.Gly12Ser), KRAS:c.34G>T (p.Gly12Cys), KRAS:c.35G>A (p.Gly12Asp), KRAS:c.35G>T (p.Gly12Val), and KRAS:c.35G>C (p.Gly12Ala) mutations using cell line gDNA diluted in buffy coat hgDNA was performed by a three-step method that employs PCR, followed by LDR and qPCR using the primers listed in Supp.	('p.Gly12Ser', 'Mutation', 'rs121913530', (254, 264))	('KRAS:c.35G>C', 'SUBSTITUTION', 'None', (352, 364))	('p.Gly12Asp', 'Mutation', 'rs121913529', (308, 318))	('KRAS:c.35G>T', 'Var', (321, 333))	('p.Val600Glu', 'Mutation', 'rs113488022', (197, 208))	('Ser', 'cellular_component', 'GO:0005790', ('261', '264'))	('KRAS:c.34G>T', 'SUBSTITUTION', 'None', (267, 279))	('p.Arg248Gln', 'Mutation', 'rs11540652', (226, 237))	('KRAS:c.35G>T', 'SUBSTITUTION', 'None', (321, 333))	('TP53:c.743G>A', 'Var', (211, 224))	('p.Gly12Ala', 'Mutation', 'rs121913529', (366, 376))	('KRAS:c.34G>A', 'SUBSTITUTION', 'None', (240, 252))	('BRAF:c.1799T>A', 'SUBSTITUTION', 'None', (181, 195))	('KRAS:c.35G>A', 'Var', (294, 306))	('BRAF:c.1799T>A', 'Var', (181, 195))	('mutations', 'Var', (378, 387))	('p.Gly12Cys', 'Mutation', 'rs121913530', (281, 291))	('KRAS:c.34G>T', 'Var', (267, 279))	('KRAS:c.34G>A', 'Var', (240, 252))	('KRAS:c.35G>C', 'Var', (352, 364))	('p.Gly12Val', 'Mutation', 'rs121913529', (335, 345))	('KRAS:c.35G>A', 'SUBSTITUTION', 'None', (294, 306))	('TP53:c.743G>A', 'SUBSTITUTION', 'None', (211, 224))
36320	31950578	Templates (3 mul) for pixel experiments using cell line gDNA (HT-29 gDNA, heterozygote for BRAF:c.1799T>A (p.Val600Glu) detection, or HEC-1-A gDNA, homozygote for TP53:c.743G>A (p.Arg248Gln) diluted in buffy coat hgDNA were: nuclease-free water for the NTC; buffy coat hgDNA at 2.925 ng/mul (thus, 8.75 ng of buffy coat hgDNA or 2,500 GE in 3 mul) for the wild-type; and cell line gDNA mixed with buffy coat hgDNA as follows: (1) 0.023 ng/mul of gDNA in 2.925 ng/mul of buffy coat hgDNA, thus 0.07 ng of gDNA and 8.75 ng of buffy coat hgDNA in 3 mul, which corresponds to 20 GE of gDNA (where 10 or 20 GE are mutated for BRAF and TP53, respectively) and 2,500 GE of buffy coat hgDNA; (2) 0.0117 ng/mul of gDNA in 2.925 ng/mul of buffy coat hgDNA, thus 0.0035 ng of gDNA and 8.75 ng of buffy coat hgDNA in 3 mul, which corresponds to 10 GE of gDNA (5 or 10 GE are mutated, respectively) and 2,500 GE of buffy coat hgDNA.	('water', 'Chemical', 'MESH:D014867', (239, 244))	('TP53:c.743G>A', 'Var', (163, 176))	('BRAF:c.1799T>A', 'SUBSTITUTION', 'None', (91, 105))	('BRAF', 'Gene', '673', (91, 95))	('TP53', 'Gene', '7157', (630, 634))	('TP53', 'Gene', '7157', (163, 167))	('BRAF', 'Gene', '673', (621, 625))	('BRAF', 'Gene', (91, 95))	('BRAF:c.1799T>A', 'Var', (91, 105))	('BRAF', 'Gene', (621, 625))	('TP53', 'Gene', (630, 634))	('HEC-1-A', 'CellLine', 'CVCL:0293', (134, 141))	('TP53', 'Gene', (163, 167))	('p.Val600Glu', 'Mutation', 'rs113488022', (107, 118))	('0.0035', 'Var', (752, 758))	('HT-29', 'CellLine', 'CVCL:0320', (62, 67))	('TP53:c.743G>A', 'SUBSTITUTION', 'None', (163, 176))	('p.Arg248Gln', 'Mutation', 'rs11540652', (178, 189))
36321	31950578	Templates (13 mul) for pixel experiments using cell line gDNA (HT-29 gDNA, heterozygote for BRAF:c.1799T>A (p.Val600Glu); or HEC-1-A gDNA, homozygote for TP53:c.743G>A (p.Arg248Gln); or SW1463 gDNA, homozygote for KRAS p.Gly12Cys; or SW480 gDNA, homozygote for KRAS p.Gly12Val detection) diluted in plasma hgDNA were: nuclease-free water for the NTC; plasma hgDNA (diluted in nuclease-free water to have 4.375 ng of plasma hgDNA or 1,250 GE in the 13 mul added to the PCR reaction for BRAF and TP53 experiments, or diluted to have 3.5 ng of plasma hgDNA or 1,000 GE in the 13 mul added to the PCR reaction for KRAS experiments) for the wild-type; and gDNA mixed with plasma hgDNA as follows: (1) 4.375 ng (for BRAF and TP53, which corresponds to 1,250 plasma hgDNA GE) or 3.5 ng (for KRAS, which corresponds to 1,000 plasma hgDNA GE) of plasma hgDNA plus 0.07 ng (for BRAF and TP53, which corresponds to 20 gDNA GE, where 10 or 20 GE are mutated for BRAF or TP53, respectively) or 0.035 ng (for KRAS, which corresponds to 10 GE, where all 10 GE are mutated) of cell line gDNA in the PCR reaction; (2) 4.375 ng (for BRAF and TP53, which corresponds to 1,250 plasma hgDNA GE) or 3.5 ng (for KRAS, which corresponds to 1,000 plasma hgDNA GE) of plasma hgDNA plus 0.035 ng (for BRAF and TP53, which corresponds to 10 gDNA GE where 5 or 10 GE are mutated for BRAF or TP53, respectively) or 0.0175 ng (for KRAS, which corresponds to 5 GE, where all 5 GE are mutated) of cell line gDNA in the PCR reaction.	('TP53', 'Gene', (1124, 1128))	('KRAS', 'Gene', (261, 265))	('KRAS', 'Gene', (1189, 1193))	('TP53', 'Gene', (958, 962))	('KRAS', 'Gene', (784, 788))	('TP53', 'Gene', (877, 881))	('TP53', 'Gene', (1362, 1366))	('TP53', 'Gene', (1283, 1287))	('KRAS', 'Gene', '3845', (1400, 1404))	('TP53', 'Gene', '7157', (494, 498))	('KRAS', 'Gene', '3845', (995, 999))	('SW1463', 'CellLine', 'CVCL:1718', (186, 192))	('TP53:c.743G>A', 'SUBSTITUTION', 'None', (154, 167))	('SW480', 'CellLine', 'CVCL:0546', (234, 239))	('TP53', 'Gene', (719, 723))	('p.Val600Glu', 'Mutation', 'rs113488022', (108, 119))	('HT-29', 'CellLine', 'CVCL:0320', (63, 68))	('KRAS', 'Gene', (1400, 1404))	('p.Arg248Gln', 'Mutation', 'rs11540652', (169, 180))	('NTC', 'cellular_component', 'GO:0000974', ('346', '349'))	('KRAS', 'Gene', (995, 999))	('TP53', 'Gene', '7157', (1124, 1128))	('BRAF', 'Gene', '673', (1115, 1119))	('p.Gly12Val', 'Mutation', 'rs121913529', (266, 276))	('BRAF', 'Gene', '673', (92, 96))	('TP53', 'Gene', (154, 158))	('BRAF', 'Gene', (1115, 1119))	('TP53', 'Gene', '7157', (958, 962))	('TP53', 'Gene', '7157', (877, 881))	('water', 'Chemical', 'MESH:D014867', (390, 395))	('BRAF', 'Gene', (92, 96))	('water', 'Chemical', 'MESH:D014867', (332, 337))	('HEC-1-A', 'CellLine', 'CVCL:0293', (125, 132))	('KRAS', 'Gene', '3845', (610, 614))	('p.Gly12Cys', 'Mutation', 'rs121913530', (219, 229))	('BRAF', 'Gene', '673', (950, 954))	('BRAF', 'Gene', '673', (1274, 1278))	('BRAF', 'Gene', (950, 954))	('TP53', 'Gene', '7157', (1283, 1287))	('BRAF', 'Gene', (1274, 1278))	('TP53', 'Gene', '7157', (1362, 1366))	('KRAS', 'Gene', '3845', (214, 218))	('BRAF', 'Gene', '673', (1354, 1358))	('TP53', 'Gene', (494, 498))	('BRAF:c.1799T>A', 'SUBSTITUTION', 'None', (92, 106))	('BRAF', 'Gene', (1354, 1358))	('KRAS', 'Gene', (610, 614))	('TP53', 'Gene', '7157', (719, 723))	('BRAF', 'Gene', (710, 714))	('KRAS', 'Gene', '3845', (261, 265))	('BRAF:c.1799T>A', 'Var', (92, 106))	('KRAS', 'Gene', (214, 218))	('KRAS', 'Gene', '3845', (1189, 1193))	('KRAS', 'Gene', '3845', (784, 788))	('BRAF', 'Gene', '673', (710, 714))	('BRAF', 'Gene', (485, 489))	('TP53:c.743G>A', 'Var', (154, 167))	('BRAF', 'Gene', '673', (485, 489))	('BRAF', 'Gene', (868, 872))	('BRAF', 'Gene', '673', (868, 872))	('TP53', 'Gene', '7157', (154, 158))
36323	31950578	The only exception was the PCR step for detection of the BRAF:c.1799T>A (p.Val600Glu) mutation diluted in plasma hgDNA, which was performed using 45 cycles instead of the 40 cycles used to detect this mutation in the single-well or 12-well experiments with BRAF:c.1799T>A (p.Val600Glu) diluted in buffy coat hgDNA.	('BRAF:c.1799T>A', 'Var', (257, 271))	('p.Val600Glu', 'Mutation', 'rs113488022', (273, 284))	('p.Val600Glu', 'Var', (273, 284))	('BRAF:c.1799T>A', 'SUBSTITUTION', 'None', (57, 71))	('BRAF:c.1799T>A', 'Var', (57, 71))	('p.Val600Glu', 'Mutation', 'rs113488022', (73, 84))	('BRAF:c.1799T>A', 'SUBSTITUTION', 'None', (257, 271))
36326	31950578	We specifically interrogated the presence of the following mutations: a) for BRAF: BRAF:c.1799T>A (p.Val600Glu) (NM_004333.4:c.1799T>A; COSV56056643), b) for TP53: TP53:c.743G>A (p.Arg248Gln) (NM_000546.5:c.743G>A; COSV52661580), c) for KRAS: KRAS:c.35G>C (p.Gly12Ala) (NM_033360.3:c.35G>C; COSV55497479), KRAS:c.35G>T (p.Gly12Val) (NM_033360.3:c.35G>T; COSV55497419), KRAS:c.34G>A (p.Gly12Ser) (NM_033360.3:c.34G>A; COSV55497461), KRAS:c.34G>T (p.Gly12Cys) (NM_033360.3:c.34G>T; COSV55497469), and KRAS:c.35G>A (p.Gly12Asp) (NM_033360.3:c.35G>A; COSV55497369).	('KRAS', 'Gene', '3845', (432, 436))	('TP53', 'Gene', (158, 162))	('KRAS', 'Gene', (237, 241))	('Ser', 'cellular_component', 'GO:0005790', ('390', '393'))	('COSV55497469', 'Chemical', '-', (480, 492))	('KRAS', 'Gene', (499, 503))	('COSV55497369', 'Chemical', '-', (547, 559))	('KRAS', 'Gene', '3845', (306, 310))	('p.Gly12Cys', 'Mutation', 'rs121913530', (446, 456))	('KRAS', 'Gene', '3845', (369, 373))	('KRAS', 'Gene', (243, 247))	('TP53:c.743G>A', 'SUBSTITUTION', 'None', (164, 177))	('KRAS', 'Gene', (432, 436))	('NM_033360.3:c.35G>C', 'Var', (270, 289))	('p.Gly12Asp', 'Mutation', 'rs121913529', (513, 523))	('TP53', 'Gene', (164, 168))	('KRAS', 'Gene', (306, 310))	('KRAS', 'Gene', (369, 373))	('KRAS:c.34G>T', 'SUBSTITUTION', 'None', (432, 444))	('NM_033360.3:c.34G>T', 'Var', (459, 478))	('p.Gly12Ala', 'Mutation', 'rs121913529', (257, 267))	('KRAS:c.35G>T', 'Var', (306, 318))	('NM_033360.3:c.34G>A', 'Var', (396, 415))	('p.Arg248Gln', 'Mutation', 'rs11540652', (179, 190))	('COSV55497479', 'Chemical', '-', (291, 303))	('KRAS:c.34G>A', 'SUBSTITUTION', 'None', (369, 381))	('p.Val600Glu', 'Mutation', 'rs113488022', (99, 110))	('TP53', 'Gene', '7157', (158, 162))	('NM_004333.4:c.1799T>A', 'Mutation', 'rs113488022', (113, 134))	('COSV52661580', 'Chemical', '-', (215, 227))	('BRAF', 'Gene', '673', (77, 81))	('KRAS:c.35G>C', 'Var', (243, 255))	('BRAF', 'Gene', (77, 81))	('p.Gly12Val', 'Mutation', 'rs121913529', (320, 330))	('KRAS:c.34G>A', 'Var', (369, 381))	('COSV56056643', 'Chemical', '-', (136, 148))	('KRAS:c.35G>T', 'SUBSTITUTION', 'None', (306, 318))	('BRAF', 'Gene', '673', (83, 87))	('TP53:c.743G>A', 'Var', (164, 177))	('BRAF', 'Gene', (83, 87))	('TP53', 'Gene', '7157', (164, 168))	('NM_033360.3:c.35G>T', 'Mutation', 'rs121913529', (333, 352))	('NM_000546.5:c.743G>A', 'Var', (193, 213))	('KRAS:c.35G>A', 'Var', (499, 511))	('KRAS:c.34G>T', 'Var', (432, 444))	('NM_033360.3:c.35G>A', 'Mutation', 'rs121913529', (526, 545))	('KRAS', 'Gene', '3845', (237, 241))	('NM_033360.3:c.34G>A', 'SUBSTITUTION', 'None', (396, 415))	('NM_033360.3:c.34G>T', 'SUBSTITUTION', 'None', (459, 478))	('NM_033360.3:c.35G>C', 'SUBSTITUTION', 'None', (270, 289))	('KRAS', 'Gene', '3845', (499, 503))	('KRAS:c.35G>C', 'SUBSTITUTION', 'None', (243, 255))	('p.Gly12Ser', 'Mutation', 'rs121913530', (383, 393))	('BRAF:c.1799T>A', 'SUBSTITUTION', 'None', (83, 97))	('COSV55497461', 'Chemical', '-', (417, 429))	('KRAS:c.35G>A', 'SUBSTITUTION', 'None', (499, 511))	('KRAS', 'Gene', '3845', (243, 247))	('BRAF:c.1799T>A', 'Var', (83, 97))	('NM_000546.5:c.743G>A', 'SUBSTITUTION', 'None', (193, 213))
36327	31950578	According to recent data released by TCGA, through cBioPortal (http://www.cbioportal.org/), these mutations are highly prevalent in some cancer types (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('mutations', 'Var', (98, 107))	('cancer', 'Disease', (137, 143))	('prevalent', 'Reg', (119, 128))
36328	31950578	For example, the BRAF:c.1799T>A (p.Val600Glu) mutation occurs most commonly in thyroid cancer (59%), and cutaneous melanoma (42%), but is also significant in colorectal cancer (9%).	('colorectal cancer', 'Phenotype', 'HP:0003003', (158, 175))	('thyroid cancer', 'Disease', 'MESH:D013964', (79, 93))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (105, 123))	('colorectal cancer', 'Disease', (158, 175))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('colorectal cancer', 'Disease', 'MESH:D015179', (158, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('BRAF:c.1799T>A', 'SUBSTITUTION', 'None', (17, 31))	('cutaneous melanoma', 'Disease', (105, 123))	('BRAF:c.1799T>A', 'Var', (17, 31))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (105, 123))	('thyroid cancer', 'Disease', (79, 93))	('p.Val600Glu', 'Mutation', 'rs113488022', (33, 44))	('thyroid cancer', 'Phenotype', 'HP:0002890', (79, 93))
36329	31950578	The KRAS:c.35G>A (p.Gly12Asp) mutation is present in 41% and 13% of pancreatic and colorectal cancer, respectively.	('colorectal cancer', 'Disease', 'MESH:D015179', (83, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (83, 100))	('pancreatic', 'Disease', 'MESH:D010195', (68, 78))	('colorectal cancer', 'Disease', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('KRAS:c.35G>A', 'SUBSTITUTION', 'None', (4, 16))	('p.Gly12Asp', 'Mutation', 'rs121913529', (18, 28))	('KRAS:c.35G>A', 'Var', (4, 16))	('pancreatic', 'Disease', (68, 78))
36330	31950578	The KRAS:c.35G>T (p.Gly12Val) mutation is also significantly present in pancreatic and colorectal cancers at 26% and 10%, respectively.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('present', 'Reg', (61, 68))	('KRAS:c.35G>T', 'Var', (4, 16))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('pancreatic and colorectal cancers', 'Disease', 'MESH:D015179', (72, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (87, 104))	('KRAS:c.35G>T', 'SUBSTITUTION', 'None', (4, 16))	('p.Gly12Val', 'Mutation', 'rs121913529', (18, 28))
36332	31950578	In single-well experiments, we detected the BRAF mutation at a level as low as 5 GE (2 or 3 mutant molecules) up to 40 GE (20 mutant molecules) in the constant background presence of 10,000 GE buffy coat wild-type hgDNA as the template for the PCR step (Figure 2A, Table 2).	('BRAF', 'Gene', (44, 48))	('BRAF', 'Gene', '673', (44, 48))	('mutation', 'Var', (49, 57))
36333	31950578	We also demonstrated the ability of the PCR-LDR-qPCR assay to detect p.Val600Glu mutations at a single-molecule level (12-well "pixel" detection assay) and in a reproducible manner using 20 (10 mutant molecules) or 10 (5 mutant molecules) GE of HT-29 gDNA diluted in a constant background of 2,500 GE of buffy coat hgDNA or 1,250 GE of plasma hgDNA in a 12-well format setting (Figures 2B-D, Table 3, and Supp.	('p.Val600Glu mutations', 'Var', (69, 90))	('HT-29', 'CellLine', 'CVCL:0320', (245, 250))	('p.Val600Glu', 'Mutation', 'rs113488022', (69, 80))	('mutations', 'Var', (81, 90))
36336	31950578	Thus, our single-well method was very sensitive and capable of detecting up to 5 TP53 mutant molecules in the presence of 10,000 wild-type molecules (1 mutant molecule in 2,000 wild-type molecules).	('mutant', 'Var', (86, 92))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
36340	31950578	KRAS:c.35G>C (p.Gly12Ala), KRAS:c.35G>T (p.Gly12Val), KRAS:c.35G>A (p.Gly12Asp), KRAS:c.34G>A (p.Gly12Ser) and KRAS:c.34G>T (p.Gly12Cys) mutations were detected using gDNA isolated from SW1116, SW480, HEC-1-A, LS123, or SW1463 cell lines, respectively.	('KRAS:c.35G>A', 'SUBSTITUTION', 'None', (54, 66))	('LS123', 'CellLine', 'CVCL:1383', (210, 215))	('p.Gly12Ala', 'Mutation', 'rs121913529', (14, 24))	('KRAS:c.35G>C', 'Var', (0, 12))	('SW1116', 'CellLine', 'CVCL:0544', (186, 192))	('SW1463', 'CellLine', 'CVCL:1718', (220, 226))	('p.Gly12Ser', 'Mutation', 'rs121913530', (95, 105))	('KRAS:c.35G>T', 'Var', (27, 39))	('p.Gly12Asp', 'Mutation', 'rs121913529', (68, 78))	('p.Gly12Cys', 'Mutation', 'rs121913530', (125, 135))	('KRAS:c.34G>T', 'Var', (111, 123))	('Ser', 'cellular_component', 'GO:0005790', ('102', '105'))	('SW480', 'CellLine', 'CVCL:0546', (194, 199))	('KRAS:c.35G>C', 'SUBSTITUTION', 'None', (0, 12))	('KRAS:c.35G>T', 'SUBSTITUTION', 'None', (27, 39))	('KRAS:c.34G>A', 'SUBSTITUTION', 'None', (81, 93))	('p.Gly12Val', 'Mutation', 'rs121913529', (41, 51))	('HEC-1-A', 'CellLine', 'CVCL:0293', (201, 208))	('KRAS:c.35G>A', 'Var', (54, 66))	('KRAS:c.34G>T', 'SUBSTITUTION', 'None', (111, 123))	('KRAS:c.34G>A', 'Var', (81, 93))
36341	31950578	The CT difference between the amplified mutant and wild-type DNA ranged from 9.6 to 5.6, 12.6 to 6.5, 6 to 4.6, 1.6 to 1.6 and 4.9 to 4.6 cycles, for 40 to 5 mutant molecules (for homozygous cell lines) or 20 to 2-3 mutant molecules (heterozygous cell lines), for the p.Gly12Ala, p.Gly12Val, p.Gly12Asp, p.Gly12Ser and p.Gly12Cys mutations, respectively (Table 6).	('p.Gly12Cys', 'Mutation', 'rs121913530', (319, 329))	('p.Gly12Cys mutations', 'Var', (319, 339))	('p.Gly12Asp', 'Var', (292, 302))	('p.Gly12Val', 'Mutation', 'rs121913529', (280, 290))	('p.Gly12Ser', 'Var', (304, 314))	('p.Gly12Asp', 'Mutation', 'rs121913529', (292, 302))	('p.Gly12Ala', 'Var', (268, 278))	('p.Gly12Ala', 'Mutation', 'rs121913529', (268, 278))	('p.Gly12Val', 'Var', (280, 290))	('p.Gly12Ser', 'Mutation', 'rs121913530', (304, 314))
36342	31950578	Therefore, our single-well method was highly sensitive for the detection of the p.Gly12Ala, p.Gly12Val, p.Gly12Asp, and p.Gly12Cys KRAS mutations.	('p.Gly12Ala', 'Var', (80, 90))	('p.Gly12Asp', 'Var', (104, 114))	('KRAS', 'Gene', (131, 135))	('KRAS', 'Gene', '3845', (131, 135))	('p.Gly12Val', 'Mutation', 'rs121913529', (92, 102))	('p.Gly12Val', 'Var', (92, 102))	('p.Gly12Ala', 'Mutation', 'rs121913529', (80, 90))	('p.Gly12Cys', 'Mutation', 'rs121913530', (120, 130))	('p.Gly12Asp', 'Mutation', 'rs121913529', (104, 114))
36343	31950578	The assay was able to detect up to 2 mutant molecules (for heterozygous mutations) in presence of 10,000 wild-type molecules (up to 1 mutant molecule in 5,000 wild-type molecules) for these common KRAS mutations.	('KRAS', 'Gene', (197, 201))	('KRAS', 'Gene', '3845', (197, 201))	('mutations', 'Var', (202, 211))
36344	31950578	To demonstrate the feasibility of our assay to detect mutations at a single-molecule level (12-well pixel detection), we used 10 or 5 GE of SW480 or SW1463 hgDNA diluted in a constant background of 1,000 GE of wild-type plasma hgDNA in a 12-well format setting to detect, respectively, the KRAS mutations KRAS:c.35G>T (p.Gly12Val) and KRAS:c.34G>T (p.Gly12Cys) (Table 7; Figures 4F and Supp.	('p.Gly12Val', 'Mutation', 'rs121913529', (319, 329))	('KRAS', 'Gene', '3845', (335, 339))	('KRAS:c.35G>T', 'SUBSTITUTION', 'None', (305, 317))	('KRAS:c.34G>T', 'SUBSTITUTION', 'None', (335, 347))	('SW1463', 'CellLine', 'CVCL:1718', (149, 155))	('SW480', 'CellLine', 'CVCL:0546', (140, 145))	('KRAS', 'Gene', (290, 294))	('KRAS', 'Gene', (305, 309))	('KRAS', 'Gene', '3845', (290, 294))	('KRAS:c.34G>T', 'Var', (335, 347))	('KRAS', 'Gene', '3845', (305, 309))	('KRAS', 'Gene', (335, 339))	('KRAS:c.35G>T', 'Var', (305, 317))	('p.Gly12Cys', 'Mutation', 'rs121913530', (349, 359))
36345	31950578	For both 10 GE (10 mutant molecules) and 5 GE (5 mutant molecules) template reactions, we detected mutant amplification signals from 3 and 3 out of 12 wells, respectively, in the presence of 1,000 GE of wild-type molecules, for the p.Gly12Cys mutation (Table 7, Supp.	('p.Gly12Cys', 'Var', (232, 242))	('p.Gly12Cys', 'Mutation', 'rs121913530', (232, 242))	('mutant', 'Var', (19, 25))
36347	31950578	Therefore, our 12-well was able to detect a single mutant molecule in the presence of up to 1,000 wild-type molecules for the two KRAS mutations tested (Table 7, Figures 4F and Supp.	('KRAS', 'Gene', (130, 134))	('mutations', 'Var', (135, 144))	('KRAS', 'Gene', '3845', (130, 134))	('detect', 'Reg', (35, 41))
36350	31950578	Detecting somatic point mutations is a crucial step in characterizing the cancer genome and holds much promise for guiding patient treatment, detecting recurrence or the emergence of resistant clones, and the early detection of cancer.	('patient', 'Species', '9606', (123, 130))	('cancer', 'Disease', (228, 234))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('Detecting', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
36352	31950578	ctDNA is most detectable in patients with metastatic disease (> 80%) and is highly variable between cancer types and patients, in part, due to factors such as copy number changes.	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('detectable', 'Reg', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('metastatic disease', 'Disease', (42, 60))	('cancer', 'Disease', (100, 106))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (28, 36))	('copy number changes', 'Var', (159, 178))
36354	31950578	However, even the presence of a specific mutation in a tumor does not always translate into the ability to detect it in ctDNA.	('mutation', 'Var', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))
36355	31950578	Advances in next-generation sequencing (NGS) technology have spurred the development of liquid biopsies, most notably the Guardant360 test, which identifies genetic alterations in 73 cancer-related genes from circulating tumor DNA.	('cancer', 'Disease', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('genetic alterations', 'Var', (157, 176))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
36357	31950578	Further, the high correlation between mutations found in white blood cells and cfDNA suggests that some mutations may not indicate the presence of a tumor.	('mutations', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (149, 154))
36367	31950578	However, existing methods sometimes fail to detect the low-allelic-fraction mutations that occur in only a subset of the sequenced cells owing to either tumor heterogeneity or contamination by normal cells.	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('mutations', 'Var', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))
36368	31950578	We have developed a PCR-LDR-qPCR based assay to detect cancer mutations at very low-abundance in the presence of a large excess of wild-type DNA.	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('mutations', 'Var', (62, 71))	('cancer', 'Disease', (55, 61))
36369	31950578	Using wild-type perfect-matching PNA or LNA based blocking oligonucleotides, we prevent amplification of wild-type DNA and preferentially enrich for mutant allele amplification in the PCR step, as well as attenuate binding of LDR probes to wild-type DNA during the LDR step, further improving the specificity of the assay.	('improving', 'PosReg', (283, 292))	('mutant', 'Var', (149, 155))	('oligonucleotides', 'Chemical', 'MESH:D009841', (59, 75))	('specificity', 'MPA', (297, 308))	('attenuate', 'NegReg', (205, 214))	('LDR', 'Gene', (226, 229))	('binding', 'Interaction', (215, 222))
36376	31950578	We used this assay to detect BRAF:c.1799T>A (p.Val600Glu), TP53:c.743G>A (p.Arg248Gln) and KRAS:c.35G>T (p.Gly12Val), KRAS:c.35G>A (p.Gly12Asp), KRAS:c.34G>T (p.Gly12Cys), and KRAS:c.34G>A (p.Gly12Ser) mutations, which are frequent in colorectal and other cancer types.	('KRAS:c.35G>A', 'SUBSTITUTION', 'None', (118, 130))	('TP53:c.743G>A', 'SUBSTITUTION', 'None', (59, 72))	('cancer', 'Disease', (256, 262))	('p.Gly12Cys', 'Mutation', 'rs121913530', (159, 169))	('KRAS:c.34G>T', 'Var', (145, 157))	('p.Gly12Ser', 'Mutation', 'rs121913530', (190, 200))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('KRAS:c.35G>T', 'Var', (91, 103))	('p.Gly12Asp', 'Mutation', 'rs121913529', (132, 142))	('colorectal', 'Disease', 'MESH:D015179', (235, 245))	('p.Val600Glu', 'Mutation', 'rs113488022', (45, 56))	('KRAS:c.35G>T', 'SUBSTITUTION', 'None', (91, 103))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('p.Arg248Gln', 'Mutation', 'rs11540652', (74, 85))	('KRAS:c.34G>A', 'SUBSTITUTION', 'None', (176, 188))	('KRAS:c.34G>T', 'SUBSTITUTION', 'None', (145, 157))	('TP53:c.743G>A', 'Var', (59, 72))	('p.Gly12Val', 'Mutation', 'rs121913529', (105, 115))	('BRAF:c.1799T>A', 'SUBSTITUTION', 'None', (29, 43))	('KRAS:c.35G>A', 'Var', (118, 130))	('BRAF:c.1799T>A', 'Var', (29, 43))	('KRAS:c.34G>A', 'Var', (176, 188))	('colorectal', 'Disease', (235, 245))
36377	31950578	Using the single-well version of the assay, we were able to detect several single point cancer mutations up to 1 mutant molecule in 5,000 genome equivalents (GE) of human genomic DNA (hgDNA).	('human', 'Species', '9606', (165, 170))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('detect', 'Reg', (60, 66))
36378	31950578	Using the 12-well version of the assay, we were able to detect these mutations at a single-molecule resolution, in the presence of an excess of wild-type DNA (1,000 to 2,500 GE of hgDNA) that is in the same range as the amount of DNA extracted (about 2,000 GE) from 1 mL of human plasma.	('mutations', 'Var', (69, 78))	('detect', 'Reg', (56, 62))	('human', 'Species', '9606', (274, 279))
36382	31950578	In summary, we have demonstrated how the orthogonal nature and flexible design of the PCR-LDR-qPCR assay enable detection of low-abundance BRAF, TP53 and KRAS single point DNA mutations in the presence of excess wild-type DNA with high sensitivity and specificity.	('KRAS', 'Gene', '3845', (154, 158))	('mutations', 'Var', (176, 185))	('BRAF', 'Gene', (139, 143))	('BRAF', 'Gene', '673', (139, 143))	('single point DNA mutations', 'Var', (159, 185))	('TP53', 'Gene', '7157', (145, 149))	('DNA', 'cellular_component', 'GO:0005574', ('222', '225'))	('TP53', 'Gene', (145, 149))	('DNA', 'cellular_component', 'GO:0005574', ('172', '175'))	('KRAS', 'Gene', (154, 158))
36383	31950578	The robust sensitivity and specificity of the assay relies on the multistep selective amplification, ligation, and detection of the mutant DNA, combined with the spatial dilution of the template DNA, and the use of UDG to prevent carryover contamination.	('UDG', 'Gene', '7374', (215, 218))	('DNA', 'Gene', (139, 142))	('mutant', 'Var', (132, 138))	('UDG', 'Gene', (215, 218))
36385	31950578	In future studies, we will evaluate the clinical application of our PCR-LDR-qPCR assay for the detection of multiple low-abundance mutations from circulating tumor DNA in a multiplexed assay format.	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('mutations', 'Var', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
36393	29037225	YAP increased COX-2 expression at the level of transcription requiring intact TEAD binding sites in the COX-2 promoter.	('COX-2', 'Gene', '5743', (14, 19))	('expression', 'MPA', (20, 30))	('COX-2', 'Gene', (104, 109))	('COX-2', 'Gene', '5743', (104, 109))	('binding', 'Interaction', (83, 90))	('expression', 'Species', '29278', (20, 30))	('YAP', 'Var', (0, 3))	('increased', 'PosReg', (4, 13))	('COX-2', 'Gene', (14, 19))
36415	29037225	Considering YAP is a transcriptional coactivator and positive correlation between these two molecules, we hypothesize that YAP activates COX-2 pathway and increases its expression, leading to resistance to drug therapy.	('COX-2', 'Gene', '5743', (137, 142))	('increases', 'PosReg', (155, 164))	('expression', 'Species', '29278', (169, 179))	('YAP', 'Var', (123, 126))	('resistance to drug therapy', 'MPA', (192, 218))	('leading to', 'Reg', (181, 191))	('expression', 'MPA', (169, 179))	('activates', 'PosReg', (127, 136))	('COX-2', 'Gene', (137, 142))	('resistance to drug therapy', 'Phenotype', 'HP:0020174', (192, 218))
36416	29037225	In this study, we provide new insights into the idea that YAP enhances COX-2 expression via interactions with transcription factors, TEA domain family members, in the COX-2 promoter.	('expression', 'MPA', (77, 87))	('COX-2', 'Gene', (71, 76))	('COX-2', 'Gene', (167, 172))	('YAP', 'Var', (58, 61))	('COX-2', 'Gene', '5743', (71, 76))	('enhances', 'PosReg', (62, 70))	('COX-2', 'Gene', '5743', (167, 172))	('transcription', 'biological_process', 'GO:0006351', ('110', '123'))	('expression', 'Species', '29278', (77, 87))	('interactions', 'Interaction', (92, 104))
36459	29037225	In contrast, shRNA knockdown of YAP in HCT15 cells greatly reduced COX-2 protein levels (Fig.	('reduced', 'NegReg', (59, 66))	('knockdown', 'Var', (19, 28))	('HCT15', 'CellLine', 'CVCL:0292', (39, 44))	('COX-2', 'Gene', (67, 72))	('COX-2', 'Gene', '5743', (67, 72))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))
36460	29037225	Moreover, in SW480 cells, COX-2 overexpression induced by CMV2-YAP was attenuated by shRNA knockdown of YAP (Fig.	('overexpression', 'PosReg', (32, 46))	('SW480', 'CellLine', 'CVCL:0546', (13, 18))	('CMV2-YAP', 'Var', (58, 66))	('knockdown', 'Var', (91, 100))	('attenuated', 'NegReg', (71, 81))	('COX-2', 'Gene', (26, 31))	('COX-2', 'Gene', '5743', (26, 31))	('expression', 'Species', '29278', (36, 46))
36462	29037225	Moreover, immunofluorescence revealed that knockdown of YAP by shRNA decreased COX-2 expression in HCT15 cells (Fig.	('expression', 'MPA', (85, 95))	('COX-2', 'Gene', '5743', (79, 84))	('decreased', 'NegReg', (69, 78))	('knockdown', 'Var', (43, 52))	('HCT15', 'CellLine', 'CVCL:0292', (99, 104))	('COX-2', 'Gene', (79, 84))	('expression', 'Species', '29278', (85, 95))
36466	29037225	Results showed that HEK293T cells transfected with CMV-YAP plasmid demonstrated higher COX-2 expression than cells with control vector (Fig.	('COX-2', 'Gene', (87, 92))	('COX-2', 'Gene', '5743', (87, 92))	('CMV-YAP', 'Var', (51, 58))	('expression', 'Species', '29278', (93, 103))	('expression', 'MPA', (93, 103))	('HEK293T', 'CellLine', 'CVCL:0063', (20, 27))	('higher', 'PosReg', (80, 86))
36468	29037225	Consequently, COX-2 could be up-regulated in several types of cells via expression of a constitutively active form of YAP or by stimulation of endogenous YAP protein that resulted from disruption of Hippo pathway upstream members.	('COX-2', 'Gene', '5743', (14, 19))	('expression', 'Species', '29278', (72, 82))	('disruption', 'Var', (185, 195))	('up-regulated', 'PosReg', (29, 41))	('YAP', 'Gene', (118, 121))	('Hippo pathway', 'Pathway', (199, 212))	('stimulation', 'PosReg', (128, 139))	('COX-2', 'Gene', (14, 19))
36478	29037225	To examine if the TEAD response elements in the COX-2 promoter were essential for the arousal of COX-2 by YAP, the deletion of the TEAD response elements was generated in the COX-2 promoter using site-directed mutagenesis as shown in Fig.	('deletion', 'Var', (115, 123))	('COX-2', 'Gene', '5743', (48, 53))	('COX-2', 'Gene', (97, 102))	('COX-2', 'Gene', '5743', (97, 102))	('mutagenesis', 'biological_process', 'GO:0006280', ('210', '221'))	('COX-2', 'Gene', (175, 180))	('COX-2', 'Gene', (48, 53))	('COX-2', 'Gene', '5743', (175, 180))
36479	29037225	Our luciferase assay showed that deletion of the TEAD response elements in the COX-2 promoter greatly diminished COX-2 transcriptional activity in 293 T cells.	('COX-2', 'Gene', '5743', (79, 84))	('deletion', 'Var', (33, 41))	('diminished', 'NegReg', (102, 112))	('293 T', 'CellLine', 'CVCL:0063', (147, 152))	('COX-2', 'Gene', (113, 118))	('COX-2', 'Gene', (79, 84))	('COX-2', 'Gene', '5743', (113, 118))
36480	29037225	Similarly, in HCT-116 cells, COX-2 transcriptional activity was significantly reduced, when deletion of the TEAD response elements in the COX-2 promoter was carried out.	('HCT-116', 'CellLine', 'CVCL:0291', (14, 21))	('COX-2', 'Gene', '5743', (138, 143))	('COX-2', 'Gene', (29, 34))	('deletion', 'Var', (92, 100))	('transcriptional activity', 'MPA', (35, 59))	('COX-2', 'Gene', '5743', (29, 34))	('reduced', 'NegReg', (78, 85))	('COX-2', 'Gene', (138, 143))
36481	29037225	Accordingly, there was a reduced COX-2 mRNA level after deletion, which was in concert with decreased COX-2 transcriptional activity (Fig.	('deletion', 'Var', (56, 64))	('reduced', 'NegReg', (25, 32))	('COX-2', 'Gene', (33, 38))	('transcriptional activity', 'MPA', (108, 132))	('COX-2', 'Gene', '5743', (33, 38))	('COX-2', 'Gene', (102, 107))	('COX-2', 'Gene', '5743', (102, 107))
36493	29037225	5a, b, HCT15 cells with high YAP/COX-2 expression had a poorer response to Taxol than IMCE cells with low YAP and COX-2.	('COX-2', 'Gene', (114, 119))	('expression', 'Var', (39, 49))	('COX-2', 'Gene', (33, 38))	('poorer', 'NegReg', (56, 62))	('COX-2', 'Gene', '5743', (114, 119))	('Taxol', 'Chemical', 'MESH:D017239', (75, 80))	('response to Taxol', 'MPA', (63, 80))	('COX-2', 'Gene', '5743', (33, 38))	('high', 'Var', (24, 28))	('expression', 'Species', '29278', (39, 49))	('HCT15', 'CellLine', 'CVCL:0292', (7, 12))
36497	29037225	5c, when we knocked down COX-2 in IMCE (YAP) cells (i.e., IMCE(YAP/shCOX-2)), they became more sensitive to Taxol treatment than intact IMCE (YAP) cells.	('COX-2', 'Gene', '5743', (69, 74))	('COX-2', 'Gene', '5743', (25, 30))	('Taxol', 'Chemical', 'MESH:D017239', (108, 113))	('more', 'PosReg', (90, 94))	('sensitive to Taxol treatment', 'MPA', (95, 123))	('knocked down', 'Var', (12, 24))	('COX-2', 'Gene', (69, 74))	('COX-2', 'Gene', (25, 30))
36517	29037225	Upon G-4 treatment, significant reduction of COX-2 expression was observed compared to the G-4-untreated cells in a concentration-dependent manner.	('G-4', 'Chemical', '-', (91, 94))	('COX-2', 'Gene', '5743', (45, 50))	('G-4', 'Var', (5, 8))	('G-4', 'Chemical', '-', (5, 8))	('expression', 'Species', '29278', (51, 61))	('reduction', 'NegReg', (32, 41))	('expression', 'MPA', (51, 61))	('COX-2', 'Gene', (45, 50))
36519	29037225	FigURE 8b showed that after transfection, YAP level was increased to a high level comparable to the pretreatment situation, while the low COX-2 expression did not change significantly following YAP increase.	('COX-2', 'Gene', '5743', (138, 143))	('expression', 'Species', '29278', (144, 154))	('increased', 'PosReg', (56, 65))	('YAP level', 'MPA', (42, 51))	('transfection', 'Var', (28, 40))	('COX-2', 'Gene', (138, 143))
36523	29037225	Collectively, G-4 affected not only COX-2 expression at posttranscriptional level but also COX-2 enzyme catalytic activity.	('COX-2', 'Gene', '5743', (91, 96))	('expression', 'Species', '29278', (42, 52))	('expression', 'MPA', (42, 52))	('COX-2', 'Gene', (91, 96))	('catalytic activity', 'molecular_function', 'GO:0003824', ('104', '122'))	('enzyme catalytic activity', 'MPA', (97, 122))	('COX-2', 'Gene', (36, 41))	('affected', 'Reg', (18, 26))	('G-4', 'Var', (14, 17))	('COX-2', 'Gene', '5743', (36, 41))	('G-4', 'Chemical', '-', (14, 17))
36530	29037225	In cell migration and invasion assays, results showed that G-4/Taxol markedly inhibited the wound closure (15%) in comparison with that of Taxol group (65%) for 24 h in HCT15/Tax cells (Fig.	('inhibited', 'NegReg', (78, 87))	('HCT15', 'CellLine', 'CVCL:0292', (169, 174))	('wound closure', 'CPA', (92, 105))	('Taxol', 'Chemical', 'MESH:D017239', (63, 68))	('G-4', 'Chemical', '-', (59, 62))	('G-4/Taxol', 'Var', (59, 68))	('Taxol', 'Chemical', 'MESH:D017239', (139, 144))
36541	29037225	G-4 induced apoptosis more significantly than either VP (a YAP inhibitor) or Cel (a selective COX-2 inhibitor) alone in HCT8 and HCT15/Tax cells.	('COX-2', 'Gene', (94, 99))	('VP', 'Chemical', 'MESH:C038467', (53, 55))	('HCT15', 'CellLine', 'CVCL:0292', (129, 134))	('COX-2', 'Gene', '5743', (94, 99))	('G-4', 'Var', (0, 3))	('G-4', 'Chemical', '-', (0, 3))	('Cel', 'Chemical', 'MESH:C054688', (77, 80))	('apoptosis', 'CPA', (12, 21))
36542	29037225	Simultaneously, G-4 resulted in more decreases of viability of HCT8 and HCT15/Tax cells than VP or Cel alone (Fig.	('HCT15', 'CellLine', 'CVCL:0292', (72, 77))	('Cel', 'Chemical', 'MESH:C054688', (99, 102))	('G-4', 'Var', (16, 19))	('G-4', 'Chemical', '-', (16, 19))	('VP', 'Chemical', 'MESH:C038467', (93, 95))	('HCT15/Tax cells', 'CPA', (72, 87))	('viability', 'CPA', (50, 59))	('decreases', 'NegReg', (37, 46))	('HCT8', 'CPA', (63, 67))
36543	29037225	According to these results, both YAP and COX-2 are important regulators in G-4-reduced drug resistance in HCT8 and 15/Tax cells.	('COX-2', 'Gene', (41, 46))	('COX-2', 'Gene', '5743', (41, 46))	('G-4', 'Chemical', '-', (75, 78))	('G-4-reduced', 'NegReg', (75, 86))	('G-4-reduced', 'Var', (75, 86))	('drug resistance', 'Phenotype', 'HP:0020174', (87, 102))	('drug resistance', 'MPA', (87, 102))
36550	29037225	Male athymic nude mice, allowing for the development of subcutaneous tumors, were used to demonstrate whether G-4 was able to reduce the tumor volume/weight in mice where the tumor was already detectable.	('reduce', 'NegReg', (126, 132))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (56, 75))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (56, 75))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('G-4', 'Chemical', '-', (110, 113))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('subcutaneous tumors', 'Disease', (56, 75))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', (137, 142))	('mice', 'Species', '10090', (18, 22))	('mice', 'Species', '10090', (160, 164))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('nude mice', 'Species', '10090', (13, 22))	('tumor', 'Disease', (69, 74))	('G-4', 'Var', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
36553	29037225	Compared with the control group, VP, celecoxib and G-4 reduced the tumor weight with percentage of 39%, 31% and 69% respectively, suggesting that G-4 had an effect on tumor proliferation in mice where the tumor was detectable at the time of treatment.	('G-4', 'Var', (146, 149))	('G-4', 'Chemical', '-', (146, 149))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('reduced', 'NegReg', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('G-4', 'Chemical', '-', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (67, 72))	('mice', 'Species', '10090', (190, 194))	('VP', 'Chemical', 'MESH:C038467', (33, 35))	('effect', 'Reg', (157, 163))	('tumor', 'Disease', (167, 172))	('celecoxib', 'Chemical', 'MESH:D000068579', (37, 46))
36554	29037225	In addition, the levels of YAP, COX-2 in mice tumors were significantly reduced by the therapy of G-4 (Fig.	('reduced', 'NegReg', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('mice', 'Species', '10090', (41, 45))	('G-4', 'Var', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('COX-2', 'Gene', (32, 37))	('G-4', 'Chemical', '-', (98, 101))	('COX-2', 'Gene', '5743', (32, 37))	('tumors', 'Disease', (46, 52))	('levels', 'MPA', (17, 23))	('YAP', 'MPA', (27, 30))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
36576	29037225	We also showed that its inactivation by G-4 effectively reduced the up-regulation of MDR, MCL1, Survivin in YAP-overexpressing cells.	('MCL1', 'Gene', '4170', (90, 94))	('MDR', 'Gene', (85, 88))	('reduced', 'NegReg', (56, 63))	('inactivation', 'Var', (24, 36))	('G-4', 'Chemical', '-', (40, 43))	('Survivin', 'Protein', (96, 104))	('up-regulation', 'PosReg', (68, 81))	('MCL1', 'Gene', (90, 94))
36577	29037225	Thus, we proposed a novel mechanism in which YAP augments COX-2 expression as well as its downstream targets, Survivin, MDR, MCL1, and thereby up-regulates the effect of drug resistance in CRC cells.	('up-regulates', 'PosReg', (143, 155))	('expression', 'MPA', (64, 74))	('effect', 'MPA', (160, 166))	('COX-2', 'Gene', '5743', (58, 63))	('MDR', 'Gene', (120, 123))	('drug resistance', 'Phenotype', 'HP:0020174', (170, 185))	('expression', 'Species', '29278', (64, 74))	('MCL1', 'Gene', '4170', (125, 129))	('Survivin', 'Protein', (110, 118))	('augments', 'PosReg', (49, 57))	('MCL1', 'Gene', (125, 129))	('COX-2', 'Gene', (58, 63))	('YAP', 'Var', (45, 48))
36582	29037225	Deletion of the TEAD binding site in the COX-2 promoter diminished COX-2 transcriptional induction by YAP indicating that an intact TEAD binding site was necessary for YAP's induction of COX-2.	('transcriptional induction', 'MPA', (73, 98))	('COX-2', 'Gene', (41, 46))	('COX-2', 'Gene', '5743', (41, 46))	('COX-2', 'Gene', (187, 192))	('COX-2', 'Gene', '5743', (187, 192))	('COX-2', 'Gene', (67, 72))	('COX-2', 'Gene', '5743', (67, 72))	('binding', 'molecular_function', 'GO:0005488', ('137', '144'))	('diminished', 'NegReg', (56, 66))	('binding', 'molecular_function', 'GO:0005488', ('21', '28'))	('Deletion', 'Var', (0, 8))
36586	29037225	Our preliminary study showed that in COX-2-overexpressing HepG2 cells, COX-2 knockdown reduced the expression of YAP.	('expression', 'MPA', (99, 109))	('reduced', 'NegReg', (87, 94))	('COX-2', 'Gene', (37, 42))	('COX-2', 'Gene', (71, 76))	('knockdown', 'Var', (77, 86))	('COX-2', 'Gene', '5743', (37, 42))	('expression', 'Species', '29278', (99, 109))	('COX-2', 'Gene', '5743', (71, 76))	('YAP', 'Gene', (113, 116))	('HepG2', 'CellLine', 'CVCL:0027', (58, 63))
36591	29037225	In this study, we found that G-4 could drive YAP from nucleus to cytosol and promote its retention in cytosol through phosphorylation, hence affecting the downstream events such as YAP transcription.	('cytosol', 'cellular_component', 'GO:0005829', ('102', '109'))	('promote', 'PosReg', (77, 84))	('YAP', 'Gene', (181, 184))	('YAP', 'Gene', (45, 48))	('G-4', 'Var', (29, 32))	('transcription', 'biological_process', 'GO:0006351', ('185', '198'))	('G-4', 'Chemical', '-', (29, 32))	('cytosol', 'cellular_component', 'GO:0005829', ('65', '72'))	('nucleus', 'cellular_component', 'GO:0005634', ('54', '61'))	('retention', 'biological_process', 'GO:0051235', ('89', '98'))	('affecting', 'Reg', (141, 150))	('retention', 'MPA', (89, 98))	('phosphorylation', 'biological_process', 'GO:0016310', ('118', '133'))	('phosphorylation', 'MPA', (118, 133))	('drive', 'PosReg', (39, 44))
36604	28503514	Among its subtypes, MSI-high colorectal cancers have distinct clinical and pathological features, such as proximal location, early-stage (predominantly stage II), poor differentiation, mucinous histology and association with BRAF mutations.	('mucin', 'Gene', '100508689', (185, 190))	('BRAF', 'Gene', (225, 229))	('BRAF', 'Gene', '673', (225, 229))	('association', 'Interaction', (208, 219))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('mucin', 'Gene', (185, 190))	('MSI-high colorectal cancers', 'Disease', (20, 47))	('colorectal cancer', 'Phenotype', 'HP:0003003', (29, 46))	('mutations', 'Var', (230, 239))	('MSI-high colorectal cancers', 'Disease', 'MESH:D015179', (20, 47))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('poor differentiation', 'CPA', (163, 183))
36630	26028992	The results further indicate a beneficial effect of adjuvant chemotherapy on I-type tumours with membranous PODXL expression, suggesting the potential utility of PODXL as a biomarker for improved treatment stratification of these patients.	('expression', 'Var', (114, 124))	('beneficial', 'PosReg', (31, 41))	('PODXL', 'Gene', '5420', (162, 167))	('I-type tumours', 'Disease', 'MESH:D017827', (77, 91))	('PODXL', 'Gene', '5420', (108, 113))	('patients', 'Species', '9606', (230, 238))	('PODXL', 'Gene', (162, 167))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('PODXL', 'Gene', (108, 113))	('I-type tumours', 'Disease', (77, 91))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))
36644	26028992	In another study, sialofucosylated PODXL was demonstrated to be a functional E- and L-selectin ligand expressed by metastatic pancreatic cancer cells in vitro, and was also found to be overexpressed, with membranous localization, in 69 % of 105 pancreatic ductal adenocarcinomas.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('overexpressed', 'PosReg', (185, 198))	('pancreatic cancer', 'Disease', 'MESH:D010190', (126, 143))	('carcinomas', 'Phenotype', 'HP:0030731', (268, 278))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (245, 277))	('pancreatic ductal adenocarcinomas', 'Disease', (245, 278))	('PODXL', 'Gene', '5420', (35, 40))	('sialofucosylated', 'Var', (18, 34))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (126, 143))	('L-selectin', 'Gene', (84, 94))	('PODXL', 'Gene', (35, 40))	('L-selectin', 'Gene', '6402', (84, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (245, 278))	('pancreatic cancer', 'Disease', (126, 143))
36710	26028992	Moreover, these findings indicate that I-type tumours with high expression of PODXL are more likely to benefit from adjuvant therapy than PB-type tumours.	('adjuvant therapy', 'CPA', (116, 132))	('I-type tumours', 'Disease', 'MESH:D017827', (39, 53))	('I-type tumours', 'Disease', (39, 53))	('benefit', 'PosReg', (103, 110))	('PODXL', 'Gene', '5420', (78, 83))	('PB-type tumours', 'Disease', (138, 153))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('high expression', 'Var', (59, 74))	('PB-type tumours', 'Disease', 'MESH:D009369', (138, 153))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('PODXL', 'Gene', (78, 83))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
36722	26028992	Previous studies have demonstrated PODXL to be a functional ligand of E- and L- selectins in pancreatic cancer suggesting that its expression may promote haemotogenic spread of metastases by facilitating binding of circulating tumour cells to selectin-expressing host cells.	('expression', 'Var', (131, 141))	('metastases', 'Disease', 'MESH:D009362', (177, 187))	('facilitating', 'PosReg', (191, 203))	('pancreatic cancer', 'Disease', (93, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumour', 'Phenotype', 'HP:0002664', (227, 233))	('pancreatic cancer', 'Disease', 'MESH:D010190', (93, 110))	('metastases', 'Disease', (177, 187))	('PODXL', 'Gene', '5420', (35, 40))	('tumour', 'Disease', 'MESH:D009369', (227, 233))	('binding', 'Interaction', (204, 211))	('PODXL', 'Gene', (35, 40))	('tumour', 'Disease', (227, 233))	('promote', 'PosReg', (146, 153))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (93, 110))
36732	26028992	The herein presented results also indicate a beneficial effect of adjuvant chemotherapy on intestinal type tumours with membranous PODXL expression, suggesting the potential utility of PODXL as a biomarker for improved treatment stratification of these patients.	('PODXL', 'Gene', '5420', (185, 190))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('beneficial', 'PosReg', (45, 55))	('intestinal type tumours', 'Disease', (91, 114))	('PODXL', 'Gene', (185, 190))	('intestinal type tumours', 'Disease', 'MESH:D007414', (91, 114))	('PODXL', 'Gene', '5420', (131, 136))	('patients', 'Species', '9606', (253, 261))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('expression', 'Var', (137, 147))	('PODXL', 'Gene', (131, 136))
36734	24279335	Targeting Cdc42 with the small molecule drug AZA197 suppresses primary colon cancer growth and prolongs survival in a preclinical mouse xenograft model by downregulation of PAK1 activity Rho GTPases play important roles in cytoskeleton organization, cell cycle progression and are key regulators of tumor progression.	('colon cancer', 'Disease', (71, 83))	('PAK1', 'Gene', '18479', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('Cdc42', 'Gene', (10, 15))	('prolongs', 'PosReg', (95, 103))	('downregulation', 'NegReg', (155, 169))	('AZA197', 'Var', (45, 51))	('AZA197', 'Chemical', 'MESH:C000589260', (45, 51))	('GTP', 'Chemical', 'MESH:D006160', (191, 194))	('colon cancer', 'Phenotype', 'HP:0003003', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mouse', 'Species', '10090', (130, 135))	('PAK1', 'Gene', (173, 177))	('tumor', 'Disease', (299, 304))	('colon cancer', 'Disease', 'MESH:D015179', (71, 83))	('primary', 'CPA', (63, 70))	('survival', 'CPA', (104, 112))	('Cdc42', 'Gene', '12540', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('suppresses', 'NegReg', (52, 62))
36739	24279335	After treatment, tumors were excised and processed for Ki-67 staining, TUNEL assays and Western blotting to evaluate proliferative and apoptotic effects induced by AZA197.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('Ki-67', 'Gene', (55, 60))	('AZA197', 'Chemical', 'MESH:C000589260', (164, 170))	('AZA197', 'Var', (164, 170))	('apoptotic', 'CPA', (135, 144))	('Ki-67', 'Gene', '17345', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
36741	24279335	AZA197 suppressed colon cancer cell proliferation, cell migration and invasion and increased apoptosis associated with down-regulation of the PAK1 and ERK signaling pathways in vitro.	('cell migration', 'biological_process', 'GO:0016477', ('51', '65'))	('down-regulation', 'NegReg', (119, 134))	('ERK', 'molecular_function', 'GO:0004707', ('151', '154'))	('AZA197', 'Var', (0, 6))	('AZA197', 'Chemical', 'MESH:C000589260', (0, 6))	('colon cancer', 'Phenotype', 'HP:0003003', (18, 30))	('apoptosis', 'CPA', (93, 102))	('apoptosis', 'biological_process', 'GO:0097194', ('93', '102'))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('increased', 'PosReg', (83, 92))	('apoptosis', 'biological_process', 'GO:0006915', ('93', '102'))	('cell migration', 'CPA', (51, 65))	('suppressed', 'NegReg', (7, 17))	('ERK', 'Gene', '5594', (151, 154))	('colon cancer', 'Disease', 'MESH:D015179', (18, 30))	('PAK1', 'Gene', (142, 146))	('PAK1', 'Gene', '5058', (142, 146))	('ERK', 'Gene', (151, 154))	('cell proliferation', 'biological_process', 'GO:0008283', ('31', '49'))	('colon cancer', 'Disease', (18, 30))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('regulation', 'biological_process', 'GO:0065007', ('124', '134'))	('invasion', 'CPA', (70, 78))
36742	24279335	Furthermore, systemic AZA197 treatment reduced tumor growth in vivo and significantly increased mouse survival in SW620 tumor xenografts.	('AZA197', 'Chemical', 'MESH:C000589260', (22, 28))	('increased', 'PosReg', (86, 95))	('mouse', 'Species', '10090', (96, 101))	('AZA197', 'Var', (22, 28))	('mouse survival', 'CPA', (96, 110))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('reduced', 'NegReg', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('SW620', 'CellLine', 'CVCL:0547', (114, 119))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', (120, 125))
36756	24279335	Increased RhoA expression has been described in various human tumors including colon cancer associated with malignant progression, although Rho GTPases also seem to have a tumor suppressive function since loss of Rho function is associated with predisposition to lymphoid cell transformation.	('RhoA', 'Gene', '387', (10, 14))	('colon cancer', 'Disease', (79, 91))	('tumor', 'Disease', (172, 177))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('loss', 'Var', (205, 209))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Rho', 'Protein', (213, 216))	('tumors', 'Disease', (62, 68))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('human', 'Species', '9606', (56, 61))	('associated', 'Reg', (229, 239))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('GTP', 'Chemical', 'MESH:D006160', (144, 147))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('RhoA', 'Gene', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('lymphoid cell transformation', 'CPA', (263, 291))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
36758	24279335	Cdc42 expression is up-regulated in breast cancer, however loss of Cdc42 enhances liver cancer development, suggesting that the multiple roles of Cdc42 affect cancer progression in a tissue-specific manner.	('cancer', 'Disease', (88, 94))	('Cdc42', 'Gene', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Cdc42', 'Gene', (67, 72))	('liver cancer', 'Disease', 'MESH:D006528', (82, 94))	('cancer', 'Disease', (159, 165))	('enhances', 'PosReg', (73, 81))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('Cdc42', 'Gene', '998', (146, 151))	('up-regulated', 'PosReg', (20, 32))	('Cdc42', 'Gene', (0, 5))	('loss', 'Var', (59, 63))	('liver cancer', 'Phenotype', 'HP:0002896', (82, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('liver cancer', 'Disease', (82, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('Cdc42', 'Gene', '998', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))	('breast cancer', 'Disease', (36, 49))	('cancer', 'Disease', (43, 49))	('Cdc42', 'Gene', '998', (0, 5))	('affect', 'Reg', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
36762	24279335	In this study, we identify a highly efficient small molecule anticancer agent AZA197 that specifically inhibits Cdc42.	('Cdc42', 'Gene', '998', (112, 117))	('AZA197', 'Var', (78, 84))	('AZA197', 'Chemical', 'MESH:C000589260', (78, 84))	('inhibits', 'NegReg', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Cdc42', 'Gene', (112, 117))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
36763	24279335	We report that, AZA197 reduces the proliferative potential of both HT-29 colorectal cancer cells and the highly invasive SW620 colorectal cell line associated with decreased PAK/ERK activation.	('AZA197', 'Chemical', 'MESH:C000589260', (16, 22))	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('decreased', 'NegReg', (164, 173))	('colorectal', 'Disease', (73, 83))	('AZA197', 'Var', (16, 22))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('HT-29', 'CellLine', 'CVCL:0320', (67, 72))	('ERK', 'molecular_function', 'GO:0004707', ('178', '181'))	('colorectal', 'Disease', 'MESH:D015179', (127, 137))	('ERK', 'Gene', '5594', (178, 181))	('colorectal', 'Disease', 'MESH:D015179', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', (73, 90))	('SW620', 'CellLine', 'CVCL:0547', (121, 126))	('proliferative potential', 'CPA', (35, 58))	('reduces', 'NegReg', (23, 30))	('ERK', 'Gene', (178, 181))	('colorectal', 'Disease', (127, 137))
36764	24279335	Moreover, AZA197 decreases SW620 colon cancer cell migration and invasion.	('colon cancer', 'Phenotype', 'HP:0003003', (33, 45))	('decreases SW620 colon cancer', 'Disease', (17, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('AZA197', 'Chemical', 'MESH:C000589260', (10, 16))	('invasion', 'CPA', (65, 73))	('AZA197', 'Var', (10, 16))	('decreases SW620 colon cancer', 'Disease', 'MESH:D015179', (17, 45))
36765	24279335	Studies in vivo showed that AZA197 reduces the growth of human SW620 colon cancer xenografts and significantly improves animal survival.	('reduces', 'NegReg', (35, 42))	('animal survival', 'CPA', (120, 135))	('SW620 colon cancer', 'Disease', (63, 81))	('SW620 colon cancer', 'Disease', 'MESH:D015179', (63, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('AZA197', 'Chemical', 'MESH:C000589260', (28, 34))	('AZA197', 'Var', (28, 34))	('colon cancer', 'Phenotype', 'HP:0003003', (69, 81))	('improves', 'PosReg', (111, 119))	('growth', 'CPA', (47, 53))	('human', 'Species', '9606', (57, 62))
36778	24279335	Cells were incubated with 1, 2, 5 or 10 muM AZA197.	('muM', 'Gene', (40, 43))	('AZA197', 'Chemical', 'MESH:C000589260', (44, 50))	('muM', 'Gene', '56925', (40, 43))	('AZA197', 'Var', (44, 50))
36779	24279335	Tumor cells were seeded in 6-well plates and allowed to adhere before treatment with 2, 5 or 10 muM AZA197.	('muM', 'Gene', '56925', (96, 99))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('muM', 'Gene', (96, 99))	('AZA197', 'Chemical', 'MESH:C000589260', (100, 106))	('AZA197', 'Var', (100, 106))
36783	24279335	Cells were incubated with 1, 2 and 5 muM of AZA197.	('AZA197', 'Chemical', 'MESH:C000589260', (44, 50))	('muM', 'Gene', (37, 40))	('muM', 'Gene', '56925', (37, 40))	('AZA197', 'Var', (44, 50))
36812	24279335	In both cancer cells and fibroblasts, a similar AZA197 toxicity profile from 1-100 muM was observed (Figure 2A for SW620 and S3T3; Additional file 1: Figure S1A for HT-29).	('S3T3', 'CellLine', 'CVCL:0594', (125, 129))	('cancer', 'Disease', (8, 14))	('muM', 'Gene', '56925', (83, 86))	('toxicity', 'Disease', 'MESH:D064420', (55, 63))	('toxicity', 'Disease', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('AZA197', 'Chemical', 'MESH:C000589260', (48, 54))	('HT-29', 'CellLine', 'CVCL:0320', (165, 170))	('muM', 'Gene', (83, 86))	('AZA197', 'Var', (48, 54))	('SW620', 'CellLine', 'CVCL:0547', (115, 120))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
36814	24279335	The LDH release profiles in all investigated cells exposed to AZA197 up to 10 muM was comparable to solvent control cultures.	('muM', 'Gene', (78, 81))	('LDH release', 'MPA', (4, 15))	('AZA197', 'Chemical', 'MESH:C000589260', (62, 68))	('AZA197', 'Var', (62, 68))	('muM', 'Gene', '56925', (78, 81))
36815	24279335	At higher AZA197 concentrations of 20, 50 and 100 muM, significantly increased levels of LDH release were observed in all cell lines investigated with a 9-fold increase in SW620 cells (P < 0.001) and 3-fold increases in HT-29 cells (P < 0.04) and S3T3 fibroblasts (P < 0.001) at 20 muM (Figure 2A; Additional file 1: Figure S1A).	('LDH release', 'MPA', (89, 100))	('increased', 'PosReg', (69, 78))	('S3T3', 'CellLine', 'CVCL:0594', (247, 251))	('increase', 'PosReg', (160, 168))	('muM', 'Gene', '56925', (282, 285))	('SW620', 'CellLine', 'CVCL:0547', (172, 177))	('muM', 'Gene', '56925', (50, 53))	('AZA197', 'Chemical', 'MESH:C000589260', (10, 16))	('muM', 'Gene', (282, 285))	('AZA197', 'Var', (10, 16))	('HT-29 cells', 'CellLine', 'CVCL:0320', (220, 231))	('muM', 'Gene', (50, 53))
36818	24279335	These data suggest that low plasma membrane damage occurs independently of the cell type after 24 h of exposure to AZA197 at concentrations up to 10 muM as evidenced by low intracellular LDH release.	('muM', 'Gene', '56925', (149, 152))	('plasma membrane', 'MPA', (28, 43))	('muM', 'Gene', (149, 152))	('AZA197', 'Chemical', 'MESH:C000589260', (115, 121))	('intracellular LDH release', 'MPA', (173, 198))	('low', 'NegReg', (169, 172))	('AZA197', 'Var', (115, 121))
36822	24279335	Treatment with 1, 2, 5 or 10 muM AZA197 did not affect Rac1 activity (Figure 2B left panel).	('muM', 'Gene', (29, 32))	('AZA197', 'Var', (33, 39))	('AZA197', 'Chemical', 'MESH:C000589260', (33, 39))	('Rac1', 'Gene', '5879', (55, 59))	('muM', 'Gene', '56925', (29, 32))	('activity', 'MPA', (60, 68))	('Rac1', 'Gene', (55, 59))
36823	24279335	AZA197 inhibited Cdc42 in a dose-dependent manner in SW620 cells.	('Cdc42', 'Gene', (17, 22))	('inhibited', 'NegReg', (7, 16))	('AZA197', 'Var', (0, 6))	('AZA197', 'Chemical', 'MESH:C000589260', (0, 6))	('Cdc42', 'Gene', '998', (17, 22))	('SW620', 'CellLine', 'CVCL:0547', (53, 58))
36824	24279335	AZA197 reduced Cdc42 activity significantly by 56.7% (P = 0.024), 75.2% (P = 0.014), 76.0% (P = 0.035) and 89.3% (P = 0.011) at 1, 2, 5 and 10 muM, respectively, compared to untreated controls (Figure 2B central panel).	('reduced', 'NegReg', (7, 14))	('muM', 'Gene', '56925', (143, 146))	('Cdc42', 'Gene', '998', (15, 20))	('muM', 'Gene', (143, 146))	('Cdc42', 'Gene', (15, 20))	('AZA197', 'Var', (0, 6))	('AZA197', 'Chemical', 'MESH:C000589260', (0, 6))	('activity', 'MPA', (21, 29))
36825	24279335	In contrast, RhoA activity was not significantly affected by AZA197 treatment in SW620 cells (Figure 2 right panel).	('SW620', 'CellLine', 'CVCL:0547', (81, 86))	('AZA197', 'Chemical', 'MESH:C000589260', (61, 67))	('RhoA', 'Gene', (13, 17))	('AZA197 treatment', 'Var', (61, 77))	('RhoA', 'Gene', '387', (13, 17))
36826	24279335	AZA197 also dose-dependently and significantly down-regulated Cdc42 activity in HT-29 colon cells by 18% (1 muM, P = 0.048), 48.5% (2 muM, P = 0.011), 52.9% (5 muM, P = 0.014) and 61.0% (10 muM, P < 0.001) as shown in Additional file 1: Figure S1B.	('muM', 'Gene', '56925', (134, 137))	('muM', 'Gene', (160, 163))	('HT-29', 'CellLine', 'CVCL:0320', (80, 85))	('Cdc42', 'Gene', (62, 67))	('Cdc42', 'Gene', '998', (62, 67))	('muM', 'Gene', (134, 137))	('AZA197', 'Chemical', 'MESH:C000589260', (0, 6))	('muM', 'Gene', '56925', (108, 111))	('muM', 'Gene', '56925', (190, 193))	('activity', 'MPA', (68, 76))	('muM', 'Gene', (108, 111))	('AZA197', 'Var', (0, 6))	('muM', 'Gene', '56925', (160, 163))	('down-regulated', 'NegReg', (47, 61))	('muM', 'Gene', (190, 193))
36827	24279335	Similar to SW620 cells, AZA197 treatment caused no suppression of Rac1 or RhoA activity in HT-29 cells (Additional file 1: Figure S1B).	('suppression', 'NegReg', (51, 62))	('RhoA', 'Gene', (74, 78))	('HT-29 cells', 'CellLine', 'CVCL:0320', (91, 102))	('AZA197', 'Chemical', 'MESH:C000589260', (24, 30))	('Rac1', 'Gene', '5879', (66, 70))	('SW620', 'CellLine', 'CVCL:0547', (11, 16))	('RhoA', 'Gene', '387', (74, 78))	('AZA197', 'Var', (24, 30))	('Rac1', 'Gene', (66, 70))
36828	24279335	These results indicate that AZA197 specifically and significantly down-regulates Cdc42 activity in the human SW620 and HT-29 colon cancer cell lines with no effects on Rac1 or RhoA GTPase family members.	('RhoA', 'Gene', (176, 180))	('SW620', 'CellLine', 'CVCL:0547', (109, 114))	('activity', 'MPA', (87, 95))	('human', 'Species', '9606', (103, 108))	('Cdc42', 'Gene', '998', (81, 86))	('HT-29 colon cancer', 'Disease', (119, 137))	('RhoA', 'Gene', '387', (176, 180))	('GTP', 'Chemical', 'MESH:D006160', (181, 184))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('down-regulates', 'NegReg', (66, 80))	('Rac1', 'Gene', '5879', (168, 172))	('AZA197', 'Chemical', 'MESH:C000589260', (28, 34))	('Rac1', 'Gene', (168, 172))	('HT-29 colon cancer', 'Disease', 'MESH:D015179', (119, 137))	('AZA197', 'Var', (28, 34))	('colon cancer', 'Phenotype', 'HP:0003003', (125, 137))	('Cdc42', 'Gene', (81, 86))
36829	24279335	Since AZA197 specifically inhibits Cdc42 activity, we hypothesized that AZA197 can act as a Cdc42-GEF interaction-specific small-molecule inhibitor.	('inhibits', 'NegReg', (26, 34))	('Cdc42', 'Gene', (92, 97))	('Cdc42', 'Gene', '998', (92, 97))	('GEF', 'Gene', '9181', (98, 101))	('AZA197', 'Chemical', 'MESH:C000589260', (6, 12))	('Cdc42', 'Gene', (35, 40))	('GEF', 'molecular_function', 'GO:0005085', ('98', '101'))	('AZA197', 'Chemical', 'MESH:C000589260', (72, 78))	('AZA197', 'Var', (6, 12))	('GEF', 'Gene', (98, 101))	('Cdc42', 'Gene', '998', (35, 40))	('AZA197', 'Var', (72, 78))	('activity', 'MPA', (41, 49))
36830	24279335	To determine whether AZA197 is active in inhibiting the GEF-stimulated guanine nucleotide-exchange reaction of Cdc42, an in vitro nucleotide-exchange assay was performed.	('guanine nucleotide', 'Chemical', 'MESH:D006150', (71, 89))	('GEF', 'molecular_function', 'GO:0005085', ('56', '59'))	('Cdc42', 'Gene', (111, 116))	('GEF', 'Gene', (56, 59))	('inhibiting', 'NegReg', (41, 51))	('AZA197', 'Var', (21, 27))	('AZA197', 'Chemical', 'MESH:C000589260', (21, 27))	('GEF', 'Gene', '9181', (56, 59))	('Cdc42', 'Gene', '998', (111, 116))
36833	24279335	Incubation with AZA197 reduced the exchange activity of Dbs domains on Cdc42 by approximately 61% compared to the GEF activity of Dbs on Cdc42 (P = 0.034).	('AZA197', 'Chemical', 'MESH:C000589260', (16, 22))	('GEF', 'Gene', (114, 117))	('Cdc42', 'Gene', '998', (71, 76))	('GEF', 'molecular_function', 'GO:0005085', ('114', '117'))	('Dbs', 'Chemical', 'MESH:C007323', (130, 133))	('AZA197', 'Var', (16, 22))	('exchange activity', 'MPA', (35, 52))	('GEF', 'Gene', '9181', (114, 117))	('Cdc42', 'Gene', '998', (137, 142))	('Cdc42', 'Gene', (71, 76))	('Dbs', 'Chemical', 'MESH:C007323', (56, 59))	('reduced', 'NegReg', (23, 30))	('Cdc42', 'Gene', (137, 142))
36834	24279335	These data indicate that AZA197 is able to block the nucleotide exchange of Cdc42 thereby preventing Cdc42 activation by disrupting the interaction of Cdc42 with GEFs in vitro.	('nucleotide exchange', 'MPA', (53, 72))	('Cdc42', 'Gene', (151, 156))	('preventing', 'NegReg', (90, 100))	('GEF', 'Gene', '9181', (162, 165))	('GEF', 'Gene', (162, 165))	('Cdc42', 'Gene', (101, 106))	('Cdc42', 'Gene', (76, 81))	('activation', 'MPA', (107, 117))	('Cdc42', 'Gene', '998', (76, 81))	('disrupting', 'NegReg', (121, 131))	('Cdc42', 'Gene', '998', (151, 156))	('AZA197', 'Var', (25, 31))	('AZA197', 'Chemical', 'MESH:C000589260', (25, 31))	('block', 'NegReg', (43, 48))	('interaction', 'Interaction', (136, 147))	('Cdc42', 'Gene', '998', (101, 106))
36835	24279335	Activation of Cdc42 stimulates many signaling cascades that alter cellular processes such as proliferation and migration.	('signaling cascades', 'Pathway', (36, 54))	('Cdc42', 'Gene', (14, 19))	('migration', 'CPA', (111, 120))	('stimulates', 'Reg', (20, 30))	('alter', 'Reg', (60, 65))	('proliferation', 'CPA', (93, 106))	('cellular processes', 'CPA', (66, 84))	('Activation', 'Var', (0, 10))	('Cdc42', 'Gene', '998', (14, 19))
36837	24279335	Treatment with AZA197 suppressed SW620 and HT-29 cell proliferation in a dose-dependent manner.	('suppressed', 'NegReg', (22, 32))	('AZA197', 'Chemical', 'MESH:C000589260', (15, 21))	('HT-29', 'CellLine', 'CVCL:0320', (43, 48))	('AZA197', 'Var', (15, 21))	('SW620', 'CellLine', 'CVCL:0547', (33, 38))
36839	24279335	Treatment with AZA197 reduced cell proliferation (reduction in S and G2/M phases, M3) and increased the number of apoptotic cells (sub G0/G1 peak, M1) in a dose-dependent manner (Figure 3B).	('cell proliferation', 'CPA', (30, 48))	('AZA197', 'Chemical', 'MESH:C000589260', (15, 21))	('reduction', 'NegReg', (50, 59))	('increased', 'PosReg', (90, 99))	('AZA197', 'Var', (15, 21))	('reduced', 'NegReg', (22, 29))
36840	24279335	These data indicate that AZA197 reduces colon cancer cell proliferation associated with increased apoptosis.	('colon cancer', 'Phenotype', 'HP:0003003', (40, 52))	('colon cancer', 'Disease', 'MESH:D015179', (40, 52))	('apoptosis', 'CPA', (98, 107))	('colon cancer', 'Disease', (40, 52))	('increased', 'PosReg', (88, 97))	('reduces', 'NegReg', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('AZA197', 'Var', (25, 31))	('AZA197', 'Chemical', 'MESH:C000589260', (25, 31))
36844	24279335	Treatment of cells with 2 or 5 muM AZA197 significantly reduced cancer cell migration by 47.4 +- 8.8% (P < 0.05) and 43.5 +- 17% (P < 0.05), respectively, compared to untreated controls (Figure 4A).	('muM', 'Gene', '56925', (31, 34))	('reduced', 'NegReg', (56, 63))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('muM', 'Gene', (31, 34))	('cell migration', 'biological_process', 'GO:0016477', ('71', '85'))	('AZA197', 'Var', (35, 41))	('AZA197', 'Chemical', 'MESH:C000589260', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
36845	24279335	Similarly, AZA197 significantly reduced cancer cell migration in a dose-dependent manner up to 77.1% (P < 0.024) in HT-29 colon cancer cells (Additional file 3: Figure S3A).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('HT-29 colon cancer', 'Disease', (116, 134))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('colon cancer', 'Phenotype', 'HP:0003003', (122, 134))	('reduced', 'NegReg', (32, 39))	('HT-29 colon cancer', 'Disease', 'MESH:D015179', (116, 134))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('AZA197', 'Var', (11, 17))	('AZA197', 'Chemical', 'MESH:C000589260', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', (128, 134))
36846	24279335	These results indicate a role for AZA197 in blocking Cdc42-dependent migration of SW620 colon cancer cells.	('SW620 colon cancer', 'Disease', (82, 100))	('SW620 colon cancer', 'Disease', 'MESH:D015179', (82, 100))	('Cdc42', 'Gene', '998', (53, 58))	('colon cancer', 'Phenotype', 'HP:0003003', (88, 100))	('AZA197', 'Chemical', 'MESH:C000589260', (34, 40))	('Cdc42', 'Gene', (53, 58))	('AZA197', 'Var', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('blocking', 'NegReg', (44, 52))
36848	24279335	As shown in Figure 4B, treatment of SW620 cells with 1, 2 and 5 muM compound AZA197 for 24 h significantly decreased SW620 invasion by 61.3 +- 18%, 71.0 +- 16.6% and 83.9 +- 12.4% (P < 0.003), respectively, compared to untreated controls.	('SW620 invasion', 'CPA', (117, 131))	('muM', 'Gene', (64, 67))	('SW620', 'CellLine', 'CVCL:0547', (36, 41))	('AZA197', 'Var', (77, 83))	('AZA197', 'Chemical', 'MESH:C000589260', (77, 83))	('decreased', 'NegReg', (107, 116))	('SW620', 'CellLine', 'CVCL:0547', (117, 122))	('muM', 'Gene', '56925', (64, 67))
36849	24279335	Similarily, AZA197 also significantly decreased invasion of HT-29 cells at corresponding concentrations up to 84.6% (P < 0.005) compared to controls (Additional file 3: Figure S3B).	('decreased', 'NegReg', (38, 47))	('AZA197', 'Var', (12, 18))	('AZA197', 'Chemical', 'MESH:C000589260', (12, 18))	('HT-29 cells', 'CellLine', 'CVCL:0320', (60, 71))	('invasion of HT-29 cells', 'CPA', (48, 71))
36850	24279335	Together, these results suggest that AZA197 is highly effective in preventing SW620 and HT-29 colon cancer cell migration and invasion in a dose-dependent manner.	('AZA197', 'Var', (37, 43))	('AZA197', 'Chemical', 'MESH:C000589260', (37, 43))	('HT-29 colon cancer', 'Disease', 'MESH:D015179', (88, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('preventing', 'NegReg', (67, 77))	('SW620', 'Disease', (78, 83))	('invasion', 'CPA', (126, 134))	('cell migration', 'biological_process', 'GO:0016477', ('107', '121'))	('HT-29 colon cancer', 'Disease', (88, 106))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))	('SW620', 'CellLine', 'CVCL:0547', (78, 83))
36854	24279335	Treatment with AZA197 at 2, 5 and 10 muM caused cells to become rounded and filopodia formation was dramatically diminished after 24 h (Figure 4C).	('filopodia formation', 'biological_process', 'GO:0046847', ('76', '95'))	('AZA197', 'Chemical', 'MESH:C000589260', (15, 21))	('filopodia formation', 'CPA', (76, 95))	('AZA197', 'Var', (15, 21))	('diminished', 'NegReg', (113, 123))	('muM', 'Gene', '56925', (37, 40))	('muM', 'Gene', (37, 40))
36855	24279335	HT-29 cells displayed spreading morphology and a normal filamentous actin distribution in the surface protrusions but cells treated with 2, 5 and 10 muM AZA197 exhibited diminished cell spreading, a rounded cell morphology with no surface protrusions and formation of submembranous cortical actin (Additional file 3: Figure S3C).	('diminished', 'NegReg', (170, 180))	('AZA197', 'Var', (153, 159))	('muM', 'Gene', '56925', (149, 152))	('rounded cell morphology', 'CPA', (199, 222))	('filamentous actin distribution', 'MPA', (56, 86))	('cell spreading', 'CPA', (181, 195))	('muM', 'Gene', (149, 152))	('HT-29 cells', 'CellLine', 'CVCL:0320', (0, 11))	('AZA197', 'Chemical', 'MESH:C000589260', (153, 159))
36856	24279335	These results suggest that treatment of colon cancer cells with AZA197 results in an alteration of the actin cytoskeleton and cell morphology in colon cancer cells and reduces filopodia formation in SW620 cells.	('colon cancer', 'Disease', 'MESH:D015179', (145, 157))	('colon cancer', 'Phenotype', 'HP:0003003', (40, 52))	('colon cancer', 'Disease', 'MESH:D015179', (40, 52))	('filopodia formation', 'biological_process', 'GO:0046847', ('176', '195'))	('colon cancer', 'Disease', (145, 157))	('reduces', 'NegReg', (168, 175))	('filopodia formation', 'CPA', (176, 195))	('SW620', 'CellLine', 'CVCL:0547', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('AZA197', 'Chemical', 'MESH:C000589260', (64, 70))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('103', '121'))	('cell morphology', 'CPA', (126, 141))	('colon cancer', 'Disease', (40, 52))	('AZA197', 'Var', (64, 70))	('actin cytoskeleton', 'MPA', (103, 121))	('alteration', 'Reg', (85, 95))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('colon cancer', 'Phenotype', 'HP:0003003', (145, 157))
36857	24279335	To analyze whether AZA197 affects Cdc42 protein expression, we measured Cdc42 protein levels by Western blot analysis.	('AZA197', 'Var', (19, 25))	('Cdc42', 'Gene', (72, 77))	('AZA197', 'Chemical', 'MESH:C000589260', (19, 25))	('Cdc42', 'Gene', '998', (34, 39))	('Cdc42', 'Gene', '998', (72, 77))	('Cdc42', 'Gene', (34, 39))
36858	24279335	In both SW620 (Figure 5A) and HT-29 (Additional file 4: Figure S4A), Cdc42 protein levels were not affected by treatment with different concentrations of AZA197 suggesting that AZA197 does not affect levels of Cdc42 protein expression.	('AZA197', 'Chemical', 'MESH:C000589260', (177, 183))	('Cdc42', 'Gene', (69, 74))	('Cdc42', 'Gene', (210, 215))	('HT-29', 'CellLine', 'CVCL:0320', (30, 35))	('AZA197', 'Var', (154, 160))	('AZA197', 'Chemical', 'MESH:C000589260', (154, 160))	('Cdc42', 'Gene', '998', (69, 74))	('Cdc42', 'Gene', '998', (210, 215))	('SW620', 'CellLine', 'CVCL:0547', (8, 13))
36861	24279335	Although no reduction in PAK expression was seen (Figure 5B, left panel), PAK1/2 phosphorylation at serine 144/141, which maintains the kinase activity of PAKs, was dose-dependently significantly reduced by 47.7 +- 6.5% (2 muM), 57.2 +- 17.3% (5 muM) and 66.2 +- 15.3% (10 muM) (P < 0.01) after treatment with 2, 5 and 10 muM AZA197 for 24 h in SW620 cells compared to untreated cells (Figure 5B), respectively.	('muM', 'Gene', (322, 325))	('muM', 'Gene', (273, 276))	('phosphorylation', 'MPA', (81, 96))	('muM', 'Gene', '56925', (223, 226))	('PAK1/2', 'Gene', '5058;5062', (74, 80))	('muM', 'Gene', '56925', (273, 276))	('muM', 'Gene', '56925', (246, 249))	('AZA197', 'Var', (326, 332))	('muM', 'Gene', (223, 226))	('kinase activity', 'MPA', (136, 151))	('AZA197', 'Chemical', 'MESH:C000589260', (326, 332))	('PAK1/2', 'Gene', (74, 80))	('SW620', 'CellLine', 'CVCL:0547', (345, 350))	('muM', 'Gene', (246, 249))	('muM', 'Gene', '56925', (322, 325))	('reduced', 'NegReg', (196, 203))
36863	24279335	These findings suggest that AZA197 mediated Cdc42 inhibition is associated with reduced PAK1/2 phosphorylation.	('PAK1/2', 'Gene', '5058;5062', (88, 94))	('Cdc42', 'Gene', '998', (44, 49))	('inhibition', 'NegReg', (50, 60))	('reduced', 'NegReg', (80, 87))	('PAK1/2', 'Gene', (88, 94))	('AZA197', 'Chemical', 'MESH:C000589260', (28, 34))	('phosphorylation', 'biological_process', 'GO:0016310', ('95', '110'))	('Cdc42', 'Gene', (44, 49))	('AZA197', 'Var', (28, 34))
36864	24279335	To identify further downstream Cdc42 effectors affected by AZA197 treatment, we analyzed MAPK activity using phospho-specific antibodies.	('AZA197', 'Chemical', 'MESH:C000589260', (59, 65))	('Cdc42', 'Gene', (31, 36))	('AZA197', 'Var', (59, 65))	('Cdc42', 'Gene', '998', (31, 36))
36865	24279335	ERK activity is decreased by PAK1 deactivation leading to decreased cell proliferation, migration/invasion and survival in colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('colon cancer', 'Phenotype', 'HP:0003003', (123, 135))	('cell proliferation', 'CPA', (68, 86))	('migration/invasion', 'CPA', (88, 106))	('decreased', 'NegReg', (58, 67))	('colon cancer', 'Disease', 'MESH:D015179', (123, 135))	('deactivation', 'Var', (34, 46))	('survival', 'CPA', (111, 119))	('ERK', 'Gene', '5594', (0, 3))	('ERK', 'Gene', (0, 3))	('colon cancer', 'Disease', (123, 135))	('activity', 'MPA', (4, 12))	('PAK1', 'Gene', '5058', (29, 33))	('decreased', 'NegReg', (16, 25))	('PAK1', 'Gene', (29, 33))
36866	24279335	Our data show that Cdc42 inhibition by AZA197 for 24 h led to a significant dose-dependent inhibition of phospho-ERK levels by 16.1 +- 4.6% (2 muM), 36.7 +- 12% (5 muM) and 40.2 +- 9.1% (10 muM) (P < 0.05) in SW620 cells, whereas total ERK protein levels were not affected by AZA197 treatment (Figure 5C).	('Cdc42', 'Gene', '998', (19, 24))	('muM', 'Gene', '56925', (143, 146))	('AZA197', 'Var', (39, 45))	('AZA197', 'Chemical', 'MESH:C000589260', (39, 45))	('AZA197', 'Chemical', 'MESH:C000589260', (276, 282))	('muM', 'Gene', (143, 146))	('ERK', 'Gene', '5594', (236, 239))	('muM', 'Gene', (164, 167))	('ERK', 'Gene', (236, 239))	('SW620', 'CellLine', 'CVCL:0547', (209, 214))	('ERK', 'Gene', '5594', (113, 116))	('Cdc42', 'Gene', (19, 24))	('ERK', 'Gene', (113, 116))	('inhibition', 'NegReg', (91, 101))	('muM', 'Gene', '56925', (164, 167))	('muM', 'Gene', '56925', (190, 193))	('inhibition', 'NegReg', (25, 35))	('muM', 'Gene', (190, 193))
36871	24279335	In SW620 colon cancer cells treated with 2, 5, and 10 muM AZA197 for 24 h, Cyclin D1 protein expression decreased significantly by 16.8 +- 2.2% (2 muM), 18.6 +- 4.5% (5 muM) and 37.1 +- 14.1% (10 muM) (P < 0.05) compared to untreated controls as shown in Figure 5D.	('SW620 colon cancer', 'Disease', (3, 21))	('muM', 'Gene', (147, 150))	('muM', 'Gene', '56925', (169, 172))	('muM', 'Gene', (169, 172))	('colon cancer', 'Phenotype', 'HP:0003003', (9, 21))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))	('decreased', 'NegReg', (104, 113))	('Cyclin', 'molecular_function', 'GO:0016538', ('75', '81'))	('SW620 colon cancer', 'Disease', 'MESH:D015179', (3, 21))	('AZA197', 'Chemical', 'MESH:C000589260', (58, 64))	('AZA197', 'Var', (58, 64))	('muM', 'Gene', '56925', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('muM', 'Gene', (54, 57))	('muM', 'Gene', '56925', (196, 199))	('Cyclin D1', 'Gene', '595', (75, 84))	('muM', 'Gene', (196, 199))	('Cyclin D1', 'Gene', (75, 84))	('muM', 'Gene', '56925', (147, 150))
36874	24279335	To analyze whether treatment with AZA197 can modulate tumor growth in vivo, we treated mice bearing human SW620 colon cancer xenografts with AZA197 or vehicle as controls.	('colon cancer', 'Phenotype', 'HP:0003003', (112, 124))	('AZA197', 'Chemical', 'MESH:C000589260', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mice', 'Species', '10090', (87, 91))	('human', 'Species', '9606', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('AZA197', 'Chemical', 'MESH:C000589260', (141, 147))	('SW620 colon cancer', 'Disease', (106, 124))	('tumor', 'Disease', (54, 59))	('AZA197', 'Var', (141, 147))	('modulate', 'Reg', (45, 53))	('SW620 colon cancer', 'Disease', 'MESH:D015179', (106, 124))
36877	24279335	On day 22, the mean tumor weight was significantly (P = 0.006) reduced in mice treated with AZA197 (676.7 +- 106 mg) compared to control mice (968 +- 208 mg) and treatment was well tolerated (Figure 6A).	('AZA197', 'Chemical', 'MESH:C000589260', (92, 98))	('reduced', 'NegReg', (63, 70))	('AZA197', 'Var', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mice', 'Species', '10090', (74, 78))	('mice', 'Species', '10090', (137, 141))	('tumor', 'Disease', (20, 25))
36879	24279335	In accordance with the tumor weight reduction findings, treatment with AZA197 decreased the number of Ki-67-positive cells in tumors based on counting 20 randomly selected microscopic fields by 27.4 +- 14.2% (P = 0.046) in AZA197-treated tumors, suggesting an anti-proliferative effect for AZA197 (Figure 6B).	('AZA197', 'Chemical', 'MESH:C000589260', (71, 77))	('AZA197-treated tumors', 'Disease', (223, 244))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('AZA197', 'Var', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('Ki-67', 'Gene', '17345', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Disease', (238, 244))	('tumors', 'Disease', (126, 132))	('AZA197-treated tumors', 'Disease', 'MESH:D019553', (223, 244))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('decreased', 'NegReg', (78, 87))	('Ki-67', 'Gene', (102, 107))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('AZA197', 'Chemical', 'MESH:C000589260', (290, 296))	('tumor', 'Disease', (238, 243))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('AZA197', 'Chemical', 'MESH:C000589260', (223, 229))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))
36882	24279335	Western blotting of isolated tumor tissue indicated that AZA197 treatment does not change Cdc42 and total PAK and ERK expression.	('PAK', 'Protein', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('ERK', 'Gene', (114, 117))	('AZA197', 'Var', (57, 63))	('AZA197', 'Chemical', 'MESH:C000589260', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('Cdc42', 'Gene', (90, 95))	('ERK', 'molecular_function', 'GO:0004707', ('114', '117'))	('tumor', 'Disease', (29, 34))	('expression', 'MPA', (118, 128))	('ERK', 'Gene', '5594', (114, 117))	('Cdc42', 'Gene', '998', (90, 95))
36883	24279335	Phospho-PAK1 expression in tumors treated with AZA197 was significantly reduced by 48.5 +- 11.4% (P = 0.027) compared to untreated controls (Figure 6D).	('PAK1', 'Gene', '5058', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('reduced', 'NegReg', (72, 79))	('PAK1', 'Gene', (8, 12))	('expression', 'MPA', (13, 23))	('AZA197', 'Var', (47, 53))	('AZA197', 'Chemical', 'MESH:C000589260', (47, 53))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))
36884	24279335	Similarly, in tumors treated with AZA197, phospho-ERK levels decreased significantly by 59.2 +- 17.1% (P = 0.003) compared to untreated controls (Figure 6D).	('ERK', 'Gene', '5594', (50, 53))	('AZA197', 'Chemical', 'MESH:C000589260', (34, 40))	('ERK', 'Gene', (50, 53))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('AZA197', 'Var', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('decreased', 'NegReg', (61, 70))	('ERK', 'molecular_function', 'GO:0004707', ('50', '53'))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
36885	24279335	These data show that the PAK-ERK signaling pathway is a downstream target of the small molecule inhibitor AZA197 in SW620 colon cancer tissue confirming our findings in vitro.	('SW620 colon cancer', 'Disease', 'MESH:D015179', (116, 134))	('ERK', 'Gene', '5594', (29, 32))	('colon cancer', 'Phenotype', 'HP:0003003', (122, 134))	('signaling pathway', 'biological_process', 'GO:0007165', ('33', '50'))	('ERK', 'Gene', (29, 32))	('AZA197', 'Var', (106, 112))	('AZA197', 'Chemical', 'MESH:C000589260', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ERK', 'molecular_function', 'GO:0004707', ('29', '32'))	('SW620 colon cancer', 'Disease', (116, 134))
36887	24279335	However, survival was significantly increased in mice following AZA197 treatment compared to control mice (P = 0.042) and the median time to death was 69 days.	('AZA197', 'Chemical', 'MESH:C000589260', (64, 70))	('mice', 'Species', '10090', (49, 53))	('AZA197', 'Var', (64, 70))	('increased', 'PosReg', (36, 45))	('mice', 'Species', '10090', (101, 105))	('survival', 'CPA', (9, 17))
36889	24279335	Control mice that died on days 45, 57 and 58 had tumor weights of 3455, 4582 and 4810 mg, respectively, whereas mice in the AZA197 treatment group at comparable time points at days 47 and 64 had tumors of 2897 and 3768 mg, respectively, showing that AZA197 treatment results in decreased tumor weight even after the end of treatment on day 22.	('tumor', 'Disease', (195, 200))	('decreased tumor', 'Disease', (278, 293))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('AZA197', 'Chemical', 'MESH:C000589260', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (288, 293))	('tumors', 'Disease', (195, 201))	('AZA197', 'Chemical', 'MESH:C000589260', (250, 256))	('AZA197', 'Var', (250, 256))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('decreased tumor', 'Disease', 'MESH:D009369', (278, 293))	('mice', 'Species', '10090', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('mice', 'Species', '10090', (8, 12))
36890	24279335	Together, these data indicate that AZA197 slows primary tumor growth of human SW620 colon cancer xenografts in mice and improves animal survival.	('slows', 'NegReg', (42, 47))	('colon cancer', 'Phenotype', 'HP:0003003', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('SW620 colon cancer', 'Disease', 'MESH:D015179', (78, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('human', 'Species', '9606', (72, 77))	('improves', 'PosReg', (120, 128))	('mice', 'Species', '10090', (111, 115))	('AZA197', 'Var', (35, 41))	('AZA197', 'Chemical', 'MESH:C000589260', (35, 41))	('SW620 colon cancer', 'Disease', (78, 96))	('animal survival', 'CPA', (129, 144))
36893	24279335	In advanced colorectal cancer patients with mutated KRAS, for example, targeted therapies have provided no benefit showing a clear need to establish new therapeutic strategies.	('colorectal cancer', 'Disease', (12, 29))	('KRAS', 'Gene', (52, 56))	('mutated', 'Var', (44, 51))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('patients', 'Species', '9606', (30, 38))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
36898	24279335	Based on these findings, we hypothesized that inhibition of Cdc42 might be effective for the treatment of colorectal cancer.	('inhibition', 'Var', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('colorectal cancer', 'Disease', (106, 123))	('Cdc42', 'Gene', '998', (60, 65))	('colorectal cancer', 'Disease', 'MESH:D015179', (106, 123))	('Cdc42', 'Gene', (60, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))
36899	24279335	We therefore designed the small molecule Cdc42 inhibitor AZA197 and show that inhibition of Cdc42 activity with AZA197 acts to reduce tumor growth and significantly improve animal survival in SW620 cells which are a model of KRAS mutant colon cancer xenografts.	('reduce', 'NegReg', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('colon cancer', 'Disease', (237, 249))	('Cdc42', 'Gene', '998', (92, 97))	('improve', 'PosReg', (165, 172))	('SW620', 'CellLine', 'CVCL:0547', (192, 197))	('inhibition', 'NegReg', (78, 88))	('animal survival', 'CPA', (173, 188))	('activity', 'MPA', (98, 106))	('Cdc42', 'Gene', (41, 46))	('colon cancer', 'Phenotype', 'HP:0003003', (237, 249))	('tumor', 'Disease', (134, 139))	('AZA197', 'Chemical', 'MESH:C000589260', (112, 118))	('AZA197', 'Chemical', 'MESH:C000589260', (57, 63))	('AZA197', 'Var', (112, 118))	('Cdc42', 'Gene', '998', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('colon cancer', 'Disease', 'MESH:D015179', (237, 249))	('Cdc42', 'Gene', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
36900	24279335	Assays in vivo and in vitro suggest that inhibition of cell proliferation and induction of apoptosis were the main mechanisms by which AZA197 exerts antitumor effects.	('AZA197', 'Var', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('apoptosis', 'CPA', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('cell proliferation', 'CPA', (55, 73))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('78', '100'))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('41', '73'))	('AZA197', 'Chemical', 'MESH:C000589260', (135, 141))	('inhibition', 'NegReg', (41, 51))
36903	24279335	The Rac-inhibitor NSC23766 inhibits Rac activation by blocking only some of the GEFs that activate Rac1, highlighting the complexity of cellular pathways regulating the activation status of RhoGTPases.	('inhibits', 'NegReg', (27, 35))	('NSC23766', 'Var', (18, 26))	('Rac1', 'Gene', '5879', (99, 103))	('GEF', 'Gene', (80, 83))	('Rac1', 'Gene', (99, 103))	('GTP', 'Chemical', 'MESH:D006160', (193, 196))	('blocking', 'NegReg', (54, 62))	('GEF', 'Gene', '9181', (80, 83))
36905	24279335	Thus it is possible, that compound screening of modifications of a known inhibitor, such as with the Rac1-GEF inhibitor NSC23766 presented here, can result in the identification of an inhibitor that could affect the activation status of another RhoGTPase which was not predicted by mechanistic in silico analysis of binding to the RhoGTPase structure.	('modifications', 'Var', (48, 61))	('GEF', 'molecular_function', 'GO:0005085', ('106', '109'))	('result in', 'Reg', (149, 158))	('GEF', 'Gene', '9181', (106, 109))	('affect', 'Reg', (205, 211))	('GTP', 'Chemical', 'MESH:D006160', (334, 337))	('GTP', 'Chemical', 'MESH:D006160', (248, 251))	('RhoGTPase', 'Enzyme', (245, 254))	('GEF', 'Gene', (106, 109))	('binding', 'molecular_function', 'GO:0005488', ('316', '323'))	('Rac1', 'Gene', (101, 105))	('Rac1', 'Gene', '5879', (101, 105))	('activation status', 'MPA', (216, 233))
36907	24279335	In this context, it is important to mention that, although our data indicate that AZA197 inhibits Cdc42-GEF interaction in vitro, analysis of the crystal structure of Cdc42 bound to AZA197 would be necessary to confirm interaction with the region where GEFs associate with Cdc42.	('Cdc42', 'Gene', '998', (98, 103))	('GEF', 'Gene', '9181', (253, 256))	('GEF', 'Gene', (104, 107))	('inhibits', 'NegReg', (89, 97))	('Cdc42', 'Gene', '998', (167, 172))	('Cdc42', 'Gene', '998', (273, 278))	('AZA197', 'Chemical', 'MESH:C000589260', (82, 88))	('AZA197', 'Var', (182, 188))	('AZA197', 'Var', (82, 88))	('AZA197', 'Chemical', 'MESH:C000589260', (182, 188))	('GEF', 'Gene', '9181', (104, 107))	('Cdc42', 'Gene', (167, 172))	('Cdc42', 'Gene', (273, 278))	('Cdc42', 'Gene', (98, 103))	('GEF', 'Gene', (253, 256))	('GEF', 'molecular_function', 'GO:0005085', ('104', '107'))
36909	24279335	To analyze AZA197 specificity for Cdc42 inhibition, we tested the effects of AZA197 on inhibition of the Rho GTPase family members Rac and Rho, which also play a role in colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (170, 182))	('colon cancer', 'Disease', 'MESH:D015179', (170, 182))	('AZA197', 'Var', (77, 83))	('AZA197', 'Chemical', 'MESH:C000589260', (77, 83))	('colon cancer', 'Disease', (170, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Cdc42', 'Gene', '998', (34, 39))	('GTP', 'Chemical', 'MESH:D006160', (109, 112))	('AZA197', 'Chemical', 'MESH:C000589260', (11, 17))	('tested', 'Reg', (55, 61))	('Cdc42', 'Gene', (34, 39))
36912	24279335	Our data show that AZA197 does not inhibit Rac activity in SW620 colon cancers.	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('colon cancers', 'Phenotype', 'HP:0003003', (65, 78))	('colon cancers', 'Disease', 'MESH:D015179', (65, 78))	('AZA197', 'Var', (19, 25))	('AZA197', 'Chemical', 'MESH:C000589260', (19, 25))	('SW620 colon cancer', 'Disease', (59, 77))	('SW620 colon cancer', 'Disease', 'MESH:D015179', (59, 77))	('colon cancer', 'Phenotype', 'HP:0003003', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('colon cancers', 'Disease', (65, 78))	('Rac activity', 'MPA', (43, 55))
36913	24279335	Thus, inhibition of Cdc42-activity alone without affecting Rac-activity could lead to a potent suppression of colon cancer growth and increased survival rates.	('colon cancer', 'Disease', (110, 122))	('Cdc42', 'Gene', '998', (20, 25))	('suppression', 'NegReg', (95, 106))	('survival rates', 'CPA', (144, 158))	('inhibition', 'Var', (6, 16))	('colon cancer', 'Disease', 'MESH:D015179', (110, 122))	('colon cancer', 'Phenotype', 'HP:0003003', (110, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('increased', 'PosReg', (134, 143))	('Cdc42', 'Gene', (20, 25))
36923	24279335	Furthermore, expression of constitutively active Cdc42 significantly increased filopodia formation and cell spread in colorectal cancer cells, which is in line with our findings.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('increased', 'PosReg', (69, 78))	('cell spread', 'CPA', (103, 114))	('Cdc42', 'Gene', (49, 54))	('filopodia formation', 'CPA', (79, 98))	('colorectal cancer', 'Disease', 'MESH:D015179', (118, 135))	('expression', 'Var', (13, 23))	('colorectal cancer', 'Phenotype', 'HP:0003003', (118, 135))	('Cdc42', 'Gene', '998', (49, 54))	('colorectal cancer', 'Disease', (118, 135))
36925	24279335	However, activation of Cdc42 can induce cell adhesion and it has been recently shown that activated Cdc42 increases SW480 colorectal cancer cell adhesion, migration and invasion.	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('migration', 'CPA', (155, 164))	('SW480', 'Gene', (116, 121))	('SW480', 'CellLine', 'CVCL:0546', (116, 121))	('Cdc42', 'Gene', '998', (23, 28))	('invasion', 'CPA', (169, 177))	('Cdc42', 'Gene', (100, 105))	('colorectal cancer', 'Disease', (122, 139))	('activated', 'Var', (90, 99))	('Cdc42', 'Gene', (23, 28))	('colorectal cancer', 'Disease', 'MESH:D015179', (122, 139))	('Cdc42', 'Gene', '998', (100, 105))	('increases', 'PosReg', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cell adhesion', 'CPA', (40, 53))
36926	24279335	It is therefore possible that AZA197 inhibition of Cdc42 also affects cell adhesion in addition to impairment of colon cancer cell proliferation, migration and invasion.	('migration', 'CPA', (146, 155))	('colon cancer', 'Phenotype', 'HP:0003003', (113, 125))	('impairment of colon cancer', 'Disease', (99, 125))	('Cdc42', 'Gene', (51, 56))	('invasion', 'CPA', (160, 168))	('cell adhesion', 'biological_process', 'GO:0007155', ('70', '83'))	('AZA197', 'Chemical', 'MESH:C000589260', (30, 36))	('cell adhesion', 'CPA', (70, 83))	('impairment of colon cancer', 'Disease', 'MESH:D015179', (99, 125))	('cell proliferation', 'biological_process', 'GO:0008283', ('126', '144'))	('affects', 'Reg', (62, 69))	('Cdc42', 'Gene', '998', (51, 56))	('AZA197 inhibition', 'Var', (30, 47))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
36930	24279335	PAK1 knockdown decreased proliferation and delayed the G1/S cell-cycle transition and increased apoptosis in vivo and in vitro.	('G1/S cell-cycle transition', 'CPA', (55, 81))	('delayed', 'NegReg', (43, 50))	('increased', 'PosReg', (86, 95))	('proliferation', 'CPA', (25, 38))	('knockdown', 'Var', (5, 14))	('PAK1', 'Gene', '5058', (0, 4))	('PAK1', 'Gene', (0, 4))	('cell-cycle transition', 'biological_process', 'GO:0044770', ('60', '81'))	('apoptosis', 'CPA', (96, 105))	('decreased', 'NegReg', (15, 24))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('cell-cycle transition', 'biological_process', 'GO:0044771', ('60', '81'))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
36932	24279335	Additionally, Cdc42 inhibition by AZA197 resulted in increased apoptosis in vivo and in vitro.	('Cdc42', 'Gene', (14, 19))	('AZA197', 'Chemical', 'MESH:C000589260', (34, 40))	('AZA197', 'Var', (34, 40))	('inhibition', 'NegReg', (20, 30))	('apoptosis', 'CPA', (63, 72))	('Cdc42', 'Gene', '998', (14, 19))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))
36936	24279335	Consequently, the observed down-regulation of the Cdc42-PAK1 signaling pathway could therefore constitute the major effector pathway of AZA197 in colon cancer.	('colon cancer', 'Disease', (146, 158))	('Cdc42', 'Gene', '998', (50, 55))	('AZA197', 'Chemical', 'MESH:C000589260', (136, 142))	('AZA197', 'Var', (136, 142))	('PAK1', 'Gene', '5058', (56, 60))	('Cdc42', 'Gene', (50, 55))	('down-regulation', 'NegReg', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('colon cancer', 'Phenotype', 'HP:0003003', (146, 158))	('colon cancer', 'Disease', 'MESH:D015179', (146, 158))	('PAK1', 'Gene', (56, 60))
36937	24279335	However, there are some limitations to the interpretation of the potential effects of AZA197 on cell proliferation and cancer cell migration and invasion in this study.	('AZA197', 'Var', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cell proliferation', 'CPA', (96, 114))	('cancer', 'Disease', (119, 125))	('cell migration', 'biological_process', 'GO:0016477', ('126', '140'))	('AZA197', 'Chemical', 'MESH:C000589260', (86, 92))	('cell proliferation', 'biological_process', 'GO:0008283', ('96', '114'))	('invasion', 'CPA', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
36938	24279335	Our data in SW620 cells suggest that AZA197 may impact cancer cell viability at concentrations that inhibit Cdc42, cell proliferation and actin cytoskeletal changes in SW620 cells.	('SW620', 'CellLine', 'CVCL:0547', (12, 17))	('AZA197', 'Var', (37, 43))	('AZA197', 'Chemical', 'MESH:C000589260', (37, 43))	('Cdc42', 'Gene', (108, 113))	('actin cytoskeletal changes', 'CPA', (138, 164))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('SW620', 'CellLine', 'CVCL:0547', (168, 173))	('cell proliferation', 'CPA', (115, 133))	('impact', 'Reg', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('Cdc42', 'Gene', '998', (108, 113))	('inhibit', 'NegReg', (100, 107))	('cancer', 'Disease', (55, 61))
36940	24279335	In contrast, in HT-29 cancer cells, viability and proliferation were not affected by AZA197 at concentrations that significantly inhibit Cdc42 activity as well as cancer cell migration and invasion.	('HT-29 cancer', 'Disease', (16, 28))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('AZA197', 'Chemical', 'MESH:C000589260', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('inhibit', 'NegReg', (129, 136))	('cancer', 'Disease', (22, 28))	('AZA197', 'Var', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Cdc42', 'Gene', '998', (137, 142))	('invasion', 'CPA', (189, 197))	('HT-29 cancer', 'Disease', 'OMIM:614890', (16, 28))	('cell migration', 'biological_process', 'GO:0016477', ('170', '184'))	('activity', 'MPA', (143, 151))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('Cdc42', 'Gene', (137, 142))
36943	24279335	Importantly, our data also demonstrate that AZA197 does not affect the viability of fibroblasts at effective concentrations indicating AZA197 to be a viable, anti-cancer therapeutic agent with only minor toxicity to normal cells.	('AZA197', 'Var', (135, 141))	('AZA197', 'Chemical', 'MESH:C000589260', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('toxicity', 'Disease', 'MESH:D064420', (204, 212))	('toxicity', 'Disease', (204, 212))	('AZA197', 'Chemical', 'MESH:C000589260', (135, 141))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
36945	24279335	It may therefore be expected that use of AZA197 as an anti-cancer therapeutic in colon cancer would result in a varying response to the compound depending on the specific genetics of the cancer cells.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('colon cancer', 'Phenotype', 'HP:0003003', (81, 93))	('cancer', 'Disease', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('colon cancer', 'Disease', 'MESH:D015179', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('colon cancer', 'Disease', (81, 93))	('result', 'Reg', (100, 106))	('AZA197', 'Var', (41, 47))	('response', 'MPA', (120, 128))	('AZA197', 'Chemical', 'MESH:C000589260', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
36947	24279335	We provide evidence that Cdc42 inhibition by AZA197 treatment suppresses proliferative and pro-survival signaling pathways via PAK1-ERK signaling and reduces colon cancer cell migration and invasion.	('ERK', 'Gene', (132, 135))	('colon cancer', 'Disease', (158, 170))	('inhibition', 'NegReg', (31, 41))	('signaling', 'biological_process', 'GO:0023052', ('104', '113'))	('PAK1', 'Gene', (127, 131))	('AZA197', 'Var', (45, 51))	('AZA197', 'Chemical', 'MESH:C000589260', (45, 51))	('reduces', 'NegReg', (150, 157))	('ERK', 'molecular_function', 'GO:0004707', ('132', '135'))	('Cdc42', 'Gene', (25, 30))	('PAK1', 'Gene', '5058', (127, 131))	('colon cancer', 'Phenotype', 'HP:0003003', (158, 170))	('suppresses', 'NegReg', (62, 72))	('ERK', 'Gene', '5594', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('pro-survival', 'biological_process', 'GO:0043066', ('91', '103'))	('colon cancer', 'Disease', 'MESH:D015179', (158, 170))	('Cdc42', 'Gene', '998', (25, 30))	('cell migration', 'biological_process', 'GO:0016477', ('171', '185'))	('signaling', 'biological_process', 'GO:0023052', ('136', '145'))
36948	24279335	Furthermore, we show that systemic AZA197 treatment in vivo reduces primary tumor growth and prolongs survival in KRAS mutant colon cancer xenograft-bearing mice.	('prolongs', 'PosReg', (93, 101))	('mice', 'Species', '10090', (157, 161))	('survival', 'CPA', (102, 110))	('colon cancer', 'Disease', (126, 138))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('KRAS', 'Gene', (114, 118))	('colon cancer', 'Disease', 'MESH:D015179', (126, 138))	('colon cancer', 'Phenotype', 'HP:0003003', (126, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('reduces', 'NegReg', (60, 67))	('AZA197', 'Var', (35, 41))	('AZA197', 'Chemical', 'MESH:C000589260', (35, 41))	('mutant', 'Var', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
36949	24279335	We propose that therapy targeting Rho GTPase Cdc42 signaling pathways may be effective for treatment of patients with advanced colon cancer overexpressing Cdc42 and particularly those with KRAS-mutant disease.	('KRAS-mutant', 'Var', (189, 200))	('Cdc42', 'Gene', (45, 50))	('Cdc42', 'Gene', (155, 160))	('colon cancer', 'Phenotype', 'HP:0003003', (127, 139))	('colon cancer', 'Disease', 'MESH:D015179', (127, 139))	('GTP', 'Chemical', 'MESH:D006160', (38, 41))	('colon cancer', 'Disease', (127, 139))	('overexpressing', 'PosReg', (140, 154))	('Cdc42', 'Gene', '998', (45, 50))	('Cdc42', 'Gene', '998', (155, 160))	('patients', 'Species', '9606', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
37032	24292449	Initially, MMPs have been considered to elicit mainly pro-tumorigenic effects by degrading the extracellular matrix, hence facilitating tumour cell migration and invasion.	('extracellular matrix', 'CPA', (95, 115))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('MMPs', 'Var', (11, 15))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('tumour', 'Disease', (136, 142))	('facilitating', 'PosReg', (123, 135))	('degrading', 'NegReg', (81, 90))	('invasion', 'CPA', (162, 170))
37038	24292449	Moreover, we have identified high expression of stroma-derived angiopoietin-2 as an independent adverse prognostic marker in colorectal lung metastases by univariate and multivariate analyses.	('high', 'Var', (29, 33))	('colorectal lung metastases', 'Disease', (125, 151))	('angiopoietin-2', 'Gene', '285', (63, 77))	('angiopoietin-2', 'Gene', (63, 77))	('colorectal lung metastases', 'Disease', 'MESH:D009362', (125, 151))
37050	33048473	MTA was shown to strongly down-regulate CDC25A and CCNE2, and their inhibitors prompted dome formation independently of MTA, suggesting that MTA may induce dome formation through dysfunction of these G1 regulators.	('down-regulate', 'NegReg', (26, 39))	('dysfunction', 'Var', (179, 190))	('CDC25', 'Gene', (40, 45))	('dome formation', 'CPA', (88, 102))	('CDC25', 'Gene', '995', (40, 45))	('dome formation', 'CPA', (156, 170))	('induce', 'Reg', (149, 155))	('CCNE2', 'Gene', (51, 56))
37054	33048473	Furthermore, MTA caused down-regulation of many genes involved in cell-cycle control, with the cyclin E2 (CCNE2) and cell division cycle 25A (CDC25A) genes being the most significantly reduced.	('regulation', 'biological_process', 'GO:0065007', ('29', '39'))	('cyclin E2', 'Gene', '9134', (95, 104))	('cyclin', 'molecular_function', 'GO:0016538', ('95', '101'))	('MTA', 'Var', (13, 16))	('CCNE2', 'Gene', (106, 111))	('cell division cycle', 'biological_process', 'GO:0007049', ('117', '136'))	('cell-cycle control', 'biological_process', 'GO:1901987', ('66', '84'))	('cyclin E2', 'Gene', (95, 104))	('CDC25A', 'Gene', (142, 148))	('down-regulation', 'NegReg', (24, 39))	('reduced', 'NegReg', (185, 192))
37079	33048473	Therefore, we performed further analysis to determine whether the methylthio group in MTA is essential for inducing dome formation, by substituting oxygen, nitrogen, or carbon for the sulphur atom.	('methylthio', 'Var', (66, 76))	('inducing', 'Reg', (107, 115))	('substituting', 'NegReg', (135, 147))	('oxygen', 'Chemical', 'MESH:D010100', (148, 154))	('dome formation', 'Disease', (116, 130))	('formation', 'biological_process', 'GO:0009058', ('121', '130'))	('nitrogen', 'Chemical', 'MESH:D009584', (156, 164))
37084	33048473	Moreover, substitution of the methylene group with either an ethylene or a trimethylene group caused the reduction or complete loss of the dome-inducing activity.	('dome-inducing activity', 'MPA', (139, 161))	('trimethylene', 'Chemical', 'MESH:C030797', (75, 87))	('substitution', 'Var', (10, 22))	('loss', 'NegReg', (127, 131))
37093	33048473	A possible explanation for this ambiguous result is that purvalanol A suppresses the roles of other cyclin/CDK complexes, such as cyclin B/CDK1, in the M phase and cyclin A/CDK2 in the S and G2 phases, aside from cyclin E (either E1 or E2)/CDK2 in the G1 phase [30], thus disturbing different aspects of cell-cycle control, although other explanations cannot be excluded.	('G1 phase', 'biological_process', 'GO:0051318', ('252', '260'))	('cyclin', 'molecular_function', 'GO:0016538', ('213', '219'))	('M phase', 'biological_process', 'GO:0000279', ('152', '159'))	('CDK', 'molecular_function', 'GO:0004693', ('173', '176'))	('disturbing', 'Reg', (272, 282))	('purvalanol', 'Var', (57, 67))	('cyclin', 'molecular_function', 'GO:0016538', ('164', '170'))	('cyclin A', 'Gene', (164, 172))	('cell-cycle control', 'CPA', (304, 322))	('cyclin', 'molecular_function', 'GO:0016538', ('100', '106'))	('cyclin A', 'Gene', '890', (164, 172))	('CDK', 'molecular_function', 'GO:0004693', ('139', '142'))	('suppresses', 'NegReg', (70, 80))	('cell-cycle control', 'biological_process', 'GO:1901987', ('304', '322'))	('cyclin', 'molecular_function', 'GO:0016538', ('130', '136'))	('CDK', 'molecular_function', 'GO:0004693', ('240', '243'))	('CDK', 'molecular_function', 'GO:0004693', ('107', '110'))
37096	32019170	Salivary MicroRNA for Diagnosis of Cancer and Systemic Diseases: A Systematic Review Background: The aberrant expression of microRNAs (miRNAs) has been associated with several diseases, including cancer, inflammatory, and autoimmune conditions.	('miR', 'Gene', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('inflammatory', 'Disease', (204, 216))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Cancer', 'Disease', (35, 41))	('cancer', 'Disease', (196, 202))	('autoimmune conditions', 'Phenotype', 'HP:0002960', (222, 243))	('associated', 'Reg', (152, 162))	('Cancer', 'Disease', 'MESH:D009369', (35, 41))	('microRNAs', 'Protein', (124, 133))	('aberrant expression', 'Var', (101, 120))	('diseases', 'Disease', (176, 184))	('miR', 'Gene', '220972', (135, 138))
37105	32019170	Genetic alterations such as chromosomal rearrangements, genomic amplifications, deletions, or point mutations presumptively play an important role in disease initiation and progression through the aberrant expression of miRNAs located in the affected regions and, subsequently, by deregulation of their downstream mRNA targets.	('deregulation', 'PosReg', (281, 293))	('expression', 'MPA', (206, 216))	('miR', 'Gene', '220972', (220, 223))	('miR', 'Gene', (220, 223))	('point mutations', 'Var', (94, 109))	('deletions', 'Var', (80, 89))
37107	32019170	The aberrant expression of miRNAs has been associated with a growing number of disease states, including cancer, inflammatory, and autoimmune diseases.	('disease', 'Disease', (79, 86))	('autoimmune diseases', 'Disease', 'MESH:D001327', (131, 150))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('aberrant expression', 'Var', (4, 23))	('autoimmune diseases', 'Disease', (131, 150))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (131, 150))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('associated', 'Reg', (43, 53))	('inflammatory', 'Disease', (113, 125))
37197	32019170	miR-140-5p is able to suppress the proliferation, migration, and invasion of GC by directly targeting the 3'-UTR of YES1.	("3'-UTR", 'MPA', (106, 112))	('YES1', 'Gene', '7525', (116, 120))	('targeting', 'Reg', (92, 101))	('proliferation', 'CPA', (35, 48))	('migration', 'CPA', (50, 59))	('GC', 'Disease', 'MESH:D013274', (77, 79))	('suppress', 'NegReg', (22, 30))	('miR-140-5p', 'Chemical', '-', (0, 10))	('miR-140-5p', 'Var', (0, 10))	('invasion', 'CPA', (65, 73))	('YES1', 'Gene', (116, 120))	('GC', 'Phenotype', 'HP:0012126', (77, 79))
37200	32019170	With specific regard to GC, it has been shown that the abnormal expression of miR-301a is associated with cancer progression and poor prognosis.	('expression', 'MPA', (64, 74))	('GC', 'Phenotype', 'HP:0012126', (24, 26))	('abnormal', 'Var', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('associated', 'Reg', (90, 100))	('cancer', 'Disease', (106, 112))	('miR-301a', 'Gene', (78, 86))	('GC', 'Disease', 'MESH:D013274', (24, 26))	('miR-301a', 'Gene', '407027', (78, 86))
37239	32019170	described how T CD4+ cells play a significant role in the pathogenesis of Graves' disease, a common immuno-mediate condition; lymphocytic infiltration in thyroid gland leads to the production of autoantibody against thyroid-stimulating hormone receptor (TSH-r), which mimics the action of TSH, causing excessive thyroid hormone production and hyperthyroidism.	('thyroid-stimulating hormone receptor', 'Gene', '7253', (216, 252))	('CD', 'Phenotype', 'HP:0100280', (16, 18))	("Graves' disease", 'Phenotype', 'HP:0100647', (74, 89))	("Graves' disease", 'Disease', (74, 89))	('excessive', 'PosReg', (302, 311))	('autoantibody', 'Var', (195, 207))	('TSH-r', 'Gene', (254, 259))	('hyperthyroidism', 'Disease', 'MESH:D006980', (343, 358))	('excessive thyroid', 'Phenotype', 'HP:0008249', (302, 319))	('thyroid-stimulating hormone receptor', 'Gene', (216, 252))	("Graves' disease", 'Disease', 'MESH:D006111', (74, 89))	('CD', 'Disease', 'MESH:D003424', (16, 18))	('TSH-r', 'Gene', '7253', (254, 259))	('excessive thyroid hormone', 'Phenotype', 'HP:0002930', (302, 327))	('hyperthyroidism', 'Phenotype', 'HP:0000836', (343, 358))	('causing', 'Reg', (294, 301))	('thyroid hormone production', 'MPA', (312, 338))	('hyperthyroidism', 'Disease', (343, 358))
37267	31366165	Furthermore, inherited mutations underlying familial adenomatous polyposis (FAP) and mismatch mutations due to defective DNA repair are important risk factors which predispose individuals to the development of CRC (for a review see).	('FAP', 'Disease', 'MESH:C567782', (76, 79))	('familial adenomatous polyposis', 'Disease', (44, 74))	('CRC', 'Phenotype', 'HP:0003003', (210, 213))	('FAP', 'Disease', (76, 79))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (44, 74))	('mutations', 'Var', (23, 32))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (53, 74))	('defective', 'NegReg', (111, 120))	('CRC', 'Disease', (210, 213))	('mismatch mutations', 'Var', (85, 103))
37268	31366165	At the molecular level, germline mutations in the tumor suppressor gene, adenomatous polyposis coli (Apc), which encodes a cytoplasmic protein that, amongst others, binds to beta-catenin thereby impairing its capability to activate the Wnt signaling pathway, seem to be critical for increased proliferation of epithelial tumor cells.	('Apc', 'Gene', (101, 104))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (73, 99))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (73, 99))	('tumor suppressor', 'biological_process', 'GO:0051726', ('50', '66'))	('increased', 'PosReg', (283, 292))	('adenomatous polyposis coli', 'Disease', (73, 99))	('Apc', 'Phenotype', 'HP:0005227', (101, 104))	('tumor', 'Disease', (321, 326))	('beta-catenin', 'Gene', (174, 186))	('Apc', 'Gene', '324', (101, 104))	('beta-catenin', 'Gene', '1499', (174, 186))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (73, 94))	('Wnt signaling pathway', 'Pathway', (236, 257))	('tumor', 'Disease', 'MESH:D009369', (321, 326))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('Apc', 'cellular_component', 'GO:0005680', ('101', '104'))	('tumor', 'Disease', (50, 55))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('236', '257'))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('epithelial tumor', 'Disease', (310, 326))	('impairing', 'NegReg', (195, 204))	('binds', 'Interaction', (165, 170))	('cap', 'Chemical', '-', (209, 212))	('epithelial tumor', 'Disease', 'MESH:D002277', (310, 326))	('epithelial tumor', 'Phenotype', 'HP:0031492', (310, 326))	('activate', 'PosReg', (223, 231))	('germline mutations', 'Var', (24, 42))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('50', '66'))
37269	31366165	However, mutations in Apc are not exclusively found in FAP patients but also in many sporadic colorectal tumors (for a review see).	('FAP', 'Disease', (55, 58))	('Apc', 'cellular_component', 'GO:0005680', ('22', '25'))	('colorectal tumors', 'Disease', 'MESH:D015179', (94, 111))	('Apc', 'Gene', (22, 25))	('mutations', 'Var', (9, 18))	('FAP', 'Disease', 'MESH:C567782', (55, 58))	('colorectal tumors', 'Disease', (94, 111))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('patients', 'Species', '9606', (59, 67))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('Apc', 'Gene', '324', (22, 25))	('Apc', 'Phenotype', 'HP:0005227', (22, 25))	('found', 'Reg', (46, 51))
37271	31366165	Alterations in these signaling cascades play a pivotal role in the process of colonic epithelial transformation and in metastasis of CRC.	('colonic epithelial transformation', 'Disease', 'MESH:D017573', (78, 111))	('Alterations', 'Var', (0, 11))	('colonic epithelial transformation', 'Disease', (78, 111))	('metastasis', 'CPA', (119, 129))	('CRC', 'Phenotype', 'HP:0003003', (133, 136))	('signaling', 'biological_process', 'GO:0023052', ('21', '30'))
37296	31366165	Consequently, global postnatal deletion of HuR is accompanied by an extensive loss of microvilli and leads to severe cachexia.	('cachexia', 'Disease', (117, 125))	('cachexia', 'Disease', 'MESH:D002100', (117, 125))	('microvilli', 'Protein', (86, 96))	('microvilli', 'cellular_component', 'GO:0005902', ('86', '96'))	('loss', 'NegReg', (78, 82))	('deletion', 'Var', (31, 39))	('cachexia', 'Phenotype', 'HP:0004326', (117, 125))	('HuR', 'Gene', '1994', (43, 46))	('leads to', 'Reg', (101, 109))	('HuR', 'Gene', (43, 46))
37309	31366165	Data from various tumor models implicate that loss of caspase-2 facilitates tumor growth and contributes to the development of cancer (for a review see).	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', (18, 23))	('development of', 'CPA', (112, 126))	('tumor', 'Disease', (76, 81))	('loss', 'Var', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('contributes', 'Reg', (93, 104))	('cancer', 'Disease', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('facilitates', 'PosReg', (64, 75))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('caspase-2', 'Protein', (54, 63))
37313	31366165	A dysfunction of this pathway critically contributes to the pathological tolerance towards aneuploid tumor cells in human colorectal carcinoma.	('aneuploid tumor', 'Disease', 'MESH:D000782', (91, 106))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (122, 142))	('contributes', 'Reg', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('colorectal carcinoma', 'Disease', (122, 142))	('dysfunction', 'Var', (2, 13))	('aneuploid tumor', 'Disease', (91, 106))	('human', 'Species', '9606', (116, 121))
37322	31366165	Functionally, the transient knockdown of HuR significantly increased the sensitivity of colon carcinoma cells to gamma-irradiation or drug-induced apoptosis and, importantly, the sensitizing effects were fully rescued after additional silencing of caspase-2.	('HuR', 'Gene', '1994', (41, 44))	('colon carcinoma', 'Disease', (88, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('HuR', 'Gene', (41, 44))	('apoptosis', 'biological_process', 'GO:0097194', ('147', '156'))	('sensitivity', 'MPA', (73, 84))	('apoptosis', 'biological_process', 'GO:0006915', ('147', '156'))	('knockdown', 'Var', (28, 37))	('increased', 'PosReg', (59, 68))	('colon carcinoma', 'Disease', 'MESH:D015179', (88, 103))
37357	31366165	In contrast, polyamines were shown to enhance HuR association to c-Myc mRNA and occludin mRNA via Chk2 dependent HuR phosphorylation, and thereby promote the translation of the corresponding proteins.	('polyamines', 'Chemical', 'MESH:D011073', (13, 23))	('occludin', 'Gene', '100506658', (80, 88))	('c-Myc', 'Gene', (65, 70))	('Chk2', 'Gene', '11200', (98, 102))	('polyamines', 'Var', (13, 23))	('enhance', 'PosReg', (38, 45))	('HuR', 'Gene', (46, 49))	('Chk2', 'Gene', (98, 102))	('proteins', 'Protein', (191, 199))	('translation', 'MPA', (158, 169))	('occludin', 'Gene', (80, 88))	('HuR', 'Gene', '1994', (46, 49))	('HuR', 'Gene', '1994', (113, 116))	('c-Myc', 'Gene', '4609', (65, 70))	('promote', 'PosReg', (146, 153))	('HuR', 'Gene', (113, 116))
37358	31366165	The seemingly contradictory results from different studies may imply that the final impact of a specific post-translational HuR modification on mRNA binding is primarily controlled by the set of target mRNAs and not by the modification.	('mRNA', 'Protein', (144, 148))	('HuR', 'Gene', '1994', (124, 127))	('modification', 'Var', (128, 140))	('HuR', 'Gene', (124, 127))
37362	31366165	Therefore, another question arising is whether severe DNA damage can induce a dissociation of HuR from caspase-2 mRNA which in turn would promote caspase-2-triggered cell death pathways.	('caspase-2-triggered', 'Pathway', (146, 165))	('HuR', 'Gene', (94, 97))	('HuR', 'Gene', '1994', (94, 97))	('dissociation', 'MPA', (78, 90))	('caspase-2', 'Protein', (103, 112))	('severe', 'Var', (47, 53))	('promote', 'PosReg', (138, 145))	('cell', 'CPA', (166, 170))	('DNA', 'cellular_component', 'GO:0005574', ('54', '57'))	('cell death', 'biological_process', 'GO:0008219', ('166', '176'))
37364	31366165	Pathologically, a deregulation of the DDR is frequently observed in various types of human malignancies including colorectal cancer.	('malignancies', 'Disease', 'MESH:D009369', (91, 103))	('observed', 'Reg', (56, 64))	('malignancies', 'Disease', (91, 103))	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('deregulation', 'Var', (18, 30))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('DDR', 'Gene', (38, 41))	('colorectal cancer', 'Disease', (114, 131))	('human', 'Species', '9606', (85, 90))
37377	31366165	Vice versa, Mdm2 can inhibit the transcriptional activity of p53 through directly binding to its N-terminal transactivation domain.	('inhibit', 'NegReg', (21, 28))	('p53', 'Gene', '7157', (61, 64))	('Mdm2', 'Var', (12, 16))	('p53', 'Gene', (61, 64))	('transcriptional activity', 'MPA', (33, 57))	('binding', 'Interaction', (82, 89))
37378	31366165	Clearly opposite to this, Mdm2 was found to promote p53 synthesis by binding to its mRNA.	('promote', 'PosReg', (44, 51))	('p53', 'Gene', (52, 55))	('mRNA', 'MPA', (84, 88))	('p53', 'Gene', '7157', (52, 55))	('synthesis', 'biological_process', 'GO:0009058', ('56', '65'))	('binding', 'Interaction', (69, 76))	('binding', 'molecular_function', 'GO:0005488', ('69', '76'))	('Mdm2', 'Var', (26, 30))
37381	31366165	Physiologically, the anti-apoptotic activity by Mdm2 seems highly relevant for the maintenance of the intestinal epithelial architecture since a decrease in Mdm2 expression as a direct consequence of HuR knockout is linked with a strong increase in intestinal epithelial cell apoptosis and a dramatic loss of intestinal microvilli.	('intestinal epithelial cell apoptosis', 'CPA', (249, 285))	('knockout', 'Var', (204, 212))	('increase', 'PosReg', (237, 245))	('Mdm2', 'Gene', (157, 161))	('HuR', 'Gene', (200, 203))	('loss', 'NegReg', (301, 305))	('expression', 'MPA', (162, 172))	('HuR', 'Gene', '1994', (200, 203))	('decrease', 'NegReg', (145, 153))
37401	31366165	Conversely, HuR depletion via increasing caspase-2 levels caused a significant raise in DNA damage-induced apoptosis as indicated by an increase in histone variant H2AX phosphorylation on serine 139 (termed gammaH2AX).	('DNA damage-induced', 'MPA', (88, 106))	('serine', 'Chemical', 'MESH:D012694', (188, 194))	('variant', 'Var', (156, 163))	('increasing', 'PosReg', (30, 40))	('HuR', 'Gene', (12, 15))	('HuR', 'Gene', '1994', (12, 15))	('H2AX', 'Gene', '3014', (212, 216))	('phosphorylation on serine 139', 'MPA', (169, 198))	('increase', 'PosReg', (136, 144))	('H2AX', 'Gene', (212, 216))	('raise', 'PosReg', (79, 84))	('H2AX', 'Gene', (164, 168))	('H2AX', 'Gene', '3014', (164, 168))
37416	31366165	Interestingly, Mdm2 was previously established as a target of caspase-2 mediated cleavage leading to an inhibition of Mdm2-triggered ubiquitination and, consequently, to the stabilization of p53 (Figure 2B).	('inhibition', 'NegReg', (104, 114))	('Mdm2-triggered', 'Var', (118, 132))	('ubiquitination', 'MPA', (133, 147))	('stabilization', 'MPA', (174, 187))	('p53', 'Gene', (191, 194))	('p53', 'Gene', '7157', (191, 194))
37428	31366165	In addition, genomic instability can origin from alterations in chromosome numbers leading to aneuploidy which represents the most common chromosome abnormality in humans (for a review see).	('alterations', 'Var', (49, 60))	('chromosome abnormality', 'Phenotype', 'HP:0031411', (138, 160))	('origin', 'Reg', (37, 43))	('aneuploidy', 'Disease', (94, 104))	('aneuploidy', 'Disease', 'MESH:D000782', (94, 104))	('humans', 'Species', '9606', (164, 170))	('genomic instability', 'CPA', (13, 32))	('leading to', 'Reg', (83, 93))
37431	31366165	Hence, caspase-2 inactivation or deficiency promotes aberrant DNA damage response and genomic instability leading to an enhanced clonogenic survival of aneuploid cells.	('inactivation', 'Var', (17, 29))	('promotes', 'PosReg', (44, 52))	('genomic instability', 'CPA', (86, 105))	('enhanced', 'PosReg', (120, 128))	('DNA damage response', 'biological_process', 'GO:0006974', ('62', '81'))	('deficiency', 'Disease', 'MESH:D007153', (33, 43))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('clonogenic survival of', 'CPA', (129, 151))	('deficiency', 'Disease', (33, 43))	('caspase-2', 'Protein', (7, 16))	('DNA damage response', 'MPA', (62, 81))
37438	31366165	Alternatively, activation of caspase-2 via cleavage of the BH3 interacting domain death agonist (Bid) which leads to an increase in truncated Bid (tBid) can promote apoptosis upstream of the mitochondrial outer membrane permeabilization (MOMP), caspase-3 and caspase-9, and independently of p53 (Figure 2B).	('apoptosis', 'biological_process', 'GO:0097194', ('165', '174'))	('apoptosis', 'biological_process', 'GO:0006915', ('165', '174'))	('mitochondrial outer membrane permeabilization', 'biological_process', 'GO:0097345', ('191', '236'))	('apoptosis', 'CPA', (165, 174))	('BH3', 'Chemical', 'MESH:C006008', (59, 62))	('caspase-3', 'Gene', '836', (245, 254))	('Bid', 'Gene', '637', (142, 145))	('tBid', 'Chemical', '-', (147, 151))	('caspase-3', 'Gene', (245, 254))	('caspase-9', 'Gene', (259, 268))	('caspase-2', 'Protein', (29, 38))	('mitochondrial outer membrane', 'cellular_component', 'GO:0005741', ('191', '219'))	('cleavage', 'Var', (43, 51))	('Bid', 'Gene', (97, 100))	('Bid', 'Gene', '637', (148, 151))	('activation', 'PosReg', (15, 25))	('promote', 'PosReg', (157, 164))	('Bid', 'Gene', (142, 145))	('p53', 'Gene', '7157', (291, 294))	('MOMP', 'biological_process', 'GO:0097345', ('238', '242'))	('p53', 'Gene', (291, 294))	('increase', 'PosReg', (120, 128))	('caspase-9', 'Gene', '842', (259, 268))	('Bid', 'Gene', (148, 151))	('Bid', 'Gene', '637', (97, 100))
37439	31366165	These findings are in accordance with our studies which demonstrated that siRNA-mediated knockdown of HuR via upregulation of caspase-2 further decreased clonogenic cell survival of colorectal carcinoma cells in response to gamma-irradiation.	('upregulation', 'PosReg', (110, 122))	('decreased', 'NegReg', (144, 153))	('caspase-2', 'Protein', (126, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('clonogenic cell survival', 'CPA', (154, 178))	('colorectal carcinoma', 'Disease', (182, 202))	('knockdown', 'Var', (89, 98))	('HuR', 'Gene', (102, 105))	('HuR', 'Gene', '1994', (102, 105))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (182, 202))
37440	31366165	Again, the caspase-2-dependent increase in apoptosis sensitivity and loss of clonogenic survival were observed in p53 wildtype RKO but also in p53 mutated DLD-1 cells, confirming that the sensitizing effects by caspase-2 occur independent of p53.	('mutated', 'Var', (147, 154))	('clonogenic survival', 'CPA', (77, 96))	('loss', 'NegReg', (69, 73))	('p53', 'Gene', '7157', (143, 146))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('p53', 'Gene', (242, 245))	('apoptosis sensitivity', 'CPA', (43, 64))	('p53', 'Gene', '7157', (242, 245))	('p53', 'Gene', (143, 146))	('increase', 'PosReg', (31, 39))
37441	31366165	By questioning the possible reasons for genomic instability frequently observed in many human tumors, a previous study revealed that loss-of-function alterations in the BCL9L are frequent in aneuploid colorectal tumors.	('BCL9L', 'Gene', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', (212, 218))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('alterations', 'Var', (150, 161))	('aneuploid colorectal tumors', 'Disease', (191, 218))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('aneuploid colorectal tumors', 'Disease', 'MESH:D000782', (191, 218))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('BCL9L', 'Gene', '283149', (169, 174))
37442	31366165	Most intriguingly, dysfunction of BCL9L promotes a survival mechanism termed aneuploidy tolerance mainly through reducing the expression of caspase-2 (Figure 2B).	('aneuploidy tolerance', 'Disease', (77, 97))	('expression', 'MPA', (126, 136))	('BCL9L', 'Gene', '283149', (34, 39))	('caspase-2', 'Protein', (140, 149))	('survival mechanism', 'CPA', (51, 69))	('BCL9L', 'Gene', (34, 39))	('aneuploidy tolerance', 'Disease', 'MESH:D000782', (77, 97))	('dysfunction', 'Var', (19, 30))	('reducing', 'NegReg', (113, 121))	('promotes', 'PosReg', (40, 48))
37443	31366165	Because caspase-2 is required for p53 stabilization and induction of aneuploidy-induced apoptosis, loss-of-function alterations in the tumor suppressor BCL9L seem to critically contribute to colorectal cancer.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('colorectal cancer', 'Disease', (191, 208))	('aneuploidy', 'Disease', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('colorectal cancer', 'Disease', 'MESH:D015179', (191, 208))	('tumor', 'Disease', (135, 140))	('BCL9L', 'Gene', '283149', (152, 157))	('aneuploidy', 'Disease', 'MESH:D000782', (69, 79))	('alterations', 'Var', (116, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (191, 208))	('loss-of-function', 'NegReg', (99, 115))	('BCL9L', 'Gene', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
37445	31366165	Therefore, HuR may impair caspase-2-mediated deletion of aneuploid intestinal carcinoma cells by apoptosis in several respects; firstly, through stabilization of Mdm-2 encoding mRNA and secondly, via suppression of caspase-2 translation which again will reduce p53 levels but additionally cause a reduction in Bid-cleavage (Figure 2B).	('Mdm-2', 'Gene', (162, 167))	('HuR', 'Gene', (11, 14))	('HuR', 'Gene', '1994', (11, 14))	('Bid', 'Gene', '637', (310, 313))	('translation', 'MPA', (225, 236))	('p53', 'Gene', '7157', (261, 264))	('translation', 'biological_process', 'GO:0006412', ('225', '236'))	('aneuploid intestinal carcinoma', 'Disease', (57, 87))	('reduction', 'NegReg', (297, 306))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('deletion', 'Var', (45, 53))	('Mdm-2', 'Gene', '4193', (162, 167))	('p53', 'Gene', (261, 264))	('caspase-2-mediated', 'Enzyme', (26, 44))	('impair', 'NegReg', (19, 25))	('apoptosis', 'CPA', (97, 106))	('Bid', 'Gene', (310, 313))	('aneuploid intestinal carcinoma', 'Disease', 'MESH:D000782', (57, 87))	('caspase-2', 'Protein', (215, 224))	('suppression', 'NegReg', (200, 211))	('apoptosis', 'biological_process', 'GO:0097194', ('97', '106'))	('apoptosis', 'biological_process', 'GO:0006915', ('97', '106'))	('reduce', 'NegReg', (254, 260))
37451	31366165	The strong impact of caspase-2 on cell survival of colon carcinoma cells, which is underscored by the finding that the HuR-silencing-dependent sensitizing effects are almost completely rescued after genetic or pharmacological depletion of caspase-2, is unexpected since HuR can promote cell survival through targeting a broad panel of apoptosis-regulatory factors.	('apoptosis', 'biological_process', 'GO:0006915', ('335', '344'))	('colon carcinoma', 'Disease', 'MESH:D015179', (51, 66))	('depletion', 'Var', (226, 235))	('colon carcinoma', 'Disease', (51, 66))	('cell survival', 'CPA', (286, 299))	('HuR', 'Gene', '1994', (119, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('HuR', 'Gene', '1994', (270, 273))	('promote', 'PosReg', (278, 285))	('HuR', 'Gene', (270, 273))	('HuR', 'Gene', (119, 122))	('apoptosis', 'biological_process', 'GO:0097194', ('335', '344'))
37452	31366165	On the basis of these pleiotropic functions in tumor development and progression, inhibition of HuR either alone or in combination with established therapeutic approaches offers an attractive novel strategy for treatment of some common human cancers including colorectal carcinoma.	('cancers', 'Disease', 'MESH:D009369', (242, 249))	('HuR', 'Gene', (96, 99))	('human', 'Species', '9606', (236, 241))	('HuR', 'Gene', '1994', (96, 99))	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('cancers', 'Disease', (242, 249))	('inhibition', 'Var', (82, 92))	('colorectal carcinoma', 'Disease', (260, 280))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (260, 280))	('tumor', 'Disease', (47, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))
37455	31366165	Finally, we anticipate that perturbations of signaling pathways controlling the negative HuR-caspase-2 axis via inhibition of the different tumor-suppressive activities by caspase-2 may have a strong pathophysiological impact for colon carcinogenesis and therapy resistance.	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (230, 250))	('inhibition', 'NegReg', (112, 122))	('colon carcinogenesis', 'Disease', (230, 250))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('perturbations', 'Var', (28, 41))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('HuR', 'Gene', (89, 92))	('HuR', 'Gene', '1994', (89, 92))	('tumor', 'Disease', (140, 145))
37501	30808336	In the meta-analysis based on ethnicity, GDF-15 testing in Caucasian and Asian patients yielded an AUC of 0.83, whereas the Asian-based test conferred a higher specificity of 0.81 (95% CI: 0.79-0.83).	('GDF-15', 'Gene', (41, 47))	('testing', 'Var', (48, 55))	('GDF-15', 'Gene', '9518', (41, 47))	('AUC', 'MPA', (99, 102))	('patients', 'Species', '9606', (79, 87))
37539	30044795	In this study, isolation of short cell-free DNA fragments is shown to enrich for tumor variants and improve correction of PCR- and sequencing-associated errors.	('correction', 'MPA', (108, 118))	('variants', 'Var', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('enrich', 'Reg', (70, 76))	('improve', 'PosReg', (100, 107))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
37546	30044795	Recently, we demonstrated that isolation of shorter ccfDNA fractions with an offset of 20-50 bp from the mononucleosomal peak of ~167 bp enriched for the EGFR T790M variant in three lung cancer patients.	('T790M', 'Var', (159, 164))	('EGFR', 'Gene', (154, 158))	('patients', 'Species', '9606', (194, 202))	('lung cancer', 'Disease', (182, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('T790M', 'Mutation', 'rs121434569', (159, 164))	('EGFR', 'Gene', '1956', (154, 158))
37548	30044795	NGS enables a broad search for both known and unknown tumor-associated variants including single nucleotide variants, copy number variations, and chromosomal rearrangements.	('single nucleotide variants', 'Var', (90, 116))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('copy number variations', 'Var', (118, 140))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
37549	30044795	In this study, we optimized and implemented a high-throughput-capable automated gel-extraction platform to isolate subfractions of the mononucleosomal peak in sequencing libraries of ccfDNA from patients with melanoma, colorectal adenocarcinoma, and pancreatic ductal adenocarcinoma with confirmed somatic BRAF or KRAS variants.	('pancreatic ductal adenocarcinoma', 'Disease', (250, 282))	('BRAF', 'Gene', (306, 310))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (250, 282))	('variants', 'Var', (319, 327))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (250, 282))	('colorectal adenocarcinoma', 'Disease', (219, 244))	('melanoma', 'Disease', 'MESH:D008545', (209, 217))	('KRAS', 'Gene', (314, 318))	('KRAS', 'Gene', '3845', (314, 318))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (219, 244))	('patients', 'Species', '9606', (195, 203))	('melanoma', 'Phenotype', 'HP:0002861', (209, 217))	('melanoma', 'Disease', (209, 217))	('BRAF', 'Gene', '673', (306, 310))
37550	30044795	We sought to determine if selection of shorter ccfDNA fragments increased VAF of tumor-associated variants as detected by ddPCR and NGS.	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('AF', 'Disease', 'MESH:D001281', (75, 77))	('increased', 'PosReg', (64, 73))	('variants', 'Var', (98, 106))
37553	30044795	Samples from 13 patients with a BRAF or KRAS variant present in solid tumor tissue from melanoma (N = 8), colorectal adenocarcinoma (N = 3), or pancreatic ductal adenocarcinoma (N = 2) and a corresponding quantifiable variant present in ccfDNA by ddPCR were analyzed (Table 1).	('BRAF', 'Gene', '673', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('BRAF', 'Gene', (32, 36))	('melanoma', 'Disease', (88, 96))	('KRAS', 'Gene', (40, 44))	('tumor', 'Disease', (70, 75))	('patients', 'Species', '9606', (16, 24))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (106, 131))	('KRAS', 'Gene', '3845', (40, 44))	('variant', 'Var', (45, 52))	('pancreatic ductal adenocarcinoma', 'Disease', (144, 176))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (144, 176))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (144, 176))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('colorectal adenocarcinoma', 'Disease', (106, 131))
37560	30044795	Here, we observed in 13 patients that the median insert sizes corresponding to the mononucleosome (< 250 bp) associated with the variant alleles present in either BRAF or KRAS were generally shorter than the corresponding wild type alleles (151.8+-12.8 vs. 166.9+-2.5 bp, respectively; P = 0.001; Fig 1C).	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('variant', 'Var', (129, 136))	('patients', 'Species', '9606', (24, 32))	('shorter', 'NegReg', (191, 198))	('KRAS', 'Gene', (171, 175))	('KRAS', 'Gene', '3845', (171, 175))
37561	30044795	Individual beeswarm plots for each patient for both WT and variant are shown in S3 Fig (insert size < 250 bp, mononucleosome) and S4 Fig (insert size > 250 bp, dinucleosome and larger).	('dinucleosome', 'Var', (160, 172))	('mononucleosome', 'MPA', (110, 124))	('insert size > 250 bp', 'Var', (138, 158))	('patient', 'Species', '9606', (35, 42))
37563	30044795	Subsequently, enrichment capabilities of gel-based ccfDNA fragment size selection were established using pooled ccfDNA from healthy controls spiked with synthetic EGFR T790M fragments (length 130 bp) and BRAF V600E fragments (length 165 bp) at similar VAF.	('AF', 'Disease', 'MESH:D001281', (206, 208))	('BRAF', 'Gene', (204, 208))	('EGFR', 'Gene', '1956', (163, 167))	('T790M', 'Mutation', 'rs121434569', (168, 173))	('V600E', 'Mutation', 'rs113488022', (209, 214))	('EGFR', 'Gene', (163, 167))	('synthetic', 'Species', '32630', (153, 162))	('T790M', 'Var', (168, 173))	('EGFR', 'molecular_function', 'GO:0005006', ('163', '167'))	('AF', 'Disease', 'MESH:D001281', (253, 255))	('BRAF', 'Gene', '673', (204, 208))
37567	30044795	Isolation of the short fraction increased VAF of the EGFR T790M variant (130 bp) in each dilution (Fig 2C).	('EGFR', 'Gene', (53, 57))	('T790M', 'Mutation', 'rs121434569', (58, 63))	('increased', 'PosReg', (32, 41))	('EGFR', 'Gene', '1956', (53, 57))	('T790M', 'Var', (58, 63))	('AF', 'Disease', 'MESH:D001281', (43, 45))
37569	30044795	The EGFR T790M variant was absent in the long fraction (Fig 2C).	('T790M', 'Var', (9, 14))	('EGFR', 'Gene', (4, 8))	('EGFR', 'molecular_function', 'GO:0005006', ('4', '8'))	('T790M', 'Mutation', 'rs121434569', (9, 14))	('EGFR', 'Gene', '1956', (4, 8))
37570	30044795	The VAF of the BRAF V600E variant (165 bp) was consistently greater than the unselected VAF in both the short and long fractions (Fig 2E), but the extent of enrichment remained relatively constant across all dilutions (Fig 2F).	('BRAF', 'Gene', '673', (15, 19))	('AF', 'Disease', 'MESH:D001281', (89, 91))	('AF', 'Disease', 'MESH:D001281', (17, 19))	('BRAF', 'Gene', (15, 19))	('V600E', 'Mutation', 'rs113488022', (20, 25))	('greater', 'PosReg', (60, 67))	('AF', 'Disease', 'MESH:D001281', (5, 7))	('V600E', 'Var', (20, 25))
37571	30044795	As such, the enrichment observed for the 165-bp BRAF V600E variant was likely due to elimination of wildtype BRAF found in the dinucleosomal and larger plasma DNA components.	('DNA', 'cellular_component', 'GO:0005574', ('159', '162'))	('BRAF', 'Gene', (109, 113))	('V600E', 'Mutation', 'rs113488022', (53, 58))	('BRAF', 'Gene', '673', (109, 113))	('V600E', 'Var', (53, 58))	('elimination', 'NegReg', (85, 96))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))
37572	30044795	For a targeted size range, longer rather than shorter fragments outside the desired range are more likely to be present as exemplified by the absence of the EGFR T790M variant (130 bp) in the long fraction and the presence of the BRAF V600E variant (165 bp) in the short fraction.	('T790M', 'Var', (162, 167))	('EGFR', 'Gene', (157, 161))	('V600E', 'Mutation', 'rs113488022', (235, 240))	('BRAF', 'Gene', '673', (230, 234))	('EGFR', 'molecular_function', 'GO:0005006', ('157', '161'))	('BRAF', 'Gene', (230, 234))	('absence', 'NegReg', (142, 149))	('EGFR', 'Gene', '1956', (157, 161))	('T790M', 'Mutation', 'rs121434569', (162, 167))
37582	30044795	We similarly found few false positives for the known patient variants in healthy control ccfDNA (Fig 5B).	('variants', 'Var', (61, 69))	('patient', 'Species', '9606', (53, 60))	('ccfDNA', 'Disease', (89, 95))
37593	30044795	The medium and long ccfDNA fractions exhibited similar improvement in VAF consistency at larger family sizes relative to the unselected ccfDNA (S11 and S12 Figs, respectively), which further supports the strengths of reducing sample complexity to improve sensitivity even though each fraction was associated with loss of variant detection in at least one patient by family size >=20.	('improvement', 'PosReg', (55, 66))	('patient', 'Species', '9606', (355, 362))	('variant', 'Var', (321, 328))	('AF', 'Disease', 'MESH:D001281', (71, 73))
37610	30044795	This was evident in the unselected ccfDNA where the lower VAF, increased sample complexity, and reduced read depth at larger family sizes led to loss of variant detection.	('variant', 'Var', (153, 160))	('read', 'MPA', (104, 108))	('loss', 'NegReg', (145, 149))	('lower', 'NegReg', (52, 57))	('AF', 'Disease', 'MESH:D001281', (59, 61))	('reduced', 'NegReg', (96, 103))
37613	30044795	Collectively, these observations support the conjecture that unique molecular identifiers, a priori physical size selection of short ccfDNA fragments, and sufficient read depth will improve variant detection in early-stage non-metastatic solid tumors or low-frequency aggressive clones in advanced cancers not only through ctDNA enrichment, but also by improving in silico error correction through production of larger family sizes.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('solid tumors', 'Disease', 'MESH:D009369', (238, 250))	('improve', 'PosReg', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (298, 305))	('cancers', 'Phenotype', 'HP:0002664', (298, 305))	('cancers', 'Disease', (298, 305))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('solid tumors', 'Disease', (238, 250))	('aggressive clones', 'CPA', (268, 285))	('variant detection', 'Var', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
37615	30044795	Although we successfully identified variants down to a VAF of 0.39% at a mean read depth of ~5,500X at FS>=1, using less input material may adversely affect sensitivity, particularly for detection of variants with an even lower VAF where using more starting material may be advantageous to minimize type II error due to sampling.	('sensitivity', 'MPA', (157, 168))	('AF', 'Disease', 'MESH:D001281', (56, 58))	('type II error', 'Disease', (299, 312))	('AF', 'Disease', 'MESH:D001281', (229, 231))	('variants', 'Var', (200, 208))	('variants', 'Var', (36, 44))	('affect', 'Reg', (150, 156))	('lower', 'NegReg', (222, 227))	('type II error', 'Disease', 'MESH:D005776', (299, 312))
37621	30044795	While that report also demonstrated a high correlation of NGS and ddPCR, VAFs in NGS were generally lower (~2X) than those detected directly by ddPCR.	('AF', 'Disease', 'MESH:D001281', (74, 76))	('NGS', 'Var', (81, 84))	('lower', 'NegReg', (100, 105))
37629	30044795	Although in some patients the VAF for the known ctDNA variants, the amount of ccfDNA per mL plasma, or both were at a level expected of early-stage lesions, studies specifically examining lower grade cancers are necessary before concluding that size selection has a similarly positive effect on sensitivity and specificity regardless of stage.	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('AF', 'Disease', 'MESH:D001281', (31, 33))	('patients', 'Species', '9606', (17, 25))	('variants', 'Var', (54, 62))	('ctDNA', 'Gene', (48, 53))
37633	30044795	Written informed consent was obtained for all study participants under approved IRB protocols #7740, #10924, and #89989.	('#10924', 'Var', (101, 107))	('#89989', 'Var', (113, 119))	('participants', 'Species', '9606', (52, 64))
37634	30044795	Healthy adult volunteers and cancer patients with a BRAF or KRAS solid tumor variant associated with a primary melanoma, pancreatic ductal adenocarcinoma, or colorectal adenocarcinoma were recruited for enrollment.	('KRAS', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('colorectal adenocarcinoma', 'Disease', (158, 183))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (121, 153))	('melanoma', 'Disease', (111, 119))	('patients', 'Species', '9606', (36, 44))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('associated', 'Reg', (85, 95))	('pancreatic ductal adenocarcinoma', 'Disease', (121, 153))	('cancer', 'Disease', (29, 35))	('variant', 'Var', (77, 84))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (158, 183))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('BRAF', 'Gene', '673', (52, 56))	('tumor', 'Disease', (71, 76))	('BRAF', 'Gene', (52, 56))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (121, 153))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('KRAS', 'Gene', '3845', (60, 64))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
37646	30044795	For detection of EGFR T790M and KRAS G13D published assays were used.	('T790M', 'Mutation', 'rs121434569', (22, 27))	('EGFR', 'molecular_function', 'GO:0005006', ('17', '21'))	('KRAS', 'Gene', (32, 36))	('T790M', 'Var', (22, 27))	('KRAS', 'Gene', '3845', (32, 36))	('G13D', 'Mutation', 'rs112445441', (37, 41))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (17, 21))
37650	30044795	Synthetic DNA gBlocks  consisting of 130 bp of genomic EGFR sequence spanning the c.2369C>T (p.T790M) point mutation and 165 bp of genomic BRAF sequence spanning the c.1799T>A (p.V600E) mutation were purchased from Integrated DNA Technologies.	('p.V600E', 'Mutation', 'rs113488022', (177, 184))	('EGFR', 'Gene', '1956', (55, 59))	('BRAF', 'Gene', (139, 143))	('p.T790M', 'Mutation', 'rs121434569', (93, 100))	('EGFR', 'Gene', (55, 59))	('c.1799T>A', 'Mutation', 'rs113488022', (166, 175))	('c.2369C>T', 'Var', (82, 91))	('c.1799T>A', 'Var', (166, 175))	('c.2369C>T', 'Mutation', 'rs121434569', (82, 91))	('Synthetic DNA', 'Species', '32630', (0, 13))	('BRAF', 'Gene', '673', (139, 143))
37651	30044795	Sufficient 130 bp EGFR T790M and 165 bp BRAF V600E gBlocks  were spiked into a sample of pooled cell-free DNA collected from healthy donors to yield a target VAF of ~10% for both alleles.	('BRAF', 'Gene', '673', (40, 44))	('T790M', 'Mutation', 'rs121434569', (23, 28))	('AF', 'Disease', 'MESH:D001281', (42, 44))	('BRAF', 'Gene', (40, 44))	('T790M', 'Var', (23, 28))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (18, 22))	('AF', 'Disease', 'MESH:D001281', (159, 161))	('V600E', 'Mutation', 'rs113488022', (45, 50))
37652	30044795	The presence of synthetic mutations in the spiked library were verified by ddPCR (EGFR T790M 11.4% VAF; BRAF V600E 12.1%).	('synthetic', 'Species', '32630', (16, 25))	('EGFR', 'Gene', (82, 86))	('AF', 'Disease', 'MESH:D001281', (106, 108))	('AF', 'Disease', 'MESH:D001281', (100, 102))	('V600E', 'Mutation', 'rs113488022', (109, 114))	('BRAF', 'Gene', '673', (104, 108))	('T790M', 'Mutation', 'rs121434569', (87, 92))	('EGFR', 'Gene', '1956', (82, 86))	('BRAF', 'Gene', (104, 108))	('T790M', 'Var', (87, 92))
37706	24699879	Young patients also have a higher proportion of tumors demonstrating microsatellite instability, which are associated with a better prognosis.	('microsatellite instability', 'Var', (69, 95))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
37768	33120912	The expression of VE-cadherin in the vascular endothelium was significantly lower in the exosome-exposed group than in the nonexposed control group (Figure 4C,D).	('VE-cadherin', 'Gene', (18, 29))	('VE-cadherin', 'Gene', '1003', (18, 29))	('exosome', 'cellular_component', 'GO:0070062', ('89', '96'))	('expression', 'MPA', (4, 14))	('lower', 'NegReg', (76, 81))	('exosome-exposed', 'Var', (89, 104))	('cadherin', 'molecular_function', 'GO:0008014', ('21', '29'))
37770	33120912	Clinical open database analysis, using the PROGgeneV2 database and dataset GSE28814, confirmed that metastasis-free survival (MFS) was significantly higher in the p120 high-expression group than that in the low-expression group (Figure 4G).	('metastasis-free survival', 'CPA', (100, 124))	('p120 high-expression', 'Var', (163, 183))	('MFS', 'Disease', 'MESH:D008382', (126, 129))	('MFS', 'Disease', (126, 129))	('higher', 'PosReg', (149, 155))
37823	33120912	This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology (17H04282; 17K19698; 18K16356; 18K16355; 18KK0251; 19K22658; 19K07688); AMED, Japan (16cm0106414h0001; 17cm0106414h0002), and JST-PRESTO (15655131).	('15655131', 'Var', (285, 293))	('Aid', 'Gene', '57379', (46, 49))	('AMED', 'Disease', (219, 223))	('17H04282; 17K19698; 18K16356;', 'Var', (148, 177))	('JST', 'Gene', '449523', (273, 276))	('JST', 'Gene', (273, 276))	('AMED', 'Disease', 'None', (219, 223))	('16cm0106414h0001;', 'Var', (232, 249))	('Aid', 'Gene', (46, 49))
37825	32377194	Mucinous Histology, BRCA1/2 Mutations, and Elevated Tumor Mutational Burden in Colorectal Cancer Mucinous colorectal carcinomas (MC) constitute 10% of colorectal malignancies.	('MC', 'Phenotype', 'HP:0031497', (129, 131))	('Elevated Tumor', 'Disease', 'MESH:D006973', (43, 57))	('Cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Mucinous colorectal carcinomas', 'Phenotype', 'HP:0031497', (97, 127))	('BRCA1/2', 'Gene', '672;675', (20, 27))	('Elevated Tumor', 'Disease', (43, 57))	('Mucinous colorectal carcinomas', 'Disease', 'MESH:D015179', (97, 127))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (79, 96))	('colorectal malignancies', 'Disease', 'MESH:D015179', (151, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('Colorectal Cancer', 'Disease', (79, 96))	('Tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Mucinous colorectal carcinomas', 'Disease', (97, 127))	('MC', 'Chemical', '-', (129, 131))	('colorectal malignancies', 'Disease', (151, 174))	('Mutations', 'Var', (28, 37))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (79, 96))	('BRCA1/2', 'Gene', (20, 27))
37826	32377194	Recently, an increased risk of colorectal cancer has been demonstrated in germline BRCA1/2 mutation carriers.	('BRCA1/2', 'Gene', (83, 90))	('colorectal cancer', 'Disease', 'MESH:D015179', (31, 48))	('mutation', 'Var', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (31, 48))	('BRCA1/2', 'Gene', '672;675', (83, 90))	('colorectal cancer', 'Disease', (31, 48))
37827	32377194	Furthermore, BRCA1/2 germline mutation carriers have exhibited a higher-than-expected frequency of MC tumors.	('BRCA1/2', 'Gene', '672;675', (13, 20))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('MC tumors', 'Disease', 'MESH:D009369', (99, 108))	('MC tumors', 'Disease', (99, 108))	('MC', 'Phenotype', 'HP:0031497', (99, 101))	('BRCA1/2', 'Gene', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('germline mutation', 'Var', (21, 38))
37829	32377194	We discovered that MC tumors exhibit a statistically significantly higher incidence of BRCA mutations in addition to a higher average mutation count when compared to AC tumors in the existing cohort.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('higher', 'PosReg', (67, 73))	('BRCA', 'Gene', '672', (87, 91))	('MC', 'Phenotype', 'HP:0031497', (19, 21))	('MC tumors', 'Disease', (19, 28))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('mutation count', 'MPA', (134, 148))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('BRCA', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (169, 175))	('tumors', 'Disease', (22, 28))	('MC tumors', 'Disease', 'MESH:D009369', (19, 28))
37830	32377194	The strongest predictor of the mutation count was mucinous histology, independently of other variables including microsatellite instability.	('mutation', 'Var', (31, 39))	('mucin', 'Gene', (50, 55))	('mucin', 'Gene', '100508689', (50, 55))
37833	32377194	We suggest that the association between MC histology, BRCA mutations, and increased TMB may open the door to the utilization of simple tests (such as histopathologic characterization) to detect patients who may benefit from immunotherapy in colorectal cancer.	('patients', 'Species', '9606', (194, 202))	('BRCA', 'Gene', (54, 58))	('MC', 'Chemical', '-', (40, 42))	('MC', 'Phenotype', 'HP:0031497', (40, 42))	('colorectal cancer', 'Phenotype', 'HP:0003003', (241, 258))	('TMB', 'MPA', (84, 87))	('colorectal cancer', 'Disease', (241, 258))	('BRCA', 'Gene', '672', (54, 58))	('mutations', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('TMB', 'Chemical', '-', (84, 87))	('colorectal cancer', 'Disease', 'MESH:D015179', (241, 258))
37844	32377194	Other common molecular aberrations in MC include higher incidence of PI3K, SMAD4, and BRAF mutations.	('PI3K', 'molecular_function', 'GO:0016303', ('69', '73'))	('PI3K', 'Var', (69, 73))	('SMAD4', 'Gene', (75, 80))	('MC', 'Chemical', '-', (38, 40))	('BRAF', 'Gene', (86, 90))	('MC', 'Phenotype', 'HP:0031497', (38, 40))	('mutations', 'Var', (91, 100))	('SMAD4', 'Gene', '4089', (75, 80))	('BRAF', 'Gene', '673', (86, 90))
37846	32377194	MSI is caused by inactivation of DNA mismatch repair genes (e.g., MLH1 and MSH2), triggering an uncontrolled tumor growth.	('inactivation', 'Var', (17, 29))	('uncontrolled', 'MPA', (96, 108))	('MSH2', 'Gene', (75, 79))	('triggering', 'Reg', (82, 92))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('MSH2', 'Gene', '4436', (75, 79))	('MSI', 'Disease', (0, 3))	('MLH1', 'Gene', '4292', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('MLH1', 'Gene', (66, 70))	('mismatch repair', 'biological_process', 'GO:0006298', ('37', '52'))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('caused by', 'Reg', (7, 16))	('tumor', 'Disease', (109, 114))
37851	32377194	Ending long-lasting debate, a new meta-analysis has clearly shown a statistically significant increased risk of colorectal cancer development in carriers of BRCA1 mutations.	('colorectal cancer', 'Disease', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('carriers', 'Reg', (145, 153))	('mutations', 'Var', (163, 172))	('BRCA1', 'Gene', (157, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('BRCA1', 'Gene', '672', (157, 162))
37852	32377194	In this study, we aim to further investigate the relationship between BRCA mutations and mucinous histology in colorectal cancer patients.	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('patients', 'Species', '9606', (129, 137))	('mucin', 'Gene', (89, 94))	('BRCA', 'Gene', '672', (70, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('BRCA', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal cancer', 'Disease', (111, 128))	('mucin', 'Gene', '100508689', (89, 94))
37865	32377194	It is important to mention that TMB assessed by WES is usually reported as the total number of mutations per tumor, while TMB outputs from gene panel assays are usually normalized to mutations per megabase (mut/Mb) because they differ in the number of genes and target region size.	('TMB', 'Chemical', '-', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('mutations', 'Var', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('TMB', 'Chemical', '-', (32, 35))	('tumor', 'Disease', (109, 114))
37867	32377194	To assess whether there is a higher incidence of BRCA1/2 mutations in MC tumors than in AC tumors, we performed an analysis of a cohort of targeted sequencing of 1134 metastatic colorectal cancer samples (hereby the MSKCC database).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (178, 195))	('BRCA1/2', 'Gene', '672;675', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('colorectal cancer', 'Disease', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('MC', 'Phenotype', 'HP:0031497', (70, 72))	('mutations', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Disease', (73, 79))	('colorectal cancer', 'Disease', 'MESH:D015179', (178, 195))	('MC tumors', 'Disease', 'MESH:D009369', (70, 79))	('MC tumors', 'Disease', (70, 79))	('BRCA1/2', 'Gene', (49, 56))
37869	32377194	Our analysis showed a significantly higher incidence of BRCA mutations in the MC tumors compared to AC (19/128 MC 14.8%, 30/725 AC 4.1%, p value <0.001, by chi-squared).	('MC', 'Phenotype', 'HP:0031497', (111, 113))	('MC tumors', 'Disease', 'MESH:D009369', (78, 87))	('MC', 'Phenotype', 'HP:0031497', (78, 80))	('MC tumors', 'Disease', (78, 87))	('BRCA', 'Gene', '672', (56, 60))	('mutations', 'Var', (61, 70))	('BRCA', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('MC 14', 'Species', '2588904', (111, 116))
37874	32377194	We noticed that BRCA mutations were linked to a higher mutation count in a statistically significant manner.	('BRCA', 'Gene', '672', (16, 20))	('mutation count', 'MPA', (55, 69))	('BRCA', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
37875	32377194	We found a much larger amount of mutations in patients with mutated BRCA somatic genotypes versus patients with the wild-type (WT) somatic BRCA genotype (average of 59.4 versus 9.4, respectively, p value <0.001).	('patients', 'Species', '9606', (46, 54))	('mutations', 'Var', (33, 42))	('patients', 'Species', '9606', (98, 106))	('BRCA', 'Gene', '672', (139, 143))	('mutated', 'Var', (60, 67))	('BRCA', 'Gene', '672', (68, 72))	('BRCA', 'Gene', (139, 143))	('BRCA', 'Gene', (68, 72))
37876	32377194	While tumors with BRCA mutations indeed tended to have higher mutation counts (Figure 1(a)), the analysis revealed two distinct groups of BRCA-mutated tumors that differ significantly in their mutation count: a group with high mutation count and group with low mutation count.	('mutation counts', 'MPA', (62, 77))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('BRCA', 'Gene', '672', (138, 142))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('BRCA', 'Gene', '672', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('BRCA', 'Gene', (138, 142))	('tumors', 'Disease', (6, 12))	('mutations', 'Var', (23, 32))	('BRCA', 'Gene', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('higher', 'PosReg', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
37881	32377194	Nearly 0.40 of the variances in the mutation count between the different patients with BRCA mutations could be explained using these variables alone.	('BRCA', 'Gene', '672', (87, 91))	('patients', 'Species', '9606', (73, 81))	('BRCA', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))
37886	32377194	Since KRAS, BRAF, and PI3K mutations are known to have a higher frequency in MC patients, we performed sequencing tests for those mutations.	('mutations', 'Var', (27, 36))	('KRAS', 'Gene', '3845', (6, 10))	('patients', 'Species', '9606', (80, 88))	('BRAF', 'Gene', (12, 16))	('MC', 'Chemical', '-', (77, 79))	('BRAF', 'Gene', '673', (12, 16))	('MC', 'Phenotype', 'HP:0031497', (77, 79))	('PI3K mutations', 'Var', (22, 36))	('KRAS', 'Gene', (6, 10))
37887	32377194	However, we found no statistically significant differences in the frequencies of these mutations between the two groups, though there was a positive trend in the KRAS mutations towards MC group (p = 0.08).	('KRAS', 'Gene', (162, 166))	('KRAS', 'Gene', '3845', (162, 166))	('mutations', 'Var', (167, 176))	('MC', 'Chemical', '-', (185, 187))	('MC', 'Phenotype', 'HP:0031497', (185, 187))
37889	32377194	All patients were tested for somatic BRCA1/2 mutations (Figure 3); among 70 CRC patients, 23 revealed a nonsynonymous BRCA mutation (i.e., 32%).	('BRCA1/2', 'Gene', '672;675', (37, 44))	('patients', 'Species', '9606', (80, 88))	('mutation', 'Var', (123, 131))	('BRCA', 'Gene', '672', (118, 122))	('CRC', 'Phenotype', 'HP:0003003', (76, 79))	('BRCA', 'Gene', '672', (37, 41))	('nonsynonymous', 'Var', (104, 117))	('BRCA', 'Gene', (118, 122))	('BRCA1/2', 'Gene', (37, 44))	('patients', 'Species', '9606', (4, 12))	('BRCA', 'Gene', (37, 41))
37890	32377194	Our cohort presents a trend towards a higher frequency of nonsynonymous mutations in either BRCA1 or BRCA2 in MC tumors compared to AC tumors, but it is not statistically significant (12/30, 40% of MC group, 11/40, 27% of AC group, p value = 0.2705, by chi-squared test).	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (113, 119))	('BRCA1', 'Gene', (92, 97))	('tumors', 'Disease', (135, 141))	('MC', 'Chemical', '-', (110, 112))	('MC tumors', 'Disease', (110, 119))	('nonsynonymous mutations', 'Var', (58, 81))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('MC', 'Chemical', '-', (198, 200))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('MC', 'Phenotype', 'HP:0031497', (110, 112))	('BRCA2', 'Gene', (101, 106))	('MC', 'Phenotype', 'HP:0031497', (198, 200))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('BRCA2', 'Gene', '675', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('BRCA1', 'Gene', '672', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('MC tumors', 'Disease', 'MESH:D009369', (110, 119))
37891	32377194	However, when analyzing BRCA2 mutations separately, we did observe a trend towards a higher frequency of mutations in the MC group (9/29, 31% of MC group, 6/40, 15% of AC group).	('MC', 'Phenotype', 'HP:0031497', (145, 147))	('BRCA2', 'Gene', '675', (24, 29))	('MC', 'Chemical', '-', (122, 124))	('MC', 'Phenotype', 'HP:0031497', (122, 124))	('mutations', 'Var', (105, 114))	('mutations', 'Var', (30, 39))	('BRCA2', 'Gene', (24, 29))	('MC', 'Chemical', '-', (145, 147))
37892	32377194	Additionally, two pathogenic mutations of BRCA2 were present only in the MC group (c.7480 C > T and c.1670 T > C).	('c.7480 C > T', 'Mutation', 'rs80358972', (83, 95))	('c.7480 C > T', 'Var', (83, 95))	('BRCA2', 'Gene', '675', (42, 47))	('c.1670 T > C', 'Mutation', 'c.1670T>C', (100, 112))	('c.1670 T > C', 'Var', (100, 112))	('MC', 'Phenotype', 'HP:0031497', (73, 75))	('BRCA2', 'Gene', (42, 47))	('MC', 'Chemical', '-', (73, 75))
37893	32377194	Notably, one common mutation (c.8850 G > T) comprised half of the BRCA2 mutations detected in the AC group.	('BRCA2', 'Gene', (66, 71))	('BRCA2', 'Gene', '675', (66, 71))	('c.8850 G > T', 'Mutation', 'rs28897754', (30, 42))	('c.8850 G > T', 'Var', (30, 42))
37894	32377194	On the BRCA1 gene, the same pathogenic mutation c.68_69delAG was present in both MC and AC groups.	('c.68_69delAG', 'Mutation', 'rs386833395', (48, 60))	('BRCA1', 'Gene', '672', (7, 12))	('MC', 'Chemical', '-', (81, 83))	('MC', 'Phenotype', 'HP:0031497', (81, 83))	('BRCA1', 'Gene', (7, 12))	('c.68_69delAG', 'Var', (48, 60))
37896	32377194	Fourteen patients were assembled in an attempt to provide a further outlook towards the role of BRCA mutations as a marker of high TMB and the relation to MC (MC: 4 BRCA-mutated, 5 BRCA wild-type (WT); AC: 2 BRCA-mutated, 3 BRCA WT).	('patients', 'Species', '9606', (9, 17))	('BRCA', 'Gene', '672', (165, 169))	('BRCA', 'Gene', '672', (96, 100))	('mutations', 'Var', (101, 110))	('BRCA', 'Gene', '672', (224, 228))	('BRCA', 'Gene', (181, 185))	('BRCA', 'Gene', (165, 169))	('BRCA', 'Gene', (96, 100))	('BRCA', 'Gene', (224, 228))	('MC', 'Phenotype', 'HP:0031497', (155, 157))	('BRCA', 'Gene', '672', (208, 212))	('TMB', 'Chemical', '-', (131, 134))	('BRCA', 'Gene', (208, 212))	('MC', 'Chemical', '-', (155, 157))	('MC', 'Chemical', '-', (159, 161))	('MC', 'Phenotype', 'HP:0031497', (159, 161))	('BRCA', 'Gene', '672', (181, 185))
37900	32377194	In the current work, we have suggested a novel correlation between CRC histology, mutational burden, and BRCA mutations.	('mutations', 'Var', (110, 119))	('CRC', 'Disease', (67, 70))	('BRCA', 'Gene', '672', (105, 109))	('CRC', 'Phenotype', 'HP:0003003', (67, 70))	('BRCA', 'Gene', (105, 109))
37901	32377194	Our analysis of the MSKCC database detected a statistically significant higher incidence of BRCA mutations in the MC group as listed above (19/128 MC 14.8%, 30/725 AC 4.1%, p value <0.001, by chi-squared test).	('MC', 'Phenotype', 'HP:0031497', (114, 116))	('mutations', 'Var', (97, 106))	('BRCA', 'Gene', '672', (92, 96))	('MC', 'Chemical', '-', (147, 149))	('higher', 'PosReg', (72, 78))	('MC 14', 'Species', '2588904', (147, 152))	('MC', 'Phenotype', 'HP:0031497', (147, 149))	('BRCA', 'Gene', (92, 96))	('MC', 'Chemical', '-', (114, 116))
37903	32377194	Our analysis might shed a light into the relationship between BRCA mutations and high mutation counts, since the mutated BRCA group has shown higher mutation counts compared with the BRCA WT group (average of 59.4 versus 9.4, respectively, p value <0.001).	('BRCA', 'Gene', '672', (62, 66))	('BRCA', 'Gene', '672', (121, 125))	('mutation counts', 'MPA', (149, 164))	('BRCA', 'Gene', '672', (183, 187))	('BRCA', 'Gene', (62, 66))	('BRCA', 'Gene', (121, 125))	('BRCA', 'Gene', (183, 187))	('mutated', 'Var', (113, 120))	('higher', 'PosReg', (142, 148))
37904	32377194	Furthermore, we demonstrated two distinct groups of tumors with BRCA mutations: a high-mutation-count group with both mucinous histology and high MSI and a low-mutation-count group with both adenocarcinoma histology and low MSI score.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutations', 'Var', (69, 78))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('adenocarcinoma', 'Disease', 'MESH:D000230', (191, 205))	('BRCA', 'Gene', '672', (64, 68))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('mucin', 'Gene', '100508689', (118, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('BRCA', 'Gene', (64, 68))	('mucin', 'Gene', (118, 123))	('adenocarcinoma', 'Disease', (191, 205))
37907	32377194	To further study what variables determine the mutation count, we constructed a linear regression model demonstrating that nearly 0.4 of the variance in the mutation count between the different patients with BRCA mutations could be explained using a small number of variables (Table 2, Table 3).	('BRCA', 'Gene', '672', (207, 211))	('patients', 'Species', '9606', (193, 201))	('BRCA', 'Gene', (207, 211))	('mutations', 'Var', (212, 221))
37909	32377194	Since the linear regression model indicated that mucinous histology, and not MSI, is the best predictor of mutation counts, it is possible that the BRCA-mutated low-MSI, high-mutation-count group is associated with mucinous histology.	('mucin', 'Gene', (215, 220))	('associated', 'Reg', (199, 209))	('BRCA', 'Gene', '672', (148, 152))	('mucin', 'Gene', '100508689', (49, 54))	('low-MSI', 'Var', (161, 168))	('BRCA', 'Gene', (148, 152))	('mucin', 'Gene', '100508689', (215, 220))	('mucin', 'Gene', (49, 54))
37911	32377194	With the intention to robustly establish the link between MC histology and BRCA mutations, we tested a cohort of AC and MC patients with similar background features in our medical center (Figure 3).	('mutations', 'Var', (80, 89))	('MC', 'Chemical', '-', (120, 122))	('MC', 'Phenotype', 'HP:0031497', (120, 122))	('patients', 'Species', '9606', (123, 131))	('MC', 'Chemical', '-', (58, 60))	('MC', 'Phenotype', 'HP:0031497', (58, 60))	('BRCA', 'Gene', '672', (75, 79))	('BRCA', 'Gene', (75, 79))
37912	32377194	Unfortunately, we could not reestablish the statistically significant link between BRCA mutations and the MC group (12/30, 40% of MC group and 11/40, 27% of AC group were BRCA-mutated).	('BRCA', 'Gene', (171, 175))	('BRCA', 'Gene', '672', (83, 87))	('MC', 'Chemical', '-', (130, 132))	('MC', 'Phenotype', 'HP:0031497', (130, 132))	('BRCA', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('MC', 'Chemical', '-', (106, 108))	('MC', 'Phenotype', 'HP:0031497', (106, 108))	('BRCA', 'Gene', '672', (171, 175))
37913	32377194	Notably, even mutations that are known to be found in significantly higher incidence in MC tumors such as KRAS, BRAF, and PI3K were not seen in our cohort, prompting a suspicion that the lack of association is related to limitations of this specific cohort itself, and may explain our failure to reestablish the link between BRCA mutations and MC histology.	('MC', 'Chemical', '-', (344, 346))	('KRAS', 'Gene', '3845', (106, 110))	('MC', 'Phenotype', 'HP:0031497', (344, 346))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('BRCA', 'Gene', (325, 329))	('MC tumors', 'Disease', 'MESH:D009369', (88, 97))	('MC tumors', 'Disease', (88, 97))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('MC', 'Chemical', '-', (88, 90))	('MC', 'Phenotype', 'HP:0031497', (88, 90))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('KRAS', 'Gene', (106, 110))	('mutations', 'Var', (14, 23))	('BRCA', 'Gene', '672', (325, 329))
37916	32377194	However, we observed a trend towards a higher frequency of BRCA2 mutations in the MC group (9/29, 31% of MC group, 6/40, 15% of AC group).	('BRCA2', 'Gene', '675', (59, 64))	('MC', 'Chemical', '-', (105, 107))	('MC', 'Phenotype', 'HP:0031497', (105, 107))	('MC', 'Chemical', '-', (82, 84))	('MC', 'Phenotype', 'HP:0031497', (82, 84))	('BRCA2', 'Gene', (59, 64))	('mutations', 'Var', (65, 74))
37922	32377194	BRCA pathogenic mutations were detected in 1.1% (n = 72) of tumors, while BRCA2 in 2.8% (n = 179).	('BRCA', 'Gene', (0, 4))	('BRCA2', 'Gene', (74, 79))	('mutations', 'Var', (16, 25))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('BRCA2', 'Gene', '675', (74, 79))	('BRCA', 'Gene', '672', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('BRCA', 'Gene', '672', (74, 78))	('BRCA', 'Gene', (74, 78))	('tumors', 'Disease', (60, 66))
37924	32377194	Among MSS cases with POLE wild-type status, BRCA1 (p = 0.0269) and BRCA2 (p = 0.0151) mutations were associated with high TMB and combining both BRCA1/2 mutations led to an even higher TMB (3.6%; p = 0.001).	('mutations', 'Var', (86, 95))	('BRCA1/2', 'Gene', (145, 152))	('BRCA1', 'Gene', (44, 49))	('TMB', 'Chemical', '-', (122, 125))	('high TMB', 'MPA', (117, 125))	('TMB', 'Chemical', '-', (185, 188))	('BRCA1/2', 'Gene', '672;675', (145, 152))	('BRCA1', 'Gene', '672', (145, 150))	('BRCA2', 'Gene', (67, 72))	('higher', 'PosReg', (178, 184))	('BRCA1', 'Gene', (145, 150))	('BRCA1', 'Gene', '672', (44, 49))	('BRCA2', 'Gene', '675', (67, 72))	('TMB', 'MPA', (185, 188))
37925	32377194	BRCA1/2 mutations are more frequent in MSI-H and independently associated with higher TMB, pathogenic POLE mutations, and right-sided tumors in MSI-H CRCs.	('TMB', 'Disease', (86, 89))	('MSI-H', 'Disease', (39, 44))	('tumors', 'Disease', (134, 140))	('BRCA1/2', 'Gene', '672;675', (0, 7))	('mutations', 'Var', (107, 116))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('TMB', 'Chemical', '-', (86, 89))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('MSI-H CRCs', 'Disease', (144, 154))	('associated', 'Reg', (63, 73))	('mutations', 'Var', (8, 17))	('MSI-H CRCs', 'Disease', 'MESH:D000848', (144, 154))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('higher', 'PosReg', (79, 85))	('BRCA1/2', 'Gene', (0, 7))	('CRC', 'Phenotype', 'HP:0003003', (150, 153))
37926	32377194	Potentially, the findings may indicate that the lack of a functioning DNA repair mechanism might be the driver for a higher-mutation load or alternatively that the mutations in the BRCA genes themselves are passenger mutations due to the overall increased mutations load.	('BRCA', 'Gene', (181, 185))	('DNA repair', 'biological_process', 'GO:0006281', ('70', '80'))	('DNA', 'cellular_component', 'GO:0005574', ('70', '73'))	('mutations load', 'MPA', (256, 270))	('increased', 'PosReg', (246, 255))	('mutations', 'Var', (164, 173))	('BRCA', 'Gene', '672', (181, 185))
37927	32377194	An intriguing question might be "what is the further impact of our findings on the evaluation of CRC patients of Jewish-Ashkenazi ancestry, for whom the incidence of germline BRCA and Lynch syndrome mutations are higher?"	('patients', 'Species', '9606', (101, 109))	('BRCA', 'Gene', (175, 179))	('Lynch syndrome', 'Disease', (184, 198))	('Lynch syndrome', 'Disease', 'MESH:D003123', (184, 198))	('CRC', 'Phenotype', 'HP:0003003', (97, 100))	('mutations', 'Var', (199, 208))	('BRCA', 'Gene', '672', (175, 179))
37929	32377194	Moreover, we tried to utilize PARP inhibition approach in one of the patients in our cohort, as PARP inhibition is synthetically lethal in BRCA-deficient tumors (FDA approved for ovarian, pancreatic, and breast tumors with BRCA1/2 mutation).	('BRCA1/2', 'Gene', (223, 230))	('breast tumors', 'Disease', 'MESH:D001943', (204, 217))	('PARP', 'Gene', '1302', (30, 34))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('PARP', 'Gene', (30, 34))	('breast tumors', 'Disease', (204, 217))	('PARP', 'Gene', '1302', (96, 100))	('PARP', 'Gene', (96, 100))	('BRCA-deficient tumors', 'Disease', (139, 160))	('ovarian, pancreatic', 'Disease', 'MESH:D010195', (179, 198))	('BRCA-deficient tumors', 'Disease', 'MESH:D009369', (139, 160))	('BRCA1/2', 'Gene', '672;675', (223, 230))	('breast tumors', 'Phenotype', 'HP:0100013', (204, 217))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('patients', 'Species', '9606', (69, 77))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('mutation', 'Var', (231, 239))
37931	32377194	He underwent somatic tumor analysis that showed pathogenic BRCA1 mutation (c.68_69delAG), later proved to be germline.	('BRCA1', 'Gene', '672', (59, 64))	('tumor', 'Disease', (21, 26))	('c.68_69delAG', 'Var', (75, 87))	('BRCA1', 'Gene', (59, 64))	('c.68_69delAG', 'Mutation', 'rs386833395', (75, 87))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('pathogenic', 'Reg', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
37935	32377194	In addition, emerging evidence suggests that BRCA1 mutation may even influence the survival outcomes among metastatic CRC patients treated with Oxaliplatin or Irinotecan-based regimens.	('survival outcomes', 'CPA', (83, 100))	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (144, 155))	('metastatic CRC', 'Disease', (107, 121))	('BRCA1', 'Gene', '672', (45, 50))	('Irinotecan', 'Chemical', 'MESH:D000077146', (159, 169))	('BRCA1', 'Gene', (45, 50))	('patients', 'Species', '9606', (122, 130))	('CRC', 'Phenotype', 'HP:0003003', (118, 121))	('mutation', 'Var', (51, 59))	('influence', 'Reg', (69, 78))
37938	32377194	Further studies are required to elucidate the real-world value of TMB analysis in MC colorectal cancer with or without BRCA1/2 mutation.	('TMB', 'Chemical', '-', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutation', 'Var', (127, 135))	('MC', 'Phenotype', 'HP:0031497', (82, 84))	('MC colorectal cancer', 'Disease', 'MESH:D015179', (82, 102))	('BRCA1/2', 'Gene', (119, 126))	('BRCA1/2', 'Gene', '672;675', (119, 126))	('MC colorectal cancer', 'Disease', (82, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
37943	32126023	Using the methylation data, the methylation status of 2 CpG sites (cg07807470 and cg15161854) and 2 CpG sites (cg00953154 and cg16459265) were negatively correlated with SNHG3 and SNHG15 expression, respectively.	('negatively', 'NegReg', (143, 153))	('cg15161854', 'Var', (82, 92))	('cg16459265', 'Var', (126, 136))	('cg07807470', 'Chemical', '-', (67, 77))	('SNHG3', 'Gene', '8420', (170, 175))	('expression', 'MPA', (187, 197))	('SNHG3', 'Gene', (170, 175))	('SNHG15', 'Gene', (180, 186))	('cg16459265', 'Chemical', '-', (126, 136))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('methylation', 'MPA', (32, 43))	('cg15161854', 'Chemical', '-', (82, 92))	('cg07807470', 'Var', (67, 77))	('SNHG15', 'Gene', '285958', (180, 186))	('methylation', 'biological_process', 'GO:0032259', ('10', '21'))	('cg00953154', 'Var', (111, 121))
37949	32126023	Mutations and inactivation of VHL lead to accumulation of HIF-alpha proteins and upregulation of HIF-alpha target genes, which has been considered as a key mechanism to promote the progression of ccRCC.	('HIF-alpha proteins', 'Protein', (58, 76))	('VHL', 'Gene', (30, 33))	('accumulation', 'PosReg', (42, 54))	('inactivation', 'Var', (14, 26))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('upregulation', 'PosReg', (81, 93))	('Mutations', 'Var', (0, 9))	('RCC', 'Disease', (198, 201))	('VHL', 'Gene', '7428', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('promote', 'PosReg', (169, 176))
37956	32126023	snoRNAs have been considered to be one of the best characterized classes of non-coding RNAs (ncRNAs) with a wide variety of cellular functions, such as chemical RNA modifications (such as methylations and pseudouridylations), pre-RNA processing and alternative splicing control.	('methylations', 'Var', (188, 200))	('snoRNA', 'Gene', (0, 6))	('snoRNA', 'Gene', '85391', (0, 6))
37969	32126023	Moreover, results of the log-rank test also showed that the high SNHG15 expression group had significantly shorter RFS than its low expression group (Figure 3B).	('high', 'Var', (60, 64))	('RFS', 'MPA', (115, 118))	('SNHG15', 'Gene', (65, 71))	('shorter', 'NegReg', (107, 114))	('SNHG15', 'Gene', '285958', (65, 71))
37980	32126023	The analysis results showed that compared with adjacent normal tissues, 2 sites of SNHG3 DNA, 3 sites of SNHG15 DNA, 6 sites of SNHG12 DNA and 8 sites of SNHG17 DNA were significantly hypomethylated in ccRCC (Figure 5E-5H).	('hypomethylated', 'Var', (184, 198))	('SNHG3', 'Gene', (83, 88))	('SNHG17', 'Gene', '388796', (154, 160))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('SNHG12', 'Gene', (128, 134))	('RCC', 'Disease', (204, 207))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('SNHG15', 'Gene', '285958', (105, 111))	('SNHG3', 'Gene', '8420', (83, 88))	('SNHG12', 'Gene', '85028', (128, 134))	('SNHG15', 'Gene', (105, 111))	('SNHG17', 'Gene', (154, 160))
37982	32126023	Correlation analysis results showed that the expressions of SNHG3, SNHG15, SNHG12 and SNHG17 were negatively associated with the methylation levels of 2 sites (cg07807470 r=-0.1963, cg15161854 r=-0.2752), 3 sites (cg00953154 r=-0.4113, cg03440944 r=-0.3342, cg16459265 r=-0.4082), 6 sites (cg03542031 r=-0.5038, cg07033395 r=-0.394, cg12640482 r=-0.3214, cg15601452 r=-0.3814, cg19712659 r=-0.5023, cg26328951 r=-0.4231) and 3 sites (cg04560741 r=-0.1919, cg13610455 r=-0.2631, cg24310959 r=-0.2744), respectively (Figure 6A-6D).	('cg13610455 r=-0.2631', 'Var', (456, 476))	('SNHG17', 'Gene', (86, 92))	('cg04560741 r=-0.1919', 'Var', (434, 454))	('cg16459265', 'Chemical', '-', (258, 268))	('negatively', 'NegReg', (98, 108))	('cg00953154 r=-0.4113', 'Var', (214, 234))	('cg16459265 r=-0.4082', 'Var', (258, 278))	('SNHG3', 'Gene', '8420', (60, 65))	('cg03440944 r=-0.3342', 'Var', (236, 256))	('SNHG12', 'Gene', (75, 81))	('SNHG17', 'Gene', '388796', (86, 92))	('cg15161854', 'Chemical', '-', (182, 192))	('methylation levels', 'MPA', (129, 147))	('cg12640482 r=-0.3214', 'Var', (333, 353))	('cg07807470', 'Chemical', '-', (160, 170))	('cg07033395 r=-0.394', 'Var', (312, 331))	('cg24310959 r=-0.2744', 'Var', (478, 498))	('SNHG15', 'Gene', (67, 73))	('cg15161854 r=-0.2752', 'Var', (182, 202))	('SNHG12', 'Gene', '85028', (75, 81))	('cg07807470', 'Var', (160, 170))	('methylation', 'biological_process', 'GO:0032259', ('129', '140'))	('cg26328951 r=-0.4231', 'Var', (399, 419))	('cg15601452 r=-0.3814', 'Var', (355, 375))	('SNHG15', 'Gene', '285958', (67, 73))	('cg19712659 r=-0.5023', 'Var', (377, 397))	('SNHG3', 'Gene', (60, 65))	('cg03542031 r=-0.5038', 'Var', (290, 310))
37983	32126023	Moreover, results of the log-rank test showed that low methylation levels of cg07807470 (SNHG3), cg15161854 (SNHG3), cg00953154 (SNHG15), cg16459265 (SNHG15) and cg07033395 (SNHG12) were significantly associated with the shorter OS of ccRCC patients (Figure 6E-6G).	('SNHG3', 'Gene', '8420', (109, 114))	('cg07033395', 'Var', (162, 172))	('SNHG15', 'Gene', '285958', (129, 135))	('SNHG3', 'Gene', (89, 94))	('cg15161854', 'Var', (97, 107))	('SNHG15', 'Gene', (150, 156))	('SNHG12', 'Gene', '85028', (174, 180))	('cg15161854', 'Chemical', '-', (97, 107))	('SNHG15', 'Gene', '285958', (150, 156))	('cg16459265', 'Chemical', '-', (138, 148))	('SNHG3', 'Gene', '8420', (89, 94))	('OS', 'Chemical', '-', (229, 231))	('RCC', 'Disease', (237, 240))	('SNHG15', 'Gene', (129, 135))	('cg00953154', 'Var', (117, 127))	('SNHG3', 'Gene', (109, 114))	('RCC', 'Phenotype', 'HP:0005584', (237, 240))	('patients', 'Species', '9606', (241, 249))	('cg07807470', 'Var', (77, 87))	('cg07807470', 'Chemical', '-', (77, 87))	('methylation', 'MPA', (55, 66))	('cg16459265', 'Var', (138, 148))	('low', 'NegReg', (51, 54))	('SNHG12', 'Gene', (174, 180))	('RCC', 'Disease', 'MESH:C538614', (237, 240))
37984	32126023	Furthermore, low methylation levels of cg07807470 (SNHG3), cg15161854 (SNHG3) and cg16459265 (SNHG15) were also related to the shorter RFS (Figure 6H, 6I).	('shorter', 'NegReg', (127, 134))	('SNHG15', 'Gene', '285958', (94, 100))	('cg16459265', 'Var', (82, 92))	('SNHG3', 'Gene', '8420', (71, 76))	('cg15161854', 'Chemical', '-', (59, 69))	('SNHG3', 'Gene', (51, 56))	('cg07807470', 'Chemical', '-', (39, 49))	('low', 'NegReg', (13, 16))	('methylation levels', 'MPA', (17, 35))	('RFS', 'MPA', (135, 138))	('cg15161854', 'Var', (59, 69))	('cg16459265', 'Chemical', '-', (82, 92))	('SNHG3', 'Gene', (71, 76))	('SNHG15', 'Gene', (94, 100))	('SNHG3', 'Gene', '8420', (51, 56))	('cg07807470', 'Var', (39, 49))
37985	32126023	Taken together, these results indicated that the expressions of SNHG3 and SNHG15 were more likely to be modulated by DNA methylation in ccRCC.	('RCC', 'Disease', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('modulated', 'Reg', (104, 113))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('SNHG15', 'Gene', '285958', (74, 80))	('SNHG3', 'Gene', '8420', (64, 69))	('SNHG3', 'Gene', (64, 69))	('DNA methylation', 'Var', (117, 132))	('SNHG15', 'Gene', (74, 80))
37990	32126023	In addition, the methylation status of 4 CpG sites (cg07807470, cg15161854, cg00953154 and cg16459265) in 15 paired clinical samples were tested through pyrosequencing.	('cg15161854', 'Var', (64, 74))	('cg16459265', 'Chemical', '-', (91, 101))	('cg07807470', 'Var', (52, 62))	('clinical samples', 'Species', '191496', (116, 132))	('cg16459265', 'Var', (91, 101))	('cg07807470', 'Chemical', '-', (52, 62))	('cg15161854', 'Chemical', '-', (64, 74))	('cg00953154', 'Var', (76, 86))
37991	32126023	The methylation levels of cg07807470, cg15161854, cg00953154 and cg16459265 were significantly lower in ccRCC compared with adjacent normal tissues (Figure 7C).	('cg07807470', 'Var', (26, 36))	('lower', 'NegReg', (95, 100))	('cg07807470', 'Chemical', '-', (26, 36))	('cg15161854', 'Var', (38, 48))	('cg00953154', 'Var', (50, 60))	('methylation levels', 'MPA', (4, 22))	('cg16459265', 'Var', (65, 75))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('cg16459265', 'Chemical', '-', (65, 75))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('cg15161854', 'Chemical', '-', (38, 48))
37992	32126023	Besides, the methylation levels of cg07807470 (r=-0.5662) and cg15161854 (r=-0.6244) were significantly negatively correlated with SNHG3 expression (Figure 7D), while the methylation levels of cg00953154 (r=-0.5461) and cg16459265 (r=-0.6629) were negatively associated with SNHG15 expression (Figure 7E), which were consistent with the results from the TCGA datasets.	('methylation', 'MPA', (13, 24))	('cg15161854', 'Chemical', '-', (62, 72))	('SNHG3', 'Gene', (131, 136))	('cg16459265', 'Var', (220, 230))	('expression', 'MPA', (137, 147))	('negatively', 'NegReg', (104, 114))	('cg00953154', 'Var', (193, 203))	('correlated', 'Interaction', (115, 125))	('SNHG15', 'Gene', (275, 281))	('cg15161854', 'Var', (62, 72))	('cg07807470', 'Var', (35, 45))	('cg16459265', 'Chemical', '-', (220, 230))	('SNHG3', 'Gene', '8420', (131, 136))	('SNHG15', 'Gene', '285958', (275, 281))	('cg07807470', 'Chemical', '-', (35, 45))
37993	32126023	Furthermore, the methylation levels of cg15161854 with a higher correlation with SNHG3 expression and cg16459265 with a higher correlation with SNHG15 expression in another 36 available ccRCC samples were tested through pyrosequencing for survival analysis.	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('cg16459265', 'Var', (102, 112))	('SNHG3', 'Gene', '8420', (81, 86))	('higher', 'PosReg', (57, 63))	('methylation levels', 'MPA', (17, 35))	('cg15161854', 'Chemical', '-', (39, 49))	('SNHG15', 'Gene', '285958', (144, 150))	('cg16459265', 'Chemical', '-', (102, 112))	('SNHG3', 'Gene', (81, 86))	('expression', 'MPA', (87, 97))	('RCC', 'Disease', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('cg15161854', 'Gene', (39, 49))	('SNHG15', 'Gene', (144, 150))
37994	32126023	Consistent with the survival analysis results of TCGA samples, our results showed that low methylation levels of cg15161854 and cg16459265 were associated with the shorter OS (Figure 7F) and RFS (Figure 7G) of ccRCC patients.	('cg15161854', 'Chemical', '-', (113, 123))	('methylation levels', 'MPA', (91, 109))	('shorter', 'NegReg', (164, 171))	('cg15161854', 'Var', (113, 123))	('OS', 'Chemical', '-', (172, 174))	('RFS', 'MPA', (191, 194))	('patients', 'Species', '9606', (216, 224))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))	('cg16459265', 'Var', (128, 138))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('RCC', 'Disease', (212, 215))	('low', 'NegReg', (87, 90))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('cg16459265', 'Chemical', '-', (128, 138))
37998	32126023	Interestingly, the modification of ribosomal biogenesis was associated with the development of cancer, suggesting that the classical function of snoRNA may contribute to the development of cancer.	('modification', 'Var', (19, 31))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Disease', (95, 101))	('snoRNA', 'Gene', '85391', (145, 151))	('ribosomal', 'MPA', (35, 44))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('snoRNA', 'Gene', (145, 151))	('associated', 'Reg', (60, 70))	('cancer', 'Disease', (189, 195))
37999	32126023	In addition to the initial evidence of snoRNA involvement in cancer development, increasing evidence has demonstrated that dysregulated small nucleolar RNA host genes may contribute to multiple cancer progression.	('snoRNA', 'Gene', (39, 45))	('snoRNA', 'Gene', '85391', (39, 45))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('small nucleolar RNA', 'cellular_component', 'GO:0005733', ('136', '155'))	('contribute', 'Reg', (171, 181))	('cancer', 'Disease', (61, 67))	('small nucleolar RNA', 'molecular_function', 'GO:0005569', ('136', '155'))	('small', 'Protein', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('dysregulated', 'Var', (123, 135))	('snoRNA', 'cellular_component', 'GO:0005733', ('39', '45'))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
38000	32126023	For example, SNHG1 was upregulated in human colorectal cancer tissues, and high SNHG1 expression was associated with shorter OS; SNHG1 contributed to sorafenib resistance by activating the Akt pathway in hepatocellular carcinoma cells; SNHG17 was upregulated in non-small-cell lung cancer (NSCLC), and the knockdown of SNHG17 inhibited the proliferation and migration and promoted the apoptosis of NSCLC cells.	('NSCLC', 'Disease', (398, 403))	('colorectal cancer', 'Disease', (44, 61))	('SNHG17', 'Gene', '388796', (319, 325))	('SNHG1', 'Gene', '23642', (236, 241))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (204, 228))	('promoted', 'PosReg', (372, 380))	('SNHG1', 'Gene', '23642', (13, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (398, 403))	('SNHG17', 'Gene', (236, 242))	('SNHG1', 'Gene', (319, 324))	('Akt', 'Gene', (189, 192))	('apoptosis', 'biological_process', 'GO:0097194', ('385', '394'))	('knockdown', 'Var', (306, 315))	('lung cancer', 'Disease', (277, 288))	('apoptosis', 'biological_process', 'GO:0006915', ('385', '394'))	('activating', 'PosReg', (174, 184))	('SNHG1', 'Gene', (80, 85))	('SNHG1', 'Gene', '23642', (129, 134))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (204, 228))	('Akt', 'Gene', '207', (189, 192))	('colorectal cancer', 'Phenotype', 'HP:0003003', (44, 61))	('SNHG17', 'Gene', '388796', (236, 242))	('NSCLC', 'Disease', 'MESH:D002289', (290, 295))	('inhibited', 'NegReg', (326, 335))	('human', 'Species', '9606', (38, 43))	('OS', 'Chemical', '-', (125, 127))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('upregulated', 'PosReg', (247, 258))	('lung cancer', 'Disease', 'MESH:D008175', (277, 288))	('NSCLC', 'Disease', (290, 295))	('hepatocellular carcinoma', 'Disease', (204, 228))	('SNHG1', 'Gene', (236, 241))	('apoptosis', 'CPA', (385, 394))	('SNHG1', 'Gene', '23642', (319, 324))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('SNHG17', 'Gene', (319, 325))	('SNHG1', 'Gene', (13, 18))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (266, 288))	('SNHG1', 'Gene', '23642', (80, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (277, 288))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('NSCLC', 'Disease', 'MESH:D002289', (398, 403))	('NSCLC', 'Phenotype', 'HP:0030358', (290, 295))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (262, 288))	('colorectal cancer', 'Disease', 'MESH:D015179', (44, 61))	('SNHG1', 'Gene', (129, 134))	('sorafenib', 'Chemical', 'MESH:D000077157', (150, 159))
38016	32126023	Moreover, a recent study demonstrated that the higher expression of SNHG3 could predict worse clinical prognosis, and knockdown of SNHG3 could significantly inhibit the proliferation and metastasis of ccRCC in vitro and in vivo.	('expression', 'MPA', (54, 64))	('SNHG3', 'Gene', (131, 136))	('knockdown', 'Var', (118, 127))	('SNHG3', 'Gene', '8420', (68, 73))	('higher', 'PosReg', (47, 53))	('metastasis', 'CPA', (187, 197))	('SNHG3', 'Gene', '8420', (131, 136))	('clinical', 'Species', '191496', (94, 102))	('proliferation', 'CPA', (169, 182))	('inhibit', 'NegReg', (157, 164))	('SNHG3', 'Gene', (68, 73))	('RCC', 'Disease', 'MESH:C538614', (203, 206))	('RCC', 'Disease', (203, 206))	('RCC', 'Phenotype', 'HP:0005584', (203, 206))
38019	32126023	Furthermore, SNHG15 was significantly upregulated in RCC tissues and cell lines compared with its adjacent normal tissues and a proximal tubule epithelial cell line, and SNHG15 knockdown could inhibit RCC proliferation, invasion and migration.	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('SNHG15', 'Gene', '285958', (170, 176))	('RCC', 'Disease', (201, 204))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('inhibit', 'NegReg', (193, 200))	('upregulated', 'PosReg', (38, 49))	('knockdown', 'Var', (177, 186))	('invasion', 'CPA', (220, 228))	('RCC', 'Disease', (53, 56))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('SNHG15', 'Gene', '285958', (13, 19))	('SNHG15', 'Gene', (170, 176))	('migration', 'CPA', (233, 242))	('SNHG15', 'Gene', (13, 19))
38021	32126023	Epigenetic alterations such as DNA methylation, histone modification, and loss of genome imprinting play crucial roles in the formation and progression of cancer.	('DNA methylation', 'Var', (31, 46))	('formation', 'biological_process', 'GO:0009058', ('126', '135'))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('histone', 'MPA', (48, 55))	('loss', 'NegReg', (74, 78))	('DNA methylation', 'biological_process', 'GO:0006306', ('31', '46'))	('histone modification', 'biological_process', 'GO:0016570', ('48', '68'))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
38023	32126023	For example, hypermethylation of the CpG shore of the Shh gene resulted in Shh loss, and inhibition of DNA methylation increased Shh expression to halt the initiation of bladder cancer at the early stage of progression; DNA methylation at an enhancer of the three prime repair exonuclease 2 gene (TREX2) was linked to decreased TREX2 gene expression and protein expression, which may affect drug-induced DNA damage repair in laryngeal cancer; and Epigenetic Silencing of miRNA-338-5p and miRNA-421 drived SPINK1-Positive Prostate Cancer.	('Prostate Cancer', 'Disease', (521, 536))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('laryngeal cancer', 'Disease', 'MESH:D007822', (425, 441))	('TREX2', 'Gene', '11219', (297, 302))	('decreased', 'NegReg', (318, 327))	('Epigenetic Silencing', 'Var', (447, 467))	('TREX2', 'Gene', '11219', (328, 333))	('Shh loss', 'Disease', (75, 83))	('Shh', 'Gene', '6469', (129, 132))	('laryngeal cancer', 'Disease', (425, 441))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (425, 441))	('initiation of bladder cancer', 'Disease', 'MESH:D001749', (156, 184))	('three prime repair exonuclease 2', 'Gene', (258, 290))	('DNA methylation', 'biological_process', 'GO:0006306', ('220', '235'))	('protein', 'cellular_component', 'GO:0003675', ('354', '361'))	('Shh', 'Gene', (54, 57))	('enhancer', 'PosReg', (242, 250))	('affect', 'Reg', (384, 390))	('initiation of bladder cancer', 'Disease', (156, 184))	('Prostate Cancer', 'Disease', 'MESH:D011471', (521, 536))	('protein', 'Protein', (354, 361))	('Shh', 'Gene', (75, 78))	('DNA', 'cellular_component', 'GO:0005574', ('404', '407'))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('drived', 'Reg', (498, 504))	('Shh', 'Gene', '6469', (75, 78))	('three prime repair exonuclease 2', 'Gene', '11219', (258, 290))	('miRNA-338-5p', 'Var', (471, 483))	('Cancer', 'Phenotype', 'HP:0002664', (530, 536))	('inhibition of DNA methylation', 'biological_process', 'GO:1905642', ('89', '118'))	('Shh', 'Gene', '6469', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (435, 441))	('miRNA-421', 'Gene', (488, 497))	('Prostate Cancer', 'Phenotype', 'HP:0012125', (521, 536))	('expression', 'MPA', (339, 349))	('DNA', 'cellular_component', 'GO:0005574', ('220', '223'))	('SPINK1', 'Gene', (505, 511))	('Shh', 'Gene', (129, 132))	('SPINK1', 'Gene', '6690', (505, 511))	('TREX2', 'Gene', (297, 302))	('TREX2', 'Gene', (328, 333))	('bladder cancer', 'Phenotype', 'HP:0009725', (170, 184))	('methylation', 'Var', (224, 235))	('Shh loss', 'Disease', 'MESH:D015431', (75, 83))	('expression', 'MPA', (362, 372))	('DNA', 'Var', (220, 223))	('gene expression', 'biological_process', 'GO:0010467', ('334', '349'))
38024	32126023	Besides, a recent study reported that downregulation of CLDN7 due to promoter hypermethylation contributed to human ccRCC progression and poor prognosis, indicating DNA methylation may also play vital roles in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('CLDN7', 'Gene', (56, 61))	('downregulation', 'NegReg', (38, 52))	('CLDN7', 'Gene', '1366', (56, 61))	('human', 'Species', '9606', (110, 115))	('RCC', 'Disease', (212, 215))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('promoter hypermethylation', 'Var', (69, 94))
38026	32126023	Results showed that the expression levels of SNHG3 and SNHG15 were more likely to be modulated by methylation in ccRCC.	('SNHG3', 'Gene', (45, 50))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('expression levels', 'MPA', (24, 41))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('methylation', 'Var', (98, 109))	('SNHG15', 'Gene', (55, 61))	('modulated', 'Reg', (85, 94))	('SNHG3', 'Gene', '8420', (45, 50))	('SNHG15', 'Gene', '285958', (55, 61))
38027	32126023	The methylation levels of cg07807470 and cg15161854 were negatively associated with SNHG3 expression, and the methylation levels of cg00953154, cg03440944 and cg16459265 were negatively correlated with SNHG15 expression in ccRCC.	('SNHG3', 'Gene', '8420', (84, 89))	('cg00953154', 'Var', (132, 142))	('expression', 'MPA', (209, 219))	('cg15161854', 'Var', (41, 51))	('cg16459265', 'Var', (159, 169))	('methylation levels', 'MPA', (4, 22))	('expression', 'MPA', (90, 100))	('cg15161854', 'Chemical', '-', (41, 51))	('cg07807470', 'Chemical', '-', (26, 36))	('RCC', 'Disease', (225, 228))	('RCC', 'Phenotype', 'HP:0005584', (225, 228))	('negatively', 'NegReg', (57, 67))	('negatively', 'NegReg', (175, 185))	('cg07807470', 'Var', (26, 36))	('SNHG3', 'Gene', (84, 89))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('cg16459265', 'Chemical', '-', (159, 169))	('SNHG15', 'Gene', (202, 208))	('cg03440944', 'Var', (144, 154))	('methylation', 'MPA', (110, 121))	('SNHG15', 'Gene', '285958', (202, 208))
38028	32126023	Moreover, low methylation levels of cg07807470, cg15161854, cg00953154 and cg16459265 were significantly associated with poor OS of ccRCC patients.	('methylation levels', 'MPA', (14, 32))	('cg16459265', 'Chemical', '-', (75, 85))	('cg15161854', 'Var', (48, 58))	('cg00953154', 'Var', (60, 70))	('cg07807470', 'Chemical', '-', (36, 46))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('poor OS', 'Disease', (121, 128))	('low', 'NegReg', (10, 13))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('RCC', 'Disease', (134, 137))	('cg16459265', 'Var', (75, 85))	('OS', 'Chemical', '-', (126, 128))	('cg15161854', 'Chemical', '-', (48, 58))	('patients', 'Species', '9606', (138, 146))	('cg07807470', 'Var', (36, 46))
38029	32126023	Low methylation levels of cg07807470, cg15161854 and cg16459265 were also related to the shorter RFS.	('cg07807470', 'Var', (26, 36))	('cg16459265', 'Chemical', '-', (53, 63))	('cg07807470', 'Chemical', '-', (26, 36))	('cg15161854', 'Var', (38, 48))	('methylation levels', 'MPA', (4, 22))	('cg16459265', 'Var', (53, 63))	('Low', 'NegReg', (0, 3))	('cg15161854', 'Chemical', '-', (38, 48))
38031	32126023	Consistent with the survival analysis results of TCGA samples, our results showed that low methylation levels of cg15161854 and cg16459265 were associated with the shorter OS and RFS of ccRCC patients.	('methylation levels', 'MPA', (91, 109))	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('cg15161854', 'Var', (113, 123))	('shorter', 'Disease', (164, 171))	('OS', 'Chemical', '-', (172, 174))	('patients', 'Species', '9606', (192, 200))	('cg16459265', 'Var', (128, 138))	('RCC', 'Disease', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('cg15161854', 'Chemical', '-', (113, 123))	('low', 'NegReg', (87, 90))	('RFS', 'CPA', (179, 182))	('cg16459265', 'Chemical', '-', (128, 138))
38032	32126023	Taken together, SNHG3 and SNHG15 expression levels might be substantially modulated by DNA methylation in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('methylation', 'Var', (91, 102))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('modulated', 'Reg', (74, 83))	('SNHG15', 'Gene', '285958', (26, 32))	('SNHG3', 'Gene', (16, 21))	('SNHG15', 'Gene', (26, 32))	('expression', 'MPA', (33, 43))	('DNA methylation', 'biological_process', 'GO:0006306', ('87', '102'))	('SNHG3', 'Gene', '8420', (16, 21))
38057	30954552	KRAS mutation was associated significantly with CIMP-H2 cancers, but not CIMP-H1 cancers.	('CIMP-H2 cancers', 'Disease', (48, 63))	('CIMP-H2 cancers', 'Disease', 'MESH:D009369', (48, 63))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('CIMP-H1 cancers', 'Disease', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('associated', 'Reg', (18, 28))	('CIMP-H1 cancers', 'Disease', 'MESH:D009369', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('KRAS', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('KRAS', 'Gene', '3845', (0, 4))
38058	30954552	Congruent with increasing methylation, there was a stepwise increase in patient age from 62 years in the CIMP-negative subgroup to 75 years in the CIMP-H1 subgroup (P < .0001).	('methylation', 'Var', (26, 37))	('CIMP-neg', 'Chemical', '-', (105, 113))	('increase', 'PosReg', (60, 68))	('patient', 'Species', '9606', (72, 79))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('CIMP-H1', 'Chemical', '-', (147, 154))
38060	30954552	Polycomb Repressive Complex-2 (PRC2)-marked loci were subjected to significant gene body methylation in CIMP cancers (P < 1.6 x 10-78).	('methylation', 'biological_process', 'GO:0032259', ('89', '100'))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('methylation', 'Var', (89, 100))	('PRC2', 'Gene', (31, 35))	('CIMP cancers', 'Disease', 'MESH:D009369', (104, 116))	('CIMP cancers', 'Disease', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
38063	30954552	We show a striking association between CIMP and age, sex, and tumor location, and identify a role for gene body methylation in the progression of serrated neoplasia.	('serrated neoplasia', 'Phenotype', 'HP:0032222', (146, 164))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('neoplasia', 'Phenotype', 'HP:0002664', (155, 164))	('tumor', 'Disease', (62, 67))	('methylation', 'Var', (112, 123))	('neoplasia', 'Disease', 'MESH:D009369', (155, 164))	('CIMP', 'Chemical', '-', (39, 43))	('neoplasia', 'Disease', (155, 164))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
38064	30954552	These data support our recent findings that CIMP is uncommon in young patients and that BRAF mutant polyps in young patients may have limited potential for malignant progression.	('patients', 'Species', '9606', (70, 78))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('patients', 'Species', '9606', (116, 124))	('polyps', 'Disease', (100, 106))	('CIMP', 'Chemical', '-', (44, 48))	('mutant', 'Var', (93, 99))	('polyps', 'Disease', 'MESH:D011127', (100, 106))
38067	30954552	These CIMP subtypes are associated with important clinical and molecular features, are correlated with mutations in different epigenetic regulator genes, and show a marked relationship with patient age.	('patient', 'Species', '9606', (190, 197))	('mutations', 'Var', (103, 112))	('correlated', 'Reg', (87, 97))	('CIMP', 'Chemical', '-', (6, 10))
38070	30954552	The remaining colorectal cancers arise from serrated polyps and have activating mutations in the BRAF proto-oncogene, frequent microsatellite instability (MSI), and the CpG island methylator phenotype (CIMP).	('serrated polyps', 'Phenotype', 'HP:0032222', (44, 59))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (80, 89))	('colorectal cancer', 'Phenotype', 'HP:0003003', (14, 31))	('polyps', 'Disease', 'MESH:D011127', (53, 59))	('MSI', 'Disease', 'None', (155, 158))	('activating', 'PosReg', (69, 79))	('colorectal cancers', 'Disease', 'MESH:D015179', (14, 32))	('CIMP', 'Chemical', '-', (202, 206))	('MSI', 'Disease', (155, 158))	('colorectal cancers', 'Disease', (14, 32))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('arise', 'Reg', (33, 38))	('BRAF', 'Gene', '673', (97, 101))	('polyps', 'Disease', (53, 59))	('BRAF', 'Gene', (97, 101))	('microsatellite instability', 'MPA', (127, 153))
38072	30954552	It is well established that CIMP can result in the silencing of key genes important for tumor progression, including the tumor-suppressor gene CDKN2A and the DNA mismatch repair gene MLH1.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor-suppressor', 'Gene', (121, 137))	('tumor', 'Disease', (121, 126))	('CIMP', 'Var', (28, 32))	('CDKN2A', 'Gene', (143, 149))	('tumor-suppressor', 'Gene', '7248', (121, 137))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CDKN2A', 'Gene', '1029', (143, 149))	('MLH1', 'Gene', '4292', (183, 187))	('MLH1', 'Gene', (183, 187))	('tumor', 'Disease', (88, 93))	('CIMP', 'Chemical', '-', (28, 32))	('silencing', 'NegReg', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
38073	30954552	Gene silencing mediated by MLH1 promoter hypermethylation impairs mismatch repair function, which leads to MSI.	('hypermethylation', 'Var', (41, 57))	('impairs', 'NegReg', (58, 65))	('MLH1', 'Gene', '4292', (27, 31))	('MLH1', 'Gene', (27, 31))	('MSI', 'Disease', 'None', (107, 110))	('MSI', 'Disease', (107, 110))	('mismatch repair function', 'MPA', (66, 90))	('leads', 'Reg', (98, 103))
38075	30954552	Activation of the mitogen-activated protein kinase signaling pathway as a result of the BRAF mutation is associated highly with CIMP-high.	('mitogen-activated protein kinase signaling pathway', 'Pathway', (18, 68))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('CIMP-high', 'Disease', (128, 137))	('Activation', 'PosReg', (0, 10))	('mutation', 'Var', (93, 101))	('CIMP', 'Chemical', '-', (128, 132))
38078	30954552	CMS1, or MSI immune subtype, is characterized by MSI, BRAF mutation, and enhanced immunogenicity.	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('MSI', 'Disease', 'None', (49, 52))	('mutation', 'Var', (59, 67))	('enhanced', 'PosReg', (73, 81))	('MSI', 'Disease', (49, 52))	('MSI', 'Disease', 'None', (9, 12))	('immunogenicity', 'CPA', (82, 96))	('MSI', 'Disease', (9, 12))
38083	30954552	CIMP-high cancers are identified primarily in older patients, hence, age-related hypermethylation might prime the intestinal epigenome for serrated neoplasia-type colorectal cancers.	('serrated neoplasia', 'Phenotype', 'HP:0032222', (139, 157))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('neoplasia-type colorectal cancers', 'Disease', (148, 181))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('neoplasia', 'Phenotype', 'HP:0002664', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('CIMP-high cancers', 'Disease', (0, 17))	('prime', 'PosReg', (104, 109))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('patients', 'Species', '9606', (52, 60))	('intestinal epigenome', 'MPA', (114, 134))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('CIMP-high cancers', 'Disease', 'MESH:D009369', (0, 17))	('hypermethylation', 'Var', (81, 97))	('neoplasia-type colorectal cancers', 'Disease', 'MESH:D015179', (148, 181))
38084	30954552	Methylation also is critical in the progression of serrated pathway precursors to invasive cancer, primarily through methylation of MLH1 at the transition to dysplasia.	('dysplasia', 'Disease', 'MESH:D004476', (158, 167))	('invasive cancer', 'Disease', (82, 97))	('invasive cancer', 'Disease', 'MESH:D009362', (82, 97))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('methylation', 'Var', (117, 128))	('dysplasia', 'Disease', (158, 167))	('MLH1', 'Gene', '4292', (132, 136))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('MLH1', 'Gene', (132, 136))	('methylation', 'biological_process', 'GO:0032259', ('117', '128'))
38087	30954552	Mutations in genes encoding epigenetic enzymes have been shown to occur frequently in cancer.	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (86, 92))
38088	30954552	In this study, we define the extent and spectrum of DNA methylation changes occurring in colorectal cancers and relate this to key clinical and molecular events characteristic of defined pathways of tumor progression.	('tumor', 'Disease', (199, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('colorectal cancers', 'Disease', 'MESH:D015179', (89, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('changes', 'Var', (68, 75))	('colorectal cancers', 'Disease', (89, 107))	('DNA', 'Gene', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('methylation changes', 'Var', (56, 75))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))
38091	30954552	Twenty-nine of 216 (13.4%) cancers had a BRAF V600E mutation, and 75 of 216 (34.7%) cancers were mutated at KRAS codons 12 or 13.	('KRAS', 'Gene', (108, 112))	('V600E', 'Mutation', 'rs113488022', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('KRAS', 'Gene', '3845', (108, 112))	('cancers', 'Disease', (84, 91))	('V600E', 'Var', (46, 51))	('BRAF', 'Gene', '673', (41, 45))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('BRAF', 'Gene', (41, 45))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('cancers', 'Disease', (27, 34))
38094	30954552	TP53 was mutated in 78 of 185 (42.2%) cancers.	('TP53', 'Gene', '7157', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('TP53', 'Gene', (0, 4))	('mutated', 'Var', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('cancers', 'Disease', (38, 45))
38095	30954552	MSI was associated significantly with BRAF mutation (18 of 29 BRAF mutant vs 9 of 187 BRAF wild-type cancers; P < .0001).	('MSI', 'Disease', 'None', (0, 3))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('mutation', 'Var', (43, 51))	('cancers', 'Disease', (101, 108))	('BRAF', 'Gene', '673', (38, 42))	('BRAF', 'Gene', '673', (86, 90))	('MSI', 'Disease', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('BRAF', 'Gene', (38, 42))	('mutant', 'Var', (67, 73))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('BRAF', 'Gene', (86, 90))
38097	30954552	CIMP-high was associated significantly with BRAF mutation compared with BRAF wild-type cancers (19 of 29 vs 5 of 186; P < .0001).	('cancers', 'Disease', (87, 94))	('BRAF', 'Gene', '673', (44, 48))	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', (44, 48))	('CIMP-high', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('mutation', 'Var', (49, 57))	('CIMP', 'Chemical', '-', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('BRAF', 'Gene', '673', (72, 76))
38098	30954552	CIMP-low was associated significantly with KRAS mutation compared with KRAS wild-type cancers (26 of 75 [34.6%] vs 18 of 141 [12.8%]; P < .001).	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('KRAS', 'Gene', (43, 47))	('KRAS', 'Gene', (71, 75))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('CIMP-low', 'Var', (0, 8))	('KRAS', 'Gene', '3845', (71, 75))	('CIMP', 'Chemical', '-', (0, 4))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('KRAS', 'Gene', '3845', (43, 47))
38105	30954552	We observed no differences in cancer stage at diagnosis and methylation cluster.	('methylation', 'Var', (60, 71))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
38107	30954552	TP53 was mutated in 12 of 21 (57.1%) CIMP-H1 cluster cancers.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cluster cancers', 'Disease', 'MESH:D009369', (45, 60))	('mutated', 'Var', (9, 16))	('cluster cancers', 'Disease', (45, 60))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('CIMP-H1', 'Chemical', '-', (37, 44))
38113	30954552	CIMP-L1 cancers were significantly enriched for KRAS mutation (65.4%; P < .0001), and were identified equally in the distal and proximal colon.	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('KRAS', 'Gene', (48, 52))	('mutation', 'Var', (53, 61))	('KRAS', 'Gene', '3845', (48, 52))	('CIMP-L1 cancers', 'Disease', 'MESH:C536029', (0, 15))	('CIMP-L1 cancers', 'Disease', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))
38115	30954552	CIMP-L2 cancers mutate KRAS with relative infrequency when compared with CIMP-H2 and CIMP-L1 cancers (28.8%), and are significantly enriched for distal colonic and rectal locations (50% and 26.6%, for distal and rectal locations, respectively; P < .0001).	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('mutate', 'Var', (16, 22))	('CIMP-L1 cancers', 'Disease', (85, 100))	('KRAS', 'Gene', '3845', (23, 27))	('CIMP-L2 cancers', 'Disease', 'MESH:D054198', (0, 15))	('distal colonic', 'Disease', (145, 159))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('KRAS', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('CIMP-H2', 'Chemical', '-', (73, 80))	('CIMP-L2 cancers', 'Disease', (0, 15))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('CIMP-L1 cancers', 'Disease', 'MESH:C536029', (85, 100))
38118	30954552	We did not identify a BRAF mutation in any CIMP-neg cancers.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('BRAF', 'Gene', '673', (22, 26))	('CIMP-neg', 'Chemical', '-', (43, 51))	('mutation', 'Var', (27, 35))	('BRAF', 'Gene', (22, 26))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
38121	30954552	We sequenced hotspots on exons 11 and 15 of BRAF, codon 61 in KRAS, and exon 18 in EGFR in CIMP-H1/H2 cancers that were wild-type at BRAF V600E and KRAS codons 12 and 13, however, we did not identify any mutations in these regions.	('EGFR', 'Gene', '1956', (83, 87))	('KRAS', 'Gene', (148, 152))	('KRAS', 'Gene', (62, 66))	('BRAF', 'Gene', '673', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('KRAS', 'Gene', '3845', (62, 66))	('V600E', 'Var', (138, 143))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (44, 48))	('EGFR', 'Gene', (83, 87))	('KRAS', 'Gene', '3845', (148, 152))	('BRAF', 'Gene', (133, 137))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('V600E', 'Mutation', 'rs113488022', (138, 143))	('EGFR', 'molecular_function', 'GO:0005006', ('83', '87'))	('CIMP-H1/H2 cancers', 'Disease', (91, 109))	('CIMP-H1/H2 cancers', 'Disease', 'MESH:D009369', (91, 109))
38127	30954552	The frequency of BRAF mutations was 9.4%, and was not significantly different from the proportion observed in the RBWH cohort.	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', '673', (17, 21))	('mutations', 'Var', (22, 31))
38133	30954552	The distribution of KRAS mutations in CIMP subtypes followed a similar bell-shaped distribution, and were most common in CIMP-L1 cancers (48 of 81; 59.3%), and least common in CIMP-H1 (5 of 22; 26.3%) and CIMP-negative cancers (21 of 102; 20.6%).	('CIMP', 'Chemical', '-', (205, 209))	('KRAS', 'Gene', '3845', (20, 24))	('CIMP-neg', 'Chemical', '-', (205, 213))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('CIMP', 'Chemical', '-', (38, 42))	('KRAS', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (25, 34))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('CIMP-L1 cancers', 'Disease', 'MESH:C536029', (121, 136))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('CIMP-L1 cancers', 'Disease', (121, 136))	('cancers', 'Disease', (219, 226))	('bell-shaped distribution', 'Phenotype', 'HP:0001591', (71, 95))	('CIMP', 'Chemical', '-', (121, 125))	('common', 'Reg', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('CIMP', 'Chemical', '-', (176, 180))	('CIMP-H1', 'Chemical', '-', (176, 183))
38136	30954552	Likewise, CIMP-neg cancers were strongly enriched for the CMS4 subtype in both cohorts (TCGA, 40.9%; RBWH, 39.6%) In contrast to the RBWH cohort, CIMP-H1 cancers were less frequent overall (TCGA, 5.1%; RBWH, 10.6%) and BRAF mutation was associated with CIMP-H1 and CIMP-H2 (CIMP-H1: TCGA, 52.6%; RBWH, 73.9%; CIMP-H2: TCGA, 48.7%; RBWH, 9.1%).	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancers', 'Disease', (19, 26))	('CIMP-H2', 'Chemical', '-', (265, 272))	('CIMP-H1', 'Chemical', '-', (253, 260))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('CIMP-H1', 'Disease', (253, 260))	('CIMP-H1 cancers', 'Disease', (146, 161))	('CIMP-H2', 'Disease', (265, 272))	('mutation', 'Var', (224, 232))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('CIMP-H1', 'Chemical', '-', (274, 281))	('CIMP-H1', 'Chemical', '-', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('BRAF', 'Gene', (219, 223))	('CIMP-H2', 'Chemical', '-', (309, 316))	('CIMP-H1 cancers', 'Disease', 'MESH:D009369', (146, 161))	('BRAF', 'Gene', '673', (219, 223))	('CIMP-neg', 'Chemical', '-', (10, 18))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancers', 'Disease', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
38137	30954552	Perhaps as a consequence of the increased frequency of BRAF mutations in TCGA CIMP-H2 cancers, MSI was significantly more enriched in CIMP-H2 cancers in the TCGA cohort (50%).	('CIMP-H2 cancers', 'Disease', 'MESH:D009369', (78, 93))	('MSI', 'Disease', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('CIMP-H2 cancers', 'Disease', (78, 93))	('CIMP-H2 cancers', 'Disease', (134, 149))	('MSI', 'Disease', 'None', (95, 98))	('BRAF', 'Gene', '673', (55, 59))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('mutations', 'Var', (60, 69))	('CIMP-H2 cancers', 'Disease', 'MESH:D009369', (134, 149))	('BRAF', 'Gene', (55, 59))	('TCGA', 'Gene', (73, 77))
38139	30954552	We identified differentially methylated probes in each cluster compared with 32 normal mucosal samples that matched a subset of cancers in the unselected series (Table 3).	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('differentially methylated', 'Var', (14, 39))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))
38142	30954552	Probe hypermethylation was most frequent in the CIMP-H1 cluster, including 21,168 hypermethylated probes occurring within 5165 unique CpG islands.	('CIMP-H1', 'Gene', (48, 55))	('CIMP-H1', 'Chemical', '-', (48, 55))	('Probe hypermethylation', 'Var', (0, 22))
38144	30954552	An additional 523 CpG islands were uniquely hypermethylated in the CIMP-H2 cluster relative to CIMP-H1.	('CIMP-H1', 'Chemical', '-', (95, 102))	('CIMP-H2', 'Chemical', '-', (67, 74))	('CIMP-H2', 'Gene', (67, 74))	('hypermethylated', 'Var', (44, 59))
38164	30954552	Although promoter methylation was most common in CIMP-H1 and CIMP-H2 clusters (Figure 3A), these subgroups had the lowest proportion of genes in which hypermethylation correlated with reduced transcript expression (13.9% and 15.6%, respectively).	('CIMP-H1', 'Chemical', '-', (49, 56))	('transcript expression', 'MPA', (192, 213))	('CIMP-H2', 'Chemical', '-', (61, 68))	('common', 'Reg', (39, 45))	('reduced', 'NegReg', (184, 191))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('hypermethylation', 'Var', (151, 167))	('CIMP-H1', 'Var', (49, 56))
38172	30954552	Consistent with this, we observed an increase in the number of methylated CpG sites that overlap with SUZ12-occupied regions with increasing CIMP cluster (P < .0001) (Figure 4A).	('CIMP', 'Chemical', '-', (141, 145))	('SUZ12', 'Gene', (102, 107))	('methylated', 'Var', (63, 73))	('increase', 'PosReg', (37, 45))	('SUZ12', 'Gene', '23512', (102, 107))
38188	30954552	Likewise, gene body methylation was significantly more likely to occur in oncogenes than tumor-suppressor genes in CIMP-H2 cancers (23.3% vs 11.6%; P = .01).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('occur', 'Reg', (65, 70))	('methylation', 'biological_process', 'GO:0032259', ('20', '31'))	('CIMP-H2 cancers', 'Disease', (115, 130))	('oncogenes', 'Gene', (74, 83))	('tumor-suppressor', 'Gene', '7248', (89, 105))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('methylation', 'Var', (20, 31))	('CIMP-H2 cancers', 'Disease', 'MESH:D009369', (115, 130))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('89', '105'))	('tumor-suppressor', 'Gene', (89, 105))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('89', '105'))
38193	30954552	We observed a lesser, but still highly significant, overlap between H3K27me3 marked loci and gene body methylation in CIMP-L1 (13.1%; P = 6.11 x 10-122) and CIMP-L2 (8.5%; P = 1.6 x 10-78) cancers, but did not observe any correlation in CIMP-neg cancers, which likely is owing to the scarcity of which gene body methylation occurs in these cancers.	('CIMP-L1', 'Disease', (118, 125))	('CIMP', 'Chemical', '-', (157, 161))	('CIMP-L2', 'Disease', (157, 164))	('cancers', 'Disease', 'MESH:D009369', (340, 347))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('CIMP', 'Chemical', '-', (237, 241))	('CIMP-neg', 'Chemical', '-', (237, 245))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('CIMP', 'Chemical', '-', (118, 122))	('methylation', 'biological_process', 'GO:0032259', ('312', '323'))	('cancers', 'Disease', (246, 253))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('L2', 'Chemical', 'MESH:D013912', (162, 164))	('methylation', 'biological_process', 'GO:0032259', ('103', '114'))	('H3K27me3', 'Var', (68, 76))	('cancers', 'Phenotype', 'HP:0002664', (340, 347))	('cancers', 'Disease', (340, 347))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('cancers', 'Disease', (189, 196))	('cancer', 'Phenotype', 'HP:0002664', (340, 346))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))
38195	30954552	Mutations in epigenetic modifier genes have been shown previously to modulate transcriptional profiles in cancer.	('epigenetic modifier genes', 'Gene', (13, 38))	('transcriptional profiles', 'MPA', (78, 102))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (106, 112))	('modulate', 'Reg', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
38198	30954552	There were 94.7% and 100% of CIMP-H1 and CIMP-H2 cancers that had at least 1 mutation in an epigenetic regulator.	('CIMP-H2 cancers', 'Disease', 'MESH:D009369', (41, 56))	('CIMP-H1', 'Disease', (29, 36))	('mutation', 'Var', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('CIMP-H1', 'Chemical', '-', (29, 36))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('CIMP-H2 cancers', 'Disease', (41, 56))
38199	30954552	The proportion of CIMP-L1, CIMP-L2, and CIMP-negative cancers with deleterious mutations in these genes was slightly lower (93.8%, 89.5%, and 93.1%, respectively), however, these proportions were not significantly different from CIMP-H1 or CIMP-H2.	('CIMP', 'Chemical', '-', (18, 22))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('CIMP', 'Chemical', '-', (40, 44))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('CIMP', 'Chemical', '-', (229, 233))	('CIMP-neg', 'Chemical', '-', (40, 48))	('lower', 'NegReg', (117, 122))	('CIMP-H2', 'Chemical', '-', (240, 247))	('CIMP-H1', 'Chemical', '-', (229, 236))	('CIMP', 'Chemical', '-', (27, 31))	('CIMP', 'Chemical', '-', (240, 244))	('L2', 'Chemical', 'MESH:D013912', (32, 34))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (79, 88))
38200	30954552	Of the 719 genes we investigated, 95.7% were mutated in at least 1 cancer (688 of 719).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('mutated', 'Var', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
38207	30954552	Thirteen genes were identified in the top 25 mutated epigenetic regulators in CIMP-H1, but not CIMP-H2, these included the DNA demethylases TET1 (mutated in 15.8% of CIMP-H1 cancers vs 10.3% of CIMP-H2 cancers) and TET3 (mutated in 26.3% of CIMP-H1 cancers vs 10.3% of CIMP-H2 cancers).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('CIMP-H2 cancers', 'Disease', (269, 284))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('CIMP-H1', 'Chemical', '-', (166, 173))	('CIMP-H1 cancers', 'Disease', 'MESH:D009369', (166, 181))	('CIMP-H2 cancers', 'Disease', 'MESH:D009369', (194, 209))	('CIMP-H1', 'Chemical', '-', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('CIMP-H1 cancers', 'Disease', (241, 256))	('CIMP-H2', 'Chemical', '-', (194, 201))	('DNA', 'cellular_component', 'GO:0005574', ('123', '126'))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('CIMP-H1', 'Chemical', '-', (241, 248))	('CIMP-H2', 'Chemical', '-', (95, 102))	('TET3', 'Gene', '200424', (215, 219))	('mutated', 'Var', (146, 153))	('TET1', 'Gene', '80312', (140, 144))	('CIMP-H1 cancers', 'Disease', 'MESH:D009369', (241, 256))	('CIMP-H2 cancers', 'Disease', 'MESH:D009369', (269, 284))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('CIMP-H2 cancers', 'Disease', (194, 209))	('CIMP-H2', 'Chemical', '-', (269, 276))	('TET3', 'Gene', (215, 219))	('CIMP-H1 cancers', 'Disease', (166, 181))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('TET1', 'Gene', (140, 144))
38208	30954552	Mutations in histone lysine demethylase KDM2B were enriched in CIMP-H1 cancers (mutated in 36.8% of CIMP-H1 cancers vs 7.7% of CIMP-H2 cancers; P = .01).	('CIMP-H1 cancers', 'Disease', (100, 115))	('CIMP-H2 cancers', 'Disease', 'MESH:D009369', (127, 142))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('CIMP-H1 cancers', 'Disease', 'MESH:D009369', (100, 115))	('KDM2B', 'Gene', '84678', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('CIMP-H1 cancers', 'Disease', 'MESH:D009369', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('CIMP-H2 cancers', 'Disease', (127, 142))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('KDM2B', 'Gene', (40, 45))	('CIMP-H1 cancers', 'Disease', (63, 78))
38210	30954552	The NCOR1 transcription factor was mutated in 20.5% of CIMP-H2 cancers compared with 5.3% of CIMP-H1 cancers, and the cohesin complex subunit NIPBL in 15.4% of CIMP-H2 cancers, despite not being identified as mutated in any CIMP-H1 cancer.	('CIMP-H1 cancer', 'Disease', 'MESH:D009369', (93, 107))	('NCOR1', 'Gene', '9611', (4, 9))	('CIMP-H1 cancers', 'Disease', (93, 108))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('CIMP-H1 cancer', 'Disease', (224, 238))	('CIMP-H1 cancers', 'Disease', 'MESH:D009369', (93, 108))	('CIMP-H2 cancers', 'Disease', 'MESH:D009369', (160, 175))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('CIMP-H1 cancer', 'Disease', 'MESH:D009369', (224, 238))	('transcription factor', 'molecular_function', 'GO:0000981', ('10', '30'))	('mutated', 'Var', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('CIMP-H2 cancers', 'Disease', 'MESH:D009369', (55, 70))	('transcription', 'biological_process', 'GO:0006351', ('10', '23'))	('cohesin complex', 'cellular_component', 'GO:0008278', ('118', '133'))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('NIPBL', 'Gene', '25836', (142, 147))	('NIPBL', 'Gene', (142, 147))	('CIMP-H2 cancers', 'Disease', (160, 175))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('NCOR1', 'Gene', (4, 9))	('CIMP-H2 cancers', 'Disease', (55, 70))
38213	30954552	The histone lysine methyltransferases KMT2B and KMT2C were among the top 25 mutated epigenetic regulators in both CIMP-L1 and CIMP-L2, however, the frequency of mutation in both KMT2B and KMT2C was lower in CIMP-L2 cancers (KMT2B CIMP-L1, 11.8%; CIMP-L2, 5.7%; KMT2C CIMP-L1, 10.5%; and CIMP-L2, 6.5%), but this was not statistically significant.	('L2', 'Chemical', 'MESH:D013912', (212, 214))	('L2', 'Chemical', 'MESH:D013912', (251, 253))	('CIMP', 'Chemical', '-', (246, 250))	('L2', 'Chemical', 'MESH:D013912', (131, 133))	('KMT2B', 'Gene', '9757', (224, 229))	('KMT2B', 'Gene', (178, 183))	('CIMP', 'Chemical', '-', (126, 130))	('KMT2B', 'Gene', '9757', (38, 43))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('CIMP-L2 cancers', 'Disease', (207, 222))	('mutation', 'Var', (161, 169))	('CIMP', 'Chemical', '-', (267, 271))	('CIMP-L2 cancers', 'Disease', 'MESH:D054198', (207, 222))	('KMT2C', 'Gene', '58508', (48, 53))	('KMT2C', 'Gene', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('KMT2B', 'Gene', (224, 229))	('KMT2B', 'Gene', (38, 43))	('KMT2C', 'Gene', '58508', (261, 266))	('KMT2C', 'Gene', (261, 266))	('lower', 'NegReg', (198, 203))	('CIMP', 'Chemical', '-', (207, 211))	('KMT2B', 'Gene', '9757', (178, 183))	('L2', 'Chemical', 'MESH:D013912', (292, 294))	('CIMP', 'Chemical', '-', (114, 118))	('CIMP', 'Chemical', '-', (287, 291))	('KMT2C', 'Gene', '58508', (188, 193))	('KMT2C', 'Gene', (188, 193))	('CIMP', 'Chemical', '-', (230, 234))
38214	30954552	There was a nonsignificant trend (P = .06) for increased ASH1L mutation in CIMP-L1 cancers (13.2%) vs CIMP-L2 cancers (4.9%).	('CIMP-L1 cancers', 'Disease', (75, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('ASH1L', 'Gene', (57, 62))	('ASH1L', 'Gene', '55870', (57, 62))	('mutation', 'Var', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('increased', 'PosReg', (47, 56))	('CIMP-L2 cancers', 'Disease', (102, 117))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('CIMP-L1 cancers', 'Disease', 'MESH:C536029', (75, 90))	('CIMP-L2 cancers', 'Disease', 'MESH:D054198', (102, 117))
38216	30954552	SETD1B, a histone lysine methyltransferase identified as a commonly mutated gene in CIMP-H cancers was mutated in 6 CIMP-L1 cancers, but was only mutated in a single CIMP-L2 cancer (P < .01).	('mutated', 'Var', (103, 110))	('CIMP', 'Chemical', '-', (166, 170))	('SETD1B', 'Gene', '23067', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('L2', 'Chemical', 'MESH:D013912', (171, 173))	('CIMP', 'Chemical', '-', (84, 88))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', (174, 180))	('CIMP-H cancers', 'Disease', (84, 98))	('CIMP', 'Chemical', '-', (116, 120))	('CIMP-H cancers', 'Disease', 'MESH:D009369', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('CIMP-L1 cancers', 'Disease', 'MESH:C536029', (116, 131))	('CIMP-L1 cancers', 'Disease', (116, 131))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancer', 'Disease', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Disease', (91, 97))	('SETD1B', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
38217	30954552	Likewise, we identified recurrent ARID1A mutations in CIMP-L1 (9.2%), however, we identified significantly fewer in CIMP-L2 cancers (1.6%; P < .01).	('mutations', 'Var', (41, 50))	('fewer', 'NegReg', (107, 112))	('ARID1A', 'Gene', '8289', (34, 40))	('ARID1A', 'Gene', (34, 40))	('CIMP', 'Chemical', '-', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('CIMP-L2 cancers', 'Disease', (116, 131))	('CIMP', 'Chemical', '-', (116, 120))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('CIMP-L2 cancers', 'Disease', 'MESH:D054198', (116, 131))
38219	30954552	Mutations in any of the SWI/SNF subunits occurred in 19.06% of cancers.	('SWI/SNF', 'Gene', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('Mutations', 'Var', (0, 9))	('occurred', 'Reg', (41, 49))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
38220	30954552	An ARID1A mutation was the most frequent genetic alteration of the complex (6.7%).	('ARID1A', 'Gene', '8289', (3, 9))	('ARID1A', 'Gene', (3, 9))	('mutation', 'Var', (10, 18))
38221	30954552	We observed a number of recurrently mutated positions in ARID1A, including 6 frameshift deletions at codon 2141, 4 deletions at codon 1850, and 3 deletions at codon 1072 (Figure 7).	('frameshift deletions', 'Var', (77, 97))	('deletions', 'Var', (146, 155))	('ARID1A', 'Gene', '8289', (57, 63))	('deletions', 'Var', (115, 124))	('ARID1A', 'Gene', (57, 63))
38223	30954552	The distribution of the mutations between CIMP subtypes was significantly skewed toward subtypes with higher overall methylation (P < .0001).	('methylation', 'MPA', (117, 128))	('mutations', 'Var', (24, 33))	('CIMP', 'Chemical', '-', (42, 46))	('higher', 'PosReg', (102, 108))
38224	30954552	SWI/SNF mutations were observed in 50% of CIMP-H1 cancers, and 38.5% of CIMP-H2 cancers.	('SWI/SNF', 'Gene', (0, 7))	('CIMP-H2 cancers', 'Disease', 'MESH:D009369', (72, 87))	('CIMP-H1 cancers', 'Disease', 'MESH:D009369', (42, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('observed', 'Reg', (23, 31))	('mutations', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('CIMP-H1 cancers', 'Disease', (42, 57))	('CIMP-H2 cancers', 'Disease', (72, 87))
38226	30954552	The R885C mutation was observed in 3 cancers in CIMP-L1.	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('observed', 'Reg', (23, 31))	('cancers', 'Disease', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('R885C', 'Mutation', 'rs281875227', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('R885C', 'Var', (4, 9))	('CIMP', 'Chemical', '-', (48, 52))
38227	30954552	Mutations in SWI/SNF subunits were similarly infrequent and significantly less prevalent in CIMP-L1 and CIMP-neg (10.6% and 11.6%, respectively; P < .0001).	('SWI/SNF', 'Gene', (13, 20))	('CIMP-neg', 'Disease', (104, 112))	('less', 'NegReg', (74, 78))	('CIMP-L1', 'Disease', (92, 99))	('CIMP', 'Chemical', '-', (92, 96))	('Mutations', 'Var', (0, 9))	('CIMP', 'Chemical', '-', (104, 108))	('prevalent', 'Reg', (79, 88))	('CIMP-neg', 'Chemical', '-', (104, 112))
38231	30954552	High-impact CHD family gene mutations were present in 22.4% of colorectal cancers in the TCGA.	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('colorectal cancers', 'Disease', 'MESH:D015179', (63, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('CHD', 'Disease', 'None', (12, 15))	('colorectal cancers', 'Disease', (63, 81))	('CHD', 'Disease', (12, 15))	('mutations', 'Var', (28, 37))
38232	30954552	CHD mutations were markedly more common in CIMP-H1 and CIMP-H2 cancers.	('CHD', 'Disease', 'None', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('CHD', 'Disease', (0, 3))	('CIMP-H1', 'Disease', (43, 50))	('common', 'Reg', (33, 39))	('CIMP-H2 cancers', 'Disease', 'MESH:D009369', (55, 70))	('mutations', 'Var', (4, 13))	('CIMP-H1', 'Chemical', '-', (43, 50))	('CIMP-H2 cancers', 'Disease', (55, 70))
38233	30954552	Family members were mutated in 50% and 51.3% of CIMP-H1 and CIMP-H2 cancers, respectively.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('CIMP-H1', 'Chemical', '-', (48, 55))	('CIMP-H2 cancers', 'Disease', (60, 75))	('CIMP-H2 cancers', 'Disease', 'MESH:D009369', (60, 75))	('CIMP-H1', 'Disease', (48, 55))	('mutated', 'Var', (20, 27))
38235	30954552	CHD mutations were less common, but still frequent, in CIMP-L1 cancers (19.7%).	('CHD', 'Disease', 'None', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('CHD', 'Disease', (0, 3))	('CIMP-L1 cancers', 'Disease', 'MESH:C536029', (55, 70))	('CIMP-L1 cancers', 'Disease', (55, 70))	('mutations', 'Var', (4, 13))
38237	30954552	The frequency of CHD mutations continued to decline as concordant with DNA methylation.	('DNA methylation', 'biological_process', 'GO:0006306', ('71', '86'))	('DNA', 'cellular_component', 'GO:0005574', ('71', '74'))	('CHD', 'Disease', (17, 20))	('CHD', 'Disease', 'None', (17, 20))	('mutations', 'Var', (21, 30))
38238	30954552	The frequency of CHD mutations in CIMP-L2 was 11.7%, and was lower than the frequency observed in CIMP-neg cancers (15%).	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('CIMP-L2', 'Gene', (34, 41))	('CHD', 'Disease', (17, 20))	('CHD', 'Disease', 'None', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('CIMP-neg', 'Chemical', '-', (98, 106))	('CIMP', 'Chemical', '-', (98, 102))	('L2', 'Chemical', 'MESH:D013912', (39, 41))	('CIMP', 'Chemical', '-', (34, 38))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('mutations', 'Var', (21, 30))
38240	30954552	At the CHD7 locus, which was mutated in 5.5% of cancers, we observed 5 frameshift deletions (D2988fs del 3) at the 3' end of the gene.	('cancers', 'Disease', (48, 55))	('CHD7', 'Gene', (7, 11))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('CHD7', 'Gene', '55636', (7, 11))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('D2988fs', 'Var', (93, 100))	('D2988fs', 'FRAMESHIFT', 'None', (93, 100))	('cancers', 'Disease', 'MESH:D009369', (48, 55))
38242	30954552	For CHD3, CHD4, and CHD9 we observed 3 recurrently mutated positions at R540fs del 16, R975H, and F760fs del 16.	('CHD9', 'Gene', '80205', (20, 24))	('R540fs', 'FRAMESHIFT', 'None', (72, 78))	('R975H', 'Mutation', 'p.R975H', (87, 92))	('CHD3', 'Gene', '1107', (4, 8))	('CHD9', 'Gene', (20, 24))	('CHD4', 'Gene', '1108', (10, 14))	('F760fs', 'FRAMESHIFT', 'None', (98, 104))	('CHD4', 'Gene', (10, 14))	('CHD3', 'Gene', (4, 8))	('R975H', 'Var', (87, 92))	('R540fs', 'Var', (72, 78))	('F760fs', 'Var', (98, 104))
38245	30954552	Here, we aimed to better understand the extent and heterogeneity of aberrant DNA methylation in colorectal cancers, and characterize the interplay between DNA methylation, somatic variation in epigenetic regulator genes, and gene transcription.	('methylation', 'Var', (81, 92))	('DNA', 'Gene', (77, 80))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('colorectal cancers', 'Disease', 'MESH:D015179', (96, 114))	('colorectal cancers', 'Disease', (96, 114))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('aberrant', 'Var', (68, 76))
38247	30954552	The 5 subtypes identified in this study are highly correlated with key clinical and molecular features, including patient age, tumor location, microsatellite instability, and oncogenic mitogen-activated protein kinase mutations.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('microsatellite instability', 'MPA', (143, 169))	('tumor', 'Disease', (127, 132))	('mutations', 'Var', (218, 227))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('patient', 'Species', '9606', (114, 121))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
38248	30954552	We show that cancers with high DNA methylation show an increased preponderance for mutating genes involved in epigenetic regulation, and namely those that are implicated in the chromatin remodeling process.	('regulation', 'biological_process', 'GO:0065007', ('121', '131'))	('high DNA', 'Var', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('mutating', 'MPA', (83, 91))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('chromatin', 'cellular_component', 'GO:0000785', ('177', '186'))	('DNA methylation', 'biological_process', 'GO:0006306', ('31', '46'))	('cancers', 'Disease', (13, 20))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('177', '197'))
38252	30954552	The dichotomization of these CIMP-H cancers identified a homogeneous subgroup of CIMP-H1 cancers with an average age of 75 years, striking over-representation of female sex, and BRAF mutant cancers arising in the proximal colon.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('cancers', 'Disease', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('CIMP-H cancers', 'Disease', (29, 43))	('mutant', 'Var', (183, 189))	('CIMP-H1 cancers', 'Disease', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('CIMP-H cancers', 'Disease', 'MESH:D009369', (29, 43))	('BRAF', 'Gene', '673', (178, 182))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('over-representation', 'PosReg', (139, 158))	('cancers', 'Disease', (190, 197))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('CIMP-H1 cancers', 'Disease', 'MESH:D009369', (81, 96))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('BRAF', 'Gene', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
38253	30954552	The newly identified CIMP-H2 subtype encompasses more KRAS mutant cancers than CIMP-H1, and the majority of cancers in this subtype would be CIMP-low using the 5-marker CIMP panel proposed by Weisenberger et al.	('CIMP', 'Chemical', '-', (141, 145))	('CIMP-H1', 'Chemical', '-', (79, 86))	('CIMP', 'Chemical', '-', (169, 173))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('mutant', 'Var', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('CIMP-H2', 'Chemical', '-', (21, 28))	('KRAS', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('CIMP', 'Chemical', '-', (21, 25))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('KRAS', 'Gene', '3845', (54, 58))	('cancers', 'Disease', (66, 73))	('CIMP', 'Chemical', '-', (79, 83))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))
38257	30954552	Numerous studies have shown age-related methylation in different tissues and we previously identified hypermethylated loci in the colons of patients even with no history of colonic disease.	('methylation', 'Var', (40, 51))	('colonic disease', 'Disease', (173, 188))	('patients', 'Species', '9606', (140, 148))	('methylation', 'biological_process', 'GO:0032259', ('40', '51'))	('colonic disease', 'Disease', 'MESH:D003108', (173, 188))
38258	30954552	In the present study, we detected a significant correlation between methylation and patient age.	('methylation', 'Var', (68, 79))	('patient', 'Species', '9606', (84, 91))	('correlation', 'Interaction', (48, 59))
38260	30954552	The subtype with the highest degree of methylation (CIMP-H1) was strongly associated with mutations in the BRAF oncogene.	('BRAF', 'Gene', (107, 111))	('mutations', 'Var', (90, 99))	('CIMP-H1', 'Chemical', '-', (52, 59))	('BRAF', 'Gene', '673', (107, 111))	('associated', 'Reg', (74, 84))
38261	30954552	BRAF mutations are a hallmark of the serrated neoplasia pathway, and indicate that these cancers probably arose in serrated precursor lesions.	('serrated neoplasia', 'Phenotype', 'HP:0032222', (37, 55))	('neoplasia', 'Disease', (46, 55))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('mutations', 'Var', (5, 14))	('neoplasia', 'Phenotype', 'HP:0002664', (46, 55))	('BRAF', 'Gene', '673', (0, 4))	('cancers', 'Disease', (89, 96))	('neoplasia', 'Disease', 'MESH:D009369', (46, 55))	('BRAF', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
38262	30954552	We previously showed that the colonoscopic incidence of sessile serrated adenomas does not differ between patients aged in their 30s and patients who are much older, whereas BRAF mutant cancers were restricted to older individuals, suggesting these BRAF mutant polyps may have limited malignant potential in young patients.	('BRAF', 'Gene', '673', (249, 253))	('adenomas', 'Disease', (73, 81))	('patients', 'Species', '9606', (314, 322))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('BRAF', 'Gene', (249, 253))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('polyps', 'Disease', (261, 267))	('cancers', 'Disease', (186, 193))	('BRAF', 'Gene', '673', (174, 178))	('patients', 'Species', '9606', (137, 145))	('BRAF', 'Gene', (174, 178))	('patients', 'Species', '9606', (106, 114))	('serrated adenomas', 'Phenotype', 'HP:0032222', (64, 81))	('polyps', 'Disease', 'MESH:D011127', (261, 267))	('adenomas', 'Disease', 'MESH:D000236', (73, 81))	('mutant', 'Var', (254, 260))
38264	30954552	Here, we report that the vast majority of BRAF mutant cancers in both the RBWH and TCGA cohorts are CIMP-H and arise in older individuals.	('BRAF', 'Gene', '673', (42, 46))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('CIMP-H', 'Chemical', '-', (100, 106))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('BRAF', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutant', 'Var', (47, 53))
38266	30954552	In older patients with more advanced DNA methylation changes in the colon, the risk of progression to cancer will be significantly greater.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('patients', 'Species', '9606', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('DNA methylation', 'biological_process', 'GO:0006306', ('37', '52'))	('cancer', 'Disease', (102, 108))	('methylation changes', 'Var', (41, 60))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
38267	30954552	Recently, we recapitulated this process in a murine model for serrated neoplasia and showed that early onset Braf mutation leads to the temporal accumulation of DNA methylation and ultimately to malignancy.	('Braf', 'Gene', '109880', (109, 113))	('malignancy', 'Disease', (195, 205))	('neoplasia', 'Disease', (71, 80))	('Braf', 'Gene', (109, 113))	('DNA methylation', 'MPA', (161, 176))	('neoplasia', 'Disease', 'MESH:D009369', (71, 80))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('accumulation', 'PosReg', (145, 157))	('serrated neoplasia', 'Phenotype', 'HP:0032222', (62, 80))	('neoplasia', 'Phenotype', 'HP:0002664', (71, 80))	('DNA methylation', 'biological_process', 'GO:0006306', ('161', '176'))	('mutation', 'Var', (114, 122))	('murine', 'Species', '10090', (45, 51))	('malignancy', 'Disease', 'MESH:D009369', (195, 205))
38268	30954552	Additional studies are necessary to fully determine the natural history of BRAF mutant cancers, and elucidate the determinants of malignant potential to inform the development of patient-centric surveillance for young and older patients who present with sessile serrated adenomas.	('cancers', 'Disease', (87, 94))	('serrated adenomas', 'Phenotype', 'HP:0032222', (262, 279))	('mutant', 'Var', (80, 86))	('BRAF', 'Gene', '673', (75, 79))	('patient', 'Species', '9606', (179, 186))	('patients', 'Species', '9606', (228, 236))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('adenomas', 'Disease', 'MESH:D000236', (271, 279))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('BRAF', 'Gene', (75, 79))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('adenomas', 'Disease', (271, 279))	('patient', 'Species', '9606', (228, 235))
38269	30954552	Probes on the north and south CpG shelves, as well as those in the open seas, frequently were hypomethylated across most cancers.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('hypomethylated', 'Var', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
38273	30954552	One hypothesis that may explain this association is that hypomethylation outside of CpG islands may predispose to copy number changes in these cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('predispose', 'Reg', (100, 110))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('hypomethylation', 'Var', (57, 72))	('cancers', 'Disease', (143, 150))	('copy number changes', 'Var', (114, 133))
38275	30954552	There were marked differences in transcriptional deregulation of key cancer-related pathways between methylation clusters.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('transcriptional deregulation', 'MPA', (33, 61))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('methylation', 'Var', (101, 112))	('cancer', 'Disease', (69, 75))
38277	30954552	This likely is owing to the higher mutational burden in these cancers, largely driven by the increased incidence of epigenetically induced microsatellite instability.	('epigenetically', 'Var', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Disease', (62, 69))
38279	30954552	In the RBWH cohort, CIMP-H2 cancers were uniquely enriched for altered bile acid metabolism, consistent with the previously described relationship between silencing of the farnesoid X bile acid receptor in KRAS mutant cancers.	('cancers', 'Disease', (28, 35))	('silencing', 'Var', (155, 164))	('KRAS', 'Gene', '3845', (206, 210))	('CIMP-H2 cancers', 'Disease', 'MESH:D009369', (20, 35))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('cancers', 'Disease', 'MESH:D009369', (218, 225))	('altered', 'Reg', (63, 70))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('bile acid', 'Chemical', 'MESH:D001647', (184, 193))	('cancers', 'Disease', (218, 225))	('bile acid metabolism', 'biological_process', 'GO:0008206', ('71', '91'))	('bile acid metabolism', 'MPA', (71, 91))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('bile acid', 'Chemical', 'MESH:D001647', (71, 80))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('CIMP-H2 cancers', 'Disease', (20, 35))	('KRAS', 'Gene', (206, 210))
38283	30954552	A better understanding of the role of bile acid signaling in KRAS mutant cancers of the proximal colon may have therapeutic implications for this cancer subgroup.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', (146, 152))	('cancers', 'Disease', (73, 80))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('mutant', 'Var', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('KRAS', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('bile acid', 'Chemical', 'MESH:D001647', (38, 47))	('KRAS', 'Gene', '3845', (61, 65))
38286	30954552	Alternatively, the increased frequency of mutations in epigenetic regulators of CIMP-H1/2 cancers may result in a reduced capacity to induce gene repression at certain loci.	('cancers', 'Disease', (90, 97))	('CIMP-H1/2', 'Gene', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('reduced', 'NegReg', (114, 121))	('induce gene repression', 'MPA', (134, 156))	('CIMP-H1', 'Chemical', '-', (80, 87))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('mutations', 'Var', (42, 51))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
38287	30954552	Methylation alone may be insufficient to induce gene repression in certain instances.	('gene', 'MPA', (48, 52))	('Methylation', 'Var', (0, 11))	('insufficient', 'Disease', (25, 37))	('insufficient', 'Disease', 'MESH:D000309', (25, 37))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))
38290	30954552	A major novel finding of the current study was the discovery that gene body methylation may be a major driver of serrated tumorigenesis, and that this may be mediated by H3K27me3 histone marks.	('H3K27me3', 'Var', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mediated', 'Reg', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))	('tumor', 'Disease', (122, 127))
38292	30954552	Alternatively, this gene body methylation may be a stochastic result of the overall increase in aberrant DNA methylation in these cancers.	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('aberrant', 'Var', (96, 104))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('increase', 'PosReg', (84, 92))	('DNA', 'Protein', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('methylation', 'MPA', (30, 41))
38294	30954552	Recently, Fang et al showed that CHD8 operates in a transcriptional repression complex to direct methylation in the setting of BRAF mutation.	('BRAF', 'Gene', '673', (127, 131))	('methylation', 'MPA', (97, 108))	('BRAF', 'Gene', (127, 131))	('CHD8', 'Gene', (33, 37))	('mutation', 'Var', (132, 140))	('CHD8', 'Gene', '57680', (33, 37))
38295	30954552	In the current study we showed BRAF and CHD8 mutations were associated with CIMP-H1.	('mutations', 'Var', (45, 54))	('CIMP-H1', 'Disease', (76, 83))	('CIMP-H1', 'Chemical', '-', (76, 83))	('CHD8', 'Gene', (40, 44))	('BRAF', 'Gene', '673', (31, 35))	('CHD8', 'Gene', '57680', (40, 44))	('associated', 'Reg', (60, 70))	('BRAF', 'Gene', (31, 35))
38296	30954552	Thus, these data suggest that CHD8 mutation may enhance repression complex activity in the setting of BRAF mutation, resulting in hypermethylation.	('CHD8', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (102, 106))	('CHD8', 'Gene', '57680', (30, 34))	('mutation', 'Var', (107, 115))	('BRAF', 'Gene', (102, 106))	('enhance', 'PosReg', (48, 55))	('hypermethylation', 'MPA', (130, 146))	('mutation', 'Var', (35, 43))	('repression complex activity', 'MPA', (56, 83))
38298	30954552	CHD8 mutations may influence CIMP by decreasing the ability of CTCF to insulate regions of the genome, and could encourage methylation spreading throughout the genome.	('influence', 'Reg', (19, 28))	('decreasing', 'NegReg', (37, 47))	('CIMP', 'Chemical', '-', (29, 33))	('CHD8', 'Gene', (0, 4))	('CTCF', 'Gene', (63, 67))	('CHD8', 'Gene', '57680', (0, 4))	('mutations', 'Var', (5, 14))	('methylation spreading', 'MPA', (123, 144))	('CTCF', 'Gene', '10664', (63, 67))	('ability', 'MPA', (52, 59))	('encourage', 'PosReg', (113, 122))
38299	30954552	Similarly, we report frequent mutations in different members of the CHD family.	('CHD', 'Disease', (68, 71))	('mutations', 'Var', (30, 39))	('CHD', 'Disease', 'None', (68, 71))
38301	30954552	Tahara et al identified mutations in CHD7 and CHD8 in 42% of CIMP1 colorectal cancers.	('colorectal cancers', 'Disease', (67, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('CHD7', 'Gene', '55636', (37, 41))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('CIMP', 'Chemical', '-', (61, 65))	('mutations', 'Var', (24, 33))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('colorectal cancers', 'Disease', 'MESH:D015179', (67, 85))	('CHD8', 'Gene', (46, 50))	('CHD7', 'Gene', (37, 41))	('CHD8', 'Gene', '57680', (46, 50))
38302	30954552	The functional consequences of CHD7 mutations are unclear.	('CHD7', 'Gene', (31, 35))	('CHD7', 'Gene', '55636', (31, 35))	('mutations', 'Var', (36, 45))
38306	30954552	In contrast, Li et al in 2018 showed that CHD4 mutations that promote protein degradation enhance stemness and contribute to the progression of endometrial cancers via the transforming growth factor-beta signaling cascade.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('endometrial cancers', 'Disease', 'MESH:D016889', (144, 163))	('protein degradation', 'MPA', (70, 89))	('endometrial cancers', 'Disease', (144, 163))	('enhance', 'PosReg', (90, 97))	('stemness', 'Disease', (98, 106))	('stemness', 'Disease', 'MESH:D020295', (98, 106))	('mutations', 'Var', (47, 56))	('CHD4', 'Gene', '1108', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('promote', 'PosReg', (62, 69))	('CHD4', 'Gene', (42, 46))
38307	30954552	Indeed, we identified 3 mutations at the R975H hotspot of CHD4 that were studied by Li et al and a number of other mutations that were predicted to be damaging.	('CHD4', 'Gene', (58, 62))	('R975H', 'Var', (41, 46))	('R975H', 'Mutation', 'p.R975H', (41, 46))	('CHD4', 'Gene', '1108', (58, 62))
38308	30954552	It is not possible to conclude from our data whether these mutations promote the hypermethylation proposed by Xia et al, and therefore support the oncogenic role of the protein or whether the enhanced protein degradation and increased stemness proposed by Li et al is the predominant purpose of these mutations.	('stemness', 'Disease', 'MESH:D020295', (235, 243))	('stemness', 'Disease', (235, 243))	('enhanced', 'PosReg', (192, 200))	('protein degradation', 'MPA', (201, 220))	('hypermethylation', 'MPA', (81, 97))	('mutations', 'Var', (59, 68))	('promote', 'PosReg', (69, 76))
38310	30954552	Here, we have examined the frequency of mutations in the SWI/SNF complex, which has been shown previously to be perturbed in various cancers.	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('57', '72'))	('cancers', 'Disease', (133, 140))	('mutations', 'Var', (40, 49))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('SWI/SNF', 'Gene', (57, 64))
38311	30954552	Interestingly, half of CIMP-H1 and more than 25% of CIMP-H2 and CIMP-L1 cancers harbored somatic mutations in SWI/SNF members that were predicted to be deleterious.	('mutations', 'Var', (97, 106))	('CIMP-L1 cancers', 'Disease', (64, 79))	('SWI/SNF members', 'Gene', (110, 125))	('CIMP-H1', 'Disease', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('CIMP-H2', 'Disease', (52, 59))	('CIMP-H1', 'Chemical', '-', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('CIMP-H2', 'Chemical', '-', (52, 59))	('CIMP-L1 cancers', 'Disease', 'MESH:C536029', (64, 79))	('harbored', 'Reg', (80, 88))
38312	30954552	We hypothesized that mutation of 1 member of the subunit would increase the reliance of the cancer on other otherwise redundant subunits.	('increase', 'PosReg', (63, 71))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutation', 'Var', (21, 29))	('reliance', 'MPA', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
38313	30954552	To test this hypothesis we used public colorectal cancer cell line dependency data in conjunction with mutational data, and identified a strong dependency conferred upon ARID1B after genetic perturbation of ARID1A.	('ARID1A', 'Gene', (207, 213))	('dependency', 'MPA', (144, 154))	('public colorectal cancer', 'Disease', (32, 56))	('public colorectal cancer', 'Disease', 'MESH:D015179', (32, 56))	('ARID1B', 'Gene', (170, 176))	('colorectal cancer', 'Phenotype', 'HP:0003003', (39, 56))	('ARID1A', 'Gene', '8289', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('genetic perturbation', 'Var', (183, 203))	('ARID1B', 'Gene', '57492', (170, 176))
38314	30954552	These data support the investigation of SWI/SNF inhibitors to exploit synthetic lethality presented by SWI/SNF mutations in CIMP-L1 cancers.	('mutations', 'Var', (111, 120))	('CIMP-L1 cancers', 'Disease', 'MESH:C536029', (124, 139))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('SWI/SNF', 'Gene', (103, 110))	('CIMP-L1 cancers', 'Disease', (124, 139))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
38315	30954552	Collectively, these data indicate a need for further functional experiments to elucidate the role of these mutations in the carcinogenic process of CIMP-H1, CIMP-H2, and CIMP-L1 cancers, and to determine whether the potential synthetic lethalities they create can be exploited.	('mutations', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('CIMP-H1', 'Gene', (148, 155))	('CIMP-H1', 'Chemical', '-', (148, 155))	('CIMP-H2', 'Chemical', '-', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('carcinogenic', 'Disease', 'MESH:D063646', (124, 136))	('CIMP-L1 cancers', 'Disease', 'MESH:C536029', (170, 185))	('carcinogenic', 'Disease', (124, 136))	('CIMP-L1 cancers', 'Disease', (170, 185))
38316	30954552	Key findings, including relationships between CIMP subtype and age, proximal location, BRAF mutation, and KRAS mutation also were identified in an analysis of the TCGA data.	('KRAS', 'Gene', '3845', (106, 110))	('mutation', 'Var', (92, 100))	('CIMP', 'Chemical', '-', (46, 50))	('KRAS', 'Gene', (106, 110))	('BRAF', 'Gene', '673', (87, 91))	('BRAF', 'Gene', (87, 91))
38317	30954552	In our unselected and consecutively collected series we observed a strong relationship between the BRAF mutation and CIMP-H1 and the KRAS mutation and CIMP-H2.	('CIMP-H1', 'Gene', (117, 124))	('CIMP-H1', 'Chemical', '-', (117, 124))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('CIMP-H2', 'Chemical', '-', (151, 158))	('KRAS', 'Gene', (133, 137))	('mutation', 'Var', (104, 112))	('KRAS', 'Gene', '3845', (133, 137))
38318	30954552	Although BRAF was still enriched in the TCGA CIMP-H1 cancers, and KRAS among the CIMP-H2 cancers, we observed a higher proportion of BRAF mutant CIMP-H2 cancers in the TCGA cohort.	('CIMP-H1 cancers', 'Disease', (45, 60))	('BRAF', 'Gene', (9, 13))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('mutant', 'Var', (138, 144))	('CIMP-H2 cancers', 'Disease', 'MESH:D009369', (145, 160))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('CIMP-H2 cancers', 'Disease', 'MESH:D009369', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('BRAF', 'Gene', '673', (133, 137))	('KRAS', 'Gene', '3845', (66, 70))	('CIMP-H1 cancers', 'Disease', 'MESH:D009369', (45, 60))	('BRAF', 'Gene', (133, 137))	('KRAS', 'Gene', (66, 70))	('CIMP-H2 cancers', 'Disease', (145, 160))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('CIMP-H2 cancers', 'Disease', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('BRAF', 'Gene', '673', (9, 13))
38328	30954552	Field DNA methylation defects have been reported in colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('methylation defects', 'Var', (10, 29))	('colorectal cancer', 'Disease', (52, 69))	('reported', 'Reg', (40, 48))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))
38334	30954552	We observed a striking association between genomic methylation and age, which further supports the investigation of the epigenetic clock in serrated neoplasia risk.	('neoplasia', 'Disease', (149, 158))	('serrated neoplasia', 'Phenotype', 'HP:0032222', (140, 158))	('genomic methylation', 'Var', (43, 62))	('neoplasia', 'Phenotype', 'HP:0002664', (149, 158))	('neoplasia', 'Disease', 'MESH:D009369', (149, 158))
38335	30954552	We identified an association between gene body methylation CIMP-H cancers, which may be mediated by H3K27me3 histone marks.	('CIMP-H cancers', 'Disease', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('methylation', 'Var', (47, 58))	('CIMP-H cancers', 'Disease', 'MESH:D009369', (59, 73))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('H3K27me3', 'Var', (100, 108))
38336	30954552	Our interrogation of the coding regions of epigenetic regulatory genes shows that they frequently are mutated in colorectal cancers and this may be partially influenced by the degree of genomic methylation.	('colorectal cancers', 'Disease', 'MESH:D015179', (113, 131))	('methylation', 'biological_process', 'GO:0032259', ('194', '205'))	('colorectal cancers', 'Disease', (113, 131))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('epigenetic regulatory genes', 'Gene', (43, 70))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('mutated', 'Var', (102, 109))
38344	30954552	In addition, we assayed mutations in KRAS codons 12 and 13, and TP53 exons 4 to 8 using previously reported methods.	('KRAS', 'Gene', (37, 41))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('mutations', 'Var', (24, 33))	('KRAS', 'Gene', '3845', (37, 41))
38361	30954552	PolyPhen2 predicts functional effects of missense mutations by examining how evolutionarily conserved the affected residue is, and computes the likelihood that the event will induce a structural change.	('missense mutations', 'Var', (41, 59))	('PolyPhen2', 'Chemical', '-', (0, 9))	('structural change', 'MPA', (184, 201))	('induce', 'Reg', (175, 181))
38362	30954552	Variants predicted to be benign were not included as part of these analyses Polycomb occupancy was inferred from SUZ12 Chromatin Immunoprecipitation (ChIP) sequencing data from hESC1 cells analyzed as part of the Encyclopedia of DNA Elements (ENCODE) ENCODE consortium.	('SUZ12', 'Gene', (113, 118))	('Variants', 'Var', (0, 8))	('DNA', 'cellular_component', 'GO:0005574', ('229', '232'))	('hESC1', 'CellLine', 'CVCL:9771', (177, 182))	('Chromatin', 'cellular_component', 'GO:0000785', ('119', '128'))	('SUZ12', 'Gene', '23512', (113, 118))
38374	31057298	Expression of autophagy-related proteins [Beclin1, microtubule-associated protein 1A/B-light chain 3 (LC3), and 4E-binding protein 1 (4E-BP1)] was examined by Western blot in CRC cells and by immunohistochemistry in cancerous and normal tissues.	('Beclin1', 'Gene', '8678', (42, 49))	('4E-binding protein 1', 'Gene', (112, 132))	('LC3', 'Gene', (102, 105))	('CRC', 'Phenotype', 'HP:0003003', (175, 178))	('4E-BP1', 'Gene', '1978', (134, 140))	('4E-binding protein 1', 'Gene', '1978', (112, 132))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('Beclin1', 'Gene', (42, 49))	('1A/B', 'Var', (82, 86))	('cancerous', 'Disease', (216, 225))	('4E-BP1', 'Gene', (134, 140))	('1A/B', 'SUBSTITUTION', 'None', (82, 86))	('LC3', 'Gene', '84557', (102, 105))	('cancerous', 'Disease', 'MESH:D009369', (216, 225))
38385	31057298	Accordingly, Beclin1, microtubule-associated protein 1A/B-light chain 3 (LC3), and 4E-binding protein 1 (4E-BP1) were studied in this research.	('4E-BP1', 'Gene', '1978', (105, 111))	('Beclin1', 'Gene', (13, 20))	('4E-binding protein 1', 'Gene', (83, 103))	('4E-binding protein 1', 'Gene', '1978', (83, 103))	('LC3', 'Gene', '84557', (73, 76))	('1A/B', 'Var', (53, 57))	('LC3', 'Gene', (73, 76))	('4E-BP1', 'Gene', (105, 111))	('1A/B', 'SUBSTITUTION', 'None', (53, 57))	('Beclin1', 'Gene', '8678', (13, 20))
38400	31057298	Autophagy-related genes (Atgs) control autophagosome formation through Atg12-Atg5 and microtubule-associated protein 1A/B-light chain 3 (LC3) complexes, and the modified form of LC3 is attached to the autophagosome membrane.	('LC3', 'Gene', '84557', (178, 181))	('LC3', 'Gene', (178, 181))	('1A/B', 'Var', (117, 121))	('LC3', 'Gene', (137, 140))	('1A/B', 'SUBSTITUTION', 'None', (117, 121))	('Atg12', 'Gene', '9140', (71, 76))	('modified', 'Var', (161, 169))	('Atg5', 'Gene', '9474', (77, 81))	('autophagosome formation', 'CPA', (39, 62))	('Atg12', 'Gene', (71, 76))	('LC3', 'Gene', '84557', (137, 140))	('Atg5', 'Gene', (77, 81))
38402	31057298	Few reports describe autophagy and the anti-cancer role of cetuximab, antibody targeting EGFR, and most of these studies have been performed on cancer cells.	('autophagy', 'CPA', (21, 30))	('EGFR', 'Gene', (89, 93))	('antibody', 'Var', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Disease', (144, 150))	('EGFR', 'Gene', '1956', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cetuximab', 'Chemical', 'MESH:D000068818', (59, 68))
38428	31057298	After incubation with primary antibodies against 4E-BP1 (1:200), Beclin-1 (1:100), and LC3 (1:400) (all from Cell Signaling Technology, United States) diluted in 1% PBS, the sections were incubated with an anti-rabbit secondary antibody (Invitrogen, United States) for 30 min.	('4E-BP1', 'Gene', (49, 55))	('antibody', 'cellular_component', 'GO:0019815', ('228', '236'))	('1:100', 'Var', (75, 80))	('LC3', 'Gene', '84557', (87, 90))	('rabbit', 'Species', '9986', (211, 217))	('antibody', 'cellular_component', 'GO:0019814', ('228', '236'))	('PBS', 'Chemical', 'MESH:D007854', (165, 168))	('antibody', 'molecular_function', 'GO:0003823', ('228', '236'))	('Beclin-1', 'Gene', (65, 73))	('LC3', 'Gene', (87, 90))	('Signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('4E-BP1', 'Gene', '1978', (49, 55))	('Beclin-1', 'Gene', '8678', (65, 73))	('antibody', 'cellular_component', 'GO:0042571', ('228', '236'))
38458	31057298	Compared to patients with the wild-type KRAS gene, patients with the mutated KRAS gene expressed higher levels of Beclin1 (100% vs 64.9%, P = 0.044) and LC3 (100% vs 64.9%, P = 0.044).	('levels', 'MPA', (104, 110))	('patients', 'Species', '9606', (12, 20))	('higher', 'PosReg', (97, 103))	('Beclin1', 'Gene', '8678', (114, 121))	('mutated', 'Var', (69, 76))	('KRAS', 'Gene', (40, 44))	('KRAS', 'Gene', (77, 81))	('LC3', 'Gene', '84557', (153, 156))	('Beclin1', 'Gene', (114, 121))	('patients', 'Species', '9606', (51, 59))	('KRAS', 'Gene', '3845', (40, 44))	('KRAS', 'Gene', '3845', (77, 81))	('LC3', 'Gene', (153, 156))
38480	31057298	We also found that autophagy was activated by cetuximab in colon cancer cells, and cetuximab increased cell death through autophagy.	('colon cancer', 'Disease', (59, 71))	('cetuximab', 'Chemical', 'MESH:D000068818', (83, 92))	('activated', 'PosReg', (33, 42))	('increased', 'PosReg', (93, 102))	('cetuximab', 'Chemical', 'MESH:D000068818', (46, 55))	('colon cancer', 'Phenotype', 'HP:0003003', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cell death', 'CPA', (103, 113))	('autophagy', 'CPA', (19, 28))	('colon cancer', 'Disease', 'MESH:D015179', (59, 71))	('cetuximab', 'Var', (83, 92))	('autophagy', 'CPA', (122, 131))
38486	31057298	Additionally, we found that patients with mutant KRAS had higher expression levels of the autophagic markers Beclin1 and LC3.	('mutant', 'Var', (42, 48))	('autophagic', 'CPA', (90, 100))	('KRAS', 'Gene', '3845', (49, 53))	('expression levels', 'MPA', (65, 82))	('LC3', 'Gene', '84557', (121, 124))	('Beclin1', 'Gene', '8678', (109, 116))	('LC3', 'Gene', (121, 124))	('higher', 'PosReg', (58, 64))	('patients', 'Species', '9606', (28, 36))	('Beclin1', 'Gene', (109, 116))	('KRAS', 'Gene', (49, 53))
38487	31057298	Several studies have shown that autophagy is upregulated in cancers with KRAS mutations.	('KRAS', 'Gene', (73, 77))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('KRAS', 'Gene', '3845', (73, 77))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('mutations', 'Var', (78, 87))	('upregulated', 'PosReg', (45, 56))	('autophagy', 'CPA', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
38489	31057298	Guo et al observed that cells with mutated KRAS require autophagy to maintain oxidative metabolism and tumorigenesis when nutrients are limiting.	('mutated', 'Var', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('autophagy', 'biological_process', 'GO:0016236', ('56', '65'))	('autophagy', 'CPA', (56, 65))	('tumor', 'Disease', (103, 108))	('autophagy', 'biological_process', 'GO:0006914', ('56', '65'))	('KRAS', 'Gene', (43, 47))	('oxidative metabolism', 'biological_process', 'GO:0045333', ('78', '98'))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('oxidative', 'MPA', (78, 87))	('KRAS', 'Gene', '3845', (43, 47))
38510	31057298	The role of Beclin1, microtubule-associated protein 1A/B-light chain 3 (LC3), and 4E-binding protein 1 (4E-BP1), the key factors in autophagy, in predicting the efficacy of cetuximab in ACRC with wild-type KRAS was explored.	('4E-binding protein 1', 'Gene', '1978', (82, 102))	('4E-BP1', 'Gene', (104, 110))	('1A/B', 'Var', (52, 56))	('4E-binding protein 1', 'Gene', (82, 102))	('1A/B', 'SUBSTITUTION', 'None', (52, 56))	('KRAS', 'Gene', '3845', (206, 210))	('Beclin1', 'Gene', '8678', (12, 19))	('LC3', 'Gene', '84557', (72, 75))	('cetuximab', 'Chemical', 'MESH:D000068818', (173, 182))	('4E-BP1', 'Gene', '1978', (104, 110))	('CRC', 'Phenotype', 'HP:0003003', (187, 190))	('LC3', 'Gene', (72, 75))	('Beclin1', 'Gene', (12, 19))	('KRAS', 'Gene', (206, 210))
38527	30087854	For oesophageal squamous cell carcinoma and oesophageal adenocarcinoma, methylation of certain genes such as APC and DAPK have been highlighted as promising biomarkers for prognostication, but these studies are limited and more comprehensive research is needed.	('APC', 'Disease', (109, 112))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (16, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('methylation', 'Var', (72, 83))	('oesophageal squamous cell carcinoma and oesophageal adenocarcinoma', 'Disease', 'MESH:D005764', (4, 70))	('DAPK', 'Gene', (117, 121))	('DAPK', 'Gene', '1612', (117, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('APC', 'Disease', 'MESH:D011125', (109, 112))
38528	30087854	Studies focusing on gastric cancer patients showed that methylation of ctDNA in SOX17 and APC were independently associated with poor survival.	('poor survival', 'CPA', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('ctDNA', 'Gene', (71, 76))	('gastric cancer', 'Disease', (20, 34))	('SOX17', 'Gene', (80, 85))	('APC', 'Disease', 'MESH:D011125', (90, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (20, 34))	('patients', 'Species', '9606', (35, 43))	('methylation', 'Var', (56, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (20, 34))	('APC', 'Disease', (90, 93))	('associated', 'Reg', (113, 123))	('SOX17', 'Gene', '64321', (80, 85))
38530	30087854	ctDNA biomarkers that identified somatic mutations were more effective if they were personalized based on mutations found in the primary tumor tissue, but ctDNA methylation studies identified various biomarkers that predicted increased risk of recurrence, poor disease free survival and overall survival.	('mutations', 'Var', (41, 50))	('tumor', 'Disease', (137, 142))	('disease free survival', 'CPA', (261, 282))	('recurrence', 'Disease', (244, 254))	('poor', 'NegReg', (256, 260))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
38557	30087854	Most gastrointestinal cancers are thought to develop through a series of epigenetic changes or somatic (non-hereditary) lesions.	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('gastrointestinal cancers', 'Disease', (5, 29))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (5, 28))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (5, 29))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('epigenetic changes', 'Var', (73, 91))
38568	30087854	Other common strategies involve assessing cell free DNA levels, tumor specific DNA mutations, and tumor specific epigenetic changes.	('tumor', 'Disease', (64, 69))	('epigenetic changes', 'Var', (113, 131))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('DNA', 'cellular_component', 'GO:0005574', ('52', '55'))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('DNA mutations', 'Var', (79, 92))	('DNA', 'cellular_component', 'GO:0005574', ('79', '82'))
38571	30087854	The following sections of this review will describe the studies that have been performed in gastrointestinal cancers to assess the utility of ctDNA for their prognostic value, whether measured as cfDNA concentration, integrity (fragment lengths), copy number alterations, mutation or methylation status.	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('gastrointestinal cancers', 'Disease', (92, 116))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (92, 116))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (92, 115))	('copy number', 'Var', (247, 258))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
38582	30087854	Changes in allele frequency in ctDNA was associated with tumor burden, and the allelic frequency increased prior to radiographic detection of recurrence (6 months before radiological evidence).	('ctDNA', 'Gene', (31, 36))	('associated', 'Reg', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Changes', 'Var', (0, 7))	('tumor', 'Disease', (57, 62))
38584	30087854	In both types of cancers, no relationship was found between recurrence and LOH; however, in SCC a trend toward shorter survival was observed for patients with LOH in tumor tissue and ctDNA.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('patients', 'Species', '9606', (145, 153))	('SCC', 'Phenotype', 'HP:0002860', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('SCC', 'Gene', '6317', (92, 95))	('LOH', 'Var', (159, 162))	('tumor', 'Disease', (166, 171))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('shorter', 'NegReg', (111, 118))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('SCC', 'Gene', (92, 95))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
38588	30087854	Presence of pre-operative DAPK methylation was associated with poorer survival (p = 0.01) and detection of post-operative methylation of APC promoter was correlated with residual tumor (p = 0.03).	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('DAPK', 'Gene', (26, 30))	('APC', 'Disease', 'MESH:D011125', (137, 140))	('DAPK', 'Gene', '1612', (26, 30))	('methylation', 'Var', (122, 133))	('poorer', 'NegReg', (63, 69))	('APC', 'Disease', (137, 140))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('methylation', 'Var', (31, 42))	('APC', 'cellular_component', 'GO:0005680', ('137', '140'))	('residual', 'Disease', (170, 178))	('survival', 'CPA', (70, 78))	('pre', 'molecular_function', 'GO:0003904', ('12', '15'))	('methylation', 'biological_process', 'GO:0032259', ('122', '133'))	('Presence', 'Var', (0, 8))	('tumor', 'Disease', (179, 184))
38595	30087854	In a study that focussed on 277 stage IV cases it was found that a high level of DNA with more mutations was present pre-operatively (p < 0.0001) and these patients had an increased risk of recurrence (p = 0.037) and lower overall survival (p = 0.039) over the 5-year follow-up period.	('patients', 'Species', '9606', (156, 164))	('recurrence', 'CPA', (190, 200))	('overall', 'MPA', (223, 230))	('lower', 'NegReg', (217, 222))	('mutations', 'Var', (95, 104))
38599	30087854	While plasma EBV DNA may useful for monitoring clinical load in patients with EBV-associated gastric carcinomas, no significant difference was found between prognosis of recurrence-free survival of those with high pre-operative EBV copy numbers compared to those with low levels.	('pre', 'molecular_function', 'GO:0003904', ('214', '217'))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (93, 110))	('patients', 'Species', '9606', (64, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('EBV', 'Species', '10376', (228, 231))	('EBV-associated', 'Reg', (78, 92))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('high', 'Var', (209, 213))	('EBV', 'Species', '10376', (13, 16))	('DNA', 'cellular_component', 'GO:0005574', ('17', '20'))	('EBV', 'Species', '10376', (78, 81))	('EBV-associated', 'Gene', (78, 92))	('EBV', 'Gene', (228, 231))	('gastric carcinomas', 'Disease', (93, 111))	('gastric carcinomas', 'Disease', 'MESH:D013274', (93, 111))
38606	30087854	One of the studies was a longitudinal study in 42 stage II gastric cancer patients undergoing surgical resection which evaluated concentration of TP53 mutations.	('TP53', 'Gene', '7157', (146, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (59, 73))	('patients', 'Species', '9606', (74, 82))	('TP53', 'Gene', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('gastric cancer', 'Disease', (59, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (59, 73))	('mutations', 'Var', (151, 160))
38609	30087854	A few papers have studied methylation of ctDNA in gastric cancer and found a significantly worse clinical outcome in patients who have aberrant methylation of various genes in ctDNA.	('aberrant methylation', 'Var', (135, 155))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('gastric cancer', 'Disease', (50, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('methylation', 'biological_process', 'GO:0032259', ('144', '155'))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))	('patients', 'Species', '9606', (117, 125))
38610	30087854	Pimson et al found 85 and 95% of 101 advanced gastric cancer patients had PCDH10 and RASSF1A methylation which was associated with a reduction in median survival to ~8 months (p < 0.001).	('RASSF1A', 'Gene', (85, 92))	('PCDH10', 'Gene', '57575', (74, 80))	('gastric cancer', 'Disease', (46, 60))	('RASSF1A', 'Gene', '11186', (85, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (46, 60))	('reduction', 'NegReg', (133, 142))	('patients', 'Species', '9606', (61, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('PCDH10', 'Gene', (74, 80))	('median survival', 'MPA', (146, 161))	('methylation', 'Var', (93, 104))
38612	30087854	APC methylation levels were also associated with high levels of the conventional tumor biomarkers, CEA and CA19-9.	('methylation levels', 'Var', (4, 22))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('high levels', 'MPA', (49, 60))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('APC', 'Disease', (0, 3))	('associated', 'Reg', (33, 43))	('CEA', 'Gene', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CEA', 'Gene', '1084', (99, 102))	('CA19-9', 'MPA', (107, 113))	('tumor', 'Disease', (81, 86))
38613	30087854	In a similar study, Balgkouranidou et al found that methylation of SOX17 in pre-operative ctDNA of 73 patients with operable gastric cancer had decreased overall survival (p = 0.049).	('gastric cancer', 'Disease', 'MESH:D013274', (125, 139))	('decreased', 'NegReg', (144, 153))	('overall survival', 'MPA', (154, 170))	('SOX17', 'Gene', '64321', (67, 72))	('patients', 'Species', '9606', (102, 110))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))	('methylation', 'Var', (52, 63))	('SOX17', 'Gene', (67, 72))	('gastric cancer', 'Disease', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
38615	30087854	Aberrant methylation of MINT2 promoter in pre-operative ctDNA was associated with peritoneal dissemination and tumor progression (p < 0.0001); and methylation of TIMP-3 was associated with poorer disease free survival rates (p < 0.001).	('MINT2', 'Gene', '321', (24, 29))	('TIMP-3', 'Gene', '7078', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('peritoneal', 'Disease', (82, 92))	('associated', 'Reg', (66, 76))	('MINT2', 'Gene', (24, 29))	('disease free survival rates', 'CPA', (196, 223))	('tumor', 'Disease', (111, 116))	('methylation', 'Var', (147, 158))	('poorer', 'NegReg', (189, 195))	('Aberrant methylation', 'Var', (0, 20))	('TIMP-3', 'Gene', (162, 168))	('ctDNA', 'Disease', (56, 61))
38616	30087854	A study by Ling et al assessed XAF1 methylation in pre-operative and post-operative follow-up ctDNA of 202 gastric cancer patients of all stages and showed that negative to positive methylation change post-surgery was associated with a poorer disease-free survival (p < 0.0001).	('disease-free survival', 'CPA', (243, 264))	('XAF1', 'Gene', '54739', (31, 35))	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('Ling', 'Species', '163112', (11, 15))	('XAF1', 'Gene', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gastric cancer', 'Disease', 'MESH:D013274', (107, 121))	('patients', 'Species', '9606', (122, 130))	('gastric cancer', 'Disease', (107, 121))	('poorer', 'NegReg', (236, 242))	('negative', 'Var', (161, 169))	('methylation', 'MPA', (182, 193))
38618	30087854	Methylation changes appear to be the most promising with methylated RASSF1A and SOX17 being independent predictors of overall survival.	('RASSF1A', 'Gene', '11186', (68, 75))	('Methylation', 'MPA', (0, 11))	('SOX17', 'Gene', (80, 85))	('SOX17', 'Gene', '64321', (80, 85))	('methylated', 'Var', (57, 67))	('RASSF1A', 'Gene', (68, 75))
38619	30087854	In 92 patients with recurrent GIST, Rawnaq et al found an association between loss of heterozygosity in microsatellite DNA and recurrence (p = 0.03), but no association with overall survival.	('recurrence', 'Disease', (127, 137))	('microsatellite DNA', 'Gene', (104, 122))	('DNA', 'cellular_component', 'GO:0005574', ('119', '122'))	('GIST', 'Phenotype', 'HP:0100723', (30, 34))	('patients', 'Species', '9606', (6, 14))	('loss of heterozygosity', 'Var', (78, 100))
38627	30087854	Schwarzenbach et al only assessed 55 stage IV CRC patients and found that high DNA levels prior to surgical resection was associated with a shorter survival period.	('survival period', 'CPA', (148, 163))	('shorter', 'NegReg', (140, 147))	('patients', 'Species', '9606', (50, 58))	('high', 'Var', (74, 78))	('CRC', 'Phenotype', 'HP:0003003', (46, 49))
38629	30087854	Spindler et al (n = 100) found patients with high level of DNA prior to second-line treatment with irinotecan had shorter progression-free survival and overall survival (p < 0.0001).	('high level', 'Var', (45, 55))	('irinotecan', 'Chemical', 'MESH:D000077146', (99, 109))	('overall survival', 'CPA', (152, 168))	('shorter', 'NegReg', (114, 121))	('patients', 'Species', '9606', (31, 39))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('progression-free survival', 'CPA', (122, 147))
38631	30087854	In 49 patients with therapy resistant metastatic CRC being treated with gemcitabine and capecitabine, it was shown that high DNA levels prior to therapy was associated with lower overall survival.	('CRC', 'Phenotype', 'HP:0003003', (49, 52))	('high', 'Var', (120, 124))	('gemcitabine', 'Chemical', 'MESH:C056507', (72, 83))	('patients', 'Species', '9606', (6, 14))	('lower', 'NegReg', (173, 178))	('overall survival', 'MPA', (179, 195))	('capecitabine', 'Chemical', 'MESH:D000069287', (88, 100))
38632	30087854	Schou et al assessed cfDNA levels longitudinally in 123 patients with locally advanced rectal cancer receiving chemotherapy and found that a high baseline level was associated with a higher risk of local/distant recurrence and a shorter time to recurrence (p = 0.002).	('patients', 'Species', '9606', (56, 64))	('local/distant recurrence', 'CPA', (198, 222))	('rectal cancer', 'Disease', 'MESH:D012004', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('rectal cancer', 'Disease', (87, 100))	('rectal cancer', 'Phenotype', 'HP:0100743', (87, 100))	('high', 'Var', (141, 145))
38634	30087854	Mohrmann et al assessed mutations in BRAF, KRAS, and EGFR genes in ctDNA of 20 advanced CRC patients and also found that lower ctDNA corresponded with longer survival.	('BRAF', 'Gene', '673', (37, 41))	('longer', 'PosReg', (151, 157))	('BRAF', 'Gene', (37, 41))	('patients', 'Species', '9606', (92, 100))	('KRAS', 'Gene', (43, 47))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('mutations', 'Var', (24, 33))	('CRC', 'Phenotype', 'HP:0003003', (88, 91))	('KRAS', 'Gene', '3845', (43, 47))
38635	30087854	These findings were supported by a study of 37 patients that evaluated the presence of KRAS mutations and p16 hypermethylation in all stages of CRC and found a strong association between detection of ctDNA, and a shorter survival and higher risk of recurrence.	('ctDNA', 'Disease', (200, 205))	('KRAS', 'Gene', (87, 91))	('hypermethylation', 'Var', (110, 126))	('shorter', 'NegReg', (213, 220))	('KRAS', 'Gene', '3845', (87, 91))	('CRC', 'Phenotype', 'HP:0003003', (144, 147))	('p16', 'Gene', (106, 109))	('patients', 'Species', '9606', (47, 55))	('mutations', 'Var', (92, 101))	('p16', 'Gene', '1029', (106, 109))
38636	30087854	Similarly, Wang et al concluded that detection of genetic alterations in APC, p53, and KRAS in a sample of 104 pre-operative CRC patients was linked to increased incidence of recurrence and metastases.	('metastases', 'Disease', (190, 200))	('KRAS', 'Gene', (87, 91))	('KRAS', 'Gene', '3845', (87, 91))	('patients', 'Species', '9606', (129, 137))	('pre', 'molecular_function', 'GO:0003904', ('111', '114'))	('metastases', 'Disease', 'MESH:D009362', (190, 200))	('genetic alterations', 'Var', (50, 69))	('CRC', 'Phenotype', 'HP:0003003', (125, 128))	('APC', 'Disease', 'MESH:D011125', (73, 76))	('p53', 'Gene', (78, 81))	('APC', 'cellular_component', 'GO:0005680', ('73', '76'))	('p53', 'Gene', '7157', (78, 81))	('APC', 'Disease', (73, 76))
38637	30087854	Ryan et al (n = 78) contradicted some of the studies above with their finding that pre-operative KRAS2 mutations in ctDNA was not an independent prognostic factor for disease recurrence.	('ctDNA', 'Gene', (116, 121))	('mutations', 'Var', (103, 112))	('KRAS2', 'Gene', (97, 102))	('KRAS2', 'Gene', '3845', (97, 102))
38643	30087854	Shin et al assessed KRAS mutations in 62 stage III/IV CRC patients undergoing surgery and found a higher rate of ctDNA mutation detection in patients with metastases, and that detectable ctDNA KRAS mutations correlated with a shorter overall survival (p = 0.03).	('KRAS', 'Gene', '3845', (20, 24))	('shorter', 'NegReg', (226, 233))	('KRAS', 'Gene', (193, 197))	('patients', 'Species', '9606', (141, 149))	('metastases', 'Disease', 'MESH:D009362', (155, 165))	('KRAS', 'Gene', '3845', (193, 197))	('mutations', 'Var', (198, 207))	('ctDNA', 'Gene', (113, 118))	('patients', 'Species', '9606', (58, 66))	('CRC', 'Phenotype', 'HP:0003003', (54, 57))	('KRAS', 'Gene', (20, 24))	('overall survival', 'MPA', (234, 250))	('metastases', 'Disease', (155, 165))
38644	30087854	Several studies have assessed recurrence in CRC patients based on selection of ctDNA mutations following primary tumor tissue analysis, including a study by Ng et al (n = 44) who found certain patients were positive pre-operatively, negative post-operatively and then positive again prior to recurrence before any clinical or radiological evidence.	('tumor', 'Disease', (113, 118))	('patients', 'Species', '9606', (193, 201))	('pre', 'molecular_function', 'GO:0003904', ('216', '219'))	('CRC', 'Phenotype', 'HP:0003003', (44, 47))	('mutations', 'Var', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('positive', 'Reg', (207, 215))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('patients', 'Species', '9606', (48, 56))	('ctDNA', 'Gene', (79, 84))
38655	30087854	In a study of 211 patients, Spindler et al found that patients with KRAS mutations in pre-therapy ctDNA, did not respond to second-line irinotecan treatment and had shorter overall survival and progression free survival (p = 0.04; p < 0.0001; p = 0.01).	('shorter', 'NegReg', (165, 172))	('patients', 'Species', '9606', (54, 62))	('irinotecan', 'Chemical', 'MESH:D000077146', (136, 146))	('ctDNA', 'Gene', (98, 103))	('overall', 'MPA', (173, 180))	('KRAS', 'Gene', (68, 72))	('KRAS', 'Gene', '3845', (68, 72))	('not', 'NegReg', (109, 112))	('patients', 'Species', '9606', (18, 26))	('mutations', 'Var', (73, 82))	('progression free survival', 'CPA', (194, 219))
38657	30087854	Tie et al assessed mutations in primary tumor present in ctDNA in 53 patients and found that the changes in level of mutant DNA correlated with radiological response to first-line chemotherapy treatment and major reductions in ctDNA seemed to be associated with a trend for increased progression free and overall survival.	('progression free', 'CPA', (284, 300))	('mutant', 'Var', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('DNA', 'Gene', (124, 127))	('reductions', 'NegReg', (213, 223))	('patients', 'Species', '9606', (69, 77))	('tumor', 'Disease', (40, 45))	('overall survival', 'CPA', (305, 321))	('increased', 'PosReg', (274, 283))
38659	30087854	Liu et al (n = 165) found a significant association between pre-operative ctDNA methylation of SST and MAL and cancer specific deaths.	('MAL', 'Disease', (103, 106))	('pre', 'molecular_function', 'GO:0003904', ('60', '63'))	('SST', 'Gene', '6750', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('methylation', 'biological_process', 'GO:0032259', ('80', '91'))	('methylation', 'Var', (80, 91))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('deaths', 'Disease', 'MESH:D003643', (127, 133))	('deaths', 'Disease', (127, 133))	('SST', 'Gene', (95, 98))
38660	30087854	Methylation of SST also correlated with tumor recurrence.	('Methylation', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('SST', 'Gene', '6750', (15, 18))	('correlated with', 'Reg', (24, 39))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('SST', 'Gene', (15, 18))	('tumor', 'Disease', (40, 45))
38661	30087854	Matthaios et al (n = 155) found an association between methylation of APC and RASSF1A in pre-operative ctDNA and poor survival in early and advanced CRC patients.	('patients', 'Species', '9606', (153, 161))	('APC', 'cellular_component', 'GO:0005680', ('70', '73'))	('poor', 'NegReg', (113, 117))	('RASSF1A', 'Gene', '11186', (78, 85))	('CRC', 'Phenotype', 'HP:0003003', (149, 152))	('methylation', 'Var', (55, 66))	('APC', 'Disease', 'MESH:D011125', (70, 73))	('APC', 'Disease', (70, 73))	('pre', 'molecular_function', 'GO:0003904', ('89', '92'))	('RASSF1A', 'Gene', (78, 85))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))
38663	30087854	While most studies have assessed hypermethylation, one study (n = 95) found that hypomethylation of CBS promoter induced by folate deficiency was also linked to recurrence and cancer-related death.	('CBS', 'Gene', (100, 103))	('folate deficiency', 'Disease', 'MESH:C562799', (124, 141))	('folate deficiency', 'Disease', (124, 141))	('death', 'Disease', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('recurrence', 'CPA', (161, 171))	('CBS', 'Gene', '875', (100, 103))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('folate deficiency', 'Phenotype', 'HP:0100507', (124, 141))	('death', 'Disease', 'MESH:D003643', (191, 196))	('hypomethylation', 'Var', (81, 96))	('linked', 'Reg', (151, 157))
38664	30087854	Several studies have investigated the prognostic value of DNA methylation for metastatic CRC patients and/or following adjuvant chemotherapy.	('metastatic CRC patients', 'Disease', (78, 101))	('CRC', 'Phenotype', 'HP:0003003', (89, 92))	('patients', 'Species', '9606', (93, 101))	('methylation', 'Var', (62, 73))
38665	30087854	Prior to therapy, two studies (n = 467 and n = 82) showed that detection of methylated HPP1, WIF1, and NPY in blood have been shown to be associated with poor overall survival.	('HPP1', 'Gene', (87, 91))	('NPY', 'Gene', (103, 106))	('overall', 'MPA', (159, 166))	('WIF1', 'Gene', (93, 97))	('NPY', 'Gene', '4852', (103, 106))	('WIF1', 'Gene', '11197', (93, 97))	('methylated', 'Var', (76, 86))	('poor', 'NegReg', (154, 158))	('HPP1', 'Gene', '780897', (87, 91))
38667	30087854	RARB and RASSF1A methylation was associated with more aggressive disease indicating poor survival.	('RARB', 'Gene', '5915', (0, 4))	('aggressive disease', 'Disease', 'MESH:D001523', (54, 72))	('methylation', 'Var', (17, 28))	('aggressive disease', 'Disease', (54, 72))	('associated', 'Reg', (33, 43))	('RASSF1A', 'Gene', (9, 16))	('RARB', 'Gene', (0, 4))	('RASSF1A', 'Gene', '11186', (9, 16))
38668	30087854	In two separate studies Philipp et al (n = 311 and n = 259) showed that methylation of HLTF or HPP1 was associated with larger and more advanced CRC stage, shorter overall survival and metastases.	('HLTF', 'Gene', '6596', (87, 91))	('HLTF', 'Gene', (87, 91))	('CRC', 'Phenotype', 'HP:0003003', (145, 148))	('HPP1', 'Gene', '780897', (95, 99))	('associated', 'Reg', (104, 114))	('methylation', 'Var', (72, 83))	('shorter', 'NegReg', (156, 163))	('metastases', 'Disease', 'MESH:D009362', (185, 195))	('metastases', 'Disease', (185, 195))	('HPP1', 'Gene', (95, 99))	('overall survival', 'CPA', (164, 180))
38670	30087854	The majority of studies searching for prognostic ctDNA biomarkers for CRC focussed on DNA mutations, with the use of blood biomarkers that have been personalized from primary tumor tissue analysis, showing promising sensitivity.	('tumor', 'Disease', (175, 180))	('mutations', 'Var', (90, 99))	('DNA', 'Gene', (86, 89))	('CRC', 'Phenotype', 'HP:0003003', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
38671	30087854	Such biomarkers are most effective though when based on known mutations in surgically resected cancer.	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('mutations', 'Var', (62, 71))	('cancer', 'Disease', (95, 101))
38672	30087854	Methylated DNA biomarkers are better suited for pre-operative prognostication and hence have been the subject of more studies of this type, with pre-operative detection of methylated SST showing promise for independent prediction of recurrence, and methylated SST, RASSF1A, and RARB being independent predictors of overall survival.	('pre', 'molecular_function', 'GO:0003904', ('145', '148'))	('SST', 'Gene', '6750', (183, 186))	('RARB', 'Gene', (278, 282))	('recurrence', 'Disease', (233, 243))	('methylated', 'Var', (249, 259))	('pre', 'molecular_function', 'GO:0003904', ('48', '51'))	('RASSF1A', 'Gene', (265, 272))	('RARB', 'Gene', '5915', (278, 282))	('SST', 'Gene', '6750', (260, 263))	('methylated', 'Var', (172, 182))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('RASSF1A', 'Gene', '11186', (265, 272))	('SST', 'Gene', (183, 186))	('SST', 'Gene', (260, 263))
38678	30087854	For gastric cancer methylated SOX17 and APC were independent predictors of survival, with an adjusted HR of 3.0 (95% CI 1.2-7.8) and 4.6 (95% CI 1.1-20.3) respectively.	('methylated', 'Var', (19, 29))	('APC', 'Disease', 'MESH:D011125', (40, 43))	('survival', 'Disease', (75, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (4, 18))	('APC', 'Disease', (40, 43))	('gastric cancer', 'Disease', 'MESH:D013274', (4, 18))	('SOX17', 'Gene', '64321', (30, 35))	('APC', 'cellular_component', 'GO:0005680', ('40', '43'))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('gastric cancer', 'Disease', (4, 18))	('SOX17', 'Gene', (30, 35))
38679	30087854	For CRC there were a number of ctDNA biomarkers that were independent predictors of prognosis including DNA levels and fragments, tumor-specific DNA mutations and DNA methylation.	('mutations', 'Var', (149, 158))	('CRC', 'Phenotype', 'HP:0003003', (4, 7))	('methylation', 'Var', (167, 178))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('fragments', 'MPA', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('DNA levels', 'MPA', (104, 114))	('tumor', 'Disease', (130, 135))
38681	30087854	Other independent predictors for recurrence included methylated SST (HR 2.60, 95% CI 1.37-4.94) and hypomethylated CBS (HR 1.54, 95% CI 1.18-3.02).	('SST', 'Gene', (64, 67))	('hypomethylated CBS', 'Disease', 'MESH:D006712', (100, 118))	('SST', 'Gene', '6750', (64, 67))	('hypomethylated CBS', 'Disease', (100, 118))	('methylated', 'Var', (53, 63))
38682	30087854	For independent prediction of survival, seven potential biomarkers (all analyzed in pre-operative blood samples) were found: Alu83 (HR 2.71, 95% CI 1.22-6.02), Alu244 (HR 2.70, 95% CI 1.25-5.84), DNA copy number (HR 2.61, 95% CI 1.31-5.19), methylated SST (HR 1.96, 95% CI 1.06-3.62), methylated RARB (HR 1.99, 95% CI 1.07-3.72), methylated RASSF1A (HR 3.35, 95% CI 1.76-6.38), and hypomethylated CBS (HR 1.35, 95% CI 1.09-2.41).	('hypomethylated CBS', 'Disease', (382, 400))	('SST', 'Gene', '6750', (252, 255))	('methylated', 'Var', (241, 251))	('hypomethylated CBS', 'Disease', 'MESH:D006712', (382, 400))	('RARB', 'Gene', '5915', (296, 300))	('methylated', 'Var', (285, 295))	('methylated', 'Var', (330, 340))	('RASSF1A', 'Gene', (341, 348))	('SST', 'Gene', (252, 255))	('RASSF1A', 'Gene', '11186', (341, 348))	('RARB', 'Gene', (296, 300))
38693	30087854	While hypermethylation of the promoter region of SEPT9 shows promise for screening and monitoring of CRC, methylated Sept9 was also detected in 44.3% of lung cancer patients.	('Sept9', 'Gene', (117, 122))	('hypermethylation', 'Var', (6, 22))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('detected', 'Reg', (132, 140))	('methylated', 'Var', (106, 116))	('CRC', 'Phenotype', 'HP:0003003', (101, 104))	('lung cancer', 'Disease', (153, 164))	('SEPT9', 'Gene', '10801', (49, 54))	('patients', 'Species', '9606', (165, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('SEPT9', 'Gene', (49, 54))	('Sept9', 'Gene', '10801', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
38694	30087854	In the current review, the lack of specificity for one cancer was seen for methylated APC and RASSF1A that have prognostic potential in both gastric and colorectal cancers.	('methylated', 'Var', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('rectal cancer', 'Phenotype', 'HP:0100743', (157, 170))	('RASSF1A', 'Gene', (94, 101))	('gastric and colorectal cancers', 'Disease', 'MESH:D013274', (141, 171))	('APC', 'Disease', 'MESH:D011125', (86, 89))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancer', 'Disease', (164, 170))	('APC', 'Disease', (86, 89))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('colorectal cancer', 'Phenotype', 'HP:0003003', (153, 170))	('RASSF1A', 'Gene', '11186', (94, 101))	('APC', 'cellular_component', 'GO:0005680', ('86', '89'))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
38695	30087854	Due to tumor heterogeneity, assessment of mutations is not easily implemented in practice, with the common genes (KRAS, BRAF, APC, TP53) mutated in only 15-40% of CRC.	('CRC', 'Disease', (163, 166))	('tumor', 'Disease', (7, 12))	('BRAF', 'Gene', '673', (120, 124))	('APC', 'Disease', 'MESH:D011125', (126, 129))	('CRC', 'Phenotype', 'HP:0003003', (163, 166))	('KRAS', 'Gene', (114, 118))	('APC', 'Disease', (126, 129))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('BRAF', 'Gene', (120, 124))	('KRAS', 'Gene', '3845', (114, 118))	('mutated', 'Var', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
38699	30087854	The consequences of promoter methylation can include transcriptional silencing which might facilitate tumor progression by allowing the accumulation of additional genetic and/or epigenetic changes.	('transcriptional', 'MPA', (53, 68))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('facilitate', 'PosReg', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('promoter methylation', 'Var', (20, 40))
38707	30087854	It is also possible that the detection of new mutations with ctDNA, or detection of a number of biomarkers identifies tumor heterogeneity, and indicates prognosis as well as guiding therapy.	('indicates', 'Reg', (143, 152))	('mutations', 'Var', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('ctDNA', 'Gene', (61, 66))	('tumor', 'Disease', (118, 123))
38721	29560130	In vivo co-inoculation studies with CRC stem cells demonstrated that fibroblasts characterized by high miR-20a expression had reduced tumor-promoting activities.	('high', 'Var', (98, 102))	('tumor', 'Disease', (134, 139))	('expression', 'MPA', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('miR-20a', 'Gene', (103, 110))	('rat', 'Species', '10116', (58, 61))	('miR-20a', 'Gene', '406982', (103, 110))	('CRC', 'Phenotype', 'HP:0003003', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('reduced', 'NegReg', (126, 133))
38733	29560130	The miRNA expression profile is highly predictive for tumor progression and targeting miRNAs has therapeutic benefits in chemoprevention or chemomodulation.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('miR', 'Gene', (4, 7))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (86, 89))	('miR', 'Gene', '220972', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('targeting', 'Var', (76, 85))	('tumor', 'Disease', (54, 59))
38737	29560130	Target specificity is determined by the seed sequence (nucleotides 2 to 8 from the 5' end of a miRNA) and is further strengthened by base pairing of flanking nucleotides.	('miR', 'Gene', '220972', (95, 98))	('miR', 'Gene', (95, 98))	('base pairing', 'Var', (133, 145))	('base pairing', 'molecular_function', 'GO:0003676', ('133', '145'))	('strengthened', 'PosReg', (117, 129))	('Target specificity', 'MPA', (0, 18))
38744	29560130	Dysregulation of miRNAs have been implicated in the function of tumor-associated fibroblasts.	('tumor', 'Disease', (64, 69))	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('implicated', 'Reg', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
38766	29560130	Mutating the miR-20a binding site in the CXCL8 3'UTR luciferase reporter rendered this construct unresponsive to the addition of exogenous miR-20a mimic (Figure 2H).	('Mutating', 'Var', (0, 8))	('miR-20a', 'Gene', '406982', (139, 146))	('miR-20a', 'Gene', (13, 20))	('CXCL8', 'Gene', '3576', (41, 46))	('miR-20a', 'Gene', '406982', (13, 20))	('CXCL8', 'Gene', (41, 46))	('miR-20a', 'Gene', (139, 146))	('binding', 'molecular_function', 'GO:0005488', ('21', '28'))
38858	29560130	Twenty-four hours after seeding, fibroblasts were transfected with either parental pMIRGLO plasmid, wild type pMIRGLO-CXCL8-3'UTR or mutagenized pMIRGLO-CXCL8-3'UTR(mut) plasmid using Lipofectamine 2000.	('mutagenized', 'Var', (133, 144))	('CXCL8', 'Gene', '3576', (153, 158))	('CXCL8', 'Gene', '3576', (118, 123))	('CXCL8', 'Gene', (118, 123))	('CXCL8', 'Gene', (153, 158))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (184, 202))
38902	29108255	Once the somatic mutations of all genes in colon adenocarcinoma were analyzed by COSMIC, the result showed that the majority of top 20 genes with somatic mutations are mRNA over expression (18/20) and CNA gain, except 2 genes (PCLO with high methylation and APC with high point mutation).	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('APC', 'Disease', 'MESH:D011125', (258, 261))	('CNA', 'Gene', (201, 204))	('gain', 'PosReg', (205, 209))	('mutations', 'Var', (154, 163))	('colon adenocarcinoma', 'Disease', (43, 63))	('APC', 'Disease', (258, 261))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (43, 63))	('mRNA', 'Var', (168, 172))
38911	29108255	For the convenience of calculations and comparable statistic results (Figure 3B), the co-expression data between all genes (20436) and STAU1 and POFUT1 in CRC was downloaded from The cBioPortal for Cancer Genomics (Colorectal Adenocarcinoma (TCGA, Provisional) 633 samples) (Supplementary Table 2).	('Colorectal Adenocarcinoma', 'Disease', 'MESH:D015179', (215, 240))	('STAU1', 'Gene', '6780', (135, 140))	('POFUT1', 'Gene', (145, 151))	('Cancer', 'Disease', 'MESH:D009369', (198, 204))	('Colorectal Adenocarcinoma', 'Disease', (215, 240))	('CRC', 'Phenotype', 'HP:0003003', (155, 158))	('20436', 'Var', (124, 129))	('POFUT1', 'Gene', '23509', (145, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('STAU1', 'Gene', (135, 140))	('Cancer', 'Phenotype', 'HP:0002664', (198, 204))	('Cancer', 'Disease', (198, 204))
38924	29108255	According to ENCODE v24 annotation, the intergenic region displayed high DNase 1 hypersensitivity and was enriched with hallmarks associated with transcription like H3K4me3, H3K4me1 and H3K27Ac.	('H3K27Ac', 'Var', (186, 193))	('high', 'MPA', (68, 72))	('DNase 1', 'Gene', '1773', (73, 80))	('DNase 1', 'Gene', (73, 80))	('hypersensitivity and', 'Disease', 'MESH:D004342', (81, 101))	('H3K4me3', 'Var', (165, 172))	('hypersensitivity and', 'Disease', (81, 101))	('H3K4me1', 'Var', (174, 181))
38927	29108255	The results of this demonstrated that this sequence was highly evolutionarily conserved and contains multiple transcription factor binding sites, including SP1, SP3, SP2, E2F4, E2F6, EGR1and TFAP2C (Figure 6B and Supplementary Figure 2).	('TFAP2C', 'Gene', '7022', (191, 197))	('SP3', 'Gene', (161, 164))	('E2F4', 'Gene', '1874', (171, 175))	('SP1', 'Var', (156, 159))	('EGR1', 'Gene', (183, 187))	('EGR1', 'Gene', '1958', (183, 187))	('SP2', 'Gene', '6668', (166, 169))	('SP2', 'Gene', (166, 169))	('SP3', 'Gene', '6670', (161, 164))	('E2F4', 'Gene', (171, 175))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('110', '138'))	('E2F6', 'Gene', '1876', (177, 181))	('E2F6', 'Gene', (177, 181))	('transcription', 'biological_process', 'GO:0006351', ('110', '123'))	('TFAP2C', 'Gene', (191, 197))
38942	29108255	Further study thereafter showed gains in 20q occurs in >65% of CRCs, the most significant of which were mostly found in 20q11 and 20q13, Patients in 20q gain were always been associated with poor prognoses.	('CRC', 'Phenotype', 'HP:0003003', (63, 66))	('CRCs', 'Disease', (63, 67))	('Patients', 'Species', '9606', (137, 145))	('20q11', 'Var', (120, 125))	('gains', 'Var', (32, 37))
38943	29108255	A few example include amplification of the MYC oncogeneof 8q24 resulting in its over-expression, assuming a role a central driver in CRCs, the amplification of 20q, which has been reported causing mRNA overexpression of AURKA (20q13.2) and TPX2 (20q11), ultimately promoting progression from colorectal adenoma to carcinoma.	('colorectal adenoma to carcinoma', 'Disease', (292, 323))	('amplification of', 'Var', (143, 159))	('promoting', 'PosReg', (265, 274))	('AURKA', 'Gene', (220, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (314, 323))	('20q', 'Gene', (160, 163))	('colorectal adenoma to carcinoma', 'Disease', 'MESH:C563365', (292, 323))	('amplification', 'Var', (22, 35))	('TPX2', 'Gene', (240, 244))	('over-expression', 'MPA', (80, 95))	('overexpression', 'PosReg', (202, 216))	('CRC', 'Phenotype', 'HP:0003003', (133, 136))	('AURKA', 'Gene', '6790', (220, 225))	('TPX2', 'Gene', '22974', (240, 244))
38956	29108255	Recent studies have confirmed that several of the 6 genes discussed above are involved in human cancer, especially colorectal cancer., TM9SF4 is a novel V-ATPase-interacting protein that modulates tumor pH alterations associated with drug resistance and invasiveness of colon cancer cells, PLAGL2 induces epithelial-mesenchymal transition via Wnt/beta-catenin signaling pathway in human colorectal adenocarcinoma and overexpression of protein POUT1 accelerates hepatocellular carcinoma progression via the Notch signaling pathway.	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (461, 485))	('human', 'Species', '9606', (90, 95))	('overexpression', 'Var', (417, 431))	('TM9SF4', 'Gene', (135, 141))	('cancer', 'Disease', (96, 102))	('colon cancer', 'Phenotype', 'HP:0003003', (270, 282))	('epithelial-mesenchymal transition', 'CPA', (305, 338))	('colorectal adenocarcinoma', 'Disease', (387, 412))	('especially colorectal cancer', 'Disease', (104, 132))	('invasiveness of colon cancer', 'Disease', (254, 282))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('TM9SF4', 'Gene', '9777', (135, 141))	('drug resistance', 'Phenotype', 'HP:0020174', (234, 249))	('hepatocellular carcinoma', 'Disease', (461, 485))	('signaling pathway', 'biological_process', 'GO:0007165', ('360', '377'))	('cancer', 'Disease', (126, 132))	('rectal cancer', 'Phenotype', 'HP:0100743', (119, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (476, 485))	('colorectal cancer', 'Phenotype', 'HP:0003003', (115, 132))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('protein', 'cellular_component', 'GO:0003675', ('435', '442'))	('invasiveness of colon cancer', 'Disease', 'MESH:D015179', (254, 282))	('induces', 'Reg', (297, 304))	('Notch signaling pathway', 'Pathway', (506, 529))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('drug resistance', 'biological_process', 'GO:0009315', ('234', '249'))	('beta-catenin', 'Gene', (347, 359))	('cancer', 'Disease', (276, 282))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (387, 412))	('V-ATPase', 'cellular_component', 'GO:0008245', ('153', '161'))	('beta-catenin', 'Gene', '1499', (347, 359))	('drug resistance', 'biological_process', 'GO:0042493', ('234', '249'))	('human', 'Species', '9606', (381, 386))	('carcinoma', 'Phenotype', 'HP:0030731', (403, 412))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('V-ATPase', 'cellular_component', 'GO:0000219', ('153', '161'))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('POUT1', 'Gene', (443, 448))	('PLAGL2', 'Gene', (290, 296))	('especially colorectal cancer', 'Disease', 'MESH:D015179', (104, 132))	('PLAGL2', 'Gene', '5326', (290, 296))	('accelerates', 'PosReg', (449, 460))	('Notch signaling pathway', 'biological_process', 'GO:0007219', ('506', '529'))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('305', '338'))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (461, 485))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Disease', (197, 202))
38965	29108255	We downloaded mRNA and CNV data for colon and rectal cancer from the Cancer Genome Atlas(TCGA) portal,.Copy-number alterations and gene-expression data for all 276 samples were detected by Affymetrix SNP 6.0 microarrays, Illumina HiSeq, Agilent microarrays and RNA-Seq.	('rectal cancer', 'Phenotype', 'HP:0100743', (46, 59))	('colon and rectal cancer', 'Disease', 'MESH:D012004', (36, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Cancer Genome Atlas', 'Disease', (69, 88))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (69, 88))	('.Copy-number alterations', 'Var', (102, 126))
38986	28747693	For example, in CAC, mutations in TP53 or a loss of p53 function are observed early in disease progression, whereas a functional loss of APC is a late event.	('APC', 'Phenotype', 'HP:0005227', (137, 140))	('TP53', 'Gene', (34, 38))	('CAC', 'Disease', (16, 19))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '22059', (52, 55))	('loss', 'NegReg', (44, 48))	('function', 'MPA', (56, 64))	('APC', 'cellular_component', 'GO:0005680', ('137', '140'))	('observed', 'Reg', (69, 77))	('TP53', 'Gene', '22059', (34, 38))	('mutations', 'Var', (21, 30))
38995	28747693	Most sporadic colorectal cancers in humans also arise from the mutations in the adenomatous polyposis coli (APC) gene, and overexpression of stem cell markers has been demonstrated in the sporadic colorectal tumors.	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('colorectal cancer', 'Phenotype', 'HP:0003003', (14, 31))	('arise from', 'Reg', (48, 58))	('humans', 'Species', '9606', (36, 42))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (80, 106))	('APC', 'Phenotype', 'HP:0005227', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (80, 106))	('colorectal cancers', 'Disease', 'MESH:D015179', (14, 32))	('APC', 'Gene', (108, 111))	('colorectal tumors', 'Disease', 'MESH:D015179', (197, 214))	('colorectal cancers', 'Disease', (14, 32))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('adenomatous polyposis coli', 'Disease', (80, 106))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('colorectal tumors', 'Disease', (197, 214))
39036	28747693	Colitis-associated cancers have distinct molecular characteristics different from sporadic colon cancers, one of which is that Wnt pathway activation caused by APC mutation, which is an early event in sporadic colon cancer, but occurs at later stages in CAC.	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('activation', 'PosReg', (139, 149))	('sporadic colon cancer', 'Disease', 'MESH:D015179', (201, 222))	('mutation', 'Var', (164, 172))	('sporadic colon cancer', 'Disease', 'MESH:D015179', (82, 103))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('APC', 'Gene', (160, 163))	('colon cancers', 'Disease', 'MESH:D015179', (91, 104))	('Colitis-associated cancers', 'Disease', 'MESH:D003092', (0, 26))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('colon cancers', 'Disease', (91, 104))	('sporadic colon cancer', 'Disease', (201, 222))	('sporadic colon cancer', 'Disease', (82, 103))	('Colitis-associated cancers', 'Disease', (0, 26))	('colon cancer', 'Phenotype', 'HP:0003003', (91, 103))	('Wnt pathway', 'Pathway', (127, 138))	('colon cancer', 'Phenotype', 'HP:0003003', (210, 222))	('APC', 'Phenotype', 'HP:0005227', (160, 163))	('Colitis', 'Phenotype', 'HP:0002583', (0, 7))	('colon cancers', 'Phenotype', 'HP:0003003', (91, 104))
39071	28747693	Abnormally enhanced Wnt signaling, via APC mutations, is a key molecular event in the early stages of sporadic colorectal carcinogenesis, whereas, in the CAC, APC mutations occur in the late stages.	('colorectal carcinogenesis', 'Disease', (111, 136))	('APC', 'Gene', (39, 42))	('Wnt signaling', 'MPA', (20, 33))	('APC', 'Phenotype', 'HP:0005227', (159, 162))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (111, 136))	('enhanced', 'PosReg', (11, 19))	('mutations', 'Var', (43, 52))	('APC', 'Phenotype', 'HP:0005227', (39, 42))
39075	28747693	Therefore, it seems that the expression of CBC stem cell markers in ACF and LGD samples does not rely on upregulated Wnt signaling activity via Apc mutations.	('mutations', 'Var', (148, 157))	('signaling', 'biological_process', 'GO:0023052', ('121', '130'))	('Apc', 'cellular_component', 'GO:0005680', ('144', '147'))	('Apc', 'Gene', '11789', (144, 147))	('CBC', 'cellular_component', 'GO:0005846', ('43', '46'))	('Apc', 'Gene', (144, 147))
39092	28747693	The TaqMan gene expression assays were used as follows: Mm00438890_m1 (Lgr5), Mm01268891_g1 (Ascl2), Mm00491553_m1 (Smoc2), Mm00477115_m1 (Prom1/CD133), Mm01181021_m1 (Ephb2), Mm01203522_m1 (Msi1), Mm03053308_g1 (Bmi1), Mm00558630_m1 (Hopx), Mm00456116_m1 (Lrig1), Mm00436931_m1 (Tert), Mm00444950_m1 (Dclk1), Mm00443610_m1 (Axin2), Mm00802553_m1 (Ephb3), Mm00552558_m1 (Rnf43), Mm01191453_m1 (Znrf3), and Mm99999915_g1 (Gapdh).	('Mm01181021_m1', 'Var', (153, 166))	('Dclk1', 'Gene', (302, 307))	('CD133', 'Gene', (145, 150))	('Ephb3', 'Gene', (348, 353))	('Mm00436931_m1', 'Var', (265, 278))	('Mm99999915_g1', 'Var', (406, 419))	('Dclk1', 'Gene', '13175', (302, 307))	('Mm01268891_g1', 'Var', (78, 91))	('Mm01203522_m1', 'Var', (176, 189))	('Mm00443610_m1', 'Var', (310, 323))	('Prom1', 'Gene', '19126', (139, 144))	('Msi1', 'Gene', '17690', (191, 195))	('Mm00456116_m1', 'Var', (242, 255))	('Znrf3', 'Gene', (394, 399))	('Znrf3', 'Gene', '407821', (394, 399))	('Rnf43', 'Gene', (371, 376))	('Ephb3', 'Gene', '13845', (348, 353))	('Prom1', 'Gene', (139, 144))	('Axin2', 'Gene', '12006', (325, 330))	('Mm03053308_g1', 'Var', (198, 211))	('CD133', 'Gene', '19126', (145, 150))	('Mm00558630_m1', 'Var', (220, 233))	('Mm00444950_m1', 'Var', (287, 300))	('gene expression', 'biological_process', 'GO:0010467', ('11', '26'))	('Axin2', 'Gene', (325, 330))	('Mm00477115_m1', 'Var', (124, 137))	('Hopx', 'Gene', '74318', (235, 239))	('Lrig1', 'Gene', (257, 262))	('Ascl2', 'Gene', '17173', (93, 98))	('Ascl2', 'Gene', (93, 98))	('Smoc2', 'Gene', (116, 121))	('Smoc2', 'Gene', '64074', (116, 121))	('Ephb2', 'Gene', (168, 173))	('Lrig1', 'Gene', '16206', (257, 262))	('Mm00802553_m1', 'Var', (333, 346))	('Mm01191453_m1', 'Var', (379, 392))	('Rnf43', 'Gene', '207742', (371, 376))	('Tert', 'Gene', '21752', (280, 284))	('Hopx', 'Gene', (235, 239))	('Msi1', 'Gene', (191, 195))	('Ephb2', 'Gene', '13844', (168, 173))	('Bmi1', 'Gene', '12151', (213, 217))	('Tert', 'Gene', (280, 284))	('Bmi1', 'Gene', (213, 217))	('Mm00491553_m1', 'Var', (101, 114))	('Mm00552558_m1', 'Var', (356, 369))
39112	25880011	The final nomogram included type of regimen, administered dose of irinotecan, gender, age, UGT1A1 genotype, Eastern Cooperative Oncology Group performance status, pre-treatment absolute neutrophil count, and total bilirubin level.	('UGT1A1', 'Gene', (91, 97))	('genotype', 'Var', (98, 106))	('total bilirubin level', 'MPA', (208, 229))	('irinotecan', 'Chemical', 'MESH:D000077146', (66, 76))	('bilirubin', 'Chemical', 'MESH:D001663', (214, 223))	('Oncology', 'Phenotype', 'HP:0002664', (128, 136))	('UGT1A1', 'Gene', '54658', (91, 97))
39116	25880011	Irinotecan is a pro-drug, and its active metabolite SN-38 has both antitumour activities and toxicities.	('SN-38', 'Chemical', 'MESH:D000077146', (52, 57))	('Irinotecan', 'Chemical', 'MESH:D000077146', (0, 10))	('tumour', 'Disease', (71, 77))	('toxicities', 'Disease', (93, 103))	('SN-38', 'Var', (52, 57))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('toxicities', 'Disease', 'MESH:D064420', (93, 103))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
39133	25880011	The UGT1A1 genetic profiles were categorised into three groups as described previously: wild-type (*1/*1), heterozygous (*1/*6, *1/*28), and homozygous (*6/*6, *6/*28, *28/*28).	('UGT1A1', 'Gene', '54658', (4, 10))	('UGT1A1', 'Gene', (4, 10))	('*1/*1', 'Var', (99, 104))	('*1/*6', 'Var', (121, 126))	('*6/*6', 'Var', (153, 158))
39150	25880011	In patients given FOLFIRI, the 3-cycle relative dose-intensities of irinotecan in the homozygous group (55.9%) were lower than those in the wild-type (66.3%) and heterozygous groups (64.1%), irrespective of regimen.	('lower', 'NegReg', (116, 121))	('FOLFIRI', 'Var', (18, 25))	('FOLFIRI', 'Chemical', '-', (18, 25))	('3-cycle relative dose-intensities of irinotecan', 'MPA', (31, 78))	('irinotecan', 'Chemical', 'MESH:D000077146', (68, 78))	('patients', 'Species', '9606', (3, 11))
39178	25880011	Although the total bilirubin level at the start of the first cycle was associated with the UGT1A1 genotype, both factors were independent predictors.	('UGT1A1', 'Gene', (91, 97))	('genotype', 'Var', (98, 106))	('bilirubin', 'Chemical', 'MESH:D001663', (19, 28))	('bilirubin level', 'MPA', (19, 34))	('UGT1A1', 'Gene', '54658', (91, 97))	('associated', 'Reg', (71, 81))
39190	25880011	Second, polymorphisms other than UGT1A1*6 or UGT1A1*28, such as UGT1A7, UGT1A9, ABCB1, ABCC2, ABCG2, and SLCO1B1, have been suggested to be associated with toxicities induced by irinotecan-based regimens.	('toxicities', 'Disease', 'MESH:D064420', (156, 166))	('UGT1A9', 'Gene', '54600', (72, 78))	('irinotecan', 'Chemical', 'MESH:D000077146', (178, 188))	('toxicities', 'Disease', (156, 166))	('SLCO1B1', 'Gene', (105, 112))	('UGT1A9', 'Gene', (72, 78))	('SLCO1B1', 'Gene', '10599', (105, 112))	('UGT1A1*6', 'Gene', '7361', (33, 41))	('UGT1A7', 'Gene', '54577', (64, 70))	('UGT1A1*6', 'Gene', (33, 41))	('UGT1A7', 'Gene', (64, 70))	('UGT1A1', 'Gene', (45, 51))	('ABCC2', 'Gene', '1244', (87, 92))	('ABCB1', 'Gene', (80, 85))	('ABCB1', 'Gene', '5243', (80, 85))	('polymorphisms', 'Var', (8, 21))	('associated', 'Reg', (140, 150))	('UGT1A1', 'Gene', '54658', (45, 51))	('ABCC2', 'Gene', (87, 92))	('UGT1A1', 'Gene', (33, 39))	('ABCG2', 'Gene', (94, 99))	('ABCG2', 'Gene', '9429', (94, 99))	('UGT1A1', 'Gene', '54658', (33, 39))
39192	25880011	Although several meta-analyses have examined the correlation between UGT1A1 genotype and the efficacy of irinotecan-based regimens, including tumour response and survival, their results remain controversial.	('tumour', 'Disease', (142, 148))	('irinotecan', 'Chemical', 'MESH:D000077146', (105, 115))	('UGT1A1', 'Gene', '54658', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('UGT1A1', 'Gene', (69, 75))	('genotype', 'Var', (76, 84))
39213	23429293	Transformation can lead to several lysosomal changes, such as increased lysosomal volume, secretion of proteases and total protease activity, and changes in the subcellular localization of cathepsins B, D and L (CatB, CatD and CatL, respectively).	('total protease activity', 'MPA', (117, 140))	('increased', 'PosReg', (62, 71))	('CatB', 'Gene', (212, 216))	('lysosomal volume', 'MPA', (72, 88))	('CatD', 'Gene', (218, 222))	('Transformation', 'Var', (0, 14))	('secretion', 'biological_process', 'GO:0046903', ('90', '99'))	('subcellular localization', 'MPA', (161, 185))	('lysosomal changes', 'Phenotype', 'HP:0031340', (35, 52))	('lysosomal', 'MPA', (35, 44))	('secretion of proteases', 'MPA', (90, 112))	('CatB', 'Gene', '1508', (212, 216))	('protease activity', 'molecular_function', 'GO:0008233', ('123', '140'))	('localization', 'biological_process', 'GO:0051179', ('173', '185'))	('changes', 'Reg', (146, 153))	('CatL', 'Gene', '1514', (227, 231))	('CatL', 'Gene', (227, 231))	('cathepsins B', 'Gene', (189, 201))	('cathepsins B', 'Gene', '1508', (189, 201))	('CatD', 'Gene', '1509', (218, 222))
39215	23429293	Cathepsins are often overexpressed in human cancers, and high expression levels have been associated with increased risk of relapse and poor prognosis.	('high expression levels', 'Var', (57, 79))	('human', 'Species', '9606', (38, 43))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('associated', 'Reg', (90, 100))	('relapse', 'CPA', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
39232	23429293	The IC50 of acetate reduced cell proliferation by approximately 30% and 65% in HCT-15 and RKO cells, respectively, as determined by SRB assay (Figure 1b).	('cell proliferation', 'biological_process', 'GO:0008283', ('28', '46'))	('reduced', 'NegReg', (20, 27))	('cell proliferation', 'CPA', (28, 46))	('SRB', 'Gene', '10575', (132, 135))	('RKO', 'CellLine', 'CVCL:0504', (90, 93))	('SRB', 'Gene', (132, 135))	('acetate', 'Chemical', 'MESH:D000085', (12, 19))	('HCT-15', 'CellLine', 'CVCL:0292', (79, 85))	('IC50', 'Var', (4, 8))
39270	23429293	The apparent decrease in cytosolic Pro-CatD levels in RKO cells treated with 2 x IC50 compared with IC50 concentrations of acetate seems to be due to increased processing to mature CatD.	('RKO', 'CellLine', 'CVCL:0504', (54, 57))	('CatD', 'Gene', '1509', (39, 43))	('processing', 'MPA', (160, 170))	('acetate', 'Chemical', 'MESH:D000085', (123, 130))	('CatD', 'Gene', '1509', (181, 185))	('decrease', 'NegReg', (13, 21))	('CatD', 'Gene', (39, 43))	('CatD', 'Gene', (181, 185))	('increased', 'PosReg', (150, 159))	('IC50', 'Var', (81, 85))
39274	23429293	E64d did not significantly alter apoptotic levels of either cell line under the same conditions (Figure 5a).	('E64d', 'Chemical', 'MESH:C108192', (0, 4))	('apoptotic', 'MPA', (33, 42))	('E64d', 'Var', (0, 4))
39276	23429293	By contrast, inhibition of CatD in cells exposed to etoposide decreased the sub-G1 population (Figures 5b and c), in agreement with previous reports showing that CatD has a pro-apoptotic role in etoposide-induced cell death.	('CatD', 'Gene', (162, 166))	('cell death', 'biological_process', 'GO:0008219', ('213', '223'))	('decreased', 'NegReg', (62, 71))	('inhibition', 'Var', (13, 23))	('CatD', 'Gene', '1509', (27, 31))	('sub-G1 population', 'CPA', (76, 93))	('CatD', 'Gene', '1509', (162, 166))	('CatD', 'Gene', (27, 31))	('etoposide', 'Chemical', 'MESH:D005047', (195, 204))	('etoposide', 'Chemical', 'MESH:D005047', (52, 61))
39282	23429293	Moreover, administration of P. freudenreichii in vivo significantly increased the number of apoptotic epithelial cells damaged by 1,2-dimethylhydrazine, a carcinogenic agent, without affecting the survival of healthy normal colonic mucosa.	('carcinogenic', 'Disease', 'MESH:D063646', (155, 167))	('P. freudenreichii', 'Var', (28, 45))	('carcinogenic', 'Disease', (155, 167))	('1,2-dimethylhydrazine', 'Chemical', 'MESH:D019813', (130, 151))	('increased', 'PosReg', (68, 77))	('P. freudenreichii', 'Species', '1744', (28, 45))
39291	23429293	SCFA produced by P. freudenreichii trigger apoptosis in HT-29 cells at pH 7.5 but necrosis at pH 5.5.	('HT-29 cells', 'CellLine', 'CVCL:0320', (56, 67))	('necrosis', 'Disease', 'MESH:D009336', (82, 90))	('apoptosis', 'CPA', (43, 52))	('P. freudenreichii', 'Var', (17, 34))	('necrosis', 'Disease', (82, 90))	('SCFA', 'Chemical', 'MESH:D005232', (0, 4))	('P. freudenreichii', 'Species', '1744', (17, 34))
39292	23429293	At pH 7.5, propionibacterial SCFA were shown to induce cell-cycle arrest in the G2/M phase and morphological characteristics of apoptotic cell death, like membrane blebbing, chromatin condensation and fragmentation, phosphatidylserine exposure and formation of apoptotic bodies.	('cell-cycle arrest in the G2/M phase', 'CPA', (55, 90))	('membrane', 'cellular_component', 'GO:0016020', ('155', '163'))	('apoptotic bodies', 'CPA', (261, 277))	('phosphatidylserine exposure', 'CPA', (216, 243))	('M phase', 'biological_process', 'GO:0000279', ('83', '90'))	('SCFA', 'Chemical', 'MESH:D005232', (29, 33))	('induce', 'PosReg', (48, 54))	('chromatin condensation', 'CPA', (174, 196))	('fragmentation', 'CPA', (201, 214))	('membrane blebbing', 'biological_process', 'GO:0032060', ('155', '172'))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('55', '72'))	('membrane blebbing', 'CPA', (155, 172))	('apoptotic cell death', 'CPA', (128, 148))	('formation', 'biological_process', 'GO:0009058', ('248', '257'))	('chromatin', 'cellular_component', 'GO:0000785', ('174', '183'))	('propionibacterial SCFA', 'Var', (11, 33))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('128', '148'))
39293	23429293	In accordance with these reports, we showed that acetate induces apoptosis in HCT-15 and RKO cells without altering the extracellular pH (complete medium).	('RKO', 'CellLine', 'CVCL:0504', (89, 92))	('HCT-15', 'CellLine', 'CVCL:0292', (78, 84))	('acetate', 'Var', (49, 56))	('acetate', 'Chemical', 'MESH:D000085', (49, 56))	('apoptosis', 'CPA', (65, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('65', '74'))	('apoptosis', 'biological_process', 'GO:0006915', ('65', '74'))	('extracellular', 'cellular_component', 'GO:0005576', ('120', '133'))
39295	23429293	We have previously demonstrated in the yeast S. cerevisiae that acetic acid induces a mitochondria-mediated apoptotic process with several features similar to apoptosis induced by SCFA in CRC cells.	('acetic acid', 'Var', (64, 75))	('yeast', 'Species', '4932', (39, 44))	('acetic acid', 'Chemical', 'MESH:D019342', (64, 75))	('apoptotic process', 'biological_process', 'GO:0006915', ('108', '125'))	('S. cerevisiae', 'Species', '4932', (45, 58))	('apoptosis', 'biological_process', 'GO:0097194', ('159', '168'))	('SCFA', 'Chemical', 'MESH:D005232', (180, 184))	('apoptosis', 'biological_process', 'GO:0006915', ('159', '168'))	('mitochondria-mediated apoptotic', 'MPA', (86, 117))	('CRC', 'Phenotype', 'HP:0030731', (188, 191))	('induces', 'Reg', (76, 83))	('mitochondria', 'cellular_component', 'GO:0005739', ('86', '98'))
39303	23429293	Overexpression of cathepsins often occurs in human cancers, and high levels of their expression can be associated with increased risk of relapse and poor prognosis.	('expression', 'MPA', (85, 95))	('cathepsins', 'Protein', (18, 28))	('associated', 'Reg', (103, 113))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('human', 'Species', '9606', (45, 50))	('relapse', 'CPA', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', (51, 58))	('high levels', 'Var', (64, 75))
39309	23429293	We also showed that inhibiting CatD with PstA, a widely used specific inhibitor of CatD enzymatic activity, increased acetate-induced apoptosis in CRC cells.	('inhibiting', 'Var', (20, 30))	('increased acetate', 'Phenotype', 'HP:0032533', (108, 125))	('CatD', 'Gene', (31, 35))	('PstA', 'Chemical', 'MESH:C031375', (41, 45))	('apoptosis', 'biological_process', 'GO:0006915', ('134', '143'))	('acetate-induced apoptosis', 'MPA', (118, 143))	('increased', 'PosReg', (108, 117))	('CatD', 'Gene', '1509', (83, 87))	('CatD', 'Gene', '1509', (31, 35))	('CatD', 'Gene', (83, 87))	('CRC', 'Phenotype', 'HP:0030731', (147, 150))	('PstA', 'Gene', (41, 45))	('acetate', 'Chemical', 'MESH:D000085', (118, 125))	('apoptosis', 'biological_process', 'GO:0097194', ('134', '143'))
39310	23429293	Interestingly, in yeast, deletion of Pep4p confers higher susceptibility to acetic acid, while cells overexpressing Pep4p display higher resistance.	('Pep4p', 'Gene', '855949', (37, 42))	('Pep4p', 'Gene', (37, 42))	('Pep4p', 'Gene', '855949', (116, 121))	('yeast', 'Species', '4932', (18, 23))	('deletion', 'Var', (25, 33))	('acetic acid', 'Chemical', 'MESH:D019342', (76, 87))	('Pep4p', 'Gene', (116, 121))	('higher', 'PosReg', (51, 57))	('susceptibility to acetic acid', 'MPA', (58, 87))
39325	23429293	According to information provided by INCELL, NCM460 cells have acquired a tumorigenic phenotype due to their extended time in culture.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (74, 79))	('NCM460', 'Var', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))
39328	23429293	In summary, our novel findings show that acetate induces partial LMP and consequent release of CatD to the cytosol in CRC cells.	('CatD', 'Gene', '1509', (95, 99))	('CRC', 'Phenotype', 'HP:0030731', (118, 121))	('LMP', 'Chemical', '-', (65, 68))	('acetate', 'Var', (41, 48))	('acetate', 'Chemical', 'MESH:D000085', (41, 48))	('partial LMP', 'MPA', (57, 68))	('CatD', 'Gene', (95, 99))
39329	23429293	Our results also indicate that inhibition of CatD enzymatic activity sensitizes CRC cells to acetate-induced apoptosis, suggesting that CatD, like Pep4p in yeast, might have a protective role in this process.	('yeast', 'Species', '4932', (156, 161))	('CatD', 'Gene', '1509', (136, 140))	('CatD', 'Gene', '1509', (45, 49))	('CRC', 'Phenotype', 'HP:0030731', (80, 83))	('CatD', 'Gene', (136, 140))	('Pep4p', 'Gene', '855949', (147, 152))	('inhibition', 'Var', (31, 41))	('CatD', 'Gene', (45, 49))	('acetate', 'Chemical', 'MESH:D000085', (93, 100))	('acetate-induced', 'MPA', (93, 108))	('Pep4p', 'Gene', (147, 152))	('sensitizes', 'Reg', (69, 79))
39331	23429293	Inhibiting CatD function therefore emerges as a novel prevention/therapeutic strategy in CRCs, particularly in the case of CRCs with decreased levels of CatD.	('CatD', 'Gene', (11, 15))	('Inhibiting', 'Var', (0, 10))	('CRCs', 'Disease', (89, 93))	('CatD', 'Gene', (153, 157))	('CRC', 'Phenotype', 'HP:0030731', (89, 92))	('CatD', 'Gene', '1509', (11, 15))	('CRC', 'Phenotype', 'HP:0030731', (123, 126))	('levels', 'MPA', (143, 149))	('CatD', 'Gene', '1509', (153, 157))	('decreased', 'NegReg', (133, 142))
39351	23429293	Cells were then washed twice with PBS, incubated with RNase A (200 mug/ml) for 15 min in the dark at 37  C and with propidium iodide (0.5 mg/ml) for 30 min at RT before analysis on a flow cytometer, as described above.	('mug', 'molecular_function', 'GO:0043739', ('67', '70'))	('PBS', 'Disease', (34, 37))	('propidium iodide', 'Chemical', 'MESH:D011419', (116, 132))	('RNase A', 'Gene', (54, 61))	('200', 'Var', (63, 66))	('PBS', 'Disease', 'MESH:D011535', (34, 37))	('RNase A', 'Gene', '6035', (54, 61))
39356	23429293	The cell pellet was then resuspended in 300 mul Isotonic Buffer with 20 mM NaF, 20 mM Na3VO4, 1 mM PMSF and 40 mul/ml Protease inhibitor cocktail and homogenized by passing through a 26-G needle 70 times.	('NaF', 'Gene', (75, 78))	('PMSF', 'Chemical', 'MESH:D010664', (99, 103))	('Na3VO4', 'Var', (86, 92))	('NaF', 'Gene', '3576', (75, 78))	('Na3VO4', 'Chemical', '-', (86, 92))
39364	32613597	CMMRD is caused by homozygous or compound heterozygous pathogenic germline variants in one of four mismatch repair (MMR) genes (i.e., MLH1, MSH2, MSH6 and PMS2), whereas mono-allelic (heterozygous) MMR gene variants result in autosomal dominant Lynch syndrome.	('CMMRD', 'Disease', (0, 5))	('caused by', 'Reg', (9, 18))	('MSH6', 'Gene', (146, 150))	('MSH2', 'Gene', (140, 144))	('PMS2', 'Gene', (155, 159))	('MLH1', 'Gene', '4292', (134, 138))	('MSH2', 'Gene', '4436', (140, 144))	('MLH1', 'Gene', (134, 138))	('variants', 'Var', (207, 215))	('result in', 'Reg', (216, 225))	('MMR', 'Gene', (198, 201))	('PMS2', 'Gene', '5395', (155, 159))	('MSH6', 'Gene', '2956', (146, 150))	('autosomal dominant Lynch syndrome', 'Disease', (226, 259))	('autosomal dominant Lynch syndrome', 'Disease', 'MESH:D003123', (226, 259))	('variants', 'Var', (75, 83))
39372	32613597	The largest number of pathogenic variants were identified in PMS2 (n = 34), followed by MSH6 (n = 19), MSH2 (n = 8) and MLH1 (n = 4).	('MLH1', 'Gene', '4292', (120, 124))	('MSH6', 'Gene', '2956', (88, 92))	('PMS2', 'Gene', '5395', (61, 65))	('MLH1', 'Gene', (120, 124))	('pathogenic', 'Reg', (22, 32))	('MSH2', 'Gene', (103, 107))	('MSH2', 'Gene', '4436', (103, 107))	('MSH6', 'Gene', (88, 92))	('PMS2', 'Gene', (61, 65))	('variants', 'Var', (33, 41))
39378	32613597	Unfortunately, molecular genetic testing is not always conclusive, and the diagnosis of CMMRD is frequently confounded by MMR variants of unknown significance (VUS) and PMS2 pseudogenes.	('pseudogenes', 'Var', (174, 185))	('variants', 'Var', (126, 134))	('MMR', 'biological_process', 'GO:0006298', ('122', '125'))	('PMS2', 'Gene', (169, 173))	('confounded', 'Reg', (108, 118))	('MMR', 'Gene', (122, 125))	('PMS2', 'Gene', '5395', (169, 173))	('CMMRD', 'Disease', (88, 93))
39387	32613597	The assay achieved 97% sensitivity and 100% specificity, including the detection of MSH6-deficient patients and patients with hypomorphic PMS2 variants.	('MSH6-deficient', 'Disease', (84, 98))	('PMS2', 'Gene', (138, 142))	('patients', 'Species', '9606', (112, 120))	('MSH6-deficient', 'Disease', 'MESH:D007153', (84, 98))	('patients', 'Species', '9606', (99, 107))	('PMS2', 'Gene', '5395', (138, 142))	('variants', 'Var', (143, 151))
39393	32613597	Moreover, blood from germline TP53, POLE, POLD1 and NF1 pathogenic variant carriers and early-onset Lynch syndrome cases did not show high hs-MSI scores, demonstrating that the assay discriminates between CMMRD and other hereditary syndromes with overlapping phenotypes.	('hereditary syndromes', 'Disease', 'MESH:D061325', (221, 241))	('NF1', 'Gene', (52, 55))	('TP53', 'Gene', (30, 34))	('POLD1', 'Gene', '5424', (42, 47))	('NF1', 'Gene', '4763', (52, 55))	('Lynch syndrome', 'Disease', (100, 114))	('variant', 'Var', (67, 74))	('Lynch syndrome', 'Disease', 'MESH:D003123', (100, 114))	('hereditary syndromes', 'Disease', (221, 241))	('CMMRD', 'Disease', (205, 210))	('TP53', 'Gene', '7157', (30, 34))	('POLD1', 'Gene', (42, 47))	('discriminates', 'Reg', (183, 196))
39398	32613597	However, he only carried a maternally-inherited pathogenic MSH2 variant and was negative for CMMRD based on all functional and MSI assays used.	('MSH2', 'Gene', (59, 63))	('pathogenic', 'Reg', (48, 58))	('MSH2', 'Gene', '4436', (59, 63))	('variant', 'Var', (64, 71))
39400	32613597	Interestingly, a number of paternally-inherited low/moderate penetrance variants in other cancer predisposing genes and genes described as genetic modifiers of Lynch syndrome were identified.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('low/moderate', 'NegReg', (48, 60))	('variants', 'Var', (72, 80))	('Lynch syndrome', 'Disease', (160, 174))	('Lynch syndrome', 'Disease', 'MESH:D003123', (160, 174))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
39401	32613597	The assembled data on this patient suggest that the combination of several low-risk modifier alleles together with a pathogenic MSH2 variant may be responsible for the CMMRD-like phenotype in this patient.	('patient', 'Species', '9606', (27, 34))	('variant', 'Var', (133, 140))	('CMMRD-like', 'Disease', (168, 178))	('MSH2', 'Gene', (128, 132))	('MSH2', 'Gene', '4436', (128, 132))	('patient', 'Species', '9606', (197, 204))	('responsible', 'Reg', (148, 159))
39403	32613597	As was the case for a POLE pathogenic variant found in a medulloblastoma patient with a "CMMRD-like" phenotype which was published after our meeting, the POLE variants found in all three patients presented at the meeting were de novo and were previously seen as somatic but never as germline mutations.	('patients', 'Species', '9606', (187, 195))	('medulloblastoma', 'Phenotype', 'HP:0002885', (57, 72))	('medulloblastoma', 'Disease', (57, 72))	('variants', 'Var', (159, 167))	('patient', 'Species', '9606', (73, 80))	('patient', 'Species', '9606', (187, 194))	('variant', 'Var', (38, 45))	('medulloblastoma', 'Disease', 'MESH:D008527', (57, 72))
39404	32613597	Taken together, these cases support the evolving notion that specific POLE exonuclease domain variants, typically seen as somatic variants in hypermutated tumors, confer a phenotype reminiscent of CMMRD resulting from a germline pathogenic variant.	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('variants', 'Var', (94, 102))	('CMMRD', 'Disease', (197, 202))
39405	32613597	Katharina Wimmer also presented two siblings, diagnosed with bowel cancer as teenagers, who both had a maternally-inherited, heterozygous PMS2 pathogenic variant and a paternally-inherited POLD1 variant likely to affect POLdelta exonuclease activity.	('activity', 'MPA', (241, 249))	('bowel cancer', 'Disease', 'MESH:D009369', (61, 73))	('POLdelta exonuclease', 'Enzyme', (220, 240))	('exonuclease activity', 'molecular_function', 'GO:0004527', ('229', '249'))	('PMS2', 'Gene', (138, 142))	('variant', 'Var', (154, 161))	('PMS2', 'Gene', '5395', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('variant', 'Var', (195, 202))	('POLD1', 'Gene', (189, 194))	('POLD1', 'Gene', '5424', (189, 194))	('affect', 'Reg', (213, 219))	('bowel cancer', 'Disease', (61, 73))
39406	32613597	Marine Le Mentec and Chrystelle Colas presented a patient with duodenal cancer at age 17 with a maternally-inherited heterozygous PMS2 pathogenic variant, as well as a paternally-inherited heterozygous POLE variant of unknown significance.	('PMS2', 'Gene', (130, 134))	('variant', 'Var', (146, 153))	('PMS2', 'Gene', '5395', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('duodenal cancer', 'Phenotype', 'HP:0006771', (63, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('patient', 'Species', '9606', (50, 57))	('cancer', 'Disease', (72, 78))
39407	32613597	Taken together, these cases demonstrate that sequencing of POLE and POLD1 should be considered in patients with a "CMMRD-like" phenotype in whom CMMRD cannot be confirmed (either molecularly or functionally).	('POLE', 'Gene', (59, 63))	('sequencing', 'Var', (45, 55))	('patients', 'Species', '9606', (98, 106))	('POLD1', 'Gene', '5424', (68, 73))	('POLD1', 'Gene', (68, 73))
39414	32613597	Based on experience and the LFS literature, a high uptake of genetic testing is expected in those who are aware of a possible hereditary risk, particularly the siblings of affected children, and it is probable that 20-30% of patients with a confirmed diagnosis will experience high levels of distress.	('patients', 'Species', '9606', (225, 233))	('genetic', 'Var', (61, 68))	('uptake', 'biological_process', 'GO:0098739', ('51', '57'))	('LFS', 'Disease', (28, 31))	('uptake', 'biological_process', 'GO:0098657', ('51', '57'))	('children', 'Species', '9606', (181, 189))	('LFS', 'Disease', 'MESH:D016864', (28, 31))
39431	32613597	In total, 18 CMMRD patients treated with PD-1 inhibitors were identified, and high-grade glioma was the indication for immunotherapy in 13 patients (2 for front-line treatment, 11 at relapse).	('inhibitors', 'Var', (46, 56))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('patients', 'Species', '9606', (19, 27))	('patients', 'Species', '9606', (139, 147))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('PD-1', 'Gene', (41, 45))	('PD-1', 'Gene', '9825', (41, 45))	('glioma', 'Disease', (89, 95))
39446	32613597	Fifteen of these patients (68%) had biallelic PMS2 variants.	('biallelic', 'Var', (36, 45))	('variants', 'Var', (51, 59))	('PMS2', 'Gene', (46, 50))	('patients', 'Species', '9606', (17, 25))	('PMS2', 'Gene', '5395', (46, 50))
39469	32252351	The modulation of gene expression by HIF-1 causes alterations in mitochondrial oxidative metabolism, glucose uptake and oxidation, energy production, and angiogenesis in order to enable cancer cell proliferation, migration, and survival.	('enable', 'PosReg', (179, 185))	('glucose uptake', 'MPA', (101, 115))	('survival', 'CPA', (228, 236))	('modulation', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('HIF-1', 'Gene', '3091', (37, 42))	('alterations', 'Reg', (50, 61))	('glucose', 'Chemical', 'MESH:D005947', (101, 108))	('mitochondrial oxidative metabolism', 'MPA', (65, 99))	('energy production', 'MPA', (131, 148))	('HIF-1', 'Gene', (37, 42))	('angiogenesis', 'CPA', (154, 166))	('migration', 'CPA', (213, 222))	('cancer', 'Disease', (186, 192))	('oxidation', 'MPA', (120, 129))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
39475	32252351	Importantly, the metabolic switches impact tumor outcome and patient responsiveness to anti-cancer therapy.	('patient', 'Species', '9606', (61, 68))	('switches', 'Var', (27, 35))	('cancer', 'Disease', (92, 98))	('impact', 'Reg', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('metabolic', 'Gene', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', (43, 48))
39488	32252351	This leads to the over-expression of key regulatory enzymes of glycolysis and pentose phosphate pathway (PPP), as well as to down-regulation or mutations in genes encoding pyruvate decarboxylase complex (PDC) and TCA cycle enzymes or ETC enzymatic complex I, as observed in various cancer types (reviewed by).	('regulation', 'biological_process', 'GO:0065007', ('130', '140'))	('TCA', 'Enzyme', (213, 216))	('TCA', 'Chemical', 'MESH:D014233', (213, 216))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('PDC', 'Gene', (204, 207))	('over-expression', 'PosReg', (18, 33))	('pyruvate', 'Chemical', 'MESH:D019289', (172, 180))	('glycolysis', 'biological_process', 'GO:0006096', ('63', '73'))	('pentose phosphate', 'Chemical', 'MESH:D010428', (78, 95))	('complex I', 'cellular_component', 'GO:0030964', ('248', '257'))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('78', '103'))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('glycolysis', 'MPA', (63, 73))	('mutations', 'Var', (144, 153))	('cancer', 'Disease', (282, 288))	('TCA cycle', 'biological_process', 'GO:0006099', ('213', '222'))	('down-regulation', 'NegReg', (125, 140))
39492	32252351	Genetic loss in the pVHL tumor suppressor has been shown to cause HIF-1 stabilization and activation, even under normoxia conditions followed by tumor cell proliferation and survival.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('25', '41'))	('cell proliferation', 'biological_process', 'GO:0008283', ('151', '169'))	('HIF-1', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (25, 30))	('activation', 'MPA', (90, 100))	('Genetic loss', 'Var', (0, 12))	('tumor', 'Disease', (145, 150))	('pVHL tumor', 'Disease', (20, 30))	('tumor suppressor', 'biological_process', 'GO:0051726', ('25', '41'))	('HIF-1', 'Gene', '3091', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('stabilization', 'MPA', (72, 85))	('pVHL tumor', 'Disease', 'MESH:D009369', (20, 30))
39502	32252351	For example, PI3K/Akt/mTOR pathway-mediated stimulation of HIF-1 mRNA translation through the activation of two downstream targets of mTOR, p70SK6, and 4E-BP1 in breast cancer cells has been observed.	('stimulation', 'PosReg', (44, 55))	('HIF-1', 'Gene', (59, 64))	('Akt', 'Gene', (18, 21))	('breast cancer', 'Disease', (162, 175))	('BP1', 'Gene', '474256', (155, 158))	('HIF-1', 'Gene', '3091', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('mTOR', 'Gene', '2475', (22, 26))	('p70SK6', 'Var', (140, 146))	('Akt', 'Gene', '207', (18, 21))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('mTOR', 'Gene', (22, 26))	('mTOR', 'Gene', (134, 138))	('mRNA translation', 'MPA', (65, 81))	('mTOR', 'Gene', '2475', (134, 138))	('BP1', 'Gene', (155, 158))	('activation', 'PosReg', (94, 104))
39513	32252351	For example, SIRT3 over-expression has been implicated in kidney cancer growth inhibition and maintaining mitochondrial homeostasis, as well as modulating ROS production to sensitize biomolecules and cells to oxidative damage, whereas low SIRT3 level is associated with poor differentiation and unfavorable prognosis in primary hepatocellular carcinoma (HCC).	('kidney cancer', 'Disease', 'MESH:D007680', (58, 71))	('kidney cancer', 'Phenotype', 'HP:0009726', (58, 71))	('low', 'Var', (235, 238))	('primary hepatocellular carcinoma', 'Disease', 'MESH:D006528', (320, 352))	('ROS', 'Chemical', 'MESH:D017382', (155, 158))	('mitochondrial homeostasis', 'MPA', (106, 131))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('SIRT3', 'Gene', (239, 244))	('biomolecules', 'MPA', (183, 195))	('kidney cancer', 'Disease', (58, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (343, 352))	('ROS production', 'MPA', (155, 169))	('SIRT3', 'Gene', '23410', (239, 244))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (328, 352))	('primary hepatocellular carcinoma', 'Disease', (320, 352))	('over-expression', 'PosReg', (19, 34))	('SIRT3', 'Gene', (13, 18))	('SIRT3', 'Gene', '23410', (13, 18))
39516	32252351	Thus, they promote TCA cycle and ETC functioning, and reduce ROS generation and oxidative stress, while a loss of SIRTs enhances metabolic reprogramming in cancer cells through destabilization of HIF-1alpha to down-regulate glycolytic genes.	('ROS generation', 'MPA', (61, 75))	('glycolytic genes', 'Gene', (224, 240))	('oxidative stress', 'Phenotype', 'HP:0025464', (80, 96))	('TCA', 'Chemical', 'MESH:D014233', (19, 22))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('reduce', 'NegReg', (54, 60))	('metabolic reprogramming', 'CPA', (129, 152))	('TCA cycle', 'biological_process', 'GO:0006099', ('19', '28'))	('enhances', 'PosReg', (120, 128))	('down-regulate', 'NegReg', (210, 223))	('SIRTs', 'Gene', (114, 119))	('ETC functioning', 'CPA', (33, 48))	('loss', 'Var', (106, 110))	('ROS', 'Chemical', 'MESH:D017382', (61, 64))	('cancer', 'Disease', (156, 162))	('oxidative stress', 'MPA', (80, 96))	('ROS generation', 'biological_process', 'GO:1903409', ('61', '75'))	('promote', 'PosReg', (11, 18))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('destabilization', 'NegReg', (177, 192))	('TCA cycle', 'CPA', (19, 28))	('HIF-1alpha', 'Protein', (196, 206))
39518	32252351	Seemingly, SIRT3 can regulate metabolic reprogramming in cancer cells also through deacetylation of p53 transcription factor at Lys-320 and Lys-382 residues to promote its UPS-mediated degradation, as shown in phosphatase and tensin homolog (PTEN)-deficient non-small cell lung cancer cells.	('cancer', 'Disease', (57, 63))	('regulate', 'Reg', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', (278, 284))	('SIRT3', 'Gene', '23410', (11, 16))	('promote', 'PosReg', (160, 167))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (258, 284))	('SIRT3', 'Gene', (11, 16))	('Lys', 'Chemical', 'MESH:D008239', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('lung cancer', 'Phenotype', 'HP:0100526', (273, 284))	('UPS-mediated degradation', 'MPA', (172, 196))	('PTEN', 'Gene', (242, 246))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (262, 284))	('Lys-382', 'Var', (140, 147))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('deficient non-small cell lung cancer', 'Disease', (248, 284))	('acetyl', 'Chemical', '-', (85, 91))	('PTEN', 'Gene', '5728', (242, 246))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('Lys-320', 'Var', (128, 135))	('metabolic reprogramming', 'CPA', (30, 53))	('deficient non-small cell lung cancer', 'Disease', 'MESH:D002289', (248, 284))	('deacetylation', 'Var', (83, 96))	('p53 transcription', 'Gene', (100, 117))	('Lys', 'Chemical', 'MESH:D008239', (140, 143))
39530	32252351	GLUT1 localization in a cell membrane can be increased by phosphorylation of thioredoxin-interacting protein (TXNIP), an alpha-arrestin family protein.	('localization', 'MPA', (6, 18))	('arrest', 'Disease', (127, 133))	('thioredoxin-interacting protein', 'Gene', (77, 108))	('TXNIP', 'Gene', (110, 115))	('increased', 'PosReg', (45, 54))	('TXNIP', 'Gene', '10628', (110, 115))	('thioredoxin-interacting protein', 'Gene', '10628', (77, 108))	('protein', 'cellular_component', 'GO:0003675', ('143', '150'))	('GLUT1', 'Protein', (0, 5))	('thioredoxin', 'molecular_function', 'GO:0030508', ('77', '88'))	('thioredoxin', 'molecular_function', 'GO:0000008', ('77', '88'))	('localization', 'biological_process', 'GO:0051179', ('6', '18'))	('phosphorylation', 'biological_process', 'GO:0016310', ('58', '73'))	('phosphorylation', 'Var', (58, 73))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))	('cell membrane', 'cellular_component', 'GO:0005886', ('24', '37'))	('arrest', 'Disease', 'MESH:D006323', (127, 133))
39556	32252351	For example, silencing the PFKFB2 gene has been shown to significantly inhibit ovarian and breast cancer growth and to enhance paclitaxel sensitivity and patient survival.	('enhance', 'PosReg', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('patient survival', 'CPA', (154, 170))	('PFKFB2', 'Gene', '5208', (27, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('ovarian', 'Disease', 'MESH:D010049', (79, 86))	('inhibit', 'NegReg', (71, 78))	('ovarian', 'Disease', (79, 86))	('PFKFB2', 'Gene', (27, 33))	('patient', 'Species', '9606', (154, 161))	('paclitaxel', 'Chemical', 'MESH:D017239', (127, 137))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('paclitaxel sensitivity', 'MPA', (127, 149))	('silencing', 'Var', (13, 22))
39559	32252351	Several single nucleotide polymorphism variants of PGK1 with decreased catalytic efficiency and thermodynamic stability due to the alterations in local protein conformation have been found in carcinoma cells.	('PGK1', 'Gene', '5230', (51, 55))	('local protein conformation', 'MPA', (146, 172))	('carcinoma', 'Disease', (192, 201))	('single nucleotide polymorphism variants', 'Var', (8, 47))	('alterations', 'Reg', (131, 142))	('thermodynamic', 'MPA', (96, 109))	('carcinoma', 'Disease', 'MESH:D009369', (192, 201))	('decreased', 'NegReg', (61, 70))	('catalytic efficiency', 'MPA', (71, 91))	('PGK1', 'Gene', (51, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))
39571	32252351	Because PPP is linked to glycolysis, inhibition of PPP enzymes can serve as a promising strategy in anti-cancer therapy.	('cancer', 'Disease', (105, 111))	('inhibition', 'Var', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
39641	32252351	Genetic and epigenetic alterations in PDC and TCA cycle enzymes promote metabolic shift in cancer cells from OXPHOS to glycolysis.	('metabolic shift', 'MPA', (72, 87))	('promote', 'Reg', (64, 71))	('epigenetic alterations', 'Var', (12, 34))	('cancer', 'Disease', (91, 97))	('TCA cycle', 'Gene', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Genetic', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('TCA', 'Chemical', 'MESH:D014233', (46, 49))	('PDC', 'Gene', (38, 41))
39642	32252351	Mutations in genes encoding aconitase, isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), fumarate hydratase (FH), and citrate synthase have been observed in many cancer types.	('SDH', 'Gene', '6390', (96, 99))	('IDH', 'Gene', (65, 68))	('cancer', 'Disease', (175, 181))	('citrate synthase', 'Gene', '1431', (131, 147))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('fumarate hydratase', 'Gene', '2271', (102, 120))	('isocitrate dehydrogenase', 'Gene', (39, 63))	('SDH', 'Gene', (96, 99))	('IDH', 'Gene', '3417', (65, 68))	('Mutations', 'Var', (0, 9))	('FH', 'Gene', '2271', (122, 124))	('observed', 'Reg', (158, 166))	('succinate dehydrogenase', 'Gene', (71, 94))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('fumarate hydratase', 'Gene', (102, 120))	('citrate synthase', 'Gene', (131, 147))	('isocitrate dehydrogenase', 'Gene', '3417', (39, 63))	('aconitase', 'Gene', (28, 37))	('succinate dehydrogenase', 'Gene', '6390', (71, 94))
39643	32252351	Impairments in the expression of these enzymes result in accumulation of Krebs cycle intermediates named oncometabolites, which stabilize HIF-1 and nuclear factor-like 2 (Nrf2) transcription factors and ROS generation, while inhibiting p53, PDH3, and the PDC enzyme pyruvate dehydrogenase isoenzyme 3 (PDH3).	('Nrf2', 'Gene', (171, 175))	('ROS generation', 'MPA', (203, 217))	('nuclear factor-like 2', 'Gene', '4780', (148, 169))	('PDH', 'molecular_function', 'GO:0004246', ('241', '244'))	('expression', 'MPA', (19, 29))	('PDH', 'molecular_function', 'GO:0033718', ('241', '244'))	('p53', 'Protein', (236, 239))	('nuclear factor-like 2', 'Gene', (148, 169))	('Impairments', 'Var', (0, 11))	('inhibiting', 'NegReg', (225, 235))	('PDH', 'molecular_function', 'GO:0004246', ('302', '305'))	('accumulation', 'PosReg', (57, 69))	('ROS generation', 'biological_process', 'GO:1903409', ('203', '217'))	('PDH', 'molecular_function', 'GO:0004739', ('241', '244'))	('stabilize', 'PosReg', (128, 137))	('PDH', 'molecular_function', 'GO:0033718', ('302', '305'))	('Krebs', 'Chemical', '-', (73, 78))	('HIF-1', 'Gene', '3091', (138, 143))	('Nrf2', 'Gene', '4780', (171, 175))	('HIF-1', 'Gene', (138, 143))	('PDH3', 'Gene', (241, 245))	('PDH', 'molecular_function', 'GO:0004739', ('302', '305'))	('ROS', 'Chemical', 'MESH:D017382', (203, 206))	('pyruvate', 'Chemical', 'MESH:D019289', (266, 274))	('Krebs cycle', 'biological_process', 'GO:0006099', ('73', '84'))	('transcription', 'biological_process', 'GO:0006351', ('177', '190'))
39644	32252351	Cancer-associated mutations in genes encoding IDH, FH, and SDH lead to the accumulation of 2-hydroxyglutarate, fumarate, and succinate, respectively.	('SDH', 'Gene', '6390', (59, 62))	('2-hydroxyglutarate', 'MPA', (91, 109))	('succinate', 'Chemical', 'MESH:D019802', (125, 134))	('FH', 'Gene', '2271', (51, 53))	('IDH', 'Gene', (46, 49))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('SDH', 'Gene', (59, 62))	('IDH', 'Gene', '3417', (46, 49))	('fumarate', 'Chemical', 'MESH:D005650', (111, 119))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('succinate', 'MPA', (125, 134))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (91, 109))	('fumarate', 'MPA', (111, 119))	('accumulation', 'PosReg', (75, 87))	('mutations', 'Var', (18, 27))
39645	32252351	Multiple mutations in IDH isoenzymes IDH1 and IDH2, which normally catalyze oxidative decarboxylation of isocitrate to alpha-KG, have been shown to occur frequently in gliomas and acute myeloid leukemia.	('IDH2', 'Gene', (46, 50))	('mutations', 'Var', (9, 18))	('IDH2', 'Gene', '3418', (46, 50))	('isocitrate', 'Chemical', 'MESH:C034219', (105, 115))	('acute myeloid leukemia', 'Disease', (180, 202))	('IDH', 'Gene', (46, 49))	('IDH', 'Gene', (22, 25))	('gliomas', 'Disease', (168, 175))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (180, 202))	('IDH1', 'Gene', (37, 41))	('alpha-KG', 'Chemical', 'MESH:D007656', (119, 127))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (180, 202))	('IDH', 'Gene', '3417', (46, 49))	('IDH', 'Gene', '3417', (22, 25))	('gliomas', 'Disease', 'MESH:D005910', (168, 175))	('IDH', 'Gene', (37, 40))	('leukemia', 'Phenotype', 'HP:0001909', (194, 202))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (186, 202))	('occur frequently', 'Reg', (148, 164))	('IDH1', 'Gene', '3417', (37, 41))	('gliomas', 'Phenotype', 'HP:0009733', (168, 175))	('IDH', 'Gene', '3417', (37, 40))
39672	32252351	FAO is the most efficient metabolic pathway, producing NADH and FADH2 and proceeding in the mitochondrial matrix to yield acetyl-CoA, which further enters the TCA cycle, and this (i) provides a link between glucose and fatty acid metabolism, (ii) enables generation of a larger amount of ATP, and (iii) produces important intermediates used in other metabolic pathways.	('ATP', 'Chemical', 'MESH:D000255', (288, 291))	('FADH2', 'Chemical', 'MESH:C058805', (64, 69))	('FADH2', 'Var', (64, 69))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (122, 132))	('NADH', 'Var', (55, 59))	('acetyl-CoA', 'MPA', (122, 132))	('NADH', 'Chemical', 'MESH:D009243', (55, 59))	('glucose', 'Chemical', 'MESH:D005947', (207, 214))	('TCA', 'Chemical', 'MESH:D014233', (159, 162))	('link', 'MPA', (194, 198))	('fatty acid', 'Chemical', 'MESH:D005227', (219, 229))	('glucose', 'MPA', (207, 214))
39679	32252351	Oppositely, inactivation of CPT1A causes a decrease in ATP production and cell cycle arrest in G0/G1 phase due to activation of cyclin-dependent kinase inhibitor p21 by FoxO transcription factor phosphorylated/activated by AMPK and JNK/p38 MAPKs.	('AMPK', 'molecular_function', 'GO:0004691', ('223', '227'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (74, 91))	('AMPK', 'Gene', '5562', (223, 227))	('inactivation', 'Var', (12, 24))	('arrest', 'Disease', (85, 91))	('activation', 'PosReg', (114, 124))	('G1 phase', 'biological_process', 'GO:0051318', ('98', '106'))	('transcription', 'biological_process', 'GO:0006351', ('174', '187'))	('AMPK', 'molecular_function', 'GO:0047322', ('223', '227'))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('128', '161'))	('CPT1A', 'Gene', '1374', (28, 33))	('CPT', 'molecular_function', 'GO:0004142', ('28', '31'))	('transcription factor', 'molecular_function', 'GO:0000981', ('174', '194'))	('decrease', 'NegReg', (43, 51))	('CPT1A', 'Gene', (28, 33))	('ATP production', 'MPA', (55, 69))	('arrest', 'Disease', 'MESH:D006323', (85, 91))	('AMPK', 'Gene', (223, 227))	('AMPK', 'molecular_function', 'GO:0050405', ('223', '227'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('145', '161'))	('JNK', 'Gene', (232, 235))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('74', '91'))	('ATP', 'Chemical', 'MESH:D000255', (55, 58))	('p21', 'Gene', (162, 165))	('JNK', 'Gene', '5599', (232, 235))	('p21', 'Gene', '644914', (162, 165))	('CPT', 'molecular_function', 'GO:0004095', ('28', '31'))	('JNK', 'molecular_function', 'GO:0004705', ('232', '235'))
39693	32252351	Over-expression of Snail1, a TGF-beta1-induced EMT mediating transcription factor, inhibits fatty acid synthase and enhances mitochondrial respiration.	('Snail1', 'Gene', (19, 25))	('EMT', 'biological_process', 'GO:0001837', ('47', '50'))	('transcription', 'biological_process', 'GO:0006351', ('61', '74'))	('respiration', 'biological_process', 'GO:0007585', ('139', '150'))	('inhibits', 'NegReg', (83, 91))	('Snail1', 'Gene', '6615', (19, 25))	('mitochondrial respiration', 'MPA', (125, 150))	('enhances', 'PosReg', (116, 124))	('fatty acid synthase', 'Gene', '2194', (92, 111))	('transcription factor', 'molecular_function', 'GO:0000981', ('61', '81'))	('TGF-beta1', 'Gene', '7040', (29, 38))	('TGF-beta1', 'Gene', (29, 38))	('respiration', 'biological_process', 'GO:0045333', ('139', '150'))	('Over-expression', 'Var', (0, 15))	('fatty acid synthase', 'Gene', (92, 111))
39694	32252351	Additionally, epigenetic-transcriptional regulation of fatty acid metabolism contributes to cancer growth and metastasis.	('fatty acid', 'Chemical', 'MESH:D005227', (55, 65))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('metastasis', 'CPA', (110, 120))	('fatty acid metabolism', 'MPA', (55, 76))	('regulation of fatty acid metabolism', 'biological_process', 'GO:0019217', ('41', '76'))	('epigenetic-transcriptional regulation', 'Var', (14, 51))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('contributes', 'Reg', (77, 88))
39703	32252351	Alterations in signal transduction pathways that control mitochondrial bioenergetics and dynamics cause mitochondrial dysfunction and elevated ROS production, which are implicated in determining cancer cell fate for survival or death.	('death', 'Disease', (228, 233))	('cause', 'Reg', (98, 103))	('ROS', 'Chemical', 'MESH:D017382', (143, 146))	('signal transduction pathways', 'Pathway', (15, 43))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (104, 129))	('mitochondrial dysfunction', 'Disease', (104, 129))	('Alterations', 'Var', (0, 11))	('ROS production', 'MPA', (143, 157))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('signal transduction', 'biological_process', 'GO:0007165', ('15', '34'))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (104, 129))	('elevated', 'PosReg', (134, 142))	('elevated ROS production', 'Phenotype', 'HP:0025464', (134, 157))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('death', 'Disease', 'MESH:D003643', (228, 233))
39713	32252351	Binding of AMP stimulates phosphorylation of Thr172 residue in the kinase domain of alpha-subunit by upstream kinases such as LKB1, which directly activates AMPK in response to energy stress.	('LKB1', 'Gene', (126, 130))	('AMPK', 'molecular_function', 'GO:0050405', ('157', '161'))	('LKB1', 'Gene', '6794', (126, 130))	('Thr172', 'Chemical', '-', (45, 51))	('AMPK', 'Gene', '5562', (157, 161))	('AMPK', 'molecular_function', 'GO:0004691', ('157', '161'))	('AMPK', 'molecular_function', 'GO:0047322', ('157', '161'))	('AMP', 'Chemical', 'MESH:D000249', (157, 160))	('AMPK', 'Gene', (157, 161))	('phosphorylation', 'biological_process', 'GO:0016310', ('26', '41'))	('AMP', 'Chemical', 'MESH:D000249', (11, 14))	('Thr172 residue', 'Var', (45, 59))	('Binding', 'Interaction', (0, 7))	('phosphorylation', 'MPA', (26, 41))
39724	32252351	AMPK can inhibit mTORC1 through direct phosphorylation of several residues, including Ser1387 in tumor suppressor TSC2, which forms heterodimeric complex with TSC1 for the activation.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('TSC1', 'Gene', (159, 163))	('phosphorylation', 'MPA', (39, 54))	('inhibit', 'NegReg', (9, 16))	('mTORC1', 'Gene', '382056', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Ser1387', 'Chemical', '-', (86, 93))	('AMPK', 'Gene', '5562', (0, 4))	('tumor', 'Disease', (97, 102))	('mTORC1', 'Gene', (17, 23))	('Ser1387', 'Var', (86, 93))	('TSC2', 'Gene', (114, 118))	('TSC2', 'Gene', '7249', (114, 118))	('AMPK', 'Gene', (0, 4))	('TSC1', 'Gene', '7248', (159, 163))
39730	32252351	The Warburg effect can be closely associated with interplay between HIF-1 stabilization and decrease in AMPK activity, which underlies cancer cell survival and chemoresistance.	('stabilization', 'Var', (74, 87))	('cancer', 'Disease', (135, 141))	('AMPK activity', 'molecular_function', 'GO:0004679', ('104', '117'))	('decrease', 'NegReg', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('HIF-1', 'Gene', '3091', (68, 73))	('Warburg effect', 'Disease', (4, 18))	('AMPK', 'Gene', '5562', (104, 108))	('AMPK', 'Gene', (104, 108))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('HIF-1', 'Gene', (68, 73))
39751	32252351	The subpopulation of dormant tumor cells with mutant KRAS oncogene has features of cancer stem cells and relies on mitochondrial respiration and OXPHOS, demonstrating decreased dependence on glycolysis as a source of energy.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('dependence', 'MPA', (177, 187))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mutant', 'Var', (46, 52))	('tumor', 'Disease', (29, 34))	('KRAS', 'Gene', (53, 57))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
39752	32252351	Small GTPse KRAS is involved in Ras-MAPK-mediated signal transduction and formation of its active, GTP-bound form is dramatically increased by GAP.	('GTP', 'Chemical', 'MESH:D006160', (99, 102))	('GAP', 'Var', (143, 146))	('MAPK', 'molecular_function', 'GO:0004707', ('36', '40'))	('signal transduction', 'biological_process', 'GO:0007165', ('50', '69'))	('GTP', 'Chemical', 'MESH:D006160', (6, 9))	('increased', 'PosReg', (130, 139))	('formation', 'biological_process', 'GO:0009058', ('74', '83'))	('formation', 'MPA', (74, 83))
39754	32252351	Enhanced glucose uptake and glycolysis rate along with increased cell survival associated with GLUT1 up-regulation has been observed in colorectal cancer cell lines with mutations in KRAS and BRAF genes under glucose deprivation conditions.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('increased', 'PosReg', (55, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (136, 153))	('glucose deprivation conditions', 'Disease', 'MESH:D012892', (209, 239))	('cell survival', 'CPA', (65, 78))	('colorectal cancer', 'Disease', (136, 153))	('glucose', 'Chemical', 'MESH:D005947', (209, 216))	('glycolysis', 'MPA', (28, 38))	('Enhanced', 'PosReg', (0, 8))	('glucose uptake', 'MPA', (9, 23))	('KRAS', 'Gene', (183, 187))	('up-regulation', 'PosReg', (101, 114))	('colorectal cancer', 'Phenotype', 'HP:0003003', (136, 153))	('glucose deprivation conditions', 'Disease', (209, 239))	('GLUT1', 'Gene', (95, 100))	('mutations', 'Var', (170, 179))	('BRAF', 'Gene', '673', (192, 196))	('glucose', 'Chemical', 'MESH:D005947', (9, 16))	('BRAF', 'Gene', (192, 196))
39755	32252351	Smolkova and co-authors hypothesized that there may be waves in metabolic changes during carcinogenesis, which start from alterations in oncogene expression, and are followed by HIF-1 stabilization and metabolic reprogramming characterized by increased glycolysis and suppression of mitochondrial oxidation and OXPHOS.	('HIF-1', 'Gene', (178, 183))	('carcinogenesis', 'Disease', 'MESH:D063646', (89, 103))	('oncogene', 'Protein', (137, 145))	('suppression', 'NegReg', (268, 279))	('glycolysis', 'MPA', (253, 263))	('carcinogenesis', 'Disease', (89, 103))	('metabolic reprogramming', 'CPA', (202, 225))	('increased', 'PosReg', (243, 252))	('HIF-1', 'Gene', '3091', (178, 183))	('OXPHOS', 'MPA', (311, 317))	('alterations', 'Var', (122, 133))	('mitochondrial oxidation', 'MPA', (283, 306))	('metabolic', 'MPA', (64, 73))
39757	32252351	This leads to resumption of mitochondrial OXPHOS, and each type of neoplasm is characterized by distinct metabolic phenotype according to waves of metabolic changes and oncogenic mutations.	('metabolic changes', 'MPA', (147, 164))	('resumption', 'MPA', (14, 24))	('neoplasm', 'Phenotype', 'HP:0002664', (67, 75))	('neoplasm', 'Disease', (67, 75))	('mutations', 'Var', (179, 188))	('mitochondrial OXPHOS', 'MPA', (28, 48))	('neoplasm', 'Disease', 'MESH:D009369', (67, 75))	('OXPHOS', 'biological_process', 'GO:0002082', ('42', '48'))
39769	30816471	Overexpression of microRNA-101 causes anti-tumor effects by targeting CREB1 in colon cancer Accumulating evidence has demonstrated that aberrantly expressed microRNAs (miRNAs) are involved in the initiation and progression of numerous types of human cancer.	('colon cancer', 'Disease', (79, 91))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Disease', (43, 48))	('CREB1', 'Gene', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('microRNAs', 'Protein', (157, 166))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('CREB1', 'Gene', '1385', (70, 75))	('human', 'Species', '9606', (244, 249))	('microRNA-101', 'Gene', (18, 30))	('cancer', 'Disease', (85, 91))	('aberrantly', 'Var', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('involved', 'Reg', (180, 188))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))
39785	30816471	A number of previous studies demonstrated that miRNAs are associated with diagnosis, progression and prognosis of colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('colon cancer', 'Disease', (114, 126))	('associated', 'Reg', (58, 68))	('miRNAs', 'Var', (47, 53))	('colon cancer', 'Phenotype', 'HP:0003003', (114, 126))	('colon cancer', 'Disease', 'MESH:D015179', (114, 126))
39825	30816471	These mice were divided into two groups; one group (n=6) was inoculated with cells transfected with miR-101 mimics, and the other group (n=6) with cells transfected with miR-NC.	('miR-101', 'Gene', (100, 107))	('miR-101', 'Gene', '387143', (100, 107))	('mice', 'Species', '10090', (6, 10))	('miR-NC', 'Var', (170, 176))
39832	30816471	Sections were incubated overnight at 4 C with primary antibodies (rabbit polyclonal antibodies against CREB1, ab31387, 1:100; Abcam) and proliferating cell nuclear antigen (PCNA, ab18197, 1:50, Abcam).	('proliferating cell nuclear antigen', 'Gene', (137, 171))	('proliferating cell nuclear antigen', 'molecular_function', 'GO:0003892', ('137', '171'))	('CREB1', 'Gene', (103, 108))	('PCNA', 'Gene', (173, 177))	('proliferating cell nuclear antigen', 'Gene', '5111', (137, 171))	('PCNA', 'Gene', '5111', (173, 177))	('ab31387', 'Var', (110, 117))	('PCNA', 'molecular_function', 'GO:0003892', ('173', '177'))	('rabbit', 'Species', '9986', (66, 72))
39841	30816471	In order to investigate the role of miR-101 on the proliferation of HT29 cells, HT29 cells were transfected with miR-101 mimics or miR-NC.	('miR-101', 'Gene', (113, 120))	('HT29 cells', 'CellLine', 'CVCL:0320', (80, 90))	('miR-NC', 'Var', (131, 137))	('HT29 cells', 'CellLine', 'CVCL:0320', (68, 78))	('miR-101', 'Gene', '387143', (36, 43))	('miR-101', 'Gene', (36, 43))	('miR-101', 'Gene', '387143', (113, 120))
39847	30816471	To investigate whether miR-101 interacts with the CREB1 transcript in vitro, the miR-101 binding sites in the 3'-UTR of CREB1 were mutated, and a dual luciferase assay was conducted (Fig.	('binding', 'molecular_function', 'GO:0005488', ('89', '96'))	('miR-101', 'Gene', (81, 88))	('mutated', 'Var', (131, 138))	('miR-101', 'Gene', '387143', (81, 88))	('miR-101', 'Gene', '387143', (23, 30))	('miR-101', 'Gene', (23, 30))
39880	30816471	Schepeler et al demonstrated that the proliferation of three colorectal cancer cell lines (LS174T, DLD1 and HCT116) was significantly inhibited following transfection with miR-145, suggesting that miR-145 may have tumor suppressive roles.	('proliferation', 'CPA', (38, 51))	('colorectal cancer', 'Disease', (61, 78))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('miR-145', 'Gene', (197, 204))	('transfection', 'Var', (154, 166))	('inhibited', 'NegReg', (134, 143))	('miR-145', 'Gene', '406937', (197, 204))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('colorectal cancer', 'Disease', 'MESH:D015179', (61, 78))	('HCT116', 'CellLine', 'CVCL:0291', (108, 114))	('tumor', 'Disease', (214, 219))	('miR-145', 'Gene', (172, 179))	('miR-145', 'Gene', '406937', (172, 179))	('colorectal cancer', 'Phenotype', 'HP:0003003', (61, 78))
39919	30353144	It is well known that the binding of CD274 (PD-L1) on tumor cells to PD-1 receptors on T cells suppresses anti-tumor T cell-mediated immune responses, inducing immunological tolerance.	('CD274', 'Var', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('immunological tolerance', 'CPA', (160, 183))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('suppresses', 'NegReg', (95, 105))	('PD-1', 'Gene', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('PD-1', 'Gene', '5133', (69, 73))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('inducing', 'PosReg', (151, 159))	('binding', 'Interaction', (26, 33))
39922	30353144	Recent reports have demonstrated a direct correlation between the densities of T lymphocyte subpopulations, such as CD8+, CD45RO+ (PTPRC+), and FOXP3+ tumor-infiltrating lymphocytes (TILs), which are associated with a favorable clinical outcome in CRC, supporting a major role of T-cell-mediated immunity in repressing tumor progression of CRC.	('tumor', 'Disease', (319, 324))	('FOXP3', 'Gene', (144, 149))	('CRC', 'Phenotype', 'HP:0003003', (340, 343))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('CD8', 'Gene', (116, 119))	('CRC', 'Phenotype', 'HP:0003003', (248, 251))	('tumor', 'Disease', (151, 156))	('CD45RO+', 'Var', (122, 129))	('FOXP3', 'Gene', '50943', (144, 149))	('CD8', 'Gene', '925', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('CRC', 'Disease', (248, 251))
39938	30353144	The antibodies used in this study were the following: anti-PD-L1 (ab205921, Abcam, Cambridge, UK), anti-MSH2 (ab92372, Abcam, Cambridge, UK), anti-MLH1 (ab92312, Abcam, Cambridge, UK), anti-MSH6 (ab92471, Abcam, Cambridge, UK), anti-PMS2 (ab110638, Abcam, Cambridge, UK) and anti-CD8 (ab4055, Abcam, Cambridge, UK).	('CD8', 'Gene', '925', (280, 283))	('ab110638', 'Var', (239, 247))	('ab4055', 'Var', (285, 291))	('PMS2', 'Gene', (233, 237))	('ab92312', 'Var', (153, 160))	('MSH6', 'Gene', (190, 194))	('PMS2', 'Gene', '5395', (233, 237))	('MLH1', 'Gene', '4292', (147, 151))	('MLH1', 'Gene', (147, 151))	('ab92471', 'Var', (196, 203))	('MSH2', 'Gene', (104, 108))	('MSH2', 'Gene', '4436', (104, 108))	('ab92372', 'Var', (110, 117))	('MSH6', 'Gene', '2956', (190, 194))	('CD8', 'Gene', (280, 283))
39965	30353144	Therefore, CD8+ infiltration was significantly higher in high CD274-positive tumors than in low CD274-positive tumors (p < 0.0001, Table 2).	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('higher', 'PosReg', (47, 53))	('tumors', 'Disease', (111, 117))	('high CD274-positive', 'Var', (57, 76))	('CD8', 'Gene', (11, 14))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('CD8', 'Gene', '925', (11, 14))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CD274-positive', 'Var', (62, 76))
39979	30353144	Patients carrying a low density of CD8+ TILs had an increased risk for a lower 5-year DFS (HR = 2.16, 95% CI = 1.63-2.86, p < 0.0001), and those with a low tumor CD274 also had an increased risk for a lower 5-year DFS (HR = 1.51, 95% CI = 1.19-1.91, p = 0.0007) compared with patients carrying a high CD8+ TIL count and high tumor CD274 (Table 4).	('patients', 'Species', '9606', (276, 284))	('low tumor', 'Disease', 'MESH:D009800', (152, 161))	('DFS', 'MPA', (214, 217))	('high tumor', 'Disease', (320, 330))	('5-year', 'CPA', (79, 85))	('low tumor', 'Disease', (152, 161))	('high tumor', 'Disease', 'MESH:D009369', (320, 330))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('Patients', 'Species', '9606', (0, 8))	('DFS', 'MPA', (86, 89))	('CD8', 'Gene', (35, 38))	('CD274', 'Var', (162, 167))	('CD8', 'Gene', '925', (35, 38))	('lower', 'NegReg', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('CD8', 'Gene', (301, 304))	('lower', 'NegReg', (201, 206))	('CD8', 'Gene', '925', (301, 304))
39986	30353144	The aim of this study was to analyze the interrelationship between tumor CD274, CD8+ TILs and microsatellite instability in a large cohort of patients with colon carcinoma and to evaluate its clinical relevance.	('CD8', 'Gene', '925', (80, 83))	('CD8', 'Gene', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('colon carcinoma', 'Disease', (156, 171))	('microsatellite instability', 'MPA', (94, 120))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('colon carcinoma', 'Disease', 'MESH:D015179', (156, 171))	('tumor', 'Disease', (67, 72))	('patients', 'Species', '9606', (142, 150))	('CD274', 'Var', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
39990	30353144	Interferon-gamma (IFN-gamma) secreted by the infiltrated CD8+ T lymphocytes was required for CD274 induction, implying that upregulation of CD274 (PD-L1) within the tumor microenvironment served as a negative feedback mechanism, which represents a compensatory immune response by CD8+ T cells and IFN-gamma within the tumor microenvironment.	('CD8', 'Gene', '925', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('CD274', 'Gene', (93, 98))	('CD8', 'Gene', (280, 283))	('tumor', 'Disease', (318, 323))	('upregulation', 'PosReg', (124, 136))	('CD8', 'Gene', (57, 60))	('CD274', 'Var', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('IFN-gamma', 'Gene', '3458', (297, 306))	('IFN-gamma', 'Gene', (297, 306))	('tumor', 'Disease', (165, 170))	('CD8', 'Gene', '925', (280, 283))	('IFN-gamma', 'Gene', '3458', (18, 27))	('IFN-gamma', 'Gene', (18, 27))	('Interferon-gamma', 'Gene', '3458', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('Interferon-gamma', 'Gene', (0, 16))
39991	30353144	Furthermore, classification of tumors based on the status of CD274 (PD-L1) and the abundance of TILs has been proposed to be a predictive biomarker for the efficacy of PD-1/PD-L1 immunotherapy: type I (PD-L1+/TIL+; adaptive immune resistance), type II (PD-L1-/TIL-; immunological ignorance), type III (PD-L1+/TIL-; intrinsic induction) and type IV (PD-L1-/TIL+; tolerance).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('immunological ignorance', 'Phenotype', 'HP:0002721', (266, 289))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('PD-1', 'Gene', (168, 172))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('PD-1', 'Gene', '5133', (168, 172))	('PD-L1-/TIL-;', 'Var', (253, 265))	('PD-L1+/TIL-;', 'Var', (302, 314))
40002	30353144	Accumulating evidence indicates that alternations of tumor molecular pathological properties by environmental factors such as diet, nutrients and smoking influence tumor-immune interactions, eventually impacting tumor progression, aggravation and clinical outcome.	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('alternations', 'Var', (37, 49))	('influence', 'Reg', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('impacting', 'Reg', (202, 211))	('aggravation', 'CPA', (231, 242))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (212, 217))
40005	30353144	Indeed, colorectal carcinoma patients with MSI-high status showed a high response rate to PD-1/PD-L1 immunotherapy and a good survival rate, suggesting that a higher mutational burden may result in the formation of more tumor antigens (neoantigens) to trigger a robust anti-tumor immune response and to upregulate tumor CD274 expression.	('upregulate', 'PosReg', (303, 313))	('tumor', 'Disease', (220, 225))	('tumor', 'Disease', (314, 319))	('tumor', 'Disease', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('expression', 'MPA', (326, 336))	('more', 'PosReg', (215, 219))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('patients', 'Species', '9606', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('PD-1', 'Gene', (90, 94))	('CD274', 'Protein', (320, 325))	('PD-1', 'Gene', '5133', (90, 94))	('MSI', 'Disease', 'None', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('MSI', 'Disease', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('colorectal carcinoma', 'Disease', (8, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('mutational', 'Var', (166, 176))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (8, 28))	('trigger', 'PosReg', (252, 259))
40011	30353144	Therefore, as a consequence of this environment, CD274 and CD8+ TILs may be considered to be independent prognostic factors for colon carcinoma.	('colon carcinoma', 'Disease', 'MESH:D015179', (128, 143))	('CD8', 'Gene', (59, 62))	('colon carcinoma', 'Disease', (128, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('CD8', 'Gene', '925', (59, 62))	('CD274', 'Var', (49, 54))
40031	30151376	However, certain cases of monoclonality in GI tract Russell body containing lesions have been reported, without evidence of a neoplastic lesion.	('neoplastic lesion', 'Disease', 'MESH:D051437', (126, 143))	('monoclonality', 'Var', (26, 39))	('neoplastic lesion', 'Disease', (126, 143))	('neoplastic lesion', 'Phenotype', 'HP:0002664', (126, 143))
40043	29088281	Patients carrying EGFR mutations may benefit from EGFR targeted therapies (e.g.	('EGFR', 'molecular_function', 'GO:0005006', ('50', '54'))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'molecular_function', 'GO:0005006', ('18', '22'))	('EGFR', 'Gene', (18, 22))	('EGFR', 'Gene', '1956', (50, 54))	('mutations', 'Var', (23, 32))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'Gene', (50, 54))	('benefit', 'PosReg', (37, 44))
40058	29088281	When EGFR binds to several specific ligands, multiple signalling pathways are activated including the RAS/RAF/ERK/MAPK pathway, resulting in cell proliferation, and the PI3K/Akt pathway, STAT (Signal Transducers and Activators of Transcription) 3 and 5 signal transduction pathways, resulting in the evasion of apoptosis.	('signalling pathways', 'Pathway', (54, 73))	('ERK', 'molecular_function', 'GO:0004707', ('110', '113'))	('cell proliferation', 'biological_process', 'GO:0008283', ('141', '159'))	('Akt', 'Gene', '207', (174, 177))	('RAF', 'Gene', (106, 109))	('binds', 'Var', (10, 15))	('EGFR', 'molecular_function', 'GO:0005006', ('5', '9'))	('EGFR', 'Gene', '1956', (5, 9))	('MAPK', 'molecular_function', 'GO:0004707', ('114', '118'))	('ERK', 'Gene', '5594', (110, 113))	('evasion', 'MPA', (300, 307))	('signal transduction', 'biological_process', 'GO:0007165', ('253', '272'))	('signalling', 'biological_process', 'GO:0023052', ('54', '64'))	('cell proliferation', 'CPA', (141, 159))	('PI3K', 'molecular_function', 'GO:0016303', ('169', '173'))	('ERK', 'Gene', (110, 113))	('activated', 'PosReg', (78, 87))	('apoptosis', 'CPA', (311, 320))	('apoptosis', 'biological_process', 'GO:0097194', ('311', '320'))	('EGFR', 'Gene', (5, 9))	('Akt', 'Gene', (174, 177))	('apoptosis', 'biological_process', 'GO:0006915', ('311', '320'))	('RAF', 'Gene', '22882', (106, 109))
40060	29088281	mAbs against EGFR are active when EGFR is altered through protein expression, typically occurring in colorectal (CRC) cancer, while TKIs can inhibit the EGFR protein when a mutation occurs in its tyrosine kinase, encoded by exons 18-21.	('occurring', 'Reg', (88, 97))	('EGFR', 'Gene', (34, 38))	('altered', 'Reg', (42, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('mutation occurs', 'Var', (173, 188))	('tyrosine', 'Chemical', 'MESH:D014443', (196, 204))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('EGFR', 'Gene', '1956', (153, 157))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('colorectal (CRC) cancer', 'Disease', 'MESH:D015179', (101, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('protein', 'cellular_component', 'GO:0003675', ('158', '165'))	('EGFR', 'molecular_function', 'GO:0005006', ('153', '157'))	('EGFR', 'Gene', (153, 157))	('EGFR', 'Gene', '1956', (13, 17))	('inhibit', 'NegReg', (141, 148))	('EGFR', 'Gene', (13, 17))	('EGFR', 'Gene', '1956', (34, 38))
40063	29088281	However, not all EGFR mutations in the tyrosine kinase domain display the same effect with respect to TKI efficacy: in-frame deletions in exon 19 as well as L858R and L861Q point mutations in exon 21 are associated with the best response to TKI.	('L858R', 'Var', (157, 162))	('L861Q point', 'Var', (167, 178))	('L858R', 'Mutation', 'rs121434568', (157, 162))	('L861Q', 'Mutation', 'rs121913444', (167, 172))	('tyrosine', 'Chemical', 'MESH:D014443', (39, 47))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (17, 21))
40067	29088281	Defects in glycosylation are known to play a role in cancer malignancy, being associated with invasiveness and metastatic potential in cancer cells.	('associated', 'Reg', (78, 88))	('cancer', 'Disease', (135, 141))	('metastatic potential', 'CPA', (111, 131))	('cancer malignancy', 'Disease', (53, 70))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('glycosylation', 'biological_process', 'GO:0070085', ('11', '24'))	('Defects', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('glycosylation', 'MPA', (11, 24))	('invasiveness', 'Disease', 'MESH:D009362', (94, 106))	('invasiveness', 'Disease', (94, 106))	('cancer malignancy', 'Disease', 'MESH:D009369', (53, 70))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
40073	29088281	The human non-small cell lung cancer (NSCLC) cell lines HCC4006 (ATCC  CRL-2871 ), H1650 (ATCC  CRL-5883 ), H2228 (ATCC  CRL-5935 ), HCC78 (DSMZ ACC 563), H1975 (ATCC  CRL-5908 ), H1734 (ATCC  CRL-5891 ) were grown in RPMI 1640 medium supplemented with heat-inactivated 10% foetal bovine serum (FBS), 2 mM L-glutamine, 100 U/ml penicillin and 100 mug/ml streptomycin.	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('H1650', 'Var', (83, 88))	('cell lung cancer', 'Disease', 'MESH:D008175', (20, 36))	('mug', 'molecular_function', 'GO:0043739', ('347', '350'))	('NSCLC', 'Disease', (38, 43))	('H2228', 'CellLine', 'CVCL:1543', (108, 113))	('H1975', 'CellLine', 'CVCL:1511', (155, 160))	('H1734', 'CellLine', 'CVCL:1491', (180, 185))	('cell lung cancer', 'Disease', (20, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (10, 36))	('HCC4006', 'CellLine', 'CVCL:1269', (56, 63))	('H2228', 'Var', (108, 113))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (14, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('HCC78', 'CellLine', 'CVCL:2061', (133, 138))	('human', 'Species', '9606', (4, 9))	('penicillin', 'Chemical', 'MESH:D010406', (328, 338))	('bovine', 'Species', '9913', (281, 287))	('streptomycin', 'Chemical', 'MESH:D013307', (354, 366))
40090	29088281	The following primary antibodies (all purchased by Cell Signaling Technology, Danvers, MA, USA) were used: anti EGFR (dilution 1:1000), phospho-EGFR (Tyr1068; dilution 1:1000), p44/42 MAPK (ERK 1/2; dilution 1:1000), phospho-p44/42 MAPK (ERK 1/2) (Thr202/Tyr204; dilution 1:1000), Akt (dilution 1:1000), phospho-Akt (Ser473; dilution 1:1000), PTEN (dilution 1:1000), vinculin (dilution 1:10000) and GAPDH (dilution 1:10000).	('GAPDH', 'Gene', '2597', (399, 404))	('dilution 1:1000', 'Var', (286, 301))	('dilution 1:1000', 'Var', (349, 364))	('Thr202/Tyr204; dilution', 'Var', (248, 271))	('p44', 'Gene', (177, 180))	('p44', 'Gene', (225, 228))	('ERK 1/2', 'Gene', '5595;5594', (190, 197))	('vinculin', 'Gene', '7414', (367, 375))	('p44', 'Gene', '10561', (177, 180))	('p44', 'Gene', '10561', (225, 228))	('GAPDH', 'Gene', (399, 404))	('PTEN', 'Gene', (343, 347))	('EGFR', 'Gene', (112, 116))	('EGFR', 'Gene', (144, 148))	('ERK 1/2', 'Gene', (238, 245))	('Akt', 'Gene', (312, 315))	('PTEN', 'Gene', '5728', (343, 347))	('Akt', 'Gene', (281, 284))	('ERK 1/2', 'Gene', (190, 197))	('vinculin', 'Gene', (367, 375))	('Akt', 'Gene', '207', (281, 284))	('Akt', 'Gene', '207', (312, 315))	('EGFR', 'Gene', '1956', (112, 116))	('EGFR', 'Gene', '1956', (144, 148))	('ERK 1/2', 'Gene', '5595;5594', (238, 245))	('dilution', 'Var', (377, 385))
40105	29088281	More in detail: H2228 cells, carrying an ALK translocation; HCC78 cells, characterized by a ROS1 rearrangement; H1975 cells, carrying a double EGFR mutation (the L858R change, an activating mutation and the T790M change, the best-known mechanism of EGFR-TKI primary and acquired resistance); and, finally, H1734 cells, presenting the KRAS G13C mutation.	('ROS1', 'Gene', '6098', (92, 96))	('T790M', 'Var', (207, 212))	('EGFR', 'Gene', (249, 253))	('L858R', 'Mutation', 'rs121434568', (162, 167))	('G13C', 'Mutation', 'rs121913535', (339, 343))	('KRAS', 'Gene', '3845', (334, 338))	('HCC78', 'CellLine', 'CVCL:2061', (60, 65))	('EGFR', 'molecular_function', 'GO:0005006', ('249', '253'))	('EGFR', 'molecular_function', 'GO:0005006', ('143', '147'))	('ROS1', 'Gene', (92, 96))	('EGFR', 'Gene', (143, 147))	('KRAS', 'Gene', (334, 338))	('H1734', 'CellLine', 'CVCL:1491', (306, 311))	('L858R', 'Var', (162, 167))	('EGFR', 'Gene', '1956', (249, 253))	('H1975', 'Var', (112, 117))	('H1975', 'CellLine', 'CVCL:1511', (112, 117))	('T790M', 'Mutation', 'rs121434569', (207, 212))	('H2228', 'CellLine', 'CVCL:1543', (16, 21))	('EGFR', 'Gene', '1956', (143, 147))
40106	29088281	The fifth cell line resistant to gefitinib was H1650, which, although carrying an activating EGFR exon 19 deletion (del E746-A750), is unsensitive to TKI inhibitors through an unknown mechanism, as already reported in the literature.	('del E746-A750', 'Var', (116, 129))	('del E746', 'Mutation', 'p.746delE', (116, 124))	('EGFR', 'Gene', '1956', (93, 97))	('activating', 'PosReg', (82, 92))	('EGFR', 'Gene', (93, 97))	('gefitinib', 'Chemical', 'MESH:D000077156', (33, 42))
40107	29088281	On the contrary, HCC4006 cells, which are characterized by the classical DeltaE746-A750 in EGFR exon 19, showed high drug sensitivity.	('EGFR', 'Gene', (91, 95))	('drug sensitivity', 'MPA', (117, 133))	('EGFR', 'molecular_function', 'GO:0005006', ('91', '95'))	('DeltaE746', 'Var', (73, 82))	('DeltaE746', 'DELETION', 'None', (73, 82))	('EGFR', 'Gene', '1956', (91, 95))	('drug sensitivity', 'Phenotype', 'HP:0020174', (117, 133))	('HCC4006', 'CellLine', 'CVCL:1269', (17, 24))
40110	29088281	Results are reported in Fig 1C: at 1 muM gefitinib, death rate corresponds to 7% and 10% for healthy HSAEC1 cells and for sensitive HCC4006 cells respectively.	('to 7', 'Species', '1214577', (75, 79))	('HSAEC1', 'CellLine', 'CVCL:X488', (101, 107))	('gefitinib', 'Chemical', 'MESH:D000077156', (41, 50))	('HCC4006', 'CellLine', 'CVCL:1269', (132, 139))	('muM', 'Gene', '56925', (37, 40))	('gefitinib', 'Var', (41, 50))	('muM', 'Gene', (37, 40))
40112	29088281	Moreover, PI staining confirmed that H1734 cells are resistant to gefitinib treatment, cell death amounting to 2% at 1 muM gefitinib, with an inhibition of proliferation of 11%.	('muM', 'Gene', (119, 122))	('gefitinib', 'Chemical', 'MESH:D000077156', (123, 132))	('gefitinib', 'Chemical', 'MESH:D000077156', (66, 75))	('proliferation', 'CPA', (156, 169))	('H1734', 'CellLine', 'CVCL:1491', (37, 42))	('gefitinib', 'Var', (123, 132))	('muM', 'Gene', '56925', (119, 122))
40120	29088281	Transfected cells were treated or not with either 27 nM (corresponding to HCC4006 IC50) or 1 muM gefitinib for 36 h post-transfection.	('HCC4006', 'Var', (74, 81))	('gefitinib', 'Chemical', 'MESH:D000077156', (97, 106))	('muM', 'Gene', '56925', (93, 96))	('muM', 'Gene', (93, 96))	('HCC4006', 'CellLine', 'CVCL:1269', (74, 81))
40144	29088281	ERK activation was completely inhibited by gefitinib both in HSAEC1 and HCC4006 cell lines, while gefitinib did not affect ERK phosphorylation level in the drug-resistant H1734 cell line (Fig 6A and 6D).	('HCC4006', 'CellLine', 'CVCL:1269', (72, 79))	('gefitinib', 'Chemical', 'MESH:D000077156', (43, 52))	('HSAEC1', 'CellLine', 'CVCL:X488', (61, 67))	('gefitinib', 'Var', (43, 52))	('inhibited', 'NegReg', (30, 39))	('ERK', 'Gene', '5594', (123, 126))	('H1734', 'CellLine', 'CVCL:1491', (171, 176))	('ERK', 'Gene', (123, 126))	('gefitinib', 'Chemical', 'MESH:D000077156', (98, 107))	('ERK', 'Gene', '5594', (0, 3))	('ERK', 'Gene', (0, 3))	('activation', 'PosReg', (4, 14))
40157	29088281	This was done by comparing the effect of EGF administration, NEU3 overexpression and treatment with a specific EGFR-targeted therapy, gefitinib, in a healthy lung mucosa cell line (HSAEC1) and in two representative NSCLC cell lines, one of which sensitive (HCC4006, carrying a classical deletion in EGFR exon 19) and one resistant (H1734, with a EGFR wild-type gene status and carrying a KRAS exon 2 mutation) to gefitinib.	('EGFR', 'Gene', (346, 350))	('EGF', 'Gene', '1950', (299, 302))	('NEU3', 'Gene', (61, 65))	('HCC4006', 'CellLine', 'CVCL:1269', (257, 264))	('EGFR', 'Gene', '1956', (111, 115))	('deletion', 'Var', (287, 295))	('gefitinib', 'Chemical', 'MESH:D000077156', (413, 422))	('H1734', 'CellLine', 'CVCL:1491', (332, 337))	('NSCLC', 'Disease', (215, 220))	('EGF', 'Gene', '1950', (346, 349))	('gefitinib', 'Chemical', 'MESH:D000077156', (134, 143))	('EGF', 'Gene', (111, 114))	('EGFR', 'Gene', '1956', (299, 303))	('EGF', 'Gene', (299, 302))	('KRAS', 'Gene', (388, 392))	('EGFR', 'Gene', '1956', (346, 350))	('EGF', 'Gene', '1950', (41, 44))	('EGF', 'Gene', (346, 349))	('EGFR', 'Gene', (111, 115))	('KRAS', 'Gene', '3845', (388, 392))	('EGFR', 'Gene', (299, 303))	('EGF', 'Gene', '1950', (111, 114))	('EGF', 'Gene', (41, 44))	('NEU3', 'Gene', '10825', (61, 65))	('HSAEC1', 'CellLine', 'CVCL:X488', (181, 187))	('NSCLC', 'Disease', 'MESH:D002289', (215, 220))
40162	29088281	Upon transfection with NEU3, Q-PCR experiments showed an increase in NEU3 mRNA levels of 50-100-30-fold in HSAEC1, HCC4006 and H1734 cell lines, respectively; moreover, an increase of 2 folds in protein expression, respect to endogenous NEU3 expressed by mock cells, was detected through Western-blot in all cell lines.	('transfection', 'Var', (5, 17))	('NEU3', 'Gene', (23, 27))	('H1734', 'CellLine', 'CVCL:1491', (127, 132))	('NEU3', 'Gene', '10825', (237, 241))	('NEU3', 'Gene', '10825', (23, 27))	('NEU3', 'Gene', (69, 73))	('NEU3', 'Gene', (237, 241))	('increase', 'PosReg', (57, 65))	('HCC4006', 'CellLine', 'CVCL:1269', (115, 122))	('mRNA levels', 'MPA', (74, 85))	('HSAEC1', 'CellLine', 'CVCL:X488', (107, 113))	('NEU3', 'Gene', '10825', (69, 73))	('protein expression', 'MPA', (195, 213))
40172	29088281	Upon EGF administration, in the normal (HSAEC1) and in the KRAS mutant (H1734) cell lines we observed a significant stimulation of EGFR phosphorylation, irrespective of NEU3 overexpression, while no stimulation was observed in the EGFR-mutant cell lines, probably because EGFR is already hyper-activated at its maximum degree due to the presence of the hyper-activating mutation in the TKI domain.	('KRAS', 'Gene', '3845', (59, 63))	('phosphorylation', 'MPA', (136, 151))	('H1734', 'CellLine', 'CVCL:1491', (72, 77))	('mutation', 'Var', (370, 378))	('EGFR', 'molecular_function', 'GO:0005006', ('231', '235'))	('EGF', 'Gene', '1950', (5, 8))	('EGFR', 'Gene', (131, 135))	('EGF', 'molecular_function', 'GO:0005154', ('5', '8'))	('hyper-activating', 'PosReg', (353, 369))	('KRAS', 'Gene', (59, 63))	('NEU3', 'Gene', '10825', (169, 173))	('EGFR', 'Gene', (272, 276))	('EGF', 'Gene', '1950', (131, 134))	('EGFR', 'Gene', (231, 235))	('NEU3', 'Gene', (169, 173))	('EGF', 'Gene', '1950', (272, 275))	('mutant', 'Var', (64, 70))	('EGFR', 'molecular_function', 'GO:0005006', ('272', '276'))	('EGF', 'Gene', (5, 8))	('HSAEC1', 'CellLine', 'CVCL:X488', (40, 46))	('EGF', 'Gene', '1950', (231, 234))	('EGFR', 'Gene', '1956', (131, 135))	('EGF', 'Gene', (131, 134))	('EGFR', 'Gene', '1956', (272, 276))	('stimulation', 'PosReg', (116, 127))	('EGFR', 'Gene', '1956', (231, 235))	('EGF', 'Gene', (272, 275))	('phosphorylation', 'biological_process', 'GO:0016310', ('136', '151'))	('EGFR', 'molecular_function', 'GO:0005006', ('131', '135'))	('EGF', 'Gene', (231, 234))
40173	29088281	Therefore, there is no additive effect of EGF to EGFR mutation.	('EGFR', 'Gene', '1956', (49, 53))	('mutation', 'Var', (54, 62))	('EGFR', 'Gene', (49, 53))	('EGF', 'Gene', (42, 45))	('EGF', 'Gene', (49, 52))	('EGF', 'Gene', '1950', (49, 52))	('EGF', 'Gene', '1950', (42, 45))
40174	29088281	After gefitinib treatment, the effect of EGF is abolished in the normal and in the KRAS mutant cell line, while, as expected, although not furtherly stimulated by EGF, EGFR phosphorylation was greatly diminished in HCC4006.	('KRAS', 'Gene', (83, 87))	('gefitinib', 'Chemical', 'MESH:D000077156', (6, 15))	('EGF', 'Gene', '1950', (163, 166))	('KRAS', 'Gene', '3845', (83, 87))	('EGFR', 'Gene', '1956', (168, 172))	('EGFR', 'Gene', (168, 172))	('EGF', 'Gene', (168, 171))	('EGF', 'Gene', '1950', (41, 44))	('EGF', 'Gene', (41, 44))	('mutant', 'Var', (88, 94))	('EGF', 'Gene', '1950', (168, 171))	('phosphorylation', 'MPA', (173, 188))	('HCC4006', 'CellLine', 'CVCL:1269', (215, 222))	('EGF', 'Gene', (163, 166))	('diminished', 'NegReg', (201, 211))	('HCC4006', 'Var', (215, 222))
40176	29088281	This finding is, again, in contrast with what we observed in colorectal cancer cell lines, where, although carrying a strong EGFR activation, the cells showed a further increase of EGFR phosphorylation upon NEU3 transfection.	('NEU3', 'Gene', '10825', (207, 211))	('EGFR', 'molecular_function', 'GO:0005006', ('181', '185'))	('EGFR', 'Gene', (181, 185))	('colorectal cancer', 'Disease', (61, 78))	('EGFR', 'Gene', '1956', (125, 129))	('transfection', 'Var', (212, 224))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('phosphorylation', 'biological_process', 'GO:0016310', ('186', '201'))	('increase', 'PosReg', (169, 177))	('EGFR', 'Gene', (125, 129))	('colorectal cancer', 'Disease', 'MESH:D015179', (61, 78))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))	('NEU3', 'Gene', (207, 211))	('colorectal cancer', 'Phenotype', 'HP:0003003', (61, 78))	('EGFR', 'Gene', '1956', (181, 185))
40195	29088281	Unexpectedly, in this condition cell viability experiments showed that, although no EGFR gene mutations are present, the cells are slightly sensitive to the EGFR TKI (significantly less:about 18-fold-with respect to the EGFR-mutant cell line).	('EGFR', 'Gene', (157, 161))	('EGFR', 'Gene', (220, 224))	('mutations', 'Var', (94, 103))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('EGFR', 'molecular_function', 'GO:0005006', ('157', '161'))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'molecular_function', 'GO:0005006', ('220', '224'))	('EGFR', 'Gene', '1956', (157, 161))	('EGFR', 'Gene', (84, 88))	('EGFR', 'Gene', '1956', (220, 224))
40210	27508057	In this review we summarize the current understanding of the ever expanding involvement of non-coding RNAs in the p53 regulatory network and its implications for our understanding of gastrointestinal cancer.	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (183, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (183, 206))	('non-coding', 'Var', (91, 101))	('gastrointestinal cancer', 'Disease', (183, 206))
40216	27508057	While our appreciation of the important functions of non-coding RNA has grown, we have achieved a much better understanding of non-coding RNAs in the p53 regulated mechanisms in cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('non-coding RNAs', 'Var', (127, 142))	('RNA', 'cellular_component', 'GO:0005562', ('64', '67'))
40218	27508057	Disruptions of p53 functions, via deletions or mutations are found in many different types of cancers, including over 50% of colorectal cancers - .	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('deletions', 'Var', (34, 43))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('mutations', 'Var', (47, 56))	('p53', 'Gene', (15, 18))	('colorectal cancers', 'Disease', 'MESH:D015179', (125, 143))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (125, 142))	('colorectal cancers', 'Disease', (125, 143))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))	('Disruptions', 'NegReg', (0, 11))
40224	27508057	We first reported a systematic analysis of miRNA profiles in colon cancer cell lines, HCT 116, containing either wild type p53 or null p53 .	('miRNA profiles', 'MPA', (43, 57))	('colon cancer', 'Phenotype', 'HP:0003003', (61, 73))	('null p53', 'Var', (130, 138))	('colon cancer', 'Disease', 'MESH:D015179', (61, 73))	('HCT 116', 'CellLine', 'CVCL:0291', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colon cancer', 'Disease', (61, 73))
40225	27508057	miR-34s, miR-192, miR-215, miR-194, miR-502, miR-200c, miR-26a, miR-15) .	('miR-215', 'Gene', '406997', (18, 25))	('miR-34', 'Gene', '407040', (0, 6))	('miR-194', 'Var', (27, 34))	('miR-502', 'Gene', (36, 43))	('miR-26a', 'Var', (55, 62))	('miR-15', 'Var', (64, 70))	('miR-215', 'Gene', (18, 25))	('miR-192', 'Gene', '406967', (9, 16))	('miR-502', 'Gene', '574504', (36, 43))	('miR-192', 'Gene', (9, 16))	('miR-200c', 'Gene', (45, 53))	('miR-34', 'Gene', (0, 6))	('miR-200c', 'Gene', '406985', (45, 53))
40227	27508057	Working with the miRNAs we identified as having putative p53 binding sites in their promoter region we validated that miR-26a was directly regulated by p53 in colon cancer .	('p53', 'Var', (152, 155))	('regulated', 'Reg', (139, 148))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('colon cancer', 'Phenotype', 'HP:0003003', (159, 171))	('miR-26a', 'Gene', (118, 125))	('colon cancer', 'Disease', 'MESH:D015179', (159, 171))	('p53 binding', 'molecular_function', 'GO:0002039', ('57', '68'))	('colon cancer', 'Disease', (159, 171))
40228	27508057	miR-26a has been found to act as a tumor suppressor in mouse intestine .	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor suppressor', 'biological_process', 'GO:0051726', ('35', '51'))	('mouse', 'Species', '10090', (55, 60))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('35', '51'))	('tumor suppressor', 'Gene', (35, 51))	('miR-26a', 'Var', (0, 7))	('tumor suppressor', 'Gene', '7248', (35, 51))
40229	27508057	In gastric cancer, miR-26a also seems to act as a tumor suppressor, by targeting fibroblast growth factor 9 (FGF9) and inhibiting cell proliferation and metastasis .	('targeting', 'Reg', (71, 80))	('miR-26a', 'Var', (19, 26))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('inhibiting', 'NegReg', (119, 129))	('tumor suppressor', 'Gene', (50, 66))	('fibroblast growth factor 9', 'Gene', '2254', (81, 107))	('tumor suppressor', 'Gene', '7248', (50, 66))	('FGF9', 'Gene', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('gastric cancer', 'Disease', (3, 17))	('FGF9', 'Gene', '2254', (109, 113))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('fibroblast growth factor 9', 'Gene', (81, 107))
40231	27508057	miR-34a regulation by p53 is important in p53 mediated apoptosis, with inhibition of miR-34a reducing p53-induced apoptosis .	('inhibition', 'Var', (71, 81))	('reducing', 'NegReg', (93, 101))	('miR-34a', 'Gene', '407040', (85, 92))	('miR-34a', 'Gene', '407040', (0, 7))	('miR-34a', 'Gene', (85, 92))	('miR-34a', 'Gene', (0, 7))
40234	27508057	miR-34a also contributes to the activation of both p53 and p21.	('activation', 'PosReg', (32, 42))	('miR-34a', 'Gene', '407040', (0, 7))	('p53', 'Protein', (51, 54))	('miR-34a', 'Gene', (0, 7))	('p21', 'Var', (59, 62))
40254	27508057	One recent study demonstrated the potential of miR-192, miR-215 and miR-194 as promising detection biomarkers for Barrett's esophagus , further supporting the importance of the p53 mediated miRNAs.	('miR-194', 'Var', (68, 75))	('miR-215', 'Gene', '406997', (56, 63))	('miR-192', 'Gene', (47, 54))	('miR-192', 'Gene', '406967', (47, 54))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (114, 133))	('miR-215', 'Gene', (56, 63))	("Barrett's esophagus", 'Disease', (114, 133))
40257	27508057	In contrast to these miRNAs, we have identified a negative correlation between miR-502 expression and p53, suggesting that rather than inducing the expression of miR-502, p53 inhibits its expression in colon cancer.	('miR-502', 'Gene', (162, 169))	('expression', 'MPA', (188, 198))	('inducing', 'PosReg', (135, 143))	('p53', 'Var', (171, 174))	('colon cancer', 'Disease', 'MESH:D015179', (202, 214))	('miR-502', 'Gene', '574504', (79, 86))	('colon cancer', 'Phenotype', 'HP:0003003', (202, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('miR-502', 'Gene', '574504', (162, 169))	('expression', 'MPA', (148, 158))	('colon cancer', 'Disease', (202, 214))	('miR-502', 'Gene', (79, 86))	('inhibits', 'NegReg', (175, 183))
40259	27508057	miR-145 is also transcriptionally regulated by p53.	('miR-145', 'Gene', '406937', (0, 7))	('p53', 'Var', (47, 50))	('miR-145', 'Gene', (0, 7))
40261	27508057	miR-1204 is transcriptionally activated by p53 and also inhibits cellular proliferation .	('miR-1204', 'Gene', (0, 8))	('p53', 'Var', (43, 46))	('inhibits', 'NegReg', (56, 64))	('miR-1204', 'Gene', '100302185', (0, 8))	('activated', 'PosReg', (30, 39))	('cellular proliferation', 'CPA', (65, 87))
40262	27508057	In addition to wild type p53, mutant p53 also plays key roles in GI cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutant', 'Var', (30, 36))	('GI cancer', 'Disease', (65, 74))	('p53', 'Gene', (37, 40))	('GI cancer', 'Disease', 'MESH:D009369', (65, 74))	('roles', 'Reg', (56, 61))	('GI cancer', 'Phenotype', 'HP:0007378', (65, 74))
40263	27508057	Studies have demonstrated that the gain-of-function of mutant p53 is an important mechanism for tumors to develop resistance and impacts tumor progression .	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('impacts tumor', 'Disease', (129, 142))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('impacts tumor', 'Disease', 'MESH:D004834', (129, 142))	('mutant', 'Var', (55, 61))	('gain-of-function', 'PosReg', (35, 51))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('develop resistance', 'CPA', (106, 124))	('p53', 'Gene', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
40264	27508057	Mutant p53 exerts oncogenic functions and promotes epithelial-mesenchymal transition (EMT) in endometrial cancer (EC) by directly binding to the promoter of miR-130b, a negative regulator of zinc finger E-box-binding homeobox 1 (ZEB-1), and inhibiting its transcription.	('transcription', 'MPA', (256, 269))	('epithelial-mesenchymal transition', 'CPA', (51, 84))	('endometrial cancer', 'Phenotype', 'HP:0012114', (94, 112))	('EMT', 'biological_process', 'GO:0001837', ('86', '89'))	('binding', 'Interaction', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('zinc finger E-box-binding homeobox 1', 'Gene', '6935', (191, 227))	('endometrial cancer', 'Disease', (94, 112))	('inhibiting', 'NegReg', (241, 251))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('51', '84'))	('endometrial cancer', 'Disease', 'MESH:D016889', (94, 112))	('zinc finger E-box-binding homeobox 1', 'Gene', (191, 227))	('ZEB-1', 'Gene', (229, 234))	('transcription', 'biological_process', 'GO:0006351', ('256', '269'))	('p53', 'Gene', (7, 10))	('ZEB-1', 'Gene', '6935', (229, 234))	('oncogenic functions', 'CPA', (18, 37))	('E-box-binding', 'molecular_function', 'GO:0070888', ('203', '216'))	('promotes', 'PosReg', (42, 50))	('EC', 'Phenotype', 'HP:0012114', (114, 116))	('miR-130b', 'Gene', '406920', (157, 165))	('Mutant', 'Var', (0, 6))	('miR-130b', 'Gene', (157, 165))	('binding', 'molecular_function', 'GO:0005488', ('130', '137'))
40265	27508057	miR-223 was recently found to be down-regulated directly by mutant p53 proteins in breast and colon cancer cell lines .	('miR-223', 'Gene', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('p53', 'Gene', (67, 70))	('breast and colon cancer', 'Disease', 'MESH:D001943', (83, 106))	('miR-223', 'Gene', '407008', (0, 7))	('mutant', 'Var', (60, 66))	('proteins', 'Protein', (71, 79))	('down-regulated', 'NegReg', (33, 47))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))
40266	27508057	Mutant p53 binds the miR-223 promoter and reduces its transcriptional activity.	('binds', 'Interaction', (11, 16))	('miR-223', 'Gene', (21, 28))	('reduces', 'NegReg', (42, 49))	('Mutant', 'Var', (0, 6))	('miR-223', 'Gene', '407008', (21, 28))	('transcriptional activity', 'MPA', (54, 78))	('p53', 'Gene', (7, 10))
40268	27508057	In addition, miR-223 exogenous expression sensitizes breast and colon cancer cell lines expressing mutant p53 to treatment with DNA-damaging drugs .	('miR-223', 'Gene', (13, 20))	('colon cancer', 'Phenotype', 'HP:0003003', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('breast and colon cancer', 'Disease', 'MESH:D001943', (53, 76))	('miR-223', 'Gene', '407008', (13, 20))	('p53', 'Gene', (106, 109))	('mutant', 'Var', (99, 105))	('sensitizes', 'Reg', (42, 52))
40269	27508057	Let-7i has also been found to be regulated by mutant p53, inhibiting invasion and migration .	('Let-7i', 'Gene', (0, 6))	('inhibiting', 'NegReg', (58, 68))	('Let-7i', 'Gene', '406891', (0, 6))	('mutant', 'Var', (46, 52))	('p53', 'Gene', (53, 56))
40278	27508057	Among the first miRNAs found to target p53 directly, were miR-125b and miR-504 .	('miR-504', 'Gene', '574507', (71, 78))	('miR-504', 'Gene', (71, 78))	('miR-125b', 'Var', (58, 66))
40302	27508057	Tusc7 is transcriptionally activated by p53 to inhibit cell growth and exerts its function by suppressing miR-211 .	('Tusc7', 'Gene', (0, 5))	('Tusc7', 'Gene', '285194', (0, 5))	('p53', 'Var', (40, 43))	('inhibit', 'NegReg', (47, 54))	('suppressing', 'NegReg', (94, 105))	('miR-211', 'Gene', '406993', (106, 113))	('miR-211', 'Gene', (106, 113))	('cell growth', 'CPA', (55, 66))
40307	27508057	Tusc7 expression is also induced by wild type p53 but not mutant p53 .	('mutant', 'Var', (58, 64))	('Tusc7', 'Gene', (0, 5))	('Tusc7', 'Gene', '285194', (0, 5))	('induced', 'Reg', (25, 32))
40315	27508057	Knockdown of Tug1 also seems to inhibit cancer cell proliferation as well as migration .	('Knockdown', 'Var', (0, 9))	('inhibit', 'NegReg', (32, 39))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('Tug1', 'Gene', '55000', (13, 17))	('cancer', 'Disease', (40, 46))	('migration', 'CPA', (77, 86))	('Tug1', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
40336	27508057	The H19 lncRNA has been demonstrated to be associated with p53 in gastric cancer .	('H19', 'Gene', (4, 7))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('H19', 'Gene', '283120', (4, 7))	('p53', 'Var', (59, 62))	('associated', 'Reg', (43, 53))	('gastric cancer', 'Disease', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
40343	27508057	LincRNA-ROR acting in a feedback loop, is also able to regulate p53, and knockdown of lincRNA-ROR leads to an increase in genes in the p53 pathway response .	('increase', 'PosReg', (110, 118))	('p53 pathway response', 'Pathway', (135, 155))	('genes', 'MPA', (122, 127))	('LincRNA-ROR', 'Gene', '100885779', (0, 11))	('lincRNA-ROR', 'Gene', (86, 97))	('LincRNA-ROR', 'Gene', (0, 11))	('p53', 'Gene', (64, 67))	('lincRNA-ROR', 'Gene', '100885779', (86, 97))	('knockdown', 'Var', (73, 82))
40354	27508057	10.5256/f1000research.8996.r13581 Tanaka Yuichiro 2016 In this review, the authors systematically summarize the interplay between non-coding RNAs and the P53 pathway, with emphasis on how this affects gastrointestinal cancer.	('P53', 'Gene', (154, 157))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (201, 224))	('interplay', 'Interaction', (112, 121))	('non-coding RNAs', 'Var', (130, 145))	('P53', 'Gene', '7157', (154, 157))	('gastrointestinal cancer', 'Disease', (201, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (201, 224))	('affects', 'Reg', (193, 200))
40370	26493588	Clinical trial identifier BACCHUS: NCT01650428 In LARC, preoperative chemoradiation and radiotherapy have become accepted as the standard of care.	('NCT01650428', 'Var', (35, 46))	('rat', 'Species', '10116', (62, 65))	('LARC', 'Disease', (50, 54))
40371	26493588	Meta-analyses and individual trials of SCPRT and CRT have demonstrated that radiotherapy improves local control, but provides no impact on OS.	('radiotherapy', 'Var', (76, 88))	('OS', 'Chemical', 'MESH:D009992', (139, 141))	('improves', 'PosReg', (89, 97))	('local control', 'CPA', (98, 111))	('rat', 'Species', '10116', (65, 68))
40372	26493588	Radiotherapy is associated with significant late-effects, including an increased risk of second malignancies.	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('Radiotherapy', 'Var', (0, 12))	('malignancies', 'Disease', (96, 108))
40447	26493588	Exploratory SPECT imaging using Tc99m-maraciclitide as the tracer in a subset of patients at baseline and post treatment will provide information regarding changes in angiogenesis with treatment.	('Tc99m-maraciclitide', 'Var', (32, 51))	('patients', 'Species', '9606', (81, 89))	('rat', 'Species', '10116', (5, 8))	('angiogenesis', 'CPA', (167, 179))	('Tc99m-maraciclitide', 'Chemical', '-', (32, 51))
40465	26493588	The Tribe study showed a high clinical response rate in both arms - viz 53 % for FOLFOX + BVZ versus 65 % FOLFOXIRI + BVZ, with Grade 3 diarrhoea manageable at 9 and 19 % respectively.	('BVZ', 'Chemical', 'MESH:D000068258', (118, 121))	('diarrhoea', 'Disease', 'MESH:D003967', (136, 145))	('BVZ', 'Chemical', 'MESH:D000068258', (90, 93))	('FOLFOXIRI + BVZ', 'Chemical', '-', (106, 121))	('diarrhoea', 'Phenotype', 'HP:0002014', (136, 145))	('FOLFOX', 'Var', (81, 87))	('FOLFOX', 'Chemical', '-', (81, 87))	('diarrhoea', 'Disease', (136, 145))	('rat', 'Species', '10116', (48, 51))	('FOLFOX', 'Chemical', '-', (106, 112))
40496	25128828	Aberrant epigenetic modifications occur at the earliest stages of neoplastic transformation and are now believed to be essential players in cancer initiation and progression.	('cancer initiation', 'Disease', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer initiation', 'Disease', 'MESH:D009369', (140, 157))	('Aberrant epigenetic modifications', 'Var', (0, 33))
40497	25128828	Recent advances in epigenetics have not only offered a deeper understanding of the underlying mechanism(s) of carcinogenesis, but have also allowed identification of clinically relevant putative biomarkers for the early detection, disease monitoring, prognosis and risk assessment of cancer patients.	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('clinical', 'Species', '191496', (166, 174))	('cancer', 'Disease', (284, 290))	('patients', 'Species', '9606', (291, 299))	('carcinogenesis', 'Disease', 'MESH:D063646', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('epigenetics', 'Var', (19, 30))	('carcinogenesis', 'Disease', (110, 124))
40498	25128828	At this moment, DNA methylation and non-coding RNA including with microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) represent the largest body of available literature on epigenetic biomarkers with the highest potential for cancer diagnosis.	('miR', 'Gene', (77, 80))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('methylation', 'Var', (20, 31))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('miR', 'Gene', '220972', (77, 80))
40511	25128828	It is also becoming apparent that microenvironment-mediated epigenetic perturbations play an important role in the development of neoplasia.	('epigenetic perturbations', 'Var', (60, 84))	('neoplasia', 'Disease', (130, 139))	('neoplasia', 'Disease', 'MESH:D009369', (130, 139))	('neoplasia', 'Phenotype', 'HP:0002664', (130, 139))
40512	25128828	Epigenetic alterations are believed to occur early in tumor development and may precede genetic changes, thus providing a rationale for developing molecular biomarkers for the early diagnosis and disease prevention.	('Epigenetic alterations', 'Var', (0, 22))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))
40513	25128828	The emergence of advanced technologies that now allow detection of genome-wide epigenetic changes provide ample promise for advancing our capacity to develop such biomarkers for detecting cancers at an early stage.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('cancers', 'Disease', (188, 195))	('epigenetic changes', 'Var', (79, 97))	('cancers', 'Disease', 'MESH:D009369', (188, 195))
40517	25128828	Recent reports have shown that methylated DNA and miRNAs could be readily detected in a wide variety of tissues, as well as various body fluids, indicating that these epigenetic biomarkers could represent the next generation of biomarkers for cancer detection.	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('DNA', 'cellular_component', 'GO:0005574', ('42', '45'))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('methylated', 'Var', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
40520	25128828	Aberrant DNA methylation contributes to cancer mainly through DNA hyper- or hypo-methylation.	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('contributes', 'Reg', (25, 36))	('cancer', 'Disease', (40, 46))	('hypo-methylation', 'Var', (76, 92))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
40521	25128828	While DNA hypermethylation refers to the gain of methylation at a locus that was originally not methylated and usually results in stable transcriptional silencing and reduced gene expression, DNA hypomethylation represents the loss of DNA methylation, affecting chromosomal stability and enhanced aneuploidy.	('gene expression', 'biological_process', 'GO:0010467', ('175', '190'))	('gene expression', 'MPA', (175, 190))	('aneuploidy', 'Disease', (297, 307))	('DNA', 'cellular_component', 'GO:0005574', ('192', '195'))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('6', '26'))	('gain', 'PosReg', (41, 45))	('affecting', 'Reg', (252, 261))	('DNA hypomethylation', 'Var', (192, 211))	('reduced', 'NegReg', (167, 174))	('DNA', 'cellular_component', 'GO:0005574', ('235', '238'))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('192', '211'))	('methylation', 'MPA', (49, 60))	('chromosomal stability', 'CPA', (262, 283))	('DNA', 'cellular_component', 'GO:0005574', ('6', '9'))	('DNA methylation', 'biological_process', 'GO:0006306', ('235', '250'))	('aneuploidy', 'Disease', 'MESH:D000782', (297, 307))	('methylation', 'biological_process', 'GO:0032259', ('49', '60'))	('transcriptional', 'MPA', (137, 152))	('enhanced', 'PosReg', (288, 296))
40522	25128828	Global DNA hypomethylation was discovered first, and is usually considered one of the hallmarks of cancer cells, and some of the genes targeted by hypomethylation overlap aberrant hypermethylation-vulnerable genes.	('hypomethylation', 'Var', (147, 162))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('7', '26'))
40528	25128828	Over the past decade we have learnt that during the initiation and tumorigenesis of human cancer, a large number of critical tumor suppressor genes undergo methylation-induced transcriptional silencing, which leads to altered cellular signaling that manifests in carcinogenesis.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('carcinogenesis', 'Disease', (263, 277))	('tumor', 'Disease', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (125, 130))	('altered', 'Reg', (218, 225))	('human', 'Species', '9606', (84, 89))	('cellular signaling', 'MPA', (226, 244))	('methylation-induced', 'Var', (156, 175))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('carcinogenesis', 'Disease', 'MESH:D063646', (263, 277))
40529	25128828	Recent evidence suggests that epigenetic deregulation may actually even precede classical genetic changes, such as mutations and deletions in various tumor suppressors or oncogenes.	('deletions', 'Var', (129, 138))	('mutations', 'Var', (115, 124))	('epigenetic deregulation', 'Var', (30, 53))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
40533	25128828	Each histological type is a consequence of a progressive accumulation of different genetic and epigenetic alterations, which play a central role in gastric carcinogenesis.	('gastric carcinogenesis', 'Disease', (148, 170))	('genetic', 'Var', (83, 90))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (148, 170))	('epigenetic alterations', 'Var', (95, 117))
40535	25128828	suggested that global DNA hypomethylation might be implicated in GC associated with H. pylori infection at an early stage.	('H. pylori', 'Species', '210', (84, 93))	('H. pylori infection', 'Phenotype', 'HP:0005202', (84, 103))	('GC', 'Phenotype', 'HP:0012126', (65, 67))	('infection', 'Disease', (94, 103))	('global DNA hypomethylation', 'Var', (15, 41))	('infection', 'Disease', 'MESH:D007239', (94, 103))	('implicated', 'Reg', (51, 61))	('H. pylori', 'Disease', (84, 93))
40536	25128828	In contrast, most reports have favored the school of thought that H. pylori infection induces aberrant methylation in a number of gene promoters in the gastric mucosa, including cell growth-related genes p16 (INK4a), p14 (ARF) and APC; DNA-repair genes, MLH1, BRCA1 and MGMT; the cell adherence gene E-cadherin; as well as LOX, FLNC, HRASLS, HAND1, and THBD, which are methylated in gastric cancer patients.	('H. pylori', 'Var', (66, 75))	('gastric cancer', 'Disease', 'MESH:D013274', (383, 397))	('BRCA1', 'Gene', (260, 265))	('induces', 'Reg', (86, 93))	('FLNC', 'Gene', (328, 332))	('p16', 'Gene', '1029', (204, 207))	('APC', 'Gene', (231, 234))	('gastric mucosa', 'Disease', (152, 166))	('E-cadherin', 'Gene', '12550', (300, 310))	('gastric mucosa', 'Disease', 'MESH:D013274', (152, 166))	('cancer', 'Phenotype', 'HP:0002664', (391, 397))	('HRASLS', 'Gene', '27281', (334, 340))	('H. pylori infection', 'Phenotype', 'HP:0005202', (66, 85))	('HAND1', 'Gene', (342, 347))	('gastric cancer', 'Phenotype', 'HP:0012126', (383, 397))	('p14', 'Gene', '1029', (217, 220))	('ARF', 'Disease', (222, 225))	('patients', 'Species', '9606', (398, 406))	('BRCA1', 'Gene', '12189', (260, 265))	('p14', 'Gene', (217, 220))	('HRASLS', 'Gene', (334, 340))	('MGMT', 'Gene', (270, 274))	('gastric cancer', 'Disease', (383, 397))	('APC', 'Gene', '324', (231, 234))	('LOX', 'Gene', '16948', (323, 326))	('HAND1', 'Gene', '15110', (342, 347))	('ARF', 'Disease', 'MESH:D058186', (222, 225))	('methylation', 'MPA', (103, 114))	('LOX', 'Gene', (323, 326))	('MLH1', 'Gene', (254, 258))	('H. pylori', 'Species', '210', (66, 75))	('infection', 'Disease', (76, 85))	('infection', 'Disease', 'MESH:D007239', (76, 85))	('E-cadherin', 'Gene', (300, 310))	('FLNC', 'Gene', '68794', (328, 332))	('p16', 'Gene', (204, 207))
40537	25128828	The epithelial cadherin gene, CDH1, which is a well-studied gene involved in cancer, is downregulated in gastric tumors and is hypermethylated more frequently in the diffuse type than in the intestinal type of GC.	('CDH1', 'Gene', '999', (30, 34))	('gastric tumors', 'Disease', (105, 119))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('epithelial cadherin', 'Gene', '999', (4, 23))	('GC', 'Phenotype', 'HP:0012126', (210, 212))	('gastric tumors', 'Phenotype', 'HP:0006753', (105, 119))	('hypermethylated', 'Var', (127, 142))	('gastric tumors', 'Disease', 'MESH:D013274', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('downregulated', 'NegReg', (88, 101))	('CDH1', 'Gene', (30, 34))	('epithelial cadherin', 'Gene', (4, 23))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
40541	25128828	Other studies have described a number of other genes that are silenced by hypermethylation in association with H. pylori or EBV infection.	('EBV infection', 'Disease', (124, 137))	('EBV infection', 'Disease', 'MESH:D020031', (124, 137))	('H. pylori', 'Species', '210', (111, 120))	('hypermethylation', 'Var', (74, 90))	('H. pylori', 'Disease', (111, 120))	('silenced', 'NegReg', (62, 70))
40547	25128828	reported that the hTERT promoter was more methylated in GC than in precancerous lesions and non-neoplastic gastric tissues, highlighting that the degree of methylation of the hTERT promoter may be useful for the early diagnosis of GC and/or may have an impact on the anti-telomerase strategy for cancer therapy.	('hTERT', 'Gene', '7015', (18, 23))	('hTERT', 'Gene', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('hTERT', 'Gene', (18, 23))	('precancerous lesions', 'Disease', (67, 87))	('GC', 'Phenotype', 'HP:0012126', (56, 58))	('impact', 'Reg', (253, 259))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('hTERT', 'Gene', '7015', (175, 180))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', (296, 302))	('GC', 'Phenotype', 'HP:0012126', (231, 233))	('neoplastic gastric tissues', 'Phenotype', 'HP:0006753', (96, 122))	('precancerous lesions', 'Disease', 'MESH:D011230', (67, 87))	('methylation', 'Var', (156, 167))
40548	25128828	Recently, aberrant hypermethylation of the newly associated metastatic suppressor gene RECK was found to be associated with GC development, which may also serve as a useful biomarker for early diagnosis and treatment.	('RECK', 'Gene', '8434', (87, 91))	('GC', 'Phenotype', 'HP:0012126', (124, 126))	('associated', 'Reg', (108, 118))	('aberrant hypermethylation', 'Var', (10, 35))	('RECK', 'Gene', (87, 91))
40549	25128828	These findings delineate that specific epigenetic alterations occur during different stages of gastric tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('epigenetic alterations', 'Var', (39, 61))	('tumor', 'Disease', (103, 108))	('occur', 'Reg', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
40551	25128828	Epigenetic alterations have now been linked to specific steps in the adenoma-carcinoma sequence, and are believed to play a central role in the initiation and progression of CRC.	('Epigenetic alterations', 'Var', (0, 22))	('CRC', 'Phenotype', 'HP:0003003', (174, 177))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (69, 86))	('role', 'Reg', (132, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('linked', 'Reg', (37, 43))	('adenoma-carcinoma', 'Disease', (69, 86))	('CRC', 'Disease', (174, 177))
40554	25128828	Global DNA hypomethylation in CRC tissues was simultaneously accompanied by hypermethylation and transcriptional silencing of tumor suppressor or DNA repair genes.	('hypermethylation', 'MPA', (76, 92))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('126', '142'))	('transcriptional', 'MPA', (97, 112))	('hypomethylation', 'Var', (11, 26))	('DNA', 'cellular_component', 'GO:0005574', ('146', '149'))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('silencing', 'NegReg', (113, 122))	('DNA repair genes', 'Gene', (146, 162))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('126', '142'))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('DNA repair', 'biological_process', 'GO:0006281', ('146', '156'))	('CRC', 'Phenotype', 'HP:0003003', (30, 33))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('7', '26'))	('tumor', 'Disease', (126, 131))
40556	25128828	Recent reviews have revealed that several genes are frequently methylated in the multiple-step process from normal colonic epithelium to adenocarcinoma.	('methylated', 'Var', (63, 73))	('adenocarcinoma', 'Disease', 'MESH:D000230', (137, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('adenocarcinoma', 'Disease', (137, 151))
40557	25128828	For instance, six genes (CDH13, CRBP1, SFRP1, SFRP2, SLC5A8, and RUNX3) and two loci (MINT1, MINT31) are consistently methylated in during transformation of normal colonic mucosa to ACF.	('MINT1', 'Gene', (86, 91))	('RUNX3', 'Gene', (65, 70))	('RUNX3', 'Gene', '864', (65, 70))	('CDH13', 'Gene', '1012', (25, 30))	('CRBP1', 'Gene', '5947', (32, 37))	('SFRP1', 'Gene', '6422', (39, 44))	('SLC5A8', 'Gene', (53, 59))	('SFRP2', 'Gene', '6423', (46, 51))	('SFRP2', 'Gene', (46, 51))	('methylated', 'Var', (118, 128))	('CRBP1', 'Gene', (32, 37))	('MINT1', 'Gene', '320', (86, 91))	('SLC5A8', 'Gene', '160728', (53, 59))	('CDH13', 'Gene', (25, 30))	('SFRP1', 'Gene', (39, 44))
40559	25128828	Furthermore, four genes (CXCL12, ID4, IRF8, and TIMP3) are frequently methylated in the late stages of the adenoma-carcinoma sequence and could have a role in CRC progression and metastasis Curiously, some of genes that are aberrantly methylation in CRC, including ESR1, IGF2 and TUSC3, are also methylated in histologically normal colonic mucosa.	('IRF8', 'Gene', '3394', (38, 42))	('CRC', 'Phenotype', 'HP:0003003', (250, 253))	('methylation', 'biological_process', 'GO:0032259', ('235', '246'))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (107, 124))	('TUSC3', 'Gene', '7991', (280, 285))	('have', 'Reg', (144, 148))	('adenoma-carcinoma', 'Disease', (107, 124))	('aberrantly methylation', 'Var', (224, 246))	('TIMP3', 'Gene', (48, 53))	('IRF8', 'Gene', (38, 42))	('TIMP3', 'Gene', '7078', (48, 53))	('IGF2', 'Gene', (271, 275))	('ESR1', 'Gene', '2099', (265, 269))	('CRC', 'Phenotype', 'HP:0003003', (159, 162))	('CXCL12', 'Gene', '6387', (25, 31))	('ESR1', 'Gene', (265, 269))	('TUSC3', 'Gene', (280, 285))	('CXCL12', 'Gene', (25, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('ID4', 'Gene', (33, 36))	('IGF2', 'Gene', '3481', (271, 275))	('ID4', 'Gene', '3400', (33, 36))	('role', 'Reg', (151, 155))
40561	25128828	For example, it was reported that the SFRP gene, which is a negative regulator of the WNT pathway, is hypermethylated, and consequently downregulated in normal colonic mucosa from patients with CRC.	('downregulated', 'NegReg', (136, 149))	('SFRP gene', 'Gene', (38, 47))	('hypermethylated', 'Var', (102, 117))	('CRC', 'Phenotype', 'HP:0003003', (194, 197))	('patients', 'Species', '9606', (180, 188))
40564	25128828	Although accumulation of DNA methylation is now expected to contribute to "field cancerization" in the colonic mucosa, further research is required to establish useful surrogate markers for CRC surveillance.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('contribute', 'Reg', (60, 70))	('cancer', 'Disease', (81, 87))	('accumulation', 'PosReg', (9, 21))	('CRC', 'Phenotype', 'HP:0003003', (190, 193))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('DNA', 'Var', (25, 28))
40568	25128828	For any diagnostic approach, candidate biomarkers and methods with high sensitivity and specificity must be adopted to allow the detection of rare cancer-specific methylation events in the large background of normal DNA.	('cancer', 'Disease', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('methylation', 'Var', (163, 174))
40582	25128828	DNA methylation is a major mechanism of silencing tumor-related genes, such as tumor suppressor genes, in neoplastic cells.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('79', '95'))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('tumor', 'Disease', (79, 84))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('methylation', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('silencing', 'NegReg', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor suppressor', 'biological_process', 'GO:0051726', ('79', '95'))	('tumor', 'Disease', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
40586	25128828	RUNX3, one of the RUNX family members that plays important roles in both normal developmental processes and carcinogenesis, is frequently inactivated by methylation-induced silencing.	('methylation-induced silencing', 'Var', (153, 182))	('inactivated', 'NegReg', (138, 149))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('RUNX3', 'Gene', (0, 5))	('methylation', 'biological_process', 'GO:0032259', ('153', '164'))	('RUNX3', 'Gene', '864', (0, 5))	('carcinogenesis', 'Disease', (108, 122))
40587	25128828	In addition, hypermethylation of RUNX3 was detected in 45.2% GC patients, which was significantly higher than that in healthy donors.	('patients', 'Species', '9606', (64, 72))	('higher', 'PosReg', (98, 104))	('detected', 'Reg', (43, 51))	('RUNX3', 'Gene', (33, 38))	('RUNX3', 'Gene', '864', (33, 38))	('GC', 'Phenotype', 'HP:0012126', (61, 63))	('hypermethylation', 'Var', (13, 29))
40588	25128828	The quantification of serum RUNX3 methylation has a great potential to detect and diagnose GC, as well as use this biomarker for postoperative monitoring of tumor recurrence in these patients.	('tumor', 'Disease', (157, 162))	('RUNX3', 'Gene', (28, 33))	('RUNX3', 'Gene', '864', (28, 33))	('methylation', 'Var', (34, 45))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('methylation', 'biological_process', 'GO:0032259', ('34', '45'))	('detect', 'Reg', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('GC', 'Phenotype', 'HP:0012126', (91, 93))	('patients', 'Species', '9606', (183, 191))
40590	25128828	Importantly, even though the sensitivity of serum RASSAF1A methylation in detecting GC patients was relatively low, the specificity of this biomarker was extremely high.	('RASSAF1A', 'Gene', (50, 58))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('methylation', 'Var', (59, 70))	('GC', 'Phenotype', 'HP:0012126', (84, 86))	('patients', 'Species', '9606', (87, 95))	('low', 'NegReg', (111, 114))
40592	25128828	Based on these results, several studies have focused on developing p16 methylation assay in cell-free DNA from serum and plasma, and have concluded that detection of p16 DNA methylation is serum may be an important biomarker for the early detection of GC.	('p16', 'Gene', '1029', (67, 70))	('methylation', 'Var', (174, 185))	('p16', 'Gene', '1029', (166, 169))	('p16', 'Gene', (67, 70))	('GC', 'Phenotype', 'HP:0012126', (252, 254))	('p16', 'Gene', (166, 169))
40594	25128828	Among these targets, MINT25 methylation demonstrated the highest sensitivity and specificity to differentiate GC patients from normal healthy controls.	('patients', 'Species', '9606', (113, 121))	('GC', 'Phenotype', 'HP:0012126', (110, 112))	('methylation', 'Var', (28, 39))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))	('MINT25', 'Gene', (21, 27))
40600	25128828	PCR-based assay of small amounts of nucleic acids can detect and quantify genetic and epigenetic alterations in circulating tumor DNA.	('tumor', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('epigenetic', 'Var', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
40601	25128828	Using the same principle, recent research has focused on the detection of methylated DNA in serum and plasma of patients with cancer vs. its absence in healthy controls.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('methylated', 'Var', (74, 84))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('DNA', 'Gene', (85, 88))
40603	25128828	In Table 2, we summarize some of the key data on aberrantly methylated genes in stool and serum/plasma samples of patients with CRC.	('CRC', 'Phenotype', 'HP:0003003', (128, 131))	('patients', 'Species', '9606', (114, 122))	('aberrantly methylated', 'Var', (49, 70))	('CRC', 'Disease', (128, 131))
40606	25128828	In particular, SEPT9 methylation had the highest probability of correctly distinguishing CRC patients from healthy controls, with 69% sensitivity and 86% specificity.	('SEPT9', 'Gene', (15, 20))	('methylation', 'Var', (21, 32))	('CRC', 'Disease', (89, 92))	('SEPT9', 'Gene', '10801', (15, 20))	('patients', 'Species', '9606', (93, 101))	('CRC', 'Phenotype', 'HP:0003003', (89, 92))
40607	25128828	Other reports concluded that the presence of aberrantly methylated SEPT9 in plasma is a valuable and non-invasive blood-based PCR test, showing a sensitivity of almost 70% and a specificity of 90% in detecting CRC patients.	('SEPT9', 'Gene', (67, 72))	('patients', 'Species', '9606', (214, 222))	('CRC', 'Phenotype', 'HP:0003003', (210, 213))	('presence', 'Var', (33, 41))	('aberrantly methylated', 'Var', (45, 66))	('SEPT9', 'Gene', '10801', (67, 72))	('CRC patients', 'Disease', (210, 222))
40610	25128828	Array-based methylation profiling implicated in carcinogenesis demonstrated that methylation analysis of a gene panel containing CYCD2, HIC1, PAX5, RASSF1A, RB1 and SRBC could differentiate CRC patients and controls with 84% sensitivity and 68% specificity.	('HIC1', 'Gene', (136, 140))	('SRBC', 'Gene', (165, 169))	('RB1', 'Gene', '5925', (157, 160))	('SRBC', 'Gene', '914', (165, 169))	('differentiate', 'Reg', (176, 189))	('methylation', 'Var', (81, 92))	('patients', 'Species', '9606', (194, 202))	('HIC1', 'Gene', '3090', (136, 140))	('CRC', 'Disease', (190, 193))	('carcinogenesis', 'Disease', 'MESH:D063646', (48, 62))	('RASSF1A', 'Gene', (148, 155))	('CYCD2', 'Gene', (129, 134))	('PAX5', 'Gene', (142, 146))	('PAX5', 'Gene', '5079', (142, 146))	('CRC', 'Phenotype', 'HP:0003003', (190, 193))	('carcinogenesis', 'Disease', (48, 62))	('RB1', 'Gene', (157, 160))	('RASSF1A', 'Gene', '11186', (148, 155))
40611	25128828	Moreover, a genome-scale marker discovery approach revealed that analysis of methylated THBD and C9orf50 outperformed CEA serum measurement and resulted in a highly sensitive and specific test for the early detection of colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (220, 237))	('CEA', 'Gene', (118, 121))	('C9orf50', 'Gene', '375759', (97, 104))	('colorectal cancer', 'Disease', (220, 237))	('CEA', 'Gene', '5670', (118, 121))	('colorectal cancer', 'Disease', 'MESH:D015179', (220, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('C9orf50', 'Gene', (97, 104))	('outperformed', 'PosReg', (105, 117))	('THBD', 'Gene', (88, 92))	('methylated', 'Var', (77, 87))
40615	25128828	The first commercially available DNA methylation test for diagnosis of early CRC is the detection of SEPT9 methylation.	('SEPT9', 'Gene', (101, 106))	('DNA methylation', 'biological_process', 'GO:0006306', ('33', '48'))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('methylation', 'biological_process', 'GO:0032259', ('107', '118'))	('CRC', 'Phenotype', 'HP:0003003', (77, 80))	('SEPT9', 'Gene', '10801', (101, 106))	('methylation', 'Var', (107, 118))
40616	25128828	In a prospective trial with 7941 asymptomatic average risk individuals undergoing screening, the first generation of the SEPT9 methylation test detected up to 48.2% of cancer cases, with a specificity as 91.5%.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('methylation', 'Var', (127, 138))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('methylation', 'biological_process', 'GO:0032259', ('127', '138'))	('SEPT9', 'Gene', '10801', (121, 126))	('cancer', 'Disease', (168, 174))	('SEPT9', 'Gene', (121, 126))	('detected', 'Reg', (144, 152))
40618	25128828	Currently, blood-based assays that detect methylated SEPT9 are being marketed as colorectal cancer screening tests under names of Epi proColon 1.0 (Epigenomics), ColoVantage  (Quest Diagnostic) and RealTime ms9 (Abbott).	('SEPT9', 'Gene', (53, 58))	('colorectal cancer', 'Disease', (81, 98))	('methylated', 'Var', (42, 52))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))	('SEPT9', 'Gene', '10801', (53, 58))
40621	25128828	High incidence of NDRG4 and GATA4/5 methylation was found in colorectal adenomas and cancers.	('found', 'Reg', (52, 57))	('GATA4', 'Gene', (28, 33))	('colorectal adenomas and cancers', 'Disease', 'MESH:D015179', (61, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('NDRG4', 'Gene', (18, 23))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('NDRG4', 'Gene', '65009', (18, 23))	('GATA4', 'Gene', '2626', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('methylation', 'Var', (36, 47))
40623	25128828	The results demonstrated that aberrant methylation of NDRG4 was detected in more than 50% of fecal DNA from CRC patients with 100% specificity.	('methylation', 'Var', (39, 50))	('NDRG4', 'Gene', '65009', (54, 59))	('NDRG4', 'Gene', (54, 59))	('aberrant methylation', 'Var', (30, 50))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('patients', 'Species', '9606', (112, 120))	('CRC', 'Phenotype', 'HP:0003003', (108, 111))	('detected', 'Reg', (64, 72))	('DNA', 'cellular_component', 'GO:0005574', ('99', '102'))	('fecal DNA', 'Disease', (93, 102))	('CRC', 'Disease', (108, 111))
40624	25128828	In addition, GATA4 methylation in stool also differentiated CRC patients from healthy controls with high sensitivity (>50%) and specificity (>84%).	('methylation', 'Var', (19, 30))	('patients', 'Species', '9606', (64, 72))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('CRC', 'Disease', (60, 63))	('differentiated', 'Reg', (45, 59))	('GATA4', 'Gene', '2626', (13, 18))	('GATA4', 'Gene', (13, 18))	('CRC', 'Phenotype', 'HP:0003003', (60, 63))
40625	25128828	Methylation of Oncostatin M receptor-B (OSMR), which is an intelukin-6 cytokine family member, was also detected in the stool of 38% of CRC patients with 95% specificity.	('detected', 'Reg', (104, 112))	('Oncostatin M receptor-B', 'Gene', '9180', (15, 38))	('CRC', 'Phenotype', 'HP:0003003', (136, 139))	('OSMR', 'Gene', (40, 44))	('Methylation', 'Var', (0, 11))	('OSMR', 'Gene', '9180', (40, 44))	('patients', 'Species', '9606', (140, 148))	('CRC', 'Disease', (136, 139))	('Oncostatin M receptor-B', 'Gene', (15, 38))
40627	25128828	A more recent study revealed that hyper-methylated FBN1 was found in stool DNA from CRC patients and showed 72% sensitivity and >90% specificity for detecting CRC.	('FBN1', 'Gene', '2200', (51, 55))	('patients', 'Species', '9606', (88, 96))	('CRC', 'Phenotype', 'HP:0003003', (159, 162))	('CRC', 'Disease', (84, 87))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('FBN1', 'Gene', (51, 55))	('CRC', 'Phenotype', 'HP:0003003', (84, 87))	('hyper-methylated', 'Var', (34, 50))	('CRC', 'Disease', (159, 162))
40628	25128828	Another study from our laboratory demonstrated that methylation of RASSF2 and SFRP2 promoters in fecal DNA from patients with gastric and colorectal cancer had a very high sensitivity and specificity in identifying cancer patients, as well as allowed discriminating between patients with GC vs. CRC.	('SFRP2', 'Gene', (78, 83))	('patients', 'Species', '9606', (222, 230))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('cancer', 'Disease', (215, 221))	('patients', 'Species', '9606', (274, 282))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('labor', 'Disease', (23, 28))	('cancer', 'Disease', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('methylation', 'Var', (52, 63))	('SFRP2', 'Gene', '6423', (78, 83))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))	('RASSF2', 'Gene', '9770', (67, 73))	('gastric', 'Disease', (126, 133))	('CRC', 'Phenotype', 'HP:0003003', (295, 298))	('labor', 'Disease', 'MESH:D048949', (23, 28))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('RASSF2', 'Gene', (67, 73))	('patients', 'Species', '9606', (112, 120))	('colorectal cancer', 'Disease', (138, 155))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('GC', 'Phenotype', 'HP:0012126', (288, 290))
40631	25128828	Collectively, these findings are encouraging, and build the promise that the performance of methylation testing in fecal DNA is reasonably accurate and perhaps better than conventional FOBT, which has a sensitivity of less than 15% for the detection of CRC or adenoma and a specificity of over 90%.	('adenoma', 'Disease', (260, 267))	('methylation testing', 'Var', (92, 111))	('CRC', 'Disease', (253, 256))	('CRC', 'Phenotype', 'HP:0003003', (253, 256))	('adenoma', 'Disease', 'MESH:D000236', (260, 267))
40634	25128828	Those transcripts that are shorter than 200 nucleotides (nt) are usually recognized as small ncRNAs, which include Piwi-interacting RNAs, small-interfering RNAs, micro-RNAs (miRNAs) and some bacterial-regulatory RNAs.	('small-interfering', 'Var', (138, 155))	('miR', 'Gene', '220972', (174, 177))	('miR', 'Gene', (174, 177))
40742	25128828	In recent years, the role of epigenetic alterations in carcinogenesis has received greater attention than before.	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('epigenetic alterations', 'Var', (29, 51))	('carcinogenesis', 'Disease', (55, 69))
40745	25128828	Undoubtedly, the clinical significance of epigenetic markers individually, or as biomarker panels, is poised to lead the way for the development of actionable, highly promising assays that will play a pivotal role in the personalized care of patients suffering from this highly morbid cancers.	('cancers', 'Disease', (285, 292))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('epigenetic', 'Var', (42, 52))	('cancers', 'Phenotype', 'HP:0002664', (285, 292))	('cancers', 'Disease', 'MESH:D009369', (285, 292))	('clinical', 'Species', '191496', (17, 25))	('patients', 'Species', '9606', (242, 250))
40756	24022702	Mutations in many of the known cancer genes, so-called 'mountains' (genes altered in a high percentage of tumors), were discovered by focused sanger sequencing or cytogenetic analyses, some of which express mutated proteins that have become successful drug targets.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('mutated', 'Var', (207, 214))	('Mutations', 'Var', (0, 9))	('proteins', 'Protein', (215, 223))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Disease', (31, 37))
40758	24022702	These pioneering studies led to the identification of a highly recurrent mutation in a novel oncogene, isocitrate dehydrogenase 1 (IDH1), involved in both cell metabolism and DNA methylation, reinforcing the promise of unbiased genomic sequencing in the identification of novel genetic driving events in human cancers.	('cancers', 'Disease', 'MESH:D009369', (310, 317))	('cancers', 'Phenotype', 'HP:0002664', (310, 317))	('IDH1', 'Gene', (131, 135))	('cancers', 'Disease', (310, 317))	('IDH1', 'Gene', '3417', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('isocitrate dehydrogenase 1', 'Gene', (103, 129))	('isocitrate dehydrogenase 1', 'Gene', '3417', (103, 129))	('mutation', 'Var', (73, 81))	('human', 'Species', '9606', (304, 309))
40759	24022702	The advancement in NGS technology has allowed the cancer research community to employ systematic sequencing to identify additional 'mountains', which include the discovery of frequent mutations in epigenetic regulators and pre-mRNA splicing machinery in many cancers (Figure 1 and described in detail below), and so-called 'hills' (genes altered less frequently in cancer).	('cancer', 'Disease', (365, 371))	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('epigenetic regulators', 'Gene', (197, 218))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('223', '240'))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('mutations', 'Var', (184, 193))	('cancers', 'Disease', (259, 266))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('pre', 'molecular_function', 'GO:0003904', ('223', '226'))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (365, 371))	('cancer', 'Disease', (259, 265))
40765	24022702	We review WES and WGS studies that have provided the clearest landscape of somatic mutations in major adult tumor types (majority of which involve deep sequencing analyses of the coding exomes and whole genomes of 20 or more samples per study), TCGA and ICGC publications, as well as a few examples of rare malignancies and cancers more prevalent in diverse geographical regions (a selection of studies is summarized in Table 1).	('mutations', 'Var', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('malignancies and cancers', 'Disease', 'MESH:D009369', (307, 331))	('adult tumor', 'Disease', 'MESH:C538052', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('adult tumor', 'Disease', (102, 113))	('cancers', 'Phenotype', 'HP:0002664', (324, 331))
40769	24022702	For example, the mutation rates for pediatric and haematological cancers possess the lowest mutation rates (~1 mutations/Mb for chronic lymphocytic leukemia (CLL)), compared to cancers where environmental mutagens are known to increase the mutation burden, such as melanoma and lung cancer (~15 mutations/Mb for melanoma).	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (128, 156))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('chronic lymphocytic leukemia', 'Disease', (128, 156))	('cancers', 'Disease', (65, 72))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))	('lowest', 'NegReg', (85, 91))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (128, 156))	('mutation', 'Var', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('melanoma', 'Disease', 'MESH:D008545', (312, 320))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (278, 289))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('haematological cancers', 'Disease', (50, 72))	('melanoma', 'Disease', (265, 273))	('haematological cancers', 'Disease', 'MESH:D009369', (50, 72))	('melanoma and lung cancer', 'Disease', 'MESH:D008175', (265, 289))	('mutation', 'MPA', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (312, 320))	('melanoma', 'Disease', (312, 320))
40770	24022702	In addition, mutation rates can vary tremendously within a cancer type, often due to the degree of exposure to an environmental mutagen, or dependent on which genes are mutated (e.g.	('mutation', 'Var', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('due', 'Reg', (78, 81))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
40771	24022702	tumors possessing mutations in mismatch repair genes).	('tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Disease', (0, 6))	('mismatch repair genes', 'Gene', (31, 52))	('tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (18, 27))
40773	24022702	For example, clustering analysis on all possible mutations (considering context of flanking residues) demonstrated natural groupings of mutation spectrum and cancer types consistent with known signatures of carcinogenesis mechanisms: lung tumors possess a high fraction of G>T transversions, attributable to exposure of polycyclic aromatic hydrocarbons from tobacco smoke; melanomas possess a high fraction of C>T transitions in dipyrimidines caused by UV-induced DNA damage and misrepair; gastrointestinal tumors (oesophageal, colorectal and gastric) possess a high frequency of transition mutations at CpG dinucleotides that may be a reflection of elevated methylation levels in these tumors; cervical, bladder, some head-and-neck and breast cancers possess frequent mutations at Cs in the context of TpC, characteristic mutations caused by the APOBEC family of cytidine deaminases; and leukemic samples (acute myeloid leukaemia (AML) and CLL) possess A to T mutations in the TpA context.	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('leukemic', 'Disease', 'MESH:D007938', (889, 897))	('breast cancer', 'Phenotype', 'HP:0003002', (737, 750))	('methylation', 'biological_process', 'GO:0032259', ('659', '670'))	('TpA', 'molecular_function', 'GO:0031299', ('978', '981'))	('AML', 'Disease', 'MESH:D015470', (932, 935))	('cancer', 'Disease', 'MESH:D009369', (744, 750))	('melanoma', 'Phenotype', 'HP:0002861', (373, 381))	('leukemic', 'Disease', (889, 897))	('lung tumors', 'Disease', (234, 245))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (907, 930))	('melanomas', 'Phenotype', 'HP:0002861', (373, 382))	('tumor', 'Phenotype', 'HP:0002664', (507, 512))	('AML', 'Phenotype', 'HP:0004808', (932, 935))	('tumors', 'Disease', (507, 513))	('AML', 'Disease', (932, 935))	('tumors', 'Disease', (239, 245))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (490, 513))	('dipyrimidines', 'Chemical', '-', (429, 442))	('colorectal', 'Disease', 'MESH:D015179', (528, 538))	('tumors', 'Phenotype', 'HP:0002664', (687, 693))	('cancer', 'Disease', (158, 164))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (907, 930))	('mutations', 'Var', (769, 778))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (687, 692))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (507, 513))	('cancers', 'Phenotype', 'HP:0002664', (744, 751))	('APOBEC', 'cellular_component', 'GO:0030895', ('847', '853'))	('tumors', 'Disease', (687, 693))	('cancer', 'Disease', (744, 750))	('acute myeloid leukaemia', 'Disease', (907, 930))	('breast cancers', 'Disease', 'MESH:D001943', (737, 751))	('tobacco', 'Species', '4097', (358, 365))	('breast cancers', 'Disease', (737, 751))	('melanomas', 'Disease', 'MESH:D008545', (373, 382))	('cancer', 'Phenotype', 'HP:0002664', (744, 750))	('gastrointestinal tumors', 'Disease', (490, 513))	('lung tumors', 'Disease', 'MESH:D008175', (234, 245))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (604, 621))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (490, 513))	('carcinogenesis', 'Disease', (207, 221))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('melanomas', 'Disease', (373, 382))	('tumors', 'Disease', 'MESH:D009369', (687, 693))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('DNA', 'cellular_component', 'GO:0005574', ('464', '467'))	('colorectal', 'Disease', (528, 538))	('lung tumors', 'Phenotype', 'HP:0100526', (234, 245))	('breast cancers', 'Phenotype', 'HP:0003002', (737, 751))	('neck', 'cellular_component', 'GO:0044326', ('728', '732'))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (913, 930))	('carcinogenesis', 'Disease', 'MESH:D063646', (207, 221))	('tumors', 'Phenotype', 'HP:0002664', (507, 513))
40775	24022702	Identifying which mutations are likely to be 'drivers' in pathogenesis and elucidating how mutated genes affect the biology of a given tumor, are fundamental challenges in cancer genomics.	('mutations', 'Var', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('affect', 'Reg', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
40780	24022702	The Sanger-sequencing of 20,661 protein coding genes from 22 glioblastoma samples mentioned above revealed a recurrent heterozygous IDH1 mutation targeting amino acid R132 in 12% of samples, which correlated with improved patient survival.	('IDH1', 'Gene', (132, 136))	('improved', 'PosReg', (213, 221))	('IDH1', 'Gene', '3417', (132, 136))	('glioblastoma', 'Disease', (61, 73))	('patient', 'Species', '9606', (222, 229))	('glioblastoma', 'Disease', 'MESH:D005909', (61, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (61, 73))	('mutation targeting amino acid R132', 'Var', (137, 171))
40781	24022702	In parallel, glioblastoma was the first cancer to undergo comprehensive genomic characterization by TCGA Research Network, which used a targeted approach consisting of Sanger-based capillary sequencing of 601 selected genes in 91 glioblastoma tumor-normal pairs to identify somatic mutations, which revealed frequent mutations in the phosphatidylinositol 3-kinase (PI3K) regulatory subunit, PIK3R1.	('mutations', 'Var', (317, 326))	('PIK3R1', 'Gene', '5295', (391, 397))	('glioblastoma', 'Disease', (13, 25))	('PI3K', 'molecular_function', 'GO:0016303', ('365', '369'))	('PIK3R1', 'Gene', (391, 397))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('glioblastoma', 'Disease', 'MESH:D005909', (13, 25))	('glioblastoma', 'Disease', (230, 242))	('cancer', 'Disease', (40, 46))	('glioblastoma', 'Disease', 'MESH:D005909', (230, 242))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('glioblastoma', 'Phenotype', 'HP:0012174', (230, 242))	('glioblastoma tumor', 'Disease', 'MESH:D005909', (230, 248))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('glioblastoma tumor', 'Disease', (230, 248))
40784	24022702	Investigation of RNA sequencing (RNA-seq) data from glioblastomas also revealed translocations involving fibroblast growth factor receptor (FGFR) genes to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, in approximately 3% (3/97) of cases.	('translocations', 'Var', (80, 94))	('FGFR', 'Gene', (140, 144))	('TACC3', 'Gene', '10460', (225, 230))	('TACC1', 'Gene', (216, 221))	('TACC3', 'Gene', (225, 230))	('glioblastomas', 'Phenotype', 'HP:0012174', (52, 65))	('glioblastomas', 'Disease', 'MESH:D005909', (52, 65))	('glioblastomas', 'Disease', (52, 65))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))	('TACC1', 'Gene', '6867', (216, 221))
40786	24022702	Somatic or germline inactivating mutations in the tumor suppressor gene, von Hippel-Lindau (VHL), a master regulator of HIF transcription factors and the hypoxia response, are found in most clear-cell renal-cell carcinoma (ccRCC) cases (somatic mutations reported in >55% of sporadic ccRCC).	('renal-cell carcinoma', 'Disease', (201, 221))	('hypoxia', 'Disease', 'MESH:D000860', (154, 161))	('germline inactivating mutations', 'Var', (11, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('50', '66'))	('found', 'Reg', (176, 181))	('transcription', 'biological_process', 'GO:0006351', ('124', '137'))	('renal-cell carcinoma', 'Disease', 'MESH:C538614', (201, 221))	('VHL', 'Gene', (92, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('ccRCC', 'Phenotype', 'HP:0006770', (223, 228))	('tumor', 'Disease', (50, 55))	('clear-cell renal-cell carcinoma', 'Phenotype', 'HP:0006770', (190, 221))	('von Hippel-Lindau', 'Gene', (73, 90))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('VHL', 'Gene', '7428', (92, 95))	('renal-cell carcinoma', 'Phenotype', 'HP:0005584', (201, 221))	('ccRCC', 'Phenotype', 'HP:0006770', (284, 289))	('hypoxia', 'Disease', (154, 161))	('von Hippel-Lindau', 'Gene', '7428', (73, 90))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('50', '66'))
40788	24022702	Indeed, focused Sanger sequencing revealed mutations in neurofibromin 2 (NF2) and in genes involved in histone methylation and demethylation: SETD2, JARID1c (also known as KDM5C) and UTX (also known as KMD6A) (Box 3 and Figure 1a).	('demethylation', 'biological_process', 'GO:0070988', ('127', '140'))	('neurofibromin 2', 'Gene', (56, 71))	('UTX', 'Gene', (183, 186))	('histone methylation', 'biological_process', 'GO:0016571', ('103', '122'))	('NF2', 'Gene', (73, 76))	('neurofibromin 2', 'Gene', '4771', (56, 71))	('JARID1c', 'Gene', '8242', (149, 156))	('UTX', 'Gene', '7403', (183, 186))	('mutations', 'Var', (43, 52))	('KDM5C', 'Gene', (172, 177))	('NF2', 'Gene', '4771', (73, 76))	('SETD2', 'Gene', '29072', (142, 147))	('KDM5C', 'Gene', '8242', (172, 177))	('JARID1c', 'Gene', (149, 156))	('SETD2', 'Gene', (142, 147))
40791	24022702	The importance of the PBAF complex was initially suggested from studies that found inactivating mutations in its core component, SMARCB1 (SNF5), in rhabdoid tumors.	('inactivating mutations', 'Var', (83, 105))	('SNF5', 'Gene', (138, 142))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (148, 163))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('SMARCB1', 'Gene', '6598', (129, 136))	('SNF5', 'Gene', '6598', (138, 142))	('SMARCB1', 'Gene', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('rhabdoid tumors', 'Disease', (148, 163))
40793	24022702	A second WES study identified frequent mutations in the two-hit tumor suppressor BRCA1-associated protein-1 (BAP1) in ccRCC, previously found to be frequently mutated in uveal melanoma and pleural mesothelioma, that functions as a deubiquitinating enzyme and regulator of histone H2A lysine 119 ubiquitination (Figure 1a).	('uveal melanoma', 'Disease', 'MESH:C536494', (170, 184))	('deubiquitinating enzyme', 'molecular_function', 'GO:0004843', ('231', '254'))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('uveal melanoma', 'Disease', (170, 184))	('BAP1', 'Gene', '8314', (109, 113))	('lysine', 'Chemical', 'MESH:D008239', (284, 290))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('BRCA1-associated protein-1', 'Gene', '8314', (81, 107))	('uveal melanoma', 'Phenotype', 'HP:0007716', (170, 184))	('BRCA1-associated protein-1', 'Gene', (81, 107))	('mutations', 'Var', (39, 48))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (189, 209))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('64', '80'))	('protein', 'cellular_component', 'GO:0003675', ('98', '105'))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (189, 209))	('BAP1', 'Gene', (109, 113))	('ccRCC', 'Disease', (118, 123))	('tumor suppressor', 'biological_process', 'GO:0051726', ('64', '80'))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('pleural mesothelioma', 'Disease', (189, 209))
40794	24022702	Interestingly, mutations in BAP1 and PBRM1 were anti-correlated, and tumors possessing BAP1 mutations were associated with high tumor grade.	('PBRM1', 'Gene', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('BAP1', 'Gene', '8314', (87, 91))	('BAP1', 'Gene', '8314', (28, 32))	('PBRM1', 'Gene', '55193', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('associated', 'Reg', (107, 117))	('mutations', 'Var', (15, 24))	('BAP1', 'Gene', (28, 32))	('BAP1', 'Gene', (87, 91))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
40795	24022702	Recent efforts from a larger WES/WGS study and TCGA confirmed PBRM1, SETD2, KDM5C and BAP1 to be significantly mutated in a cohort of 417 ccRCC tumors, as well as a novel hotspot mutation in a component the VHL E3 ligase complex, TCEB1.	('tumors', 'Disease', (144, 150))	('KDM5C', 'Gene', '8242', (76, 81))	('mutated', 'Var', (111, 118))	('VHL', 'Gene', '7428', (207, 210))	('BAP1', 'Gene', '8314', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('PBRM1', 'Gene', '55193', (62, 67))	('KDM5C', 'Gene', (76, 81))	('TCEB1', 'Gene', (230, 235))	('BAP1', 'Gene', (86, 90))	('PBRM1', 'Gene', (62, 67))	('SETD2', 'Gene', (69, 74))	('ccRCC', 'Disease', (138, 143))	('TCEB1', 'Gene', '6921', (230, 235))	('VHL', 'Gene', (207, 210))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('SETD2', 'Gene', '29072', (69, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
40796	24022702	Importantly, TCGA was able to show widespread DNA hypomethylation in SETD2-mutant tumors and transcriptional network analysis suggest mutations in the chromatin remodeling complex (PBRM1, ARID1A, and SMARCA4) are linked to RAS signaling, immune function, DNA repair, beta-catenin and TGF-beta signaling.	('DNA', 'cellular_component', 'GO:0005574', ('46', '49'))	('tumors', 'Disease', (82, 88))	('ARID1A', 'Gene', '8289', (188, 194))	('signaling', 'biological_process', 'GO:0023052', ('227', '236'))	('SMARCA4', 'Gene', (200, 207))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('151', '171'))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('DNA repair', 'biological_process', 'GO:0006281', ('255', '265'))	('PBRM1', 'Gene', '55193', (181, 186))	('mutations', 'Var', (134, 143))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('151', '179'))	('linked', 'Reg', (213, 219))	('PBRM1', 'Gene', (181, 186))	('signaling', 'biological_process', 'GO:0023052', ('293', '302'))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('beta-catenin', 'Gene', (267, 279))	('SETD2', 'Gene', (69, 74))	('SMARCA4', 'Gene', '6597', (200, 207))	('beta-catenin', 'Gene', '1499', (267, 279))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('ARID1A', 'Gene', (188, 194))	('SETD2', 'Gene', '29072', (69, 74))	('DNA', 'cellular_component', 'GO:0005574', ('255', '258'))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('46', '65'))
40797	24022702	RNA-seq analysis also revealed recurrent SFPQ-TEF3 fusions found by in 5/416 samples, all five lacking a VHL mutation.	('VHL', 'Gene', (105, 108))	('TEF3', 'Gene', '7004', (46, 50))	('VHL', 'Gene', '7428', (105, 108))	('SFPQ', 'Gene', '6421', (41, 45))	('TEF3', 'Gene', (46, 50))	('fusions', 'Var', (51, 58))	('SFPQ', 'Gene', (41, 45))
40798	24022702	A first global view of the somatic mutations in HNSCC was published in two studies in 2011, based on WES characterization of 32 and 74 HNSCC tumor-normal pairs, respectively.	('SCC', 'Phenotype', 'HP:0002860', (137, 140))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (135, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('HNSCC tumor', 'Disease', (135, 146))	('HNSCC', 'Gene', (48, 53))	('SCC', 'Phenotype', 'HP:0002860', (50, 53))	('mutations', 'Var', (35, 44))
40803	24022702	also looked for enrichment in functional gene sets among the list of SMGs and discovered that the highest scoring set was involved in epidermal development, particularly in squamous cell differentiation, pointing to disruption of the stratified squamous differentiation program as a candidate route to HNSCC.	('cell differentiation', 'biological_process', 'GO:0030154', ('182', '202'))	('involved', 'Reg', (122, 130))	('squamous cell', 'Disease', (173, 186))	('disruption', 'Var', (216, 226))	('epidermal development', 'CPA', (134, 155))	('SMG', 'Gene', (69, 72))	('SCC', 'Phenotype', 'HP:0002860', (304, 307))	('SMG', 'Gene', '23034', (69, 72))
40804	24022702	Both studies identified previously unrecognized NOTCH1 mutations in HNSCC in approximately 10-15% of samples.	('mutations', 'Var', (55, 64))	('HNSCC', 'Gene', (68, 73))	('NOTCH1', 'Gene', '4851', (48, 54))	('SCC', 'Phenotype', 'HP:0002860', (70, 73))	('NOTCH1', 'Gene', (48, 54))
40805	24022702	Although oncogenic activating NOTCH1 mutations have been observed in a number of hematological malignancies, the mutations in NOTCH1 identified in HNSCC possessed characteristics indicative of loss of function (LOF) mutations, hence suggesting a tumor-suppressive role in this cancer.	('a tumor', 'Disease', (244, 251))	('hematological malignancies', 'Disease', (81, 107))	('NOTCH1', 'Gene', '4851', (30, 36))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('NOTCH1', 'Gene', '4851', (126, 132))	('NOTCH1', 'Gene', (126, 132))	('hematological malignancies', 'Disease', 'MESH:D019337', (81, 107))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('SCC', 'Phenotype', 'HP:0002860', (149, 152))	('NOTCH1', 'Gene', (30, 36))	('mutations', 'Var', (37, 46))	('mutations', 'Var', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('hematological malignancies', 'Phenotype', 'HP:0004377', (81, 107))	('a tumor', 'Disease', 'MESH:D009369', (244, 251))	('loss of function', 'NegReg', (193, 209))	('HNSCC', 'Disease', (147, 152))
40808	24022702	This example highlights the increasingly recognized context-dependent nature of cancer gene functions and that different mutations of the same gene likely confer different cancer-relevant biological activities (Box 4), adding to the complexity of applying genomic information in therapeutic decisions.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('mutations', 'Var', (121, 130))	('confer', 'Reg', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (80, 86))
40810	24022702	Although 9 SMGs were identified using two algorithms (MutSig and MuSiC), the landscape of somatic mutations in this cancer type was dominated by near universal presence of TP53 mutations (found in 96% of samples).	('TP53', 'Gene', '7157', (172, 176))	('TP53', 'Gene', (172, 176))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('mutations', 'Var', (177, 186))	('SMG', 'Gene', (11, 14))	('presence', 'Reg', (160, 168))	('SMG', 'Gene', '23034', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
40813	24022702	The discovery of the BRAF V600E mutation in over 50% of melanomas in 2002 and the subsequent development of an inhibitor to treat patients with BRAF-mutant metastatic disease is the proof-of-concept for genomics-informed personalized therapy.	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('BRAF', 'Gene', '673', (21, 25))	('V600E', 'Mutation', 'rs113488022', (26, 31))	('BRAF', 'Gene', '673', (144, 148))	('patients', 'Species', '9606', (130, 138))	('melanomas', 'Disease', (56, 65))	('BRAF', 'Gene', (21, 25))	('BRAF', 'Gene', (144, 148))	('V600E', 'Var', (26, 31))	('melanomas', 'Disease', 'MESH:D008545', (56, 65))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
40814	24022702	It is known that an additional 20% of melanomas are characterized by recurrent NRAS hotspot mutations; however, the driver mutations in the remaining melanoma cases remain poorly understood.	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('NRAS', 'Gene', '4893', (79, 83))	('melanomas', 'Disease', (38, 47))	('mutations', 'Var', (92, 101))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanomas', 'Phenotype', 'HP:0002861', (38, 47))	('melanoma', 'Disease', (150, 158))	('melanomas', 'Disease', 'MESH:D008545', (38, 47))	('melanoma', 'Disease', (38, 46))	('NRAS', 'Gene', (79, 83))
40815	24022702	The search for additional driver mutations in melanoma has been complicated by the fact that melanoma has the highest basal mutation rate of any cancer sequenced to date, which can be almost entirely attributable to the abundance of UV-induced C>T transitions in dipyrimidines.	('cancer', 'Disease', (145, 151))	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('basal', 'MPA', (118, 123))	('dipyrimidines', 'Chemical', '-', (263, 276))	('C>T transitions', 'Var', (244, 259))
40819	24022702	This method led to the identification of several novel SMGs, many of which harbored hotspot mutations, a pattern of mutation that signifies strong biological selection.	('SMG', 'Gene', (55, 58))	('SMG', 'Gene', '23034', (55, 58))	('harbored', 'Reg', (75, 83))	('mutations', 'Var', (92, 101))
40824	24022702	Significant progress in personalized treatment for this disease has been made in recent years with the demonstration that epidermal growth factor receptor (EGFR)-activating mutations or gene fusion events involving the receptor tyrosine kinase gene ALK identify NSCLC patients who are responsive to inhibitors of these tyrosine kinases (reviewed in).	('NSCLC', 'Disease', (262, 267))	('epidermal growth factor receptor', 'Gene', (122, 154))	('EGFR', 'molecular_function', 'GO:0005006', ('156', '160'))	('ALK', 'Gene', (249, 252))	('EGFR', 'Gene', '1956', (156, 160))	('epidermal growth factor receptor', 'Gene', '1956', (122, 154))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('122', '145'))	('mutations', 'Var', (173, 182))	('NSCLC', 'Disease', 'MESH:D002289', (262, 267))	('EGFR', 'Gene', (156, 160))	('gene fusion', 'Var', (186, 197))	('ALK', 'Gene', '238', (249, 252))	('patients', 'Species', '9606', (268, 276))
40829	24022702	The authors found that mutations in U2 small nuclear RNA auxiliary factor 1 (U2AF1) (Figure 1b) and TP53 correlated negatively with progression-free survival.	('TP53', 'Gene', '7157', (100, 104))	('small nuclear RNA', 'molecular_function', 'GO:0005570', ('39', '56'))	('TP53', 'Gene', (100, 104))	('U2AF', 'cellular_component', 'GO:0089701', ('77', '81'))	('RNA', 'cellular_component', 'GO:0005562', ('53', '56'))	('progression-free survival', 'CPA', (132, 157))	('mutations', 'Var', (23, 32))	('U2AF1', 'Gene', (77, 82))	('negatively', 'NegReg', (116, 126))	('U2AF1', 'Gene', '7307', (77, 82))
40830	24022702	Together with frequent mutations in RNA binding motif protein 10 (RBM10), the mutations in U2AF1 point towards a role for RNA splicing deregulation in lung cancer as seen in a number of hematological malignancies (Figure 1b and described in detail below).	('RBM10', 'Gene', '8241', (66, 71))	('RNA binding motif protein 10', 'Gene', '8241', (36, 64))	('hematological malignancies', 'Phenotype', 'HP:0004377', (186, 212))	('RBM10', 'Gene', (66, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('RNA binding motif protein 10', 'Gene', (36, 64))	('mutations', 'Var', (78, 87))	('lung cancer', 'Disease', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('U2AF1', 'Gene', (91, 96))	('U2AF1', 'Gene', '7307', (91, 96))	('hematological malignancies', 'Disease', (186, 212))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('hematological malignancies', 'Disease', 'MESH:D019337', (186, 212))	('RNA', 'MPA', (122, 125))
40832	24022702	These included previously unreported LOF mutations in HLA-A and widespread TP53 mutations in nearly all samples analyzed.	('mutations', 'Var', (41, 50))	('HLA-A', 'Gene', '3105', (54, 59))	('mutations', 'Var', (80, 89))	('HLA-A', 'Gene', (54, 59))	('LOF', 'NegReg', (37, 40))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))
40833	24022702	Integrative analysis identified pathways frequently deregulated in lung SCC, which included confirmation of the oxidative stress response due to frequent mutations and SCNAs in the CUL3 and KEAP1 components of an E3 ubiquitin ligase and its target substrate, NFE2L2, in 34% of samples (Box 3).	('deregulated', 'Reg', (52, 63))	('lung SCC', 'Disease', (67, 75))	('oxidative stress', 'Phenotype', 'HP:0025464', (112, 128))	('CUL3', 'Gene', '8452', (181, 185))	('oxidative stress response', 'MPA', (112, 137))	('CUL3', 'Gene', (181, 185))	('E3 ubiquitin ligase', 'Enzyme', (213, 232))	('KEAP1', 'Gene', '9817', (190, 195))	('NFE2L2', 'Gene', '4780', (259, 265))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('NFE2L2', 'Gene', (259, 265))	('mutations', 'Var', (154, 163))	('KEAP1', 'Gene', (190, 195))
40834	24022702	took into account gene expression levels in their significance analysis to identify 22 SMGs (Supplementary Figure 1), including frequent mutations and SCNAs in SOX family members not previously recognized in SCLC.	('SCLC', 'Disease', (208, 212))	('SCLC', 'Disease', 'MESH:D018288', (208, 212))	('mutations', 'Var', (137, 146))	('gene expression', 'biological_process', 'GO:0010467', ('18', '33'))	('SMG', 'Gene', (87, 90))	('SMG', 'Gene', '23034', (87, 90))
40838	24022702	An analysis of WES data from 112 treatment-naive prostate adenocarcinoma-normal pairs identified 12 SMGs (Supplementary Figure 1); notably, SPOP, a substrate-binding subunit of a Cullin-based E3 ubiquitin ligase complex, was mutated in ~13% of samples.	('binding', 'molecular_function', 'GO:0005488', ('158', '165'))	('ubiquitin ligase complex', 'cellular_component', 'GO:0000151', ('195', '219'))	('SPOP', 'Gene', (140, 144))	('prostate adenocarcinoma', 'Disease', (49, 72))	('ubiquitin', 'molecular_function', 'GO:0031386', ('195', '204'))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (49, 72))	('mutated', 'Var', (225, 232))	('SMG', 'Gene', (100, 103))	('SPOP', 'Gene', '8405', (140, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('SMG', 'Gene', '23034', (100, 103))
40844	24022702	These were characterized by high levels of microsatellite instability (MSI), frequent epigenetic silencing of the DNA mismatch-repair pathway gene, MLH1, mutations in other mismatch repair genes or a DNA polymerase catalytic subunit, POLE, providing molecular insights into the underlying causes for the elevated mutation rate.	('MSI', 'Disease', (71, 74))	('mismatch repair', 'biological_process', 'GO:0006298', ('173', '188'))	('MLH1', 'Gene', (148, 152))	('MSI', 'Disease', 'None', (71, 74))	('mutations', 'Var', (154, 163))	('mismatch-repair', 'biological_process', 'GO:0006298', ('118', '133'))	('MLH1', 'Gene', '4292', (148, 152))	('epigenetic', 'MPA', (86, 96))	('microsatellite instability', 'MPA', (43, 69))	('DNA', 'cellular_component', 'GO:0005574', ('200', '203'))	('DNA', 'cellular_component', 'GO:0005574', ('114', '117'))
40845	24022702	Interestingly, the hypermutated samples possessed few SCNAs and harbored frequent concurrent BRAF V600E mutations.	('BRAF', 'Gene', (93, 97))	('BRAF', 'Gene', '673', (93, 97))	('V600E', 'Var', (98, 103))	('V600E', 'Mutation', 'rs113488022', (98, 103))
40847	24022702	The two signature genes of CRC, TP53 and the WNT signaling pathway antagonist APC, were found to be more frequently mutated in the non-hypermutated tumors.	('CRC', 'Gene', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('APC', 'Disease', 'MESH:D011125', (78, 81))	('TP53', 'Gene', '7157', (32, 36))	('APC', 'Disease', (78, 81))	('TP53', 'Gene', (32, 36))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('CRC', 'Phenotype', 'HP:0030731', (27, 30))	('mutated', 'Var', (116, 123))
40850	24022702	The RSPO fusions were found to be mutually exclusive with APC mutations, and exogenous expression of plasmids encoding fusions were shown to activate WNT signaling in a human colon cancer cell line.	('WNT signaling', 'Pathway', (150, 163))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('APC', 'Disease', 'MESH:D011125', (58, 61))	('colon cancer', 'Phenotype', 'HP:0003003', (175, 187))	('RSPO', 'Gene', '284654', (4, 8))	('fusions', 'Var', (119, 126))	('APC', 'Disease', (58, 61))	('colon cancer', 'Disease', 'MESH:D015179', (175, 187))	('activate', 'PosReg', (141, 149))	('RSPO', 'Gene', (4, 8))	('human', 'Species', '9606', (169, 174))	('colon cancer', 'Disease', (175, 187))
40851	24022702	In a separate WGS study, a recurrent fusion of VTI1A and TCF7L2 (encodes a WNT signaling effector, TCF4 transcription factor) was found in 3/97 of colorectal cancer samples, and a colorectal carcinoma cell line harboring the fusion was shown to be dependent on its expression for anchorage-independent growth.	('TCF7L2', 'Gene', (57, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('colorectal cancer', 'Disease', (147, 164))	('transcription factor', 'molecular_function', 'GO:0000981', ('104', '124'))	('colorectal carcinoma', 'Disease', (180, 200))	('TCF7L2', 'Gene', '6934', (57, 63))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (180, 200))	('VTI1A', 'Gene', (47, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('VTI1A', 'Gene', '143187', (47, 52))	('transcription', 'biological_process', 'GO:0006351', ('104', '117'))	('found', 'Reg', (130, 135))	('colorectal cancer', 'Disease', 'MESH:D015179', (147, 164))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('fusion', 'Var', (37, 43))	('TCF4', 'Gene', (99, 103))	('TCF4', 'Gene', '6925', (99, 103))
40855	24022702	Interestingly, a member of the SWI/SNF chromatin remodeling family, ARID1A, was found to be mutated more frequently and had decreased expression in MSI (83%) and Epstein-Barr virus (EBV)-infected MSS (73%) gastric cancers, compared to non-EBV-infected MSS cancers (11%).	('cancers', 'Phenotype', 'HP:0002664', (256, 263))	('ARID1A', 'Gene', (68, 74))	('MSI', 'Disease', 'None', (148, 151))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('MSI', 'Disease', (148, 151))	('ARID1A', 'Gene', '8289', (68, 74))	('chromatin', 'cellular_component', 'GO:0000785', ('39', '48'))	('non-EBV-infected MSS cancers', 'Disease', 'MESH:D013132', (235, 263))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('mutated', 'Var', (92, 99))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('39', '59'))	('expression', 'MPA', (134, 144))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('Epstein-Barr virus (EBV)-infected MSS', 'Disease', 'MESH:D020031', (162, 199))	('gastric cancers', 'Disease', 'MESH:D013274', (206, 221))	('gastric cancers', 'Disease', (206, 221))	('gastric cancers', 'Phenotype', 'HP:0012126', (206, 221))	('non-EBV-infected MSS cancers', 'Disease', (235, 263))	('gastric cancer', 'Phenotype', 'HP:0012126', (206, 220))	('decreased', 'NegReg', (124, 133))
40856	24022702	Alterations in ARID1A were also predictive of improved disease-free survival, suggesting deregulation of the SWI/SNF complex represents a unique mechanism of carcinogenesis associated with a distinct clinical behavior.	('ARID1A', 'Gene', (15, 21))	('deregulation', 'Var', (89, 101))	('Alterations', 'Var', (0, 11))	('carcinogenesis', 'Disease', 'MESH:D063646', (158, 172))	('disease-free survival', 'CPA', (55, 76))	('improved', 'PosReg', (46, 54))	('carcinogenesis', 'Disease', (158, 172))	('SWI/SNF', 'Gene', (109, 116))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('109', '124'))	('ARID1A', 'Gene', '8289', (15, 21))
40858	24022702	Recently, a number of large-scale WES and WGS studies of breast cancer have developed new algorithms to reconstruct the clonal evolution of the tumors (Box 5), shedding light on the mutational processes responsible for the generation of somatic mutations in breast cancer in addition to identifying SMGs that correlated with well-established clinically relevant subtypes.	('tumors', 'Disease', (144, 150))	('breast cancer', 'Disease', (57, 70))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('mutations', 'Var', (245, 254))	('breast cancer', 'Disease', 'MESH:D001943', (258, 271))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('breast cancer', 'Disease', (258, 271))	('breast cancer', 'Phenotype', 'HP:0003002', (258, 271))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('SMG', 'Gene', (299, 302))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('SMG', 'Gene', '23034', (299, 302))
40860	24022702	Clonal frequency analysis provided evidence that somatic mutations in TP53, PIK3CA and PTEN are clonally dominant in most tumors in which they are found, consistent with a founder mutation status role in most, but not all TNBCs.	('tumors', 'Disease', (122, 128))	('PTEN', 'Gene', (87, 91))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('PTEN', 'Gene', '5728', (87, 91))	('TP53', 'Gene', '7157', (70, 74))	('PIK3CA', 'Gene', (76, 82))	('TP53', 'Gene', (70, 74))	('mutations', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('PIK3CA', 'Gene', '5290', (76, 82))
40864	24022702	The authors identified 18 SMGs by MuSiC, and found that GATA3 mutations correlated with response to aromatase inhibitor treatment.	('correlated', 'Reg', (72, 82))	('mutations', 'Var', (62, 71))	('GATA3', 'Gene', '2625', (56, 61))	('SMG', 'Gene', (26, 29))	('SMG', 'Gene', '23034', (26, 29))	('response to aromatase', 'MPA', (88, 109))	('GATA3', 'Gene', (56, 61))
40869	24022702	Forward genetics (in the form of a Sleeping Beauty transposon mutagenesis screen in a mouse model of PDAC) and functional genomics (in the form of a shRNA screen in pancreatic cell lines) were also leveraged to explore the functional relevance of SMGs identified by sequencing.	('PDAC', 'Phenotype', 'HP:0006725', (101, 105))	('mutagenesis', 'Var', (62, 73))	('mouse', 'Species', '10090', (86, 91))	('SMG', 'Gene', (247, 250))	('SMG', 'Gene', '23034', (247, 250))
40873	24022702	All the studies confirmed previously known mutations in TP53 in HCC, but they also shed light on the importance of deregulation by somatic mutations of genes involved in chromatin remodeling, the WNT-beta-catenin pathway, cell cycle control, the PI3K pathway, and oxidative and endoplasmic reticulum stress pathway (Supplementary Figure 1).	('HCC', 'Gene', (64, 67))	('PI3K', 'molecular_function', 'GO:0016303', ('246', '250'))	('mutations', 'Var', (139, 148))	('TP53', 'Gene', '7157', (56, 60))	('PI3K pathway', 'Pathway', (246, 258))	('HCC', 'Gene', '619501', (64, 67))	('beta-catenin', 'Gene', (200, 212))	('TP53', 'Gene', (56, 60))	('mutations', 'Var', (43, 52))	('beta-catenin', 'Gene', '1499', (200, 212))	('HCC', 'Phenotype', 'HP:0001402', (64, 67))	('cell cycle control', 'biological_process', 'GO:1901987', ('222', '240'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('170', '190'))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('278', '299'))	('chromatin', 'cellular_component', 'GO:0000785', ('170', '179'))
40874	24022702	Although most of the mutations were not associated with a specific type of chronic liver disease, in one study, mutations in interferon regulatory factor 2 (IRF2) were exclusively found in hepatitis B virus (HBV)-related tumors.	('IRF2', 'Gene', (157, 161))	('hepatitis', 'Phenotype', 'HP:0012115', (189, 198))	('hepatitis B virus', 'Species', '10407', (189, 206))	('HBV', 'Species', '10407', (208, 211))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('hepatitis B virus', 'Disease', (189, 206))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('liver disease', 'Disease', 'MESH:D008107', (83, 96))	('mutations', 'Var', (112, 121))	('IRF2', 'Gene', '3660', (157, 161))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumors', 'Disease', (221, 227))	('liver disease', 'Phenotype', 'HP:0001392', (83, 96))	('liver disease', 'Disease', (83, 96))	('found', 'Reg', (180, 185))
40875	24022702	WGS has also revealed that the number of HBV integration sites in HCC tumors was associated with poor survival, and identified recurrent integration events in the TERT, MLL4 and CCNE1 loci, which resulted in concurrent increase in gene expression, reaffirming the powerful analytical capacity of NGS to investigate the potential role of pathogens in human cancers.	('gene expression', 'MPA', (231, 246))	('integration sites', 'Var', (45, 62))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('cancers', 'Disease', 'MESH:D009369', (356, 363))	('human', 'Species', '9606', (350, 355))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('gene expression', 'biological_process', 'GO:0010467', ('231', '246'))	('HCC tumors', 'Disease', (66, 76))	('TERT', 'Gene', (163, 167))	('increase', 'PosReg', (219, 227))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('poor', 'NegReg', (97, 101))	('TERT', 'Gene', '7015', (163, 167))	('HBV', 'Gene', (41, 44))	('CCNE1', 'Gene', (178, 183))	('HBV', 'Species', '10407', (41, 44))	('cancers', 'Phenotype', 'HP:0002664', (356, 363))	('HCC tumors', 'Disease', 'MESH:D006528', (66, 76))	('cancers', 'Disease', (356, 363))	('HCC', 'Phenotype', 'HP:0001402', (66, 69))	('MLL', 'Gene', '4297', (169, 172))	('MLL', 'Gene', (169, 172))	('associated', 'Reg', (81, 91))
40880	24022702	Identification of gene fusions as the predominant drivers of certain leukemias has led to the development and clinical success of targeted therapies, including imatinib in chronic myeloid leukemia (CML) and acute lymphocytic leukemia (ALL) cases with the BCR-ABL1 fusion and all-trans-retinoic acid (ATRA) in acute promyelocytic leukemia (APL) cases with PML-RARA fusion.	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (309, 337))	('leukemias', 'Disease', 'MESH:D007938', (69, 78))	('chronic myeloid leukemia', 'Disease', (172, 196))	('acute lymphocytic leukemia', 'Disease', (207, 233))	('leukemias', 'Phenotype', 'HP:0001909', (69, 78))	('leukemia', 'Phenotype', 'HP:0001909', (188, 196))	('trans-retinoic acid', 'Chemical', 'MESH:D014212', (279, 298))	('leukemia', 'Phenotype', 'HP:0001909', (69, 77))	('BCR-ABL1', 'Gene', (255, 263))	('CML', 'Disease', 'MESH:D015464', (198, 201))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (180, 196))	('leukemias', 'Disease', (69, 78))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (309, 337))	('acute lymphocytic leukemia', 'Disease', 'MESH:D054198', (207, 233))	('CML', 'Disease', (198, 201))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (207, 233))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (172, 196))	('fusion', 'Var', (264, 270))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (172, 196))	('leukemia', 'Phenotype', 'HP:0001909', (225, 233))	('ATRA', 'Chemical', 'MESH:D014212', (300, 304))	('acute promyelocytic leukemia', 'Disease', (309, 337))	('BCR-ABL1', 'Gene', '613;25', (255, 263))	('ALL', 'Phenotype', 'HP:0006721', (235, 238))	('leukemia', 'Phenotype', 'HP:0001909', (329, 337))	('APL', 'Phenotype', 'HP:0004836', (339, 342))	('imatinib', 'Chemical', 'MESH:D000068877', (160, 168))	('CML', 'Phenotype', 'HP:0005506', (198, 201))
40881	24022702	However, substantial numbers of leukemias do not possess such gene fusions, and the search for other genetic drivers led to the identification of somatic mutations in genes such as FLT3, RAS, CEBPA, KIT, JAK2, RUNX1, TET2, ASXL1, EZH2, and TP53 prior to the era of NGS-based studies.	('TP53', 'Gene', '7157', (240, 244))	('leukemias', 'Phenotype', 'HP:0001909', (32, 41))	('FLT3', 'Gene', '2322', (181, 185))	('CEBPA', 'Gene', '1050', (192, 197))	('TET2', 'Gene', '54790', (217, 221))	('EZH2', 'Gene', (230, 234))	('EZH2', 'Gene', '2146', (230, 234))	('leukemias', 'Disease', (32, 41))	('RAS', 'Gene', (187, 190))	('CEBPA', 'Gene', (192, 197))	('KIT', 'molecular_function', 'GO:0005020', ('199', '202'))	('JAK2', 'Gene', '3717', (204, 208))	('TET2', 'Gene', (217, 221))	('TP53', 'Gene', (240, 244))	('RUNX1', 'Gene', (210, 215))	('RUNX1', 'Gene', '861', (210, 215))	('ASXL1', 'Gene', '171023', (223, 228))	('JAK', 'molecular_function', 'GO:0004713', ('204', '207'))	('KIT', 'Gene', (199, 202))	('JAK2', 'Gene', (204, 208))	('ASXL1', 'Gene', (223, 228))	('leukemia', 'Phenotype', 'HP:0001909', (32, 40))	('mutations', 'Var', (154, 163))	('FLT3', 'Gene', (181, 185))	('leukemias', 'Disease', 'MESH:D007938', (32, 41))
40882	24022702	The first WGS of a patient with French-American-British (FAB) classification M1 acute myeloid leukemia (AML) not only confirmed mutations in previously known genes, but led to the subsequent identification of new somatic mutations in genes involved in DNA methylation, such as DNA methyltransferase 3A (DNMT3A), IDH1, and IDH2 (Figure 1a).	('acute myeloid leukemia', 'Disease', (80, 102))	('patient', 'Species', '9606', (19, 26))	('DNA', 'cellular_component', 'GO:0005574', ('252', '255'))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (86, 102))	('AML', 'Disease', 'MESH:D015470', (104, 107))	('IDH1', 'Gene', '3417', (312, 316))	('DNMT3A', 'Gene', '1788', (303, 309))	('mutations', 'Var', (221, 230))	('IDH2', 'Gene', (322, 326))	('AML', 'Phenotype', 'HP:0004808', (104, 107))	('AML', 'Disease', (104, 107))	('mutations', 'Var', (128, 137))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (80, 102))	('IDH2', 'Gene', '3418', (322, 326))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (80, 102))	('leukemia', 'Phenotype', 'HP:0001909', (94, 102))	('DNA methylation', 'biological_process', 'GO:0006306', ('252', '267'))	('DNA methyltransferase 3A', 'Gene', '1788', (277, 301))	('DNA methyltransferase 3A', 'Gene', (277, 301))	('DNMT3A', 'Gene', (303, 309))	('DNA', 'cellular_component', 'GO:0005574', ('277', '280'))	('IDH1', 'Gene', (312, 316))
40885	24022702	In this study, MuSiC identified 23 SMGs that included known mutations in AML, as well as mutations in the mRNA splicing machinery (U2AF1) (Figure 1b) or cohesin complex (SMC1A, SMC3.	('U2AF1', 'Gene', '7307', (131, 136))	('SMC3', 'Gene', '9126', (177, 181))	('AML', 'Disease', (73, 76))	('SMC1A', 'Gene', '8243', (170, 175))	('SMC3', 'Gene', (177, 181))	('AML', 'Phenotype', 'HP:0004808', (73, 76))	('U2AF1', 'Gene', (131, 136))	('SMG', 'Gene', (35, 38))	('mutations', 'Var', (89, 98))	('SMC1A', 'Gene', (170, 175))	('mutations', 'Var', (60, 69))	('SMG', 'Gene', '23034', (35, 38))	('AML', 'Disease', 'MESH:D015470', (73, 76))
40889	24022702	For example, mutations in spliceosome complex genes are more abundant in MDS than AML and approximately 40% of MDS cases are found to have mutations in one of the spliceosome complex genes (SF3B1, SRSF2, U2AF1, ZRSR2, SF3A1, PRPF40B, U2AF2, and SF1) in a mutually exclusive manner, suggesting that deregulation in pre-mRNA splicing plays a crucial role in MDS pathogenesis (Figure 1b).	('MDS', 'Phenotype', 'HP:0002863', (73, 76))	('AML', 'Disease', 'MESH:D015470', (82, 85))	('U2AF1', 'Gene', '7307', (204, 209))	('AML', 'Disease', (82, 85))	('SRSF2', 'Gene', '6427', (197, 202))	('AML', 'Phenotype', 'HP:0004808', (82, 85))	('MDS', 'Disease', 'MESH:D009190', (73, 76))	('SRSF2', 'Gene', (197, 202))	('MDS', 'Phenotype', 'HP:0002863', (111, 114))	('PRPF40B', 'Gene', '25766', (225, 232))	('ZRSR2', 'Gene', (211, 216))	('SF3B1', 'Gene', (190, 195))	('MDS', 'Phenotype', 'HP:0002863', (356, 359))	('U2AF2', 'Gene', (234, 239))	('MDS', 'Disease', (73, 76))	('SF3A1', 'Gene', '10291', (218, 223))	('MDS', 'Disease', 'MESH:D009190', (111, 114))	('U2AF2', 'Gene', '11338', (234, 239))	('SF1', 'Gene', (245, 248))	('mutations', 'Var', (13, 22))	('SF1', 'Gene', '7536', (245, 248))	('MDS', 'Disease', 'MESH:D009190', (356, 359))	('spliceosome complex genes', 'Gene', (26, 51))	('SF3B1', 'Gene', '23451', (190, 195))	('PRPF40B', 'Gene', (225, 232))	('mutations', 'Var', (139, 148))	('MDS', 'Disease', (111, 114))	('U2AF1', 'Gene', (204, 209))	('SF3A1', 'Gene', (218, 223))	('ZRSR2', 'Gene', '8233', (211, 216))	('MDS', 'Disease', (356, 359))
40890	24022702	Recently, sequencing of longitudinal samples from MDS patients identified hotspot mutations in SET binding protein 1 (SETBP1) that was acquired during leukemic evolution to AML.	('SETBP1', 'Gene', '26040', (118, 124))	('patients', 'Species', '9606', (54, 62))	('AML', 'Phenotype', 'HP:0004808', (173, 176))	('AML', 'Disease', (173, 176))	('leukemic', 'Disease', (151, 159))	('MDS', 'Disease', (50, 53))	('MDS', 'Disease', 'MESH:D009190', (50, 53))	('MDS', 'Phenotype', 'HP:0002863', (50, 53))	('mutations', 'Var', (82, 91))	('SET binding protein 1', 'Gene', '26040', (95, 116))	('SETBP1', 'Gene', (118, 124))	('SET binding protein 1', 'Gene', (95, 116))	('AML', 'Disease', 'MESH:D015470', (173, 176))	('leukemic', 'Disease', 'MESH:D007938', (151, 159))
40893	24022702	Examples of findings for CLL include three independent WES and WGS studies that revealed known mutations in TP53 and ATM, and previously unknown SMGs in NOTCH1, myeloid differentiation primary response gene 88 (MYD88), and the splicing factor SF3B1 (Figure 1b).	('NOTCH1', 'Gene', '4851', (153, 159))	('NOTCH1', 'Gene', (153, 159))	('ATM', 'Gene', '472', (117, 120))	('SF3B1', 'Gene', (243, 248))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('SF3B1', 'Gene', '23451', (243, 248))	('MYD88', 'Gene', '4615', (211, 216))	('mutations', 'Var', (95, 104))	('MYD88', 'Gene', (211, 216))	('SMG', 'Gene', (145, 148))	('splicing', 'biological_process', 'GO:0045292', ('227', '235'))	('SMG', 'Gene', '23034', (145, 148))	('ATM', 'Gene', (117, 120))
40895	24022702	For example, RNA-seq has identified hotspot mutations in NOTCH1 in some cases of MCL, suggesting a common role of NOTCH signaling deregulation in B cell malignancies.	('MCL', 'Disease', 'MESH:C535516', (81, 84))	('hotspot', 'PosReg', (36, 43))	('malignancies', 'Disease', (153, 165))	('NOTCH1', 'Gene', (57, 63))	('NOTCH1', 'Gene', '4851', (57, 63))	('MCL', 'Disease', (81, 84))	('mutations', 'Var', (44, 53))	('RNA', 'cellular_component', 'GO:0005562', ('13', '16'))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))	('malignancies', 'Disease', 'MESH:D009369', (153, 165))
40896	24022702	MYD88 mutations were also observed in DLBCL and Waldenstrom macroglobulinemia.	('Waldenstrom macroglobulinemia', 'Phenotype', 'HP:0005508', (48, 77))	('macroglobulinemia', 'Disease', (60, 77))	('DLBCL', 'Disease', (38, 43))	('MYD88', 'Gene', '4615', (0, 5))	('observed', 'Reg', (26, 34))	('macroglobulinemia', 'Disease', 'MESH:D008258', (60, 77))	('mutations', 'Var', (6, 15))	('MYD88', 'Gene', (0, 5))
40897	24022702	The landscape of somatic mutations has also been characterized in multiple myeloma in two recent WES/WGS studies, confirming known deregulation of RAS, NF-kappaB, and histone methyltransferase activity, while revealing previously unknown mutations in genes involved in RNA processing and protein homeostasis.	('mutations', 'Var', (25, 34))	('NF-kappaB', 'Protein', (152, 161))	('multiple myeloma', 'Phenotype', 'HP:0006775', (66, 82))	('multiple myeloma', 'Disease', 'MESH:D009101', (66, 82))	('multiple myeloma', 'Disease', (66, 82))	('RAS', 'Protein', (147, 150))	('histone methyltransferase', 'Gene', '56979', (167, 192))	('activity', 'MPA', (193, 201))	('deregulation', 'PosReg', (131, 143))	('histone methyltransferase', 'Gene', (167, 192))
40898	24022702	The pattern of somatic mutations in DLBCL is more complex, but a significant number of cases harbor mutations in regulators of histone and chromatin modification including MLL2, CREBBP, EP300 and activating mutation in EZH2 (Figure 1a).	('chromatin modification', 'biological_process', 'GO:0006325', ('139', '161'))	('mutations', 'Var', (100, 109))	('EZH2', 'Gene', '2146', (219, 223))	('chromatin modification', 'biological_process', 'GO:0016569', ('139', '161'))	('activating mutation', 'Var', (196, 215))	('EZH2', 'Gene', (219, 223))	('MLL2', 'Gene', '9757', (172, 176))	('CREBBP', 'Gene', (178, 184))	('EP300', 'Gene', (186, 191))	('EP300', 'Gene', '2033', (186, 191))	('CREBBP', 'Gene', '1387', (178, 184))	('MLL2', 'Gene', (172, 176))	('chromatin', 'cellular_component', 'GO:0000785', ('139', '148'))
40900	24022702	NGS also has the potential to reveal major actionable genetic alterations in rare cancers, such as the discovery of NOTCH2 mutations in 25% of splenic marginal zone lymphoma (SMZL), mutations in signal transducer and activator of transcription 3 (STAT3) in 40% of large granular lymphocytic leukemia (LGL), and BRAF V600E mutation present in 100% of hairy-cell leukemia (HCL) samples tested to date.	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('BRAF', 'Gene', (311, 315))	('BRAF', 'Gene', '673', (311, 315))	('NOTCH2', 'Gene', (116, 122))	('STAT3', 'Gene', '6774', (247, 252))	('granular lymphocytic leukemia', 'Disease', (270, 299))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('hairy-cell leukemia', 'Disease', (350, 369))	('splenic marginal zone lymphoma', 'Disease', (143, 173))	('granular lymphocytic leukemia', 'Disease', 'MESH:D054066', (270, 299))	('splenic marginal zone lymphoma', 'Disease', 'MESH:D018442', (143, 173))	('mutations', 'Var', (182, 191))	('leukemia', 'Phenotype', 'HP:0001909', (291, 299))	('mutations', 'Var', (123, 132))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('lymphoma', 'Phenotype', 'HP:0002665', (165, 173))	('signal transducer and activator of transcription 3', 'Gene', '6774', (195, 245))	('leukemia', 'Phenotype', 'HP:0001909', (361, 369))	('NOTCH2', 'Gene', '4853', (116, 122))	('V600E', 'Mutation', 'rs113488022', (316, 321))	('STAT3', 'Gene', (247, 252))	('hairy-cell leukemia', 'Disease', 'MESH:D007943', (350, 369))
40903	24022702	In addition to the examples described above, TP53 is mutated in 96% of HGS-OvCa samples, but clear-cell and endometrioid ovarian cancer tumors have lower rates of TP53 mutations and instead possess frequent recurrent mutations in PIK3CA and ARID1A, which were identified using NGS technology.	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('endometrioid ovarian cancer tumors', 'Disease', 'MESH:D010051', (108, 142))	('TP53', 'Gene', (45, 49))	('TP53', 'Gene', '7157', (163, 167))	('PIK3CA', 'Gene', (230, 236))	('ARID1A', 'Gene', '8289', (241, 247))	('ovarian cancer', 'Phenotype', 'HP:0100615', (121, 135))	('ARID1A', 'Gene', (241, 247))	('lower', 'NegReg', (148, 153))	('TP53', 'Gene', (163, 167))	('endometrioid ovarian cancer tumors', 'Disease', (108, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('PIK3CA', 'Gene', '5290', (230, 236))	('clear-cell', 'Disease', (93, 103))	('mutations', 'Var', (217, 226))	('TP53', 'Gene', '7157', (45, 49))	('mutations', 'Var', (168, 177))
40904	24022702	Most cutaneous melanomas are driven by BRAF or NRAS mutations; by contrast ocular melanomas, have frequent hotspot mutations in the G-proteins GNA11, GNAQ, and LOF mutations in deubiquitinating enzyme, BAP1.	('cutaneous melanomas', 'Disease', (5, 24))	('ocular melanomas', 'Disease', (75, 91))	('melanomas', 'Phenotype', 'HP:0002861', (15, 24))	('GNAQ', 'Gene', (150, 154))	('GNA11', 'Gene', (143, 148))	('NRAS', 'Gene', '4893', (47, 51))	('BRAF', 'Gene', '673', (39, 43))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('BRAF', 'Gene', (39, 43))	('BAP1', 'Gene', '8314', (202, 206))	('LOF', 'NegReg', (160, 163))	('NRAS', 'Gene', (47, 51))	('melanomas', 'Phenotype', 'HP:0002861', (82, 91))	('ocular melanomas', 'Phenotype', 'HP:0025534', (75, 91))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (5, 24))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (5, 24))	('GNA11', 'Gene', '2767', (143, 148))	('mutations', 'Var', (164, 173))	('ocular melanomas', 'Disease', 'MESH:D008545', (75, 91))	('mutations', 'Var', (52, 61))	('BAP1', 'Gene', (202, 206))	('mutations', 'Var', (115, 124))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('GNAQ', 'Gene', '2776', (150, 154))
40905	24022702	Recent glioblastoma studies support the notion that pediatric and adult cancers need to be characterized separately at the molecular level, as pediatric and adult glioblastoma tumors possess distinct genetic driving events, which includes mutations in ATRX, DAXX, and the replication-independent histone variant, H3F3A, which were much more prevalent in the pediatric setting (Figure 1a and Supplementary Figure 1).	('mutations', 'Var', (239, 248))	('glioblastoma', 'Disease', (163, 175))	('glioblastoma', 'Disease', (7, 19))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('glioblastoma', 'Phenotype', 'HP:0012174', (163, 175))	('glioblastoma', 'Phenotype', 'HP:0012174', (7, 19))	('ATRX', 'Gene', (252, 256))	('ATRX', 'Gene', '546', (252, 256))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('DAXX', 'Gene', (258, 262))	('glioblastoma tumors', 'Disease', (163, 182))	('adult cancers', 'Disease', (66, 79))	('DAXX', 'Gene', '1616', (258, 262))	('H3F3A', 'Gene', '3020', (313, 318))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('adult cancers', 'Disease', 'MESH:C535836', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('glioblastoma tumors', 'Disease', 'MESH:D005909', (163, 182))	('H3F3A', 'Gene', (313, 318))	('glioblastoma', 'Disease', 'MESH:D005909', (7, 19))	('glioblastoma', 'Disease', 'MESH:D005909', (163, 175))
40907	24022702	One example of this is the V617F mutation in Janus kinase 2 (JAK2) in the diagnosis of the myeloproliferative neoplasm, polycythemia vera (PV), the incidence of which is estimated at 95% and is currently incorporated as one of the diagnostic criteria for PV.	('JAK2', 'Gene', '3717', (61, 65))	('V617F', 'SUBSTITUTION', 'None', (27, 32))	('polycythemia vera', 'Disease', (120, 137))	('V617F', 'Var', (27, 32))	('Janus kinase 2', 'Gene', '3717', (45, 59))	('myeloproliferative neoplasm', 'Phenotype', 'HP:0005547', (91, 118))	('neoplasm', 'Phenotype', 'HP:0002664', (110, 118))	('myeloproliferative neoplasm', 'Disease', (91, 118))	('polycythemia', 'Phenotype', 'HP:0001901', (120, 132))	('JAK2', 'Gene', (61, 65))	('myeloproliferative neoplasm', 'Disease', 'MESH:D009196', (91, 118))	('polycythemia vera', 'Disease', 'MESH:D011087', (120, 137))	('Janus kinase 2', 'Gene', (45, 59))
40910	24022702	Chromosomal alterations remain the strongest prognostic factor in both AML and MDS, but recent efforts incorporating somatic mutations have shown promise in creating more sophisticated prognostic models.	('AML', 'Disease', 'MESH:D015470', (71, 74))	('Chromosomal alterations', 'Var', (0, 23))	('AML', 'Disease', (71, 74))	('AML', 'Phenotype', 'HP:0004808', (71, 74))	('MDS', 'Phenotype', 'HP:0002863', (79, 82))	('MDS', 'Disease', (79, 82))	('MDS', 'Disease', 'MESH:D009190', (79, 82))
40911	24022702	For instance, in intermediate-risk AML identified by the conventional prognostic model, by incorporating information of additional genetic alterations, which include the internal tandem duplication in fms-related tyrosine kinase 3 gene (FLT3-ITD) and mutations in NPM1, CEBPA, and MLL genes, physicians are able to identify patients that will benefit from stem cell transplant during the first complete remission.	('AML', 'Disease', (35, 38))	('mutations', 'Var', (251, 260))	('FLT3', 'Gene', (237, 241))	('patients', 'Species', '9606', (324, 332))	('MLL', 'Gene', '4297', (281, 284))	('NPM1', 'Gene', '4869', (264, 268))	('MLL', 'Gene', (281, 284))	('fms', 'molecular_function', 'GO:0005011', ('201', '204'))	('CEBPA', 'Gene', (270, 275))	('tyrosine kinase 3', 'Gene', (213, 230))	('CEBPA', 'Gene', '1050', (270, 275))	('tyrosine kinase 3', 'Gene', '2241', (213, 230))	('internal tandem duplication', 'Var', (170, 197))	('FLT3', 'Gene', '2322', (237, 241))	('AML', 'Disease', 'MESH:D015470', (35, 38))	('NPM1', 'Gene', (264, 268))	('AML', 'Phenotype', 'HP:0004808', (35, 38))
40913	24022702	In this regard, two groups have recently shown recurrent mutations in the TERT promoter in approximately 70% of melanomas, which highlights the discovery potential in examining somatic mutations in non-coding regions in cancer.	('melanomas', 'Disease', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('TERT', 'Gene', '7015', (74, 78))	('melanomas', 'Phenotype', 'HP:0002861', (112, 121))	('mutations', 'Var', (57, 66))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('melanomas', 'Disease', 'MESH:D008545', (112, 121))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('cancer', 'Disease', (220, 226))	('TERT', 'Gene', (74, 78))
40914	24022702	Third, we need to begin to systematically explore the interaction of host genome variation with the somatic genome of the tumor in ultimately influencing outcomes.	('tumor', 'Disease', (122, 127))	('variation', 'Var', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))
40920	24022702	Driver mutations Somatic mutations in a gene that confer a selective advantage to cancer cells as reflected in statistical evidence of positive selection.	('Somatic mutations', 'Var', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('advantage', 'PosReg', (69, 78))	('mutations Somatic', 'Var', (7, 24))
40922	24022702	Hotspot mutations Recurrent mutations resulting in the same amino acid change in a gene observed in cancer, signifying strong positive selection.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mutations', 'Var', (8, 17))	('amino acid', 'MPA', (60, 70))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
40924	24022702	Two-hit tumor suppressor The Knudson two-hit hypothesis was proposed to explain the early onset of cancer in hereditary syndromes whereby inheritance of one germline copy of a mutated gene in all cells substantially increases the likelihood any cell undergoing mutation of the other allele, thus giving rise to earlier onset disease compared to sporadic forms of the disease.	('inheritance', 'Var', (138, 149))	('giving rise to', 'Reg', (296, 310))	('earlier onset disease', 'Disease', (311, 332))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('cancer', 'Disease', (99, 105))	('mutation', 'Var', (261, 269))	('tumor', 'Disease', (8, 13))	('increases', 'PosReg', (216, 225))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
40925	24022702	It specifically relates to the necessity to inactivate both alleles of a recessive cancer gene.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('inactivate', 'Var', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (83, 89))
40928	24022702	CpG island methylator phenotype A classification of cancers by their degree of methylation at CpG rich promoter regions, first characterized in human colorectal cancers, and often associated with distinct epidemiology, histological and molecular distinct features.	('CpG', 'Gene', (94, 97))	('colorectal cancers', 'Disease', 'MESH:D015179', (150, 168))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('human', 'Species', '9606', (144, 149))	('colorectal cancers', 'Disease', (150, 168))	('methylation', 'biological_process', 'GO:0032259', ('79', '90'))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('methylation', 'Var', (79, 90))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', (161, 168))	('colorectal cancer', 'Phenotype', 'HP:0003003', (150, 167))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
40939	24022702	A phenomenon, identified in breast cancers, of localized hypermutations almost exclusively involving C base pair substitutions at TpC dinucleotides.	('breast cancers', 'Phenotype', 'HP:0003002', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancers', 'Disease', 'MESH:D001943', (28, 42))	('TpC dinucleotides', 'Chemical', '-', (130, 147))	('breast cancers', 'Disease', (28, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('C base pair substitutions', 'Var', (101, 126))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('involving', 'Reg', (91, 100))
40940	24022702	Actionable genetic alterations A genetic alteration with sufficient scientific evidence supporting its use to inform a treatment decision Briefly, to identify mutated cancer-relevant genes, the first step is to generate high quality NGS data covering the genomic regions of interest (e.g.	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (167, 173))	('genetic alterations', 'Var', (11, 30))	('cancer', 'Disease', 'MESH:D009369', (167, 173))
40943	24022702	Once aligned, sophisticated analytical algorithms are used to call sequence variants in the tumor DNA compared to the human reference genome, and to determine whether a variant is "somatic" by comparison with the germline DNA.	('variant', 'Var', (169, 176))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('variants', 'Var', (76, 84))	('human', 'Species', '9606', (118, 123))
40948	24022702	Controlling for type I errors (false positives) is difficult as mutations in a gene can occur in excess of the calculated BMR if resident in a hypermutable region of the genome (a vs b).	('type I errors', 'Disease', 'MESH:D005776', (16, 29))	('type I errors', 'Disease', (16, 29))	('mutations', 'Var', (64, 73))
40951	24022702	Based on the assumption that mutations in intronic and UTR sequences are more likely under neutral selective pressure, whereas coding mutations will undergo selection during tumor progression, InVEx employs a permutation-based framework to determine whether the observed coding mutations experience positive selection against the inferred gene-specific BMR.	('tumor', 'Disease', (174, 179))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('UTR', 'Gene', (55, 58))
40954	24022702	However, given driver mutations can be present at low frequency in many cancer genes, the ICGC calculated that 500 tumor samples are needed to detect, with 80% power, genes mutated in 3% of samples assuming a typical BMR of 1.5 mutations/Mb.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutated', 'Var', (173, 180))	('tumor', 'Disease', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('cancer', 'Disease', (72, 78))
40957	24022702	The same mutations may be found as drivers in other cancers.	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('mutations', 'Var', (9, 18))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
40958	24022702	Algorithms that score mutational impact by amino acid conservation can infer likely functional mutations in cancer genes.	('cancer', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (95, 104))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
40962	24022702	Integration with copy number and mutation data showed that the classical subtype is enriched for EGFR alterations, whereas the mesenchymal subtype contains cases with NF1 loss, and the proneural subtype has specific alterations in PDGFRA and IDH1.	('EGFR', 'Gene', '1956', (97, 101))	('IDH1', 'Gene', (242, 246))	('NF1', 'Gene', (167, 170))	('EGFR', 'Gene', (97, 101))	('IDH1', 'Gene', '3417', (242, 246))	('PDGFRA', 'Gene', (231, 237))	('NF1', 'Gene', '4763', (167, 170))	('alterations', 'Var', (102, 113))	('alterations', 'Reg', (216, 227))	('loss', 'NegReg', (171, 175))	('PDGFRA', 'Gene', '5156', (231, 237))	('EGFR', 'molecular_function', 'GO:0005006', ('97', '101'))
40963	24022702	Similarly, analysis of promoter methylation alterations in 272 glioblastoma tumors identified a subset of patient samples with characteristic promoter DNA methylation classified as glioma CpG island methylator phenotype (G-CIMP) which is associated with IDH1 mutations.	('IDH1', 'Gene', '3417', (254, 258))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('mutations', 'Var', (259, 268))	('glioblastoma tumors', 'Disease', 'MESH:D005909', (63, 82))	('patient', 'Species', '9606', (106, 113))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('G-CIMP', 'Chemical', '-', (221, 227))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('glioblastoma tumors', 'Disease', (63, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('DNA methylation', 'biological_process', 'GO:0006306', ('151', '166'))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('IDH1', 'Gene', (254, 258))	('glioma', 'Disease', (181, 187))	('DNA', 'cellular_component', 'GO:0005574', ('151', '154'))
40966	24022702	For example, NF2 mutations were found in tumors possessing a non-hypoxic signature and were mutually exclusive with VHL mutations, suggesting mutations in NF2 is a key driver event in this ccRCC subgroup.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mutations', 'Var', (142, 151))	('NF2', 'Gene', '4771', (13, 16))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('NF2', 'Gene', (155, 158))	('non-hypoxic signature', 'MPA', (61, 82))	('found', 'Reg', (32, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (189, 194))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('VHL', 'Gene', (116, 119))	('NF2', 'Gene', '4771', (155, 158))	('ccRCC', 'Disease', (189, 194))	('VHL', 'Gene', '7428', (116, 119))	('NF2', 'Gene', (13, 16))	('mutations', 'Var', (17, 26))
40967	24022702	Conversely, significant co-occurrence of mutations in epigenetic regulators, SETD2, JARID1C and PBRM1 were found in tumor possessing VHL mutations or hypoxic expression signature, supporting the notion that mutations in this class of genes may act as the second hit to widespread inactivation of VHL in ccRCC.	('SETD2', 'Gene', '29072', (77, 82))	('VHL', 'Gene', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('inactivation', 'NegReg', (280, 292))	('PBRM1', 'Gene', '55193', (96, 101))	('mutations', 'Var', (41, 50))	('ccRCC', 'Disease', (303, 308))	('VHL', 'Gene', '7428', (133, 136))	('mutations', 'Var', (207, 216))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('VHL', 'Gene', (296, 299))	('PBRM1', 'Gene', (96, 101))	('ccRCC', 'Phenotype', 'HP:0006770', (303, 308))	('JARID1C', 'Gene', '8242', (84, 91))	('VHL', 'Gene', '7428', (296, 299))	('SETD2', 'Gene', (77, 82))	('mutations', 'Var', (137, 146))	('JARID1C', 'Gene', (84, 91))	('tumor', 'Disease', (116, 121))
40968	24022702	The authors of the TCGA lung squamous cell carcinoma (SQCC) study observed many of the genes involved in oxidative stress and squamous cell differentiation pathways frequently altered by mutations, SCNAs, and identified genomic alterations associated with reported lung SQCC gene signatures (classical, primitive, basal, and secretory).	('oxidative stress', 'Phenotype', 'HP:0025464', (105, 121))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (24, 52))	('primitive', 'Disease', (303, 312))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (24, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (29, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('altered', 'Reg', (176, 183))	('mutations', 'Var', (187, 196))	('lung squamous cell carcinoma', 'Disease', (24, 52))	('SQCC', 'Phenotype', 'HP:0002860', (270, 274))	('lung SQCC', 'Disease', (265, 274))	('SQCC', 'Phenotype', 'HP:0002860', (54, 58))
40970	24022702	Such associations include GATA3, high frequency of PIK3CA, and likely inactivating MAP3K1 and MAP2K4 mutations in the luminal A expression subtype, enrichment of TP53 and PIK3CA mutations in the HER2 expression subtype, and a high frequency of TP53 mutations in the basal-like expression tumors.	('PIK3CA', 'Gene', (171, 177))	('TP53', 'Gene', (244, 248))	('GATA3', 'Gene', (26, 31))	('HER2', 'Gene', (195, 199))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('MAP2K4', 'Gene', '6416', (94, 100))	('MAP2K4', 'Gene', (94, 100))	('TP53', 'Gene', (162, 166))	('PIK3CA', 'Gene', (51, 57))	('inactivating', 'NegReg', (70, 82))	('TP53', 'Gene', '7157', (244, 248))	('mutations', 'Var', (101, 110))	('PIK3CA', 'Gene', '5290', (171, 177))	('HER2', 'Gene', '2064', (195, 199))	('PIK3CA', 'Gene', '5290', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('TP53', 'Gene', '7157', (162, 166))	('mutations', 'Var', (249, 258))	('MAP3K1', 'Gene', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('mutations', 'Var', (178, 187))	('GATA3', 'Gene', '2625', (26, 31))	('MAP3K1', 'Gene', '4214', (83, 89))	('tumors', 'Disease', (288, 294))
40973	24022702	One example is the mutually exclusive mutations in the CUL3-KEAP1 E3 ligase complex and its target substrate NFE2L2 in the oxidative response pathway in lung squamous carcinomas.	('NFE2L2', 'Gene', '4780', (109, 115))	('KEAP1', 'Gene', (60, 65))	('NFE2L2', 'Gene', (109, 115))	('lung squamous carcinomas', 'Disease', (153, 177))	('CUL3', 'Gene', '8452', (55, 59))	('lung squamous carcinomas', 'Disease', 'MESH:D002294', (153, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('CUL3', 'Gene', (55, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('mutations', 'Var', (38, 47))	('KEAP1', 'Gene', '9817', (60, 65))	('oxidative response pathway', 'Pathway', (123, 149))
40975	24022702	The utility of testing whether known pathways are enriched in SMG lists has been demonstrated in many studies, including the WES analysis of HNSCC that observed deregulation of squamous cell differentiation via somatic mutations, and the recent ICGC pancreatic study that observed enrichment of mutations in genes in the axon guidance pathway.	('SCC', 'Phenotype', 'HP:0002860', (143, 146))	('squamous cell differentiation', 'CPA', (177, 206))	('axon guidance pathway', 'Pathway', (321, 342))	('deregulation', 'MPA', (161, 173))	('SMG', 'Gene', (62, 65))	('mutations', 'Var', (295, 304))	('SMG', 'Gene', '23034', (62, 65))	('mutations', 'Var', (219, 228))
40977	24022702	Functional validation of SMGs and candidate driver mutations requires equal consideration in the selection and interpretation of biological assays employed to determine cancer relevance.	('mutations', 'Var', (51, 60))	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('SMG', 'Gene', (25, 28))	('SMG', 'Gene', '23034', (25, 28))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
40979	24022702	The example of NOTCH1, which acts as a tumor suppressor with loss-of-function mutations in some tumor types (a) and as an oncogene with activating mutation in another tumor type (b), highlights the challenges in functional validation of SMGs and candidate driver mutations identified by cancer genomics.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Disease', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('a tumor', 'Disease', (37, 44))	('NOTCH1', 'Gene', (15, 21))	('mutations', 'Var', (78, 87))	('SMG', 'Gene', '23034', (237, 240))	('tumor', 'Disease', (167, 172))	('NOTCH1', 'Gene', '4851', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('a tumor', 'Disease', 'MESH:D009369', (37, 44))	('SMG', 'Gene', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('loss-of-function', 'NegReg', (61, 77))
40981	24022702	For example, if functional assays are performed in primary cells that have been immortalized by engineering specific genetic alterations, or cancer lines possessing inactivation of a tumor suppressor or activation of an oncogene that a candidate SMG may function through, a phenotype may not be observed due to prior deregulation.	('a tumor', 'Disease', (181, 188))	('SMG', 'Gene', (246, 249))	('function', 'Reg', (254, 262))	('SMG', 'Gene', '23034', (246, 249))	('inactivation', 'Var', (165, 177))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('alterations', 'Var', (125, 136))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('a tumor', 'Disease', 'MESH:D009369', (181, 188))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('oncogene', 'Gene', (220, 228))	('activation', 'PosReg', (203, 213))	('cancer', 'Disease', (141, 147))
40983	24022702	An example is the lineage-specific melanoma oncogene, MITF, which, when overexpressed alone, did not affect the proliferation or colony-formation of immortalized melanocytes in two-dimensional culture but did so with co-expression of BRAF V600E mutant, which co-occur at a high frequency in melanoma samples.	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('MITF', 'Gene', '4286', (54, 58))	('MITF', 'Gene', (54, 58))	('V600E', 'Mutation', 'rs113488022', (239, 244))	('formation', 'biological_process', 'GO:0009058', ('136', '145'))	('BRAF', 'Gene', '673', (234, 238))	('melanoma', 'Disease', 'MESH:D008545', (291, 299))	('melanoma', 'Phenotype', 'HP:0002861', (291, 299))	('melanoma', 'Disease', (291, 299))	('V600E', 'Var', (239, 244))	('BRAF', 'Gene', (234, 238))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))
40984	24022702	For example, PREX2A, a gene found to possess widespread distribution of missense and truncating mutations discovered from WGS of 25 metastatic melanoma-normal pairs indicative of a tumor-suppressive function.	('missense and', 'Var', (72, 84))	('a tumor', 'Disease', 'MESH:D009369', (179, 186))	('truncating', 'MPA', (85, 95))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('PR', 'Gene', '5241', (13, 15))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))	('a tumor', 'Disease', (179, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
40985	24022702	However, missense mutations were found to produce mild phenotypes in in vivo tumorigenic assays, whereas, truncating mutations were shown to possess oncogenic activity that could have only been elucidated through functional experiments.	('oncogenic activity', 'CPA', (149, 167))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('missense mutations', 'Var', (9, 27))	('tumor', 'Disease', (77, 82))
40986	24022702	A similar observation was made in the case of a p53-inducible phosphatase, PPM1D, where truncating variants were shown to possess gain-of-function effects in functional studies.	('truncating variants', 'Var', (88, 107))	('p53', 'Gene', (48, 51))	('PPM1D', 'Gene', (75, 80))	('p53', 'Gene', '7157', (48, 51))	('gain-of-function', 'PosReg', (130, 146))	('PPM1D', 'Gene', '8493', (75, 80))
40992	24022702	More recently, WGS of mouse APL tumors was performed to identify cooperating somatic mutations in a mouse model expressing a PML-RARA fusion oncogene known to initiate APL in mice.	('mice', 'Species', '10090', (175, 179))	('mouse', 'Species', '10090', (100, 105))	('APL tumors', 'Disease', (28, 38))	('mutations', 'Var', (85, 94))	('APL tumors', 'Disease', 'MESH:D015473', (28, 38))	('APL', 'Phenotype', 'HP:0004836', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mouse', 'Species', '10090', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('APL', 'Phenotype', 'HP:0004836', (28, 31))
40993	24022702	The authors identified a deletion in a demethylase gene, Kdm6a, and a recurrent mutation in Jak1 V657F.	('Jak1', 'Gene', '3716', (92, 96))	('V657F', 'Var', (97, 102))	('V657F', 'Mutation', 'rs1057519753', (97, 102))	('deletion', 'Var', (25, 33))	('Jak1', 'Gene', (92, 96))	('Kdm6a', 'Gene', (57, 62))	('Kdm6a', 'Gene', '7403', (57, 62))
40994	24022702	The human JAK1 V658F mutation has been previously reported in APL, demonstrating analysis of WGS from GEM model tumors can be used as an unbiased approach for discovering functionally relevant mutations.	('human', 'Species', '9606', (4, 9))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('JAK1', 'Gene', '3716', (10, 14))	('JAK1', 'Gene', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('V658F', 'Var', (15, 20))	('JAK', 'molecular_function', 'GO:0004713', ('10', '13'))	('APL', 'Phenotype', 'HP:0004836', (62, 65))	('V658F', 'Mutation', 'rs1057519753', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
40999	24022702	For example, WGS analysis from 17 NSCLC tumor-normal pairs validated the presence of EGFR and KRAS mutations in founder clones supporting their roles in cancer initiation.	('EGFR', 'Gene', (85, 89))	('cancer initiation', 'Disease', 'MESH:D009369', (153, 170))	('KRAS', 'Gene', (94, 98))	('cancer initiation', 'Disease', (153, 170))	('EGFR', 'molecular_function', 'GO:0005006', ('85', '89'))	('KRAS', 'Gene', '3845', (94, 98))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('NSCLC tumor', 'Disease', 'MESH:D009369', (34, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('EGFR', 'Gene', '1956', (85, 89))	('NSCLC tumor', 'Disease', (34, 45))
41001	24022702	Recently, geographical sampling and multi-region sequencing of primary renal carcinomas and associated distant metastatic sites demonstrated that 63-69% of all somatic mutations were not detected across every tumor region, and gene expression signatures indicative of both good and poor prognosis were detected in different regions of the same tumor.	('tumor', 'Disease', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('primary renal carcinomas', 'Disease', (63, 87))	('tumor', 'Disease', (344, 349))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('primary renal carcinomas', 'Disease', 'MESH:C538614', (63, 87))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('renal carcinomas', 'Phenotype', 'HP:0005584', (71, 87))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('mutations', 'Var', (168, 177))	('tumor', 'Disease', 'MESH:D009369', (344, 349))
41005	24022702	Such studies are enabling classifications of cancers based on genetic alterations rather than tissues of origin.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Disease', (45, 52))	('genetic alterations', 'Var', (62, 81))
41010	33247170	Our results found that high AQP9 expression was significantly correlated with worse prognosis in breast, colon and lung cancers, while predicted better prognosis in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('lung cancers', 'Phenotype', 'HP:0100526', (115, 127))	('high', 'Var', (23, 27))	('gastric cancer', 'Phenotype', 'HP:0012126', (165, 179))	('AQP9', 'Gene', (28, 32))	('breast', 'Disease', (97, 103))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('colon and lung cancers', 'Disease', 'MESH:D008175', (105, 127))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('expression', 'MPA', (33, 43))	('better', 'PosReg', (145, 151))	('gastric cancer', 'Disease', (165, 179))	('gastric cancer', 'Disease', 'MESH:D013274', (165, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
41022	33247170	Lymphocyte activation gene 3 (LAG-3) is expressed in NK cells and activated T cells and blockade of LAG-3 promotes T-cell proliferation, activation and effector function.	('blockade', 'Var', (88, 96))	('Lymphocyte activation gene 3', 'Gene', (0, 28))	('promotes', 'PosReg', (106, 114))	('LAG-3', 'Gene', '3902', (30, 35))	('Lymphocyte activation gene 3', 'Gene', '3902', (0, 28))	('T-cell proliferation', 'biological_process', 'GO:0042098', ('115', '135'))	('LAG-3', 'Gene', (30, 35))	('Lymphocyte activation', 'biological_process', 'GO:0046649', ('0', '21'))	('T-cell proliferation', 'CPA', (115, 135))	('activation', 'CPA', (137, 147))	('LAG-3', 'Gene', '3902', (100, 105))	('effector function', 'CPA', (152, 169))	('LAG-3', 'Gene', (100, 105))
41030	33247170	AQP9 can inhibit the invasion of liver cancer cells and the proliferation of xenograft tumors.	('liver cancer', 'Disease', (33, 45))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('inhibit', 'NegReg', (9, 16))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('liver cancer', 'Phenotype', 'HP:0002896', (33, 45))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('AQP9', 'Var', (0, 4))	('liver cancer', 'Disease', 'MESH:D006528', (33, 45))
41032	33247170	Moreover, AQP9 can also activate RAS signal and sensitize tumor cells to chemotherapy drugs in colorectal cancer.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('colorectal cancer', 'Disease', (95, 112))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('activate', 'PosReg', (24, 32))	('RAS signal', 'MPA', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('AQP9', 'Var', (10, 14))	('sensitize', 'Reg', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
41048	33247170	It showed that higher AQP9 expression was associated with the mutant of TP53 in BRCA and BRAF in COAD.	('COAD', 'Disease', 'MESH:D029424', (97, 101))	('mutant', 'Var', (62, 68))	('higher', 'PosReg', (15, 21))	('TP53', 'Gene', '7157', (72, 76))	('BRCA', 'Phenotype', 'HP:0003002', (80, 84))	('BRCA', 'Gene', '672', (80, 84))	('COAD', 'Disease', (97, 101))	('TP53', 'Gene', (72, 76))	('BRCA', 'Gene', (80, 84))	('expression', 'MPA', (27, 37))	('BRAF', 'Gene', '673', (89, 93))	('BRAF', 'Gene', (89, 93))	('AQP9', 'Gene', (22, 26))
41056	33247170	In conclusion, the expression of AQP9 can make a profound difference to the prognosis of breast, lung and gastric cancers.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('gastric cancers', 'Disease', 'MESH:D013274', (106, 121))	('difference', 'Reg', (58, 68))	('expression', 'Var', (19, 29))	('gastric cancers', 'Disease', (106, 121))	('lung', 'Disease', (97, 101))	('gastric cancers', 'Phenotype', 'HP:0012126', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('AQP9', 'Gene', (33, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('breast', 'Disease', (89, 95))
41058	33247170	It was found that the overexpression of AQP9 was correlated with the prognosis at different lymph node status in BRCA, among which high AQP9 expression predicted poorer OS and RFS prognosis in Lymph node negative BRCA, and poorer RFS prognosis in Lymph node positive BRCA (Supplementary Table S2).	('BRCA', 'Phenotype', 'HP:0003002', (213, 217))	('RFS', 'Gene', (230, 233))	('RFS', 'Gene', '65211', (230, 233))	('BRCA', 'Gene', '672', (213, 217))	('RFS', 'Gene', '65211', (176, 179))	('BRCA', 'Gene', (213, 217))	('RFS', 'Gene', (176, 179))	('BRCA', 'Phenotype', 'HP:0003002', (113, 117))	('BRCA', 'Phenotype', 'HP:0003002', (267, 271))	('AQP9', 'Gene', (136, 140))	('expression', 'MPA', (141, 151))	('BRCA', 'Gene', '672', (113, 117))	('BRCA', 'Gene', '672', (267, 271))	('poorer', 'NegReg', (162, 168))	('BRCA', 'Gene', (113, 117))	('high', 'Var', (131, 135))	('BRCA', 'Gene', (267, 271))
41060	33247170	The high AQP9 expression was also found to have better impact on the prognosis of patients at stage N0, N2 and N1+2+3 in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('AQP9', 'Protein', (9, 13))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('patients', 'Species', '9606', (82, 90))	('better', 'PosReg', (48, 54))	('high', 'Var', (4, 8))	('impact', 'Reg', (55, 61))	('gastric cancer', 'Disease', (121, 135))	('N1+2+3', 'Var', (111, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))
41063	33247170	The results suggested that high AQP9 expression correlated with the prognosis of patients with lymphatic metastasis in breast, gastric and lung cancers.	('breast', 'Disease', (119, 125))	('lung cancers', 'Disease', 'MESH:D008175', (139, 151))	('gastric', 'Disease', (127, 134))	('lung cancers', 'Phenotype', 'HP:0100526', (139, 151))	('patients', 'Species', '9606', (81, 89))	('high', 'Var', (27, 31))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('correlated with', 'Reg', (48, 63))	('lung cancers', 'Disease', (139, 151))	('lymphatic metastasis', 'CPA', (95, 115))	('AQP9', 'Gene', (32, 36))	('expression', 'MPA', (37, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
41067	33247170	Furthermore, one cohort (GSE17536) revealed that high AQP9 expression predicted worse prognosis for colorectal cancer patients (Fig.	('colorectal cancer', 'Disease', 'MESH:D015179', (100, 117))	('colorectal cancer', 'Phenotype', 'HP:0003003', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('colorectal cancer', 'Disease', (100, 117))	('expression', 'MPA', (59, 69))	('high', 'Var', (49, 53))	('AQP9', 'Gene', (54, 58))	('patients', 'Species', '9606', (118, 126))
41081	33247170	These results strongly indicated that AQP9 might have an important effect on tumor immune infiltration, especially on the infiltrating levels of neutrophils, macrophages and DCs in breast, colorectal, lung and gastric cancers.	('breast', 'Disease', (181, 187))	('gastric cancer', 'Phenotype', 'HP:0012126', (210, 224))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('effect', 'Reg', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('gastric cancers', 'Disease', (210, 225))	('lung', 'Disease', (201, 205))	('infiltrating levels of neutrophils', 'MPA', (122, 156))	('gastric cancers', 'Disease', 'MESH:D013274', (210, 225))	('gastric cancers', 'Phenotype', 'HP:0012126', (210, 225))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('AQP9', 'Var', (38, 42))	('tumor', 'Disease', (77, 82))	('colorectal', 'Disease', (189, 199))	('DCs', 'MPA', (174, 177))
41086	33247170	The results suggested that AQP9 might correlate with macrophage polarization in BRCA, COAD, LUAD, LUSC and STAD.	('COAD', 'Disease', 'MESH:D029424', (86, 90))	('macrophage polarization', 'biological_process', 'GO:0042116', ('53', '76'))	('BRCA', 'Phenotype', 'HP:0003002', (80, 84))	('BRCA', 'Gene', '672', (80, 84))	('macrophage polarization', 'CPA', (53, 76))	('correlate', 'Reg', (38, 47))	('COAD', 'Disease', (86, 90))	('LUSC', 'Phenotype', 'HP:0030359', (98, 102))	('BRCA', 'Gene', (80, 84))	('LUAD', 'Phenotype', 'HP:0030078', (92, 96))	('AQP9', 'Var', (27, 31))
41103	33247170	As it has been reported in previous studies, AQP9 was required for efficient DCs maturation and affected macrophage function by regulating cell volume, shape and protrusion development via water fluxes.	('macrophage function', 'CPA', (105, 124))	('affected', 'Reg', (96, 104))	('water', 'Chemical', 'MESH:D014867', (189, 194))	('AQP9', 'Var', (45, 49))	('regulating', 'Reg', (128, 138))	('protrusion development', 'CPA', (162, 184))	('cell volume', 'CPA', (139, 150))
41107	33247170	We also found that the mutant TP53 in BRCA and mutant BRAF in COAD were correlated with higher AQP9 expression.	('higher', 'PosReg', (88, 94))	('COAD', 'Disease', 'MESH:D029424', (62, 66))	('TP53', 'Gene', (30, 34))	('BRCA', 'Gene', '672', (38, 42))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('BRCA', 'Gene', (38, 42))	('COAD', 'Disease', (62, 66))	('BRCA', 'Phenotype', 'HP:0003002', (38, 42))	('TP53', 'Gene', '7157', (30, 34))	('mutant', 'Var', (47, 53))	('mutant', 'Var', (23, 29))	('AQP9', 'Gene', (95, 99))
41108	33247170	It has been reported that TP53 mutations have different clinical relevance in molecular subtypes of BRCA and TP53 can affect tumor energy metabolism such as increasing glycolysis.	('TP53', 'Gene', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('mutations', 'Var', (31, 40))	('TP53', 'Gene', '7157', (26, 30))	('BRCA', 'Gene', '672', (100, 104))	('affect', 'Reg', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('BRCA', 'Gene', (100, 104))	('increasing', 'PosReg', (157, 167))	('TP53', 'Gene', '7157', (109, 113))	('tumor', 'Disease', (125, 130))	('metabolism', 'biological_process', 'GO:0008152', ('138', '148'))	('glycolysis', 'biological_process', 'GO:0006096', ('168', '178'))	('glycolysis', 'MPA', (168, 178))	('TP53', 'Gene', (109, 113))	('BRCA', 'Phenotype', 'HP:0003002', (100, 104))
41109	33247170	Although TP53 is recognized as a tumor suppressor gene in various cancers, the mutant TP53 does not necessarily represent its inactivation as a tumor suppressor gene, and it's highly likely to have a carcinogenic effect.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('144', '160'))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('TP53', 'Gene', (86, 90))	('TP53', 'Gene', '7157', (9, 13))	('tumor suppressor', 'biological_process', 'GO:0051726', ('144', '160'))	('tumor', 'Disease', (33, 38))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('carcinogenic', 'Disease', (200, 212))	('tumor', 'Disease', (144, 149))	('TP53', 'Gene', '7157', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('mutant', 'Var', (79, 85))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('TP53', 'Gene', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('carcinogenic', 'Disease', 'MESH:D063646', (200, 212))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
41110	33247170	BRAF mutations are common in colorectal cancer and confers significant prognosis to advanced diseases.	('colorectal cancer', 'Disease', 'MESH:D015179', (29, 46))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('colorectal cancer', 'Phenotype', 'HP:0003003', (29, 46))	('common', 'Reg', (19, 25))	('BRAF', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('colorectal cancer', 'Disease', (29, 46))
41111	33247170	Our study found that the difference in AQP9 expression was correlated with TP53 and BRAF mutants, which indicated a potential factor that might regulate AQP9 expression in breast and colon cancers.	('expression', 'MPA', (44, 54))	('BRAF', 'Gene', '673', (84, 88))	('expression', 'MPA', (158, 168))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('BRAF', 'Gene', (84, 88))	('regulate', 'Reg', (144, 152))	('colon cancers', 'Phenotype', 'HP:0003003', (183, 196))	('breast and colon cancers', 'Disease', 'MESH:D001943', (172, 196))	('mutants', 'Var', (89, 96))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))	('AQP9', 'Gene', (39, 43))
41114	33247170	This result suggested that AQP9 expression might also be affected by epigenetics to some extent, but the regulating effect varies from cancer to cancer.	('cancer', 'Disease', (145, 151))	('affected', 'Reg', (57, 65))	('cancer', 'Disease', (135, 141))	('AQP9', 'Gene', (27, 31))	('epigenetics', 'Var', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('expression', 'MPA', (32, 42))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
41115	33247170	Then, we further reported that discrepancies in AQP9 expression level had significant correlations with the prognosis of different tumors.	('correlations', 'Reg', (86, 98))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('AQP9', 'Gene', (48, 52))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('expression level', 'MPA', (53, 69))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('discrepancies', 'Var', (31, 44))
41119	33247170	Our findings were consistent with the previous study that high expression of AQP9 was associated with favorable OS in all gastric cancer patients including intestinal and diffused types , while high expression of AQP9 was accompanied by worse prognosis in patients with lymph node-negative breast cancer and was increased in higher SBR (Scarff-Bloom-Richardson) grades of all types of breast cancer in particular.	('high expression', 'Var', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (290, 303))	('high expression', 'Var', (194, 209))	('increased', 'PosReg', (312, 321))	('breast cancer', 'Disease', 'MESH:D001943', (290, 303))	('breast cancer', 'Disease', (290, 303))	('patients', 'Species', '9606', (137, 145))	('gastric cancer', 'Disease', (122, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (385, 398))	('AQP9', 'Var', (213, 217))	('AQP9', 'Gene', (77, 81))	('patients', 'Species', '9606', (256, 264))	('breast cancer', 'Disease', 'MESH:D001943', (385, 398))	('breast cancer', 'Disease', (385, 398))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))
41120	33247170	However, it may contradict and therefore discredit the results that AQP9 overexpression enhanced the cytotoxic response to 5-FU and promoted the activation of RAS through glycerol transport in CRC cells .	('glycerol transport', 'MPA', (171, 189))	('glycerol', 'Chemical', 'MESH:D005990', (171, 179))	('overexpression', 'Var', (73, 87))	('RAS', 'Protein', (159, 162))	('activation', 'MPA', (145, 155))	('cytotoxic response to 5-FU', 'MPA', (101, 127))	('promoted', 'PosReg', (132, 140))	('AQP9', 'Gene', (68, 72))	('enhanced', 'PosReg', (88, 96))	('5-FU', 'Chemical', 'MESH:D005472', (123, 127))
41124	33247170	It seemed that AQP9 could not only predict the clinical prognosis for tumor patients, but also be used as an indicator for the clinical treatment effect, providing directions for further improving the prognosis of patients.	('patients', 'Species', '9606', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('patients', 'Species', '9606', (214, 222))	('tumor', 'Disease', (70, 75))	('AQP9', 'Var', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('predict', 'Reg', (35, 42))
41126	33247170	Further studies should be conducted to explore whether AQP9 can promote the uptake of specific drugs by tumor cells based on its own transport properties to enhance the sensitivity of chemotherapy.	('enhance', 'PosReg', (157, 164))	('promote', 'PosReg', (64, 71))	('AQP9', 'Var', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('sensitivity of chemotherapy', 'CPA', (169, 196))	('tumor', 'Disease', (104, 109))	('uptake of specific drugs', 'MPA', (76, 100))	('transport properties', 'MPA', (133, 153))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
41132	33247170	These findings revealed the underlying regulatory role AQP9 might play in the polarization of TAMs, indicating AQP9 may be involved in the immunosuppression in the focused cancers.	('involved', 'Reg', (123, 131))	('AQP9', 'Var', (111, 115))	('TAMs', 'Chemical', 'MESH:D013629', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))
41136	33247170	These findings suggested that AQP9 might affect tumor immune through neutrophils and the correlation with CD11b.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('correlation', 'Interaction', (89, 100))	('affect', 'Reg', (41, 47))	('AQP9', 'Var', (30, 34))	('CD11b', 'Gene', '3684', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('CD11b', 'Gene', (106, 111))
41143	33247170	It was reported that DCs could increase Treg cells and reduce cytotoxicity of CD8+T cells, thus promoting tumor metastasis.	('cytotoxicity', 'Disease', 'MESH:D064420', (62, 74))	('CD8', 'Gene', (78, 81))	('promoting', 'PosReg', (96, 105))	('CD8', 'Gene', '925', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('Treg cells', 'CPA', (40, 50))	('cytotoxicity', 'Disease', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('increase', 'PosReg', (31, 39))	('reduce', 'NegReg', (55, 61))	('tumor', 'Disease', (106, 111))	('DCs', 'Var', (21, 24))
41149	33247170	In conclusion, AQP9 expression had a significant impact on the regulation of immune infiltration levels and tumor-immune interaction in BRCA, COAD, LUAD, LUSC and STAD.	('COAD', 'Disease', 'MESH:D029424', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('BRCA', 'Gene', (136, 140))	('LUAD', 'Phenotype', 'HP:0030078', (148, 152))	('expression', 'Var', (20, 30))	('immune infiltration levels', 'MPA', (77, 103))	('tumor', 'Disease', (108, 113))	('COAD', 'Disease', (142, 146))	('AQP9', 'Gene', (15, 19))	('BRCA', 'Gene', '672', (136, 140))	('BRCA', 'Phenotype', 'HP:0003002', (136, 140))	('impact', 'Reg', (49, 55))	('LUSC', 'Phenotype', 'HP:0030359', (154, 158))	('regulation', 'MPA', (63, 73))
41162	33247170	IL1RN polymorphism has been reported to promote the development of lung cancer through inflammatory response.	('promote', 'PosReg', (40, 47))	('polymorphism', 'Var', (6, 18))	('inflammatory response', 'CPA', (87, 108))	('IL1RN', 'Gene', '3557', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('IL1RN', 'Gene', (0, 5))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))
41168	33247170	It should also be addressed through molecular biology techniques to confirm whether AQP9 can be used as a therapeutic target in the immunotherapy of cancers and the specific mechanism in which AQP9 affects the prognosis and immune infiltrates in breast, colon, lung and gastric cancers.	('cancers', 'Disease', 'MESH:D009369', (278, 285))	('AQP9', 'Var', (193, 197))	('affects', 'Reg', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('cancers', 'Phenotype', 'HP:0002664', (278, 285))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('cancers', 'Disease', (278, 285))	('prognosis', 'CPA', (210, 219))	('gastric cancers', 'Disease', 'MESH:D013274', (270, 285))	('cancers', 'Disease', (149, 156))	('gastric cancers', 'Disease', (270, 285))	('gastric cancers', 'Phenotype', 'HP:0012126', (270, 285))	('colon', 'Disease', (254, 259))	('lung', 'Disease', (261, 265))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('gastric cancer', 'Phenotype', 'HP:0012126', (270, 284))	('immune infiltrates', 'CPA', (224, 242))	('breast', 'Disease', (246, 252))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
41186	32792685	BRAFV600E drives dedifferentiation in small intestinal and colonic organoids and cooperates with mutant p53 and Apc loss in transformation BRAFV600E confers poor prognosis and is associated with a distinct subtype of colorectal cancer (CRC).	('p53', 'Gene', (104, 107))	('colonic', 'Disease', 'MESH:D003110', (59, 66))	('associated with', 'Reg', (179, 194))	('p53', 'Gene', '22059', (104, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (217, 234))	('BRAFV600E', 'Var', (139, 148))	('colorectal cancer', 'Disease', (217, 234))	('Apc', 'Gene', (112, 115))	('colonic', 'Disease', (59, 66))	('Apc', 'Gene', '11789', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('CRC', 'Phenotype', 'HP:0003003', (236, 239))	('dedifferentiation', 'CPA', (17, 34))	('colorectal cancer', 'Disease', 'MESH:D015179', (217, 234))	('BRAFV600E', 'Var', (0, 9))
41188	32792685	Using these isogenic models, we observe tissue-specific differences toward sudden BRAFV600E expression, which can be attributed to different ERK-pathway ground states in small and large intestinal crypts.	('BRAFV600E', 'Var', (82, 91))	('ERK', 'Gene', (141, 144))	('ERK', 'Gene', '26413', (141, 144))
41189	32792685	BRAFV600E alone causes transient proliferation and suppresses epithelial organization, followed by organoid disintegration.	('epithelial organization', 'CPA', (62, 85))	('organoid disintegration', 'CPA', (99, 122))	('V600E', 'Mutation', 'rs113488022', (4, 9))	('suppresses', 'NegReg', (51, 61))	('BRAFV600E', 'Var', (0, 9))
41190	32792685	Moreover, BRAFV600E induces a fetal-like dedifferentiation transcriptional program in colonic organoids, which resembles human BRAFV600E-driven CRC.	('V600E', 'Mutation', 'rs113488022', (131, 136))	('BRAFV600E', 'Var', (10, 19))	('CRC', 'Phenotype', 'HP:0003003', (144, 147))	('colonic', 'Disease', 'MESH:D003110', (86, 93))	('induces', 'Reg', (20, 27))	('colonic', 'Disease', (86, 93))	('dedifferentiation transcriptional program', 'MPA', (41, 82))	('human', 'Species', '9606', (121, 126))	('V600E', 'Mutation', 'rs113488022', (14, 19))	('fetal-like', 'CPA', (30, 40))
41191	32792685	Co-expression of p53R172H delays organoid disintegration, confers anchorage-independent growth, and induces invasive properties.	('organoid disintegration', 'CPA', (33, 56))	('induces', 'PosReg', (100, 107))	('p53R172H', 'Var', (17, 25))	('anchorage-independent growth', 'CPA', (66, 94))	('R172H', 'Mutation', 'p.R172H', (20, 25))	('invasive properties', 'CPA', (108, 127))	('confers', 'PosReg', (58, 65))	('delays', 'NegReg', (26, 32))
41192	32792685	Interestingly, p53R172H cooperates with BRAFV600E to modulate the abundance of transcripts linked to carcinogenesis, in particular within colonic organoids.	('p53R172H', 'Var', (15, 23))	('carcinogenesis', 'Disease', (101, 115))	('modulate', 'Reg', (53, 61))	('colonic', 'Disease', 'MESH:D003110', (138, 145))	('colonic', 'Disease', (138, 145))	('abundance of transcripts', 'MPA', (66, 90))	('carcinogenesis', 'Disease', 'MESH:D063646', (101, 115))
41193	32792685	Remarkably, WNT-pathway activation by Apc deletion fully protects organoids against BRAFV600E-induced disintegration and confers growth/niche factor independence.	('Apc', 'Gene', '11789', (38, 41))	('WNT-pathway', 'Pathway', (12, 23))	('activation', 'PosReg', (24, 34))	('deletion', 'Var', (42, 50))	('Apc', 'Gene', (38, 41))	('BRAFV600E-induced', 'Var', (84, 101))
41194	32792685	Still, Apc-deficient BRAFV600E-mutant organoids remain sensitive toward the MEK inhibitor trametinib, albeit p53R172H confers partial resistance against this clinically relevant compound.	('MEK', 'Gene', '17242', (76, 79))	('Apc', 'cellular_component', 'GO:0005680', ('7', '10'))	('BRAFV600E-mutant', 'Gene', (21, 37))	('resistance', 'MPA', (134, 144))	('MEK', 'Gene', (76, 79))	('Apc', 'Gene', (7, 10))	('trametinib', 'Chemical', 'MESH:C560077', (90, 100))	('Apc', 'Gene', '11789', (7, 10))	('p53R172H', 'Var', (109, 117))
41197	32792685	This heterogeneity is explained by a multistep carcinogenesis, involving the dysregulation of several signaling axes with combinations of Wnt, ERK, PI3K, TGFbeta, and Notch pathway alterations.	('alterations', 'Var', (181, 192))	('TGFbeta', 'Gene', '21802', (154, 161))	('TGFbeta', 'Gene', (154, 161))	('carcinogenesis', 'Disease', (47, 61))	('dysregulation', 'MPA', (77, 90))	('ERK', 'Gene', '26413', (143, 146))	('Notch pathway', 'Pathway', (167, 180))	('PI3K', 'molecular_function', 'GO:0016303', ('148', '152'))	('ERK', 'molecular_function', 'GO:0004707', ('143', '146'))	('signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('PI3K', 'Gene', (148, 152))	('ERK', 'Gene', (143, 146))	('carcinogenesis', 'Disease', 'MESH:D063646', (47, 61))
41199	32792685	Frequent ERK-pathway alterations comprise KRAS and BRAF mutations, although both oncogenes trigger overlapping and distinct processes.	('KRAS', 'Gene', (42, 46))	('mutations', 'Var', (56, 65))	('ERK', 'molecular_function', 'GO:0004707', ('9', '12'))	('ERK', 'Gene', (9, 12))	('ERK', 'Gene', '26413', (9, 12))	('BRAF', 'Gene', (51, 55))	('KRAS', 'Gene', '16653', (42, 46))	('alterations', 'Reg', (21, 32))
41200	32792685	The most common BRAF mutation, the V600E substitution, generates a constitutively active oncoprotein and occurs in 11% of CRCs.	('constitutively active', 'MPA', (67, 88))	('CRC', 'Phenotype', 'HP:0003003', (122, 125))	('occurs', 'Reg', (105, 111))	('V600E', 'Var', (35, 40))	('generates', 'PosReg', (55, 64))	('oncoprotein', 'Protein', (89, 100))	('V600E', 'Mutation', 'rs113488022', (35, 40))
41201	32792685	BRAFV600E predicts poor survival, particularly in microsatellite-stable (MSS) tumors.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('poor', 'NegReg', (19, 23))	('microsatellite-stable', 'Disease', (50, 71))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('BRAFV600E', 'Var', (0, 9))
41202	32792685	Most BRAFV600E-driven CRCs arise via the so-called serrated pathway that differs from the classical adenoma-carcinoma sequence in which cancers are generated by early arising Wnt-pathway alterations followed by KRAS, SMAD4, and TP53 mutations.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('KRAS', 'Gene', '16653', (211, 215))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (100, 117))	('BRAFV600E-driven', 'Var', (5, 21))	('cancers', 'Disease', (136, 143))	('KRAS', 'Gene', (211, 215))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('SMAD4', 'Gene', (217, 222))	('TP53', 'Gene', '22059', (228, 232))	('TP53', 'Gene', (228, 232))	('arise', 'Reg', (27, 32))	('CRC', 'Phenotype', 'HP:0003003', (22, 25))	('adenoma-carcinoma', 'Disease', (100, 117))	('SMAD4', 'Gene', '17128', (217, 222))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('CRCs', 'Disease', (22, 26))
41204	32792685	Moreover, BRAFV600E-mutant CRCs predominantly occur in the proximal colon, display mucinous histology and a poor differentiation status.	('CRC', 'Phenotype', 'HP:0003003', (27, 30))	('mucin', 'Gene', '100508689', (83, 88))	('CRCs', 'Disease', (27, 31))	('BRAFV600E-mutant', 'Var', (10, 26))	('mucin', 'Gene', (83, 88))	('occur', 'Reg', (46, 51))
41205	32792685	Indeed, BRAFV600E signaling suppresses CDX2 expression and thereby differentiation, whereas BRAF inhibitors induce epithelial re-differentiation in human CRC cell lines.	('expression', 'MPA', (44, 54))	('CDX2', 'Gene', (39, 43))	('BRAFV600E signaling', 'Var', (8, 27))	('V600E', 'Mutation', 'rs113488022', (12, 17))	('epithelial re-differentiation', 'CPA', (115, 144))	('differentiation', 'CPA', (67, 82))	('human', 'Species', '9606', (148, 153))	('suppresses', 'NegReg', (28, 38))	('induce', 'Reg', (108, 114))	('CRC', 'Phenotype', 'HP:0003003', (154, 157))
41206	32792685	In contrast to the classical APC-KRAS-TP53 sequence, BRAFV600E-mutant CRC is less studied.	('TP53', 'Gene', (38, 42))	('KRAS', 'Gene', '16653', (33, 37))	('V600E', 'Mutation', 'rs113488022', (57, 62))	('KRAS', 'Gene', (33, 37))	('CRC', 'Phenotype', 'HP:0003003', (70, 73))	('APC', 'Gene', '11789', (29, 32))	('BRAFV600E-mutant', 'Var', (53, 69))	('APC', 'Gene', (29, 32))	('TP53', 'Gene', '22059', (38, 42))
41207	32792685	The fact that BRAFV600E by itself cannot trigger metastatic disease in mice raises the question with which other genetic alterations it cooperates in carcinogenesis.	('mice', 'Species', '10090', (71, 75))	('carcinogenesis', 'Disease', (150, 164))	('carcinogenesis', 'Disease', 'MESH:D063646', (150, 164))	('BRAFV600E', 'Var', (14, 23))
41208	32792685	BRAF-mutant CRC cell lines often carry TP53 mutations, suggesting their contribution to CRC progression, as observed in other entities.	('CRC', 'Disease', (88, 91))	('CRC', 'Phenotype', 'HP:0003003', (12, 15))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '22059', (39, 43))	('CRC', 'Phenotype', 'HP:0003003', (88, 91))	('contribution', 'Reg', (72, 84))	('TP53', 'Gene', (39, 43))
41209	32792685	Indeed, several observations pinpoint to a functional relationship between BRAFV600E and TP53 mutations in establishing metastatic CRCs.	('TP53', 'Gene', '22059', (89, 93))	('TP53', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('establishing', 'Disease', (107, 119))	('CRC', 'Phenotype', 'HP:0003003', (131, 134))	('V600E', 'Mutation', 'rs113488022', (79, 84))	('BRAFV600E', 'Var', (75, 84))
41211	32792685	showed in their mouse model that BRAFV600E is more likely to induce metastatic disease in combination with Tp53R172H, although the underlying mechanisms were not addressed.	('induce', 'PosReg', (61, 67))	('metastatic disease', 'CPA', (68, 86))	('BRAFV600E', 'Var', (33, 42))	('mouse', 'Species', '10090', (16, 21))	('R172H', 'Mutation', 'p.R172H', (111, 116))
41212	32792685	Second, 58% of serrated adenocarcinoma displayed strong nuclear p53 staining, indicating mutant p53 protein.	('serrated adenocarcinoma', 'Phenotype', 'HP:0032222', (15, 38))	('p53', 'Gene', (96, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('protein', 'Protein', (100, 107))	('adenocarcinoma', 'Disease', (24, 38))	('nuclear', 'MPA', (56, 63))	('adenocarcinoma', 'Disease', 'MESH:D000230', (24, 38))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('mutant', 'Var', (89, 95))
41213	32792685	A very recent analysis showed that CRCs with co-alterations in RAS or BRAF together with TP53 mutations were associated with worse overall survival and metastasis.	('TP53', 'Gene', '22059', (89, 93))	('TP53', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('CRC', 'Phenotype', 'HP:0003003', (35, 38))	('metastasis', 'CPA', (152, 162))	('overall survival', 'CPA', (131, 147))	('worse', 'NegReg', (125, 130))	('CRCs', 'Disease', (35, 39))	('RAS', 'Protein', (63, 66))	('co-alterations', 'Var', (45, 59))	('BRAF', 'Gene', (70, 74))
41214	32792685	For example, increased nuclear beta-catenin localization and WNT target gene expression have been observed during tumor progression in BRAFV600E knock-in mice, while WNT signaling promoting alterations, e.g, RNF43 mutations or RSPO3 fusions, have been recently detected in BRAFV600E-mutant human CRCs.	('RNF43', 'Gene', (208, 213))	('beta-catenin', 'Gene', '12387', (31, 43))	('localization', 'biological_process', 'GO:0051179', ('44', '56'))	('RNF43', 'Gene', '207742', (208, 213))	('BRAFV600E-mutant', 'Var', (273, 289))	('increased', 'PosReg', (13, 22))	('beta-catenin', 'Gene', (31, 43))	('CRC', 'Phenotype', 'HP:0003003', (296, 299))	('RSPO3', 'Gene', (227, 232))	('mutations', 'Var', (214, 223))	('tumor', 'Disease', (114, 119))	('WNT signaling', 'MPA', (166, 179))	('RSPO3', 'Gene', '72780', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('mice', 'Species', '10090', (154, 158))	('signaling', 'biological_process', 'GO:0023052', ('170', '179'))	('CRCs', 'Disease', (296, 300))	('BRAFV600E', 'Var', (135, 144))	('expression', 'MPA', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('human', 'Species', '9606', (290, 295))	('gene expression', 'biological_process', 'GO:0010467', ('72', '87'))
41219	32792685	Here, we address this question by systematically comparing the cellular behavior and transcriptomes of SI and COL organoids from knock-in mice allowing the conditional expression of BRAFV600E and p53R172H, either singly or in combination.	('BRAFV600E', 'Var', (182, 191))	('V600E', 'Mutation', 'rs113488022', (186, 191))	('p53R172H', 'Var', (196, 204))	('COL organoids', 'Chemical', '-', (110, 123))	('mice', 'Species', '10090', (138, 142))	('R172H', 'Mutation', 'p.R172H', (199, 204))
41220	32792685	However, restoration of WNT signaling by Apc deficiency rescues organoids confronted with BRAFV600E.	('WNT signaling', 'MPA', (24, 37))	('BRAFV600E', 'Var', (90, 99))	('organoids', 'CPA', (64, 73))	('Apc deficiency', 'Disease', 'MESH:C566056', (41, 55))	('Apc deficiency', 'Disease', (41, 55))	('rescues', 'PosReg', (56, 63))
41221	32792685	Moreover, mutant p53 cooperates with BRAFV600E in inducing prerequisites for metastasis and in recapitulating human CRC signatures.	('CRC', 'Phenotype', 'HP:0003003', (116, 119))	('mutant', 'Var', (10, 16))	('human', 'Species', '9606', (110, 115))	('inducing', 'PosReg', (50, 58))	('p53', 'Gene', (17, 20))	('V600E', 'Mutation', 'rs113488022', (41, 46))
41223	32792685	In the absence of Cre activity, the BraffloxV600E allele ensures expression of wild-type BRAF, while Trp53LSL-R172H contains a loxP-STOP-loxP cassette preventing p53R172H expression.	('p53R172H', 'Var', (162, 170))	('V600E', 'Mutation', 'rs113488022', (44, 49))	('Braf', 'Gene', (36, 40))	('R172H', 'Mutation', 'p.R172H', (165, 170))	('expression', 'MPA', (65, 75))	('R172H', 'Mutation', 'p.R172H', (110, 115))	('BRAF', 'Gene', (89, 93))	('Trp53LSL-R172H', 'Var', (101, 115))	('Braf', 'Gene', '109880', (36, 40))
41224	32792685	The R172H substitution confers dominant-negative effects and corresponds to the R175H mutation found in human tumors, incl.	('R175H', 'Mutation', 'rs28934578', (80, 85))	('dominant-negative', 'NegReg', (31, 48))	('effects', 'MPA', (49, 56))	('R175H', 'Var', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('human', 'Species', '9606', (104, 109))	('tumors', 'Disease', (110, 116))	('R172H', 'Mutation', 'p.R172H', (4, 9))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('R172H', 'Var', (4, 9))
41226	32792685	BRAFV600E expression and its downstream effects on ERK-pathway activation were confirmed by western blotting (Supplementary Fig.	('ERK', 'Gene', '26413', (51, 54))	('ERK', 'Gene', (51, 54))	('BRAFV600E', 'Var', (0, 9))
41227	32792685	Previous studies using either SI or COL organoids noted that BRAFV600E induces organoid disintegration and cell death.	('COL organoids', 'Chemical', '-', (36, 49))	('cell death', 'CPA', (107, 117))	('BRAFV600E', 'Var', (61, 70))	('induces', 'Reg', (71, 78))	('organoid disintegration', 'CPA', (79, 102))
41228	32792685	Interestingly, our comparison uncovered that COL organoids disintegrated earlier than their SI counterparts, and that disintegration was slightly but significantly delayed in COL organoids by co-expression of p53R172H (Supplementary Fig.	('p53R172H', 'Var', (209, 217))	('COL organoids', 'Chemical', '-', (45, 58))	('COL organoids', 'Chemical', '-', (175, 188))	('delayed', 'NegReg', (164, 171))
41230	32792685	S2c-f, BRAFV600E induced proliferation outside of morphologically defined ISC niches, irregularities in epithelial organization, impaired tight junction function, and loss of the stem cell niches.	('BRAFV600E', 'Var', (7, 16))	('proliferation', 'CPA', (25, 38))	('impaired tight junction function', 'Disease', (129, 161))	('S2c-f', 'Var', (0, 5))	('loss', 'NegReg', (167, 171))	('induced', 'Reg', (17, 24))	('tight junction', 'cellular_component', 'GO:0070160', ('138', '152'))	('impaired tight junction function', 'Disease', 'MESH:D003072', (129, 161))
41231	32792685	In summary, our BRAFV600E knock-in approach confirms previous findings on SI organoids showing a profound impact of transgenic BRAFV600K or BRAFV600E on organoid organization and demonstrates for the first time that BRAFV600E affects similar processes in COL organoids.	('BRAFV600E', 'Var', (140, 149))	('organoid organization', 'CPA', (153, 174))	('SI organoids', 'Chemical', '-', (74, 86))	('affects', 'Reg', (226, 233))	('transgenic', 'Species', '10090', (116, 126))	('BRAFV600K', 'Mutation', 'rs121913227', (127, 136))	('BRAFV600E', 'Var', (216, 225))	('BRAFV600K', 'Var', (127, 136))	('COL organoids', 'Chemical', '-', (255, 268))
41232	32792685	Following the analysis of BRAFV600E (and p53R172H)-induced changes in SI and COL organoids, we assessed the impact and functional relationship of the two oncogenic mutations in both organoid types by RNA sequencing (RNA-Seq).	('p53R172H', 'Var', (41, 49))	('BRAFV600E', 'Var', (26, 35))	('COL organoids', 'Chemical', '-', (77, 90))	('V600E', 'Mutation', 'rs113488022', (30, 35))
41235	32792685	Gene set enrichment analysis (GSEA) confirmed that p53R172H-mutant organoids displayed altered expression of p53 pathway genes, indicating successful loss of p53 wild-type function (Fig.	('altered', 'Reg', (87, 94))	('R172H', 'Mutation', 'p.R172H', (54, 59))	('p53 pathway genes', 'Gene', (109, 126))	('p53R172H-mutant', 'Var', (51, 66))	('loss', 'NegReg', (150, 154))	('wild-type', 'MPA', (162, 171))	('expression', 'MPA', (95, 105))	('GSEA', 'Chemical', '-', (30, 34))
41236	32792685	Oncogene induction in BRAFV600E and BRAFV600E/p53R172H organoids induced a strong p53 signature; however, diminished p53 target gene activation could still be detected within the double-mutant organoids.	('p53 signature', 'MPA', (82, 95))	('BRAFV600E', 'Var', (22, 31))	('V600E', 'Mutation', 'rs113488022', (40, 45))	('V600E', 'Mutation', 'rs113488022', (26, 31))	('BRAFV600E/p53R172H', 'Var', (36, 54))	('induced', 'Reg', (65, 72))	('Oncogene', 'Gene', (0, 8))
41238	32792685	In both organoid types, BRAFV600E induced transcripts associated with metabolic rewiring (e.g., the glycolytic key enzymes HK1/2) as well as an immediate early gene response as reflected by the FOS family transcription factors (Fosl1, Fos) and negative feedback regulators of the EGFR/RAS/RAF/MEK/ERK pathway, such as Dusp4/5/6, Spry4, and Errfi1.	('Spry4', 'Gene', (329, 334))	('Fos', 'Gene', '14281', (228, 231))	('ERK', 'Gene', (297, 300))	('MEK', 'Gene', (293, 296))	('EGFR', 'Gene', (280, 284))	('EGFR', 'Gene', '13649', (280, 284))	('induced', 'Reg', (34, 41))	('V600E', 'Mutation', 'rs113488022', (28, 33))	('Fos', 'Gene', (235, 238))	('Spry4', 'Gene', '24066', (329, 334))	('Fos', 'Gene', '14281', (235, 238))	('Fosl1', 'Gene', '14283', (228, 233))	('ERK', 'Gene', '26413', (297, 300))	('FOS', 'Gene', '14281', (194, 197))	('Errfi1', 'Gene', (340, 346))	('BRAFV600E', 'Var', (24, 33))	('Dusp4/5/6', 'Gene', '319520;240672;67603', (318, 327))	('HK1/2', 'Gene', '15275;15277', (123, 128))	('Dusp4/5/6', 'Gene', (318, 327))	('HK1/2', 'Gene', (123, 128))	('Fosl1', 'Gene', (228, 233))	('MEK', 'Gene', '17242', (293, 296))	('transcripts', 'MPA', (42, 53))	('Errfi1', 'Gene', '74155', (340, 346))	('FOS', 'Gene', (194, 197))	('Fos', 'Gene', (228, 231))
41239	32792685	Of note, these and other transcripts were shown to be reversely affected by BRAF inhibitors in human CRC cell lines, and their cross-validation in clinical CRC samples and prognostic relevance is presented in a literature survey in Supplementary Table S2.	('BRAF', 'Gene', (76, 80))	('human', 'Species', '9606', (95, 100))	('affected', 'Reg', (64, 72))	('inhibitors', 'Var', (81, 91))	('CRC', 'Phenotype', 'HP:0003003', (156, 159))	('CRC', 'Phenotype', 'HP:0003003', (101, 104))
41245	32792685	Likewise, BRAFV600E-mutant organoids more abundantly expressed transcripts associated with human CRC and, in line with the mucinous phenotype of human BRAFV600E-positive tumors, mucin biosynthesis (Fig.	('mucin', 'Gene', '100508689', (123, 128))	('expressed transcripts', 'MPA', (53, 74))	('BRAFV600E-mutant', 'Var', (10, 26))	('more', 'PosReg', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('mucin', 'Gene', (178, 183))	('mucin', 'Gene', (123, 128))	('human', 'Species', '9606', (145, 150))	('CRC', 'Phenotype', 'HP:0003003', (97, 100))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('biosynthesis', 'biological_process', 'GO:0009058', ('184', '196'))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('V600E', 'Mutation', 'rs113488022', (155, 160))	('V600E', 'Mutation', 'rs113488022', (14, 19))	('tumors', 'Disease', (170, 176))	('mucin', 'Gene', '100508689', (178, 183))	('human CRC', 'Disease', (91, 100))	('human', 'Species', '9606', (91, 96))
41246	32792685	Indeed, BRAFV600E-expressing organoids secreted Mucin2 (Muc2) into their lumina, while expression of this glycoprotein was largely confined to Goblet cells in control and p53R127H-positive organoids (Fig.	('Muc2', 'Gene', (56, 60))	('V600E', 'Mutation', 'rs113488022', (12, 17))	('Mucin2', 'Gene', '17831', (48, 54))	('Mucin2', 'Gene', (48, 54))	('Muc2', 'Gene', '17831', (56, 60))	('secreted', 'MPA', (39, 47))	('BRAFV600E-expressing', 'Var', (8, 28))
41248	32792685	Moreover, genes like Cldn18 and the two cell-junction protein genes Gjb5 and Vsig1, which all have been associated with the serrated pathway, were only detected in COL organoids and especially upregulated in the double-mutant ones (Fig.	('double-mutant', 'Var', (212, 225))	('Vsig1', 'Gene', '78789', (77, 82))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('serrated pathway', 'Pathway', (124, 140))	('Gjb5', 'Gene', '14622', (68, 72))	('Vsig1', 'Gene', (77, 82))	('Gjb5', 'Gene', (68, 72))	('cell-junction', 'cellular_component', 'GO:0030054', ('40', '53'))	('Cldn18', 'Gene', (21, 27))	('COL organoids', 'Chemical', '-', (164, 177))	('upregulated', 'PosReg', (193, 204))
41249	32792685	This is in line with a highly significant correlation of the BRAFV600E-expressing COL organoids with gene expression profiles from human sessile-serrated adenoma (SSA) patients (Supplementary Fig.	('serrated adenoma', 'Phenotype', 'HP:0032222', (145, 161))	('human', 'Species', '9606', (131, 136))	('BRAFV600E-expressing', 'Var', (61, 81))	('COL organoids', 'Chemical', '-', (82, 95))	('patients', 'Species', '9606', (168, 176))	('sessile-serrated adenoma', 'Disease', 'MESH:D000236', (137, 161))	('gene expression', 'biological_process', 'GO:0010467', ('101', '116'))	('sessile-serrated adenoma', 'Disease', (137, 161))
41250	32792685	Given that BRAFV600E has been implicated in ISC exhaustion in SI organoids, we were interested whether BRAFV600E (and p53R172H) would affect transcripts associated with intestinal stemness and the Lgr5/Wnt-signaling pathway.	('transcripts', 'MPA', (141, 152))	('Wnt-signaling pathway', 'biological_process', 'GO:0016055', ('202', '223'))	('V600E', 'Mutation', 'rs113488022', (15, 20))	('SI organoids', 'Chemical', '-', (62, 74))	('intestinal stemness', 'Disease', (169, 188))	('Lgr5', 'Gene', '14160', (197, 201))	('Lgr5', 'Gene', (197, 201))	('affect', 'Reg', (134, 140))	('p53R172H', 'Var', (118, 126))	('intestinal stemness', 'Disease', 'MESH:D007410', (169, 188))	('V600E', 'Mutation', 'rs113488022', (107, 112))	('R172H', 'Mutation', 'p.R172H', (121, 126))
41251	32792685	1b, BRAFV600E suppressed many transcripts, which have been linked to ISC biology, in both organoid types.	('BRAFV600E', 'Var', (4, 13))	('transcripts', 'MPA', (30, 41))	('V600E', 'Mutation', 'rs113488022', (8, 13))	('suppressed', 'NegReg', (14, 24))
41253	32792685	Moreover, induction of BRAFV600E also decreased intestinal differentiation markers, in particular in COL organoids (Fig.	('decreased', 'NegReg', (38, 47))	('COL organoids', 'Chemical', '-', (101, 114))	('COL', 'MPA', (101, 104))	('intestinal differentiation markers', 'MPA', (48, 82))	('BRAFV600E', 'Var', (23, 32))
41254	32792685	This agrees with our previous study showing that BRAFV600E inhibitors induce epithelial differentiation markers such as Claudin-15, AMACR, and carboxyesterases (Ces) in human CRC cell lines.	('carboxyesterases', 'Disease', (143, 159))	('CRC', 'Phenotype', 'HP:0003003', (175, 178))	('V600E', 'Mutation', 'rs113488022', (53, 58))	('Claudin-15', 'Gene', '24146', (120, 130))	('induce', 'PosReg', (70, 76))	('human', 'Species', '9606', (169, 174))	('inhibitors', 'Var', (59, 69))	('BRAFV600E', 'Gene', (49, 58))	('Claudin-15', 'Gene', (120, 130))	('epithelial differentiation', 'CPA', (77, 103))	('AMACR', 'Disease', (132, 137))
41258	32792685	Importantly, our side-by-side comparison revealed that the BRAFV600E-mutant COL organoids more abundantly express transcripts associated with human CRC.	('BRAFV600E-mutant', 'Var', (59, 75))	('COL organoids', 'Chemical', '-', (76, 89))	('human', 'Species', '9606', (142, 147))	('transcripts', 'MPA', (114, 125))	('CRC', 'Phenotype', 'HP:0003003', (148, 151))	('V600E', 'Mutation', 'rs113488022', (63, 68))
41268	32792685	On the other hand, induction of BRAFV600E also markedly reduced intestinal differentiation markers, in particular in COL organoids (Fig.	('COL', 'MPA', (117, 120))	('intestinal', 'MPA', (64, 74))	('reduced', 'NegReg', (56, 63))	('BRAFV600E', 'Var', (32, 41))	('COL organoids', 'Chemical', '-', (117, 130))
41270	32792685	Of note, especially the BRAFV600E/p53R172H double-mutant COL organoids resembled the Cdx1/Cdx2 knockout signature.	('BRAFV600E/p53R172H', 'Var', (24, 42))	('R172H', 'Mutation', 'p.R172H', (37, 42))	('Cdx1', 'Gene', (85, 89))	('COL organoids', 'Chemical', '-', (57, 70))	('Cdx1', 'Gene', '12590', (85, 89))	('V600E', 'Mutation', 'rs113488022', (28, 33))
41275	32792685	This indicates that BRAFV600E and BRAFV600E/p53R172H induce a fetal spheroid-like program within intestinal organoids isolated from adult mice.	('BRAFV600E/p53R172H', 'Var', (34, 52))	('mice', 'Species', '10090', (138, 142))	('V600E', 'Mutation', 'rs113488022', (38, 43))	('fetal spheroid-like program', 'CPA', (62, 89))	('induce', 'PosReg', (53, 59))	('V600E', 'Mutation', 'rs113488022', (24, 29))	('BRAFV600E', 'Var', (20, 29))
41279	32792685	First, we compared 54 BRAFV600E-mutant colorectal adenocarcinoma (COAD) to 41 healthy colon samples listed in the TCGA database and then calculated the correlation to the LGR5-independent fetal signature (Fig.	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (39, 64))	('LGR5', 'Gene', (171, 175))	('LGR5', 'Gene', '8549', (171, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('COAD', 'Disease', (66, 70))	('COAD', 'Disease', 'MESH:D029424', (66, 70))	('BRAFV600E-mutant', 'Var', (22, 38))	('colorectal adenocarcinoma', 'Disease', (39, 64))
41281	32792685	Indeed, we observe a highly significant correlation between the fetal signature and BRAFV600E-mutant COAD.	('V600E', 'Mutation', 'rs113488022', (88, 93))	('COAD', 'Disease', (101, 105))	('COAD', 'Disease', 'MESH:D029424', (101, 105))	('BRAFV600E-mutant', 'Var', (84, 100))
41283	32792685	Thus, two independent approaches support the operation of a BRAFV600E-induced fetal dedifferentiation program in human CRC, which is recapitulated by our murine organoids.	('BRAFV600E-induced', 'Var', (60, 77))	('fetal dedifferentiation program', 'CPA', (78, 109))	('murine', 'Species', '10090', (154, 160))	('V600E', 'Mutation', 'rs113488022', (64, 69))	('CRC', 'Phenotype', 'HP:0003003', (119, 122))	('human', 'Species', '9606', (113, 118))
41284	32792685	Our above-described RNA-Seq analysis of BRAFV600E and/or p53R172H-mutant COL organoids revealed that 72 out of the 129 selected BRAFV600E-responsive transcripts, outside of the ERK target gene category, were more strongly modulated when p53R172H was present (Fig.	('V600E', 'Mutation', 'rs113488022', (132, 137))	('ERK', 'molecular_function', 'GO:0004707', ('177', '180'))	('ERK', 'Gene', (177, 180))	('V600E', 'Mutation', 'rs113488022', (44, 49))	('modulated', 'Reg', (222, 231))	('RNA', 'cellular_component', 'GO:0005562', ('20', '23'))	('p53R172H', 'Var', (237, 245))	('ERK', 'Gene', '26413', (177, 180))	('BRAFV600E', 'Var', (40, 49))	('p53R172H-mutant', 'Var', (57, 72))	('BRAFV600E-responsive', 'Var', (128, 148))	('strongly', 'PosReg', (213, 221))	('COL organoids', 'Chemical', '-', (73, 86))
41286	32792685	Validation of the RNA-Seq analysis revealed that co-expression of p53R172H further suppressed protein expression of NR2E3, which emerged as a potential tumor suppressor in breast and liver cancer (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('breast and liver cancer', 'Disease', 'MESH:D001943', (172, 195))	('tumor suppressor', 'biological_process', 'GO:0051726', ('152', '168'))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('liver cancer', 'Phenotype', 'HP:0002896', (183, 195))	('RNA', 'cellular_component', 'GO:0005562', ('18', '21'))	('tumor', 'Disease', (152, 157))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('152', '168'))	('protein expression', 'MPA', (94, 112))	('p53R172H', 'Var', (66, 74))	('NR2E3', 'Gene', (116, 121))	('NR2E3', 'Gene', '23958', (116, 121))	('suppressed', 'NegReg', (83, 93))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))
41287	32792685	Conversely, Ephrin type-A receptor 2 (EPHA2), a transcriptional RAS/RAF target, which is overexpressed in several human cancers, including CRC, was more strongly upregulated at the protein level when p53R172H was present (Supplementary Fig.	('Ephrin type-A receptor 2', 'Gene', (12, 36))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Ephrin type-A receptor 2', 'Gene', '1969', (12, 36))	('CRC', 'Disease', (139, 142))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('EPHA2', 'Gene', (38, 43))	('cancers', 'Disease', (120, 127))	('human', 'Species', '9606', (114, 119))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('upregulated', 'PosReg', (162, 173))	('CRC', 'Phenotype', 'HP:0003003', (139, 142))	('p53R172H', 'Var', (200, 208))
41288	32792685	Similarly, co-expression of p53R172H increased expression of CTSE (Fig.	('CTSE', 'Gene', '13034', (61, 65))	('CTSE', 'Gene', (61, 65))	('p53R172H', 'Var', (28, 36))	('increased', 'PosReg', (37, 46))	('expression', 'MPA', (47, 57))
41291	32792685	Moreover, increased CAV1 expression in T4-stage CRCs was associated with increased invasiveness, and depletion of CAV1 reduced the invasive properties of human CRC cell lines.	('invasiveness', 'CPA', (83, 95))	('increased', 'PosReg', (73, 82))	('human', 'Species', '9606', (154, 159))	('expression', 'MPA', (25, 35))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('CAV1', 'Gene', (20, 24))	('invasive properties of human CRC cell lines', 'CPA', (131, 174))	('depletion', 'Var', (101, 110))	('CRC', 'Phenotype', 'HP:0003003', (160, 163))	('reduced', 'NegReg', (119, 126))	('increased', 'PosReg', (10, 19))
41292	32792685	All these observations already support the collaboration between BRAFV600E and p53R172H.	('BRAFV600E', 'Var', (65, 74))	('R172H', 'Mutation', 'p.R172H', (82, 87))	('p53R172H', 'Var', (79, 87))
41293	32792685	To further investigate the functional relationship of the two oncogenic mutations, we introduced the delta log2 fold change between the double-mutant and BRAFV600E-only organoids and subjected it to GSEA.	('double-mutant', 'Var', (136, 149))	('V600E', 'Mutation', 'rs113488022', (158, 163))	('BRAFV600E-only', 'Var', (154, 168))	('delta log2', 'Var', (101, 111))	('GSEA', 'Chemical', '-', (199, 203))
41298	32792685	The activation of these invasion-associated signatures by the addition of p53R172H, especially within the COL organoids, ties in with the higher expression of selected "metastasis & invasion" associated genes (Fig.	('p53R172H', 'Var', (74, 82))	('COL organoids', 'Chemical', '-', (106, 119))	('expression', 'MPA', (145, 155))	('higher', 'PosReg', (138, 144))	('activation', 'PosReg', (4, 14))
41300	32792685	As RNA-Seq further revealed that BRAFV600E/p53R172H-expressing COL organoids display a transcriptional signature reflecting processes contributing to tumor progression and metastasis, we set up three experimental assays that reflect key prerequisites for tumor cell dissemination.	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('transcriptional', 'MPA', (87, 102))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('BRAFV600E/p53R172H-expressing', 'Var', (33, 62))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('COL organoids', 'Chemical', '-', (63, 76))	('tumor', 'Disease', (150, 155))
41303	32792685	The BRAFV600E/p53R172H double-mutants, however, displayed increased anchorage-independent growth (Fig.	('BRAFV600E/p53R172H', 'Var', (4, 22))	('increased', 'PosReg', (58, 67))	('R172H', 'Mutation', 'p.R172H', (17, 22))	('anchorage-independent growth', 'CPA', (68, 96))
41305	32792685	Indeed, BRAFV600E/p53R172H double-mutant organoids displayed higher CAV1 expression than the BRAFV600E single-mutants (Fig.	('CAV1', 'Gene', (68, 72))	('V600E', 'Mutation', 'rs113488022', (12, 17))	('higher', 'PosReg', (61, 67))	('expression', 'MPA', (73, 83))	('BRAFV600E/p53R172H', 'Var', (8, 26))	('R172H', 'Mutation', 'p.R172H', (21, 26))	('V600E', 'Mutation', 'rs113488022', (97, 102))
41307	32792685	Collectively, these data support the metastasis-associated transcriptomic signatures and further imply that p53R172H promotes the fitness and invasive properties of BRAFV600E-expressing organoids, which supports the assumption that TP53 mutations are important for the transition from adenoma to carcinoma.	('adenoma to carcinoma', 'Disease', 'MESH:D000236', (285, 305))	('TP53', 'Gene', '22059', (232, 236))	('fitness', 'Disease', (130, 137))	('fitness', 'Disease', 'MESH:D012640', (130, 137))	('adenoma to carcinoma', 'Disease', (285, 305))	('p53R172H', 'Var', (108, 116))	('promotes', 'PosReg', (117, 125))	('metastasis-associated', 'CPA', (37, 58))	('TP53', 'Gene', (232, 236))	('invasive properties', 'CPA', (142, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))
41308	32792685	Given that Wnt target genes are strongly reduced in BRAFV600E expressing COL organoids, and that survival of SI organoids is augmented by pharmacological or ligand-induced WNT-pathway activation, we tested whether this phenomenon is also applicable to COL organoids.	('reduced', 'NegReg', (41, 48))	('BRAFV600E', 'Var', (52, 61))	('SI organoids', 'Chemical', '-', (109, 121))	('augmented', 'PosReg', (125, 134))	('COL organoids', 'Chemical', '-', (252, 265))	('Wnt', 'Gene', (11, 14))	('survival', 'CPA', (97, 105))	('V600E', 'Mutation', 'rs113488022', (56, 61))	('COL organoids', 'Chemical', '-', (73, 86))
41309	32792685	Indeed, the GSK3 inhibitor CHIR-99021 improved the survival of BRAFV600E expressing COL organoids (Supplementary Fig.	('BRAFV600E', 'Var', (63, 72))	('improved', 'PosReg', (38, 46))	('COL organoids', 'Chemical', '-', (84, 97))	('GSK3', 'Gene', (12, 16))	('survival', 'CPA', (51, 59))	('GSK3', 'Gene', '56637', (12, 16))
41310	32792685	In addition to promoting beta-catenin degradation and thereby suppressing canonical Wnt signaling, GSK3 is involved in many other cellular processes, and hence this pharmacological approach by itself does not provide enough mechanistic support for a protection against BRAFV600E-induced organoid disintegration by Wnt signaling.	('canonical Wnt signaling', 'MPA', (74, 97))	('signaling', 'biological_process', 'GO:0023052', ('88', '97'))	('GSK3', 'Gene', '56637', (99, 103))	('signaling', 'biological_process', 'GO:0023052', ('318', '327'))	('promoting', 'PosReg', (15, 24))	('GSK', 'molecular_function', 'GO:0050321', ('99', '102'))	('suppressing', 'NegReg', (62, 73))	('involved', 'Reg', (107, 115))	('beta-catenin', 'Gene', '12387', (25, 37))	('GSK3', 'Gene', (99, 103))	('BRAFV600E-induced', 'Var', (269, 286))	('beta-catenin', 'Gene', (25, 37))	('degradation', 'biological_process', 'GO:0009056', ('38', '49'))
41313	32792685	Cre-mediated recombination occurred very efficiently as reflected by the recombination of the Apc locus and the switch to mGFP expression (Supplementary Fig.	('mGFP', 'Gene', (122, 126))	('Apc', 'Gene', (94, 97))	('recombination', 'Var', (73, 86))	('Apc', 'Gene', '11789', (94, 97))
41316	32792685	While APC loss alone could not prevent organoid death in the absence of the growth factors (GF) EGF, R-Spondin, Noggin, and Wnt3a, its combination with BRAFV600E or BRAFV600E/p53R172H conferred strong GF independence.	('BRAFV600E/p53R172H', 'Var', (165, 183))	('GF independence', 'MPA', (201, 216))	('BRAFV600E', 'Var', (152, 161))	('EGF', 'molecular_function', 'GO:0005154', ('96', '99'))	('Noggin', 'Gene', '18121', (112, 118))	('APC', 'cellular_component', 'GO:0005680', ('6', '9'))	('APC loss', 'Disease', 'MESH:D011125', (6, 14))	('APC loss', 'Disease', (6, 14))	('Wnt3a', 'Gene', '22416', (124, 129))	('Noggin', 'Gene', (112, 118))	('Wnt3a', 'Gene', (124, 129))
41317	32792685	This prompted us to define whether BRAFV600E-derived signals were still required in the context of APC inactivation.	('BRAFV600E-derived', 'Var', (35, 52))	('V600E', 'Mutation', 'rs113488022', (39, 44))	('APC', 'cellular_component', 'GO:0005680', ('99', '102'))	('APC', 'Gene', '11789', (99, 102))	('APC', 'Gene', (99, 102))
41319	32792685	Interestingly, trametinib impaired growth of the double- and triple-mutant COL organoids, while APC-deficient ones already died at the lowest trametinib concentration, indicating that the BRAF/MEK axis still acts as the driver of proliferation (Fig.	('MEK', 'Gene', '17242', (193, 196))	('growth', 'CPA', (35, 41))	('COL organoids', 'Chemical', '-', (75, 88))	('APC-deficient', 'Disease', 'MESH:D011125', (96, 109))	('double-', 'Var', (49, 56))	('impaired', 'NegReg', (26, 34))	('triple-mutant', 'Var', (61, 74))	('MEK', 'Gene', (193, 196))	('trametinib', 'Chemical', 'MESH:C560077', (15, 25))	('trametinib', 'Chemical', 'MESH:C560077', (142, 152))	('APC-deficient', 'Disease', (96, 109))
41324	32792685	S9, however, none of these read-outs were significantly elevated by p53R172H in trametinib-treated organoids, indicating that mutant p53 cannot counteract acute drug-induced ERK-pathway inhibition.	('p53R172H', 'Var', (68, 76))	('R172H', 'Mutation', 'p.R172H', (71, 76))	('trametinib', 'Chemical', 'MESH:C560077', (80, 90))	('ERK', 'Gene', (174, 177))	('p53', 'Gene', (133, 136))	('ERK', 'Gene', '26413', (174, 177))	('mutant', 'Var', (126, 132))
41325	32792685	Nevertheless, we observed a strong trend for higher phosphorylation of ERK and FOS and, although to a lesser extent, increased FOS and DUSP6 expression in the triple-mutant organoids under steady-state conditions (Supplementary Fig.	('FOS', 'Gene', (127, 130))	('FOS', 'Gene', (79, 82))	('increased', 'PosReg', (117, 126))	('FOS', 'Gene', '14281', (127, 130))	('triple-mutant', 'Var', (159, 172))	('DUSP6', 'Gene', (135, 140))	('FOS', 'Gene', '14281', (79, 82))	('ERK', 'Gene', (71, 74))	('ERK', 'Gene', '26413', (71, 74))	('ERK', 'molecular_function', 'GO:0004707', ('71', '74'))	('expression', 'MPA', (141, 151))	('higher', 'PosReg', (45, 51))	('phosphorylation', 'biological_process', 'GO:0016310', ('52', '67'))	('DUSP6', 'Gene', '67603', (135, 140))	('phosphorylation', 'MPA', (52, 67))
41326	32792685	This raises the possibility that p53R172H could induce ERK-mediated processes that pre-adapt triple-mutant organoids to trametinib treatment und other stressors.	('p53R172H', 'Var', (33, 41))	('trametinib', 'Chemical', 'MESH:C560077', (120, 130))	('ERK', 'Gene', '26413', (55, 58))	('induce', 'PosReg', (48, 54))	('R172H', 'Mutation', 'p.R172H', (36, 41))	('ERK', 'Gene', (55, 58))
41327	32792685	Indeed, the triple-mutant organoids displayed increased fitness as reflected by enhanced colony-forming capacity after single-cell disruption (Fig.	('fitness', 'Disease', (56, 63))	('fitness', 'Disease', 'MESH:D012640', (56, 63))	('increased', 'PosReg', (46, 55))	('colony-forming capacity', 'CPA', (89, 112))	('triple-mutant', 'Var', (12, 25))	('enhanced', 'PosReg', (80, 88))
41328	32792685	The identification of the precise mechanisms by which p53R172H confers trametinib resistance represents an area for future studies.	('p53R172H', 'Var', (54, 62))	('trametinib', 'Chemical', 'MESH:C560077', (71, 81))	('confers', 'Reg', (63, 70))	('trametinib resistance', 'MPA', (71, 92))
41329	32792685	In summary, the profound effect of APC deficiency on organoid survival highlights the importance of an intact stem cell niche for nascent tumor cells and support our hypothesis that BRAFV600E and p53R172H cooperate in colorectal carcinogenesis by conferring survival signals, MEK inhibitor resistance, and invasive properties.	('BRAFV600E', 'Var', (182, 191))	('survival signals', 'CPA', (258, 274))	('APC deficiency', 'Disease', (35, 49))	('p53R172H', 'Var', (196, 204))	('tumor', 'Disease', (138, 143))	('MEK', 'Gene', '17242', (276, 279))	('APC deficiency', 'Disease', 'MESH:D011125', (35, 49))	('colorectal carcinogenesis', 'Disease', (218, 243))	('colorectal carcinogenesis', 'Disease', 'MESH:D015179', (218, 243))	('R172H', 'Mutation', 'p.R172H', (199, 204))	('MEK', 'Gene', (276, 279))	('invasive properties', 'CPA', (306, 325))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('cooperate', 'Reg', (205, 214))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
41330	32792685	In this study, we have systematically compared the effects of BRAFV600E and p53R172H, either singly or in combination, on oncogene naive organoids from the small and large intestine of knock-in mice.	('R172H', 'Mutation', 'p.R172H', (79, 84))	('p53R172H', 'Var', (76, 84))	('mice', 'Species', '10090', (194, 198))	('BRAFV600E', 'Var', (62, 71))
41332	32792685	Previous work on SI organoids revealed that pharmacological inhibition of the BRAF-MEK-ERK axis prevents disintegration, indicating that this process is driven by aberrant ERK activity.	('ERK', 'Gene', (87, 90))	('MEK', 'Gene', '17242', (83, 86))	('ERK', 'Gene', '26413', (172, 175))	('ERK', 'Gene', '26413', (87, 90))	('SI organoids', 'Chemical', '-', (17, 29))	('MEK', 'Gene', (83, 86))	('pharmacological inhibition', 'Var', (44, 70))	('prevents', 'NegReg', (96, 104))	('disintegration', 'MPA', (105, 119))	('ERK', 'Gene', (172, 175))
41338	32792685	This is in line with our previous study on human CRC cell lines showing that BRAFV600E depletion or inhibition leads to differentiation, in part through increasing CDX2 levels.	('differentiation', 'CPA', (120, 135))	('BRAFV600E', 'Gene', (77, 86))	('CDX2 levels', 'MPA', (164, 175))	('CRC', 'Phenotype', 'HP:0003003', (49, 52))	('human', 'Species', '9606', (43, 48))	('depletion', 'Var', (87, 96))	('inhibition', 'NegReg', (100, 110))	('increasing', 'PosReg', (153, 163))
41339	32792685	This ties in with recent studies identifying Cdx2 as an important suppressor of BRAFV600E-driven CRC transformation.	('BRAFV600E-driven', 'Var', (80, 96))	('CRC', 'Phenotype', 'HP:0003003', (97, 100))	('CRC transformation', 'Disease', (97, 115))	('V600E', 'Mutation', 'rs113488022', (84, 89))
41340	32792685	Our transcriptomic analyses indicate that both at first sight contrasting mechanisms, namely the loss of Lgr5/Wnt target gene expression in combination with the induction of dedifferentiation patterns, operate simultaneously upon BRAFV600E expression.	('gene expression', 'biological_process', 'GO:0010467', ('121', '136'))	('loss', 'NegReg', (97, 101))	('expression', 'MPA', (126, 136))	('Lgr5', 'Gene', (105, 109))	('Lgr5', 'Gene', '14160', (105, 109))	('V600E', 'Mutation', 'rs113488022', (234, 239))	('dedifferentiation', 'biological_process', 'GO:0043696', ('174', '191'))	('BRAFV600E', 'Var', (230, 239))	('dedifferentiation patterns', 'CPA', (174, 200))
41343	32792685	Interestingly, we also observed a marked upregulation of several members of the Hippo target gene signature in COL organoids, even by BRAFV600E alone (Supplementary Fig.	('BRAFV600E', 'Var', (134, 143))	('COL organoids', 'Chemical', '-', (111, 124))	('upregulation', 'PosReg', (41, 53))	('Hippo target gene', 'Gene', (80, 97))
41344	32792685	In summary, we suggest that sudden BRAFV600E expression in organoids causes an imbalance of the stem-to-differentiation homeostasis and a poorly differentiated phenotype.	('imbalance of', 'MPA', (79, 91))	('imbalance', 'Phenotype', 'HP:0002172', (79, 88))	('V600E', 'Mutation', 'rs113488022', (39, 44))	('BRAFV600E', 'Var', (35, 44))	('poorly differentiated phenotype', 'CPA', (138, 169))	('homeostasis', 'biological_process', 'GO:0042592', ('120', '131'))	('causes', 'Reg', (69, 75))
41345	32792685	The genetic complexity of BRAFV600E-mutant CRC not only aggravates their treatment but also their reconstruction in carcinogenesis models.	('carcinogenesis', 'Disease', 'MESH:D063646', (116, 130))	('aggravates', 'PosReg', (56, 66))	('carcinogenesis', 'Disease', (116, 130))	('V600E', 'Mutation', 'rs113488022', (30, 35))	('BRAFV600E-mutant', 'Var', (26, 42))	('CRC', 'Phenotype', 'HP:0003003', (43, 46))	('CRC', 'Gene', (43, 46))
41347	32792685	Here, we report the first analysis of the cooperation between BRAFV600E and p53R172H in SI as well as COL organoid models.	('V600E', 'Mutation', 'rs113488022', (66, 71))	('p53R172H', 'Var', (76, 84))	('BRAFV600E', 'Var', (62, 71))
41348	32792685	As mutant p53 contributes to escape from cell death, senescence, or genomic stress, we speculated that p53R172H helps to overcome the oncogenic stress of organoids with BRAFV600E expression.	('R172H', 'Mutation', 'p.R172H', (106, 111))	('mutant', 'Var', (3, 9))	('p53', 'Gene', (10, 13))	('p53R172H', 'Var', (103, 111))
41349	32792685	Indeed, p53R172H slightly extended survival of BRAFV600E expressing organoids and conveyed several key properties of metastatic cells, such as increased fitness, invasive behavior and anoikis resistance (Fig.	('increased', 'PosReg', (143, 152))	('fitness', 'Disease', (153, 160))	('fitness', 'Disease', 'MESH:D012640', (153, 160))	('survival', 'CPA', (35, 43))	('extended', 'PosReg', (26, 34))	('conveyed', 'Reg', (82, 90))	('R172H', 'Mutation', 'p.R172H', (11, 16))	('p53R172H', 'Var', (8, 16))	('V600E', 'Mutation', 'rs113488022', (51, 56))	('anoikis resistance', 'CPA', (184, 202))	('BRAFV600E', 'Gene', (47, 56))	('invasive behavior', 'CPA', (162, 179))
41350	32792685	This might explain the association and collaboration between BRAF and TP53 mutations in metastatic CRC.	('association', 'Interaction', (23, 34))	('TP53', 'Gene', '22059', (70, 74))	('metastatic CRC', 'Disease', (88, 102))	('BRAF', 'Gene', (61, 65))	('TP53', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))	('CRC', 'Phenotype', 'HP:0003003', (99, 102))
41352	32792685	In contrast, Wnt-pathway activation by bi-allelic Apc deficiency alone prevented the disintegrative phenotype and conferred growth/niche factor independence to BRAFV600E expressing COL organoids (Fig.	('Apc deficiency', 'Disease', 'MESH:C566056', (50, 64))	('Apc deficiency', 'Disease', (50, 64))	('bi-allelic', 'Var', (39, 49))	('Wnt-pathway', 'Pathway', (13, 24))	('disintegrative phenotype', 'MPA', (85, 109))	('COL organoids', 'Chemical', '-', (181, 194))	('activation', 'PosReg', (25, 35))	('prevented', 'NegReg', (71, 80))
41355	32792685	reported an extremely aggressive subset (20.8%) of BRAFV600E-mutant CRCs that is characterized by co-existing APC truncations.	('CRC', 'Phenotype', 'HP:0003003', (68, 71))	('BRAFV600E-mutant', 'Var', (51, 67))	('APC', 'Gene', '11789', (110, 113))	('APC', 'Gene', (110, 113))	('APC', 'cellular_component', 'GO:0005680', ('110', '113'))	('CRCs', 'Disease', (68, 72))
41356	32792685	Poor survival was recapitulated in Apcmin/+ mice, in which BRAFV600E accelerated disease progression by promoting massive polyp load.	('massive polyp load', 'MPA', (114, 132))	('Apc', 'Gene', '11789', (35, 38))	('promoting', 'PosReg', (104, 113))	('disease progression', 'CPA', (81, 100))	('V600E', 'Mutation', 'rs113488022', (63, 68))	('Apc', 'Gene', (35, 38))	('mice', 'Species', '10090', (44, 48))	('accelerated', 'PosReg', (69, 80))	('BRAFV600E', 'Var', (59, 68))
41357	32792685	The underlying mechanisms and the behavior of BrafV600E/Apc double-mutant tumor cells were not investigated by Fennell et al., but our organoid data support their concept that BRAFV600E and APC truncations induce an overt proliferative phenotype.	('Apc', 'Gene', (56, 59))	('BRAFV600E', 'Var', (176, 185))	('Apc', 'Gene', '11789', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('induce', 'Reg', (206, 212))	('APC', 'Gene', '11789', (190, 193))	('tumor', 'Disease', (74, 79))	('Apc', 'cellular_component', 'GO:0005680', ('56', '59'))	('APC', 'Gene', (190, 193))	('APC', 'cellular_component', 'GO:0005680', ('190', '193'))	('BrafV600E', 'Mutation', 'rs113488022', (46, 55))
41358	32792685	Despite the critical contribution of Apc deficiency to the fitness of BRAFV600E-expressing organoids, we observed that their growth and survival were still dependent on MEK activity.	('Apc deficiency to the fitness', 'Disease', 'MESH:D012640', (37, 66))	('MEK', 'Gene', '17242', (169, 172))	('MEK activity', 'molecular_function', 'GO:0004708', ('169', '181'))	('Apc deficiency to the fitness', 'Disease', (37, 66))	('Apc', 'cellular_component', 'GO:0005680', ('37', '40'))	('MEK', 'Gene', (169, 172))	('BRAFV600E-expressing', 'Var', (70, 90))
41359	32792685	Remarkably, p53R172H added a clear survival benefit to Apc-deficient BRAFV600E expressing organoids exposed to the relatively high trametinib concentration of 100 nM.	('Apc', 'Gene', '11789', (55, 58))	('BRAFV600E', 'Gene', (69, 78))	('trametinib', 'Chemical', 'MESH:C560077', (131, 141))	('p53R172H', 'Var', (12, 20))	('Apc', 'Gene', (55, 58))	('survival benefit', 'CPA', (35, 51))
41362	32792685	Villin::CreERT2 transgenic animals were intercrossed with mice carrying conditional BraffloxV600E/+ and/or Trp53LSL-R172H/+ (Olive et al.)	('Braf', 'Gene', '109880', (84, 88))	('V600E', 'Mutation', 'rs113488022', (92, 97))	('Olive', 'Species', '4146', (125, 130))	('transgenic', 'Species', '10090', (16, 26))	('Trp53LSL-R172H/+', 'Var', (107, 123))	('Braf', 'Gene', (84, 88))	('mice', 'Species', '10090', (58, 62))	('R172H', 'Mutation', 'p.R172H', (116, 121))
41368	32792685	COL organoids were disrupted into single cells by Accutase treatment for 10 min at 37  C. Single cells were seeded in 50 microl Matrigel supplemented with 10 microM Y27632 onto a pre-warmed 24-well culture dish, and oncogene expression was subsequently induced with 3 microM 4-HT.	('Y27632', 'Chemical', 'MESH:C108830', (165, 171))	('4-HT', 'Chemical', 'MESH:C016601', (275, 279))	('induced', 'Reg', (253, 260))	('Y27632', 'Var', (165, 171))	('COL organoids', 'Chemical', '-', (0, 13))	('oncogene', 'Gene', (216, 224))	('pre', 'molecular_function', 'GO:0003904', ('179', '182'))
41378	32792685	The sections were processed and stained using standard methods with the following primary antibodies against: CTSE (1:100, ab36996, Abcam), ECAD (1:200, 610181, BD Biosciences), ITGB1 (1:150, 610467, BD Biosceiences), KI-67 (1:400, #9129, Cell Signaling), LYSC (1:50, sc-27958, Santa Cruz), PKCzeta (1:300, sc-216, Santa Cruz), MUC2 (1:50, sc-15334, Santa Cruz).	('1:400', 'Var', (225, 230))	('ITGB1', 'Gene', '16412', (178, 183))	('MUC2', 'Gene', (328, 332))	('1:150', 'Var', (185, 190))	('1:50', 'Var', (334, 338))	('1:50', 'Var', (262, 266))	('ITGB1', 'Gene', (178, 183))	('CTSE', 'Gene', '13034', (110, 114))	('1:300', 'Var', (300, 305))	('KI-67', 'Gene', '17345', (218, 223))	('KI-67', 'Gene', (218, 223))	('PKCzeta', 'molecular_function', 'GO:0004697', ('291', '298'))	('Signaling', 'biological_process', 'GO:0023052', ('244', '253'))	('CTSE', 'Gene', (110, 114))	('1:200', 'Var', (146, 151))	('MUC2', 'Gene', '17831', (328, 332))
41430	29845348	When analyzing non-pleural-based metastases alone, minimal ablation margin retained significance as a predictor of LTP on univariate analysis (p < 0.001) (Table 7, Fig.	('minimal ablation margin', 'Var', (51, 74))	('metastases', 'Disease', 'MESH:D009362', (33, 43))	('LTP', 'Disease', (115, 118))	('metastases', 'Disease', (33, 43))
41432	29845348	LTP rate of tumors >= 1 cm in size was 41% when minimal margin was < 5 mm, compared to 0% when minimal margin was >= 5 mm (p = 0.0004, Fig.	('LTP', 'biological_process', 'GO:0060291', ('0', '3'))	('< 5', 'Var', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
41478	30687400	Among the synthesized analogues, QMJ-2 and QMJ-5 were cytotoxic against HCT116 cells with an IC50 value of 68 +- 2.3 and 27.4 +- 1.8 microM, respectively.	('QMJ-5', 'Chemical', '-', (43, 48))	('QMJ-2', 'Var', (33, 38))	('QMJ-5', 'Var', (43, 48))	('cytotoxic', 'CPA', (54, 63))	('QMJ-2', 'Chemical', '-', (33, 38))	('HCT116', 'CellLine', 'CVCL:0291', (72, 78))
41482	30687400	In vivo studies revealed a significant decrease in colon weight to length ratio in QMJ-2 and QMJ-5 treatment groups compared to DMH control.	('decrease in colon weight', 'Phenotype', 'HP:0005210', (39, 63))	('decrease', 'NegReg', (39, 47))	('QMJ-2', 'Chemical', '-', (83, 88))	('DMH', 'Chemical', 'MESH:D019813', (128, 131))	('colon weight', 'Disease', 'MESH:D015431', (51, 63))	('QMJ-5', 'Chemical', '-', (93, 98))	('QMJ-2', 'Var', (83, 88))	('QMJ-5 treatment', 'Var', (93, 108))	('colon weight', 'Disease', (51, 63))
41491	30687400	Studies have shown that epigenetic alterations play a crucial role in the transformation of normal colon epithelial cells into adenomatous polyps.	('adenomatous polyps', 'Phenotype', 'HP:0005227', (127, 145))	('epigenetic alterations', 'Var', (24, 46))	('adenomatous polyps', 'Disease', 'MESH:D018256', (127, 145))	('adenomatous polyps', 'Disease', (127, 145))
41494	30687400	Studies have shown that knockdown of HDAC8 inhibits the proliferation of various cancer cells including colon cancer cells.	('colon cancer', 'Disease', (104, 116))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('HDAC8', 'Gene', (37, 42))	('cancer', 'Disease', (81, 87))	('proliferation', 'CPA', (56, 69))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('colon cancer', 'Phenotype', 'HP:0003003', (104, 116))	('colon cancer', 'Disease', 'MESH:D015179', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('knockdown', 'Var', (24, 33))	('inhibits', 'NegReg', (43, 51))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('HDAC8', 'Gene', '55869', (37, 42))
41499	30687400	The presence of C2=C3 double bond and the 3-OH group in quercetin is highly decisive for its antitumor properties.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('quercetin', 'Chemical', 'MESH:D011794', (56, 65))	('C2=C3', 'Var', (16, 21))
41524	30687400	Yield = 76%, m. p. 270 +- 1 C uncorrected; IR (KBr): 3305.99 (-OH, Str), 1606.7 (C=O, Str), 1118.71 (C-O-C, Str), and 1070.4 (N-C, Str) cm-1; 1H NMR (DMSO-d6); delta = 3.022 (s, 6H, N-C2H6), 6.842 (d, 2H, Ar), 7.425 (t, 1H, Ar), 7.716 (m, 2H, Ar), 8.081 (m, 3H, Ar), and 9.188 (s, 1H, -OH) ppm.	('1118.71', 'Var', (92, 99))	('1H', 'Chemical', '-', (281, 283))	('7.716', 'Var', (229, 234))	('1H', 'Chemical', '-', (220, 222))	('DMSO-d6', 'Chemical', '-', (150, 157))	('1H', 'Chemical', '-', (142, 144))	('N-C2H6', 'CellLine', 'CVCL:H592', (182, 188))	('1606.7', 'Var', (73, 79))	('3305.99', 'Var', (53, 60))
41525	30687400	13C NMR (DMSO-d6); delta = 111.88, 118.39, 118.61, 121.91, 124.77, 125.09, 129.43, 133.56, 137.73, 147.28, 151.50, 154.74, and 172.41 ppm.	('137.73', 'Var', (91, 97))	('133.56', 'Var', (83, 89))	('151.50', 'Var', (107, 113))	('147.28', 'Var', (99, 105))	('129.43', 'Var', (75, 81))	('13C', 'Chemical', '-', (0, 3))	('125.09', 'Var', (67, 73))	('121.91', 'Var', (51, 57))	('124.77', 'Var', (59, 65))	('DMSO-d6', 'Chemical', '-', (9, 16))	('118.61', 'Var', (43, 49))
41528	30687400	13C NMR (DMSO-d6); delta = 111.87, 118.43, 121.60, 124.25, 129.37, 134.19, 134.78, 137.69, 147.10, 151.45, 153.09, and 172.33 ppm.	('137.69', 'Var', (83, 89))	('13C', 'Chemical', '-', (0, 3))	('DMSO-d6', 'Chemical', '-', (9, 16))	('121.60', 'Var', (43, 49))	('134.19', 'Var', (67, 73))	('129.37', 'Var', (59, 65))	('151.45', 'Var', (99, 105))	('134.78', 'Var', (75, 81))	('147.10', 'Var', (91, 97))
41530	30687400	13C NMR (DMSO-d6); 20.91, 21.51, 118.68, 121.50, 124.31, 128.02, 129.06, 129.62, 134.50, 135.40, 139.18, 140.21, 145.75, 153.37, and 173.24 ppm.	('135.40', 'Var', (89, 95))	('121.50', 'Var', (41, 47))	('129.62', 'Var', (73, 79))	('13C', 'Chemical', '-', (0, 3))	('134.50', 'Var', (81, 87))	('145.75', 'Var', (113, 119))	('DMSO-d6', 'Chemical', '-', (9, 16))	('139.18', 'Var', (97, 103))	('129.06', 'Var', (65, 71))	('140.21', 'Var', (105, 111))
41531	30687400	Yield = 81%, m. p. 145 +- 1 C uncorrected; IR (KBr); 3261.63 (-OH, Str), 1610.56 (C=O, Str), 1166.93 (C-O-C, Str), and 2918.30 (C-H, Str) cm-1; 1H NMR (DMSO-d6); delta = 2.394 (s, 3H, -CH3), 2.481 (s, 3H, -CH3), 7.286 (d, 1H, Ar), 7.373 (d, 2H, Ar), 7.576 (s, 1H, Ar), 7.986 (d, 1H, Ar), 8.110 (d, 2H, Ar), and 9.449 (s, 1H, -OH) ppm; 13C NMR (DMSO-d6); delta = 21.51, 21.76, 145.46, 140.14, 173.17, 125.05, 126.55, 139.08, 118.33, 155.13, 119.58, 129.07, 127.95, 129.62, and 145.04 ppm.	('1H', 'Chemical', '-', (321, 323))	('155.13', 'Var', (432, 438))	('1H', 'Chemical', '-', (260, 262))	('1H', 'Chemical', '-', (144, 146))	('DMSO-d6', 'Chemical', '-', (344, 351))	('DMSO-d6', 'Chemical', '-', (152, 159))	('126.55', 'Var', (408, 414))	('118.33', 'Var', (424, 430))	('1H', 'Chemical', '-', (279, 281))	('139.08', 'Var', (416, 422))	('129.07', 'Var', (448, 454))	('1H', 'Chemical', '-', (222, 224))	('13C', 'Chemical', '-', (335, 338))
41532	30687400	Yield = 72%, m. p. 195 +- 1 C uncorrected; IR (KBr); 3277.06 (-OH, Str), 1604.77 (C=O, Str), 1166.93 (C-O-C, Str), 2845.00 (-OCH3, Str), and 2972.31 (C-H, Str) cm-1; 1H NMR (DMSO-d6); delta = 2.400 (s, 3H, -CH3), 3.926 (s, 3H, -OCH3), 7.043 (s, 1H, Ar), 7.063 (s, 1H, Ar), 7.374 (d, 2H, Ar), 8.002 (s, 1H, Ar), 8.150 (d, 2H, Ar), and 9.437 (s, 1H, -OH) ppm.	('7.043', 'Var', (235, 240))	('1H', 'Chemical', '-', (302, 304))	('DMSO-d6', 'Chemical', '-', (174, 181))	('1H', 'Chemical', '-', (264, 266))	('delta = 2.400', 'Var', (184, 197))	('1H', 'Chemical', '-', (166, 168))	('1H', 'Chemical', '-', (344, 346))	('1H', 'Chemical', '-', (245, 247))
41533	30687400	13C NMR (DMSO-d6); delta = 21.49, 56.55, 100.74, 115.11, 115.63, 126.60, 127.79, 129.09, 129.58, 138.94, 139.97, 145.17, 156.93, 164.10, and 172.76 ppm.	('164.10', 'Var', (129, 135))	('13C', 'Chemical', '-', (0, 3))	('139.97', 'Var', (105, 111))	('115.63', 'Var', (57, 63))	('DMSO-d6', 'Chemical', '-', (9, 16))	('129.58', 'Var', (89, 95))	('127.79', 'Var', (73, 79))	('115.11', 'Var', (49, 55))	('126.60', 'Var', (65, 71))	('129.09', 'Var', (81, 87))	('145.17', 'Var', (113, 119))	('138.94', 'Var', (97, 103))
41563	30687400	The safe dose of the promising two analogues (QMJ-2 and QMJ-5) and quercetin were evaluated using Organization for Economic Cooperation and Development (OECD), 425 guidelines.	('quercetin', 'Chemical', 'MESH:D011794', (67, 76))	('QMJ-2', 'Chemical', '-', (46, 51))	('QMJ-5', 'Chemical', '-', (56, 61))	('QMJ-2', 'Var', (46, 51))	('QMJ-5', 'Var', (56, 61))
41580	30687400	QMJ-1, QMJ-2, QMJ-3, QMJ-5, and QMJ-6 were found to be cytotoxic against colon cancer cells after 48 h of treatment.	('colon cancer', 'Disease', (73, 85))	('QMJ-2', 'Chemical', '-', (7, 12))	('QMJ', 'Chemical', '-', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('QMJ-1', 'Var', (0, 5))	('QMJ', 'Chemical', '-', (21, 24))	('QMJ', 'Chemical', '-', (7, 10))	('cytotoxic', 'CPA', (55, 64))	('QMJ', 'Chemical', '-', (14, 17))	('QMJ-5', 'Var', (21, 26))	('QMJ-5', 'Chemical', '-', (21, 26))	('QMJ-2', 'Var', (7, 12))	('colon cancer', 'Phenotype', 'HP:0003003', (73, 85))	('QMJ-3', 'Var', (14, 19))	('QMJ', 'Chemical', '-', (32, 35))	('colon cancer', 'Disease', 'MESH:D015179', (73, 85))	('QMJ-6', 'Var', (32, 37))
41581	30687400	Among them, QMJ-2 and QMJ-5 were most cytotoxic with an IC50 value of 68 +- 2.3 and 27.4 +- 1.8 microM, respectively.	('QMJ-5', 'Var', (22, 27))	('QMJ-2', 'Var', (12, 17))	('cytotoxic', 'CPA', (38, 47))	('QMJ-2', 'Chemical', '-', (12, 17))	('QMJ-5', 'Chemical', '-', (22, 27))
41582	30687400	However, in Vero cells, the IC50 values of QMJ-2 and QMJ-5 was found to be 140 +- 6.8 and 55.6 +- 3.8 microM.	('QMJ-2', 'Chemical', '-', (43, 48))	('QMJ-5', 'Chemical', '-', (53, 58))	('QMJ-5', 'Gene', (53, 58))	('QMJ-2', 'Var', (43, 48))
41584	30687400	Dose-dependent enzyme inhibition was observed in QMJ-2- and QMJ-5-treated cells with an IC50 value of 181.7 +- 22.04 and 70.2 +- 4.3 microM, respectively.	('QMJ-5', 'Chemical', '-', (60, 65))	('enzyme', 'Enzyme', (15, 21))	('inhibition', 'NegReg', (22, 32))	('QMJ-2', 'Chemical', '-', (49, 54))	('QMJ-2-', 'Var', (49, 55))
41587	30687400	QMJ-2 and QMJ-5 were found to be specific toward class I HDAC enzyme with an IC50 value of 34.11 and 47.7 microM, respectively, against HDAC1 enzyme and 36.03 and 24.0 microM, respectively, against HDAC8 enzyme.	('HDAC1', 'Gene', (136, 141))	('HDAC', 'Gene', (198, 202))	('QMJ-5', 'Chemical', '-', (10, 15))	('HDAC8', 'Gene', (198, 203))	('QMJ-5', 'Var', (10, 15))	('HDAC', 'Gene', '9734', (198, 202))	('HDAC', 'Gene', (57, 61))	('HDAC1', 'Gene', '3065', (136, 141))	('HDAC', 'Gene', (136, 140))	('HDAC', 'Gene', '9734', (57, 61))	('QMJ-2', 'Chemical', '-', (0, 5))	('HDAC', 'Gene', '9734', (136, 140))	('HDAC8', 'Gene', '55869', (198, 203))
41594	30687400	The expression of the cell cycle regulatory protein p21Waf1/Cip1 was also increased in SAHA-, QMJ-2-, and QMJ-5-treated groups which were significant compared to normal control.	('QMJ-5', 'Chemical', '-', (106, 111))	('QMJ-2-', 'Var', (94, 100))	('Cip1', 'Gene', (60, 64))	('cell cycle', 'biological_process', 'GO:0007049', ('22', '32'))	('expression', 'MPA', (4, 14))	('QMJ-2', 'Chemical', '-', (94, 99))	('p21', 'Gene', (52, 55))	('increased', 'PosReg', (74, 83))	('p21', 'Gene', '644914', (52, 55))	('SAHA', 'Chemical', 'MESH:D000077337', (87, 91))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))	('QMJ-5-treated', 'Var', (106, 119))	('Cip1', 'Gene', '1026', (60, 64))
41596	30687400	It was observed that the percentage of live cells in the normal control group was 70.85%, whereas treatment with QMJ-2 and QMJ-5 decreased the percentage of live cells drastically to 57.25% and 51.35%, respectively.	('QMJ-5', 'Chemical', '-', (123, 128))	('QMJ-5', 'Var', (123, 128))	('QMJ-2', 'Var', (113, 118))	('decreased', 'NegReg', (129, 138))	('QMJ-2', 'Chemical', '-', (113, 118))
41597	30687400	Furthermore, it was found that the percentage of cells undergoing late apoptosis was 35.20% and 38.65% in QMJ-2 and QMJ-5 groups, respectively, compared to that of 21.30% in the normal control group.	('QMJ-5', 'Chemical', '-', (116, 121))	('QMJ-5', 'Var', (116, 121))	('QMJ-2', 'Var', (106, 111))	('QMJ-2', 'Chemical', '-', (106, 111))
41601	30687400	The percentage of live cells was found to be 37.40% and 8.05% in QMJ-2- and QMJ-5-treated groups when compared to 69.40% in normal control.	('QMJ-5-treated', 'Var', (76, 89))	('QMJ-2-', 'Var', (65, 71))	('QMJ-5', 'Chemical', '-', (76, 81))	('QMJ-2', 'Chemical', '-', (65, 70))
41602	30687400	An increase in the percentage of apoptotic cells was observed in QMJ-2- and QMJ-5-treated groups and was found to be 55.70% and 83.55%, respectively, when compared to that of 24.60% in the normal control group.	('QMJ-2-', 'Var', (65, 71))	('QMJ-2', 'Chemical', '-', (65, 70))	('QMJ-5-treated', 'Var', (76, 89))	('QMJ-5', 'Chemical', '-', (76, 81))	('apoptotic cells', 'CPA', (33, 48))
41605	30687400	Treatment with QMJ-2 and QMJ-5 caused an increase in the percentage of cells in G0/G1 phase.	('QMJ-2', 'Var', (15, 20))	('QMJ-5', 'Chemical', '-', (25, 30))	('QMJ-2', 'Chemical', '-', (15, 20))	('G1 phase', 'biological_process', 'GO:0051318', ('83', '91'))	('QMJ-5', 'Var', (25, 30))	('increase', 'PosReg', (41, 49))
41611	30687400	A significant (p < 0.05) reduction in the ACF count was observed in 5-FU-, QMJ-2- and QMJ-5-treated groups when compared to that of the DMH control group.	('reduction', 'NegReg', (25, 34))	('ACF count', 'CPA', (42, 51))	('5-FU-', 'Var', (68, 73))	('5-FU', 'Chemical', 'MESH:D005472', (68, 72))	('DMH', 'Chemical', 'MESH:D019813', (136, 139))	('QMJ-2-', 'Var', (75, 81))	('QMJ-5', 'Chemical', '-', (86, 91))	('QMJ-2', 'Chemical', '-', (75, 80))
41614	30687400	A significant (p < 0.05) increase in colon weight/length ratio was observed in DMH control when compared with the normal control group.	('DMH', 'Chemical', 'MESH:D019813', (79, 82))	('DMH control', 'Var', (79, 90))	('colon weight', 'Disease', (37, 49))	('increase', 'PosReg', (25, 33))	('colon weight', 'Disease', 'MESH:D015431', (37, 49))
41615	30687400	Treatment with 5-FU and other test compounds significantly (p < 0.05) reduced the colon weight/length ratio when compared with DMH control.	('colon weight', 'Disease', 'MESH:D015431', (82, 94))	('DMH', 'Chemical', 'MESH:D019813', (127, 130))	('reduced', 'NegReg', (70, 77))	('reduced the colon weight', 'Phenotype', 'HP:0005210', (70, 94))	('5-FU', 'Var', (15, 19))	('5-FU', 'Chemical', 'MESH:D005472', (15, 19))	('colon weight', 'Disease', (82, 94))
41616	30687400	Among the test compounds, QMJ-5 was comparatively better in reducing colon weight/length ratio compared to other groups (Figure 6).	('QMJ-5', 'Chemical', '-', (26, 31))	('QMJ-5', 'Var', (26, 31))	('colon weight', 'Disease', (69, 81))	('colon weight', 'Disease', 'MESH:D015431', (69, 81))	('reducing colon weight', 'Phenotype', 'HP:0005210', (60, 81))	('reducing', 'NegReg', (60, 68))
41617	30687400	An increase in the kidney index was observed in the DMH control group which was significantly reduced in 5-FU, QMJ-2 and QMJ-5 treatment groups.	('reduced', 'NegReg', (94, 101))	('kidney index', 'MPA', (19, 31))	('QMJ-2', 'Chemical', '-', (111, 116))	('DMH', 'Chemical', 'MESH:D019813', (52, 55))	('QMJ-5', 'Chemical', '-', (121, 126))	('QMJ-5', 'Var', (121, 126))	('5-FU', 'Chemical', 'MESH:D005472', (105, 109))	('increase', 'PosReg', (3, 11))
41619	30687400	Significant reduction in the liver index was observed in QMJ-2 and QMJ-5 treatment groups when compared with the normal control and a significant reduction in 5-FU, quercetin, QMJ-2, and QMJ-5 was observed when compared with DMH control (Figure 7).	('liver index', 'MPA', (29, 40))	('QMJ-5', 'Var', (67, 72))	('QMJ-2', 'Var', (57, 62))	('QMJ-5', 'Chemical', '-', (67, 72))	('reduction', 'NegReg', (12, 21))	('quercetin', 'MPA', (165, 174))	('QMJ-2', 'Chemical', '-', (176, 181))	('QMJ-2', 'Chemical', '-', (57, 62))	('quercetin', 'Chemical', 'MESH:D011794', (165, 174))	('5-FU', 'Chemical', 'MESH:D005472', (159, 163))	('DMH', 'Chemical', 'MESH:D019813', (225, 228))	('QMJ-5', 'Chemical', '-', (187, 192))	('5-FU', 'MPA', (159, 163))	('reduction', 'NegReg', (146, 155))
41634	30687400	MTT assay was used to determine cytotoxicity where it was found that, out of all the compounds synthesized and tested against colon cancer cells, two analogues QMJ-2 and QMJ-5 were found to be most promising.	('QMJ-2', 'Var', (160, 165))	('cytotoxicity', 'Disease', 'MESH:D064420', (32, 44))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('colon cancer', 'Phenotype', 'HP:0003003', (126, 138))	('colon cancer', 'Disease', 'MESH:D015179', (126, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('QMJ-5', 'Chemical', '-', (170, 175))	('QMJ-2', 'Chemical', '-', (160, 165))	('colon cancer', 'Disease', (126, 138))	('cytotoxicity', 'Disease', (32, 44))
41636	30687400	Studies have reported the role of epigenetic alterations in understanding the pathophysiology of colon cancer.	('colon cancer', 'Disease', 'MESH:D015179', (97, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('colon cancer', 'Disease', (97, 109))	('epigenetic alterations', 'Var', (34, 56))	('colon cancer', 'Phenotype', 'HP:0003003', (97, 109))
41639	30687400	It was observed that, QMJ-2, QMJ-5, and quercetin had a dose-dependent inhibition on HDAC enzyme.	('QMJ-5', 'Var', (29, 34))	('QMJ-2', 'Var', (22, 27))	('quercetin', 'Chemical', 'MESH:D011794', (40, 49))	('inhibition', 'NegReg', (71, 81))	('QMJ-2', 'Chemical', '-', (22, 27))	('HDAC', 'Gene', (85, 89))	('QMJ-5', 'Chemical', '-', (29, 34))	('HDAC', 'Gene', '9734', (85, 89))
41642	30687400	It was evident from our study that QMJ-2 and QMJ-5 inhibited HDAC8 and HDAC1 enzymes with an IC50 value of less than 50 microM.	('HDAC8', 'Gene', '55869', (61, 66))	('HDAC1', 'Gene', (71, 76))	('QMJ-2', 'Chemical', '-', (35, 40))	('QMJ-5', 'Chemical', '-', (45, 50))	('QMJ-5', 'Var', (45, 50))	('HDAC8', 'Gene', (61, 66))	('HDAC1', 'Gene', '3065', (71, 76))	('inhibited', 'NegReg', (51, 60))	('QMJ-2', 'Var', (35, 40))
41644	30687400	In addition, QMJ-5 inhibited HDAC8 enzyme at a lower concentration compared with HDAC1 enzyme suggesting its specificity towards HDAC8.	('inhibited', 'NegReg', (19, 28))	('HDAC1', 'Gene', (81, 86))	('QMJ-5', 'Chemical', '-', (13, 18))	('HDAC8', 'Gene', (29, 34))	('QMJ-5', 'Var', (13, 18))	('HDAC8', 'Gene', (129, 134))	('HDAC1', 'Gene', '3065', (81, 86))	('HDAC8', 'Gene', '55869', (129, 134))	('HDAC8', 'Gene', '55869', (29, 34))
41653	30687400	It was found that, QMJ-2 and QMJ-5 were able to induce apoptosis in colon cancer cells evident from the percentage of cells in the early and late stages of apoptosis.	('QMJ-5', 'Var', (29, 34))	('QMJ-2', 'Var', (19, 24))	('colon cancer', 'Phenotype', 'HP:0003003', (68, 80))	('colon cancer', 'Disease', 'MESH:D015179', (68, 80))	('induce', 'PosReg', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('QMJ-2', 'Chemical', '-', (19, 24))	('colon cancer', 'Disease', (68, 80))	('QMJ-5', 'Chemical', '-', (29, 34))	('apoptosis', 'CPA', (55, 64))
41659	30687400	In the present study, cell cycle analysis revealed that both QMJ-2 and QMJ-5 arrested the cell cycle of colon cancer cells at the G0/G1 phase.	('QMJ-5', 'Chemical', '-', (71, 76))	('QMJ-5', 'Gene', (71, 76))	('colon cancer', 'Disease', (104, 116))	('cell cycle', 'biological_process', 'GO:0007049', ('90', '100'))	('QMJ-2', 'Var', (61, 66))	('arrested', 'NegReg', (77, 85))	('cell cycle', 'biological_process', 'GO:0007049', ('22', '32'))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('colon cancer', 'Phenotype', 'HP:0003003', (104, 116))	('colon cancer', 'Disease', 'MESH:D015179', (104, 116))	('cell cycle of', 'CPA', (90, 103))	('QMJ-2', 'Chemical', '-', (61, 66))	('G1 phase', 'biological_process', 'GO:0051318', ('133', '141'))
41664	30687400	Moreover, studies have demonstrated that polyphenols induce cell cycle arrest and apoptosis through the inhibition of histone deacetylase enzyme.	('inhibition', 'NegReg', (104, 114))	('apoptosis', 'CPA', (82, 91))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (60, 77))	('polyphenols', 'Chemical', 'MESH:D059808', (41, 52))	('cell cycle arrest', 'CPA', (60, 77))	('histone deacetylase', 'Gene', '9734', (118, 137))	('polyphenols', 'Var', (41, 52))	('histone deacetylase', 'Gene', (118, 137))
41665	30687400	Similar results were obtained from our study where QMJ-2 and QMJ-5 inhibited HDAC8 expression and increased the levels of acetylated histone H3K9.	('QMJ-5', 'Chemical', '-', (61, 66))	('levels of acetylated histone H3K9', 'MPA', (112, 145))	('inhibited', 'NegReg', (67, 76))	('QMJ-5', 'Var', (61, 66))	('HDAC8', 'Gene', '55869', (77, 82))	('QMJ-2', 'Chemical', '-', (51, 56))	('HDAC8', 'Gene', (77, 82))	('increased', 'PosReg', (98, 107))	('expression', 'MPA', (83, 93))	('QMJ-2', 'Var', (51, 56))
41668	30687400	DMH is an extremely precise colorectal carcinogen that along with its metabolite azoxymethane (AOM) hastens the development of colorectal cancer in rats.	('AOM', 'Disease', 'MESH:C537492', (95, 98))	('DMH', 'Chemical', 'MESH:D019813', (0, 3))	('azoxymethane', 'Chemical', 'MESH:D001397', (81, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('DMH', 'Var', (0, 3))	('development', 'CPA', (112, 123))	('hastens', 'PosReg', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('colorectal cancer', 'Disease', (127, 144))	('rats', 'Species', '10116', (148, 152))	('colorectal cancer', 'Disease', 'MESH:D015179', (127, 144))	('AOM', 'Disease', (95, 98))
41671	30687400	It was observed that both QMJ-2 and QMJ-5 significantly reduced the ACF formation compared with that of DMH control group, suggesting their role in protecting the colon mucosa.	('QMJ-5', 'Chemical', '-', (36, 41))	('colon mucosa', 'Disease', (163, 175))	('QMJ-5', 'Var', (36, 41))	('QMJ-2', 'Var', (26, 31))	('reduced', 'NegReg', (56, 63))	('DMH', 'Chemical', 'MESH:D019813', (104, 107))	('colon mucosa', 'Disease', 'MESH:D015179', (163, 175))	('formation', 'biological_process', 'GO:0009058', ('72', '81'))	('QMJ-2', 'Chemical', '-', (26, 31))	('ACF formation', 'CPA', (68, 81))
41673	30687400	A marked reduction in the adenocarcinoma formation was observed in the QMJ-5-treated group when compared with that of the DMH control group further supporting their protective effect.	('QMJ-5', 'Chemical', '-', (71, 76))	('adenocarcinoma', 'Disease', (26, 40))	('DMH', 'Chemical', 'MESH:D019813', (122, 125))	('adenocarcinoma', 'Disease', 'MESH:D000230', (26, 40))	('reduction', 'NegReg', (9, 18))	('QMJ-5-treated', 'Var', (71, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
41674	30687400	Administration of DMH causes alteration in the colonic mucosa and the formation of adenocarcinoma, leading to an increase in colon weight and shortening in the length of colon.	('adenocarcinoma', 'Disease', 'MESH:D000230', (83, 97))	('colon weight', 'Disease', (125, 137))	('colon weight', 'Disease', 'MESH:D015431', (125, 137))	('adenocarcinoma', 'Disease', (83, 97))	('alteration', 'Reg', (29, 39))	('DMH', 'Chemical', 'MESH:D019813', (18, 21))	('colonic mucosa', 'Disease', 'MESH:D015179', (47, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('DMH', 'Var', (18, 21))	('increase', 'PosReg', (113, 121))	('shortening', 'NegReg', (142, 152))	('colonic mucosa', 'Disease', (47, 61))
41675	30687400	Similar results were obtained from our study where an increase in colon weight/length ratio was observed in the DMH control group compared to normal.	('DMH', 'Var', (112, 115))	('colon weight', 'Disease', (66, 78))	('increase', 'PosReg', (54, 62))	('colon weight', 'Disease', 'MESH:D015431', (66, 78))	('DMH', 'Chemical', 'MESH:D019813', (112, 115))
41676	30687400	QMJ-2 and QMJ-5 reduced the ratio which demonstrated their protective effect against colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal cancer', 'Disease', (85, 102))	('ratio', 'MPA', (28, 33))	('reduced', 'NegReg', (16, 23))	('QMJ-5', 'Chemical', '-', (10, 15))	('QMJ-5', 'Var', (10, 15))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('QMJ-2', 'Chemical', '-', (0, 5))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
41677	30687400	Organ index studies exhibited that there was no significant change in the kidney index of QMJ-2 and QMJ-5 treatment groups compared to normal.	('QMJ-2', 'Chemical', '-', (90, 95))	('kidney index', 'MPA', (74, 86))	('QMJ-5', 'Chemical', '-', (100, 105))	('QMJ-5', 'Gene', (100, 105))	('QMJ-2', 'Var', (90, 95))
41678	30687400	However, there was a significant reduction in the liver index of animals treated with QMJ-2 and QMJ-5 suggesting further studies to determine the mechanism.	('liver index', 'MPA', (50, 61))	('reduction', 'NegReg', (33, 42))	('QMJ-2', 'Chemical', '-', (86, 91))	('QMJ-5', 'Chemical', '-', (96, 101))	('QMJ-5', 'Var', (96, 101))	('QMJ-2', 'Var', (86, 91))
41680	30687400	From the present study, it was evident that QMJ-2 and QMJ-5 inhibited HDAC enzyme in vitro and had a protective role against DMH-induced colon cancer in vivo.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('HDAC', 'Gene', (70, 74))	('QMJ-5', 'Var', (54, 59))	('QMJ-2', 'Var', (44, 49))	('colon cancer', 'Phenotype', 'HP:0003003', (137, 149))	('HDAC', 'Gene', '9734', (70, 74))	('inhibited', 'NegReg', (60, 69))	('colon cancer', 'Disease', 'MESH:D015179', (137, 149))	('DMH', 'Chemical', 'MESH:D019813', (125, 128))	('colon cancer', 'Disease', (137, 149))	('QMJ-2', 'Chemical', '-', (44, 49))	('QMJ-5', 'Chemical', '-', (54, 59))
41681	30687400	The present study revealed that both analogues QMJ-2 and QMJ-5 and the polyphenol quercetin were found to be cytotoxic and inhibited HDAC enzyme, where QMJ-5 showed greater specificity towards HDAC8.	('QMJ-5', 'Chemical', '-', (57, 62))	('HDAC', 'Gene', (193, 197))	('QMJ-5', 'Var', (57, 62))	('QMJ-2', 'Var', (47, 52))	('HDAC', 'Gene', '9734', (193, 197))	('polyphenol quercetin', 'Chemical', '-', (71, 91))	('HDAC8', 'Gene', (193, 198))	('inhibited', 'NegReg', (123, 132))	('QMJ-5', 'Chemical', '-', (152, 157))	('HDAC', 'Gene', (133, 137))	('QMJ-2', 'Chemical', '-', (47, 52))	('HDAC', 'Gene', '9734', (133, 137))	('HDAC8', 'Gene', '55869', (193, 198))
41718	30595800	Moreover, Kitajima et al previously found a rate of lymph node metastasis of zero in head invasion cases (the deepest portion of invasion limited to above the baseline) and in stalk invasion cases with a depth of submucosal invasion < 3000 mum (MPCP with the level 2 line according to Haggitt's classification used as the baseline and depth of submucosal invasion measured to the deepest portion in the submucosa).	('zero', 'NegReg', (77, 81))	('head invasion', 'Disease', (85, 98))	('< 3000', 'Var', (233, 239))	('MPCP', 'Chemical', '-', (245, 249))	('mum', 'Gene', '56925', (240, 243))	('mum', 'Gene', (240, 243))	('lymph node metastasis', 'CPA', (52, 73))
41741	30595800	However, the exact incidence of discordant diagnosis cannot be estimated; moreover, misplaced epithelium in pedunculated polyps has a lobular contour with a rim of lamina propria, along with hemorrhage, and/or hemosiderin.	('hemorrhage', 'Disease', 'MESH:D006470', (191, 201))	('polyps', 'Disease', (121, 127))	('hemorrhage', 'Disease', (191, 201))	('misplaced', 'Var', (84, 93))	('polyps', 'Disease', 'MESH:D011127', (121, 127))
41752	30595800	Pedunculated polyps have a higher risk of bleeding compared to sessile polyps.	('polyps', 'Disease', (13, 19))	('Pedunculated', 'Var', (0, 12))	('polyps', 'Disease', 'MESH:D011127', (71, 77))	('polyps', 'Disease', 'MESH:D011127', (13, 19))	('sessile polyps', 'Disease', (63, 77))	('bleeding', 'Disease', 'MESH:D006470', (42, 50))	('sessile polyps', 'Disease', 'MESH:D011127', (63, 77))	('bleeding', 'Disease', (42, 50))	('polyps', 'Disease', (71, 77))
41772	30595800	Different risk factors for postpolypectomy complications, such as old age (older than 65 years of age), underlying diseases (cardiovascular or chronic renal disease), anticoagulant use, polyp size > 10 mm, a stalk size > 5 mm, polyps located on the right side of the colon, malignant polyps, use of cutting mode and low-volume endoscopists, have been described.	('polyps', 'Disease', (284, 290))	('> 5', 'Var', (219, 222))	('postpolypectomy complications', 'Disease', (27, 56))	('polyps', 'Disease', (227, 233))	('malignant polyps', 'Disease', (274, 290))	('polyps', 'Disease', 'MESH:D011127', (284, 290))	('chronic renal disease', 'Phenotype', 'HP:0003774', (143, 164))	('chronic renal disease', 'Disease', 'MESH:D051436', (143, 164))	('polyp', 'Disease', (186, 191))	('renal disease', 'Phenotype', 'HP:0000112', (151, 164))	('chronic renal disease', 'Disease', (143, 164))	('polyps', 'Disease', 'MESH:D011127', (227, 233))	('malignant polyps', 'Disease', 'MESH:D011127', (274, 290))
41834	23494117	As for p53 status, NCI-N87 has mutation, KATOIII has gross deletion, and the other two cell lines were wild type.	('mutation', 'Var', (31, 39))	('NCI-N87', 'Gene', (19, 26))	('p53', 'Gene', (7, 10))	('p53', 'Gene', '7157', (7, 10))
41844	23494117	TaqMan Gene Expression Assays (Applied Biosystems), prevalidated assays that include specific primers and probes for each gene, were used for cDNA quantification of the TS, DPD, TP, and OPRT genes (assay IDs: [TS (TYMS)], Hs00426591_m1; [DPD (DPYD)], Hs00559278_m1; [TP (TYMP)], Hs00157317_m1; [OPRT (UMPS)]).	('UMPS', 'Gene', '7372', (301, 305))	('TP', 'Gene', '1890', (267, 269))	('DPYD', 'Gene', (243, 247))	('DPD', 'Gene', '1806', (173, 176))	('DPD', 'Gene', (173, 176))	('TYMS', 'Gene', '7298', (214, 218))	('TYMP', 'Gene', '1890', (271, 275))	('OPRT', 'Gene', '7372', (186, 190))	('TP', 'Gene', '1890', (178, 180))	('Hs00426591_m1', 'Var', (222, 235))	('DPYD', 'Gene', '1806', (243, 247))	('OPRT', 'Gene', (186, 190))	('UMPS', 'Gene', (301, 305))	('Hs00559278_m1', 'Var', (251, 264))	('Hs00157317_m1', 'Var', (279, 292))	('TYMS', 'Gene', (214, 218))	('OPRT', 'Gene', '7372', (295, 299))	('TYMP', 'Gene', (271, 275))	('OPRT', 'Gene', (295, 299))	('DPD', 'Gene', '1806', (238, 241))	('TS', 'Gene', '7298', (210, 212))	('DPD', 'Gene', (238, 241))	('TS', 'Gene', '7298', (169, 171))
41884	23494117	TS enzyme activity has been shown to significantly correlate with 5FU sensitivity in vitro and vivo, and correlations among TS copy number, TS mRNA expression level, and drug sensitivity have been demonstrated in several cancer cell lines.	('enzyme activity', 'molecular_function', 'GO:0003824', ('3', '18'))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('activity', 'MPA', (10, 18))	('drug sensitivity', 'Phenotype', 'HP:0020174', (170, 186))	('cancer', 'Disease', (221, 227))	('TS', 'Gene', '7298', (140, 142))	('copy number', 'Var', (127, 138))	('TS', 'Gene', '7298', (0, 2))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('TS', 'Gene', '7298', (124, 126))	('5FU sensitivity', 'MPA', (66, 81))	('correlate', 'Reg', (51, 60))	('5FU', 'Chemical', 'MESH:D005472', (66, 69))
41897	23494117	Their results suggested that enhancement of the antitumor effect of 5FU by LV was most prominent in 5FU-resistant colorectal tumor xenografts with high TS expression.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('colorectal tumor', 'Disease', (114, 130))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('LV', 'Chemical', 'MESH:D002955', (75, 77))	('5FU-resistant', 'Var', (100, 113))	('enhancement', 'PosReg', (29, 40))	('colorectal tumor', 'Disease', 'MESH:D015179', (114, 130))	('tumor', 'Disease', (125, 130))	('5FU', 'Chemical', 'MESH:D005472', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('5FU', 'Chemical', 'MESH:D005472', (100, 103))	('TS', 'Gene', '7298', (152, 154))
41898	23494117	reported that resistance to 5FU was caused by low FdUMP levels in more than half (53 %) of all colorectal specimens that showed 5FU resistance associated with poor TS inhibition, with 40 % of the specimens showing low FdUMP levels as the sole mechanism for resistance to 5FU.	('low', 'NegReg', (46, 49))	('5FU', 'Chemical', 'MESH:D005472', (128, 131))	('colorectal', 'Disease', 'MESH:D015179', (95, 105))	('FdUMP levels', 'MPA', (50, 62))	('5FU', 'Chemical', 'MESH:D005472', (28, 31))	('TS', 'Gene', '7298', (164, 166))	('FdUMP', 'Chemical', '-', (218, 223))	('colorectal', 'Disease', (95, 105))	('FdUMP', 'Chemical', '-', (50, 55))	('resistance', 'Var', (132, 142))	('5FU', 'Chemical', 'MESH:D005472', (271, 274))
41909	23494117	It was reported that postoperative treatment with 5FU/LV (RPMI) in patients with gastric cancer was noninferior to S-1, which is an oral fluoropyrimidine derivative consisting of tegafur and two modulators.	('S-1', 'Gene', (115, 118))	('5FU/LV', 'Var', (50, 56))	('patients', 'Species', '9606', (67, 75))	('LV', 'Chemical', 'MESH:D002955', (54, 56))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('5FU', 'Chemical', 'MESH:D005472', (50, 53))	('gastric cancer', 'Disease', (81, 95))	('fluoropyrimidine', 'Chemical', '-', (137, 153))	('S-1', 'Gene', '5707', (115, 118))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
41914	23717813	The tumorigenesis of CRC is either because of the chromosomal instability (CIN) or microsatellite instability (MIN) or involving various proto-oncogenes, tumor-suppressor genes, and also epigenetic changes in the DNA.	('chromosomal', 'MPA', (50, 61))	('tumor', 'Disease', (4, 9))	('epigenetic changes', 'Var', (187, 205))	('microsatellite instability', 'MPA', (83, 109))	('involving', 'Reg', (119, 128))	('CIN', 'Disease', 'MESH:D007674', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('CRC', 'Disease', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('chromosomal instability', 'Phenotype', 'HP:0040012', (50, 73))	('CIN', 'Disease', (75, 78))	('tumor', 'Disease', (154, 159))
41915	23717813	In this review I have focused on the mutations and polymorphisms of various important genes of the CIN and MIN pathways which have been implicated in the development of CRC.	('CRC', 'Disease', (169, 172))	('CIN', 'Disease', 'MESH:D007674', (99, 102))	('polymorphisms', 'Var', (51, 64))	('men', 'Species', '9606', (161, 164))	('CIN', 'Disease', (99, 102))
41958	23717813	These genetic changes ultimately result in uninhibited cell growth, proliferation, and clonal tumor development.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('proliferation', 'CPA', (68, 81))	('men', 'Species', '9606', (107, 110))	('result in', 'Reg', (33, 42))	('uninhibited cell growth', 'CPA', (43, 66))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('changes', 'Var', (14, 21))	('cell growth', 'biological_process', 'GO:0016049', ('55', '66'))
41960	23717813	The salient features of the Vogelstein's model of CRC carcinogenesis for sporadic cancers, can be conclusively drawn as: 1) the mutational activation of oncogenes and/or the inactivation of tumor suppressor genes results in colorectal carcinogenesis; 2) at least four or five genes of a cell must undergo somatic mutations so as to get malignantly transformed; 3) the characteristics of the tumor is dependent upon the accumulation of multiple genetic mutations rather than the sequence of mutations of the genes involved; and 4) the features of the tumorigenic process of colorectal cancer also apply to other solid tumors, such as breast, stomach and pancreatic cancer.	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('breast', 'Disease', (633, 639))	('tumor', 'Phenotype', 'HP:0002664', (617, 622))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (653, 670))	('colorectal cancer', 'Disease', 'MESH:D015179', (573, 590))	('solid tumors', 'Disease', 'MESH:D009369', (611, 623))	('tumor', 'Disease', (391, 396))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (617, 623))	('tumor', 'Disease', (550, 555))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (224, 249))	('colorectal cancer', 'Disease', (573, 590))	('tumor', 'Disease', 'MESH:D009369', (391, 396))	('sporadic cancers', 'Disease', 'MESH:D009369', (73, 89))	('tumor', 'Disease', 'MESH:D009369', (550, 555))	('mutational', 'Var', (128, 138))	('pancreatic cancer', 'Disease', 'MESH:D010190', (653, 670))	('cancer', 'Phenotype', 'HP:0002664', (664, 670))	('tumor', 'Disease', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('rectal cancer', 'Phenotype', 'HP:0100743', (577, 590))	('tumor', 'Disease', (617, 622))	('sporadic cancers', 'Disease', (73, 89))	('cancer', 'Phenotype', 'HP:0002664', (584, 590))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (550, 555))	('pancreatic cancer', 'Disease', (653, 670))	('colorectal cancer', 'Phenotype', 'HP:0003003', (573, 590))	('solid tumors', 'Disease', (611, 623))	('tumor', 'Disease', 'MESH:D009369', (617, 622))	('stomach', 'Disease', (641, 648))	('colorectal carcinogenesis', 'Disease', (224, 249))
41969	23717813	Mutations in DNA mismatch repair (MMR) genes result in a failure to repair errors that occur during DNA replication in repetitive sequences [microsatellites (MSI)], resulting in an accumulation of frameshift mutations in genes that contain MSI.	('DNA', 'cellular_component', 'GO:0005574', ('13', '16'))	('MMR', 'biological_process', 'GO:0006298', ('34', '37'))	('accumulation', 'PosReg', (181, 193))	('MSI', 'Disease', (158, 161))	('MSI', 'Disease', 'None', (240, 243))	('mismatch repair', 'biological_process', 'GO:0006298', ('17', '32'))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('MSI', 'Disease', (240, 243))	('Mutations', 'Var', (0, 9))	('failure', 'NegReg', (57, 64))	('frameshift mutations', 'Var', (197, 217))	('DNA replication', 'biological_process', 'GO:0006260', ('100', '115'))	('MMR', 'Gene', (34, 37))	('MSI', 'Disease', 'None', (158, 161))
41974	23717813	The mutations whether point or gross mutations in a number of tumor suppressor or oncogenes have been implicated in the development of colorectal cancer in every corner and every population of the world.	('colorectal cancer', 'Disease', 'MESH:D015179', (135, 152))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('gross mutations', 'Var', (31, 46))	('tumor', 'Disease', (62, 67))	('men', 'Species', '9606', (127, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('point', 'Var', (22, 27))	('implicated', 'Reg', (102, 112))	('colorectal cancer', 'Disease', (135, 152))	('rectal cancer', 'Phenotype', 'HP:0100743', (139, 152))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
41976	23717813	The TP53 gene is located on the short (p) arm of chromosome 17, and 17p deletions are found in 6-25% of colonic adenomas and in as many as 75% of colonic carcinomas (Baker et al.,).	('found', 'Reg', (86, 91))	('colonic adenomas', 'Disease', 'MESH:D000236', (104, 120))	('TP53', 'Gene', (4, 8))	('colonic carcinomas', 'Disease', 'MESH:D015179', (146, 164))	('colonic carcinomas', 'Disease', (146, 164))	('deletions', 'Var', (72, 81))	('colonic adenomas', 'Disease', (104, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))	('TP53', 'Gene', '7157', (4, 8))
41978	23717813	Mutations in TP53 gene occur in almost half of all CRCs, proposed as a late event in the transition of an adenoma to carcinoma (Harris and Hollstein,).	('TP53', 'Gene', (13, 17))	('adenoma to carcinoma', 'Disease', 'MESH:D000236', (106, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('CRCs', 'Disease', (51, 55))	('adenoma to carcinoma', 'Disease', (106, 126))	('Mutations', 'Var', (0, 9))	('occur', 'Reg', (23, 28))	('TP53', 'Gene', '7157', (13, 17))
41979	23717813	The mutations in p53 are thought to cause an increase in the half life of the protein and also often associated with overexpression in the nucleus, in one view (Remvikos et al.,).	('overexpression in the nucleus', 'MPA', (117, 146))	('half life of the protein', 'MPA', (61, 85))	('associated', 'Reg', (101, 111))	('mutations', 'Var', (4, 13))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))	('increase', 'PosReg', (45, 53))
41980	23717813	Also, most of the mutations in TP53 gene occur in exons 5-8, in highly preserved regions, and in the three main structural domains of the p53 protein (L2, L3, and loop-sheet-helix) (Borrensen-Dale et al.,).	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('p53', 'Gene', (138, 141))	('TP53', 'Gene', '7157', (31, 35))	('p53', 'Gene', '7157', (138, 141))	('TP53', 'Gene', (31, 35))	('mutations', 'Var', (18, 27))
41985	23717813	Human cancers frequently express mutant Ras proteins, termed "oncogenic Ras."	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('Ras', 'Chemical', 'MESH:D011883', (72, 75))	('mutant', 'Var', (33, 39))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('Ras', 'Chemical', 'MESH:D011883', (40, 43))	('Ras proteins', 'Protein', (40, 52))	('cancers', 'Disease', (6, 13))
41986	23717813	Activating ras mutations can be found in human malignancies with an overall frequency of 15-20% (Schubbert et al.,).	('malignancies', 'Disease', 'MESH:D009369', (47, 59))	('Activating', 'PosReg', (0, 10))	('mutations', 'Var', (15, 24))	('malignancies', 'Disease', (47, 59))	('human', 'Species', '9606', (41, 46))	('ras', 'Gene', (11, 14))
41987	23717813	Activating mutations in the KRAS proto-oncogene gene are involved in 25-60% of CRCs (Vogelstein et al.,; Fearon and Vogelstein,).	('KRAS', 'Gene', (28, 32))	('KRAS', 'Gene', '3845', (28, 32))	('Activating mutations', 'Var', (0, 20))	('CRCs', 'Disease', (79, 83))	('involved', 'Reg', (57, 65))
41988	23717813	The activating oncogenic mutations, in particular of KRAS are found mostly (90%) in codons 12 and 13, but may also affect codon 61 (Fearon,; Bazan et al.,).	('mutations', 'Var', (25, 34))	('affect', 'Reg', (115, 121))	('activating', 'PosReg', (4, 14))	('codon 61', 'MPA', (122, 130))	('KRAS', 'Gene', (53, 57))	('KRAS', 'Gene', '3845', (53, 57))
41996	23717813	BRAF presents somatic mutations in different sort of tumors, predominantly in malignant melanoma, sporadic colorectal tumors showing MMR defects in MSI, low-grade ovarian serous carcinoma and thyroid papillary cancer.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('MSI', 'Disease', 'None', (148, 151))	('BRAF', 'Gene', '673', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('defects', 'Var', (137, 144))	('ovarian serous carcinoma and thyroid papillary cancer', 'Disease', 'MESH:D000077273', (163, 216))	('BRAF', 'Gene', (0, 4))	('MSI', 'Disease', (148, 151))	('malignant melanoma', 'Disease', (78, 96))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('colorectal tumors', 'Disease', (107, 124))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', (53, 59))	('thyroid papillary cancer', 'Phenotype', 'HP:0002895', (192, 216))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('malignant melanoma', 'Phenotype', 'HP:0002861', (78, 96))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('malignant melanoma', 'Disease', 'MESH:D008545', (78, 96))	('colorectal tumors', 'Disease', 'MESH:D015179', (107, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))
41997	23717813	About 80% of these mutations correspond to the hotspot transversion mutation T1799A that causes the amino acidic substitution V600E (Davies et al.,) The other 20% accounts for a wide variable range of missense mutations and all of them reside in the glycines of the G-loop in the exon 11 or in the AS in exon 15 near the V600.	('V600E', 'Var', (126, 131))	('T1799A', 'Var', (77, 83))	('glycines', 'Chemical', 'MESH:D005998', (250, 258))	('mutations', 'Var', (19, 28))	('V600E', 'Mutation', 'rs113488022', (126, 131))	('T1799A', 'Mutation', 'rs113488022', (77, 83))
41998	23717813	The mutation V600E confers transformant activity to the cells because it mimics the phosphorylation of T599 and/or S602 in the AS and so Braf rests constitutively active in a RAS independent manner (Wan et al.,).	('V600E', 'Var', (13, 18))	('V600E', 'Mutation', 'rs113488022', (13, 18))	('transformant activity', 'MPA', (27, 48))	('S602', 'Var', (115, 119))	('Braf', 'Gene', (137, 141))	('Braf', 'Gene', '673', (137, 141))	('mimics', 'Reg', (73, 79))	('phosphorylation', 'MPA', (84, 99))
42003	23717813	Apc binding to beta-catenin leads to ubiquitin-mediated beta catenin destruction; loss of Apc function increases transcription of beta catenin targets.	('increases', 'PosReg', (103, 112))	('beta catenin', 'Gene', '1499', (130, 142))	('binding', 'Interaction', (4, 11))	('beta catenin', 'Gene', (130, 142))	('transcription of', 'MPA', (113, 129))	('beta-catenin', 'Gene', (15, 27))	('beta catenin', 'Gene', '1499', (56, 68))	('loss', 'Var', (82, 86))	('beta-catenin', 'Gene', '1499', (15, 27))	('beta catenin', 'Gene', (56, 68))
42007	23717813	In many tumors the hypermethylation of CpG islands in gene promoters has been found to be a frequent epigenetic change in cancers, and is usually associated with the loss of transcription of APC (Esteller et al.,; Rowan et al.,; Tsuchiya et al.,; Virmani et al.,; Esteller and Herman,; Kang et al.,; Lind et al.,; Zare et al.,).	('APC', 'Gene', '324', (191, 194))	('APC', 'cellular_component', 'GO:0005680', ('191', '194'))	('transcription', 'MPA', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('loss', 'NegReg', (166, 170))	('transcription', 'biological_process', 'GO:0006351', ('174', '187'))	('APC', 'Gene', (191, 194))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('tumors', 'Disease', (8, 14))	('hypermethylation', 'Var', (19, 35))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancers', 'Disease', (122, 129))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('Rowan', 'Species', '36599', (214, 219))
42008	23717813	Hypermethylation of the APC gene promoters has been reported to be present in about 20-48 per cent of human CRCs (Hiltunen et al.,; Esteller et al.,; Arnold et al.,; Lind et al.,).	('human CRCs', 'Disease', (102, 112))	('APC', 'cellular_component', 'GO:0005680', ('24', '27'))	('Hypermethylation', 'Var', (0, 16))	('APC', 'Gene', (24, 27))	('APC', 'Gene', '324', (24, 27))	('human', 'Species', '9606', (102, 107))
42014	23717813	beta-Catenin is mutated in up to 10% of all sporadic colorectal carcinoma by point mutations or in frame deletions of the serine and threonine residues that are phosphorylated by GSK-3beta (Polakis,).	('point mutations', 'Var', (77, 92))	('beta-Catenin', 'Gene', (0, 12))	('colorectal carcinoma', 'Disease', (53, 73))	('beta-Catenin', 'Gene', '1499', (0, 12))	('threonine', 'Chemical', 'MESH:D013912', (133, 142))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (53, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('GSK-3beta', 'Gene', '2932', (179, 188))	('GSK-3beta', 'Gene', (179, 188))	('serine', 'Chemical', 'MESH:D012694', (122, 128))
42015	23717813	These mutations result in stabilization of beta-Catenin and activation of WNT-signaling.	('signaling', 'biological_process', 'GO:0023052', ('78', '87'))	('stabilization', 'MPA', (26, 39))	('beta-Catenin', 'Gene', (43, 55))	('beta-Catenin', 'Gene', '1499', (43, 55))	('activation', 'PosReg', (60, 70))	('mutations', 'Var', (6, 15))	('WNT-signaling', 'Pathway', (74, 87))
42016	23717813	Mutations in beta-Catenin occur in exclusivity to APC aberrations as both molecules are the components of the same pathway (Behrens,).	('APC aberrations', 'Disease', (50, 65))	('beta-Catenin', 'Gene', (13, 25))	('beta-Catenin', 'Gene', '1499', (13, 25))	('Mutations', 'Var', (0, 9))	('APC aberrations', 'Disease', 'MESH:D011125', (50, 65))
42028	23717813	The tissue restriction of alterations in DPC4, as in many other tumor-suppressor genes, emphasizes the complexity of rate-limiting checkpoints in human tumorigenesis (Schutte et al.,).	('DPC4', 'Gene', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', (64, 69))	('DPC4', 'Gene', '4089', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('64', '80'))	('tumor', 'Disease', (152, 157))	('alterations', 'Var', (26, 37))	('human', 'Species', '9606', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('64', '80'))
42030	23717813	Mutant Smad4 proteins, identified in human carcinomas, were found to be impaired in their ability to regulate gene transcription.	('regulate gene transcription', 'MPA', (101, 128))	('impaired', 'NegReg', (72, 80))	('Smad4', 'Gene', (7, 12))	('Smad4', 'Gene', '4089', (7, 12))	('transcription', 'biological_process', 'GO:0006351', ('115', '128'))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('carcinomas', 'Disease', 'MESH:D002277', (43, 53))	('Mutant', 'Var', (0, 6))	('human', 'Species', '9606', (37, 42))	('ability', 'MPA', (90, 97))	('carcinomas', 'Disease', (43, 53))	('proteins', 'Protein', (13, 21))
42031	23717813	Most of Smad4 gene mutations in human cancer are missense, nonsense, and frameshift mutations at the mad homology 2 region (MH2) which interfere with the homo-oligomer formation of Smad4 protein and hetero-oligomer formation between Smad4 and Smad2 proteins, resulting in disruption of TGF-beta signaling (Shi,; Woodford-Richens et al.,; Roth et al.,).	('signaling', 'biological_process', 'GO:0023052', ('295', '304'))	('Smad4', 'Gene', '4089', (233, 238))	('homo-oligomer formation', 'MPA', (154, 177))	('hetero-oligomer formation', 'MPA', (199, 224))	('formation', 'biological_process', 'GO:0009058', ('168', '177'))	('Smad2', 'Gene', (243, 248))	('disruption', 'NegReg', (272, 282))	('missense', 'Var', (49, 57))	('formation', 'biological_process', 'GO:0009058', ('215', '224'))	('Smad4', 'Gene', '4089', (8, 13))	('mad', 'biological_process', 'GO:0072671', ('101', '104'))	('human', 'Species', '9606', (32, 37))	('cancer', 'Disease', (38, 44))	('Smad4', 'Gene', (233, 238))	('TGF-beta', 'Gene', '7040', (286, 294))	('Smad4', 'Gene', '4089', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('frameshift', 'Var', (73, 83))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))	('TGF-beta', 'Gene', (286, 294))	('Smad2', 'Gene', '4087', (243, 248))	('mutations', 'Var', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('Smad4', 'Gene', (8, 13))	('Smad4', 'Gene', (181, 186))	('interfere', 'NegReg', (135, 144))
42038	23717813	In addition somatic point mutations and deletions have been identified in CRC, hepatocellular carcinomas, ovarian endometrioid adenocarcinomas, and hepatoblastomas.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('deletions', 'Var', (40, 49))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (79, 104))	('hepatocellular carcinomas', 'Disease', (79, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('ovarian endometrioid adenocarcinomas', 'Disease', 'MESH:D016889', (106, 142))	('hepatoblastomas', 'Disease', 'MESH:D018197', (148, 163))	('CRC', 'Disease', (74, 77))	('hepatoblastomas', 'Disease', (148, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('identified', 'Reg', (60, 70))	('ovarian endometrioid adenocarcinomas', 'Disease', (106, 142))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (79, 104))
42039	23717813	The human genome contains a massive amount of genetic variation, such as the insertion/deletion of one or more nucleotides, the copy-number variations (CNVs) that can involve DNA sequences of a few kilobases up to millions of bases, and single-nucleotide polymorphisms (SNPs), which are the substitution of a single-nucleotide along the DNA (Ionita-Laza et al.,; Savas and Liu,).	('single-nucleotide polymorphisms', 'Var', (237, 268))	('human', 'Species', '9606', (4, 9))	('insertion/deletion', 'Var', (77, 95))
42041	23717813	These days several molecular and epidemiological studies are focusing on the role of SNP's in modulating the risk of various cancer and quite a number of studies have implicated various gene polymorphisms in affecting the risk of cancer in almost all the populations around the world.	('polymorphisms', 'Var', (191, 204))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('affecting', 'Reg', (208, 217))
42044	23717813	Codon 72 (Arg72Pro) - a frequent functional SNP that leads to an arginine-proline amino acid change has been reported by many authors (Thomas et al.,; Dumont et al.,).	('Arg72Pro', 'SUBSTITUTION', 'None', (10, 18))	('proline amino acid', 'Chemical', '-', (74, 92))	('arginine', 'Chemical', 'MESH:D001120', (65, 73))	('Arg72Pro', 'Var', (10, 18))	('leads to', 'Reg', (53, 61))	('arginine-proline amino acid change', 'MPA', (65, 99))
42045	23717813	Dumont et al., reported that the Arg72 allele, if in homozygous, has an apoptosis-inducing ability 15-fold higher than does the Pro72 allele.	('higher', 'PosReg', (107, 113))	('apoptosis-inducing ability', 'CPA', (72, 98))	('Arg72', 'Chemical', '-', (33, 38))	('Arg72', 'Var', (33, 38))
42047	23717813	Studies on this SNP function were the basis for testing its impact on the risk and progression of tumors, where the less apoptotic allele Pro72 was associated with increased risk for development of tumors (Marin et al.,; Ignaszak-Szczepaniak et al.,; Toyama et al.,).	('tumors', 'Disease', (98, 104))	('Pro72', 'Var', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('men', 'Species', '9606', (190, 193))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))
42050	23717813	In a pioneer study by Li et al., 106, it was found that the serine 47 polymorphic variant, which replaces the proline residue - necessary for recognition by proline-directed kinases, is a markedly poorer substrate for phosphorylation.	('serine', 'Chemical', 'MESH:D012694', (60, 66))	('phosphorylation', 'MPA', (218, 233))	('proline', 'Chemical', 'MESH:D011392', (157, 164))	('phosphorylation', 'biological_process', 'GO:0016310', ('218', '233'))	('proline', 'Chemical', 'MESH:D011392', (110, 117))	('serine 47', 'Var', (60, 69))	('poorer', 'NegReg', (197, 203))
42061	23717813	CYP2E1 gene contains six restriction fragment length polymorphisms, of these are the two important - RsaI polymorphism (CYP2E1*5B; C-1054T substitution) and the 96-bp insertion in its 5'-flanking region have drawn much interest (Morita et al.,; Wang et al.,; Zhou et al.,).	('C-1054T', 'Mutation', 'c.-1054C>T', (131, 138))	('CYP2E1', 'Gene', (0, 6))	('CYP2E1', 'Gene', '1571', (120, 126))	('C-1054T substitution', 'Var', (131, 151))	('CYP2E1', 'Gene', '1571', (0, 6))	('men', 'Species', '9606', (41, 44))	('CYP2E1', 'Gene', (120, 126))
42062	23717813	The variant type of this polymorphic site can enhance the transcription and increase the level of CYP2E1 enzymatic activity in vitro (Hayashi et al.,).	('level', 'MPA', (89, 94))	('enhance', 'PosReg', (46, 53))	('increase', 'PosReg', (76, 84))	('transcription', 'MPA', (58, 71))	('CYP2E1', 'Gene', '1571', (98, 104))	('variant', 'Var', (4, 11))	('CYP2E1', 'Gene', (98, 104))
42068	23717813	Two common functional polymorphisms have been defined in the MTHFR gene - one is C677T and other A1298C.	('C677T', 'Mutation', 'rs1801133', (81, 86))	('A1298C', 'Mutation', 'rs1801131', (97, 103))	('A1298C', 'Var', (97, 103))	('C677T', 'Var', (81, 86))	('MTHFR', 'Gene', (61, 66))	('MTHFR', 'Gene', '4524', (61, 66))
42069	23717813	MTHFR C677T polymorphism is the most important one regulating the function of this enzyme.	('MTHFR', 'Gene', '4524', (0, 5))	('C677T', 'Mutation', 'rs1801133', (6, 11))	('C677T', 'Var', (6, 11))	('function', 'MPA', (66, 74))	('MTHFR', 'Gene', (0, 5))	('regulating', 'Reg', (51, 61))
42070	23717813	This polymorphism results in an alanine-to-valine substitution at codon 222 of the protein (Frosst et al.,).	('alanine-to-valine substitution at codon 222', 'Mutation', 'rs1801133', (32, 75))	('alanine-to-valine substitution', 'Var', (32, 62))	('results in', 'Reg', (18, 28))
42071	23717813	This polymorphism has a profound effect on the MTHFR protein, not only does it decrease the thermal stability of this enzyme but also reduces its activity (Cicek et al.,).	('activity', 'MPA', (146, 154))	('MTHFR', 'Gene', (47, 52))	('thermal stability', 'MPA', (92, 109))	('decrease', 'NegReg', (79, 87))	('polymorphism', 'Var', (5, 17))	('reduces', 'NegReg', (134, 141))	('MTHFR', 'Gene', '4524', (47, 52))
42072	23717813	This substitution also results in lower levels of 5-methyltetrahydrofolate, an accumulation of 5,10-methylenetetrahydrofolate and increased plasma homocysteine levels (Frosst et al.,; Ma et al.,; Bagley and Selhub,).	('5-methyltetrahydrofolate', 'Chemical', 'MESH:C005984', (50, 74))	('accumulation', 'PosReg', (79, 91))	('substitution', 'Var', (5, 17))	('lower', 'NegReg', (34, 39))	('plasma homocysteine levels', 'MPA', (140, 166))	('5,10-methylenetetrahydrofolate', 'Chemical', 'MESH:C013123', (95, 125))	('levels', 'MPA', (40, 46))	('homocysteine', 'Chemical', 'MESH:D006710', (147, 159))	('increased', 'PosReg', (130, 139))
42075	23717813	In addition there is the question of the epigenetic silencing of the various CIN and MIN pathway genes also which occurs exclusive or in addition to the mutations of the genes thus adding a second dimension of complexity in the molecular mechanism of the tumor development.	('CIN', 'Disease', (77, 80))	('men', 'Species', '9606', (199, 202))	('MIN', 'Pathway', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('CIN', 'Disease', 'MESH:D007674', (77, 80))	('epigenetic silencing', 'Var', (41, 61))	('men', 'Species', '9606', (268, 271))	('tumor', 'Disease', 'MESH:D009369', (255, 260))
42106	32816852	Testing for MSI, CIMP, and mutations in the BRAF and KRAS gene was conducted previously by each study and according to individual study protocols.	('mutations', 'Var', (27, 36))	('BRAF', 'Gene', '673', (44, 48))	('BRAF', 'Gene', (44, 48))	('CIMP', 'Chemical', '-', (17, 21))	('KRAS', 'Gene', (53, 57))	('KRAS', 'Gene', '3845', (53, 57))
42111	32816852	With regard to colorectal carcinogenic pathways, previous studies reported that three different pathways to CRC development may be affected by the combination of molecular subtypes: a) a serrated pathway [Type 1: MSI-high, CIMP-positive, BRAF-mutated, KRAS-wildtype and Type 2: MSS/MSI-low, CIMP-positive, BRAF-mutated, KRAS-wildtype], b) an alternate pathway [Type 3: MSS/MSI-low, CIMP-negative, BRAF-wildtype, KRAS-mutated], and c) a traditional pathway [Type 4: MSS/MSI-low, CIMP-negative, BRAF-wildtype, KRAS-wildtype and Type 5: MSI-high, CIMP-negative, BRAF-wildtype, KRAS-wildtype].	('KRAS', 'Gene', (412, 416))	('BRAF', 'Gene', '673', (493, 497))	('BRAF', 'Gene', (493, 497))	('KRAS', 'Gene', (252, 256))	('BRAF', 'Gene', '673', (238, 242))	('BRAF', 'Gene', '673', (397, 401))	('BRAF', 'Gene', (238, 242))	('BRAF', 'Gene', (397, 401))	('KRAS', 'Gene', '3845', (320, 324))	('CIMP', 'Chemical', '-', (291, 295))	('KRAS', 'Gene', '3845', (574, 578))	('men', 'Species', '9606', (119, 122))	('colorectal carcinogenic', 'Disease', 'MESH:D015179', (15, 38))	('CIMP', 'Chemical', '-', (544, 548))	('KRAS', 'Gene', (320, 324))	('KRAS', 'Gene', '3845', (508, 512))	('KRAS', 'Gene', (574, 578))	('CIMP', 'Chemical', '-', (478, 482))	('colorectal carcinogenic', 'Disease', (15, 38))	('BRAF', 'Gene', '673', (306, 310))	('BRAF', 'Gene', (306, 310))	('KRAS', 'Gene', (508, 512))	('KRAS', 'Gene', '3845', (412, 416))	('CIMP', 'Chemical', '-', (382, 386))	('MSS/MSI-low', 'Var', (465, 476))	('BRAF', 'Gene', '673', (559, 563))	('BRAF', 'Gene', (559, 563))	('KRAS', 'Gene', '3845', (252, 256))	('CIMP', 'Chemical', '-', (223, 227))
42137	32816852	CRC development is caused by different etiological pathways underlying different genetic and epigenetic aberrations, which have been defined by specific molecular subtypes associated with distinct development trajectories.	('CRC development', 'Disease', (0, 15))	('epigenetic', 'Var', (93, 103))	('caused by', 'Reg', (19, 28))	('men', 'Species', '9606', (204, 207))	('men', 'Species', '9606', (11, 14))
42139	32816852	For specific molecular subtypes, the mutation in the KRAS oncogene has been widely known as an acting driver of CRC development.	('mutation', 'Var', (37, 45))	('men', 'Species', '9606', (123, 126))	('CRC', 'Disease', (112, 115))	('KRAS', 'Gene', (53, 57))	('KRAS', 'Gene', '3845', (53, 57))
42140	32816852	In addition, mutation of the BRAF oncogene induces proliferation and inhibits normal apoptosis of colonic epithelial cells.	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('mutation', 'Var', (13, 21))	('inhibits', 'NegReg', (69, 77))	('normal apoptosis', 'CPA', (78, 94))	('induces', 'PosReg', (43, 50))
42143	32816852	Widespread methylation of numerous promoter CpG island loci are responsible for inactivation of tumor suppressor genes and other tumor-related genes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('96', '112'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('methylation', 'biological_process', 'GO:0032259', ('11', '22'))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (96, 101))	('inactivation', 'NegReg', (80, 92))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('methylation', 'Var', (11, 22))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (129, 134))	('tumor suppressor', 'biological_process', 'GO:0051726', ('96', '112'))
42145	32816852	Silencing of tumor suppressor genes such as p16INK4a and IGFBP7 via the synergistic effects of mutation of BRAF and CIMP resulting from hypermethylation could facilitate progression to serrated colorectal polyps.	('tumor', 'Disease', (13, 18))	('IGFBP7', 'Gene', (57, 63))	('colorectal polyps', 'Disease', (194, 211))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('hypermethylation', 'Var', (136, 152))	('p16INK4a', 'Gene', (44, 52))	('colorectal polyps', 'Phenotype', 'HP:0200063', (194, 211))	('CIMP', 'Gene', (116, 120))	('CIMP', 'Chemical', '-', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('mutation', 'Var', (95, 103))	('facilitate', 'PosReg', (159, 169))	('Silencing', 'NegReg', (0, 9))	('p16INK4a', 'Gene', '1029', (44, 52))	('serrated colorectal polyps', 'Phenotype', 'HP:0032222', (185, 211))	('colorectal polyps', 'Disease', 'MESH:D003111', (194, 211))	('BRAF', 'Gene', '673', (107, 111))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('13', '29'))	('BRAF', 'Gene', (107, 111))	('tumor suppressor', 'biological_process', 'GO:0051726', ('13', '29'))	('IGFBP7', 'Gene', '3490', (57, 63))
42146	32816852	MSI is recognized by high-frequency of genetic alterations in repeated microsatellite sequences of DNA resulting from a DNA mismatch repair deficiency.	('genetic alterations', 'Var', (39, 58))	('deficiency', 'Disease', 'MESH:D007153', (140, 150))	('deficiency', 'Disease', (140, 150))	('DNA', 'Gene', (99, 102))
42152	32816852	For recall bias to explain the case-only finding, cases with and without BRAF mutation would need to recall their fruit intake differently.	('BRAF', 'Gene', (73, 77))	('BRAF', 'Gene', '673', (73, 77))	('mutation', 'Var', (78, 86))
42155	32816852	To our knowledge, only one study has published findings on fruit intake and CRC risk by BRAF mutation status.	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('mutation status', 'Var', (93, 108))	('CRC', 'Disease', (76, 79))
42162	32816852	Inhibition of GAPDH in BRAF-mutated CRC cells leads to an energetic crisis and cell death through inhibiting glycolysis and depleting ATP.	('depleting', 'NegReg', (124, 133))	('GAPDH', 'Gene', '2597', (14, 19))	('GAPDH', 'Gene', (14, 19))	('BRAF', 'Gene', '673', (23, 27))	('ATP', 'Chemical', 'MESH:D000255', (134, 137))	('BRAF', 'Gene', (23, 27))	('glycolysis', 'MPA', (109, 119))	('Inhibition', 'Var', (0, 10))	('energetic crisis', 'MPA', (58, 74))	('leads to', 'Reg', (46, 54))	('death', 'Disease', 'MESH:D003643', (84, 89))	('death', 'Disease', (84, 89))	('inhibiting', 'NegReg', (98, 108))
42163	32816852	However, two randomized, double-blind, placebo-controlled trials with a mean follow-up period ranging from 8.0 to 9.4 years did not find that 500mg of vitamin C supplementation daily was associated with a decreased CRC incidence in both men and women.	('CRC', 'Disease', (215, 218))	('vitamin C', 'Chemical', 'MESH:D001205', (151, 160))	('women', 'Species', '9606', (245, 250))	('500mg', 'Var', (142, 147))	('decreased', 'NegReg', (205, 214))	('men', 'Species', '9606', (247, 250))	('men', 'Species', '9606', (167, 170))	('men', 'Species', '9606', (237, 240))
42192	31611916	GB polyps were independently associated with proximal colon polyps, including both hyperplastic polyps (odds ratio, 1.523; P = 0.034) and adenomatous polyps (odds ratio, 1.351; P = 0.048).	('adenomatous polyps', 'Disease', 'MESH:D018256', (138, 156))	('adenomatous', 'Disease', (138, 149))	('hyperplastic polyps', 'Disease', (83, 102))	('proximal colon polyps', 'Disease', (45, 66))	('adenoma', 'Disease', 'MESH:D000236', (138, 145))	('adenomatous', 'Disease', 'MESH:D011125', (138, 149))	('adenomatous polyp', 'Phenotype', 'HP:0005227', (138, 155))	('hyperplastic polyps', 'Disease', 'MESH:D011127', (83, 102))	('adenomatous polyps', 'Disease', (138, 156))	('polyps', 'Var', (3, 9))	('adenomatous polyp', 'Disease', 'MESH:D018256', (138, 155))	('adenoma', 'Disease', (138, 145))	('associated', 'Reg', (29, 39))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (138, 156))
42230	31252648	In this sense, deregulated expression of many miRNAs has been shown to play an important role for CRC carcinogenesis and dissemination.	('miR', 'Gene', (46, 49))	('deregulated', 'Var', (15, 26))	('CRC', 'Phenotype', 'HP:0003003', (98, 101))	('play', 'Reg', (71, 75))	('CRC carcinogenesis', 'Disease', (98, 116))	('expression', 'MPA', (27, 37))	('CRC carcinogenesis', 'Disease', 'MESH:D015179', (98, 116))	('miR', 'Gene', '220972', (46, 49))
42350	31252648	Finally, high levels of miR-122 were associated with a shorter OS and relapse-free survival in both metastatic and non-metastatic CRC.	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('relapse-free survival', 'CPA', (70, 91))	('shorter', 'NegReg', (55, 62))	('non-metastatic CRC', 'Disease', (115, 133))	('metastatic', 'Disease', (100, 110))	('high levels', 'Var', (9, 20))	('miR-122', 'Gene', '406906', (24, 31))	('miR-122', 'Gene', (24, 31))
42370	31252648	Among CRC patients, high miR-21 expression levels were significantly associated with a poor prognosis, determining a significantly worse disease-free survival (DFS) and OS in stages II-III CRC, while in stage IV only the OS was significantly worse in patients with high exosome-derived miR-21.	('CRC', 'Phenotype', 'HP:0003003', (6, 9))	('miR-21', 'Gene', (25, 31))	('disease-free', 'Disease', (137, 149))	('CRC', 'Phenotype', 'HP:0003003', (189, 192))	('miR-21', 'Gene', (286, 292))	('worse', 'NegReg', (131, 136))	('high', 'Var', (20, 24))	('miR-21', 'Gene', '406991', (25, 31))	('patients', 'Species', '9606', (251, 259))	('patients', 'Species', '9606', (10, 18))	('expression levels', 'MPA', (32, 49))	('exosome', 'cellular_component', 'GO:0070062', ('270', '277'))	('miR-21', 'Gene', '406991', (286, 292))
42372	31252648	Similarly, high serum exosomal miR-6803-5p levels were significantly and independently associated with shorter DFS and OS in CRC patients, with this predictive value higher in patients with advanced stages and liver metastasis.	('patients', 'Species', '9606', (176, 184))	('patients', 'Species', '9606', (129, 137))	('miR-6803', 'Gene', (31, 39))	('liver metastasis', 'Disease', 'MESH:D009362', (210, 226))	('liver metastasis', 'Disease', (210, 226))	('shorter', 'NegReg', (103, 110))	('CRC', 'Phenotype', 'HP:0003003', (125, 128))	('high', 'Var', (11, 15))	('miR-6803', 'Gene', '102466739', (31, 39))	('DFS', 'MPA', (111, 114))
42421	31252648	Importantly, the mechanisms behind miRNAs alteration in CRC are still quite unknown.	('CRC', 'Phenotype', 'HP:0003003', (56, 59))	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', (35, 38))	('alteration', 'Var', (42, 52))
42441	29922091	Both univariate and multivariate analysis for survival indicated that high SATB1 reactivity significantly predicted poor prognosis.	('high', 'Var', (70, 74))	('SATB1', 'Gene', (75, 80))	('SATB1', 'Gene', '6304', (75, 80))	('reactivity', 'MPA', (81, 91))
42445	29922091	The meta-analysis indicated that high SATB1 reactivity is significantly correlated with decreased survival in most cases of solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (124, 136))	('high', 'Var', (33, 37))	('SATB1', 'Gene', (38, 43))	('SATB1', 'Gene', '6304', (38, 43))	('solid tumors', 'Disease', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('survival', 'MPA', (98, 106))	('decreased', 'NegReg', (88, 97))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('reactivity', 'MPA', (44, 54))
42464	29922091	Two investigators (Wang and Liu) aimed to assess studies that included independently patient number, sex, median age, country, cancer type, follow-up duration, references, cutoff value for SATB1 positivity, cutoff definition, and hazard ratios (HRs) for OS with corresponding 95% confidence intervals (CIs).	('patient', 'Species', '9606', (85, 92))	('positivity', 'Var', (195, 205))	('OS', 'Chemical', '-', (254, 256))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('SATB1', 'Gene', (189, 194))	('SATB1', 'Gene', '6304', (189, 194))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))
42489	29922091	Regarding solid tumors of different tissues, high SATB1 expression was relevant to poor OS in gastric cancer, colorectal carcinoma, and glioma.	('colorectal carcinoma', 'Disease', (110, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (110, 130))	('solid tumors', 'Disease', 'MESH:D009369', (10, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('SATB1', 'Gene', (50, 55))	('gastric cancer', 'Disease', (94, 108))	('high', 'Var', (45, 49))	('expression', 'MPA', (56, 66))	('glioma', 'Disease', (136, 142))	('OS', 'Chemical', '-', (88, 90))	('gastric cancer', 'Disease', 'MESH:D013274', (94, 108))	('SATB1', 'Gene', '6304', (50, 55))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('solid tumors', 'Disease', (10, 22))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))
42492	29922091	First, SATB1 expression is associated with adverse outcomes in various human solid tumors, indicating that SATB1 may be of use as a new therapeutic target.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('solid tumors', 'Disease', (77, 89))	('SATB1', 'Gene', (7, 12))	('associated', 'Reg', (27, 37))	('SATB1', 'Gene', '6304', (7, 12))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('expression', 'Var', (13, 23))	('SATB1', 'Gene', (107, 112))	('SATB1', 'Gene', '6304', (107, 112))	('solid tumors', 'Disease', 'MESH:D009369', (77, 89))	('human', 'Species', '9606', (71, 76))
42493	29922091	Second, in a subgroup of tumors, tumor tissues with high SATB1 expression were shown to have worse OS, including gastric cancer, colorectal carcinoma, and glioma.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('glioma', 'Disease', 'MESH:D005910', (155, 161))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('SATB1', 'Gene', (57, 62))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('tumor', 'Disease', (33, 38))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('SATB1', 'Gene', '6304', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', (25, 30))	('colorectal carcinoma', 'Disease', (129, 149))	('high', 'Var', (52, 56))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (129, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('gastric cancer', 'Disease', (113, 127))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('OS', 'Chemical', '-', (99, 101))	('glioma', 'Disease', (155, 161))
42549	29273089	Up to the last follow-up, disease progression and death occurred in 83 (83.8%) and 82 (82.8%) patients in the famitinib group and in 47 (85.5%) and 42 (76.4%) patients in the placebo group.	('patients', 'Species', '9606', (94, 102))	('death', 'Disease', 'MESH:D003643', (50, 55))	('famitinib', 'Chemical', 'MESH:C584390', (110, 119))	('death', 'Disease', (50, 55))	('disease progression', 'CPA', (26, 45))	('famitinib', 'Var', (110, 119))	('patients', 'Species', '9606', (159, 167))
42552	29273089	Stratified analysis including age, gender, LDH level, number of metastatic organs, and treatment line demonstrated that the famitinib group had longer PFS than the placebo group (Fig.	('longer', 'PosReg', (144, 150))	('PFS', 'MPA', (151, 154))	('famitinib', 'Var', (124, 133))	('famitinib', 'Chemical', 'MESH:C584390', (124, 133))
42565	29273089	Other SAEs included infection, hemoptysis, hypertension, fatigue, renal failure, upper gastrointestinal hemorrhage, and hepatic encephalopathy in the famitinib group, whereas cerebral infarction, cerebral hemorrhage, fatigue, and thrombocytopenia were observed in the placebo group.	('fatigue', 'Phenotype', 'HP:0012378', (57, 64))	('thrombocytopenia', 'Disease', (230, 246))	('encephalopathy', 'Phenotype', 'HP:0001298', (128, 142))	('cerebral hemorrhage', 'Phenotype', 'HP:0001342', (196, 215))	('famitinib', 'Chemical', 'MESH:C584390', (150, 159))	('cerebral hemorrhage', 'Disease', (196, 215))	('cerebral hemorrhage', 'Disease', 'MESH:D002543', (196, 215))	('hypertension', 'Disease', 'MESH:D006973', (43, 55))	('famitinib', 'Var', (150, 159))	('hypertension', 'Disease', (43, 55))	('hemoptysis', 'Disease', 'MESH:D006469', (31, 41))	('fatigue', 'Disease', 'MESH:D005221', (57, 64))	('fatigue', 'Disease', (57, 64))	('thrombocytopenia', 'Disease', 'MESH:D013921', (230, 246))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (230, 246))	('fatigue', 'Disease', (217, 224))	('gastrointestinal hemorrhage', 'Phenotype', 'HP:0002239', (87, 114))	('fatigue', 'Phenotype', 'HP:0012378', (217, 224))	('hypertension', 'Phenotype', 'HP:0000822', (43, 55))	('cerebral infarction', 'Disease', 'MESH:D002544', (175, 194))	('hepatic encephalopathy', 'Phenotype', 'HP:0002480', (120, 142))	('hemoptysis', 'Phenotype', 'HP:0002105', (31, 41))	('hepatic encephalopathy', 'Disease', (120, 142))	('hemoptysis', 'Disease', (31, 41))	('upper gastrointestinal hemorrhage', 'Disease', (81, 114))	('SAEs', 'Chemical', '-', (6, 10))	('infection', 'Disease', (20, 29))	('cerebral infarction', 'Disease', (175, 194))	('infection', 'Disease', 'MESH:D007239', (20, 29))	('renal failure', 'Phenotype', 'HP:0000083', (66, 79))	('hepatic encephalopathy', 'Disease', 'MESH:D006501', (120, 142))	('upper gastrointestinal hemorrhage', 'Disease', 'MESH:D006471', (81, 114))	('renal failure', 'Disease', 'MESH:D051437', (66, 79))	('fatigue', 'Disease', 'MESH:D005221', (217, 224))	('renal failure', 'Disease', (66, 79))
42566	29273089	The majority of SAEs were resolved, whereas four patients died of SAEs (three in the famitinib group and one in the placebo group).	('famitinib', 'Var', (85, 94))	('SAEs', 'Chemical', '-', (66, 70))	('famitinib', 'Chemical', 'MESH:C584390', (85, 94))	('SAEs', 'Disease', (16, 20))	('patients', 'Species', '9606', (49, 57))	('SAEs', 'Chemical', '-', (16, 20))
42584	29273089	The rate of hypertension caused by famitinib in the present study was higher than that caused by regorafenib, suggesting that famitinib may have stronger anti-angiogenesis effect than regorafenib.	('famitinib', 'Chemical', 'MESH:C584390', (35, 44))	('famitinib', 'Var', (126, 135))	('angiogenesis', 'biological_process', 'GO:0001525', ('159', '171'))	('hypertension', 'Disease', 'MESH:D006973', (12, 24))	('regorafenib', 'Chemical', 'MESH:C559147', (97, 108))	('regorafenib', 'Chemical', 'MESH:C559147', (184, 195))	('famitinib', 'Chemical', 'MESH:C584390', (126, 135))	('anti-angiogenesis effect', 'CPA', (154, 178))	('hypertension', 'Disease', (12, 24))	('hypertension', 'Phenotype', 'HP:0000822', (12, 24))
42651	24312138	It has been reported that mutations in genes encoding EGFR pathway proteins result in multiple aberrations in the signal-transduction pathways and dysregulation of the tyrosine kinase activity, and lead to tumor cell proliferation, inhibition of apoptosis, and dissemination.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('lead to', 'Reg', (198, 205))	('apoptosis', 'CPA', (246, 255))	('inhibition', 'NegReg', (232, 242))	('tumor', 'Disease', (206, 211))	('signal-transduction pathways', 'Pathway', (114, 142))	('dysregulation', 'MPA', (147, 160))	('dissemination', 'CPA', (261, 274))	('mutations', 'Var', (26, 35))	('EGFR', 'Gene', '1956', (54, 58))	('tyrosine kinase activity', 'MPA', (168, 192))	('EGFR', 'Gene', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('result in', 'Reg', (76, 85))
42653	24312138	The frequency of tumor EGFR mutations was found to be higher in East Asian ethnicity, such as Taiwan.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('EGFR', 'Gene', '1956', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('EGFR', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
42654	24312138	found that multiple primary malignancies occurred more frequently in patients with lung adenocarcinoma and classic EGFR mutation.	('malignancies', 'Disease', 'MESH:D009369', (28, 40))	('lung adenocarcinoma', 'Disease', (83, 102))	('EGFR', 'Gene', '1956', (115, 119))	('mutation', 'Var', (120, 128))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (83, 102))	('patients', 'Species', '9606', (69, 77))	('EGFR', 'molecular_function', 'GO:0005006', ('115', '119'))	('malignancies', 'Disease', (28, 40))	('EGFR', 'Gene', (115, 119))	('occurred', 'Reg', (41, 49))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (83, 102))
42655	24312138	Amplification and overexpression of EGFR also have been involved in development of numerous types of human cancer.	('Amplification', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('EGFR', 'Gene', '1956', (36, 40))	('human', 'Species', '9606', (101, 106))	('men', 'Species', '9606', (75, 78))	('involved', 'Reg', (56, 64))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('EGFR', 'Gene', (36, 40))	('cancer', 'Disease', (107, 113))	('overexpression', 'PosReg', (18, 32))
42658	24312138	Besides, amplification or overexpression of EGFR is present in gastric carcinomas with independent prognostic value.	('amplification', 'Var', (9, 22))	('overexpression', 'PosReg', (26, 40))	('EGFR', 'Gene', '1956', (44, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('EGFR', 'Gene', (44, 48))	('gastric carcinomas', 'Disease', 'MESH:D013274', (63, 81))	('gastric carcinomas', 'Disease', (63, 81))	('EGFR', 'molecular_function', 'GO:0005006', ('44', '48'))
42667	32391554	The MTT, transwell, and flow cytometry were adopted for analysis on the proliferation, invasion, and apoptosis of transfected cells, respectively, and a dual luciferase reporter (DLR) assay was carried out for correlation determination between TUG1 and miR-138-5p and between miR-138-5p and ZEB2.	('ZEB2', 'Gene', '9839', (291, 295))	('TUG1', 'Gene', (244, 248))	('miR-138-5p', 'Chemical', '-', (276, 286))	('miR-138-5p', 'Var', (276, 286))	('ZEB2', 'Gene', (291, 295))	('apoptosis', 'biological_process', 'GO:0006915', ('101', '110'))	('apoptosis', 'biological_process', 'GO:0097194', ('101', '110'))	('miR-138-5p', 'Chemical', '-', (253, 263))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('miR-138-5p', 'Var', (253, 263))
42668	32391554	In addition, siRNA-TUG1, shRNA-TUG1, miR-138-5p-mimics, and miR-138-5p-inhibitor were transfected into cells, and it turned out that overexpressing miR-138-5p and inhibiting ZEB2 exerted the same effects.	('miR-138-5p', 'Chemical', '-', (148, 158))	('miR-138-5p', 'Chemical', '-', (37, 47))	('ZEB2', 'Gene', '9839', (174, 178))	('miR-138-5p', 'Var', (148, 158))	('miR-138-5p', 'Chemical', '-', (60, 70))	('ZEB2', 'Gene', (174, 178))	('overexpressing', 'PosReg', (133, 147))	('inhibiting', 'NegReg', (163, 173))
42697	32391554	We selected LoVo cells for transfection, finding that in contrast with NC group, the miR-138-5p-mimics group showed significantly higher expression of miR-138-5p and the miR-138-5p-inhibition group showed significantly lower expression of it.	('miR-138-5p', 'Var', (151, 161))	('expression', 'MPA', (137, 147))	('higher', 'PosReg', (130, 136))	('miR-138-5p', 'Chemical', '-', (170, 180))	('lower', 'NegReg', (219, 224))	('miR-138-5p', 'Chemical', '-', (85, 95))	('LoVo', 'CellLine', 'CVCL:0399', (12, 16))	('miR-138-5p', 'Chemical', '-', (151, 161))	('expression', 'MPA', (225, 235))
42698	32391554	The CCK-8 assay uncovered that in contrast with the NC group, the miR-138-5p-mimics group presented significantly weaker proliferation ability and the miR-138-5p-inhibition group showed significantly stronger proliferation ability (P<0.001).	('proliferation ability', 'CPA', (121, 142))	('miR-138-5p', 'Chemical', '-', (151, 161))	('stronger', 'PosReg', (200, 208))	('miR-138-5p', 'Chemical', '-', (66, 76))	('proliferation ability', 'CPA', (209, 230))	('miR-138-5p-inhibition', 'Var', (151, 172))	('weaker', 'NegReg', (114, 120))
42700	32391554	In addition, according to the Transwell assay, in contrast with the NC group, the miR-138-5p-mimics group showed significantly weaker invasion ability (P<0.001) and the miR-138-5p-inhibition group showed significantly stronger invasion ability (P<0.001).	('miR-138-5p', 'Chemical', '-', (169, 179))	('stronger', 'PosReg', (218, 226))	('invasion ability', 'CPA', (134, 150))	('miR-138-5p-inhibition', 'Var', (169, 190))	('weaker', 'NegReg', (127, 133))	('miR-138-5p', 'Chemical', '-', (82, 92))	('invasion ability', 'CPA', (227, 243))
42703	32391554	We selected LoVo for transfection and carried out a DLR gene assay for determination of the luciferase activity of cells transfected with pmirGLO-ZEB2WT/MUT and miR-138-5p mimics.	('luciferase activity', 'molecular_function', 'GO:0047077', ('92', '111'))	('activity', 'MPA', (103, 111))	('luciferase', 'Enzyme', (92, 102))	('luciferase activity', 'molecular_function', 'GO:0045289', ('92', '111'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('92', '111'))	('ZEB2', 'Gene', '9839', (146, 150))	('LoVo', 'CellLine', 'CVCL:0399', (12, 16))	('luciferase activity', 'molecular_function', 'GO:0050397', ('92', '111'))	('miR-138-5p', 'Chemical', '-', (161, 171))	('luciferase activity', 'molecular_function', 'GO:0050248', ('92', '111'))	('miR-138-5p', 'Var', (161, 171))	('ZEB2', 'Gene', (146, 150))
42706	32391554	Correlation analysis revealed that TUG1 was negatively correlated with miR-138-5p; miR-138-5p was negatively correlated with ZEB2, and TUG1 was positively correlated with ZEB2.	('ZEB2', 'Gene', '9839', (171, 175))	('miR-138-5p', 'Chemical', '-', (83, 93))	('miR-138-5p', 'Var', (83, 93))	('correlated', 'Interaction', (155, 165))	('miR-138-5p', 'Chemical', '-', (71, 81))	('ZEB2', 'Gene', (171, 175))	('negatively', 'NegReg', (98, 108))	('ZEB2', 'Gene', '9839', (125, 129))	('TUG1', 'Gene', (135, 139))	('negatively', 'NegReg', (44, 54))	('ZEB2', 'Gene', (125, 129))	('correlated', 'Interaction', (109, 119))
42711	32391554	One study has uncovered that knockdown of TUG1 via shRNA can inhibit the formation of renal cell carcinoma in vivo and in vitro through the miR-299-3p/VEGF axis, and one other study by Yang et al.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (86, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('knockdown', 'Var', (29, 38))	('formation', 'biological_process', 'GO:0009058', ('73', '82'))	('shRNA', 'Gene', (51, 56))	('TUG1', 'Gene', (42, 46))	('VEGF', 'Gene', '22339', (151, 155))	('inhibit', 'NegReg', (61, 68))	('VEGF', 'Gene', (151, 155))	('renal cell carcinoma', 'Disease', (86, 106))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (86, 106))	('formation of', 'CPA', (73, 85))
42719	32391554	In addition, through TargetScan database, we found a targeted relation between lncRNA TUG1 and miR-138-5p and between miR-138-5p and ZEB2, and also found a correlation of miR-138-5p and ZEB2 with CRC differentiation.	('CRC differentiation', 'CPA', (196, 215))	('ZEB2', 'Gene', (186, 190))	('CRC', 'Phenotype', 'HP:0003003', (196, 199))	('miR-138-5p', 'Chemical', '-', (118, 128))	('miR-138-5p', 'Chemical', '-', (95, 105))	('lncRNA TUG1', 'Protein', (79, 90))	('ZEB2', 'Gene', (133, 137))	('miR-138-5p', 'Var', (118, 128))	('miR-138-5p', 'Chemical', '-', (171, 181))	('miR-138-5p', 'Gene', (95, 105))	('miR-138-5p', 'Var', (171, 181))	('ZEB2', 'Gene', '9839', (186, 190))	('correlation', 'Interaction', (156, 167))	('ZEB2', 'Gene', '9839', (133, 137))
42720	32391554	MiR-138-5p was significantly down-regulated in CRC tissue specimens and cell lines.	('MiR-138-5p', 'Var', (0, 10))	('CRC', 'Phenotype', 'HP:0003003', (47, 50))	('MiR-138-5p', 'Chemical', '-', (0, 10))	('down-regulated', 'NegReg', (29, 43))
42721	32391554	Human telomerase reverse transcriptase (hTERT) is a direct target of miR-138-5p in CRC cells, and miR-138-5p acts as a tumor suppressor in CRC by directly targeting hTERT.	('hTERT', 'Gene', (40, 45))	('tumor', 'Disease', (119, 124))	('Human', 'Species', '9606', (0, 5))	('miR-138-5p', 'Var', (69, 79))	('hTERT', 'Gene', (165, 170))	('CRC', 'Disease', (139, 142))	('miR-138-5p', 'Chemical', '-', (98, 108))	('CRC', 'Phenotype', 'HP:0003003', (83, 86))	('hTERT', 'Gene', '7015', (40, 45))	('targeting', 'Reg', (155, 164))	('miR-138-5p', 'Var', (98, 108))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('CRC', 'Phenotype', 'HP:0003003', (139, 142))	('hTERT', 'Gene', '7015', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('miR-138-5p', 'Chemical', '-', (69, 79))
42725	32391554	The correlation analysis uncovered that TUG1 was negatively correlated with miR-138-5p; miR-138-5p was negatively correlated with ZEB2, and TUG1 was positively related to ZEB2.	('miR-138-5p', 'Chemical', '-', (76, 86))	('miR-138-5p', 'Var', (76, 86))	('TUG1', 'Gene', (140, 144))	('ZEB2', 'Gene', '9839', (171, 175))	('ZEB2', 'Gene', '9839', (130, 134))	('negatively', 'NegReg', (103, 113))	('miR-138-5p', 'Chemical', '-', (88, 98))	('miR-138-5p', 'Var', (88, 98))	('negatively', 'NegReg', (49, 59))	('related', 'Interaction', (160, 167))	('ZEB2', 'Gene', (130, 134))	('correlated', 'Interaction', (114, 124))	('ZEB2', 'Gene', (171, 175))
42727	32391554	has verified that miR-138-5p inhibits the EMT, proliferation, and metastasis of lung adenocarcinoma cells by targeting ZEB2.	('miR-138-5p', 'Chemical', '-', (18, 28))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (80, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('EMT', 'CPA', (42, 45))	('lung adenocarcinoma', 'Disease', (80, 99))	('miR-138-5p', 'Var', (18, 28))	('targeting', 'Reg', (109, 118))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (80, 99))	('EMT', 'biological_process', 'GO:0001837', ('42', '45'))	('ZEB2', 'Gene', (119, 123))	('inhibits', 'NegReg', (29, 37))	('proliferation', 'CPA', (47, 60))	('metastasis', 'CPA', (66, 76))	('ZEB2', 'Gene', '9839', (119, 123))
42728	32391554	In our study, analysis of the biological function of cells showed that inhibition of TUG1 expression and overexpression of miR-138-5p strongly inhibited cell proliferation and invasion, down-regulated apoptosis-related protein beta-catenin, and up-regulated Bax and Caspase-3.	('TUG1', 'Gene', (85, 89))	('beta-catenin', 'Gene', (227, 239))	('Bax', 'Gene', '581', (258, 261))	('beta-catenin', 'Gene', '1499', (227, 239))	('overexpression', 'PosReg', (105, 119))	('inhibited', 'NegReg', (143, 152))	('Caspase-3', 'Gene', (266, 275))	('inhibition', 'NegReg', (71, 81))	('cell proliferation', 'CPA', (153, 171))	('expression', 'MPA', (90, 100))	('miR-138-5p', 'Chemical', '-', (123, 133))	('down-regulated', 'NegReg', (186, 200))	('up-regulated', 'PosReg', (245, 257))	('invasion', 'CPA', (176, 184))	('miR-138-5p', 'Var', (123, 133))	('Caspase-3', 'Gene', '836', (266, 275))	('Bax', 'Gene', (258, 261))
42730	32391554	Finally, we carried out in vitro experiments, verifying that TUG1 inhibits the miR-138-5p/ZEB2 molecular axis to promote EMT of CRC cells.	('TUG1', 'Var', (61, 65))	('EMT', 'biological_process', 'GO:0001837', ('121', '124'))	('promote', 'PosReg', (113, 120))	('inhibits', 'NegReg', (66, 74))	('CRC', 'Phenotype', 'HP:0003003', (128, 131))	('miR-138-5p', 'Chemical', '-', (79, 89))	('ZEB2', 'Gene', '9839', (90, 94))	('EMT of CRC cells', 'CPA', (121, 137))	('ZEB2', 'Gene', (90, 94))
42734	32391554	In this study, down-regulating TUG1 significantly inhibited the mRNA expression of ZEB2 in CRC, and strongly hindered the proliferation and EMT of CRC cells, while overexpressing miR-144-3p or down-regulating ZEB2 reversed the inhibition on the EMT caused by down-regulation of TUG1.	('CRC', 'Phenotype', 'HP:0003003', (147, 150))	('EMT', 'biological_process', 'GO:0001837', ('245', '248'))	('ZEB2', 'Gene', '9839', (209, 213))	('regulation', 'biological_process', 'GO:0065007', ('264', '274'))	('mRNA expression', 'MPA', (64, 79))	('ZEB2', 'Gene', '9839', (83, 87))	('down-regulation', 'NegReg', (259, 274))	('TUG1', 'Gene', (31, 35))	('ZEB2', 'Gene', (209, 213))	('down-regulating', 'Var', (15, 30))	('CRC', 'Phenotype', 'HP:0003003', (91, 94))	('EMT', 'biological_process', 'GO:0001837', ('140', '143'))	('hindered', 'NegReg', (109, 117))	('ZEB2', 'Gene', (83, 87))	('inhibited', 'NegReg', (50, 59))	('miR-144-3p', 'Chemical', '-', (179, 189))
42736	32391554	Overexpression of miR-138-5p inhibits EMT in breast cancer cells through up-regulating E-cadherin and down-regulating N-cadherin and vimentin.	('miR-138-5p', 'Chemical', '-', (18, 28))	('N-cadherin', 'Gene', '1000', (118, 128))	('E-cadherin', 'Gene', (87, 97))	('E-cadherin', 'Gene', '999', (87, 97))	('miR-138-5p', 'Var', (18, 28))	('up-regulating', 'PosReg', (73, 86))	('inhibits', 'NegReg', (29, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('vimentin', 'cellular_component', 'GO:0045098', ('133', '141'))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Disease', (45, 58))	('vimentin', 'Gene', '7431', (133, 141))	('EMT in', 'CPA', (38, 44))	('EMT', 'biological_process', 'GO:0001837', ('38', '41'))	('vimentin', 'Gene', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cadherin', 'molecular_function', 'GO:0008014', ('120', '128'))	('down-regulating', 'NegReg', (102, 117))	('vimentin', 'cellular_component', 'GO:0045099', ('133', '141'))	('cadherin', 'molecular_function', 'GO:0008014', ('89', '97'))	('N-cadherin', 'Gene', (118, 128))
42738	32391554	Inhibition of TUG1 can inhibit the proliferation and invasion of cells by up-regulating miR-498 and down-regulating CDC42 in esophageal squamous cell carcinoma cells.	('CDC42', 'Gene', (116, 121))	('TUG1', 'Gene', (14, 18))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (125, 159))	('proliferation', 'CPA', (35, 48))	('invasion of cells', 'CPA', (53, 70))	('up-regulating', 'PosReg', (74, 87))	('inhibit', 'NegReg', (23, 30))	('CDC42', 'Gene', '998', (116, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('miR-498', 'Gene', '574460', (88, 95))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('Inhibition', 'Var', (0, 10))	('esophageal squamous cell carcinoma', 'Disease', (125, 159))	('down-regulating', 'NegReg', (100, 115))	('miR-498', 'Gene', (88, 95))
42742	32391554	To sum up, lncRNA TUG1/miR-138-5p/ZEB2 axis inhibits the proliferation and EMT of CRC cells, and regulation of lncRNA TUG1 on the miR-138-5p/ZEB2 axis is a promising treatment method for CRC and is expected to be adopted in clinical practice.	('ZEB2', 'Gene', (141, 145))	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('regulation', 'Var', (97, 107))	('regulation', 'biological_process', 'GO:0065007', ('97', '107'))	('CRC', 'Disease', (187, 190))	('ZEB2', 'Gene', '9839', (34, 38))	('miR-138-5p', 'Chemical', '-', (23, 33))	('miR-138-5p', 'Chemical', '-', (130, 140))	('ZEB2', 'Gene', '9839', (141, 145))	('CRC', 'Phenotype', 'HP:0003003', (187, 190))	('EMT', 'biological_process', 'GO:0001837', ('75', '78'))	('proliferation', 'CPA', (57, 70))	('ZEB2', 'Gene', (34, 38))	('inhibits', 'NegReg', (44, 52))
42745	28287627	Nowadays, there is convincing evidence of positive associations between T2D and the incidence or prognosis of a wide spectrum of cancers, for example, breast, colon, liver and pancreas.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast', 'Disease', (151, 157))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('T2D', 'Phenotype', 'HP:0005978', (72, 75))	('cancers', 'Disease', (129, 136))	('colon', 'Disease', (159, 164))	('liver', 'Disease', (166, 171))	('pancreas', 'Disease', (176, 184))	('T2D', 'Var', (72, 75))
42750	28287627	This review addresses the molecular and clinical associations between PFAA alterations and both T2D and cancers, and interprets possible mechanisms involved.	('T2D', 'Phenotype', 'HP:0005978', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('PFAA', 'Chemical', '-', (70, 74))	('alterations', 'Var', (75, 86))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('PFAA', 'Gene', (70, 74))	('T2D', 'Disease', (96, 99))
42790	28287627	In order to build AICS, 19 amino acids including threonine (Thr), asparagine (Asn), Ser, Gln, Pro, Gly, Ala, citrulline (Cit), Val, Met, Ile, Leu, Tyr, Phe, His, tryptophan (Trp), ornithine (Orn), Lys and Arg, were measured and statistically analyzed.	('His', 'Chemical', 'MESH:D006639', (157, 160))	('Ile', 'Chemical', 'MESH:D007532', (137, 140))	('threonine', 'Chemical', 'MESH:D013912', (49, 58))	('Phe', 'Chemical', 'MESH:D010649', (152, 155))	('Ser', 'Chemical', 'MESH:D012694', (84, 87))	('Tyr', 'Chemical', 'MESH:D014443', (147, 150))	('Met', 'Chemical', 'MESH:D008715', (132, 135))	('citrulline', 'Chemical', 'MESH:D002956', (109, 119))	('Thr', 'Chemical', 'MESH:D013912', (60, 63))	('Trp', 'Chemical', 'MESH:D014364', (174, 177))	('Orn', 'Chemical', 'MESH:D009952', (191, 194))	('Asn', 'Chemical', 'MESH:D001216', (78, 81))	('Leu', 'Var', (142, 145))	('Val', 'Chemical', 'MESH:D014633', (127, 130))	('Phe', 'Var', (152, 155))	('Ser', 'cellular_component', 'GO:0005790', ('84', '87'))	('Cit', 'Chemical', 'MESH:D002956', (121, 124))	('Ala', 'Chemical', 'MESH:D000409', (104, 107))	('Gly', 'Chemical', 'MESH:D005998', (99, 102))	('tryptophan', 'Chemical', 'MESH:D014364', (162, 172))	('Arg', 'Chemical', 'MESH:D001120', (205, 208))	('Lys', 'Chemical', 'MESH:D008239', (197, 200))	('asparagine', 'Chemical', 'MESH:D001216', (66, 76))	('ornithine', 'Chemical', 'MESH:D009952', (180, 189))	('Cit', 'biological_process', 'GO:0106106', ('121', '124'))	('Leu', 'Chemical', 'MESH:D007930', (142, 145))	('Gln', 'Chemical', 'MESH:D005973', (89, 92))	('Pro', 'Chemical', 'MESH:D011392', (94, 97))	('Gln', 'MPA', (89, 92))
42796	28287627	They also analyzed the levels of 19 amino acids and a significant increase in Ser level and significant decreases in the levels of Thr, Asn, Pro, Ala, Cit, Val, Met, Leu, Tyr, Phe, His, Trp, Lys and Arg were observed in pancreatic cancer patients.	('pancreatic cancer', 'Disease', 'MESH:D010190', (220, 237))	('Val', 'MPA', (156, 159))	('Trp', 'Chemical', 'MESH:D014364', (186, 189))	('Phe', 'MPA', (176, 179))	('His', 'Chemical', 'MESH:D006639', (181, 184))	('Phe', 'Chemical', 'MESH:D010649', (176, 179))	('Pro', 'MPA', (141, 144))	('Thr', 'MPA', (131, 134))	('pancreatic cancer', 'Disease', (220, 237))	('Tyr', 'Chemical', 'MESH:D014443', (171, 174))	('Asn', 'Chemical', 'MESH:D001216', (136, 139))	('Lys', 'MPA', (191, 194))	('Ala', 'Chemical', 'MESH:D000409', (146, 149))	('Lys', 'Chemical', 'MESH:D008239', (191, 194))	('Arg', 'MPA', (199, 202))	('Cit', 'MPA', (151, 154))	('Ala', 'MPA', (146, 149))	('Trp', 'MPA', (186, 189))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('Arg', 'Chemical', 'MESH:D001120', (199, 202))	('Leu', 'Var', (166, 169))	('Thr', 'Chemical', 'MESH:D013912', (131, 134))	('Met', 'MPA', (161, 164))	('Asn', 'MPA', (136, 139))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (220, 237))	('Cit', 'Chemical', 'MESH:D002956', (151, 154))	('Met', 'Chemical', 'MESH:D008715', (161, 164))	('patients', 'Species', '9606', (238, 246))	('levels', 'MPA', (121, 127))	('increase', 'PosReg', (66, 74))	('Tyr', 'MPA', (171, 174))	('decreases', 'NegReg', (104, 113))	('Leu', 'Chemical', 'MESH:D007930', (166, 169))	('Val', 'Chemical', 'MESH:D014633', (156, 159))	('His', 'MPA', (181, 184))	('Ser level', 'MPA', (78, 87))	('Pro', 'Chemical', 'MESH:D011392', (141, 144))	('Ser', 'Chemical', 'MESH:D012694', (78, 81))
42824	28287627	Additionally, emerging evidence suggested that aberrant activation of the biosynthetic pathway of Ser was an essential process in cancer pathogenesis.	('aberrant', 'Var', (47, 55))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('Ser', 'cellular_component', 'GO:0005790', ('98', '101'))	('cancer', 'Disease', (130, 136))	('pathogenesis', 'biological_process', 'GO:0009405', ('137', '149'))	('Ser', 'Gene', (98, 101))	('biosynthetic', 'Enzyme', (74, 86))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('activation', 'PosReg', (56, 66))	('Ser', 'Chemical', 'MESH:D012694', (98, 101))
42846	28287627	Further studies are required to verify the significance of PFAA alterations in cancers development and management.	('cancers', 'Disease', (79, 86))	('PFAA', 'Chemical', '-', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('alterations', 'Var', (64, 75))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
42854	28287627	Increasing evidence suggests that elevated plasma BCAAs levels may have adverse effects on the regulation of glucose homeostasis, because the oxidation of BCAAs spares glucose utilization in skeletal muscle.	('glucose utilization in skeletal muscle', 'MPA', (168, 206))	('BCAAs', 'Chemical', 'MESH:D000597', (155, 160))	('regulation', 'MPA', (95, 105))	('glucose homeostasis', 'Disease', 'MESH:D018149', (109, 128))	('glucose', 'Chemical', 'MESH:D005947', (109, 116))	('oxidation', 'Var', (142, 151))	('glucose homeostasis', 'Disease', (109, 128))	('spares', 'NegReg', (161, 167))	('glucose', 'Chemical', 'MESH:D005947', (168, 175))	('BCAAs', 'Chemical', 'MESH:D000597', (50, 55))	('BCAAs', 'Gene', (155, 160))
42864	28287627	The combination of three amino acids, that is, Ile, Phe and Tyr, predicted future DM with a four- to six-fold increased risk for participants in top quartile.	('DM', 'Phenotype', 'HP:0000819', (82, 84))	('participants', 'Species', '9606', (129, 141))	('DM', 'Disease', 'MESH:D009223', (82, 84))	('Ile', 'Chemical', 'MESH:D007532', (47, 50))	('predicted', 'Reg', (65, 74))	('Phe', 'Chemical', 'MESH:D010649', (52, 55))	('Tyr', 'Chemical', 'MESH:D014443', (60, 63))	('Phe', 'Var', (52, 55))	('Tyr', 'Var', (60, 63))
42865	28287627	The combination of Ile, Phe and Tyr also helped to predict future cardiovascular diseases during a long-term follow-up, probably through increased tendency towards the development of atherosclerosis.	('atherosclerosis', 'Disease', 'MESH:D050197', (183, 198))	('predict', 'Reg', (51, 58))	('Phe', 'Chemical', 'MESH:D010649', (24, 27))	('cardiovascular diseases', 'Disease', (66, 89))	('atherosclerosis', 'Disease', (183, 198))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (66, 89))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (66, 89))	('Tyr', 'Chemical', 'MESH:D014443', (32, 35))	('Phe', 'Var', (24, 27))	('Tyr', 'Var', (32, 35))	('atherosclerosis', 'Phenotype', 'HP:0002621', (183, 198))	('Ile', 'Chemical', 'MESH:D007532', (19, 22))
42869	28287627	Increased circulating levels of Phe and Tyr (or AAAs) have been reported to be associated with insulin resistant, T2D or cardiovascular diseases states.	('T2D', 'Disease', (114, 117))	('associated', 'Reg', (79, 89))	('T2D', 'Phenotype', 'HP:0005978', (114, 117))	('insulin', 'Gene', (95, 102))	('cardiovascular diseases', 'Disease', (121, 144))	('circulating', 'MPA', (10, 21))	('insulin', 'Gene', '3630', (95, 102))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (121, 144))	('Tyr', 'Chemical', 'MESH:D014443', (40, 43))	('Tyr', 'Var', (40, 43))	('Increased', 'PosReg', (0, 9))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (121, 144))	('Phe', 'Chemical', 'MESH:D010649', (32, 35))	('AAAs', 'Chemical', 'MESH:D024322', (48, 52))	('Phe', 'Var', (32, 35))	('insulin', 'molecular_function', 'GO:0016088', ('95', '102'))
42871	28287627	In the studies using blood metabolites to predict T2D and determining correlations between metabolites and insulin sensitivity, Phe and Tyr provided some of the strongest associations.	('Tyr', 'Chemical', 'MESH:D014443', (136, 139))	('insulin', 'Gene', '3630', (107, 114))	('Tyr', 'Var', (136, 139))	('Phe', 'Chemical', 'MESH:D010649', (128, 131))	('T2D', 'Disease', (50, 53))	('T2D', 'Phenotype', 'HP:0005978', (50, 53))	('Phe', 'Var', (128, 131))	('insulin', 'Gene', (107, 114))	('associations', 'Interaction', (171, 183))
42872	28287627	The positive correlation between Phe and/or Tyr and insulin secretion may be involved in pathways to compensate early stage of insulin resistance through stimulating insulin secretion (Table 4).	('insulin', 'Gene', '3630', (52, 59))	('Tyr', 'Chemical', 'MESH:D014443', (44, 47))	('insulin', 'molecular_function', 'GO:0016088', ('52', '59'))	('Tyr', 'Var', (44, 47))	('Phe', 'Chemical', 'MESH:D010649', (33, 36))	('insulin secretion', 'biological_process', 'GO:0030073', ('166', '183'))	('insulin', 'molecular_function', 'GO:0016088', ('127', '134'))	('insulin secretion', 'biological_process', 'GO:0030073', ('52', '69'))	('insulin secretion', 'Disease', 'MESH:D007333', (52, 69))	('insulin', 'molecular_function', 'GO:0016088', ('166', '173'))	('insulin', 'Gene', '3630', (127, 134))	('insulin secretion', 'Disease', (166, 183))	('insulin', 'Gene', (52, 59))	('Phe', 'Var', (33, 36))	('insulin', 'Gene', '3630', (166, 173))	('stimulating', 'PosReg', (154, 165))	('involved', 'Reg', (77, 85))	('insulin', 'Gene', (127, 134))	('insulin secretion', 'Disease', 'MESH:D007333', (166, 183))	('insulin secretion', 'Disease', (52, 69))	('insulin resistance', 'Phenotype', 'HP:0000855', (127, 145))	('insulin', 'Gene', (166, 173))
42879	28287627	Some other studies in healthy obese and in pre-diabetic subjects suggested that the levels of Ala, Gly, Gln, Glu, Trp, Tyr and BCAAs were correlated with visceral adiposity which was associated with deregulated insulin signaling.	('Gln', 'Chemical', 'MESH:D005973', (104, 107))	('Gly', 'MPA', (99, 102))	('Gln', 'MPA', (104, 107))	('insulin', 'Gene', (211, 218))	('correlated', 'Reg', (138, 148))	('Trp', 'MPA', (114, 117))	('pre', 'molecular_function', 'GO:0003904', ('43', '46'))	('Glu', 'Chemical', 'MESH:D018698', (109, 112))	('signaling', 'biological_process', 'GO:0023052', ('219', '228'))	('diabetic', 'Disease', 'MESH:D003920', (47, 55))	('Gly', 'Chemical', 'MESH:D005998', (99, 102))	('BCAAs', 'Chemical', 'MESH:D000597', (127, 132))	('diabetic', 'Disease', (47, 55))	('obese', 'Disease', (30, 35))	('visceral adiposity', 'MPA', (154, 172))	('Tyr', 'Chemical', 'MESH:D014443', (119, 122))	('insulin', 'molecular_function', 'GO:0016088', ('211', '218'))	('Tyr', 'Var', (119, 122))	('insulin', 'Gene', '3630', (211, 218))	('Ala', 'Chemical', 'MESH:D000409', (94, 97))	('obese', 'Disease', 'MESH:D009765', (30, 35))	('Glu', 'MPA', (109, 112))	('Trp', 'Chemical', 'MESH:D014364', (114, 117))
42884	28287627	The underlying link between obesity, T2D, and cancer is related to insulin resistance, hyperinsulinemia, and disturbances in IGF signaling systems (Figure 1).	('insulin', 'Gene', (67, 74))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (87, 103))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('disturbances', 'Var', (109, 121))	('insulin', 'Gene', (92, 99))	('insulin', 'Gene', '3630', (67, 74))	('cancer', 'Disease', (46, 52))	('obesity', 'Phenotype', 'HP:0001513', (28, 35))	('insulin', 'Gene', '3630', (92, 99))	('insulin resistance', 'Phenotype', 'HP:0000855', (67, 85))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (87, 103))	('T2D', 'Disease', (37, 40))	('hyperinsulinemia', 'Disease', (87, 103))	('obesity', 'Disease', 'MESH:D009765', (28, 35))	('T2D', 'Phenotype', 'HP:0005978', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('obesity', 'Disease', (28, 35))	('IGF signaling systems', 'MPA', (125, 146))
42887	28287627	Although PFAA alterations can be used for diagnosis of cancers or T2D with sufficient sensitivity and robustness, the specificity is low.	('alterations', 'Var', (14, 25))	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('cancers', 'Disease', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('PFAA', 'Chemical', '-', (9, 13))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('T2D', 'Phenotype', 'HP:0005978', (66, 69))
42897	27447746	BTG1 might be employed as a biomarker for carcinogenesis and a target for gene therapy in colorectal cancers Here, BTG1 overexpression inhibited proliferation, induced differentiation, autophagy, and apoptosis in colorectal cancer cells (p2 arrest might be related to Cyclin B1 and Cdc25B hypoexpression in HCT-15 transfectants, while G1 arrest in HCT-116 transfectants overexpressing p21 and p27.	('Cdc25B', 'Gene', (282, 288))	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('HCT-116', 'CellLine', 'CVCL:0291', (348, 355))	('hypoexpression', 'Var', (289, 303))	('colorectal cancers', 'Disease', 'MESH:D015179', (90, 108))	('BTG1', 'Gene', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('BTG1', 'Gene', '694', (115, 119))	('carcinogenesis', 'Disease', (42, 56))	('p27', 'Gene', (393, 396))	('p27', 'Gene', '3429', (393, 396))	('colorectal cancer', 'Disease', 'MESH:D015179', (213, 230))	('BTG1', 'Gene', (0, 4))	('induced differentiation', 'CPA', (160, 183))	('colorectal cancer', 'Disease', (213, 230))	('carcinogenesis', 'Disease', 'MESH:D063646', (42, 56))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('colorectal cancers', 'Disease', (90, 108))	('inhibited', 'NegReg', (135, 144))	('BTG1', 'Gene', '694', (0, 4))	('apoptosis', 'CPA', (200, 209))	('autophagy', 'CPA', (185, 194))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('p21', 'Gene', (385, 388))	('p21', 'Gene', '644914', (385, 388))	('proliferation', 'CPA', (145, 158))	('Cdc25B', 'Gene', '994', (282, 288))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (213, 230))
42898	27447746	BTG1 overexpression decreased the expression of Bcl-2, Bcl-xL, XIAP, Akt1 or survivin and increased the expression of Bax or p53 in colorectal cancer cells.	('Bcl-2', 'Gene', '596', (48, 53))	('expression', 'MPA', (34, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (132, 149))	('overexpression', 'Var', (5, 19))	('XIAP', 'Gene', '331', (63, 67))	('expression', 'MPA', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('Bax', 'Gene', (118, 121))	('BTG1', 'Gene', (0, 4))	('colorectal cancer', 'Disease', 'MESH:D015179', (132, 149))	('Akt1', 'Gene', (69, 73))	('increased', 'PosReg', (90, 99))	('p53', 'Gene', '7157', (125, 128))	('Bax', 'Gene', '581', (118, 121))	('colorectal cancer', 'Disease', (132, 149))	('Bcl-xL', 'Gene', (55, 61))	('survivin', 'Gene', (77, 85))	('Bcl-2', 'Gene', (48, 53))	('XIAP', 'Gene', (63, 67))	('decreased', 'NegReg', (20, 29))	('Bcl-2', 'molecular_function', 'GO:0015283', ('48', '53'))	('p53', 'Gene', (125, 128))	('Bcl-xL', 'Gene', '598', (55, 61))	('Akt1', 'Gene', '207', (69, 73))
42900	27447746	BTG1 overexpression might weaken beta-catenin pathway in colorectal cancer cells.	('colorectal cancer', 'Disease', (57, 74))	('beta-catenin', 'Gene', '1499', (33, 45))	('BTG1', 'Gene', (0, 4))	('weaken', 'NegReg', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('colorectal cancer', 'Disease', 'MESH:D015179', (57, 74))	('weaken beta-catenin pathway', 'Phenotype', 'HP:0040209', (26, 53))	('beta-catenin', 'Gene', (33, 45))	('colorectal cancer', 'Phenotype', 'HP:0003003', (57, 74))	('overexpression', 'Var', (5, 19))
42901	27447746	The chemosensitivity of BTG1 transfectants to paclitaxel, cisplatin, MG132 or SAHA was positively correlated with its apoptotic induction.	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('BTG1', 'Gene', (24, 28))	('MG132', 'Chemical', 'MESH:C072553', (69, 74))	('SAHA', 'Chemical', 'MESH:D000077337', (78, 82))	('paclitaxel', 'Chemical', 'MESH:D017239', (46, 56))	('apoptotic induction', 'CPA', (118, 137))	('correlated', 'Reg', (98, 108))	('transfectants', 'Var', (29, 42))
42915	27447746	BTG1 hypoexpression was observed in gastric cancer and negatively correlated with depth of invasion, lymphatic and venous invasion, lymph node metastasis, TNM staging and worse prognosis of gastric cancer.	('correlated', 'Reg', (66, 76))	('lymph node metastasis', 'CPA', (132, 153))	('BTG1', 'Gene', (0, 4))	('gastric cancer', 'Disease', 'MESH:D013274', (190, 204))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('TNM', 'Gene', '10178', (155, 158))	('gastric cancer', 'Disease', (36, 50))	('negatively', 'NegReg', (55, 65))	('ser', 'Chemical', 'MESH:D012694', (26, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (190, 204))	('gastric cancer', 'Disease', 'MESH:D013274', (36, 50))	('hypoexpression', 'Var', (5, 19))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('TNM', 'Gene', (155, 158))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('depth of invasion', 'CPA', (82, 99))	('gastric cancer', 'Disease', (190, 204))
42920	27447746	BTG1 overexpression caused G2 arrest in HCT-15 cells (p<0.05), while G1 arrest in HCT-116 cells (p<0.05) by PI staining (Figure 1D).	('HCT-116', 'CellLine', 'CVCL:0291', (82, 89))	('overexpression', 'Var', (5, 19))	('G2 arrest', 'MPA', (27, 36))	('BTG1', 'Gene', (0, 4))
42921	27447746	BTG1 transfectants of HCT-15 showed the reduced expression of Cyclin D1, Cyclin E, Cdc2, p21 and p27, compared with the control and mock by real-time PCR (p<0.05, Figure 1E).	('Cyclin D1', 'Gene', (62, 71))	('Cyclin', 'Gene', (73, 79))	('p21', 'Gene', '644914', (89, 92))	('Cyclin', 'molecular_function', 'GO:0016538', ('73', '79'))	('p21', 'Gene', (89, 92))	('expression', 'MPA', (48, 58))	('Cdc2', 'Gene', (83, 87))	('Cyclin', 'Gene', '5111', (62, 68))	('Cdc2', 'Gene', '983', (83, 87))	('reduced', 'NegReg', (40, 47))	('p27', 'Gene', (97, 100))	('Cyclin', 'Gene', '5111', (73, 79))	('p27', 'Gene', '3429', (97, 100))	('Cyclin', 'molecular_function', 'GO:0016538', ('62', '68'))	('Cyclin D1', 'Gene', '595', (62, 71))	('Cyclin', 'Gene', (62, 68))	('transfectants', 'Var', (5, 18))	('HCT-15', 'Gene', (22, 28))
42926	27447746	A higher autophagy was evidenced by autophagosomes (Figure 2B) and LC-3B expression (Figure 2C) in both BTG1 transfectants than the control.	('LC-3B', 'Gene', '81631', (67, 72))	('higher', 'PosReg', (2, 8))	('transfectants', 'Var', (109, 122))	('BTG1', 'Gene', (104, 108))	('autophagy', 'CPA', (9, 18))	('LC-3B', 'Gene', (67, 72))	('expression', 'MPA', (73, 83))	('autophagosomes', 'CPA', (36, 50))
42928	27447746	There was a higher apoptosis, evidenced by Annexin V-FITC staining in both BTG1 transfectants than the control and mock (Figure 3A, p<0.05).	('Annexin V', 'Gene', (43, 52))	('apoptosis', 'CPA', (19, 28))	('higher', 'PosReg', (12, 18))	('transfectants', 'Var', (80, 93))	('Annexin V', 'Gene', '308', (43, 52))	('BTG1', 'Gene', (75, 79))
42929	27447746	A lower mitochondrial membrane potential by JC-1 staining and a higher senescence by beta-galactosidase staining were detectable in HCT-116 transfectants than the mock and control (Figure 3B and 3C, p<0.05), while there was no significant alteration in HCT-15 transfectants (Figure 3B and 3C, p>0.05).	('lower', 'NegReg', (2, 7))	('HCT-116', 'CellLine', 'CVCL:0291', (132, 139))	('beta-galactosidase', 'Gene', '2720', (85, 103))	('mitochondrial membrane potential', 'MPA', (8, 40))	('HCT-116', 'Gene', (132, 139))	('higher', 'PosReg', (64, 70))	('transfectants', 'Var', (140, 153))	('beta-galactosidase', 'Gene', (85, 103))	('senescence', 'MPA', (71, 81))	('lower mitochondrial membrane potential', 'Phenotype', 'HP:0040013', (2, 40))
42930	27447746	As shown in Figure 3D, BTG1 transfectants of HCT-15 showed reduced expression of Bcl-2, Bax, Bcl-xL, Bad, Akt1 and survivin, compared with the control and mock by real-time PCR (p<0.05).	('Akt1', 'Gene', (106, 110))	('reduced', 'NegReg', (59, 66))	('Bad', 'MPA', (101, 104))	('Bax', 'Gene', (88, 91))	('Akt1', 'Gene', '207', (106, 110))	('HCT-15', 'Gene', (45, 51))	('survivin', 'Protein', (115, 123))	('transfectants', 'Var', (28, 41))	('Bcl-2', 'Gene', (81, 86))	('Bcl-xL', 'Gene', '598', (93, 99))	('Bcl-2', 'Gene', '596', (81, 86))	('Bax', 'Gene', '581', (88, 91))	('expression', 'MPA', (67, 77))	('Bcl-xL', 'Gene', (93, 99))
42932	27447746	At the protein level (Figure 3E), BTG1 overexpression increased the p53 expression (p<0.05), but decreased the expression of Bcl-2 and Bax in HCT-15 transfectants (p<0.05).	('Bax', 'Gene', (135, 138))	('Bcl-2', 'Gene', (125, 130))	('BTG1', 'Gene', (34, 38))	('Bcl-2', 'Gene', '596', (125, 130))	('increased', 'PosReg', (54, 63))	('expression', 'MPA', (72, 82))	('expression', 'MPA', (111, 121))	('decreased', 'NegReg', (97, 106))	('overexpression', 'Var', (39, 53))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('Bax', 'Gene', '581', (135, 138))
42935	27447746	Dual luciferase gene assay demonstrated that BTG1 overexpression might suppress TCF-4 promoter activity and TCF-4-mediated gene transcription activity (Figure 4D and 4E, p >0.05).	('BTG1', 'Gene', (45, 49))	('TCF-4', 'Gene', (80, 85))	('TCF-4', 'Gene', (108, 113))	('TCF-4', 'Gene', '6925', (80, 85))	('suppress', 'NegReg', (71, 79))	('TCF-4', 'Gene', '6925', (108, 113))	('promoter activity', 'MPA', (86, 103))	('overexpression', 'Var', (50, 64))
42938	27447746	After exposed to paclitaxel, cisplatin (DDP), and MG132, HCT-15 transfectants showed lower viability and higher apoptosis than the control in both time- and dose-dependent manners (Figure 5A and 5B, p <0.05), while the converse for SAHA.	('MG132', 'Chemical', 'MESH:C072553', (50, 55))	('apoptosis', 'biological_process', 'GO:0097194', ('112', '121'))	('apoptosis', 'biological_process', 'GO:0006915', ('112', '121'))	('apoptosis', 'CPA', (112, 121))	('lower', 'NegReg', (85, 90))	('higher', 'PosReg', (105, 111))	('SAHA', 'Chemical', 'MESH:D000077337', (232, 236))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('DDP', 'Gene', '1678', (40, 43))	('paclitaxel', 'Chemical', 'MESH:D017239', (17, 27))	('MG132', 'Var', (50, 55))	('HCT-15', 'Gene', (57, 63))	('transfectants', 'Var', (64, 77))	('DDP', 'Gene', (40, 43))
42939	27447746	After treatment with DDP and SAHA, lower viability and higher apoptosis were observed in HCT-116 transfectants than the control in both time- and dose-dependent manners (Figure 5A and 5B, p <0.05), while the converse for paclitaxel and MG132.	('MG132', 'Chemical', 'MESH:C072553', (236, 241))	('DDP', 'Gene', (21, 24))	('SAHA', 'Chemical', 'MESH:D000077337', (29, 33))	('apoptosis', 'CPA', (62, 71))	('lower', 'NegReg', (35, 40))	('HCT-116', 'Gene', (89, 96))	('paclitaxel', 'Chemical', 'MESH:D017239', (221, 231))	('transfectants', 'Var', (97, 110))	('ser', 'Chemical', 'MESH:D012694', (79, 82))	('HCT-116', 'CellLine', 'CVCL:0291', (89, 96))	('DDP', 'Gene', '1678', (21, 24))	('higher', 'PosReg', (55, 61))	('men', 'Species', '9606', (11, 14))
42940	27447746	In addition, we found that mRNA expression of GRP78, BCRP, MRP1 and GST-pi was up-regulated in both transfectants, compared with the control and mock (Figure 5C, p <0.05).	('BCRP', 'Gene', (53, 57))	('MRP1', 'Gene', '4194', (59, 63))	('up-regulated', 'PosReg', (79, 91))	('GST-pi', 'Gene', (68, 74))	('GRP78', 'Gene', (46, 51))	('MRP1', 'Gene', (59, 63))	('GRP78', 'Gene', '3309', (46, 51))	('BCRP', 'Gene', '644079', (53, 57))	('mRNA expression', 'MPA', (27, 42))	('transfectants', 'Var', (100, 113))
42944	27447746	Among 36 colorectal cancers, 25 cancers overexpressed 19kDa BTG1 protein in comparison to NNM.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancers', 'Disease', (20, 27))	('cancers', 'Disease', (32, 39))	('protein', 'Protein', (65, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (9, 26))	('colorectal cancers', 'Disease', 'MESH:D015179', (9, 27))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('19kDa', 'Var', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('overexpressed', 'PosReg', (40, 53))	('BTG1', 'Gene', (60, 64))	('cancers', 'Disease', 'MESH:D009369', (20, 27))	('colorectal cancers', 'Disease', (9, 27))
42951	27447746	The tumors from BTG1 transfectants displayed lower blood supply than the control by Maximum intensity (Imax) of contrast-enhanced ultrasonic imaging (Figure 8G and 8H, p<0.05).	('blood supply', 'MPA', (51, 63))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('transfectants', 'Var', (21, 34))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('lower', 'NegReg', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('BTG1', 'Gene', (16, 20))
42958	27447746	In agreement with the findings in breast, lung, ovarian and hepatocellular cancers, our functional experiments showed that BTG1 overexpression suppressed proliferation, cell cycle progression and induced apoptosis, autophagy and differentiation in colorectal cancer cells.	('apoptosis', 'biological_process', 'GO:0097194', ('204', '213'))	('men', 'Species', '9606', (105, 108))	('apoptosis', 'biological_process', 'GO:0006915', ('204', '213'))	('autophagy', 'biological_process', 'GO:0006914', ('215', '224'))	('colorectal cancer', 'Disease', (248, 265))	('autophagy', 'CPA', (215, 224))	('apoptosis', 'CPA', (204, 213))	('ovarian and hepatocellular cancers', 'Disease', 'MESH:D006528', (48, 82))	('men', 'Species', '9606', (8, 11))	('suppressed', 'NegReg', (143, 153))	('cell cycle', 'biological_process', 'GO:0007049', ('169', '179'))	('induced', 'PosReg', (196, 203))	('colorectal cancer', 'Phenotype', 'HP:0003003', (248, 265))	('overexpression', 'Var', (128, 142))	('cell cycle progression', 'CPA', (169, 191))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('proliferation', 'CPA', (154, 167))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('autophagy', 'biological_process', 'GO:0016236', ('215', '224'))	('differentiation', 'CPA', (229, 244))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('colorectal cancer', 'Disease', 'MESH:D015179', (248, 265))	('BTG1', 'Gene', (123, 127))
42959	27447746	In xenograft models, BTG1 overexpression might suppress tumor growth, blood supply and proliferation, and induce apoptosis and autophagy.	('BTG1', 'Gene', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('autophagy', 'biological_process', 'GO:0016236', ('127', '136'))	('apoptosis', 'CPA', (113, 122))	('blood supply', 'CPA', (70, 82))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('induce', 'PosReg', (106, 112))	('tumor', 'Disease', (56, 61))	('autophagy', 'biological_process', 'GO:0006914', ('127', '136'))	('suppress', 'NegReg', (47, 55))	('apoptosis', 'biological_process', 'GO:0097194', ('113', '122'))	('overexpression', 'Var', (26, 40))	('autophagy', 'CPA', (127, 136))	('apoptosis', 'biological_process', 'GO:0006915', ('113', '122'))
42965	27447746	In HCT-15 transfectants, BTG1-induced G2 arrest might be associated with Cyclin B1 and Cdc25B hypoexpression, while G1 progression to p21 and p27 hypoexpression.	('HCT-15', 'Gene', (3, 9))	('Cdc25B', 'Gene', (87, 93))	('hypoexpression', 'Var', (94, 108))	('Cyclin', 'molecular_function', 'GO:0016538', ('73', '79'))	('p21', 'Gene', '644914', (134, 137))	('p27', 'Gene', '3429', (142, 145))	('G2 arrest', 'CPA', (38, 47))	('p27', 'Gene', (142, 145))	('Cyclin B1', 'Protein', (73, 82))	('BTG1-induced', 'Gene', (25, 37))	('Cdc25B', 'Gene', '994', (87, 93))	('p21', 'Gene', (134, 137))
42967	27447746	The higher expression of Cyclin B1 and Cdc2 might result in the low ratio of G2-phase cells in HCT-116 transfectants.	('Cdc2', 'Gene', (39, 43))	('Cyclin', 'molecular_function', 'GO:0016538', ('25', '31'))	('G2-phase', 'biological_process', 'GO:0051319', ('77', '85'))	('low', 'NegReg', (64, 67))	('expression', 'MPA', (11, 21))	('Cdc2', 'Gene', '983', (39, 43))	('transfectants', 'Var', (103, 116))	('HCT-116', 'CellLine', 'CVCL:0291', (95, 102))	('Cyclin B1', 'Protein', (25, 34))	('higher', 'PosReg', (4, 10))
42969	27447746	BTG1 overexpression induced apoptosis in HCT-15 and HCT-116 cells, but only reduced the mitochondrial potential and increased the cellular senescence in HCT-116 transfectants, suggesting the mechanisms underlying the apoptosis in these two cell lines are different.	('cellular senescence', 'MPA', (130, 149))	('BTG1', 'Gene', (0, 4))	('HCT-116', 'CellLine', 'CVCL:0291', (52, 59))	('HCT-116', 'CellLine', 'CVCL:0291', (153, 160))	('mitochondrial potential', 'MPA', (88, 111))	('reduced', 'NegReg', (76, 83))	('increased', 'PosReg', (116, 125))	('overexpression', 'Var', (5, 19))
42971	27447746	In line with previous studies, we observed that BTG1 overexpression down-regulated the protein levels of Bcl-2, Bax and up-regulated the expression of p53 in HCT-15 cells.	('Bax', 'Gene', '581', (112, 115))	('expression', 'MPA', (137, 147))	('down-regulated', 'NegReg', (68, 82))	('p53', 'Gene', '7157', (151, 154))	('ser', 'Chemical', 'MESH:D012694', (36, 39))	('BTG1', 'Gene', (48, 52))	('Bax', 'Gene', (112, 115))	('Bcl-2', 'Gene', (105, 110))	('Bcl-2', 'Gene', '596', (105, 110))	('overexpression', 'Var', (53, 67))	('Bcl-2', 'molecular_function', 'GO:0015283', ('105', '110'))	('p53', 'Gene', (151, 154))	('up-regulated', 'PosReg', (120, 132))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
42972	27447746	However, HCT-116 transfectants showed the decrease of AIF and XIAP and the elevation of Bcl-2, Bax and p53 proteins.	('XIAP', 'Gene', (62, 66))	('Bax', 'Gene', (95, 98))	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('HCT-116', 'CellLine', 'CVCL:0291', (9, 16))	('elevation', 'PosReg', (75, 84))	('transfectants', 'Var', (17, 30))	('XIAP', 'Gene', '331', (62, 66))	('AIF', 'Gene', '9131', (54, 57))	('HCT-116', 'Gene', (9, 16))	('Bcl-2', 'Gene', (88, 93))	('AIF', 'Gene', (54, 57))	('Bcl-2', 'Gene', '596', (88, 93))	('decrease', 'NegReg', (42, 50))	('Bax', 'Gene', '581', (95, 98))
42975	27447746	Here, we found that ectopic BTG1 expression reduced the mRNA and protein expression of beta-catenin and down-regulated its phosphorylation in colorectal cancer cells.	('colorectal cancer', 'Disease', 'MESH:D015179', (142, 159))	('beta-catenin', 'Gene', (87, 99))	('phosphorylation', 'MPA', (123, 138))	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('BTG1', 'Gene', (28, 32))	('beta-catenin', 'Gene', '1499', (87, 99))	('down-regulated', 'NegReg', (104, 118))	('colorectal cancer', 'Disease', (142, 159))	('ectopic', 'Var', (20, 27))	('reduced', 'NegReg', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('phosphorylation', 'biological_process', 'GO:0016310', ('123', '138'))
42977	27447746	Therefore, we hypothesized that BTG1 overexpression could weaken the beta-catenin pathway from transcription via TCF-4 transcriptional factor.	('TCF-4', 'Gene', (113, 118))	('TCF-4', 'Gene', '6925', (113, 118))	('beta-catenin', 'Gene', (69, 81))	('beta-catenin', 'Gene', '1499', (69, 81))	('BTG1', 'Gene', (32, 36))	('weaken', 'NegReg', (58, 64))	('overexpression', 'Var', (37, 51))	('transcription', 'MPA', (95, 108))
42978	27447746	Reportedly, activated p38 MAP kinase by phosphorylation at Thr-180 and Tyr-182 has been shown to phosphorylate and activate MAPKAP kinase 2 and to phosphorylate the transcription factors ATF2, Mac and MEF2, finally to modulate the transcriptional expression of inflammatory cytokines such as interleukins.	('MAPKAP kinase 2', 'Gene', '9261', (124, 139))	('Thr-180', 'Var', (59, 66))	('transcription', 'biological_process', 'GO:0006351', ('165', '178'))	('MEF2', 'Gene', '4205', (201, 205))	('p38', 'Gene', '1432', (22, 25))	('modulate', 'Reg', (218, 226))	('activate', 'PosReg', (115, 123))	('MEF2', 'Gene', (201, 205))	('Thr', 'Chemical', 'MESH:D013912', (59, 62))	('Mac', 'cellular_component', 'GO:0097423', ('193', '196'))	('MAPKAP kinase 2', 'Gene', (124, 139))	('phosphorylation', 'biological_process', 'GO:0016310', ('40', '55'))	('Tyr', 'Chemical', 'MESH:D014443', (71, 74))	('MAP', 'molecular_function', 'GO:0004239', ('26', '29'))	('transcriptional expression', 'MPA', (231, 257))	('ATF2', 'Gene', (187, 191))	('p38', 'Gene', (22, 25))	('ATF2', 'Gene', '1386', (187, 191))	('Mac', 'cellular_component', 'GO:0005579', ('193', '196'))	('Tyr-182', 'Var', (71, 78))
42981	27447746	Subsequently, autophagosome formation is induced by class III PI3K, Beclin-1 and ATG14, finally to promote ATG12-ATG7 conjugation.	('ATG14', 'Gene', '22863', (81, 86))	('autophagosome formation', 'CPA', (14, 37))	('Beclin-1', 'Gene', (68, 76))	('promote', 'PosReg', (99, 106))	('Beclin-1', 'Gene', '8678', (68, 76))	('PI3K', 'Var', (62, 66))	('conjugation', 'Interaction', (118, 129))	('ATG14', 'Gene', (81, 86))	('ATG7', 'Gene', (113, 117))	('ATG12', 'Gene', '9140', (107, 112))	('ATG12', 'Gene', (107, 112))	('ATG7', 'Gene', '10533', (113, 117))
43053	24743384	The MLH1 c.1852_1853delinsGC (p.K618A) Variant in Colorectal Cancer: Genetic Association Study in 18,723 Individuals Colorectal cancer is one of the most frequent neoplasms and an important cause of mortality in the developed world.	('p.K618A', 'Mutation', 'rs35502531', (30, 37))	('Colorectal cancer', 'Disease', 'MESH:D015179', (117, 134))	('neoplasms', 'Phenotype', 'HP:0002664', (163, 172))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (117, 134))	('c.1852_1853delinsGC', 'Mutation', 'rs35502531', (9, 28))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (50, 67))	('c.1852_1853delinsGC', 'Var', (9, 28))	('neoplasms', 'Disease', 'MESH:D009369', (163, 172))	('MLH1', 'Gene', '4292', (4, 8))	('neoplasms', 'Disease', (163, 172))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('MLH1', 'Gene', (4, 8))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (50, 67))	('neoplasm', 'Phenotype', 'HP:0002664', (163, 171))	('Colorectal Cancer', 'Disease', (50, 67))	('Colorectal cancer', 'Disease', (117, 134))
43055	24743384	Lynch syndrome tumors develop mainly as a consequence of defective DNA mismatch repair associated with germline mutations in MLH1, MSH2, MSH6 and PMS2.	('MSH6', 'Gene', '2956', (137, 141))	('Lynch syndrome tumors', 'Disease', (0, 21))	('MLH1', 'Gene', (125, 129))	('defective', 'NegReg', (57, 66))	('mismatch repair', 'biological_process', 'GO:0006298', ('71', '86'))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('PMS2', 'Gene', (146, 150))	('mutations', 'Var', (112, 121))	('PMS2', 'Gene', '5395', (146, 150))	('Lynch syndrome tumors', 'Disease', 'MESH:D003123', (0, 21))	('DNA mismatch repair', 'MPA', (67, 86))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('MSH6', 'Gene', (137, 141))	('MLH1', 'Gene', '4292', (125, 129))	('MSH2', 'Gene', (131, 135))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('MSH2', 'Gene', '4436', (131, 135))
43056	24743384	A significant proportion of variants identified by screening these genes correspond to missense or noncoding changes without a clear pathogenic consequence, and they are designated as "variants of uncertain significance", being the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene a clear example.	('p.K618A', 'Mutation', 'rs35502531', (253, 260))	('MLH1', 'Gene', '4292', (277, 281))	('c.1852_1853delinsGC', 'Mutation', 'rs35502531', (232, 251))	('MLH1', 'Gene', (277, 281))	('missense', 'Var', (87, 95))	('noncoding changes', 'MPA', (99, 116))	('c.1852_1853delinsGC', 'Var', (232, 251))
43057	24743384	The implication of this variant as a low-penetrance risk variant for CRC was assessed in the present study by performing a case-control study within a large cohort from the COGENT consortium-COST Action BM1206 including 18,723 individuals (8,055 colorectal cancer cases and 10,668 controls) and a case-only genotype-phenotype correlation with several clinical and pathological characteristics restricted to the Epicolon cohort.	('colorectal cancer', 'Disease', (246, 263))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('CRC', 'Phenotype', 'HP:0003003', (69, 72))	('BM1206', 'CellLine', 'CVCL:9E46', (203, 209))	('colorectal cancer', 'Disease', 'MESH:D015179', (246, 263))	('colorectal cancer', 'Phenotype', 'HP:0003003', (246, 263))	('variant', 'Var', (24, 31))	('CRC', 'Disease', (69, 72))
43058	24743384	Our results showed no involvement of this variant as a low-penetrance variant for colorectal cancer genetic susceptibility and no association with any clinical and pathological characteristics including family history for this neoplasm or Lynch syndrome.	('colorectal cancer', 'Disease', (82, 99))	('neoplasm', 'Disease', (227, 235))	('neoplasm', 'Disease', 'MESH:D009369', (227, 235))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('neoplasm', 'Phenotype', 'HP:0002664', (227, 235))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('Lynch syndrome', 'Disease', (239, 253))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))	('Lynch syndrome', 'Disease', 'MESH:D003123', (239, 253))	('variant', 'Var', (42, 49))
43061	24743384	Lynch syndrome tumors develop mainly as a consequence of defective DNA mismatch repair (MMR) associated with germline mutations in the MLH1, MSH2, MSH6 and PMS2 genes.	('MLH1', 'Gene', (135, 139))	('MMR', 'biological_process', 'GO:0006298', ('88', '91'))	('Lynch syndrome tumors', 'Disease', (0, 21))	('defective', 'NegReg', (57, 66))	('mismatch repair', 'biological_process', 'GO:0006298', ('71', '86'))	('mutations', 'Var', (118, 127))	('MSH6', 'Gene', '2956', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('PMS2', 'Gene', (156, 160))	('MSH2', 'Gene', (141, 145))	('Lynch syndrome tumors', 'Disease', 'MESH:D003123', (0, 21))	('DNA mismatch repair', 'MPA', (67, 86))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('MSH6', 'Gene', (147, 151))	('MSH2', 'Gene', '4436', (141, 145))	('MLH1', 'Gene', '4292', (135, 139))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('PMS2', 'Gene', '5395', (156, 160))
43063	24743384	Noteworthy, a significant proportion of variants identified in the MMR genetic screening correspond to missense or noncoding changes without a clear pathogenic consequence, and they are designated as "variants of uncertain significance" (VUS).	('MMR', 'Gene', (67, 70))	('MMR', 'biological_process', 'GO:0006298', ('67', '70'))	('missense', 'Var', (103, 111))	('VUS', 'Chemical', '-', (238, 241))	('variants', 'Var', (40, 48))	('noncoding', 'MPA', (115, 124))
43064	24743384	The c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene corresponds to a clear example of VUS in Lynch syndrome.	('Lynch syndrome', 'Disease', (100, 114))	('p.K618A', 'Mutation', 'rs35502531', (25, 32))	('Lynch syndrome', 'Disease', 'MESH:D003123', (100, 114))	('MLH1', 'Gene', '4292', (49, 53))	('VUS', 'Chemical', '-', (93, 96))	('MLH1', 'Gene', (49, 53))	('c.1852_1853delinsGC (p.K618A', 'Var', (4, 32))	('c.1852_1853delinsGC', 'Mutation', 'rs35502531', (4, 23))
43065	24743384	Available past studies reached contradictory conclusions about its pathogenicity reporting harmful in silico predictions, absence of splicing or mRNA alteration, presence in patients with a defective MMR tumor, co-occurrence with clearly pathogenic MMR mutations, apparent segregation with disease, and a majority of non-altered in vitro functional studies.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('splicing', 'MPA', (133, 141))	('mRNA alteration', 'MPA', (145, 160))	('co-occurrence', 'Var', (211, 224))	('pathogenic', 'Reg', (238, 248))	('MMR', 'Gene', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('mutations', 'Var', (253, 262))	('MMR', 'Gene', (249, 252))	('patients', 'Species', '9606', (174, 182))	('tumor', 'Disease', (204, 209))
43068	24743384	In agreement with this rationale, the main aim of the present study was to assess the implication of the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene as a low-penetrance risk variant for CRC by performing a case-control study within a large cohort from the COGENT consortium-COST Action BM1206, an international effort to facilitate the study of inherited genetic predisposition to CRC.	('variant', 'Var', (135, 142))	('c.1852_1853delinsGC', 'Mutation', 'rs35502531', (105, 124))	('p.K618A', 'Mutation', 'rs35502531', (126, 133))	('CRC', 'Disease', (197, 200))	('MLH1', 'Gene', '4292', (150, 154))	('CRC', 'Phenotype', 'HP:0003003', (392, 395))	('MLH1', 'Gene', (150, 154))	('CRC', 'Phenotype', 'HP:0003003', (197, 200))	('BM1206', 'CellLine', 'CVCL:9E46', (297, 303))	('c.1852_1853delinsGC', 'Var', (105, 124))
43079	24743384	Allelic discrimination to genotype the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene was performed by using a custom assay with the TaqMan allelic discrimination system (Life Technologies, Foster City, USA).	('c.1852_1853delinsGC', 'Var', (39, 58))	('MLH1', 'Gene', '4292', (84, 88))	('MLH1', 'Gene', (84, 88))	('c.1852_1853delinsGC', 'Mutation', 'rs35502531', (39, 58))	('p.K618A', 'Mutation', 'rs35502531', (60, 67))
43080	24743384	To test the association between the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene and CRC risk, odds ratios (OR) and 95%CI were calculated for each genotype by using PLINK v1.07, separately in each cohort and globally.	('c.1852_1853delinsGC', 'Var', (36, 55))	('p.K618A', 'Mutation', 'rs35502531', (57, 64))	('MLH1', 'Gene', '4292', (81, 85))	('c.1852_1853delinsGC', 'Mutation', 'rs35502531', (36, 55))	('MLH1', 'Gene', (81, 85))	('CRC', 'Disease', (95, 98))	('CRC', 'Phenotype', 'HP:0003003', (95, 98))
43081	24743384	In order to explore if personal and/or familial characteristics were associated with the presence of the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene, univariate analysis was performed restricted to the CRC cases from the Epicolon cohort due to data availability in this cohort.	('CRC', 'Phenotype', 'HP:0003003', (213, 216))	('c.1852_1853delinsGC', 'Mutation', 'rs35502531', (105, 124))	('p.K618A', 'Mutation', 'rs35502531', (126, 133))	('MLH1', 'Gene', '4292', (150, 154))	('MLH1', 'Gene', (150, 154))	('c.1852_1853delinsGC', 'Var', (105, 124))
43083	24743384	Genotyping for the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene was successful in 8,055 CRC cases and 10,668 controls from 7 independent cohorts.	('MLH1', 'Gene', (64, 68))	('p.K618A', 'Mutation', 'rs35502531', (40, 47))	('MLH1', 'Gene', '4292', (64, 68))	('c.1852_1853delinsGC', 'Mutation', 'rs35502531', (19, 38))	('CRC', 'Disease', (98, 101))	('CRC', 'Phenotype', 'HP:0003003', (98, 101))	('c.1852_1853delinsGC', 'Var', (19, 38))
43084	24743384	In order to further explore the putative implication of this MLH1 variant with CRC risk, we performed a case-only genotype-phenotype correlation restricted to the Epicolon cohort (2,001 CRC cases) with several clinical and pathological characteristics.	('CRC', 'Phenotype', 'HP:0003003', (79, 82))	('CRC', 'Disease', (79, 82))	('MLH1', 'Gene', '4292', (61, 65))	('MLH1', 'Gene', (61, 65))	('CRC', 'Phenotype', 'HP:0003003', (186, 189))	('variant', 'Var', (66, 73))
43087	24743384	The c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene is a prominent example of a VUS that has been controversial for many years in the context of Lynch syndrome genetic diagnosis.	('Lynch syndrome', 'Disease', (152, 166))	('p.K618A', 'Mutation', 'rs35502531', (25, 32))	('MLH1', 'Gene', '4292', (49, 53))	('VUS', 'Chemical', '-', (87, 90))	('Lynch syndrome', 'Disease', 'MESH:D003123', (152, 166))	('MLH1', 'Gene', (49, 53))	('c.1852_1853delinsGC (p.K618A', 'Var', (4, 32))	('c.1852_1853delinsGC', 'Mutation', 'rs35502531', (4, 23))
43090	24743384	Regarding its putative implication in familial CRC, this variant was also seen to be over-represented in families with suspected Lynch syndrome in a previous study.	('CRC', 'Phenotype', 'HP:0003003', (47, 50))	('variant', 'Var', (57, 64))	('Lynch syndrome', 'Disease', (129, 143))	('familial CRC', 'Disease', (38, 50))	('Lynch syndrome', 'Disease', 'MESH:D003123', (129, 143))
43091	24743384	Our results will be not in agreement with this previous observation since the K618A variant was not linked in the Epicolon cohort to the presence of CRC family history and Lynch syndrome family history.	('Lynch syndrome', 'Disease', (172, 186))	('CRC', 'Disease', (149, 152))	('K618A', 'Mutation', 'rs35502531', (78, 83))	('Lynch syndrome', 'Disease', 'MESH:D003123', (172, 186))	('K618A', 'Var', (78, 83))	('CRC', 'Phenotype', 'HP:0003003', (149, 152))
43092	24743384	Finally, we can conclude from our results and previous evidence that the c.1852_1853delinsGC (p.K618A) variant in the MLH1 gene should be regarded from now on as a polymorphism without functional effect on the MLH1 protein, no role in genetic predisposition to Lynch syndrome, as well as no apparent effect as a low-penetrance variant for CRC genetic susceptibility.	('Lynch syndrome', 'Disease', 'MESH:D003123', (261, 275))	('MLH1', 'Gene', '4292', (210, 214))	('MLH1', 'Gene', (210, 214))	('p.K618A', 'Mutation', 'rs35502531', (94, 101))	('c.1852_1853delinsGC', 'Var', (73, 92))	('Lynch syndrome', 'Disease', (261, 275))	('CRC', 'Phenotype', 'HP:0003003', (339, 342))	('MLH1', 'Gene', '4292', (118, 122))	('c.1852_1853delinsGC', 'Mutation', 'rs35502531', (73, 92))	('MLH1', 'Gene', (118, 122))
43250	32172320	Recently, a study of 2266 patients reported that POCs are associated with adverse oncological outcomes, with an increased effect at higher CDC grades.	('POCs', 'Var', (49, 53))	('oncological outcomes', 'CPA', (82, 102))	('patients', 'Species', '9606', (26, 34))
43314	32172320	The patients with POCs had a significantly worse disease-free survival (65.2%) than patients without POCs (75.6%; p < 0.001).	('patients', 'Species', '9606', (84, 92))	('disease-free survival', 'CPA', (49, 70))	('patients', 'Species', '9606', (4, 12))	('POCs', 'Var', (18, 22))	('worse', 'NegReg', (43, 48))
43316	32172320	Patients with CDC grade IV POCs were found to have the worst disease-free survival compared to patients without POCs (HR 1.8; p = 0.002; Table 5, Fig.	('disease-free survival', 'CPA', (61, 82))	('worst', 'NegReg', (55, 60))	('patients', 'Species', '9606', (95, 103))	('POCs', 'Var', (27, 31))	('Patients', 'Species', '9606', (0, 8))	('CDC', 'Disease', (14, 17))
43317	32172320	The patients with POCs had a strikingly decreased overall survival (73.5%) compared to patients without POCs (83.5% p < 0.001).	('overall survival', 'MPA', (50, 66))	('patients', 'Species', '9606', (87, 95))	('patients', 'Species', '9606', (4, 12))	('POCs', 'Var', (18, 22))	('decreased', 'NegReg', (40, 49))
43325	32172320	In addition, patients with CDC grade IV POCs showed significantly worse disease-free and overall survival rates, which is also consistent with the results of the study mentioned above.	('overall survival rates', 'CPA', (89, 111))	('patients', 'Species', '9606', (13, 21))	('worse', 'NegReg', (66, 71))	('disease-free', 'CPA', (72, 84))	('CDC grade', 'Var', (27, 36))	('men', 'Species', '9606', (168, 171))
43381	32340123	AJ511872) that results in the substitution of cysteine with tyrosine in the D3 domain in the N terminus of the Mucin 2 (Muc2) gene.	('tyrosine', 'MPA', (60, 68))	('results in', 'Reg', (15, 25))	('cysteine', 'MPA', (46, 54))	('Mucin 2', 'Gene', (111, 118))	('cysteine', 'Chemical', 'MESH:D003545', (46, 54))	('substitution', 'Var', (30, 42))	('tyrosine', 'Chemical', 'MESH:D014443', (60, 68))	('Muc2', 'Gene', (120, 124))	('Mucin 2', 'Gene', '17831', (111, 118))	('Muc2', 'Gene', '17831', (120, 124))
43382	32340123	This mutation induces aberrant Muc2 biosynthesis, a thinner mucus barrier with increased intestinal permeability, and enhanced local production of inflammatory cytokines in the distal colon.	('Muc2', 'Gene', (31, 35))	('increased', 'PosReg', (79, 88))	('intestinal', 'MPA', (89, 99))	('biosynthesis', 'biological_process', 'GO:0009058', ('36', '48'))	('local production of inflammatory cytokines', 'MPA', (127, 169))	('Muc2', 'Gene', '17831', (31, 35))	('enhanced', 'PosReg', (118, 126))	('induces', 'Reg', (14, 21))	('mucus', 'cellular_component', 'GO:0070701', ('60', '65'))	('thinner', 'NegReg', (52, 59))	('mutation', 'Var', (5, 13))
43387	32340123	With the intent to create the Winnie-ApcMin/+ model, we performed a breeding strategy using mice carrying double heterozygote mutations for males (on the Apc and Muc2 genes in ApcMin/+ and Winnie mice, respectively) and a single heterozygote mutation (on the Muc2 gene in Winnie mice) for females (Figure 1A).	('Muc2', 'Gene', (162, 166))	('Apc', 'Gene', (176, 179))	('Muc2', 'Gene', (259, 263))	('mice', 'Species', '10090', (196, 200))	('Apc', 'Gene', '11789', (176, 179))	('Muc2', 'Gene', '17831', (162, 166))	('Apc', 'cellular_component', 'GO:0005680', ('154', '157'))	('mice', 'Species', '10090', (279, 283))	('Apc', 'Gene', (37, 40))	('Apc', 'Gene', (154, 157))	('Apc', 'Gene', '11789', (154, 157))	('Apc', 'Gene', '11789', (37, 40))	('Muc2', 'Gene', '17831', (259, 263))	('mutations', 'Var', (126, 135))	('mice', 'Species', '10090', (92, 96))
43389	32340123	Comparing breeders used to obtain Winnie and Winnie-ApcMin/+ mice, we demonstrated that the ApcMin/+ mutation induced a dramatic reduction in the survival rate (28.6% vs. 10.8%, respectively; Figure 1B) and an overall decrease in the fertility rate (Supplementary Table S1).	('Apc', 'Gene', (52, 55))	('mice', 'Species', '10090', (61, 65))	('decrease', 'NegReg', (218, 226))	('reduction', 'NegReg', (129, 138))	('Apc', 'Gene', '11789', (52, 55))	('decrease in the fertility rate', 'Phenotype', 'HP:0000144', (218, 248))	('Apc', 'Gene', (92, 95))	('survival rate', 'CPA', (146, 159))	('Apc', 'Gene', '11789', (92, 95))	('mutation', 'Var', (101, 109))	('fertility rate', 'CPA', (234, 248))
43394	32340123	Dysplastic ACFs were carefully classified according to incidence and multiplicity into four groups, based on the number of crypts and tumor grading: unicryptic lesions; microadenoma >1 <= 5 crypts low-grade (LG); microadenoma >5 crypts low-grade (LG) and microadenoma >5 crypts high-grade (HG) (Table 1).	('microadenoma', 'Var', (213, 225))	('microadenoma', 'Disease', (169, 181))	('unicryptic lesions', 'Disease', (149, 167))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
43524	32206180	Moreover, using the univariate Cox analysis, we observed that patients with plasma basal levels of TNF-alpha >= 7.41 pg/mL had a significant increased risk to get progression disease compared to those with plasma basal levels of TNF-alpha < 7.41 pg/mL (HR: 7.203, 95%CI: 1.531-33.882, P = 0.012) (Figure 4).	('Cox', 'Gene', '1351', (31, 34))	('>= 7.41 pg/mL', 'Var', (109, 122))	('TNF-alpha', 'Gene', '7124', (229, 238))	('Cox', 'Gene', (31, 34))	('progression disease', 'Disease', (163, 182))	('TNF-alpha', 'Gene', (229, 238))	('TNF-alpha', 'Gene', '7124', (99, 108))	('patients', 'Species', '9606', (62, 70))	('TNF-alpha', 'Gene', (99, 108))
43543	32206180	CCL-4 is involved in the recruitment of CD103+-DCs.	('CCL-4', 'Gene', '6351', (0, 5))	('men', 'Species', '9606', (32, 35))	('CD103+-DCs', 'Var', (40, 50))	('CCL-4', 'Gene', (0, 5))	('CCL', 'molecular_function', 'GO:0044101', ('0', '3'))
43544	32206180	The failure of Batf3-dependent recruitment CD103+-DCs together with the activation of Wnt/beta-catenin pathway is a cause of non-T cell-inflamed tumor development.	('men', 'Species', '9606', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('cause', 'Reg', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('beta-catenin', 'Gene', (90, 102))	('Batf3', 'Gene', '55509', (15, 20))	('Batf3', 'Gene', (15, 20))	('CD103+-DCs', 'Var', (43, 53))	('tumor', 'Disease', (145, 150))	('beta-catenin', 'Gene', '1499', (90, 102))	('men', 'Species', '9606', (158, 161))
43562	32206180	Regorafenib is a multi-kinase inhibitor targeting VEGFR1-3, TIE2, fibroblast growth factor receptors 1 and platelet-derived growth factor receptors beta, c-KIT, RET, c-RAF/RAF-1, BRAF V600E mutant.	('TIE2', 'Gene', (60, 64))	('RAF-1', 'Gene', '5894', (172, 177))	('RET', 'Gene', '5979', (161, 164))	('Regorafenib', 'Chemical', 'MESH:C559147', (0, 11))	('V600E', 'Mutation', 'rs113488022', (184, 189))	('TIE2', 'Gene', '7010', (60, 64))	('c-RAF', 'Gene', (166, 171))	('c-KIT', 'Gene', '3815', (154, 159))	('V600E', 'Var', (184, 189))	('BRAF', 'Gene', '673', (179, 183))	('RET', 'Gene', (161, 164))	('c-RAF', 'Gene', '5894', (166, 171))	('BRAF', 'Gene', (179, 183))	('VEGFR1', 'Gene', '2321', (50, 56))	('RAF-1', 'Gene', (172, 177))	('c-KIT', 'Gene', (154, 159))	('VEGFR1', 'Gene', (50, 56))
43622	31243668	When considering PCI, CCR, and tumor grade, LFS remained associated with non-inferior OS (HR: 0.73, p = 0.42).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('LFS', 'Var', (44, 47))	('tumor', 'Disease', (31, 36))	('non-inferior OS', 'Disease', (73, 88))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
43656	29760449	Here we first performed differential expression analysis (DEA) of AURKA knockdown in two colorectal cancer (CRC) cell lines with 20q gain and AURKA overexpression.	('AURKA', 'Gene', '6790', (66, 71))	('overexpression', 'PosReg', (148, 162))	('AURKA', 'Gene', '6790', (142, 147))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('AURKA', 'Gene', (66, 71))	('colorectal cancer', 'Disease', (89, 106))	('AURKA', 'Gene', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('DEA', 'Chemical', '-', (58, 61))	('knockdown', 'Var', (72, 81))
43660	29760449	In the early stages of CRC development, proliferative signalling is sustained by hyperactivation of the Wnt and Ras-MAPK signalling pathways due to mutations in key regulatory genes.	('mutations', 'Var', (148, 157))	('signalling', 'biological_process', 'GO:0023052', ('54', '64'))	('MAPK', 'molecular_function', 'GO:0004707', ('116', '120'))	('MAPK signalling', 'biological_process', 'GO:0000165', ('116', '131'))	('hyperactivation', 'PosReg', (81, 96))	('proliferative signalling', 'MPA', (40, 64))	('men', 'Species', '9606', (34, 37))
43661	29760449	Disruption of Wnt signalling, caused by mutations in the APC tumour suppressor gene or other genes such as CTNNB1 (hereafter referred to as beta-catenin), AXIN1 or AXIN2, promotes the progression from normal colon epithelium to a benign precursor lesion, called adenoma.	('AXIN1', 'Gene', '8312', (155, 160))	('AXIN2', 'Gene', '8313', (164, 169))	('CTNNB1', 'Gene', (107, 113))	('progression', 'CPA', (184, 195))	('promotes', 'PosReg', (171, 179))	('mutations', 'Var', (40, 49))	('APC tumour', 'Disease', 'MESH:D011125', (57, 67))	('adenoma', 'Disease', (262, 269))	('signalling', 'biological_process', 'GO:0023052', ('18', '28'))	('APC tumour', 'Disease', (57, 67))	('AXIN2', 'Gene', (164, 169))	('adenoma', 'Disease', 'MESH:D000236', (262, 269))	('AXIN1', 'Gene', (155, 160))	('APC', 'cellular_component', 'GO:0005680', ('57', '60'))	('beta-catenin', 'Gene', (140, 152))	('Disruption', 'NegReg', (0, 10))	('beta-catenin', 'Gene', '1499', (140, 152))	('CTNNB1', 'Gene', '1499', (107, 113))	('Wnt signalling', 'MPA', (14, 28))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
43662	29760449	Subsequently, adenoma-to-carcinoma progression is driven by further genetic and epigenetic alterations.	('adenoma-to-carcinoma', 'Disease', (14, 34))	('adenoma-to-carcinoma', 'Disease', 'MESH:D000236', (14, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('epigenetic alterations', 'Var', (80, 102))
43663	29760449	the KRAS gene, other pathways important in carcinoma development are the TGFbeta pathway, disrupted by mutation in e.g.	('disrupted', 'NegReg', (90, 99))	('KRAS', 'Gene', '3845', (4, 8))	('carcinoma', 'Disease', 'MESH:D002277', (43, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('TGFbeta pathway', 'Pathway', (73, 88))	('men', 'Species', '9606', (60, 63))	('mutation', 'Var', (103, 111))	('carcinoma', 'Disease', (43, 52))	('KRAS', 'Gene', (4, 8))
43664	29760449	SMAD4, and the TP53 pathway, disrupted by mutations in the TP53 gene.	('disrupted', 'NegReg', (29, 38))	('TP53', 'Gene', '7157', (59, 63))	('SMAD4', 'Gene', '4089', (0, 5))	('TP53', 'Gene', (59, 63))	('SMAD4', 'Gene', (0, 5))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('mutations', 'Var', (42, 51))
43665	29760449	Recently, it has been shown that adenoma organoids harbouring all these mutations can induce invasive cancers in mice only when a background of chromosomal instability is present.	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mice', 'Species', '10090', (113, 117))	('adenoma', 'Disease', (33, 40))	('chromosomal instability', 'Phenotype', 'HP:0040012', (144, 167))	('induce', 'Reg', (86, 92))	('invasive cancers', 'Disease', 'MESH:D009362', (93, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('adenoma', 'Disease', 'MESH:D000236', (33, 40))	('invasive cancers', 'Disease', (93, 109))
43666	29760449	Chromosomal arm 20q is frequently gained in CRC and has a strong association with the progression of colorectal adenoma to carcinoma.	('colorectal adenoma to carcinoma', 'Disease', (101, 132))	('association with', 'Reg', (65, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('colorectal adenoma to carcinoma', 'Disease', 'MESH:C563365', (101, 132))	('Chromosomal arm 20q', 'Var', (0, 19))
43668	29760449	There is a significant correlation between the 20q copy number and increased AURKA mRNA and protein expression.	('20q copy number', 'Var', (47, 62))	('protein', 'cellular_component', 'GO:0003675', ('92', '99'))	('increased', 'PosReg', (67, 76))	('AURKA', 'Gene', '6790', (77, 82))	('AURKA', 'Gene', (77, 82))
43669	29760449	Gain of 20q and/or AURKA overexpression is associated with a poor prognosis in many cancer types including CRC.	('CRC', 'Disease', (107, 110))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('Gain', 'Var', (0, 4))	('AURKA', 'Gene', '6790', (19, 24))	('AURKA', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('overexpression', 'PosReg', (25, 39))
43670	29760449	AURKA overexpression has been shown to stabilize beta-catenin levels and thereby activating Wnt signalling in gastric cancer cells by phosphorylating the negative regulator of beta-catenin, GSK3B.	('AURKA', 'Gene', (0, 5))	('beta-catenin', 'Gene', (49, 61))	('GSK3B', 'Gene', (190, 195))	('gastric cancer', 'Disease', (110, 124))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('Wnt signalling', 'Pathway', (92, 106))	('phosphorylating', 'Var', (134, 149))	('overexpression', 'Var', (6, 20))	('beta-catenin', 'Gene', (176, 188))	('beta-catenin', 'Gene', '1499', (49, 61))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('beta-catenin', 'Gene', '1499', (176, 188))	('stabilize', 'PosReg', (39, 48))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('AURKA', 'Gene', '6790', (0, 5))	('GSK3B', 'Gene', '2932', (190, 195))	('activating', 'PosReg', (81, 91))
43677	29760449	In this study, we used two distinct cell lines, SW480 and Caco2, both derived from colon carcinomas with 20q copy number gain and mutated TP53.	('TP53', 'Gene', '7157', (138, 142))	('colon carcinomas', 'Disease', 'MESH:D015179', (83, 99))	('Caco2', 'Chemical', '-', (58, 63))	('TP53', 'Gene', (138, 142))	('mutated', 'Var', (130, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('colon carcinomas', 'Disease', (83, 99))
43693	29760449	In order to gain understanding from the sets of genes differentially expressed by AURKA knockdown, we applied the Heinz algorithm.	('knockdown', 'Var', (88, 97))	('AURKA', 'Gene', '6790', (82, 87))	('AURKA', 'Gene', (82, 87))
43743	29760449	Finally, the shortest path analysis added 8 connecting genes that may be relevant to explain how AURKA modulation may affect the activity of these pathways, and thereby further induce proliferation in developing carcinoma cells.	('carcinoma', 'Disease', (212, 221))	('AURKA', 'Gene', '6790', (97, 102))	('modulation', 'Var', (103, 113))	('affect', 'Reg', (118, 124))	('AURKA', 'Gene', (97, 102))	('proliferation', 'CPA', (184, 197))	('carcinoma', 'Disease', 'MESH:D002277', (212, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('activity', 'MPA', (129, 137))	('induce', 'PosReg', (177, 183))
43755	29760449	While both SW480 and Caco2 are CRC cell lines with 20q gain, AURKA overexpression, and TP53 mutation, they also show differences.	('TP53', 'Gene', '7157', (87, 91))	('mutation', 'Var', (92, 100))	('overexpression', 'PosReg', (67, 81))	('Caco2', 'Chemical', '-', (21, 26))	('gain', 'PosReg', (55, 59))	('TP53', 'Gene', (87, 91))	('AURKA', 'Gene', '6790', (61, 66))	('AURKA', 'Gene', (61, 66))
43757	29760449	One specific difference is that KRAS is mutated in SW480 but not in Caco2.	('SW480', 'Var', (51, 56))	('Caco2', 'Chemical', '-', (68, 73))	('KRAS', 'Gene', (32, 36))	('KRAS', 'Gene', '3845', (32, 36))
43759	29760449	Consequently, the underlying molecular biology of SW480 and Caco2 differs and they are therefore expected to respond differently to a perturbation such as AURKA downmodulation when looking at the expression of individual genes, although the overall changes in pathways could still be the same.	('AURKA', 'Gene', '6790', (155, 160))	('Caco2', 'Chemical', '-', (60, 65))	('AURKA', 'Gene', (155, 160))	('Caco2', 'Gene', (60, 65))	('SW480', 'Var', (50, 55))
43760	29760449	For instance, KRAS is one of the most connected genes in both cell lines in our two network aware analyses (Figs 2 and 3), while at the same time the differentially expressed networks upon AURKA knockdown show different genes connected to KRAS in both cell lines.	('AURKA', 'Gene', (189, 194))	('KRAS', 'Gene', '3845', (14, 18))	('connected', 'Reg', (226, 235))	('KRAS', 'Gene', (239, 243))	('knockdown', 'Var', (195, 204))	('KRAS', 'Gene', '3845', (239, 243))	('KRAS', 'Gene', (14, 18))	('AURKA', 'Gene', '6790', (189, 194))
43763	29760449	However, in SW480, where KRAS is mutated, KRAS in addition is connected to LCK, WNT5A, PPP3CA, JUN, and RAC2.	('KRAS', 'Gene', (42, 46))	('PPP3CA', 'Gene', (87, 93))	('KRAS', 'Gene', '3845', (42, 46))	('RAC2', 'Gene', '5880', (104, 108))	('KRAS', 'Gene', '3845', (25, 29))	('WNT5A', 'Gene', (80, 85))	('mutated', 'Var', (33, 40))	('RAC2', 'Gene', (104, 108))	('connected', 'Reg', (62, 71))	('LCK', 'Gene', (75, 78))	('WNT5A', 'Gene', '7474', (80, 85))	('KRAS', 'Gene', (25, 29))	('LCK', 'Gene', '3932', (75, 78))	('PPP3CA', 'Gene', '5530', (87, 93))
43802	29760449	To describe the nodes (genes) and edges (interactions), one node-file and one edge-file were constructed for each cell line, SW480 and Caco2, based on the intersection of nodes (Ensembl ids) in the AURKA knockdown DEA data and the STRING PPI data.	('knockdown', 'Var', (204, 213))	('AURKA', 'Gene', '6790', (198, 203))	('DEA', 'Chemical', '-', (214, 217))	('AURKA', 'Gene', (198, 203))	('Caco2', 'Chemical', '-', (135, 140))
43826	29760449	Designed the experiments and provided advice: A.J., L.J.W.B., S.R.M.d.K., B.C., A.H.S.H., R.J.D., E.d.R., G.A.M., S.A., J.H., R.J.A.F., K.A.F.	('R.J.D.', 'Var', (90, 96))	('R.J.A.F.', 'Var', (126, 134))	('men', 'Species', '9606', (19, 22))
43828	29061341	Drug resistance induces the upregulation of H2S-producing enzymes in HCT116 colon cancer cells Hydrogen sulfide (H2S) production in colon cancer cells supports cellular bioenergetics and proliferation.	('Drug resistance', 'Phenotype', 'HP:0020174', (0, 15))	('H2S-producing', 'Enzyme', (44, 57))	('Hydrogen sulfide', 'MPA', (95, 111))	('colon cancer', 'Disease', 'MESH:D015179', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('colon cancer', 'Disease', (76, 88))	('colon cancer', 'Disease', (132, 144))	('Drug resistance', 'Var', (0, 15))	('H2S', 'Chemical', 'MESH:D006862', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('H2S', 'Chemical', 'MESH:D006862', (113, 116))	('HCT116', 'CellLine', 'CVCL:0291', (69, 75))	('Hydrogen sulfide', 'Chemical', 'MESH:D006862', (95, 111))	('colon cancer', 'Phenotype', 'HP:0003003', (76, 88))	('colon cancer', 'Phenotype', 'HP:0003003', (132, 144))	('colon cancer', 'Disease', 'MESH:D015179', (132, 144))	('upregulation', 'PosReg', (28, 40))	('cellular bioenergetics', 'CPA', (160, 182))
43838	29061341	Taken together, the current data suggest that 5-FU resistance in HCT116 cells is associated with the upregulation of drug-metabolizing enzymes and an enhancement of endogenous H2S production.	('drug-metabolizing enzymes', 'Enzyme', (117, 142))	('H2S', 'Chemical', 'MESH:D006862', (176, 179))	('upregulation', 'PosReg', (101, 113))	('enhancement', 'PosReg', (150, 161))	('endogenous H2S production', 'MPA', (165, 190))	('5-FU', 'Var', (46, 50))	('HCT116', 'CellLine', 'CVCL:0291', (65, 71))	('5-FU', 'Chemical', 'MESH:D005472', (46, 50))
43850	29061341	The mechanisms involved in the stimulation of mitochondrial function by H2S are multiple; they involve direct electron donation to Complex II of the mitochondrial electron transport chain inhibition of mitochondrial cAMP phosphodiesterases, followed by cAMP-stimulated increases in mitochondrial electron transport, mitochondrial antioxidant effects, stimulation of mitochondrial DNA repair, direct stimulation of mitochondrial ATP synthase via posttranslational modification (via protein S-sulfhydration) as well as the stimulation of lactate dehydrogenase activity (via protein S-sulfhydration).	('posttranslational modification', 'Var', (445, 475))	('ATP', 'Chemical', 'MESH:D000255', (428, 431))	('mitochondrial ATP synthase', 'Enzyme', (414, 440))	('activity', 'MPA', (558, 566))	('protein S-sulfhydration', 'Var', (481, 504))	('lactate dehydrogenase', 'Enzyme', (536, 557))	('lactate dehydrogenase activity', 'molecular_function', 'GO:0004457', ('536', '566'))	('Complex II', 'molecular_function', 'GO:0008177', ('131', '141'))	('mitochondrial antioxidant effects', 'MPA', (316, 349))	('hydrogen', 'Chemical', 'MESH:D006859', (546, 554))	('ATP synthase', 'molecular_function', 'GO:0016468', ('428', '440'))	('H2S', 'Chemical', 'MESH:D006862', (72, 75))	('protein', 'cellular_component', 'GO:0003675', ('481', '488'))	('cAMP', 'Chemical', '-', (216, 220))	('inhibition', 'NegReg', (188, 198))	('posttranslational modification', 'biological_process', 'GO:0043687', ('445', '475'))	('mitochondrial electron transport', 'biological_process', 'GO:0042775', ('282', '314'))	('electron transport chain', 'biological_process', 'GO:0022900', ('163', '187'))	('mitochondrial electron transport', 'MPA', (282, 314))	('protein', 'cellular_component', 'GO:0003675', ('572', '579'))	('mitochondrial DNA repair', 'biological_process', 'GO:0043504', ('366', '390'))	('ATP synthase', 'molecular_function', 'GO:0016467', ('428', '440'))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('366', '383'))	('cAMP', 'Chemical', '-', (253, 257))	('increases', 'PosReg', (269, 278))	('mitochondrial electron transport', 'biological_process', 'GO:0042775', ('149', '181'))	('mitochondrial DNA', 'Enzyme', (366, 383))	('stimulation', 'PosReg', (399, 410))	('mitochondrial electron transport chain', 'cellular_component', 'GO:0005746', ('149', '187'))
43853	29061341	Pharmacological inhibition or silencing of CBS reduced tumor bioenergetic function, inhibited tumor angiogenesis and suppressed tumor growth.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('CBS reduced tumor', 'Disease', (43, 60))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('CBS reduced tumor', 'Disease', 'MESH:D006712', (43, 60))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', (94, 99))	('suppressed', 'NegReg', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('silencing', 'Var', (30, 39))	('inhibited', 'NegReg', (84, 93))
43907	29061341	These findings indicate that the current protocol of 5-FU-resistance, in fact, creates multi-drug-resistant cells and predict that the development of 5-FU-resistance is associated with a significant degree of reprogramming of various cellular processes.	('reprogramming', 'CPA', (209, 222))	('5-FU', 'Chemical', 'MESH:D005472', (150, 154))	('5-FU-resistance', 'Var', (150, 165))	('multi-drug-resistant cells', 'MPA', (87, 113))	('creates', 'Reg', (79, 86))	('associated with', 'Reg', (169, 184))	('5-FU', 'Chemical', 'MESH:D005472', (53, 57))
43911	29061341	In agreement with the protein expression data, the enzymatic activities of CBS and 3-MST were enhanced in 5-FU-resistant cells compared to parental HCT116 cells (Fig.	('CBS', 'Enzyme', (75, 78))	('5-FU', 'Chemical', 'MESH:D005472', (106, 110))	('5-FU-resistant cells', 'Var', (106, 126))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('HCT116', 'CellLine', 'CVCL:0291', (148, 154))	('enhanced', 'PosReg', (94, 102))	('enzymatic activities', 'MPA', (51, 71))	('3-MST', 'Enzyme', (83, 88))
43915	29061341	We found no change in the protein level of MRP1 in 5-FU-resistant cells compared to parental HCT116 cells (Fig.	('MRP1', 'Gene', (43, 47))	('5-FU', 'Chemical', 'MESH:D005472', (51, 55))	('MRP1', 'Gene', '4363', (43, 47))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('5-FU-resistant', 'Var', (51, 65))	('HCT116', 'CellLine', 'CVCL:0291', (93, 99))
43917	29061341	Densitometric analysis showed a ~40% increase in GOT1 protein level in 5-FU-resistant cells compared to parental HCT116 cells (Fig.	('5-FU', 'Chemical', 'MESH:D005472', (71, 75))	('HCT116', 'CellLine', 'CVCL:0291', (113, 119))	('5-FU-resistant cells', 'Var', (71, 91))	('increase', 'PosReg', (37, 45))	('GOT1', 'Gene', '2805', (49, 53))	('GOT1', 'Gene', (49, 53))
43937	29061341	When analyzing bioenergetic responses, we noted that 5-FU-resistant cells had a comparable basal respiration rate as parental control cells, but an increased respiratory spare capacity (in response to the uncoupling agent FCCP) (Fig.	('5-FU-resistant', 'Var', (53, 67))	('increased', 'PosReg', (148, 157))	('respiratory spare capacity', 'MPA', (158, 184))	('FCCP', 'Chemical', 'MESH:D002259', (222, 226))	('5-FU', 'Chemical', 'MESH:D005472', (53, 57))
43939	29061341	5-FU-resistant cells exhibited a lower basal glycolytic rate compared to the parental HCT116 cells and AOAA inhibited glycolysis to a comparable degree in both wild-type and resistant cells (Fig.	('AOAA', 'Chemical', 'MESH:D000625', (103, 107))	('glycolysis', 'MPA', (118, 128))	('glycolytic rate', 'MPA', (45, 60))	('5-FU-resistant', 'Var', (0, 14))	('5-FU', 'Chemical', 'MESH:D005472', (0, 4))	('HCT116', 'CellLine', 'CVCL:0291', (86, 92))	('lower', 'NegReg', (33, 38))	('inhibited', 'NegReg', (108, 117))
43940	29061341	Taken together, the bioenergetic data indicate that the 5-FU resistant cells, compared to the parental controls, tend to rely more on oxidative phosphorylation than on glycolysis.	('oxidative phosphorylation', 'MPA', (134, 159))	('5-FU', 'Chemical', 'MESH:D005472', (56, 60))	('5-FU resistant', 'Var', (56, 70))
43951	29061341	The presence of functionally active CYP450 enzymes in tumor cells can inhibit the efficacy of chemotherapy-mediated tumor cell death through the deactivation of various anti-cancer drugs.	('deactivation', 'NegReg', (145, 157))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('CYP450 enzymes', 'Enzyme', (36, 50))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('presence', 'Var', (4, 12))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('inhibit', 'NegReg', (70, 77))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (116, 121))
43952	29061341	In the current study, CYP1A2 and 2A6 protein levels were significantly upregulated in 5-FU-resistant cells.	('2A6 protein levels', 'MPA', (33, 51))	('CYP1A2', 'Gene', '1544', (22, 28))	('5-FU-resistant', 'Var', (86, 100))	('5-FU', 'Chemical', 'MESH:D005472', (86, 90))	('CYP1A2', 'Gene', (22, 28))	('upregulated', 'PosReg', (71, 82))
43965	29061341	The mechanism responsible for the loss of AOAA's efficacy may be due to the fact that: (a) other H2S-producing enzymes, such as the 3-MST system are also contributing to H2S production in these cells and therefore inhibition of CBS results in a lesser suppression of cellular H2S levels; (b) AOAA may be metabolized and inactivated by the upregulated cytochrome P450 enzymes and/or; (c) in 5-FU-resistant cells other pathways are mobilized to maintain cell viability and cell proliferation and these pathways are not affected by AOAA.	('inhibition', 'Var', (214, 224))	('AOAA', 'Chemical', 'MESH:D000625', (529, 533))	('AOAA', 'Chemical', 'MESH:D000625', (42, 46))	('upregulated', 'PosReg', (339, 350))	('H2S', 'Chemical', 'MESH:D006862', (97, 100))	('H2S', 'Chemical', 'MESH:D006862', (170, 173))	('H2S', 'Chemical', 'MESH:D006862', (276, 279))	('cellular H2S levels', 'MPA', (267, 286))	('cell proliferation', 'CPA', (471, 489))	('suppression', 'NegReg', (252, 263))	('5-FU', 'Chemical', 'MESH:D005472', (390, 394))	('cell viability', 'CPA', (452, 466))	('AOAA', 'Chemical', 'MESH:D000625', (292, 296))
43968	29061341	Furthermore, the cells with upregulated H2S-producing enzyme expression underwent a significant degree of dedifferentiation, which was, at least in part, due to elevation of intracellular NAD+ levels in the damage-recovered cells.	('dedifferentiation', 'biological_process', 'GO:0043696', ('106', '123'))	('NAD+', 'Chemical', 'MESH:D009243', (188, 192))	('dedifferentiation', 'CPA', (106, 123))	('expression', 'Var', (61, 71))	('elevation', 'PosReg', (161, 170))	('H2S', 'Chemical', 'MESH:D006862', (40, 43))	('upregulated', 'PosReg', (28, 39))	('intracellular NAD+ levels', 'MPA', (174, 199))	('intracellular', 'cellular_component', 'GO:0005622', ('174', '187'))
43993	29061341	For example, it has been previously suggested that 5-FU leads to the activation of ataxia-telangiectasia mutated serine/threonine protein kinase (ATM), AMP kinase (AMPK) and PGC-1alpha, which could promote mitochondrial biogenesis and thus stimulate OXPHOS.	('ATM', 'Gene', (146, 149))	('telangiectasia', 'Phenotype', 'HP:0001009', (90, 104))	('ataxia-telangiectasia', 'Disease', (83, 104))	('5-FU', 'Chemical', 'MESH:D005472', (51, 55))	('OXPHOS', 'MPA', (250, 256))	('PGC-1alpha', 'Gene', '10891', (174, 184))	('AMPK', 'Gene', (164, 168))	('5-FU', 'Var', (51, 55))	('PGC-1alpha', 'Gene', (174, 184))	('ataxia', 'Phenotype', 'HP:0001251', (83, 89))	('promote', 'PosReg', (198, 205))	('ATM', 'Gene', '472', (146, 149))	('ataxia-telangiectasia', 'Disease', 'MESH:D001260', (83, 104))	('AMP kinase', 'Gene', (152, 162))	('AMPK', 'Gene', '5563', (164, 168))	('AMP kinase', 'Gene', '5563', (152, 162))	('mitochondrial biogenesis', 'MPA', (206, 230))	('stimulate', 'PosReg', (240, 249))	('activation', 'PosReg', (69, 79))
43994	29061341	In fact, H2S was shown to enhance the expression and activity of PGC-1alpha leading to increased mitochondrial biogenesis in primary hepatocytes.	('increased', 'PosReg', (87, 96))	('expression', 'MPA', (38, 48))	('H2S', 'Chemical', 'MESH:D006862', (9, 12))	('H2S', 'Var', (9, 12))	('activity', 'MPA', (53, 61))	('PGC-1alpha', 'Gene', (65, 75))	('PGC-1alpha', 'Gene', '10891', (65, 75))	('mitochondrial biogenesis', 'MPA', (97, 121))	('enhance', 'PosReg', (26, 33))
44012	29434452	PIK3CA and TP53 mutations predict overall survival of stage II/III colorectal cancer patients To investigate the predictive value of PIK3CA and TP53 mutation status in colorectal cancer (CRC) patients treated with 5-fluorouracil-based chemotherapy.	('PIK3CA', 'Gene', (133, 139))	('TP53', 'Gene', '7157', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('CRC', 'Phenotype', 'HP:0003003', (187, 190))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))	('TP53', 'Gene', '7157', (144, 148))	('mutations', 'Var', (16, 25))	('colorectal cancer', 'Disease', (168, 185))	('patients', 'Species', '9606', (85, 93))	('predict', 'Reg', (26, 33))	('PIK3CA', 'Gene', '5290', (0, 6))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (214, 228))	('TP53', 'Gene', (11, 15))	('PIK3CA', 'Gene', '5290', (133, 139))	('patients', 'Species', '9606', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('TP53', 'Gene', (144, 148))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('PIK3CA', 'Gene', (0, 6))	('colorectal cancer', 'Disease', (67, 84))
44019	29434452	Compared with patients without PIK3CA and TP53 mutations, those with double PIK3CA-TP53 mutations showed a significantly worse survival (univariate HR = 2.21; 95%CI: 1.15-4.24; multivariate HR = 2.02; 95%CI: 1.04-3.91).	('TP53', 'Gene', '7157', (83, 87))	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', (83, 87))	('TP53', 'Gene', (42, 46))	('worse', 'NegReg', (121, 126))	('mutations', 'Var', (88, 97))	('PIK3CA', 'Gene', (31, 37))	('PIK3CA', 'Gene', (76, 82))	('PIK3CA', 'Gene', '5290', (31, 37))	('survival', 'MPA', (127, 135))	('patients', 'Species', '9606', (14, 22))	('PIK3CA', 'Gene', '5290', (76, 82))
44020	29434452	The PIK3CA mutation located in the kinase domain showed a trend toward a shorter OS compared with wild-type tumors (multivariate HR = 1.56; 95%CI: 1.00-2.44; P = 0.052).	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('PIK3CA', 'Gene', (4, 10))	('shorter', 'NegReg', (73, 80))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('PIK3CA', 'Gene', '5290', (4, 10))	('OS', 'Chemical', '-', (81, 83))	('mutation', 'Var', (11, 19))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
44021	29434452	The Kaplan-Meier curve showed that patients harboring the PIK3CA mutation located in the kinase domain had a worse clinical outcome than those with wild-type status (Log-rank P = 0.041) Double mutation of PIK3CA and TP53 is correlated with a shorter OS in stage II/III CRC patients treated with 5-fluorouracil-based therapy.	('PIK3CA', 'Gene', (205, 211))	('TP53', 'Gene', (216, 220))	('PIK3CA', 'Gene', '5290', (205, 211))	('stage II/III CRC', 'Disease', (256, 272))	('patients', 'Species', '9606', (273, 281))	('CRC', 'Phenotype', 'HP:0003003', (269, 272))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (295, 309))	('PIK3CA', 'Gene', (58, 64))	('PIK3CA', 'Gene', '5290', (58, 64))	('Double mutation', 'Var', (186, 201))	('mutation', 'Var', (65, 73))	('OS', 'Chemical', '-', (250, 252))	('patients', 'Species', '9606', (35, 43))	('TP53', 'Gene', '7157', (216, 220))
44022	29434452	This manuscript is by far the first to report the predictive value of the combined mutation status of PIK3CA and TP53 in colorectal cancer patients receiving 5-FU-based adjuvant chemotherapy.	('PIK3CA', 'Gene', (102, 108))	('patients', 'Species', '9606', (139, 147))	('5-FU', 'Chemical', 'MESH:D005472', (158, 162))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutation', 'Var', (83, 91))	('PIK3CA', 'Gene', '5290', (102, 108))	('TP53', 'Gene', '7157', (113, 117))	('colorectal cancer', 'Disease', (121, 138))	('TP53', 'Gene', (113, 117))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))
44023	29434452	Our data revealed that the double mutation of PIK3CA and TP53 is an independent predictive factor for overall survival in stage II/III patients receiving 5-FU-based chemotherapy.	('patients', 'Species', '9606', (135, 143))	('PIK3CA', 'Gene', '5290', (46, 52))	('5-FU', 'Chemical', 'MESH:D005472', (154, 158))	('double mutation', 'Var', (27, 42))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('PIK3CA', 'Gene', (46, 52))
44032	29434452	It is well documented that the effect of the aberrant regulation of the PI3K/AKT signaling pathway on cell growth and apoptosis induced by anti-cancer drugs was observed in vitro and in vivo.	('apoptosis', 'CPA', (118, 127))	('signaling pathway', 'biological_process', 'GO:0007165', ('81', '98'))	('regulation', 'biological_process', 'GO:0065007', ('54', '64'))	('AKT', 'Gene', '207', (77, 80))	('AKT signaling', 'biological_process', 'GO:0043491', ('77', '90'))	('aberrant', 'Var', (45, 53))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('apoptosis', 'biological_process', 'GO:0097194', ('118', '127'))	('apoptosis', 'biological_process', 'GO:0006915', ('118', '127'))	('cancer', 'Disease', (144, 150))	('PI3K', 'molecular_function', 'GO:0016303', ('72', '76'))	('cell growth', 'biological_process', 'GO:0016049', ('102', '113'))	('AKT', 'Gene', (77, 80))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cell growth', 'CPA', (102, 113))
44033	29434452	Given the role of the PI3K/AKT signaling pathway in the development of resistance to anticancer drugs, it is conceivable that genetic mutations (such as PIK3CA) in the molecules of the PI3K/AKT signaling pathway could be a promising predictive biomarker for chemotherapy efficacy.	('PIK3CA', 'Gene', '5290', (153, 159))	('AKT', 'Gene', (27, 30))	('PI3K', 'molecular_function', 'GO:0016303', ('185', '189'))	('AKT signaling', 'biological_process', 'GO:0043491', ('27', '40'))	('AKT', 'Gene', '207', (190, 193))	('signaling pathway', 'biological_process', 'GO:0007165', ('194', '211'))	('signaling pathway', 'biological_process', 'GO:0007165', ('31', '48'))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('AKT', 'Gene', '207', (27, 30))	('cancer', 'Disease', (89, 95))	('genetic mutations', 'Var', (126, 143))	('AKT', 'Gene', (190, 193))	('PI3K', 'molecular_function', 'GO:0016303', ('22', '26'))	('AKT signaling', 'biological_process', 'GO:0043491', ('190', '203'))	('PIK3CA', 'Gene', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
44036	29434452	Thus, we proposed that PIK3CA and TP53 mutation status is likely well associated with clinical outcome in patients undergoing chemotherapy.	('PIK3CA', 'Gene', (23, 29))	('TP53', 'Gene', (34, 38))	('mutation', 'Var', (39, 47))	('associated', 'Reg', (70, 80))	('PIK3CA', 'Gene', '5290', (23, 29))	('patients', 'Species', '9606', (106, 114))	('TP53', 'Gene', '7157', (34, 38))
44037	29434452	In the present study, we evaluated the predictive value of PIK3CA and TP53 mutation status in CRC patients undergoing 5-FU-based chemotherapy after curative surgery and identified subgroups of patients who greatly benefited from specific treatment regimens.	('patients', 'Species', '9606', (193, 201))	('TP53', 'Gene', '7157', (70, 74))	('mutation', 'Var', (75, 83))	('patients', 'Species', '9606', (98, 106))	('CRC', 'Phenotype', 'HP:0003003', (94, 97))	('PIK3CA', 'Gene', (59, 65))	('TP53', 'Gene', (70, 74))	('5-FU', 'Chemical', 'MESH:D005472', (118, 122))	('PIK3CA', 'Gene', '5290', (59, 65))	('CRC', 'Disease', (94, 97))
44051	29434452	Genomic DNA from FFPE lesion samples of the patients with curatively resected CRC was screened for somatic mutations in the PIK3CA and TP53 genes.	('patients', 'Species', '9606', (44, 52))	('mutations', 'Var', (107, 116))	('TP53', 'Gene', '7157', (135, 139))	('CRC', 'Phenotype', 'HP:0003003', (78, 81))	('PIK3CA', 'Gene', (124, 130))	('TP53', 'Gene', (135, 139))	('PIK3CA', 'Gene', '5290', (124, 130))
44052	29434452	Among the 315 patients, the incidence of PIK3CA and TP53 mutations was 38.4% (n = 121) and 65.1% (n = 205), respectively, while wild type was detected in 61.6% (n = 194) and 34.9% (n = 110), respectively.	('TP53', 'Gene', '7157', (52, 56))	('PIK3CA', 'Gene', (41, 47))	('TP53', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))	('PIK3CA', 'Gene', '5290', (41, 47))	('patients', 'Species', '9606', (14, 22))
44054	29434452	The frequency of PIK3CA mutations in the proximal, distal, and rectum location was 50% (39/78), 38.7% (29/75), and 32.7% (53/162), respectively.	('PIK3CA', 'Gene', (17, 23))	('mutations', 'Var', (24, 33))	('PIK3CA', 'Gene', '5290', (17, 23))
44055	29434452	Among the 241 patients with stage II/III disease in this cohort, the PIK3CA and/or TP53 mutation was detected in 177 patients, of whom 54 had PIK3CA and TP53 double mutations.	('PIK3CA', 'Gene', '5290', (142, 148))	('TP53', 'Gene', '7157', (83, 87))	('mutation', 'Var', (88, 96))	('TP53', 'Gene', (83, 87))	('detected', 'Reg', (101, 109))	('TP53', 'Gene', '7157', (153, 157))	('PIK3CA', 'Gene', (69, 75))	('PIK3CA', 'Gene', (142, 148))	('TP53', 'Gene', (153, 157))	('PIK3CA', 'Gene', '5290', (69, 75))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (14, 22))
44057	29434452	For individual sites of PIK3CA mutation, the most frequent mutation in CRC was the mutation of Glu545Lys (5.1%), followed by Glu542Lys (2.2%).	('PIK3CA', 'Gene', (24, 30))	('Glu542Lys', 'Var', (125, 134))	('PIK3CA', 'Gene', '5290', (24, 30))	('CRC', 'Phenotype', 'HP:0003003', (71, 74))	('CRC', 'Gene', (71, 74))	('Glu545Lys', 'SUBSTITUTION', 'None', (95, 104))	('Glu542Lys', 'SUBSTITUTION', 'None', (125, 134))	('Glu545Lys', 'Var', (95, 104))
44058	29434452	The most frequent TP53 mutations included: Arg175His (5.1%), Arg282Trp (3.5%), Gly245Ser (2.9%), and Arg248Gln (2.9%) (Table 2).	('Arg282Trp', 'Var', (61, 70))	('TP53', 'Gene', '7157', (18, 22))	('Arg282Trp', 'SUBSTITUTION', 'None', (61, 70))	('Gly245Ser', 'SUBSTITUTION', 'None', (79, 88))	('TP53', 'Gene', (18, 22))	('Gly245Ser', 'Var', (79, 88))	('Arg175His', 'Var', (43, 52))	('Arg248Gln', 'Var', (101, 110))	('Arg175His', 'SUBSTITUTION', 'None', (43, 52))	('Arg248Gln', 'SUBSTITUTION', 'None', (101, 110))
44059	29434452	Predictive value of PIK3CA or TP53 mutation in stage II/III CRC patients All stage II/III CRC patients (n = 241) received 5-FU-based adjuvant chemotherapy for at least six cycles as first-line treatment after operation.	('5-FU', 'Chemical', 'MESH:D005472', (122, 126))	('TP53', 'Gene', (30, 34))	('patients', 'Species', '9606', (94, 102))	('patients', 'Species', '9606', (64, 72))	('PIK3CA', 'Gene', (20, 26))	('CRC', 'Phenotype', 'HP:0003003', (90, 93))	('PIK3CA', 'Gene', '5290', (20, 26))	('stage II/III CRC', 'Disease', (47, 63))	('CRC', 'Phenotype', 'HP:0003003', (60, 63))	('mutation', 'Var', (35, 43))	('TP53', 'Gene', '7157', (30, 34))
44061	29434452	The Kaplan-Meier curve showed that patients harboring the TP53 mutation had a worse clinical outcome than patients with wild-type status (Log-rank P = 0.046; Figure 1A), and no association was found between PIK3CA and clinical outcome (Log-rank P = 0.150; Figure 1B).	('PIK3CA', 'Gene', '5290', (207, 213))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('mutation', 'Var', (63, 71))	('clinical outcome', 'MPA', (84, 100))	('patients', 'Species', '9606', (106, 114))	('PIK3CA', 'Gene', (207, 213))	('patients', 'Species', '9606', (35, 43))	('worse', 'NegReg', (78, 83))
44062	29434452	Predictive value of double PIK3CA-TP53 mutations in stage II/III CRC patients We assessed the predictive value of double PIK3CA-TP53 mutations for survival in stage II/III CRC patients treated with 5-FU-based chemotherapy according to the statistical results of Cox proportional hazards and Kaplan-Meier analyses.	('patients', 'Species', '9606', (176, 184))	('CRC', 'Phenotype', 'HP:0003003', (172, 175))	('PIK3CA', 'Gene', '5290', (27, 33))	('TP53', 'Gene', (34, 38))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('CRC', 'Phenotype', 'HP:0003003', (65, 68))	('PIK3CA', 'Gene', (27, 33))	('mutations', 'Var', (39, 48))	('PIK3CA', 'Gene', (121, 127))	('PIK3CA', 'Gene', '5290', (121, 127))	('patients', 'Species', '9606', (69, 77))	('stage', 'Disease', (52, 57))	('TP53', 'Gene', '7157', (34, 38))	('5-FU', 'Chemical', 'MESH:D005472', (198, 202))
44063	29434452	Compared with concomitant PIK3CA and TP53 wild-type tumors, double PIK3CA-TP53 mutations were a significantly poor predictive factor for OS (univariate HR = 2.21; 95%CI: 1.15-4.24; multivariate HR = 2.02; 95%CI: 1.04-3.91) (Table 3).	('PIK3CA', 'Gene', '5290', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('PIK3CA', 'Gene', '5290', (26, 32))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', '7157', (74, 78))	('poor', 'NegReg', (110, 114))	('OS', 'Chemical', '-', (137, 139))	('PIK3CA', 'Gene', (26, 32))	('TP53', 'Gene', (37, 41))	('TP53', 'Gene', (74, 78))	('PIK3CA', 'Gene', (67, 73))	('mutations', 'Var', (79, 88))
44065	29434452	The Kaplan-Meier curve showed a shorter OS in patients harboring double PIK3CA and TP53 mutations compared with concomitant PIK3CA and TP53 wild-type patients (Log-rank P = 0.034; Figure 1C).	('TP53', 'Gene', '7157', (83, 87))	('patients', 'Species', '9606', (46, 54))	('TP53', 'Gene', (83, 87))	('TP53', 'Gene', '7157', (135, 139))	('mutations', 'Var', (88, 97))	('PIK3CA', 'Gene', (72, 78))	('PIK3CA', 'Gene', (124, 130))	('shorter', 'NegReg', (32, 39))	('TP53', 'Gene', (135, 139))	('patients', 'Species', '9606', (150, 158))	('OS', 'Chemical', '-', (40, 42))	('PIK3CA', 'Gene', '5290', (72, 78))	('PIK3CA', 'Gene', '5290', (124, 130))
44066	29434452	Association of PIK3CA mutation in a functional domain with clinical outcome in stage II/III CRC patients In the multivariable analysis of the association of PIK3CA functional domain mutation with OS, no significant difference was observed.	('mutation', 'Var', (22, 30))	('PIK3CA', 'Gene', '5290', (15, 21))	('PIK3CA', 'Gene', (157, 163))	('PIK3CA', 'Gene', '5290', (157, 163))	('patients', 'Species', '9606', (96, 104))	('Association', 'Interaction', (0, 11))	('CRC', 'Phenotype', 'HP:0003003', (92, 95))	('PIK3CA', 'Gene', (15, 21))	('OS', 'Chemical', '-', (196, 198))
44067	29434452	As suggested by the results, the PIK3CA mutation located in the kinase domain showed a trend toward a shorter OS compared with wild-type tumors (multivariate HR = 1.56; 95%CI: 1.00-2.44; P = 0.052).	('mutation', 'Var', (40, 48))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('OS', 'Chemical', '-', (110, 112))	('PIK3CA', 'Gene', '5290', (33, 39))	('shorter OS', 'CPA', (102, 112))	('PIK3CA', 'Gene', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
44068	29434452	The Kaplan-Meier curve showed that patients harboring the PIK3CA mutation located in the kinase domain had a worse clinical outcome than those with wild-type status (Log-rank P = 0.041; Figure 2).	('PIK3CA', 'Gene', '5290', (58, 64))	('mutation', 'Var', (65, 73))	('PIK3CA', 'Gene', (58, 64))	('patients', 'Species', '9606', (35, 43))
44071	29434452	Moreover, co-occurring genetic alterations have been detected in multiple malignancies.	('malignancies', 'Disease', 'MESH:D009369', (74, 86))	('genetic alterations', 'Var', (23, 42))	('detected', 'Reg', (53, 61))	('malignancies', 'Disease', (74, 86))
44073	29434452	We found that the double mutation of PIK3CA and TP53 was greatly associated with worse clinical outcomes in 241 stage II/III CRC patients receiving 5-FU-based adjuvant chemotherapy.	('PIK3CA', 'Gene', '5290', (37, 43))	('TP53', 'Gene', '7157', (48, 52))	('patients', 'Species', '9606', (129, 137))	('double mutation', 'Var', (18, 33))	('TP53', 'Gene', (48, 52))	('stage II/III CRC', 'Disease', (112, 128))	('CRC', 'Phenotype', 'HP:0003003', (125, 128))	('associated', 'Reg', (65, 75))	('5-FU', 'Chemical', 'MESH:D005472', (148, 152))	('PIK3CA', 'Gene', (37, 43))
44074	29434452	In contrast, mutations in PIK3CA or TP53 alone had no effect on the OS of CRC patients.	('OS', 'Chemical', '-', (68, 70))	('PIK3CA', 'Gene', '5290', (26, 32))	('patients', 'Species', '9606', (78, 86))	('TP53', 'Gene', '7157', (36, 40))	('CRC patients', 'Disease', (74, 86))	('TP53', 'Gene', (36, 40))	('mutations', 'Var', (13, 22))	('CRC', 'Phenotype', 'HP:0003003', (74, 77))	('PIK3CA', 'Gene', (26, 32))
44076	29434452	The frequencies of PIK3CA and TP53 mutations were 35% (85/241) and 65% (156/241), respectively, which are consistent with previously published studies reporting PIK3CA and TP53 mutations in 10%-32% and 40%-60% of CRC patients, respectively, in Western studies.	('CRC', 'Phenotype', 'HP:0003003', (213, 216))	('PIK3CA', 'Gene', (19, 25))	('TP53', 'Gene', (30, 34))	('PIK3CA', 'Gene', '5290', (19, 25))	('TP53', 'Gene', '7157', (172, 176))	('TP53', 'Gene', (172, 176))	('CRC', 'Disease', (213, 216))	('PIK3CA', 'Gene', (161, 167))	('PIK3CA', 'Gene', '5290', (161, 167))	('patients', 'Species', '9606', (217, 225))	('TP53', 'Gene', '7157', (30, 34))	('mutations', 'Var', (35, 44))
44077	29434452	The present results are consistent with those of two previous studies, showing that the proximal colon showed a higher frequency of PIK3CA mutations than any other sites.	('PIK3CA', 'Gene', (132, 138))	('PIK3CA', 'Gene', '5290', (132, 138))	('mutations', 'Var', (139, 148))
44079	29434452	A meta-analysis showed that the PIK3CA mutation in KRAS wild-type patients with metastatic CRC could predict responses to anti-EGFR monoclonal antibody therapy, while another study identified the PIK3CA mutation in exon 20.	('KRAS', 'Gene', '3845', (51, 55))	('PIK3CA', 'Gene', '5290', (32, 38))	('mutation', 'Var', (39, 47))	('antibody', 'cellular_component', 'GO:0042571', ('143', '151'))	('metastatic CRC', 'Disease', (80, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('127', '131'))	('predict', 'Reg', (101, 108))	('PIK3CA', 'Gene', (196, 202))	('antibody', 'molecular_function', 'GO:0003823', ('143', '151'))	('PIK3CA', 'Gene', '5290', (196, 202))	('antibody', 'cellular_component', 'GO:0019815', ('143', '151'))	('CRC', 'Phenotype', 'HP:0003003', (91, 94))	('antibody', 'cellular_component', 'GO:0019814', ('143', '151'))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', (127, 131))	('KRAS', 'Gene', (51, 55))	('patients', 'Species', '9606', (66, 74))	('PIK3CA', 'Gene', (32, 38))
44082	29434452	In clinical studies, there was no evidence that a mutation in PIK3CA was associated with 5-FU-based treatment benefits in colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('PIK3CA', 'Gene', (62, 68))	('colorectal cancer', 'Disease', (122, 139))	('5-FU', 'Chemical', 'MESH:D005472', (89, 93))	('colorectal cancer', 'Disease', 'MESH:D015179', (122, 139))	('PIK3CA', 'Gene', '5290', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('mutation', 'Var', (50, 58))
44084	29434452	The inactivation of tumor suppressor genes plays a key role in tumorigenesis.	('tumor', 'Disease', (63, 68))	('inactivation', 'Var', (4, 16))	('tumor suppressor', 'biological_process', 'GO:0051726', ('20', '36'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('20', '36'))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (20, 25))
44091	29434452	Indeed, gene alteration of PIK3CA or TP53 can result in cell apoptosis and drug-resistance of tumor cells through activating specific signaling pathways.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('TP53', 'Gene', (37, 41))	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('result in', 'Reg', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))	('activating', 'Reg', (114, 124))	('PIK3CA', 'Gene', (27, 33))	('signaling', 'biological_process', 'GO:0023052', ('134', '143'))	('tumor', 'Disease', (94, 99))	('drug-resistance', 'biological_process', 'GO:0009315', ('75', '90'))	('gene alteration', 'Var', (8, 23))	('drug-resistance', 'CPA', (75, 90))	('drug-resistance', 'Phenotype', 'HP:0020174', (75, 90))	('TP53', 'Gene', '7157', (37, 41))	('PIK3CA', 'Gene', '5290', (27, 33))	('cell apoptosis', 'CPA', (56, 70))	('drug-resistance', 'biological_process', 'GO:0042493', ('75', '90'))
44095	29434452	Interestingly, the double mutation of PIK3CA and TP53 has previously been correlated with a shorter OS.	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('OS', 'Chemical', '-', (100, 102))	('PIK3CA', 'Gene', (38, 44))	('PIK3CA', 'Gene', '5290', (38, 44))	('correlated', 'Reg', (74, 84))	('double mutation', 'Var', (19, 34))	('shorter', 'Disease', (92, 99))
44096	29434452	Remarkably, multivariate analysis showed that this correlation was independent of age, gender, stage, and tumor location, thereby confirming that the combined analysis of PIK3CA and TP53 mutation status could become a marker to identify subgroups of patients who have a poor prognosis and provide valuable information for more clinical therapy projects.	('TP53', 'Gene', '7157', (182, 186))	('PIK3CA', 'Gene', (171, 177))	('TP53', 'Gene', (182, 186))	('PIK3CA', 'Gene', '5290', (171, 177))	('patients', 'Species', '9606', (250, 258))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mutation', 'Var', (187, 195))	('tumor', 'Disease', (106, 111))
44097	29434452	The PIK3CA gene is divided into five functional domains: p85 binding domain, Ras binding domain, C2 domain, helical domain, and kinase domain.	('binding', 'molecular_function', 'GO:0005488', ('81', '88'))	('p85', 'Var', (57, 60))	('PIK3CA', 'Gene', (4, 10))	('helical', 'MPA', (108, 115))	('PIK3CA', 'Gene', '5290', (4, 10))	('Ras', 'Protein', (77, 80))	('p85 binding', 'molecular_function', 'GO:0036312', ('57', '68'))
44099	29434452	Recent studies have shown that patients treated with anti-EGFR monoclonal antibodies (MoAbs) and harboring PIK3CA mutations in exon 20 were significantly associated with worsening outcomes in KRAS wild-type mCRC.	('mutations in', 'Var', (114, 126))	('EGFR', 'Gene', '1956', (58, 62))	('EGFR', 'Gene', (58, 62))	('PIK3CA', 'Gene', (107, 113))	('KRAS', 'Gene', (192, 196))	('patients', 'Species', '9606', (31, 39))	('PIK3CA', 'Gene', '5290', (107, 113))	('CRC', 'Phenotype', 'HP:0003003', (208, 211))	('KRAS', 'Gene', '3845', (192, 196))
44100	29434452	In the present study, the Cox proportional hazard model analysis of the effect of the PIK3CA mutation occurring in the kinase domain on clinical outcome reached marginally statistical significance (P = 0.052), whereas the Kaplan-Meier curve achieved statistical significance (Log-rank P = 0.041; Figure 2).	('PIK3CA', 'Gene', '5290', (86, 92))	('mutation', 'Var', (93, 101))	('PIK3CA', 'Gene', (86, 92))
44104	29434452	In conclusion, the present study suggests that the double mutation of PIK3CA and TP53 is correlated with a shorter OS of stage II/III CRC patients receiving 5-FU-based therapy and hence serves as a novel biomarker to identify subgroups of patients who have poor clinical outcome, with potential clinical utility.	('CRC', 'Phenotype', 'HP:0003003', (134, 137))	('5-FU', 'Chemical', 'MESH:D005472', (157, 161))	('double mutation', 'Var', (51, 66))	('OS', 'Chemical', '-', (115, 117))	('patients', 'Species', '9606', (239, 247))	('PIK3CA', 'Gene', (70, 76))	('PIK3CA', 'Gene', '5290', (70, 76))	('TP53', 'Gene', '7157', (81, 85))	('patients', 'Species', '9606', (138, 146))	('TP53', 'Gene', (81, 85))
44108	29434452	Multiple studies have indicated that PIK3CA and TP53 mutation status was correlated with drug resistance of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('PIK3CA', 'Gene', '5290', (37, 43))	('TP53', 'Gene', '7157', (48, 52))	('drug resistance', 'biological_process', 'GO:0042493', ('89', '104'))	('mutation', 'Var', (53, 61))	('correlated', 'Reg', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('TP53', 'Gene', (48, 52))	('tumor', 'Disease', (108, 113))	('drug resistance', 'biological_process', 'GO:0009315', ('89', '104'))	('PIK3CA', 'Gene', (37, 43))	('drug resistance', 'Phenotype', 'HP:0020174', (89, 104))
44110	29434452	The objectives of this study were to detect gene mutations of PIK3CA and TP53 by using targeted next-generation sequencing (NGS) in a large cohort of CRC patients, and to investigate the predictive value of the mutational status of PIK3CA and TP53, alone or in combination.	('PIK3CA', 'Gene', '5290', (232, 238))	('TP53', 'Gene', '7157', (73, 77))	('mutations', 'Var', (49, 58))	('PIK3CA', 'Gene', (62, 68))	('TP53', 'Gene', (73, 77))	('patients', 'Species', '9606', (154, 162))	('PIK3CA', 'Gene', '5290', (62, 68))	('TP53', 'Gene', '7157', (243, 247))	('TP53', 'Gene', (243, 247))	('CRC', 'Phenotype', 'HP:0003003', (150, 153))	('PIK3CA', 'Gene', (232, 238))
44115	29434452	The associations between mutation status of PIK3CA and TP53 and OS were evaluated using Cox proportional hazards models adjusted for clinicopathologic variables.	('PIK3CA', 'Gene', (44, 50))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('mutation', 'Var', (25, 33))	('PIK3CA', 'Gene', '5290', (44, 50))	('OS', 'Chemical', '-', (64, 66))	('associations', 'Interaction', (4, 16))
44116	29434452	Among the 315 patients, the incidence of PIK3CA and TP53 mutations was 38.4% (n = 121) and 65.1% (n = 205), respectively.	('TP53', 'Gene', '7157', (52, 56))	('PIK3CA', 'Gene', (41, 47))	('TP53', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))	('PIK3CA', 'Gene', '5290', (41, 47))	('patients', 'Species', '9606', (14, 22))
44118	29434452	The PIK3CA and/or TP53 mutation was detected in 177 out of 241 patients with stage II/III CRC receiving 5-FU-based adjuvant chemotherapy, of whom 54 had PIK3CA and TP53 double mutations.	('PIK3CA', 'Gene', '5290', (153, 159))	('TP53', 'Gene', '7157', (164, 168))	('TP53', 'Gene', (164, 168))	('TP53', 'Gene', '7157', (18, 22))	('detected', 'Reg', (36, 44))	('PIK3CA', 'Gene', (4, 10))	('5-FU', 'Chemical', 'MESH:D005472', (104, 108))	('TP53', 'Gene', (18, 22))	('CRC', 'Phenotype', 'HP:0003003', (90, 93))	('double mutations', 'Var', (169, 185))	('PIK3CA', 'Gene', '5290', (4, 10))	('patients', 'Species', '9606', (63, 71))	('PIK3CA', 'Gene', (153, 159))
44119	29434452	In both univariate and multivariate analyses, neither PIK3CA nor TP53 mutation was significantly correlated with OS.	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('correlated', 'Reg', (97, 107))	('PIK3CA', 'Gene', '5290', (54, 60))	('mutation', 'Var', (70, 78))	('OS', 'Chemical', '-', (113, 115))	('PIK3CA', 'Gene', (54, 60))
44120	29434452	In Kaplan-Meier survival curve, patients with TP53 mutation had a worse clinical outcome than patients with wild-type TP53 (Log-rank P = 0.046).	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (94, 102))	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('TP53', 'Gene', (46, 50))	('mutation', 'Var', (51, 59))
44121	29434452	Compared with patients without PIK3CA and TP53 mutations, those with double PIK3CA-TP53 mutations had a significantly poorer OS (univariate HR = 2.21; 95%CI: 1.15-4.24; multivariate HR = 2.02; 95%CI: 1.04-3.91).	('TP53', 'Gene', '7157', (83, 87))	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', (83, 87))	('OS', 'Chemical', '-', (125, 127))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (88, 97))	('PIK3CA', 'Gene', (31, 37))	('PIK3CA', 'Gene', (76, 82))	('poorer', 'NegReg', (118, 124))	('PIK3CA', 'Gene', '5290', (31, 37))	('patients', 'Species', '9606', (14, 22))	('PIK3CA', 'Gene', '5290', (76, 82))
44123	29434452	The Kaplan-Meier curve showed that shorter OS was detected in patients harboring double PIK3CA and TP53 mutations (Log-rank P = 0.034).	('TP53', 'Gene', (99, 103))	('mutations', 'Var', (104, 113))	('PIK3CA', 'Gene', '5290', (88, 94))	('OS', 'Chemical', '-', (43, 45))	('TP53', 'Gene', '7157', (99, 103))	('PIK3CA', 'Gene', (88, 94))	('patients', 'Species', '9606', (62, 70))
44124	29434452	In Kaplan-Meier survival curve, patients harboring the PIK3CA mutation located in the kinase domain experienced a significantly shorter OS when compared with wild-type status (Log-rank P = 0.041).	('patients', 'Species', '9606', (32, 40))	('shorter', 'NegReg', (128, 135))	('mutation', 'Var', (62, 70))	('PIK3CA', 'Gene', (55, 61))	('OS', 'Chemical', '-', (136, 138))	('PIK3CA', 'Gene', '5290', (55, 61))
44126	29434452	Our data revealed that the double mutation of PIK3CA and TP53 is correlated with a shorter OS of stage II/III CRC patients receiving 5-FU-based therapy and hence serves as a novel biomarker to identify subgroups of patients who have poor clinical outcome, with potential clinical utility.	('patients', 'Species', '9606', (215, 223))	('PIK3CA', 'Gene', '5290', (46, 52))	('5-FU', 'Chemical', 'MESH:D005472', (133, 137))	('double mutation', 'Var', (27, 42))	('CRC', 'Phenotype', 'HP:0003003', (110, 113))	('OS', 'Chemical', '-', (91, 93))	('TP53', 'Gene', '7157', (57, 61))	('patients', 'Species', '9606', (114, 122))	('TP53', 'Gene', (57, 61))	('PIK3CA', 'Gene', (46, 52))
44127	26485756	Prognostic impact of mismatch repair genes germline defects in colorectal cancer patients: are all mutations equal?	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('patients', 'Species', '9606', (81, 89))	('colorectal cancer', 'Disease', (63, 80))	('germline defects', 'Var', (43, 59))	('mismatch repair genes', 'Gene', (21, 42))	('mismatch repair', 'biological_process', 'GO:0006298', ('21', '36'))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
44128	26485756	Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, caused by germline mutations in MisMatch Repair (MMR) genes, particularly in MLH1, MSH2 and MSH6.	('MSH2', 'Gene', (167, 171))	('mutations', 'Var', (103, 112))	('MSH2', 'Gene', '4436', (167, 171))	('MisMatch Repair', 'biological_process', 'GO:0006298', ('116', '131'))	('MSH6', 'Gene', (176, 180))	('caused by', 'Reg', (84, 93))	('MLH1', 'Gene', '4292', (161, 165))	('MMR', 'biological_process', 'GO:0006298', ('133', '136'))	('MLH1', 'Gene', (161, 165))	('MMR', 'Gene', (133, 136))	('MSH6', 'Gene', '2956', (176, 180))	('Lynch syndrome', 'Disease', (0, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('hereditary colorectal cancer (CRC) syndrome', 'Disease', 'MESH:D015179', (39, 82))
44130	26485756	Aim of our study is to compare survival outcomes of different types of MMR mutations in patients with LS-related CRC.	('MMR', 'Gene', (71, 74))	('patients', 'Species', '9606', (88, 96))	('LS-related CRC', 'Disease', (102, 116))	('mutations', 'Var', (75, 84))
44133	26485756	A deleterious MMR mutation was found in 38/302 patients.	('MMR', 'Gene', (14, 17))	('MMR', 'biological_process', 'GO:0006298', ('14', '17'))	('patients', 'Species', '9606', (47, 55))	('mutation', 'Var', (18, 26))
44136	26485756	In addition, not all mutations could be considered equal: the better prognosis in CRC patients with MMR pathogenic missense or splicing site mutation could be due to different functional activity of the encoded MMR protein.	('MMR', 'biological_process', 'GO:0006298', ('100', '103'))	('splicing', 'biological_process', 'GO:0045292', ('127', '135'))	('protein', 'cellular_component', 'GO:0003675', ('215', '222'))	('functional activity', 'MPA', (176, 195))	('MMR', 'Gene', (100, 103))	('MMR', 'biological_process', 'GO:0006298', ('211', '214'))	('missense or splicing site mutation', 'Var', (115, 149))	('patients', 'Species', '9606', (86, 94))
44138	26485756	Lynch syndrome is caused by germline mutations in any of the MisMatch Repair (MMR) genes, even if mutations in MLH1 (located on 3p21), MSH2 (on 2p22-p21) and MSH6 (2p16) account for almost 90% of identified defects.	('p21', 'Gene', (149, 152))	('MSH2', 'Gene', '4436', (135, 139))	('MLH1', 'Gene', '4292', (111, 115))	('MSH6', 'Gene', (158, 162))	('MSH6', 'Gene', '2956', (158, 162))	('MMR', 'biological_process', 'GO:0006298', ('78', '81'))	('mutations', 'Var', (98, 107))	('p21', 'Gene', '644914', (149, 152))	('MMR', 'Gene', (78, 81))	('Lynch syndrome', 'Disease', (0, 14))	('MisMatch Repair', 'biological_process', 'GO:0006298', ('61', '76'))	('MSH2', 'Gene', (135, 139))	('p21', 'Gene', (129, 132))	('caused by', 'Reg', (18, 27))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))	('MLH1', 'Gene', (111, 115))	('p21', 'Gene', '644914', (129, 132))
44140	26485756	Genetic testing for Lynch syndrome has evolved as a powerful clinical tool: the detection of a pathogenic MMR mutation in the proband enables the identification of other mutation carriers into the same family who would benefit from risk-reduction strategies, such as cancer surveillance and prophylactic surgery.	('Lynch syndrome', 'Disease', 'MESH:D003123', (20, 34))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('MMR', 'biological_process', 'GO:0006298', ('106', '109'))	('pathogenic', 'Reg', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('mutation', 'Var', (110, 118))	('MMR', 'Gene', (106, 109))	('Lynch syndrome', 'Disease', (20, 34))
44141	26485756	However, mutation testing can provide three categories of possible results: pathogenic mutation, variant of uncertain significance (VUS), or informative negative finding, if no mutations are found.	('pathogenic', 'Reg', (76, 86))	('mutation', 'Var', (87, 95))	('VUS', 'Chemical', '-', (132, 135))
44144	26485756	The aim of our study is to compare survival outcomes of different types of MMR-genes mutations in patients with Lynch Syndrome-related CRC.	('Lynch Syndrome-related CRC', 'Disease', (112, 138))	('MMR-genes', 'Gene', (75, 84))	('mutations', 'Var', (85, 94))	('patients', 'Species', '9606', (98, 106))
44151	26485756	Moreover, the presence at diagnosis of multiple synchronous colorectal malignancies, metachronous colorectal cancers or other HNPCC-associated tumours resulted more frequent among mutation-positive patients than mutation negative cases (50% vs 23.4%, p = 0.0012) (Table 1).	('colorectal cancers', 'Disease', (98, 116))	('HNPCC-associated tumours', 'Disease', (126, 150))	('patients', 'Species', '9606', (198, 206))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('tumours', 'Phenotype', 'HP:0002664', (143, 150))	('synchronous colorectal malignancies', 'Disease', 'MESH:D009378', (48, 83))	('HNPCC-associated tumours', 'Disease', 'MESH:D009369', (126, 150))	('synchronous colorectal malignancies', 'Disease', (48, 83))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutation-positive', 'Var', (180, 197))	('colorectal cancers', 'Disease', 'MESH:D015179', (98, 116))
44154	26485756	MSI-H was found in 22 patients (28.2%), among them 13 harboured a MMR genes pathogenic mutation; 14 patients (18%) had MSI-L tumour and in 42 cases (53.8%) MSS was observed.	('MMR', 'biological_process', 'GO:0006298', ('66', '69'))	('pathogenic', 'Reg', (76, 86))	('MSI-L tumour', 'Disease', (119, 131))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('patients', 'Species', '9606', (22, 30))	('MSI-H', 'Disease', (0, 5))	('patients', 'Species', '9606', (100, 108))	('mutation', 'Var', (87, 95))	('MSI-L tumour', 'Disease', 'MESH:D009369', (119, 131))	('MSI-H', 'Disease', 'MESH:D000848', (0, 5))	('MMR genes', 'Gene', (66, 75))
44156	26485756	The CAT25 microsatellite analysis showed instability in all 22 patients with MSI-H.	('MSI-H', 'Disease', 'MESH:D000848', (77, 82))	('MSI-H', 'Disease', (77, 82))	('CAT25', 'Var', (4, 9))	('patients', 'Species', '9606', (63, 71))
44160	26485756	Globally, 43 different mutations in 65 patients were found, while in 237 patients the test resulted negative.	('found', 'Reg', (53, 58))	('mutations', 'Var', (23, 32))	('patients', 'Species', '9606', (73, 81))	('patients', 'Species', '9606', (39, 47))
44161	26485756	We found 26 patients with MLH1 gene mutations: 1 patient had a large rearrangement, 8 patients harboured splice-site mutations, 14 patients had a missense mutation and 3 patients had a silent mutation.	('patients', 'Species', '9606', (131, 139))	('patients', 'Species', '9606', (170, 178))	('patients', 'Species', '9606', (12, 20))	('missense mutation', 'Var', (146, 163))	('MLH1', 'Gene', '4292', (26, 30))	('MLH1', 'Gene', (26, 30))	('mutations', 'Var', (36, 45))	('patient', 'Species', '9606', (49, 56))	('patient', 'Species', '9606', (86, 93))	('splice-site mutations', 'MPA', (105, 126))	('patient', 'Species', '9606', (131, 138))	('patient', 'Species', '9606', (12, 19))	('patient', 'Species', '9606', (170, 177))	('patients', 'Species', '9606', (86, 94))
44162	26485756	We identified 35 patients harbouring MSH2 gene mutations: 6 patients had a large rearrangement, 4 patients harboured a frameshift, 3 patients had a non-sense mutation, 18 patients carried a missense mutation, 2 patients a silent mutation and other 2 an intronic variant.	('patients', 'Species', '9606', (211, 219))	('MSH2', 'Gene', '4436', (37, 41))	('patients', 'Species', '9606', (60, 68))	('patients', 'Species', '9606', (133, 141))	('mutations', 'Var', (47, 56))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (171, 179))	('frameshift', 'Var', (119, 129))	('missense mutation', 'Var', (190, 207))	('patients', 'Species', '9606', (17, 25))	('MSH2', 'Gene', (37, 41))
44163	26485756	Even in this group of MSH2-mutated patients heterogeneity of mutation types was observed, with 23 different mutations types (3 large rearrangements, 4 frameshift mutations, 2 non-sense mutations, 10 missense, 2 silent-mutations and 2 intronic variants) discovered.	('MSH2', 'Gene', (22, 26))	('MSH2', 'Gene', '4436', (22, 26))	('missense', 'Var', (199, 207))	('patients', 'Species', '9606', (35, 43))	('frameshift mutations', 'Var', (151, 171))
44164	26485756	In the MSH6 gene 4 different mutations were found in 4 patients: 1 frameshift, 1 missense mutation and two intronic variants.	('frameshift', 'Var', (67, 77))	('found', 'Reg', (44, 49))	('MSH6', 'Gene', '2956', (7, 11))	('patients', 'Species', '9606', (55, 63))	('missense mutation', 'Var', (81, 98))	('MSH6', 'Gene', (7, 11))
44165	26485756	Among mutation carriers, we identified 38 patients who carried a definitely pathogenic or likely pathogenic mutation (Table 2), 15 patients who carried a not pathogenic or a likely not pathogenic mutation and 12 patients who carried a Variant of Uncertain Significance (VUS): this latter group of patients, as previously stated, was excluded from further analysis.	('patients', 'Species', '9606', (131, 139))	('pathogenic', 'Reg', (76, 86))	('patients', 'Species', '9606', (297, 305))	('patients', 'Species', '9606', (212, 220))	('mutation', 'Var', (108, 116))	('patients', 'Species', '9606', (42, 50))	('VUS', 'Chemical', '-', (270, 273))
44166	26485756	Out of 38 patients who carried pathogenic MMR-genes mutations, in 31 patients the mutations were found using direct sequencing while in 7 patients the mutations were detected using MLPA.	('mutations', 'Var', (52, 61))	('MMR-genes', 'Gene', (42, 51))	('patients', 'Species', '9606', (10, 18))	('patients', 'Species', '9606', (69, 77))	('MMR', 'biological_process', 'GO:0006298', ('42', '45'))	('patients', 'Species', '9606', (138, 146))
44167	26485756	Eighty-four patients (27.8%) fulfilled Amsterdam criteria and the mutation rate in this group of patients was 33%: 28/84 patients were found to have a pathogenic mutation, 1/84 resulted carrier of a VUS, while the remaining 57/84 patients resulted negative to mutation testing.	('patients', 'Species', '9606', (12, 20))	('VUS', 'Chemical', '-', (199, 202))	('patients', 'Species', '9606', (230, 238))	('mutation', 'Var', (162, 170))	('pathogenic', 'Reg', (151, 161))	('patients', 'Species', '9606', (121, 129))	('patients', 'Species', '9606', (97, 105))
44178	26485756	Immune activity could be explained due to the accumulation of mutations in genes encoding cell surface proteins caused by MMR-system deficiency.	('MMR-system deficiency', 'Disease', 'MESH:C536143', (122, 143))	('Immune activity', 'MPA', (0, 15))	('accumulation', 'PosReg', (46, 58))	('mutations', 'Var', (62, 71))	('MMR-system deficiency', 'Disease', (122, 143))
44180	26485756	In addition, recent data seem to suggest that both sporadic MSI-H and Lynch Syndrome-related colorectal cancer could share some therapeutically important biomarkers, such as significantly higher Thymidylate Synthase (TS) expression (potentially explaining the supposed reduced clinical benefit from 5-Fluorouracil), higher Programmed cell death-1 (PD-1)-positive tumor infiltrating lymphocytes (TIL), BRCA1/2 and CTNNB1 mutations.	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('higher', 'PosReg', (316, 322))	('BRCA1/2', 'Gene', '672;675', (401, 408))	('mutations', 'Var', (420, 429))	('CTNNB1', 'Gene', '1499', (413, 419))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('higher', 'PosReg', (188, 194))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('MSI-H', 'Disease', (60, 65))	('colorectal cancer', 'Disease', (93, 110))	('death-1 (PD-1)-positive tumor', 'Disease', 'MESH:D010300', (339, 368))	('expression', 'MPA', (221, 231))	('CTNNB1', 'Gene', (413, 419))	('Thymidylate Synthase', 'Gene', (195, 215))	('5-Fluorouracil', 'Chemical', 'MESH:D005472', (299, 313))	('BRCA1/2', 'Gene', (401, 408))	('MSI-H', 'Disease', 'MESH:D000848', (60, 65))	('Thymidylate Synthase', 'Gene', '7298', (195, 215))
44184	26485756	Moreover, MSI-positive CRC seem to show a reduced microvessel density, due to a lower vascular endothelial growth factor (VEGF) levels and, consequently, a reduced metastatic potential.	('VEGF', 'Gene', '7422', (122, 126))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('86', '120'))	('reduced', 'NegReg', (42, 49))	('vascular endothelial growth factor', 'Gene', (86, 120))	('reduced', 'NegReg', (156, 163))	('lower', 'NegReg', (80, 85))	('VEGF', 'Gene', (122, 126))	('microvessel density', 'CPA', (50, 69))	('vascular endothelial growth factor', 'Gene', '7422', (86, 120))	('MSI-positive', 'Var', (10, 22))	('metastatic potential', 'CPA', (164, 184))
44185	26485756	Another explanation could be that MMR defects can affect the viability of tumour cells through the accumulation of mutations in genes necessary for cancer cell survival.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('mutations', 'Var', (115, 124))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('affect', 'Reg', (50, 56))	('MMR', 'Gene', (34, 37))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('defects', 'Var', (38, 45))
44186	26485756	To support this hypothesis the evidence showed that MSI-positive CRC are less likely to carry mutations of TP53, KRAS and DCC genes, which are usually associated with uncontrolled cell proliferation and poor prognosis.	('mutations', 'Var', (94, 103))	('associated', 'Reg', (151, 161))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('KRAS', 'Gene', (113, 117))	('DCC genes', 'Gene', (122, 131))	('KRAS', 'Gene', '3845', (113, 117))	('CRC', 'Disease', (65, 68))
44188	26485756	If we compare this result with the10-year survival rate of mutation-negative patients included in the analysis (about 30%) it is easy to refuse the claim that all MMR mutations have the same prognostic impact.	('patients', 'Species', '9606', (77, 85))	('MMR', 'Gene', (163, 166))	('MMR', 'biological_process', 'GO:0006298', ('163', '166'))	('mutations', 'Var', (167, 176))
44190	26485756	In fact, while the pathogenic role of some mutations, such as frameshift and non-sense, is clearly predictable because their product consists in a truncated protein, for patients with a missense mutation, the molecular mechanism underlying abnormalities of MMR function is more complex and still to be fully clarified: it may be linked both to the effects that a missense mutation cause on the encoded protein (such as functional and structural alterations related to chemical and physical properties of the involved aminoacid), or to the mutation-affected site of the protein.	('patients', 'Species', '9606', (170, 178))	('cause', 'Reg', (381, 386))	('protein', 'Protein', (402, 409))	('missense mutation', 'Var', (363, 380))
44192	26485756	In this setting, in silico and in vitro functional assays may be used in order to extensively comprehend the defect that each type of mutation causes on the corresponding protein and to estimate its residual functionality and, thus, to verify a possible correlation between the genotype (represented by different types of mutation) and the patient phenotype.	('patient', 'Species', '9606', (340, 347))	('mutation', 'Var', (134, 142))	('protein', 'Protein', (171, 178))	('causes', 'Reg', (143, 149))
44195	26485756	Indeed, while our analyses prove that this group of patients does not harbour mutations in hMLH1, hMSH2, hMSH6 genes, we do not know if those patients harbour other (less frequently represented) mutations.	('hMSH2', 'Gene', '4436', (98, 103))	('hMLH1', 'Gene', '4292', (91, 96))	('hMSH2', 'Gene', (98, 103))	('hMSH6', 'Gene', (105, 110))	('hMSH', 'molecular_function', 'GO:0018775', ('98', '102'))	('mutations', 'Var', (78, 87))	('hMSH6', 'Gene', '2956', (105, 110))	('hMSH', 'molecular_function', 'GO:0018775', ('105', '109'))	('patients', 'Species', '9606', (142, 150))	('patients', 'Species', '9606', (52, 60))	('hMLH1', 'Gene', (91, 96))
44196	26485756	For example, PMS2 mutations are nowadays considered as other potential mechanisms of familial colorectal cancer syndromes akin to the more common Lynch Syndrome.	('PMS2', 'Gene', (13, 17))	('familial colorectal cancer syndromes akin', 'Disease', (85, 126))	('PMS2', 'Gene', '5395', (13, 17))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('familial colorectal cancer syndromes akin', 'Disease', 'MESH:D015179', (85, 126))	('mutations', 'Var', (18, 27))
44197	26485756	Our laboratory is unable to perform PMS2 mutations analysis, due to the technical difficulties in analysing PMS2 gene as a result of a large number of pseudogenes has possibly lead to underreporting of PMS2 mutations in patients with LS.	('PMS2', 'Gene', (202, 206))	('PMS2', 'Gene', '5395', (202, 206))	('PMS2', 'Gene', (108, 112))	('mutations', 'Var', (207, 216))	('patients', 'Species', '9606', (220, 228))	('PMS2', 'Gene', '5395', (108, 112))	('PMS2', 'Gene', (36, 40))	('PMS2', 'Gene', '5395', (36, 40))
44199	26485756	Accounting for the relatively small frequence of PMS2 mutations (up to 8% of all Lynch syndromes) there is a relatively small probability that it would influence the results of our work.	('PMS2', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('PMS2', 'Gene', '5395', (49, 53))	('Lynch syndrome', 'Disease', (81, 95))	('influence', 'Reg', (152, 161))	('Lynch syndrome', 'Disease', 'MESH:D003123', (81, 95))
44200	26485756	In conclusions, our study suggests that, even if MMR-genes pathogenic mutations are generally associated with an improved overall survival in patients with CRC, not all the mutations could be considered equal: their prognostic impact may differ on the basis of the type of mutation and the better prognosis in CRC patients harbouring a MMR pathogenic missense or splicing site mutation could be due to a different functional activity of the encoded MMR protein.	('protein', 'cellular_component', 'GO:0003675', ('453', '460'))	('mutations', 'Var', (70, 79))	('patients', 'Species', '9606', (314, 322))	('MMR-genes', 'Gene', (49, 58))	('MMR', 'biological_process', 'GO:0006298', ('336', '339'))	('MMR', 'biological_process', 'GO:0006298', ('449', '452'))	('MMR', 'Gene', (336, 339))	('patients', 'Species', '9606', (142, 150))	('pathogenic', 'Reg', (340, 350))	('missense or splicing site mutation', 'Var', (351, 385))	('splicing', 'biological_process', 'GO:0045292', ('363', '371'))	('MMR', 'biological_process', 'GO:0006298', ('49', '52'))
44208	26485756	Colorectal cancer DNA was investigated for MSI using the 5-markers panel (two mononucleotide repeats - BAT25 and BAT26- and three dinucleotide repeats -D2S123, D5S346, D17S250) recommended by international guidelines.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('mononucleotide', 'Chemical', '-', (78, 92))	('D5S346', 'Var', (160, 166))	('BAT26-', 'Var', (113, 119))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('D17S250', 'Var', (168, 175))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('Colorectal cancer', 'Disease', (0, 17))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))
44216	26485756	Cases who tested negative for the mutational analyses were investigated for the presence of genomic rearrangements, including the deletion or duplication of one of more exons in the MLH1, MSH2 and MSH6 genes by Multiplex Ligation-dependent Probe Amplification (MLPA) analysis.	('MSH2', 'Gene', '4436', (188, 192))	('MSH6', 'Gene', '2956', (197, 201))	('MLH1', 'Gene', '4292', (182, 186))	('deletion', 'Var', (130, 138))	('MLH1', 'Gene', (182, 186))	('MSH6', 'Gene', (197, 201))	('duplication', 'Var', (142, 153))	('MSH2', 'Gene', (188, 192))
44220	26485756	A 40-55% decrease of the area of an MLH1, MSH2, MSH6 exon peak compared to the wild-type control samples was considered as indicative of a heterozygous deletion of that exon.	('MLH1', 'Gene', '4292', (36, 40))	('deletion', 'Var', (152, 160))	('MSH6', 'Gene', (48, 52))	('MLH1', 'Gene', (36, 40))	('MSH2', 'Gene', (42, 46))	('area', 'MPA', (25, 29))	('MSH2', 'Gene', '4436', (42, 46))	('MSH6', 'Gene', '2956', (48, 52))	('decrease', 'NegReg', (9, 17))
44223	26485756	We assumed that exposed patients are those who harbour mutations of MMR genes with high likelihood of lacking gene function such as frameshift, nonsense mutations and large genetic rearrangements, whereas control patients are those who harbour mutations of MMR genes with more favourable outcome such as splice-site alterations and missense mutations.	('missense mutations', 'Var', (332, 350))	('mutations', 'Var', (55, 64))	('lacking', 'NegReg', (102, 109))	('MMR genes', 'Gene', (68, 77))	('frameshift', 'Var', (132, 142))	('MMR', 'biological_process', 'GO:0006298', ('257', '260'))	('gene function', 'MPA', (110, 123))	('patients', 'Species', '9606', (213, 221))	('patients', 'Species', '9606', (24, 32))	('splice-site alterations', 'Var', (304, 327))	('nonsense mutations', 'Var', (144, 162))	('MMR', 'biological_process', 'GO:0006298', ('68', '71'))
44229	25099886	If not repaired, oxidative DNA damage can lead to disease-causing mutations, such as in cancer.	('mutations', 'Var', (66, 75))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('lead to', 'Reg', (42, 49))	('oxidative DNA damage', 'MPA', (17, 37))
44230	25099886	This is particularly relevant in cancer where mismatch repair genes are frequently mutated or epigenetically silenced.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('epigenetically silenced', 'Var', (94, 117))	('mismatch repair genes', 'Gene', (46, 67))
44242	25099886	H2O2 is highly diffusible through different cellular compartments but possesses low chemical reactivity and therefore is only directly responsible for modifying proteins via thiol groups.	('low', 'NegReg', (80, 83))	('modifying', 'Reg', (151, 160))	('chemical reactivity', 'MPA', (84, 103))	('thiol', 'Chemical', 'MESH:D013438', (174, 179))	('thiol groups', 'MPA', (174, 186))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('H2O2', 'Var', (0, 4))	('proteins', 'Protein', (161, 169))
44247	25099886	Addition reactions occurring at these sites generate C4-OH-, C5-OH- and C8-OH-adduct radicals of guanine and adenine and C5-OH- and C6-OH-adduct radicals of thymidine and cytosine.	('radical', 'Chemical', '-', (85, 92))	('C5-OH', 'Chemical', '-', (61, 66))	('C6-OH-adduct', 'Var', (132, 144))	('C5-OH-', 'Var', (121, 127))	('cytosine', 'Chemical', 'MESH:D003596', (171, 179))	('C8-OH-adduct', 'Var', (72, 84))	('guanine', 'Chemical', 'MESH:D006147', (97, 104))	('C4-OH-', 'Var', (53, 59))	('radical', 'Chemical', '-', (145, 152))	('adenine', 'Chemical', 'MESH:D000225', (109, 116))	('C5-OH', 'Chemical', '-', (121, 126))	('thymidine', 'Chemical', 'MESH:D013936', (157, 166))	('C5-OH-', 'Var', (61, 67))
44252	25099886	C to T transitions are another commonly observed mutation generated by oxidative damage, particularly due to the cytosine-derived products uracil glycol and 5-hydroxyuracil mispairing with adenine.	('cytosine', 'Chemical', 'MESH:D003596', (113, 121))	('adenine', 'Chemical', 'MESH:D000225', (189, 196))	('uracil glycol', 'Chemical', 'MESH:C111900', (139, 152))	('mispairing', 'Var', (173, 183))	('5-hydroxyuracil', 'Chemical', 'MESH:C045975', (157, 172))	('C to T transitions', 'Disease', (0, 18))
44265	25099886	Whilst BER acts to repair individual nucleotides, the NER system generally removes oligodeoxynucleotide chains containing large, DNA-distorting lesions such as intra-strand crosslinks, tandem lesions and bulky adducts.	('BER', 'biological_process', 'GO:0006284', ('7', '10'))	('NER', 'biological_process', 'GO:0006289', ('54', '57'))	('tandem lesions', 'Var', (185, 199))	('DNA', 'cellular_component', 'GO:0005574', ('129', '132'))	('intra-strand crosslinks', 'Var', (160, 183))	('bulky adducts', 'Var', (204, 217))	('oligodeoxynucleotide chains', 'MPA', (83, 110))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (83, 103))	('removes', 'NegReg', (75, 82))
44279	25099886	Lack of one or more MMR genes in these cancers has been attributed to epigenetic silencing, in addition to both germline (inherited) and somatic (acquired) mutations.	('Lack', 'NegReg', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('cancers', 'Disease', (39, 46))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('epigenetic silencing', 'Var', (70, 90))	('MMR genes', 'Gene', (20, 29))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
44280	25099886	Lynch syndrome, an autosomal dominant condition associated with a predisposition to several cancers, occurs due to inheritance of a single amorphic mutation in MSH2, MSH6, MLH1 or PMS2, followed by subsequent sporadic loss of the second allele.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('occurs due', 'Reg', (101, 111))	('PMS2', 'Gene', '5395', (180, 184))	('MSH6', 'Gene', (166, 170))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('PMS2', 'Gene', (180, 184))	('MLH1', 'Gene', (172, 176))	('Lynch syndrome', 'Disease', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('MSH2', 'Gene', (160, 164))	('mutation', 'Var', (148, 156))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))
44282	25099886	The mutator phenotype leads to downstream mutations in tumour suppressor genes and oncogenes, particularly in those harbouring microsatellites such as PTEN, BAX, IGF2R and TGFBR2, thereby promoting tumourigenesis.	('tumour', 'Disease', (55, 61))	('TGFBR2', 'Gene', (172, 178))	('tumour', 'Disease', (198, 204))	('promoting', 'PosReg', (188, 197))	('BAX', 'Gene', (157, 160))	('PTEN', 'Gene', '5728', (151, 155))	('BAX', 'Gene', '581', (157, 160))	('IGF2R', 'Gene', (162, 167))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('IGF2R', 'Gene', '3482', (162, 167))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('TGFBR2', 'Gene', '7048', (172, 178))	('oncogenes', 'Gene', (83, 92))	('PTEN', 'Gene', (151, 155))	('mutations', 'Var', (42, 51))	('tumour', 'Disease', 'MESH:D009369', (198, 204))	('microsatellites', 'Var', (127, 142))
44284	25099886	Embryonic stem (ES) cells and mouse embryo fibroblasts (MEFs) derived from mice deficient in MSH2 (Msh2+/- and Msh2-/-) have higher levels of both basal and ROS-induced genomic 8-oxoG in comparison to wild-type controls.	('Msh2-/-', 'Gene', (111, 118))	('ROS', 'Chemical', 'MESH:D017382', (157, 160))	('mice', 'Species', '10090', (75, 79))	('basal', 'MPA', (147, 152))	('Msh2-/-)', 'Gene', '17685', (111, 119))	('deficient', 'Var', (80, 89))	('higher', 'PosReg', (125, 131))	('MSH2', 'Gene', (93, 97))	('MEFs', 'CellLine', 'CVCL:9115', (56, 60))	('8-oxoG', 'Chemical', 'MESH:C024829', (177, 183))	('mouse', 'Species', '10090', (30, 35))	('ROS-induced genomic 8-oxoG', 'MPA', (157, 183))
44286	25099886	showed that baseline 8-oxoG levels were higher in DNA extracted from MSH2 and MLH1 deficient cell lines.	('MLH1', 'Gene', (78, 82))	('baseline 8-oxoG levels', 'MPA', (12, 34))	('higher', 'PosReg', (40, 46))	('MSH2', 'Gene', (69, 73))	('8-oxoG', 'Chemical', 'MESH:C024829', (21, 27))	('deficient', 'Var', (83, 92))
44292	25099886	mutS mutant variants were more sensitive to ROS inducing drugs including H2O2 and had increased 8-oxoG accumulation when exposed to oxidative stress, in comparison to wild type mutS.	('H2O2', 'Chemical', 'MESH:D006861', (73, 77))	('increased', 'PosReg', (86, 95))	('more', 'PosReg', (26, 30))	('mutS', 'Gene', (0, 4))	('8-oxoG accumulation', 'MPA', (96, 115))	('variants', 'Var', (12, 20))	('mutant variants', 'Var', (5, 20))	('8-oxoG', 'Chemical', 'MESH:C024829', (96, 102))	('H2O2', 'MPA', (73, 77))	('oxidative stress', 'Phenotype', 'HP:0025464', (132, 148))	('ROS', 'Chemical', 'MESH:D017382', (44, 47))	('sensitive', 'MPA', (31, 40))
44293	25099886	further elucidated the distinct roles of the MMR proteins in oxidative repair by showing that MutSalpha, but not MutSbeta is activated by the presence of a mismatched 8-oxoG lesion.	('MMR', 'biological_process', 'GO:0006298', ('45', '48'))	('mismatched', 'Var', (156, 166))	('presence', 'Var', (142, 150))	('8-oxoG', 'Chemical', 'MESH:C024829', (167, 173))
44303	25099886	In addition to 8-oxoG, thymine glycol and OCDLs, MMR has also been implicated in the removal of 2-hydroxyadenine in the context of frameshifts.	('8-oxoG', 'Chemical', 'MESH:C024829', (15, 21))	('removal of 2-hydroxyadenine', 'MPA', (85, 112))	('2-hydroxyadenine', 'Chemical', 'MESH:C008183', (96, 112))	('OCDLs', 'Chemical', '-', (42, 47))	('thymine glycol', 'Chemical', 'MESH:C029389', (23, 37))	('frameshifts', 'Var', (131, 142))
44307	25099886	analysing MMR and BER contributions to oxidative DNA damage repair, identified increased mutation rates due to G:C-to-T:A tranversions in combined MMR and BER mutants (MSH2/MSH6+ogg1) compared to the single ogg1 mutants.	('increased', 'PosReg', (79, 88))	('ogg1', 'Gene', '854942', (178, 182))	('ogg1', 'Gene', (207, 211))	('MSH6+ogg1', 'Gene', '851671;854942', (173, 182))	('mutants', 'Var', (159, 166))	('ogg1', 'Gene', '854942', (207, 211))	('MSH6+ogg1', 'Gene', (173, 182))	('BER', 'Gene', (155, 158))	('G:C-to-T:A', 'Var', (111, 121))	('MMR', 'Gene', (147, 150))	('ogg1', 'Gene', (178, 182))	('mutation rates', 'MPA', (89, 103))
44314	25099886	examined nine microsatellite sequences in the mtDNA of 45 sporadic CRCs and found that in 44% of these cancers there was an alteration in a polycytidine (C)n tract within the non-coding displacement-loop (D-loop) region and that three of the samples exhibited frameshift mutations within microsatellite tracts in NADH dehydrogenase genes.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('alteration', 'Reg', (124, 134))	('NADH dehydrogenase', 'Gene', (313, 331))	('NADH', 'Chemical', 'MESH:D009243', (313, 317))	('polycytidine', 'Chemical', '-', (140, 152))	('CRC', 'Phenotype', 'HP:0003003', (67, 70))	('mtDNA', 'cellular_component', 'GO:0000262', ('46', '51'))	('exhibited', 'Reg', (250, 259))	('frameshift mutations', 'Var', (260, 280))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
44319	25099886	However, they identified the repair factor Y-box binding protein (YB-1) as required for mitochondrial MMR, such that silencing of YB-1 reduced MMR activity in mitochondrial extracts.	('YB-1', 'Gene', '4904', (66, 70))	('silencing', 'Var', (117, 126))	('MMR activity', 'MPA', (143, 155))	('YB-1', 'Gene', (130, 134))	('MMR', 'biological_process', 'GO:0006298', ('102', '105'))	('reduced', 'NegReg', (135, 142))	('MMR', 'biological_process', 'GO:0006298', ('143', '146'))	('YB-1', 'Gene', '4904', (130, 134))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('YB-1', 'Gene', (66, 70))	('binding', 'molecular_function', 'GO:0005488', ('49', '56'))
44320	25099886	Our data suggest that silencing of POLB is synthetically lethal with MSH2 deficiency due to an increase in nuclear 8-oxoG lesions (Figure 2a).	('MSH2 deficiency', 'Disease', 'MESH:D007153', (69, 84))	('increase', 'PosReg', (95, 103))	('nuclear 8-oxoG lesions', 'MPA', (107, 129))	('POLB', 'Gene', '5423', (35, 39))	('silencing', 'Var', (22, 31))	('MSH2 deficiency', 'Disease', (69, 84))	('POLB', 'Gene', (35, 39))	('8-oxoG', 'Chemical', 'MESH:C024829', (115, 121))
44321	25099886	Whereas, silencing of the mitochondrial DNA polymerase gamma (POLG) is synthetically lethal with MLH1, but not MSH2 deficiency, due to an increase in mitochondrial 8-oxoG lesions (Figure 2b).	('increase', 'PosReg', (138, 146))	('POLG', 'Gene', '5428', (62, 66))	('MSH2 deficiency', 'Disease', (111, 126))	('silencing', 'Var', (9, 18))	('8-oxoG', 'Chemical', 'MESH:C024829', (164, 170))	('MSH2 deficiency', 'Disease', 'MESH:D007153', (111, 126))	('POLG', 'Gene', (62, 66))	('MLH1', 'Gene', (97, 101))	('mitochondrial 8-oxoG lesions', 'MPA', (150, 178))
44323	25099886	Furthermore, we have shown that silencing of PTEN-induced putative kinase (PINK1) is synthetically lethal with MLH1, MSH2 and MSH6 deficiency, due to an increase in both mitochondrial and nuclear 8-oxoG lesions.	('nuclear 8-oxoG lesions', 'MPA', (188, 210))	('PTEN', 'Gene', '5728', (45, 49))	('8-oxoG', 'Chemical', 'MESH:C024829', (196, 202))	('silencing', 'Var', (32, 41))	('increase', 'PosReg', (153, 161))	('MSH2', 'Gene', (117, 121))	('PINK1', 'Gene', '65018', (75, 80))	('MSH6 deficiency', 'Disease', 'MESH:D007153', (126, 141))	('PTEN', 'Gene', (45, 49))	('MLH1', 'Gene', (111, 115))	('PINK1', 'Gene', (75, 80))	('MSH6 deficiency', 'Disease', (126, 141))
44329	25099886	Conversely, it has been suggested that MLH1 deficient, HCT116 cells are less sensitive to H2O2 than their MMR-proficient counterparts (HCT116+Chr3).	('MLH1', 'Gene', (39, 43))	('sensitive', 'MPA', (77, 86))	('deficient', 'Var', (44, 53))	('H2O2', 'Chemical', 'MESH:D006861', (90, 94))	('HCT116', 'CellLine', 'CVCL:0291', (55, 61))	('HCT116', 'CellLine', 'CVCL:0291', (135, 141))	('MMR', 'biological_process', 'GO:0006298', ('106', '109'))	('less', 'NegReg', (72, 76))
44332	25099886	It has recently been shown in a model for oxidative damage-induced tumours that loss of MSH2 significantly increased the formation of epithelial tumours in the small intestine.	('damage-induced tumours', 'Disease', 'MESH:D056486', (52, 74))	('increased', 'PosReg', (107, 116))	('epithelial tumours', 'Disease', (134, 152))	('loss', 'Var', (80, 84))	('tumours', 'Phenotype', 'HP:0002664', (145, 152))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('damage-induced tumours', 'Disease', (52, 74))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('epithelial tumours', 'Disease', 'MESH:D000077216', (134, 152))	('formation', 'biological_process', 'GO:0009058', ('121', '130'))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))	('MSH2', 'Gene', (88, 92))
44335	25099886	Clinically, it would seem logical to use anti-oxidant or ROS scavenging agents in the treatment of cancers since oxidative DNA damage has been shown to induce mutagenesis.	('ROS', 'Chemical', 'MESH:D017382', (57, 60))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('mutagenesis', 'MPA', (159, 170))	('cancers', 'Disease', (99, 106))	('oxidative', 'Var', (113, 122))	('induce', 'Reg', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
44347	25099886	NQO1 levels are known to be elevated in several solid tumours and in these cancers, beta-Lapachone results in excessive ROS formation.	('NQO1', 'molecular_function', 'GO:0003955', ('0', '4'))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('ROS', 'Chemical', 'MESH:D017382', (120, 123))	('excessive', 'PosReg', (110, 119))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('tumours', 'Disease', (54, 61))	('cancers', 'Disease', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('ROS formation', 'biological_process', 'GO:1903409', ('120', '133'))	('beta-Lapachone', 'Chemical', 'MESH:C014638', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('NQO1', 'Gene', (0, 4))	('beta-Lapachone', 'Var', (84, 98))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('elevated', 'PosReg', (28, 36))	('NQO1', 'Gene', '1728', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('ROS formation', 'MPA', (120, 133))
44355	25099886	It has also been shown that cytosine based nucleoside analogs are selectively lethal with MLH1 and MSH2-deficient cell lines due to an increase in ROS levels and elevated oxidative DNA damage leading to apoptosis.	('nucleoside', 'Chemical', 'MESH:D009705', (43, 53))	('DNA', 'cellular_component', 'GO:0005574', ('181', '184'))	('ROS levels', 'MPA', (147, 157))	('elevated', 'PosReg', (162, 170))	('ROS', 'Chemical', 'MESH:D017382', (147, 150))	('increase', 'PosReg', (135, 143))	('cytosine', 'Var', (28, 36))	('apoptosis', 'biological_process', 'GO:0006915', ('203', '212'))	('apoptosis', 'biological_process', 'GO:0097194', ('203', '212'))	('increase in ROS levels', 'Phenotype', 'HP:0025464', (135, 157))	('MSH2-deficient cell lines', 'Disease', 'MESH:C538614', (99, 124))	('MSH2-deficient cell lines', 'Disease', (99, 124))	('cytosine', 'Chemical', 'MESH:D003596', (28, 36))	('oxidative DNA damage', 'MPA', (171, 191))	('MLH1', 'Gene', (90, 94))
44360	25099886	Although ROS can cause oxidative DNA damage, it is also involved in the regulation of molecules involved in tumour biology and therefore could play a role in inhibiting carcinogenesis.	('tumour', 'Disease', (108, 114))	('regulation of molecules', 'MPA', (72, 95))	('carcinogenesis', 'Disease', (169, 183))	('inhibiting', 'NegReg', (158, 168))	('ROS', 'Var', (9, 12))	('cause', 'Reg', (17, 22))	('play', 'Reg', (143, 147))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('ROS', 'Chemical', 'MESH:D017382', (9, 12))	('involved', 'Reg', (56, 64))	('oxidative DNA damage', 'MPA', (23, 43))	('carcinogenesis', 'Disease', 'MESH:D063646', (169, 183))	('tumour', 'Disease', 'MESH:D009369', (108, 114))
44363	25099886	Additionally, ROS can deregulate cell cycle progression, thereby interfering with cell-cycle targeted drugs.	('interfering', 'NegReg', (65, 76))	('ROS', 'Var', (14, 17))	('cell cycle', 'biological_process', 'GO:0007049', ('33', '43'))	('cell-cycle', 'biological_process', 'GO:0007049', ('82', '92'))	('ROS', 'Chemical', 'MESH:D017382', (14, 17))	('cell cycle progression', 'CPA', (33, 55))	('deregulate', 'Reg', (22, 32))
44373	32868877	To test whether loss of TMPRSS13 impacts tumor progression, TMPRSS13 was genetically ablated in the oncogene-induced transgenic MMTV-PymT tumor model.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('impacts tumor', 'Disease', 'MESH:D014095', (33, 46))	('impacts tumor', 'Disease', (33, 46))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', (41, 46))	('MMTV', 'Species', '11757', (128, 132))	('TMPRSS13', 'Gene', (60, 68))	('loss', 'Var', (16, 20))	('TMPRSS13', 'Gene', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
44374	32868877	TMPRSS13 deficiency resulted in a significant decrease in overall tumor burden and growth rate, as well as a delayed formation of detectable mammary tumors, thus suggesting a causal relationship between TMPRSS13 expression and the progression of breast cancer.	('breast cancer', 'Disease', (246, 259))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (66, 71))	('growth rate', 'CPA', (83, 94))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (149, 155))	('TMPRSS13', 'Gene', (203, 211))	('tumor', 'Disease', (149, 154))	('TMPRSS13', 'Gene', (0, 8))	('deficiency', 'Var', (9, 19))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('breast cancer', 'Disease', 'MESH:D001943', (246, 259))	('decrease', 'NegReg', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
44375	32868877	Complementary studies using human breast cancer cell culture models revealed that siRNA-mediated silencing of TMPRSS13 expression decreases proliferation, induces apoptosis, and attenuates invasion.	('apoptosis', 'CPA', (163, 172))	('proliferation', 'CPA', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('attenuates', 'NegReg', (178, 188))	('silencing', 'Var', (97, 106))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('human', 'Species', '9606', (28, 33))	('breast cancer', 'Disease', (34, 47))	('induces', 'Reg', (155, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('invasion', 'CPA', (189, 197))	('decreases', 'NegReg', (130, 139))	('TMPRSS13', 'Gene', (110, 118))
44376	32868877	Importantly, targeting TMPRSS13 expression renders aggressive triple-negative breast cancer cell lines highly responsive to chemotherapy.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('TMPRSS13', 'Gene', (23, 31))	('targeting', 'Var', (13, 22))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
44377	32868877	At the molecular level, knockdown of TMPRSS13 in breast cancer cells led to increased protein levels of the tumor-suppressive protease prostasin.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('increased', 'PosReg', (76, 85))	('TMPRSS13', 'Gene', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Disease', (108, 113))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('knockdown', 'Var', (24, 33))	('protein levels of the', 'MPA', (86, 107))
44392	32868877	We demonstrate here that TMPRSS13 expression is increased in breast cancer, and that genetic ablation of TMPRSS13 in mice causes decreased proliferation and increased apoptosis in tumor cells leading to abated cancer progression.	('ablation', 'Var', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('expression', 'MPA', (34, 44))	('TMPRSS13', 'Gene', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('mice', 'Species', '10090', (117, 121))	('TMPRSS13', 'Gene', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('breast cancer', 'Disease', (61, 74))	('proliferation', 'CPA', (139, 152))	('apoptosis', 'biological_process', 'GO:0097194', ('167', '176'))	('apoptosis', 'biological_process', 'GO:0006915', ('167', '176'))	('abated', 'NegReg', (203, 209))	('increased', 'PosReg', (48, 57))	('apoptosis', 'CPA', (167, 176))	('tumor', 'Disease', (180, 185))	('increased', 'PosReg', (157, 166))	('cancer', 'Disease', (68, 74))	('decreased', 'NegReg', (129, 138))	('cancer', 'Disease', (210, 216))
44393	32868877	TMPRSS13 silencing in human breast cancer cell lines impairs cell survival and invasion, increases apoptosis, and reduces resistance to chemotherapy.	('impairs', 'NegReg', (53, 60))	('human', 'Species', '9606', (22, 27))	('silencing', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('apoptosis', 'CPA', (99, 108))	('reduces', 'NegReg', (114, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('breast cancer', 'Disease', (28, 41))	('resistance to chemotherapy', 'CPA', (122, 148))	('TMPRSS13', 'Gene', (0, 8))	('invasion', 'CPA', (79, 87))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('cell survival', 'CPA', (61, 74))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('increases', 'PosReg', (89, 98))
44394	32868877	Mechanistically, loss of TMPRSS13 leads to increased protein levels of prostasin, and we demonstrate that elevated prostasin impairs cell survival and invasion in human breast cancer cells.	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('breast cancer', 'Disease', (169, 182))	('invasion', 'CPA', (151, 159))	('human', 'Species', '9606', (163, 168))	('TMPRSS13', 'Gene', (25, 33))	('increased', 'PosReg', (43, 52))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('impairs', 'NegReg', (125, 132))	('cell survival', 'CPA', (133, 146))	('protein levels of prostasin', 'MPA', (53, 80))	('loss', 'Var', (17, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
44398	32868877	Gene expression data from a cohort of breast cancer patients indicated that high expression of TMPRSS13 is a significant prognostic factor for poor overall survival (Fig.	('overall survival', 'MPA', (148, 164))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('TMPRSS13', 'Gene', (95, 103))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('breast cancer', 'Disease', (38, 51))	('poor', 'NegReg', (143, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('high', 'Var', (76, 80))	('patients', 'Species', '9606', (52, 60))
44413	32868877	Whole-mount mammary glands and lungs from heterozygous TMPRSS13+/- mice with or without the MMTV-PymT transgene were examined and TMPRSS13 was detected in mammary carcinomas (Fig.	('TMPRSS13', 'Var', (130, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('carcinomas', 'Disease', 'MESH:D009369', (163, 173))	('carcinomas', 'Phenotype', 'HP:0030731', (163, 173))	('MMTV', 'Species', '11757', (92, 96))	('carcinomas', 'Disease', (163, 173))	('mice', 'Species', '10090', (67, 71))
44421	32868877	TMPRSS13 deficiency affected all tumorigenic parameters measured (Fig.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('affected', 'Reg', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('TMPRSS13', 'Gene', (0, 8))	('deficiency', 'Var', (9, 19))	('tumor', 'Disease', (33, 38))
44422	32868877	Genetic ablation of TMPRSS13 resulted in a significant delay in the formation of palpable mammary tumors in TMPRSS13-deficient mice (Fig.	('mice', 'Species', '10090', (127, 131))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('delay', 'NegReg', (55, 60))	('TMPRSS13', 'Gene', (20, 28))	('Genetic ablation', 'Var', (0, 16))
44423	32868877	Moreover, a significant decrease in the overall final tumor burden was observed in TMPRSS13-deficient mice compared to control, with a 52% overall reduction in the final tumor burden in TMPRSS13-/-/MMTV-PymT mice (median tumor burden of TMPRSS13+/MMTV-PymT, 3.03 g, TMPRSS13-/-/MMTV-PymT, 1.46 g) (Fig.	('MMTV', 'Species', '11757', (278, 282))	('mice', 'Species', '10090', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('TMPRSS13-/-/MMTV-PymT', 'Var', (186, 207))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('MMTV', 'Species', '11757', (247, 251))	('tumor', 'Disease', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('reduction', 'NegReg', (147, 156))	('decrease', 'NegReg', (24, 32))	('tumor', 'Disease', (170, 175))	('MMTV', 'Species', '11757', (198, 202))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('mice', 'Species', '10090', (208, 212))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
44427	32868877	TMPRSS13 deficiency results in a decreased final tumor burden and tumor growth rate in vivo.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', (49, 54))	('TMPRSS13', 'Gene', (0, 8))	('deficiency', 'Var', (9, 19))	('decreased', 'NegReg', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
44428	32868877	To determine whether the decreased tumor growth in TMPRSS13-/- mice was due to decreased proliferative abilities and/or increased programmed cell death rates, tumor tissues were stained for BrdU incorporation as a measure of cells in S-phase (Fig.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('decreased tumor', 'Disease', (25, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('decreased', 'NegReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('decreased tumor', 'Disease', 'MESH:D002303', (25, 40))	('proliferative abilities', 'CPA', (89, 112))	('tumor', 'Disease', (35, 40))	('mice', 'Species', '10090', (63, 67))	('tumor', 'Disease', (159, 164))	('TMPRSS13-/-', 'Var', (51, 62))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('BrdU', 'MPA', (190, 194))
44431	32868877	Tumors in TMPRSS13-/- mice also displayed a marked increase in apoptotic cell death compared to control littermate mice, with a six-fold increase in the number of apoptotic cells in TMPRSS13-/- mice (Fig.	('increase', 'PosReg', (51, 59))	('TMPRSS13-/-', 'Var', (182, 193))	('Tumors', 'Disease', (0, 6))	('TMPRSS13-/-', 'Var', (10, 21))	('increase', 'PosReg', (137, 145))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('apoptotic cell death', 'CPA', (63, 83))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mice', 'Species', '10090', (115, 119))	('mice', 'Species', '10090', (194, 198))	('mice', 'Species', '10090', (22, 26))
44432	32868877	To test whether loss of TMPRSS13 affects cancer cell proliferation/survival in human breast cancer cells, TMPRSS13 expression was silenced in three separate breast cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('loss', 'Var', (16, 20))	('TMPRSS13', 'Gene', (106, 114))	('cancer', 'Disease', (41, 47))	('cell proliferation', 'biological_process', 'GO:0008283', ('48', '66'))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('human', 'Species', '9606', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', (157, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('TMPRSS13', 'Gene', (24, 32))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('cancer', 'Disease', (92, 98))	('breast cancer', 'Disease', (85, 98))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('affects', 'Reg', (33, 40))
44436	32868877	BT-20 and HCC1937 are both highly invasive, triple-negative (ER-, PR-, HER2-) cell lines (TNBC) of the basal subtype, and HCC1937 cells carry mutated BRCA1.	('BRCA1', 'Gene', (150, 155))	('ER', 'Gene', '2069', (61, 63))	('HER2', 'Gene', (71, 75))	('mutated', 'Var', (142, 149))	('HER2', 'Gene', '2064', (71, 75))	('HCC1937', 'CellLine', 'CVCL:0290', (122, 129))	('HCC1937', 'CellLine', 'CVCL:0290', (10, 17))	('BRCA1', 'Gene', '672', (150, 155))	('ER', 'Gene', '2069', (72, 74))	('carry', 'Reg', (136, 141))	('PR', 'Gene', '140738', (66, 68))
44438	32868877	MCF-7 cells displayed a decrease in cell numbers at day 3 after TMPRSS13 silencing, indicative of cell death.	('silencing', 'Var', (73, 82))	('MCF-7', 'CellLine', 'CVCL:0031', (0, 5))	('TMPRSS13', 'Gene', (64, 72))	('decrease', 'NegReg', (24, 32))	('cell numbers', 'CPA', (36, 48))
44446	32868877	These data, together with the mouse tumor data above, demonstrate that loss of TMPRSS13 expression reduces proliferation and increases apoptotic cell death in breast cancer.	('apoptotic cell death', 'CPA', (135, 155))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('135', '155'))	('mouse', 'Species', '10090', (30, 35))	('proliferation', 'CPA', (107, 120))	('increases', 'PosReg', (125, 134))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('reduces', 'NegReg', (99, 106))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('TMPRSS13', 'Gene', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Disease', (159, 172))	('loss', 'Var', (71, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('tumor', 'Disease', (36, 41))
44450	32868877	Upon silencing of TMPRSS13 using two non-overlapping synthetic RNA duplexes, a significant decrease in invasive potential was observed in TNBC cells.	('RNA', 'cellular_component', 'GO:0005562', ('63', '66'))	('silencing', 'Var', (5, 14))	('invasive potential', 'CPA', (103, 121))	('TMPRSS13', 'Gene', (18, 26))	('synthetic RNA', 'Species', '2086595', (53, 66))	('decrease', 'NegReg', (91, 99))
44451	32868877	These data suggest that loss of TMPRSS13 impairs breast cancer cell invasion.	('loss', 'Var', (24, 28))	('TMPRSS13', 'Gene', (32, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('impairs breast cancer', 'Disease', 'MESH:D001943', (41, 62))	('impairs breast cancer', 'Disease', (41, 62))
44457	32868877	Interestingly, transient knockdown of TMPRSS13 led to a simultaneous increase in both prostasin and zonula occludens-1 (ZO-1), a tight junction protein lost during EMT (Supplementary Fig.	('increase', 'PosReg', (69, 77))	('prostasin', 'MPA', (86, 95))	('ZO-1', 'Gene', (120, 124))	('zonula occludens-1', 'Gene', (100, 118))	('ZO-1', 'Gene', '7082', (120, 124))	('TMPRSS13', 'Gene', (38, 46))	('zonula occludens-1', 'Gene', '7082', (100, 118))	('knockdown', 'Var', (25, 34))
44459	32868877	6c), confirming that prostasin expression suppresses the aggressive/invasive phenotype in breast cancer cells.	('aggressive/invasive phenotype in', 'CPA', (57, 89))	('prostasin', 'Protein', (21, 30))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('suppresses', 'NegReg', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('expression', 'Var', (31, 41))
44462	32868877	Prostasin is a ~40-kDa inactive trypsin-like serine protease zymogen that is activated by a single proteolytic cleavage after Arg12.	('serine protease', 'Gene', '2147', (45, 60))	('Arg12', 'Var', (126, 131))	('serine protease', 'Gene', (45, 60))	('Arg12', 'Chemical', '-', (126, 131))
44465	32868877	This mobility change required catalytically competent TMPRSS13, since no change was observed when prostasin was co-expressed with a catalytically dead (CD) form of TMPRSS13 (S506A mutation in catalytic triad, CD-TMPRSS13-V5; Supplementary Fig.	('S506A', 'Mutation', 'p.S506A', (174, 179))	('S506A', 'Var', (174, 179))	('TMPRSS13-V5', 'Gene', '84000', (212, 223))	('TMPRSS13-V5', 'Gene', (212, 223))	('triad', 'cellular_component', 'GO:0030315', ('202', '207'))
44475	32868877	In addition, expression of the uncleavable, ZL-prostasin mutant control co-transfected with WT-TMPRSS13 showed no prostasin/PN-1 complex formation (Fig.	('formation', 'biological_process', 'GO:0009058', ('137', '146'))	('mutant', 'Var', (57, 63))	('PN-1', 'Gene', (124, 128))	('PN-1', 'Gene', '5270', (124, 128))
44481	32868877	The effects of silencing TMPRSS13 alone, drug treatment alone, or combination in HCC1937 and BT-20 TNBC cell lines were assessed by measuring cell viability (Fig.	('silencing', 'Var', (15, 24))	('TMPRSS13', 'Gene', (25, 33))	('HCC1937', 'CellLine', 'CVCL:0290', (81, 88))
44483	32868877	HCC1937 cells showed significantly increased sensitivity to paclitaxel upon TMPRSS13 silencing as compared to either treatment alone (Fig.	('increased', 'PosReg', (35, 44))	('HCC1937', 'CellLine', 'CVCL:0290', (0, 7))	('sensitivity to paclitaxel', 'MPA', (45, 70))	('paclitaxel', 'Chemical', 'MESH:D017239', (60, 70))	('silencing', 'Var', (85, 94))	('TMPRSS13', 'Gene', (76, 84))
44487	32868877	Silencing TMPRSS13 results in increased expression of the tumor suppressor prostasin (Fig.	('expression', 'MPA', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('increased', 'PosReg', (30, 39))	('TMPRSS13', 'Gene', (10, 18))	('Silencing', 'Var', (0, 9))	('tumor suppressor', 'biological_process', 'GO:0051726', ('58', '74'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('58', '74'))
44492	32868877	To further analyze whether TMPRSS13 and prostasin are mechanistically linked in breast cancer, we performed double-silencing of TMPRSS13 and prostasin compared to single silencing of either TMPRSS13 or prostasin alone, and control cells were transfected with scrambled siRNA.	('double-silencing', 'Var', (108, 124))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('TMPRSS13', 'Gene', (128, 136))
44493	32868877	Silencing TMPRSS13 led to an increase in cleaved PARP protein as expected when assessed by western blot analysis.	('PARP', 'Gene', '142', (49, 53))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('increase', 'PosReg', (29, 37))	('cleaved', 'MPA', (41, 48))	('PARP', 'Gene', (49, 53))	('TMPRSS13', 'Gene', (10, 18))	('Silencing', 'Var', (0, 9))
44494	32868877	Silencing of prostasin led to reduced PARP cleavage both when cells received no chemotherapy and when treated with paclitaxel (Supplementary Fig.	('prostasin', 'Protein', (13, 22))	('paclitaxel', 'Chemical', 'MESH:D017239', (115, 125))	('PARP', 'Gene', (38, 42))	('reduced', 'NegReg', (30, 37))	('PARP', 'Gene', '142', (38, 42))	('Silencing', 'Var', (0, 9))
44496	32868877	Taken together, these experiments indicate that loss of TMPRSS13 expression decreases TNBC viability and increases chemosensitivity and that TMPRSS13-mediated regulation of prostasin protein levels may contribute to these effects.	('regulation', 'MPA', (159, 169))	('protein', 'cellular_component', 'GO:0003675', ('183', '190'))	('loss', 'Var', (48, 52))	('regulation', 'biological_process', 'GO:0065007', ('159', '169'))	('chemosensitivity', 'CPA', (115, 131))	('decreases TNBC viability', 'Disease', (76, 100))	('prostasin protein levels', 'MPA', (173, 197))	('decreases TNBC viability', 'Disease', 'MESH:D002303', (76, 100))	('TMPRSS13', 'Gene', (56, 64))	('increases', 'PosReg', (105, 114))
44498	32868877	At the cellular level, loss of TMPRSS13 decreased proliferation and increased apoptotic cell death both in mouse mammary tumors and in human breast cancer cell culture models, and silencing of TMPRSS13 in TNBC cells led to increased sensitivity to chemotherapy.	('TMPRSS13', 'Gene', (193, 201))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('loss', 'Var', (23, 27))	('silencing', 'Var', (180, 189))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('human', 'Species', '9606', (135, 140))	('breast cancer', 'Disease', (141, 154))	('TMPRSS13', 'Gene', (31, 39))	('decreased', 'NegReg', (40, 49))	('increased', 'PosReg', (68, 77))	('mouse', 'Species', '10090', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('proliferation', 'CPA', (50, 63))	('increased', 'PosReg', (223, 232))	('apoptotic cell death', 'CPA', (78, 98))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('sensitivity to chemotherapy', 'MPA', (233, 260))	('tumors', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))
44499	32868877	Furthermore, a reduced incidence of lung metastasis was observed in TMPRSS13-/- mice compared to control mice, and decreased invasion potential was observed upon TMPRSS13 silencing in human TNBC cells.	('TMPRSS13', 'Gene', (162, 170))	('lung metastasis', 'CPA', (36, 51))	('decreased', 'NegReg', (115, 124))	('invasion potential', 'CPA', (125, 143))	('TMPRSS13-/-', 'Gene', (68, 79))	('reduced', 'NegReg', (15, 22))	('mice', 'Species', '10090', (80, 84))	('silencing', 'Var', (171, 180))	('human', 'Species', '9606', (184, 189))	('mice', 'Species', '10090', (105, 109))
44504	32868877	The mechanisms by which TMPRSS13 silencing in TNBC cells decreases protein levels of Bcl-xL awaits further study.	('Bcl-xL', 'Gene', (85, 91))	('silencing', 'Var', (33, 42))	('TMPRSS13', 'Gene', (24, 32))	('decreases', 'NegReg', (57, 66))	('Bcl-xL', 'Gene', '598', (85, 91))
44509	32868877	Conversely, mice with conditional deletion of prostasin in the colon displayed enhanced colorectal carcinogenesis and metastasis accompanied by increased intestinal cell proliferation and invasion and decreased cell differentiation.	('colon', 'Disease', 'MESH:D003110', (63, 68))	('metastasis', 'CPA', (118, 128))	('colorectal carcinogenesis', 'Disease', (88, 113))	('invasion', 'CPA', (188, 196))	('decreased', 'NegReg', (201, 210))	('colon', 'Disease', (63, 68))	('cell differentiation', 'CPA', (211, 231))	('enhanced', 'PosReg', (79, 87))	('colorectal carcinogenesis', 'Disease', 'MESH:D015179', (88, 113))	('intestinal cell proliferation', 'CPA', (154, 183))	('deletion', 'Var', (34, 42))	('mice', 'Species', '10090', (12, 16))	('prostasin', 'Gene', (46, 55))	('increased', 'PosReg', (144, 153))
44510	32868877	In TNBC cells, we observed that forced overexpression of prostasin alone led to decreased cell viability both with and without chemotherapy treatment and silencing of prostasin enhanced their invasive potential, further supporting a tumor-suppressive role for prostasin in breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('overexpression', 'PosReg', (39, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('prostasin', 'Gene', (167, 176))	('invasive potential', 'CPA', (192, 210))	('tumor', 'Disease', (233, 238))	('cell viability', 'CPA', (90, 104))	('decreased', 'NegReg', (80, 89))	('silencing', 'Var', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('enhanced', 'PosReg', (177, 185))	('breast cancer', 'Disease', (273, 286))
44513	32868877	Increased prostasin levels observed upon TMPRSS13 silencing may lead to enhanced suppression of these pathways causing a decreased EMT phenotype and increased chemosensitivity in breast cancer.	('prostasin levels', 'MPA', (10, 26))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('increased', 'PosReg', (149, 158))	('chemosensitivity', 'CPA', (159, 175))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('silencing', 'Var', (50, 59))	('breast cancer', 'Disease', (179, 192))	('decreased', 'NegReg', (121, 130))	('EMT phenotype', 'CPA', (131, 144))	('enhanced', 'PosReg', (72, 80))	('TMPRSS13', 'Gene', (41, 49))	('Increased', 'PosReg', (0, 9))	('suppression', 'NegReg', (81, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('decreased EMT', 'Phenotype', 'HP:0032198', (121, 134))	('these pathways', 'Pathway', (96, 110))
44514	32868877	In support of this, we observed an increase in the epithelial marker ZO-1 and decreased invasive potential upon TMPRSS13 knockdown in TNBC.	('knockdown', 'Var', (121, 130))	('ZO-1', 'Gene', '7082', (69, 73))	('increase', 'PosReg', (35, 43))	('TNBC', 'Gene', (134, 138))	('TMPRSS13', 'Gene', (112, 120))	('decreased', 'NegReg', (78, 87))	('invasive potential', 'CPA', (88, 106))	('ZO-1', 'Gene', (69, 73))
44522	32868877	Since prostasin is capable of mediating molecular functions in cultured cancer cell models and in vivo independent of its catalytic activity, it is possible that cleavage-activation of prostasin, under some conditions, represents a mechanism to regulate prostasin functions via regulation of its total protein levels.	('cancer', 'Disease', (72, 78))	('total protein levels', 'MPA', (296, 316))	('regulate', 'Reg', (245, 253))	('regulation', 'Reg', (278, 288))	('prostasin', 'Gene', (185, 194))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('prostasin functions', 'MPA', (254, 273))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cleavage-activation', 'Var', (162, 181))
44523	32868877	Examples of prostasin having catalytic activity-independent functions in cancer include the findings that the expression of the tumor promoters urokinase-type plasminogen activator (uPA), the uPA receptor (uPAR), cyclooxygenase-2 (COX-2), and the inducible nitric oxide synthase (iNOS) were decreased by both the WT and the active-site mutant prostasin in prostate cancer cells.	('uPA receptor', 'Gene', '5329', (192, 204))	('prostasin', 'Gene', (343, 352))	('inducible nitric oxide synthase', 'Gene', (247, 278))	('COX-2', 'Gene', '5743', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('uPAR', 'Gene', (206, 210))	('uPA', 'Gene', '5328', (182, 185))	('uPA', 'Gene', (182, 185))	('uPA', 'Gene', (206, 209))	('uPA', 'Gene', '5328', (206, 209))	('cyclooxygenase-2', 'Gene', '5743', (213, 229))	('cancer', 'Disease', (365, 371))	('cancer', 'Disease', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('urokinase-type plasminogen activator', 'Gene', (144, 180))	('cyclooxygenase-2', 'Gene', (213, 229))	('uPAR', 'Gene', '5329', (206, 210))	('uPA receptor', 'Gene', (192, 204))	('urokinase-type plasminogen activator', 'Gene', '5328', (144, 180))	('iNOS', 'Gene', (280, 284))	('expression', 'MPA', (110, 120))	('tumor', 'Disease', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (365, 371))	('decreased', 'NegReg', (291, 300))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('COX-2', 'Gene', (231, 236))	('prostate cancer', 'Disease', 'MESH:D011471', (356, 371))	('prostate cancer', 'Phenotype', 'HP:0012125', (356, 371))	('inducible nitric oxide synthase', 'Gene', '4843', (247, 278))	('uPA', 'Gene', (192, 195))	('iNOS', 'Gene', '4843', (280, 284))	('active-site mutant', 'Var', (324, 342))	('uPA', 'Gene', '5328', (192, 195))	('prostate cancer', 'Disease', (356, 371))
44524	32868877	Interestingly, the epithelial differentiation protein, E-cadherin, was increased selectively by the activesite mutant prostasin.	('E-cadherin', 'Gene', (55, 65))	('E-cadherin', 'Gene', '999', (55, 65))	('mutant', 'Var', (111, 117))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('cadherin', 'molecular_function', 'GO:0008014', ('57', '65'))	('epithelial differentiation', 'CPA', (19, 45))	('increased', 'PosReg', (71, 80))	('prostasin', 'Gene', (118, 127))
44527	32868877	While TMPRSS13 has been reported to activate pro-HGF in a cell-free system, we did not observe any changes in activation of the HGF-receptor c-MET or the downstream targets AKT and Gab1 upon TMPRSS13 silencing in human breast cancer cell lines (C. Martin and K. List, unpublished data).	('AKT', 'Gene', '207', (173, 176))	('human', 'Species', '9606', (213, 218))	('TMPRSS13', 'Gene', (191, 199))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('silencing', 'Var', (200, 209))	('HGF', 'Gene', (49, 52))	('AKT', 'Gene', (173, 176))	('breast cancer', 'Disease', (219, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('TMPRSS13', 'Gene', (6, 14))	('HGF', 'Gene', (128, 131))	('HGF', 'Gene', '3082', (49, 52))	('HGF', 'Gene', '3082', (128, 131))	('Gab1', 'Gene', '2549', (181, 185))	('Gab1', 'Gene', (181, 185))
44530	32868877	However, a recent whole-exome sequencing study identified somatic mutations in TMPRSS13 in renal cancer patients and found that these mutations might be predictive of programmed death-ligand 1 (PD-L1) positive expression in cells of this tumor type.	('mutations', 'Var', (66, 75))	('PD-L1', 'Gene', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('renal cancer', 'Phenotype', 'HP:0009726', (91, 103))	('ligand', 'molecular_function', 'GO:0005488', ('184', '190'))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('PD-L1', 'Gene', '29126', (194, 199))	('expression', 'MPA', (210, 220))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', (238, 243))	('renal cancer', 'Disease', (91, 103))	('TMPRSS13', 'Gene', (79, 87))	('mutations', 'Var', (134, 143))	('positive', 'PosReg', (201, 209))	('programmed death-ligand 1', 'Gene', (167, 192))	('programmed death-ligand 1', 'Gene', '29126', (167, 192))	('patients', 'Species', '9606', (104, 112))	('renal cancer', 'Disease', 'MESH:D007680', (91, 103))
44544	32868877	Full-length human prostasin cDNA was used for the generation of the S238A and R44Q mutants as previously described.	('R44Q', 'Var', (78, 82))	('S238A', 'Mutation', 'p.S238A', (68, 73))	('S238A', 'Var', (68, 73))	('human', 'Species', '9606', (12, 17))	('R44Q', 'Mutation', 'p.R44Q', (78, 82))
44548	32868877	Chemotherapy drugs were paclitaxel (T7402 - Sigma-Aldrich, St. Louis, MO) and carboplatin (C2538, Sigma-Aldrich St. Louis, MO).	('C2538', 'Var', (91, 96))	('carboplatin', 'Chemical', 'MESH:D016190', (78, 89))	('paclitaxel', 'Chemical', 'MESH:D017239', (24, 34))	('T7402 - Sigma-Aldrich', 'Var', (36, 57))
44610	33922197	HNPCC is an autosomal dominant disease caused by mutations in genes known as mismatch repair errors.	('mutations', 'Var', (49, 58))	('caused by', 'Reg', (39, 48))	('autosomal dominant disease', 'Disease', (12, 38))	('HNPCC', 'Phenotype', 'HP:0006716', (0, 5))	('HNPCC', 'Disease', 'None', (0, 5))	('autosomal dominant disease', 'Disease', 'MESH:D030342', (12, 38))	('HNPCC', 'Disease', (0, 5))
44611	33922197	Most cases of HNPCC are associated with mutations in MLH1 and MSH2 genes.	('HNPCC', 'Disease', 'None', (14, 19))	('MLH1', 'Gene', (53, 57))	('HNPCC', 'Disease', (14, 19))	('associated', 'Reg', (24, 34))	('MLH1', 'Gene', '4292', (53, 57))	('MSH2', 'Gene', (62, 66))	('mutations', 'Var', (40, 49))	('MSH2', 'Gene', '4436', (62, 66))	('HNPCC', 'Phenotype', 'HP:0006716', (14, 19))
44612	33922197	However, there are several other genes mutations in which give rise to HNPCC (e.g., MSH6, MLH3, TGBR2, PMS1 and PMS2).	('MSH6', 'Gene', '2956', (84, 88))	('PMS2', 'Gene', '5395', (112, 116))	('PMS1', 'Gene', (103, 107))	('PMS1', 'Gene', '5378', (103, 107))	('PMS2', 'Gene', (112, 116))	('mutations', 'Var', (39, 48))	('MSH6', 'Gene', (84, 88))	('HNPCC', 'Disease', 'None', (71, 76))	('HNPCC', 'Phenotype', 'HP:0006716', (71, 76))	('HNPCC', 'Disease', (71, 76))	('MLH3', 'Gene', '27030', (90, 94))	('MLH3', 'Gene', (90, 94))	('TGBR2', 'Gene', (96, 101))	('give rise', 'Reg', (58, 67))
44615	33922197	It is caused by adenomatous polyposis coli (APC) gene defects.	('APC', 'Phenotype', 'HP:0005227', (44, 47))	('APC', 'Disease', 'MESH:D011125', (44, 47))	('APC', 'Disease', (44, 47))	('adenomatous polyposis coli', 'Gene', '324', (16, 42))	('gene defects', 'Var', (49, 61))	('adenomatous polyposis coli', 'Gene', (16, 42))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (16, 42))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (16, 37))	('caused by', 'Reg', (6, 15))
44655	33922197	HACs and PAHs are considered genotoxic substances that have the potential to cause point mutations (deletions, insertions and substitutions) and, in consequence, initiate the process of carcinogenesis.	('HACs', 'Chemical', '-', (0, 4))	('cause', 'Reg', (77, 82))	('initiate', 'Reg', (162, 170))	('insertions', 'Var', (111, 121))	('PAHs', 'Chemical', 'MESH:D011084', (9, 13))	('carcinogenesis', 'Disease', 'MESH:D063646', (186, 200))	('substitutions', 'Var', (126, 139))	('point', 'Disease', (83, 88))	('carcinogenesis', 'Disease', (186, 200))
44659	33922197	It was demonstrated that heme increases oxidative stress and induce lipid peroxidation of intestinal cells.	('lipid', 'Chemical', 'MESH:D008055', (68, 73))	('heme', 'Var', (25, 29))	('oxidative stress', 'MPA', (40, 56))	('heme', 'Chemical', 'MESH:D006418', (25, 29))	('lipid peroxidation', 'MPA', (68, 86))	('induce', 'Reg', (61, 67))	('increases', 'PosReg', (30, 39))	('oxidative stress', 'Phenotype', 'HP:0025464', (40, 56))
44678	33922197	The roles of vitamin D and calcium are closely related since the primary function of vitamin D is the maintenance of calcium homeostasis by enhancing its intestinal absorption.	('calcium', 'Chemical', 'MESH:D002118', (117, 124))	('vitamin D', 'Chemical', 'MESH:D014807', (13, 22))	('enhancing', 'PosReg', (140, 149))	('intestinal absorption', 'MPA', (154, 175))	('calcium homeostasis', 'MPA', (117, 136))	('vitamin', 'Var', (85, 92))	('calcium', 'Chemical', 'MESH:D002118', (27, 34))	('vitamin D', 'Chemical', 'MESH:D014807', (85, 94))
44700	33922197	Mutations in colorectal epithelial cells may lead to polyposis development, which, in turn, may transit into invasive adenocarcinoma.	('transit', 'Reg', (96, 103))	('men', 'Species', '9606', (70, 73))	('lead to', 'Reg', (45, 52))	('Mutations', 'Var', (0, 9))	('polyposis', 'Disease', 'MESH:D044483', (53, 62))	('invasive adenocarcinoma', 'Disease', (109, 132))	('polyposis', 'Disease', (53, 62))	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (109, 132))
44705	33922197	They include the production of reactive oxygen species and nitrogen species (during the oxidative metabolism of ethanol), production of mutagenic acetaldehyde (the first metabolite of ethanol), depletion of S-adenosylmethionine (epigenetic alternations), inactivation of the tumor suppressor genes, hormonal imbalance, reduction in folate concentration and impairment of retinoic acid metabolism.	('hormonal', 'Disease', (299, 307))	('folate', 'Chemical', 'MESH:D005492', (332, 338))	('tumor', 'Disease', (275, 280))	('ethanol', 'Chemical', 'MESH:D000431', (184, 191))	('production', 'MPA', (17, 27))	('depletion of S-adenosylmethionine', 'MPA', (194, 227))	('ethanol', 'Chemical', 'MESH:D000431', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('imbalance', 'Phenotype', 'HP:0002172', (308, 317))	('acetaldehyde', 'Chemical', 'MESH:D000079', (146, 158))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (31, 54))	('age', 'Gene', (139, 142))	('impairment of retinoic acid metabolism', 'Disease', 'MESH:D000592', (357, 395))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('inactivation', 'Var', (255, 267))	('reduction', 'NegReg', (319, 328))	('S-adenosylmethionine', 'Chemical', 'MESH:D012436', (207, 227))	('folate concentration', 'MPA', (332, 352))	('age', 'Gene', '5973', (139, 142))	('impairment of retinoic acid metabolism', 'Disease', (357, 395))	('nitrogen', 'Chemical', 'MESH:D009584', (59, 67))	('reduction in folate concentration', 'Phenotype', 'HP:0100507', (319, 352))
44709	33922197	According to the latest research that explored the microbiome of the individuals with colorectal cancer, alternation in the composition and functionality of the normal gut microbiota may lead to initiation, promotion and progression of this cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('cancer', 'Disease', (97, 103))	('alternation', 'Var', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('colorectal cancer', 'Disease', (86, 103))	('promotion', 'PosReg', (207, 216))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('rectal cancer', 'Phenotype', 'HP:0100743', (90, 103))	('progression', 'CPA', (221, 232))	('lead to', 'Reg', (187, 194))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
44743	33922197	Moreover, the process is driven by the accumulation of mutations and genetic changes and takes 10-15 years, but maybe faster in some conditions, e.g., in patients with Lynch syndrome.	('Lynch syndrome', 'Disease', 'MESH:D003123', (168, 182))	('mutations', 'Var', (55, 64))	('genetic changes', 'Var', (69, 84))	('patients', 'Species', '9606', (154, 162))	('Lynch syndrome', 'Disease', (168, 182))
44749	33922197	HNPCC is associated with pathogenic variants of the MLH1, MSH2, MSH6, PMS2 and EPCAM genes, and is also characterized by an increased risk of CRC, the pathological feature of which is the presence of mucinous adenocarcinoma (lifetime risk at 52-82%, mean age at diagnosis 44-61 years).	('PMS2', 'Gene', (70, 74))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (200, 223))	('MSH2', 'Gene', '4436', (58, 62))	('MLH1', 'Gene', (52, 56))	('mucinous adenocarcinoma', 'Disease', (200, 223))	('HNPCC', 'Disease', 'None', (0, 5))	('HNPCC', 'Disease', (0, 5))	('EPCAM', 'Gene', '4072', (79, 84))	('age', 'Gene', (255, 258))	('PMS2', 'Gene', '5395', (70, 74))	('MLH1', 'Gene', '4292', (52, 56))	('CRC', 'Disease', (142, 145))	('CRC', 'Phenotype', 'HP:0003003', (142, 145))	('MSH2', 'Gene', (58, 62))	('EPCAM', 'Gene', (79, 84))	('HNPCC', 'Phenotype', 'HP:0006716', (0, 5))	('variants', 'Var', (36, 44))	('MSH6', 'Gene', (64, 68))	('age', 'Gene', '5973', (255, 258))	('MSH6', 'Gene', '2956', (64, 68))
44754	33922197	Changes within these genes lead to mutational activation of oncogenes or inactivation of tumor suppressors, which consequently causes malignant transformation.	('mutational', 'Var', (35, 45))	('activation', 'PosReg', (46, 56))	('inactivation', 'NegReg', (73, 85))	('causes', 'Reg', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('Changes', 'Var', (0, 7))	('oncogenes', 'Protein', (60, 69))	('malignant transformation', 'CPA', (134, 158))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
44757	33922197	It is associated with hypermethylation of numerous gene promoters (including MLH1), the V300E mutation in the BRAF gene, and loss of TP53 and p16 functions.	('loss', 'NegReg', (125, 129))	('MLH1', 'Gene', '4292', (77, 81))	('hypermethylation', 'MPA', (22, 38))	('MLH1', 'Gene', (77, 81))	('V300E', 'Var', (88, 93))	('functions', 'MPA', (146, 155))	('p16', 'Gene', '1029', (142, 145))	('BRAF', 'Gene', '673', (110, 114))	('p16', 'Gene', (142, 145))	('V300E', 'Mutation', 'p.V300E', (88, 93))	('TP53', 'Gene', '7157', (133, 137))	('BRAF', 'Gene', (110, 114))	('TP53', 'Gene', (133, 137))
44765	33922197	In 10% of all colorectal cancers, serrated adenocarcinomas develop by replacing adenomatous polyps with serrated polyps on the so-called serrated lesion pathway, showing the presence of the BRAF mutation and epigenetic silencing of various genes, but without APC gene involvement, as is the case in other pathways.	('colorectal cancer', 'Phenotype', 'HP:0003003', (14, 31))	('polyps', 'Disease', 'MESH:D011127', (113, 119))	('mutation', 'Var', (195, 203))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('polyps', 'Disease', (92, 98))	('BRAF', 'Gene', '673', (190, 194))	('adenomatous polyps', 'Disease', 'MESH:D018256', (80, 98))	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('APC', 'cellular_component', 'GO:0005680', ('259', '262'))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('BRAF', 'Gene', (190, 194))	('colorectal cancers', 'Disease', (14, 32))	('APC', 'Phenotype', 'HP:0005227', (259, 262))	('APC', 'Disease', 'MESH:D011125', (259, 262))	('adenocarcinomas', 'Disease', 'MESH:D000230', (43, 58))	('adenocarcinomas', 'Disease', (43, 58))	('APC', 'Disease', (259, 262))	('polyps', 'Disease', 'MESH:D011127', (92, 98))	('serrated lesion', 'Phenotype', 'HP:0032222', (137, 152))	('men', 'Species', '9606', (275, 278))	('polyps', 'Disease', (113, 119))	('serrated polyps', 'Phenotype', 'HP:0032222', (104, 119))	('colorectal cancers', 'Disease', 'MESH:D015179', (14, 32))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (80, 98))	('serrated adenocarcinomas', 'Phenotype', 'HP:0032222', (34, 58))	('adenomatous polyps', 'Disease', (80, 98))	('rectal cancer', 'Phenotype', 'HP:0100743', (18, 31))	('epigenetic silencing', 'Var', (208, 228))
44808	33922197	Additionally, results of deep neural network demonstrated better polyps detection with using narrow-band imaging than white light endoscopy (WLE) (accuracy 95% vs. 74%) and using the two-channel red plus green images than full-color WLE images (74% vs.91%).	('age', 'Gene', (239, 242))	('better', 'PosReg', (58, 64))	('age', 'Gene', (212, 215))	('polyps', 'Disease', (65, 71))	('age', 'Gene', '5973', (239, 242))	('narrow-band', 'Var', (93, 104))	('age', 'Gene', '5973', (212, 215))	('polyps', 'Disease', 'MESH:D011127', (65, 71))
44835	33922197	Mutations in the KRAS and B-RAF genes lead to hence constitutive activation of RAS/RAF proteins despite EGFR activation is blocked, and are considered to be an early event in CRC carcinogenesis with presence in about 20-50% cases.	('CRC', 'Phenotype', 'HP:0003003', (175, 178))	('B-RAF', 'Gene', '673', (26, 31))	('RAF', 'Gene', (28, 31))	('EGFR', 'Gene', (104, 108))	('RAF', 'Gene', '673', (28, 31))	('RAF', 'Gene', (83, 86))	('RAF', 'Gene', '673', (83, 86))	('B-RAF', 'Gene', (26, 31))	('Mutations', 'Var', (0, 9))	('CRC carcinogenesis', 'Disease', (175, 193))	('KRAS', 'Gene', (17, 21))	('CRC carcinogenesis', 'Disease', 'MESH:D015179', (175, 193))	('KRAS', 'Gene', '3845', (17, 21))	('activation', 'PosReg', (65, 75))	('EGFR', 'Gene', '1956', (104, 108))
44836	33922197	Mutation or silencing of MMR genes (such as MSH2, MSH6, PMS2 and MLH1) may cause MSI.	('cause', 'Reg', (75, 80))	('MSH2', 'Gene', (44, 48))	('MSI', 'Disease', (81, 84))	('MSH2', 'Gene', '4436', (44, 48))	('silencing', 'NegReg', (12, 21))	('Mutation', 'Var', (0, 8))	('MMR', 'biological_process', 'GO:0006298', ('25', '28'))	('MSH6', 'Gene', (50, 54))	('MLH1', 'Gene', '4292', (65, 69))	('PMS2', 'Gene', (56, 60))	('MLH1', 'Gene', (65, 69))	('MMR genes', 'Gene', (25, 34))	('PMS2', 'Gene', '5395', (56, 60))	('MSH6', 'Gene', '2956', (50, 54))
44837	33922197	Patients with advanced CRC lacking KRAS or B-RAF mutations will prefer anti-EGFR therapy.	('KRAS', 'Gene', (35, 39))	('mutations', 'Var', (49, 58))	('B-RAF', 'Gene', (43, 48))	('EGFR', 'Gene', '1956', (76, 80))	('CRC', 'Disease', (23, 26))	('KRAS', 'Gene', '3845', (35, 39))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'Gene', (76, 80))	('CRC', 'Phenotype', 'HP:0003003', (23, 26))	('B-RAF', 'Gene', '673', (43, 48))
44838	33922197	In contrast, standard therapy based on 5-fluorouracil (5-FU) will be predisposed by testing for the presence or absence of chromosome deletions 18q and determining the tumor phenotype based on microsatellite instability (MSI) or microsatellite stability (MSS).	('tumor', 'Disease', (168, 173))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (39, 53))	('microsatellite stability', 'MPA', (229, 253))	('testing', 'Reg', (84, 91))	('5-FU', 'Chemical', 'MESH:D005472', (55, 59))	('chromosome deletions 18q', 'Var', (123, 147))	('microsatellite instability', 'MPA', (193, 219))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
44840	33922197	Abnormally methylated genes may affect the function of DNA repair (MGMT), apoptosis (BNIP3, DAPK and PCDH10), cell migration (vimentin and TIMP3), proliferation (CDKN2A, IGF2, MYOD1, RARbeta2, SFRP1 and SFRP2), and differentiation (NDRG4), transcriptional regulation (GATA4 and TFAP2E) and others, and support prediction of clinical outcomes, such as treatment and survival prognosis, metastasis occurrence and therapy-resistant.	('SFRP1', 'Gene', (193, 198))	('function', 'MPA', (43, 51))	('DAPK', 'Gene', (92, 96))	('TIMP3', 'Gene', (139, 144))	('TIMP3', 'Gene', '7078', (139, 144))	('SFRP2', 'Gene', '6423', (203, 208))	('BNIP3', 'Gene', (85, 90))	('DNA repair', 'CPA', (55, 65))	('DNA repair', 'biological_process', 'GO:0006281', ('55', '65'))	('GATA4', 'Gene', '2626', (268, 273))	('MYOD1', 'Gene', '4654', (176, 181))	('DAPK', 'Gene', '1612', (92, 96))	('CDKN2A', 'Gene', (162, 168))	('IGF2', 'Gene', (170, 174))	('men', 'Species', '9606', (128, 131))	('SFRP2', 'Gene', (203, 208))	('SFRP1', 'Gene', '6422', (193, 198))	('MGMT', 'Gene', (67, 71))	('BNIP3', 'Gene', '664', (85, 90))	('PCDH10', 'Gene', (101, 107))	('regulation', 'biological_process', 'GO:0065007', ('256', '266'))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('proliferation', 'CPA', (147, 160))	('PCDH10', 'Gene', '57575', (101, 107))	('apoptosis', 'CPA', (74, 83))	('vimentin', 'cellular_component', 'GO:0045098', ('126', '134'))	('NDRG4', 'Gene', '65009', (232, 237))	('CDKN2A', 'Gene', '1029', (162, 168))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('TFAP2E', 'Gene', '339488', (278, 284))	('vimentin', 'Gene', '7431', (126, 134))	('differentiation', 'CPA', (215, 230))	('MGMT', 'molecular_function', 'GO:0003908', ('67', '71'))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('cell migration', 'biological_process', 'GO:0016477', ('110', '124'))	('men', 'Species', '9606', (356, 359))	('NDRG4', 'Gene', (232, 237))	('metastasis', 'CPA', (385, 395))	('vimentin', 'Gene', (126, 134))	('GATA4', 'Gene', (268, 273))	('IGF2', 'Gene', '3481', (170, 174))	('MYOD1', 'Gene', (176, 181))	('cell migration', 'CPA', (110, 124))	('affect', 'Reg', (32, 38))	('MGMT', 'Gene', '4255', (67, 71))	('Abnormally methylated genes', 'Var', (0, 27))	('vimentin', 'cellular_component', 'GO:0045099', ('126', '134'))	('transcriptional', 'MPA', (240, 255))	('TFAP2E', 'Gene', (278, 284))
44845	33922197	The recent systematic review indicates that epigenetic ctDNA markers are potentially the most promising blood-based assay for CRC detection, and a high sensitivity and specificity screening test ctDNA SEPT9 methylation was approved to use.	('epigenetic', 'Var', (44, 54))	('CRC', 'Phenotype', 'HP:0003003', (126, 129))	('SEPT9', 'Gene', (201, 206))	('SEPT9', 'Gene', '10801', (201, 206))
44847	33922197	Their role in clinical practice can be associated with diagnostic (miR-329, miR-181a, miR-199b, miR-382, miR-215 and miR-21), also in the early-stage (miR-125a-3p, miR-320c and miRNA-486-5p), prognostic (miR-181a-5p, miR-18a-5p and miR-18b-5p), tumor growth (miR-21, miR-23a, miR-92a and miR-1246) or predictive risk for high risk adenomas to transform in CRC (miR-21, miR-29a, miR-92a and miR-135b) and prognosis place of metastasis (miR-548c-5p and miR-328), predictive for adjuvant treatment and recurrence (miR-4772-3p) or stratification for chemotherapy (miR-21).	('CRC', 'Phenotype', 'HP:0003003', (356, 359))	('miR-199b', 'Gene', (86, 94))	('miR-215', 'Gene', (105, 112))	('miR-328', 'Gene', (451, 458))	('miR-21', 'Gene', (117, 123))	('miR-548c-5p', 'Var', (435, 446))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('miR-21', 'Gene', (259, 265))	('miR-29a', 'Gene', (369, 376))	('miR-29a', 'Gene', '407021', (369, 376))	('miR-18b', 'Gene', (232, 239))	('miR-18a', 'Gene', (217, 224))	('adenomas', 'Disease', 'MESH:D000236', (331, 339))	('miR-4772-3p', 'Var', (511, 522))	('adjuvant treatment', 'CPA', (476, 494))	('adenomas', 'Disease', (331, 339))	('miR-1246', 'Gene', (288, 296))	('miR-18b', 'Gene', '574033', (232, 239))	('miR-21', 'Gene', '406991', (105, 111))	('miR-21', 'Gene', (560, 566))	('miR-199b', 'Gene', '406978', (86, 94))	('miR-21', 'Gene', (361, 367))	('age', 'Gene', (146, 149))	('miR-328', 'Gene', '442901', (451, 458))	('miR-18a', 'Gene', '406953', (217, 224))	('miR-135b', 'Gene', '442891', (390, 398))	('men', 'Species', '9606', (490, 493))	('tumor', 'Disease', (245, 250))	('miR-21', 'Gene', '406991', (117, 123))	('miR-1246', 'Gene', '100302142', (288, 296))	('miR-21', 'Gene', (105, 111))	('miR-21', 'Gene', '406991', (259, 265))	('miR-382', 'Gene', '494331', (96, 103))	('miR-135b', 'Gene', (390, 398))	('age', 'Gene', '5973', (146, 149))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('miR-23a', 'Gene', '407010', (267, 274))	('miR-23a', 'Gene', (267, 274))	('miR-215', 'Gene', '406997', (105, 112))	('miR-382', 'Gene', (96, 103))	('miR-21', 'Gene', '406991', (560, 566))	('miR-21', 'Gene', '406991', (361, 367))
44866	30559928	Deregulation of the Wnt pathway, often due to loss of the negative regulator APC, is found in ~80% of colorectal cancer (CRC).	('APC', 'cellular_component', 'GO:0005680', ('77', '80'))	('colorectal cancer', 'Disease', (102, 119))	('APC', 'Disease', (77, 80))	('Deregulation', 'Var', (0, 12))	('loss', 'NegReg', (46, 50))	('Wnt pathway', 'Pathway', (20, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('APC', 'Disease', 'MESH:D011125', (77, 80))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
44868	30559928	The ApcMin/+Lect2-/- mice had a reduced mean survival and a significantly increased number of adenomas in the small intestine with increased severity.	('mice', 'Species', '10090', (21, 25))	('reduced', 'NegReg', (32, 39))	('adenomas', 'Disease', (94, 102))	('ApcMin/+Lect2-/-', 'Var', (4, 20))	('increased', 'PosReg', (74, 83))	('adenomas', 'Disease', 'MESH:D000236', (94, 102))
44870	30559928	In summary, in the murine intestine loss of Lect2 promotes the initiation and progression of Wnt-driven colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (104, 121))	('progression', 'CPA', (78, 89))	('murine', 'Species', '10090', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('loss', 'Var', (36, 40))	('colorectal cancer', 'Phenotype', 'HP:0003003', (104, 121))	('Lect2', 'Gene', (44, 49))	('colorectal cancer', 'Disease', (104, 121))	('promotes', 'PosReg', (50, 58))
44875	30559928	In the liver, Lect2 has a protective anti-inflammatory role in beta-catenin-induced tumorigenesis and loss of this chemokine results in tumour progression and metastatic disease.	('anti-inflammatory', 'MPA', (37, 54))	('Lect2', 'Protein', (14, 19))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('tumour', 'Disease', (136, 142))	('metastatic disease', 'CPA', (159, 177))	('loss', 'Var', (102, 106))	('results in', 'Reg', (125, 135))	('beta-catenin-induced', 'MPA', (63, 83))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
44879	30559928	Our study demonstrates that loss of Lect2 in the ApcMin/+ mouse had a significant pro-tumorigenic effect, confirming a protective tumour suppressor role for Lect2 in Wnt-driven CRC.	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('loss', 'Var', (28, 32))	('mouse', 'Species', '10090', (58, 63))	('tumour', 'Disease', (130, 136))	('Lect2', 'Gene', (36, 41))	('rat', 'Species', '10116', (17, 20))	('pro-tumorigenic effect', 'CPA', (82, 104))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))
44881	30559928	The ApcMin/+ mouse model is a well-established CRC model that is heterozygous for a mutation in the Apc gene and develops multiple intestinal neoplasia.	('develops', 'Reg', (113, 121))	('neoplasia', 'Disease', (142, 151))	('mouse', 'Species', '10090', (13, 18))	('neoplasia', 'Disease', 'MESH:D009369', (142, 151))	('neoplasia', 'Phenotype', 'HP:0002664', (142, 151))	('multiple intestinal neoplasia', 'Phenotype', 'HP:0200008', (122, 151))	('Apc', 'Gene', (100, 103))	('mutation', 'Var', (84, 92))
44885	30559928	The decrease in survival of ApcMin/+Lect2-/- mice correlated with a significantly increased number of adenomas in the small intestine compared to the ApcMin/+Lect2+/+ mice at death (mean of 26.8 tumours versus 15.2 tumours, Mann-Whitney U-test, P = 0.0138; Figure 1B).	('survival', 'CPA', (16, 24))	('tumours versus 15.2 tumours', 'Disease', (195, 222))	('mice', 'Species', '10090', (45, 49))	('tumours', 'Phenotype', 'HP:0002664', (215, 222))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))	('adenomas', 'Disease', 'MESH:D000236', (102, 110))	('ApcMin/+Lect2-/-', 'Var', (28, 44))	('decrease', 'NegReg', (4, 12))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('adenomas', 'Disease', (102, 110))	('tumour', 'Phenotype', 'HP:0002664', (215, 221))	('mice', 'Species', '10090', (167, 171))	('tumours versus 15.2 tumours', 'Disease', 'MESH:D009369', (195, 222))
44887	30559928	By contrast, a significant reduction in mean tumour size was observed in the ApcMin/+Lect2-/- cohort, both in the small (5.6 mm2 versus 8.9 mm2, Mann-Whitney U-test, P = 0.0001) and large (7.1 mm2 versus 9.2 mm2, Mann-Whitney U-test, P = 0.0038) intestine (Figure 1C).	('ApcMin/+Lect2-/-', 'Var', (77, 93))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('tumour', 'Disease', (45, 51))	('reduction', 'NegReg', (27, 36))
44888	30559928	As further analysis of intestinal tumour burden at survival endpoint (Figure 1D) indicated no significant difference between cohorts the reduction of mean tumour size in the ApcMin/+Lect2-/- is likely a reflection of the animals' shortened longevity.	('ApcMin/+Lect2-/-', 'Var', (174, 190))	('intestinal tumour', 'Disease', 'MESH:D007414', (23, 40))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour', 'Disease', (34, 40))	('reduction', 'NegReg', (137, 146))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('intestinal tumour', 'Disease', (23, 40))	('tumour', 'Disease', (155, 161))
44890	30559928	However, the additional loss of Lect2 failed to reverse the suppression of tumour initiation observed in the ApcMin/+Mbd2-/- mice (Supplementary Figure 1A and 1B) indicating Lect2 does not play a significant role in the suppression of intestinal tumourigenesis observed in that model.	('loss', 'Var', (24, 28))	('Mbd2', 'Gene', (117, 121))	('tumour initiation', 'Disease', (75, 92))	('intestinal tumour', 'Disease', 'MESH:D007414', (235, 252))	('Mbd2', 'Gene', '17191', (117, 121))	('mice', 'Species', '10090', (125, 129))	('intestinal tumour', 'Disease', (235, 252))	('tumour initiation', 'Disease', 'MESH:D009369', (75, 92))	('tumour', 'Phenotype', 'HP:0002664', (246, 252))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
44895	30559928	The ApcMin/+Lect2-/- displayed a significant shift in progression with a reduction in the percentage of mice with early T1 lesions to 72.8% (n = 8/11) with a corresponding increase in early invasive T3 lesions to 36.4% (n = 4/11) (Chi-Squared Test P < 0.0001; Figure 2A (bottom panel) and 2B).	('early invasive', 'MPA', (184, 198))	('increase', 'PosReg', (172, 180))	('mice', 'Species', '10090', (104, 108))	('ApcMin/+Lect2-/-', 'Var', (4, 20))	('reduction', 'NegReg', (73, 82))
44896	30559928	To understand whether progression was due to alteration in cell homeostasis we next performed immunohistochemical analysis for Ki67, a marker of proliferation, and cleaved Caspase-3, a marker of apoptosis.	('Caspase-3', 'Gene', (172, 181))	('rat', 'Species', '10116', (152, 155))	('Ki67', 'Gene', (127, 131))	('Caspase-3', 'Gene', '12367', (172, 181))	('rat', 'Species', '10116', (49, 52))	('Ki67', 'Gene', '17345', (127, 131))	('cleaved', 'Var', (164, 171))
44897	30559928	The percentage of positively-staining cells in tumours of both the ApcMin/+Lect2+/+ (N = 4) and ApcMin/+Lect2-/- (N = 5) cohorts indicated that loss of Lect2 had no significant effect on either cell proliferation (Figure 2C) or cell death (Figure 2D) in our Wnt-driven tumours.	('tumours', 'Disease', (269, 276))	('loss', 'Var', (144, 148))	('Lect2', 'Gene', (152, 157))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('tumours', 'Disease', 'MESH:D009369', (269, 276))	('tumour', 'Phenotype', 'HP:0002664', (269, 275))	('tumours', 'Phenotype', 'HP:0002664', (269, 276))	('tumours', 'Disease', (47, 54))	('rat', 'Species', '10116', (206, 209))	('cell proliferation', 'CPA', (194, 212))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('cell death', 'CPA', (228, 238))
44909	30559928	The data for the control mice (AhCre+Apc+/+Lect2+/+, AhCre+Apcfl/flLect2+/+; Figure 3C and 3D) at day 5 PI were consistent with previous reports with a significant increase in mitosis and apoptosis between the AhCre+Apcfl/flLect2+/+ (Mann-Whitney U-test, P = 0.0404) and wild-type mice, with no significant effect of Lect2 deletion (Figure 3C and 3D).	('mitosis', 'Disease', (176, 183))	('mice', 'Species', '10090', (25, 29))	('mice', 'Species', '10090', (281, 285))	('mitosis', 'Disease', 'None', (176, 183))	('apoptosis', 'CPA', (188, 197))	('AhCre+Apcfl/flLect2+/+', 'Var', (210, 232))	('Lect2', 'Gene', (317, 322))	('increase', 'PosReg', (164, 172))
44918	30559928	The AhCre+Apcfl/+ tumour model was used in our short-term cohorts as this model develops tumours at a similar latency to that of the ApcMin/+ model, inducing Apc deletion at a fixed time point provides experimental consistency and Apc remains intact within the immune system.	('deletion', 'Var', (162, 170))	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumours', 'Disease', 'MESH:D009369', (89, 96))	('tumour', 'Disease', (89, 95))	('tumours', 'Disease', (89, 96))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('inducing', 'Reg', (149, 157))	('Apc', 'Gene', (158, 161))	('tumour', 'Disease', 'MESH:D009369', (18, 24))	('tumour', 'Disease', (18, 24))
44922	30559928	In addition several other key cytokines showed trends towards a decrease in their levels although this was not significant, such as IFN-gamma (AhCre+Apcfl/+Lect2-/- versus AhCre+Apcfl/+Lect2+/+; median concentration 4.11 pg/ml versus 8.68 pg/ml; P = 0.1914; Figure 4E), IL-4 (AhCre+Apcfl/+Lect2-/- versus AhCre+Apcfl/+Lect2+/+; median concentration 0.66 pg/ml versus 1.26 pg/ml; P = 0.3313; Figure 4F) and IL-2 (AhCre+Apcfl/+Lect2-/- versus AhCre+Apcfl/+Lect2+/+; median concentration 1.62 pg/ml versus 6.73 pg/ml; P = 0.0952; Figure 4G).	('IL-4', 'Gene', (270, 274))	('IL-4', 'Gene', '16189', (270, 274))	('decrease', 'NegReg', (64, 72))	('rat', 'Species', '10116', (342, 345))	('IL-2', 'Gene', '16183', (406, 410))	('rat', 'Species', '10116', (209, 212))	('AhCre+Apcfl/+Lect2-/-', 'Var', (412, 433))	('IFN-gamma', 'Gene', (132, 141))	('IL-2', 'Gene', (406, 410))	('rat', 'Species', '10116', (478, 481))	('IFN-gamma', 'Gene', '15978', (132, 141))
44938	30559928	Immunohistochemical analysis of the groups indicated no overall difference density of CD4+ or CD8+ between polyps from ApcMin/+Lect2+/+ and ApcMin/+Lect2-/- cohorts (Figure 6B and 6C).	('CD4', 'Gene', (86, 89))	('CD8+', 'Var', (94, 98))	('CD4', 'Gene', '12504', (86, 89))	('polyps', 'Disease', (107, 113))	('polyps', 'Disease', 'MESH:D011127', (107, 113))	('ApcMin/+Lect2+/+', 'Var', (119, 135))
44940	30559928	Subsequent analysis of CD4+FoxP3+ Treg cells indicated no significant difference in the spleen and a non-significant trend towards an increase in the intestine (Figure 6F; ApcMin/+Lect2-/- (N = 4) and ApcMin/+Lect2+/+(N = 5)).	('ApcMin/+Lect2-/-', 'Var', (172, 188))	('ApcMin/+Lect2+/+', 'Var', (201, 217))	('increase', 'PosReg', (134, 142))	('CD4', 'Gene', (23, 26))	('CD4', 'Gene', '12504', (23, 26))
44945	30559928	To confirm and further investigate the function of Lect2 in Wnt-driven CRC, we homozygously deleted Lect2 in the ApcMin/+ mouse model.	('Lect2', 'Gene', (100, 105))	('mouse', 'Species', '10090', (122, 127))	('deleted', 'Var', (92, 99))
44948	30559928	In addition, the number of advanced tumour lesions was increased, despite the 30% reduction in the longevity of the mice, indicating that the homozygous loss of Lect2 enhances both Wnt-activated tumour initiation and progression, identifying a clear protective role for Lect2 in intestinal tumorigenesis.	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('mice', 'Species', '10090', (116, 120))	('longevity', 'CPA', (99, 108))	('tumour initiation', 'Disease', (195, 212))	('reduction', 'NegReg', (82, 91))	('progression', 'CPA', (217, 228))	('loss', 'Var', (153, 157))	('enhances', 'PosReg', (167, 175))	('Lect2', 'Gene', (161, 166))	('tumour lesions', 'Disease', 'MESH:D009062', (36, 50))	('tumour initiation', 'Disease', 'MESH:D009369', (195, 212))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))	('tumour lesions', 'Disease', (36, 50))
44949	30559928	However, our data indicating the loss of Lect2 had no impact on the phenotype of the Apc+/minMbd2-/- mice suggests that epigenetic silencing of Lect2 doesn't play a key role in intestinal tumour initiation but is more relevant to inflammation and tumour progression.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('tumour', 'Phenotype', 'HP:0002664', (247, 253))	('epigenetic silencing', 'Var', (120, 140))	('Mbd2', 'Gene', (93, 97))	('intestinal tumour initiation', 'Disease', (177, 205))	('intestinal tumour initiation', 'Disease', 'MESH:D007414', (177, 205))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('tumour', 'Disease', 'MESH:D009369', (247, 253))	('Mbd2', 'Gene', '17191', (93, 97))	('tumour', 'Disease', (188, 194))	('tumour', 'Disease', (247, 253))	('mice', 'Species', '10090', (101, 105))	('inflammation', 'Disease', 'MESH:D007249', (230, 242))	('Lect2', 'Gene', (144, 149))	('inflammation', 'Disease', (230, 242))
44952	30559928	Our results demonstrate that whilst Lect2 is a downstream target of the Wnt pathway, homozygous loss of this tumour suppressor had no effect on the activated Wnt signature, indicating that the protective role of Lect2 may be independent of Wnt signalling in the mouse intestine.	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('loss', 'Var', (96, 100))	('mouse', 'Species', '10090', (262, 267))	('rat', 'Species', '10116', (19, 22))	('tumour', 'Disease', (109, 115))	('activated Wnt signature', 'MPA', (148, 171))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
44955	30559928	Furthermore, Lect2 has been shown to be a mediator of the beta-catenin inflammatory response during hepatocellular carcinoma and loss of this tumour suppressor results an increase in tumorigenesis.	('tumour', 'Disease', (142, 148))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (100, 124))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (100, 124))	('tumorigenesis', 'CPA', (183, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('hepatocellular carcinoma', 'Disease', (100, 124))	('loss', 'Var', (129, 133))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('increase', 'PosReg', (171, 179))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('Lect2', 'Protein', (13, 18))
44956	30559928	Our results demonstrated that the loss of Lect2 in our Wnt-activated model significantly altered the levels of circulating cytokines.	('loss', 'Var', (34, 38))	('levels of circulating cytokines', 'MPA', (101, 132))	('rat', 'Species', '10116', (19, 22))	('altered', 'Reg', (89, 96))	('Lect2', 'Gene', (42, 47))
44957	30559928	A similarly altered cytokine secretion profile in response to the loss of Lect2 has been previously shown in the liver and this altered profile in Lect2-/- mice was shown to be associated with an alteration in the profile of infiltrating immune cells.	('alteration', 'Reg', (196, 206))	('cytokine secretion profile', 'MPA', (20, 46))	('loss', 'Var', (66, 70))	('rat', 'Species', '10116', (200, 203))	('rat', 'Species', '10116', (231, 234))	('Lect2', 'Gene', (74, 79))	('altered', 'Reg', (12, 19))	('mice', 'Species', '10090', (156, 160))	('profile of infiltrating immune cells', 'MPA', (214, 250))
44960	30559928	It is well established that genetic alterations involved in driving tumorigenesis activate an inflammatory program that has a significant impact on tumour development and several studies have highlighted the role of inflammation in CRC.	('activate', 'PosReg', (82, 90))	('tumour', 'Disease', (148, 154))	('genetic alterations', 'Var', (28, 47))	('CRC', 'Disease', (232, 235))	('tumour', 'Disease', 'MESH:D009369', (148, 154))	('rat', 'Species', '10116', (40, 43))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('inflammation', 'Disease', 'MESH:D007249', (216, 228))	('inflammatory program', 'CPA', (94, 114))	('impact', 'Reg', (138, 144))	('inflammation', 'Disease', (216, 228))
44964	30559928	The Il-10 reduction is consistent with other studies that have shown that T cell-restricted ablation of IL-10 increased the number of polyps by promoting the accumulation of microbes and eosinophils and IL-10 deficient mice are more susceptible to spontaneous intestinal tumour development.	('polyps', 'Disease', (134, 140))	('Il-10', 'molecular_function', 'GO:0005141', ('4', '9'))	('Il-10', 'Gene', (4, 9))	('tumour', 'Phenotype', 'HP:0002664', (271, 277))	('mice', 'Species', '10090', (219, 223))	('intestinal tumour', 'Disease', 'MESH:D007414', (260, 277))	('ablation', 'Var', (92, 100))	('Il-10', 'Gene', '16153', (4, 9))	('accumulation', 'MPA', (158, 170))	('eosin', 'Chemical', 'MESH:D004801', (187, 192))	('polyps', 'Disease', 'MESH:D011127', (134, 140))	('IL-10', 'molecular_function', 'GO:0005141', ('104', '109'))	('IL-10', 'Gene', (104, 109))	('IL-10', 'molecular_function', 'GO:0005141', ('203', '208'))	('promoting', 'PosReg', (144, 153))	('intestinal tumour', 'Disease', (260, 277))
44965	30559928	Our results show that the loss of Lect2 leads to a significant increase in the proportion of the CD4+ subpopulation of T cells in the spleen.	('increase', 'PosReg', (63, 71))	('CD4', 'Gene', (97, 100))	('CD4', 'Gene', '12504', (97, 100))	('loss', 'Var', (26, 30))	('Lect2', 'Gene', (34, 39))
44969	30559928	demonstrated that loss of Lect2 significantly altered the inflammatory microenvironment by shifting the balance towards a Th2 pro-tumorigenic inflammatory program, which allowed tumour growth and progression.	('Th2', 'Gene', (122, 125))	('Th2', 'Gene', '15111', (122, 125))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('loss', 'Var', (18, 22))	('tumour growth', 'Disease', (178, 191))	('allowed', 'PosReg', (170, 177))	('tumour growth', 'Disease', 'MESH:D006130', (178, 191))	('altered', 'Reg', (46, 53))	('progression', 'CPA', (196, 207))	('rat', 'Species', '10116', (7, 10))	('Lect2', 'Gene', (26, 31))	('shifting', 'Reg', (91, 99))	('balance', 'MPA', (104, 111))
44970	30559928	As the presence of CD4+ cells can be anti- or pro-tumourigenic depending on the lineages present we therefore investigated whether loss of Lect2 resulted in an alteration in the expression of key transcription factors required for the differential development of the antigen-activated CD4+ T cells.	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Disease', (50, 56))	('CD4', 'Gene', (285, 288))	('expression', 'MPA', (178, 188))	('Lect2', 'Gene', (139, 144))	('CD4', 'Gene', '12504', (285, 288))	('alteration', 'Reg', (160, 170))	('loss', 'Var', (131, 135))	('rat', 'Species', '10116', (164, 167))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('CD4', 'Gene', (19, 22))	('CD4', 'Gene', '12504', (19, 22))
44971	30559928	Our results demonstrate that loss of Lect2 significantly increased the expression of GATA-3 and FoxP3 in the spleen.	('expression', 'MPA', (71, 81))	('GATA-3', 'Gene', '14462', (85, 91))	('Lect2', 'Gene', (37, 42))	('FoxP3', 'Gene', (96, 101))	('rat', 'Species', '10116', (19, 22))	('loss', 'Var', (29, 33))	('increased', 'PosReg', (57, 66))	('GATA-3', 'Gene', (85, 91))
44977	30559928	This alteration in T cell regulators may alter CD4+ T cell subsets and disrupt the immune environment, promoting tumour growth, although further studies are required to confirm this.	('CD4', 'Gene', '12504', (47, 50))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('rat', 'Species', '10116', (9, 12))	('promoting', 'PosReg', (103, 112))	('alteration', 'Var', (5, 15))	('disrupt', 'Reg', (71, 78))	('tumour growth', 'Disease', (113, 126))	('tumour growth', 'Disease', 'MESH:D006130', (113, 126))	('alter', 'Reg', (41, 46))	('immune environment', 'MPA', (83, 101))	('CD4', 'Gene', (47, 50))
44986	30559928	The following antibodies were used for immunohistochemistry: anti-Cd4(1:100; eBioscience), anti-Cd8 (1:200; eBioscience) anti-Caspase 3 (1:750; R&D systems), anti-beta-catenin (1/50; Becton Dickinson), anti-Ki67 (1:200; Vector Labs) and mouse anti-BrdU (1:100; Becton Dickinson).	('Cd4', 'Gene', (66, 69))	('Ki67', 'Gene', (207, 211))	('mouse', 'Species', '10090', (237, 242))	('anti-Cd8', 'Var', (91, 99))	('Cd4', 'Gene', '12504', (66, 69))	('Ki67', 'Gene', '17345', (207, 211))	('Caspase 3', 'Gene', (126, 135))	('Caspase 3', 'Gene', '12367', (126, 135))
44997	30559928	The gene expression levels in intestinal tumours relative to the control intestinal normal tissues were calculated using the following formulae: DeltaDeltaCt = DeltaCt test-DeltaCt control, fold change = 2-DeltaDeltaCt.	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('intestinal tumours', 'Disease', (30, 48))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('intestinal tumours', 'Disease', 'MESH:D007414', (30, 48))	('DeltaDeltaCt', 'Var', (145, 157))
45066	29435282	A number of studies have reported that alteration in the expression level of clock genes is correlated with several pathological conditions, including cancer.	('alteration', 'Var', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('correlated', 'Reg', (92, 102))	('clock genes', 'Gene', (77, 88))	('expression level', 'MPA', (57, 73))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
45070	29435282	The circadian clock gene period (PER)1 has been associated with oral cancer pathogenesis and it is suggested that changes in the expression of PER1 may exhibit an important role in the development, invasion, and metastasis of oral squamous cell carcinoma.	('metastasis of oral squamous cell carcinoma', 'Disease', (212, 254))	('invasion', 'CPA', (198, 206))	('oral cancer', 'Disease', (64, 75))	('associated', 'Reg', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('PER1', 'Gene', (143, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('PER', 'Gene', (33, 36))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (231, 254))	('metastasis of oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (212, 254))	('oral cancer', 'Disease', 'MESH:D009062', (64, 75))	('changes', 'Var', (114, 121))
45076	29435282	There are studies showing the effect of dysfunctional circadian machinery in humans, for example mutations, non-standard expression, and translocation of clock genes, which has led to different cancer types including breast, colorectal, gastric, kidney, lung, prostate, pancreatic, and oral cancer.	('mutations', 'Var', (97, 106))	('colorectal', 'Disease', (225, 235))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('led to', 'Reg', (177, 183))	('kidney', 'Disease', (246, 252))	('dysfunctional', 'Disease', 'MESH:D006331', (40, 53))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('lung', 'Disease', (254, 258))	('humans', 'Species', '9606', (77, 83))	('translocation', 'Var', (137, 150))	('breast', 'Disease', (217, 223))	('gastric', 'Disease', (237, 244))	('cancer', 'Disease', (291, 297))	('prostate', 'Disease', (260, 268))	('pancreatic', 'Disease', 'MESH:D010195', (270, 280))	('dysfunctional', 'Disease', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cancer', 'Disease', (194, 200))	('pancreatic', 'Disease', (270, 280))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('oral cancer', 'Disease', 'MESH:D009062', (286, 297))	('oral cancer', 'Disease', (286, 297))
45095	29435282	The disruption of the circadian clock has not only been shown to increase the risk of disease, but also to affect the prognosis and treatment outcome of patients.	('increase', 'PosReg', (65, 73))	('affect', 'Reg', (107, 113))	('patients', 'Species', '9606', (153, 161))	('disruption', 'Var', (4, 14))
45097	29435282	Although these findings suggest that the circadian clock undergoes significant changes in human tumorigenesis, the direct links between aberrant circadian clock gene expression and human malignancies, including oral and head and neck carcinomas, remain largely elusive.	('human', 'Species', '9606', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('oral', 'Disease', (211, 215))	('aberrant', 'Var', (136, 144))	('neck carcinomas', 'Disease', (229, 244))	('tumor', 'Disease', (96, 101))	('malignancies', 'Disease', 'MESH:D009369', (187, 199))	('human', 'Species', '9606', (90, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('neck carcinomas', 'Disease', 'MESH:D006258', (229, 244))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('changes', 'Reg', (79, 86))	('malignancies', 'Disease', (187, 199))	('carcinomas', 'Phenotype', 'HP:0030731', (234, 244))
45123	29435282	The main risk factors are tobacco use and alcohol consumption with combined multiplicative effects possibly leading to DNA damage or mutations.	('tobacco', 'Species', '4097', (26, 33))	('DNA damage', 'Disease', (119, 129))	('leading', 'Reg', (108, 115))	('alcohol', 'Chemical', 'MESH:D000438', (42, 49))	('mutations', 'Var', (133, 142))
45124	29435282	Human papilloma virus infection and genetic polymorphism can also be mentioned as risk factors.	('papilloma virus infection', 'Disease', (6, 31))	('genetic polymorphism', 'Var', (36, 56))	('papilloma virus infection', 'Disease', 'MESH:D010212', (6, 31))	('papilloma', 'Phenotype', 'HP:0012740', (6, 15))
45131	29435282	Studies have confirmed that cyclinbeta1 and p53 are targets of human clock genes where loss of BMAL1 reduces the expression of p53 along with PER1, PER2, and PER3.	('expression', 'MPA', (113, 123))	('loss', 'Var', (87, 91))	('human', 'Species', '9606', (63, 68))	('BMAL1', 'Gene', (95, 100))	('BMAL1', 'Gene', '406', (95, 100))	('PER3', 'Gene', (158, 162))	('reduces', 'NegReg', (101, 108))	('cyclin', 'Gene', '18538', (28, 34))	('cyclin', 'Gene', (28, 34))	('PER3', 'Gene', '8863', (158, 162))	('p53', 'Gene', (127, 130))
45132	29435282	It has also been hypothesized that p53 is involved in regulating PER2 expression by blocking the CLOCK/BMAL1 complex from binding to a promotor region.	('binding', 'Interaction', (122, 129))	('binding', 'molecular_function', 'GO:0005488', ('122', '129'))	('expression', 'MPA', (70, 80))	('blocking', 'NegReg', (84, 92))	('BMAL1', 'Gene', (103, 108))	('BMAL1', 'Gene', '406', (103, 108))	('p53', 'Var', (35, 38))	('PER2', 'Gene', (65, 69))
45148	29435282	PER1 gene knockdown in OSCC cell line SCC15 led to immediate abnormal behavior in terms of cell growth, proliferation, apoptosis resistance, migration and invasion in vitro.	('migration', 'CPA', (141, 150))	('apoptosis resistance', 'CPA', (119, 139))	('SCC15', 'CellLine', 'CVCL:1681', (38, 43))	('cell growth', 'CPA', (91, 102))	('PER1', 'Gene', (0, 4))	('invasion', 'CPA', (155, 163))	('knockdown', 'Var', (10, 19))
45149	29435282	Mice injected with these modified cells subcutaneously experienced enhanced tumor development.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('modified', 'Var', (25, 33))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('enhanced', 'PosReg', (67, 75))
45151	29435282	Suppression of PER1 leads to disturbance in the cell cycle and inhibits DNA damage control, which again makes clock genes and PER1 a key research subject in the field of carcinogenesis.	('carcinogenesis', 'Disease', (170, 184))	('cell cycle', 'biological_process', 'GO:0007049', ('48', '58'))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('cell cycle', 'CPA', (48, 58))	('inhibits', 'NegReg', (63, 71))	('Suppression', 'Var', (0, 11))	('carcinogenesis', 'Disease', 'MESH:D063646', (170, 184))	('disturbance', 'Reg', (29, 40))	('DNA damage control', 'MPA', (72, 90))	('PER1', 'Gene', (15, 19))
45156	29435282	This suggests that PER1 not only regulates the downstream genes, but it also plays a role in the synergy of the rest of the clock genes in the circadian machinery in SCC15 cell lines.	('regulates', 'Reg', (33, 42))	('SCC15', 'CellLine', 'CVCL:1681', (166, 171))	('PER1', 'Var', (19, 23))	('plays', 'Reg', (77, 82))
45165	28611337	BRAF mutation is associated with poor clinicopathological outcomes in colorectal cancer: A meta-analysis The clinical relevance of the BRAF mutation in colorectal carcinoma (CRC) remains controversial.	('BRAF', 'Gene', '673', (135, 139))	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('colorectal carcinoma', 'Disease', (152, 172))	('BRAF', 'Gene', (135, 139))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('mutation', 'Var', (140, 148))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (152, 172))	('BRAF', 'Gene', '673', (0, 4))	('colorectal cancer', 'Disease', (70, 87))	('BRAF', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('mutation', 'Var', (5, 13))
45170	28611337	Our meta-analysis revealed that, in patients with CRC, the BRAF mutation was associated with female, proximal site, poor differentiation, >5 cm size, and advanced AJCC stage.	('mutation', 'Var', (64, 72))	('patients', 'Species', '9606', (36, 44))	('AJCC', 'Disease', (163, 167))	('poor differentiation', 'CPA', (116, 136))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('associated', 'Reg', (77, 87))
45171	28611337	This meta-analysis demonstrated that BRAF mutation was closely related to adverse pathological features and poor outcome of CRC.	('CRC', 'Disease', (124, 127))	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('related', 'Reg', (63, 70))
45173	28611337	The development of CRC is a multistep process which included chromosomal abnormalities, gene mutations, and epigenetic modifications.	('chromosomal abnormalities', 'Disease', (61, 86))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (61, 86))	('CRC', 'Disease', (19, 22))	('epigenetic modifications', 'Var', (108, 132))	('gene mutations', 'Var', (88, 102))
45175	28611337	Mutations of the genes encoding the KRAS and BRAF have been implicated in colorectal carcinogenesis.	('colorectal carcinogenesis', 'Disease', (74, 99))	('KRAS', 'Gene', (36, 40))	('implicated', 'Reg', (60, 70))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('KRAS', 'Gene', '3845', (36, 40))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (74, 99))
45177	28611337	BRAF mutations occurred in 5-11% of CRC cases, and BRAF-mutant CRC has been associated with clinicopathological features, including sex, tumor location, differentiation, lymph node involvement, and clinical stage.	('CRC', 'Disease', (36, 39))	('tumor', 'Disease', (137, 142))	('mutations', 'Var', (5, 14))	('associated', 'Reg', (76, 86))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', '673', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', (51, 55))	('CRC', 'Disease', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
45178	28611337	Some previous reports indicated that CRCs with BRAF mutations tend to be at a lower clinical stage, whereas other studies revealed CRCs with altered BRAF apt to have a poor prognosis.	('mutations', 'Var', (52, 61))	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('BRAF', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (47, 51))	('CRCs', 'Disease', (37, 41))	('lower', 'NegReg', (78, 83))
45180	28611337	Thus, we conducted this meta-analysis to assess the correlation between the BRAF mutation and clinicopathological characteristics of the CRC.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('CRC', 'Disease', (137, 140))	('mutation', 'Var', (81, 89))
45182	28611337	Criteria for eligibility of a study included in this meta-analysis were (1) Detection of the BRAF mutation in the CRC tissues; (2) the studies published in English and Chinese; (3) when several studies were reported from the same authors or organizations, the meta-analysis enrolling the most recent or highest quality study only if the most recent one did not fit the inclusion criteria.	('BRAF', 'Gene', (93, 97))	('BRAF', 'Gene', '673', (93, 97))	('mutation', 'Var', (98, 106))
45184	28611337	The following variables were recorded: authors, sex, number of patients, age of patients, histological cancer type, clinicopathological characteristics, and BRAF mutation rate.	('patients', 'Species', '9606', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('BRAF', 'Gene', '673', (157, 161))	('mutation', 'Var', (162, 170))	('BRAF', 'Gene', (157, 161))	('patients', 'Species', '9606', (63, 71))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
45185	28611337	For the pooled analysis of the correlation between BRAF mutation and clinicopathological features (sex, tumor location, differentiation, lymph node involvement, and clinical stage), odds ratios (ORs), and 95% CI were combined to estimate the effect.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('BRAF', 'Gene', '673', (51, 55))	('mutation', 'Var', (56, 64))	('BRAF', 'Gene', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
45190	28611337	Twenty-four studies including 13043 patients demonstrated that there was a significant association between BRAF mutation and female gender (OR = 1.87; 95% CI = 1.66-2.09) [Figure 2].	('BRAF', 'Gene', (107, 111))	('BRAF', 'Gene', '673', (107, 111))	('patients', 'Species', '9606', (36, 44))	('mutation', 'Var', (112, 120))
45191	28611337	Except this above mentioned parameter, controversies also existed on the correlation among tumor location, differentiation, lymph node metastasis, tumor size, AJCC stage, and BRAF mutation in these included studies.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('BRAF', 'Gene', (175, 179))	('BRAF', 'Gene', '673', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', (91, 96))	('mutation', 'Var', (180, 188))
45192	28611337	Eleven studies including 5307 patients were analyzed for the association between BRAF mutation and the location of the colorectal tumor.	('BRAF', 'Gene', '673', (81, 85))	('patients', 'Species', '9606', (30, 38))	('BRAF', 'Gene', (81, 85))	('colorectal tumor', 'Disease', (119, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('mutation', 'Var', (86, 94))	('colorectal tumor', 'Disease', 'MESH:D015179', (119, 135))	('association', 'Interaction', (61, 72))
45194	28611337	Twelve studies including 3569 patients were analyzed for the association between BRAF mutation and colorectal differentiation.	('BRAF', 'Gene', '673', (81, 85))	('BRAF', 'Gene', (81, 85))	('patients', 'Species', '9606', (30, 38))	('colorectal differentiation', 'Disease', (99, 125))	('mutation', 'Var', (86, 94))	('association', 'Interaction', (61, 72))
45195	28611337	There was a significant association between BRAF mutation and poor differentiation (OR = 3.57; 95% CI = 2.82-4.53) [Figure 3b].	('BRAF', 'Gene', (44, 48))	('poor differentiation', 'CPA', (62, 82))	('BRAF', 'Gene', '673', (44, 48))	('mutation', 'Var', (49, 57))
45196	28611337	In addition, two studies including 399 patients and 9 studies including 4154 patients reported the association between BRAF mutation and tumor size or AJCC stage.	('AJCC', 'Disease', (151, 155))	('tumor', 'Disease', (137, 142))	('patients', 'Species', '9606', (39, 47))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', (119, 123))	('patients', 'Species', '9606', (77, 85))	('mutation', 'Var', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('association', 'Interaction', (99, 110))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
45197	28611337	There was a significant correlation between the BRAF mutation and tumor size (OR = 2.63; 95% CI = 1.08-6.39) [Figure 3d], advanced AJCC stage [OR = 1.63; 95% CI = 1.26-2.13) [Figure 3e].	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutation', 'Var', (53, 61))	('tumor', 'Disease', (66, 71))	('AJCC', 'Disease', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))
45199	28611337	The meta-analysis suggested that BRAF mutation was not correlated with lymph node metastasis (OR = 0.74; 95% CI = 0.47-1.17) [Figure 3c].	('lymph node metastasis', 'CPA', (71, 92))	('BRAF', 'Gene', (33, 37))	('BRAF', 'Gene', '673', (33, 37))	('mutation', 'Var', (38, 46))
45200	28611337	In our study, we confirmed that BRAF mutation was significantly associated with the high-risk clinicopathological factors of CRC and poor clinical outcome.	('associated', 'Reg', (64, 74))	('BRAF', 'Gene', '673', (32, 36))	('CRC', 'Disease', (125, 128))	('mutation', 'Var', (37, 45))	('BRAF', 'Gene', (32, 36))
45202	28611337	In our study, CRC patients with BRAF mutation exhibited 5.8 fold increase in female gender, poor differentiation, higher AJCC stages, proximal site, and size >5 cm comapared with patients with the wild-type form of the BRAF gene.	('increase', 'PosReg', (65, 73))	('BRAF', 'Gene', '673', (32, 36))	('mutation', 'Var', (37, 45))	('BRAF', 'Gene', (32, 36))	('poor differentiation', 'CPA', (92, 112))	('BRAF', 'Gene', (219, 223))	('BRAF', 'Gene', '673', (219, 223))	('patients', 'Species', '9606', (179, 187))	('patients', 'Species', '9606', (18, 26))
45203	28611337	The BRAF V600E mutation has been validated independently as prognostic for overall survival and variable results have been obtained related to this mutation's association with traditional risk factors for higher mortality rate of CRC patients.	('V600E', 'Mutation', 'rs113488022', (9, 14))	('V600E', 'Var', (9, 14))	('patients', 'Species', '9606', (234, 242))	('BRAF', 'Gene', (4, 8))	('CRC', 'Disease', (230, 233))	('BRAF', 'Gene', '673', (4, 8))
45204	28611337	Recently, significant correlations were found between BRAF mutation and the presence of right-sided tumors, poor differentiation, and mucinous histology.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('mutation', 'Var', (59, 67))	('right-sided', 'Disease', (88, 99))	('poor differentiation', 'CPA', (108, 128))
45205	28611337	Our meta-analysis provides new insights into the clinicopathological importance of the BRAF mutation in CRC and includes studies published after 2005.	('CRC', 'Disease', (104, 107))	('BRAF', 'Gene', (87, 91))	('mutation', 'Var', (92, 100))	('BRAF', 'Gene', '673', (87, 91))
45206	28611337	Cantwell-Dorris reported the BRAF mutation of CRC with lymphatic metastasis as 5 to 10 times higher than that of CRC with lymph node negative.	('higher', 'PosReg', (93, 99))	('BRAF', 'Gene', '673', (29, 33))	('Dorris', 'Chemical', '-', (9, 15))	('BRAF', 'Gene', (29, 33))	('CRC', 'Disease', (46, 49))	('mutation', 'Var', (34, 42))
45207	28611337	Compared to our study, the BRAF mutation did not show statistically significant association with lymph node metastasis.	('BRAF', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))	('lymph node metastasis', 'CPA', (97, 118))	('BRAF', 'Gene', '673', (27, 31))
45208	28611337	Several mechanisms are involved in the aggressive phenotype of CRC that is promoted by the BRAF mutation.	('BRAF', 'Gene', '673', (91, 95))	('promoted', 'PosReg', (75, 83))	('mutation', 'Var', (96, 104))	('BRAF', 'Gene', (91, 95))	('CRC', 'Disease', (63, 66))
45209	28611337	indicated that the BRAF mutations of CRC can promote the activation of ERK, which activates downstream transcription factors to induce a range of biochemical processes including cell differentiation, proliferation, growth, while acting as the inhibitor of apoptosis.	('BRAF', 'Gene', '673', (19, 23))	('transcription', 'biological_process', 'GO:0006351', ('103', '116'))	('ERK', 'Gene', '5594', (71, 74))	('apoptosis', 'biological_process', 'GO:0097194', ('256', '265'))	('apoptosis', 'biological_process', 'GO:0006915', ('256', '265'))	('BRAF', 'Gene', (19, 23))	('proliferation', 'CPA', (200, 213))	('ERK', 'Gene', (71, 74))	('mutations', 'Var', (24, 33))	('ERK', 'molecular_function', 'GO:0004707', ('71', '74'))	('growth', 'CPA', (215, 221))	('induce', 'PosReg', (128, 134))	('cell differentiation', 'biological_process', 'GO:0030154', ('178', '198'))	('CRC', 'Gene', (37, 40))	('cell differentiation', 'CPA', (178, 198))
45210	28611337	BRAF mutation of CRC also display deficiency in mismatch repair (MMR).	('CRC also display deficiency', 'Disease', (17, 44))	('mismatch repair', 'biological_process', 'GO:0006298', ('48', '63'))	('MMR', 'biological_process', 'GO:0006298', ('65', '68'))	('BRAF', 'Gene', '673', (0, 4))	('CRC also display deficiency', 'Disease', 'MESH:D015179', (17, 44))	('BRAF', 'Gene', (0, 4))	('mismatch repair', 'MPA', (48, 63))	('mutation', 'Var', (5, 13))
45211	28611337	The prevalence of BRAF mutation in MMR-deficient tumors has been shown to be three-fold greater than in MMR-proficient tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('MMR', 'biological_process', 'GO:0006298', ('35', '38'))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mutation', 'Var', (23, 31))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('MMR-deficient tumors', 'Disease', 'MESH:C536928', (35, 55))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('MMR', 'biological_process', 'GO:0006298', ('104', '107'))	('MMR-deficient tumors', 'Disease', (35, 55))	('tumors', 'Disease', (49, 55))	('BRAF', 'Gene', '673', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('greater', 'PosReg', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('BRAF', 'Gene', (18, 22))
45212	28611337	First, we did not evaluate the methods used to detect BRAF mutations for lacking data, which may affect the results.	('BRAF', 'Gene', '673', (54, 58))	('affect', 'Reg', (97, 103))	('mutations', 'Var', (59, 68))	('BRAF', 'Gene', (54, 58))
45213	28611337	Second, we did not collect data on the treatment and clinical outcomes to analyze effect of the BRAF mutation on the overall clinical outcome.	('BRAF', 'Gene', '673', (96, 100))	('mutation', 'Var', (101, 109))	('BRAF', 'Gene', (96, 100))
45214	28611337	BRAF mutation should be considered as a poor prognostic marker in CRC, and BRAF mutational analysis could result in better management for individual CRC patients.	('CRC', 'Disease', (66, 69))	('CRC', 'Disease', (149, 152))	('patients', 'Species', '9606', (153, 161))	('BRAF', 'Gene', '673', (75, 79))	('result', 'Reg', (106, 112))	('BRAF', 'Gene', (75, 79))	('BRAF', 'Gene', '673', (0, 4))	('mutational analysis', 'Var', (80, 99))	('BRAF', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
45262	28210074	In 2013 Tentes et al published a prospective study comparing the adjuvant setting in patients with pT3 or pT4 colorectal cancer receiving systemic chemotherapy (40 patients) vs intraperitoneally by HIPEC with mitomycin (41 patients).	('colorectal cancer', 'Disease', 'MESH:D015179', (110, 127))	('pT3', 'Gene', (99, 102))	('pT4', 'Var', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('patients', 'Species', '9606', (85, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (110, 127))	('mitomycin', 'Chemical', 'MESH:D016685', (209, 218))	('patients', 'Species', '9606', (164, 172))	('patients', 'Species', '9606', (223, 231))	('colorectal cancer', 'Disease', (110, 127))	('pT3', 'Gene', '7694', (99, 102))
45264	28210074	The PROMENADE trial NCT02974556 in Rome led by Sammartino randomizes patients with T3/T4 colorectal cancer into two arms, one for conventional surgery of the primary tumor followed by adjuvant systemic chemotherapy vs surgery of the primary tumor with risk-reducing surgery (omentectomy, appendectomy, removal of the round ligament and bilateral oophorectomy in postmenopausal patients) and HIPEC followed by adjuvant therapy.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('appendectomy', 'Disease', (288, 300))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (241, 246))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Disease', (89, 106))	('tumor', 'Disease', (166, 171))	('patients', 'Species', '9606', (377, 385))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('patients', 'Species', '9606', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('NCT02974556', 'Var', (20, 31))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
45265	28210074	Also for high-risk patients with pT4 or perforated tumors, the Dutch trial COLOPEC randomizes these patients to receive treatment with conventional surgery followed by systemic adjuvant therapy vs surgery of the primary tumor and administration of HIPEC (intraperitoneal oxaliplatin and intravenous 5-FU) during the intervention or within 5 to 8 wk after the intervention.	('oxaliplatin', 'Chemical', 'MESH:D000077150', (271, 282))	('pT4', 'Var', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('patients', 'Species', '9606', (19, 27))	('tumor', 'Disease', (220, 225))	('tumor', 'Disease', (51, 56))	('5-FU', 'Chemical', 'MESH:D005472', (299, 303))	('tumors', 'Disease', (51, 57))	('patients', 'Species', '9606', (100, 108))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
45282	26872740	Exome sequencing in one family with gastric- and rectal cancer Heritable factors are well known to increase the risk of cancer in families.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('rectal cancer', 'Phenotype', 'HP:0100743', (49, 62))	('cancer', 'Disease', (120, 126))	('gastric-', 'Disease', (36, 44))	('Exome sequencing', 'Var', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
45286	26872740	The mutations were found in 12 different genes; DZIP1L, PCOLCE2, IGSF10, SUCNR1, OR13C8, EPB41L4B, SEC16A, NOTCH1, TAS2R7, SF3A1, GAL3ST1, and TRIOBP.	('PCOLCE2', 'Gene', (56, 63))	('IGSF10', 'Gene', (65, 71))	('SEC16A', 'Gene', '9919', (99, 105))	('SUCNR1', 'Gene', '56670', (73, 79))	('GAL3ST1', 'Gene', (130, 137))	('TAS2R7', 'Gene', '50837', (115, 121))	('TAS2R7', 'Gene', (115, 121))	('GAL3ST1', 'Gene', '9514', (130, 137))	('OR13C8', 'Gene', (81, 87))	('NOTCH1', 'Gene', (107, 113))	('DZIP1L', 'Gene', '199221', (48, 54))	('TRIOBP', 'Gene', (143, 149))	('EPB41L4B', 'Gene', '54566', (89, 97))	('TRIOBP', 'Gene', '11078', (143, 149))	('SF3A1', 'Gene', '10291', (123, 128))	('mutations', 'Var', (4, 13))	('NOTCH1', 'Gene', '4851', (107, 113))	('DZIP1L', 'Gene', (48, 54))	('EPB41L4B', 'Gene', (89, 97))	('SUCNR1', 'Gene', (73, 79))	('OR13C8', 'Gene', '138802', (81, 87))	('SEC16A', 'Gene', (99, 105))	('SF3A1', 'Gene', (123, 128))	('PCOLCE2', 'Gene', '26577', (56, 63))
45320	26872740	Sequencing libraries were prepared according to the TruSeq DNA Sample Preparation Kit EUC 15005180 or EUC 15026489 (Illumina).	('rat', 'Species', '10116', (75, 78))	('EUC 15026489', 'Var', (102, 114))	('EUC 15005180', 'Var', (86, 98))
45331	26872740	Of the five family members tested for the 34 variants, only two (Co-634 and Co-667) had cancer, and both had rectal cancer and were therefore considered to be gene carriers.	('rectal cancer', 'Disease', 'MESH:D012004', (109, 122))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('Co', 'Chemical', 'MESH:D003035', (76, 78))	('Co', 'Chemical', 'MESH:D003035', (65, 67))	('cancer', 'Disease', (116, 122))	('variants', 'Var', (45, 53))	('rectal cancer', 'Disease', (109, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('rectal cancer', 'Phenotype', 'HP:0100743', (109, 122))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
45343	26872740	One interesting candidate variant was a frameshift deletion in the TRIOBP gene but it did not segregate in a family.	('TRIOBP', 'Gene', '11078', (67, 73))	('frameshift deletion', 'Var', (40, 59))	('TRIOBP', 'Gene', (67, 73))
45344	26872740	Another variant was a non-frameshift deletion in the SEC16A gene but it did not segregate with cancer in the family either.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('non-frameshift deletion', 'Var', (22, 45))	('cancer', 'Disease', (95, 101))	('SEC16A', 'Gene', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('SEC16A', 'Gene', '9919', (53, 59))
45345	26872740	One other potential mutation was a stop-gain in the DZIP1L gene but it also did not segregate in the family.	('DZIP1L', 'Gene', (52, 58))	('DZIP1L', 'Gene', '199221', (52, 58))	('mutation', 'Var', (20, 28))	('stop-gain', 'Var', (35, 44))
45347	26872740	All 12 variants but one (SEC16A) were predicted to have a pathogenic effect based on at least one predictor algorithm (Table 2).	('SEC16A', 'Gene', '9919', (25, 31))	('SEC16A', 'Gene', (25, 31))	('variants', 'Var', (7, 15))
45366	26872740	We could identify up to five or even 12 different genes and mutations, which all could have contributed more or less to the development of tumors in this family.	('mutations', 'Var', (60, 69))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
45373	26872740	The region identified in the present study (the variants in the genes OR13C8, EPB41L4B, SEC16A and NOTCH1), is just proximal to that region on 9q.	('OR13C8', 'Gene', (70, 76))	('EPB41L4B', 'Gene', '54566', (78, 86))	('NOTCH1', 'Gene', '4851', (99, 105))	('variants', 'Var', (48, 56))	('NOTCH1', 'Gene', (99, 105))	('SEC16A', 'Gene', (88, 94))	('OR13C8', 'Gene', '138802', (70, 76))	('EPB41L4B', 'Gene', (78, 86))	('SEC16A', 'Gene', '9919', (88, 94))
45379	26872740	The NOTCH1 variant in our family was found in three other families, where it did not segregate.	('NOTCH1', 'Gene', (4, 10))	('variant', 'Var', (11, 18))	('NOTCH1', 'Gene', '4851', (4, 10))
45388	26872740	Further studies are needed to find out more about these variants and other gene variants possibly contributing to the increased cancer risk in this family.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('variants', 'Var', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (128, 134))
45389	25928810	A Two-Gene Blood Test for Methylated DNA Sensitive for Colorectal Cancer Specific genes are methylated with high frequency in colorectal neoplasia, and may leak into blood.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (55, 72))	('Colorectal Cancer', 'Disease', (55, 72))	('leak', 'Reg', (156, 160))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('colorectal neoplasia', 'Disease', (126, 146))	('neoplasia', 'Phenotype', 'HP:0002664', (137, 146))	('methylated', 'Var', (92, 102))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (126, 146))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (55, 72))
45392	25928810	Methylation-specific PCR assays were developed to measure the level of methylated BCAT1 and IKZF1 in DNA extracted from plasma obtained from colonoscopy-confirmed 144 healthy controls and 74 CRC cases.	('BCAT1', 'Gene', (82, 87))	('IKZF1', 'Gene', (92, 97))	('BCAT1', 'Gene', '586', (82, 87))	('IKZF1', 'Gene', '10320', (92, 97))	('methylated', 'Var', (71, 81))
45393	25928810	Methylated BCAT1 and IKZF1 DNA were detected in respectively 48 (65%) and 50 (68%) of the 74 cancers.	('BCAT1', 'Gene', '586', (11, 16))	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('detected', 'Reg', (36, 44))	('IKZF1', 'Gene', '10320', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('BCAT1', 'Gene', (11, 16))	('Methylated', 'Var', (0, 10))	('IKZF1', 'Gene', (21, 26))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
45396	25928810	Detection of methylated BCAT1 and/or IKZF1 DNA in plasma may have clinical application as a novel blood test for CRC.	('IKZF1', 'Gene', (37, 42))	('methylated', 'Var', (13, 23))	('clinical', 'Species', '191496', (66, 74))	('CRC', 'Disease', (113, 116))	('BCAT1', 'Gene', (24, 29))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('IKZF1', 'Gene', '10320', (37, 42))	('BCAT', 'molecular_function', 'GO:0043840', ('24', '28'))	('BCAT1', 'Gene', '586', (24, 29))
45400	25928810	In particular, there is accumulating literature documenting circulating tumour-specific mutated and/or methylated DNA and RNA.	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('DNA', 'Gene', (114, 117))	('methylated', 'Var', (103, 113))	('mutated', 'Var', (88, 95))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))
45401	25928810	We have previously described the discovery and validation of a range of novel hypermethylated genes characteristic of colorectal neoplastic tissue.	('colorectal neoplastic', 'Disease', 'MESH:D015179', (118, 139))	('colorectal neoplastic', 'Disease', (118, 139))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (129, 146))	('hypermethylated genes', 'Var', (78, 99))
45403	25928810	We report the evaluation of two methylation-specific PCR assays for detection of methylated BCAT1 and IKZF1 DNA extracted from plasma samples from 218 colonoscopy-examined individuals (144 healthy controls and 74 CRC cases) to determine if the methylation biomarkers were complementary for detection of CRC.	('BCAT1', 'Gene', (92, 97))	('methylated', 'Var', (81, 91))	('CRC', 'Disease', (303, 306))	('IKZF1', 'Gene', (102, 107))	('BCAT1', 'Gene', '586', (92, 97))	('IKZF1', 'Gene', '10320', (102, 107))
45418	25928810	Briefly, the two real-time PCR assays targeted methylated CpG sites in regions spanning 102- or 95- nucleotides, either within, or just upstream of the first exon of the BCAT1 and IKZF1 genes, respectively (see S2 Fig).	('methylated', 'Var', (47, 57))	('BCAT', 'molecular_function', 'GO:0043840', ('170', '174'))	('BCAT1', 'Gene', '586', (170, 175))	('IKZF1', 'Gene', '10320', (180, 185))	('BCAT1', 'Gene', (170, 175))	('IKZF1', 'Gene', (180, 185))
45419	25928810	The BCAT1 PCR assay (hydrolysis probe) and IKZF1 PCR assay (SYBR green/melt) were qualitatively called "positive" for BCAT1 methylation if a total change in fluorescence intensity above background levels was measured within 50 PCR amplification cycles.	('fluorescence intensity', 'MPA', (157, 179))	('IKZF1', 'Gene', (43, 48))	('BCAT1', 'Gene', (4, 9))	('IKZF1', 'Gene', '10320', (43, 48))	('BCAT1', 'Gene', '586', (118, 123))	('BCAT1', 'Gene', '586', (4, 9))	('methylation', 'Var', (124, 135))	('BCAT1', 'Gene', (118, 123))
45429	25928810	For density plots of amounts of methylated BCAT1 or IKZF1 DNA, samples with "no signal" results were omitted.	('BCAT1', 'Gene', (43, 48))	('IKZF1', 'Gene', '10320', (52, 57))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('BCAT', 'molecular_function', 'GO:0043840', ('43', '47'))	('BCAT1', 'Gene', '586', (43, 48))	('IKZF1', 'Gene', (52, 57))	('methylated', 'Var', (32, 42))
45443	25928810	Fig 3A shows that a combined qualitative result based on at least one positive replicate in either the BCAT1 or IKZF1 methylation assay produced the highest classification accuracy (0.8469, 95%CI: 0.7848-0.9091) compared to either of the markers alone (BCAT1; 0.8070, 95%CI 0.7368-0.8771, IKZF1; 0.8135, 95%CI: 0.7448-0.8822).	('IKZF1', 'Gene', (289, 294))	('BCAT1', 'Gene', (253, 258))	('BCAT', 'molecular_function', 'GO:0043840', ('103', '107'))	('BCAT1', 'Gene', '586', (103, 108))	('IKZF1', 'Gene', (112, 117))	('BCAT', 'molecular_function', 'GO:0043840', ('253', '257'))	('methylation', 'biological_process', 'GO:0032259', ('118', '129'))	('IKZF1', 'Gene', '10320', (289, 294))	('BCAT1', 'Gene', '586', (253, 258))	('BCAT1', 'Gene', (103, 108))	('methylation', 'Var', (118, 129))	('IKZF1', 'Gene', '10320', (112, 117))
45445	25928810	Good correlation was observed in the cycle-threshold (Ct) values measured in specimens positive for both BCAT1 and IKZF1 DNA methylation (correlation co-efficiency R2 = 0.9053, Fig 4A).	('BCAT1', 'Gene', (105, 110))	('cycle-threshold', 'MPA', (37, 52))	('positive', 'Reg', (87, 95))	('IKZF1', 'Gene', '10320', (115, 120))	('BCAT1', 'Gene', '586', (105, 110))	('IKZF1', 'Gene', (115, 120))	('methylation', 'Var', (125, 136))
45446	25928810	The average masses of methylated BCAT1 or IKZF1 DNA measured in CRC stages II, III and IV were significantly higher compared to the average mass of methylation measured in the limited number of controls that were positive (Fig 4B and 4C).	('BCAT1', 'Gene', (33, 38))	('masses', 'MPA', (12, 18))	('IKZF1', 'Gene', '10320', (42, 47))	('higher', 'PosReg', (109, 115))	('BCAT1', 'Gene', '586', (33, 38))	('IKZF1', 'Gene', (42, 47))	('methylated', 'Var', (22, 32))
45450	25928810	We determined that less than 8% of positive control plasma specimens are found to contain at least 20 pg of methylated BCAT1 or IKZF1 DNA, while 63-77% of early stage cancers had 20 pg or more.	('IKZF1', 'Gene', (128, 133))	('BCAT1', 'Gene', (119, 124))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('cancers', 'Disease', (167, 174))	('methylated', 'Var', (108, 118))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('IKZF1', 'Gene', '10320', (128, 133))	('BCAT', 'molecular_function', 'GO:0043840', ('119', '123'))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('BCAT1', 'Gene', '586', (119, 124))	('DNA', 'cellular_component', 'GO:0005574', ('134', '137'))
45451	25928810	Thus the likelihood of a plasma specimen with >= 20 pg methylated BCAT1 or IKZF1 DNA to be an early stage cancer is approximately 9:1 and 210:1, respectively (early stage CRC: control).	('BCAT1', 'Gene', '586', (66, 71))	('IKZF1', 'Gene', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('methylated', 'Var', (55, 65))	('BCAT1', 'Gene', (66, 71))	('IKZF1', 'Gene', '10320', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
45452	25928810	Further, a plasma specimen with 100 pg of methylated IKZF1 DNA is approximately 2.5 times more likely to be drawn from a subject with late stage CRC (Stage III or IV) than a subject with early stage CRC (Stage I or II).	('IKZF1', 'Gene', (53, 58))	('more', 'PosReg', (90, 94))	('IKZF1', 'Gene', '10320', (53, 58))	('methylated', 'Var', (42, 52))
45455	25928810	In this case-control study we demonstrate that methylated BCAT1 and IKZF1 DNA is detected more frequently in CRC cases (65% and 68%, respectively) than in colonoscopy-confirmed healthy controls (4% and 5%, respectively) and that the two methylation DNA markers are complementary (combined positivity of 77% and 7.6% in CRC and healthy controls, respectively).	('BCAT1', 'Gene', '586', (58, 63))	('methylated', 'Var', (47, 57))	('DNA', 'cellular_component', 'GO:0005574', ('249', '252'))	('DNA', 'cellular_component', 'GO:0005574', ('74', '77'))	('IKZF1', 'Gene', '10320', (68, 73))	('BCAT', 'molecular_function', 'GO:0043840', ('58', '62'))	('CRC', 'Disease', (109, 112))	('BCAT1', 'Gene', (58, 63))	('IKZF1', 'Gene', (68, 73))	('methylation', 'biological_process', 'GO:0032259', ('237', '248'))
45456	25928810	A total of 41/74 cancer cases were positive for both methylated BCAT1 and IKZF1 DNA compared to only 1/144 control).	('IKZF1', 'Gene', (74, 79))	('positive', 'Reg', (35, 43))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('BCAT', 'molecular_function', 'GO:0043840', ('64', '68'))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('BCAT1', 'Gene', (64, 69))	('cancer', 'Disease', (17, 23))	('BCAT1', 'Gene', '586', (64, 69))	('IKZF1', 'Gene', '10320', (74, 79))	('methylated', 'Var', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
45458	25928810	Detection of methylated BCAT1 and IKZF1 DNA in blood did not depend on age or gender of subject, or amount of recovered bisulphite converted cfDNA.	('methylated', 'Var', (13, 23))	('IKZF1', 'Gene', '10320', (34, 39))	('bisulphite', 'Chemical', 'MESH:C042345', (120, 130))	('BCAT1', 'Gene', (24, 29))	('IKZF1', 'Gene', (34, 39))	('BCAT1', 'Gene', '586', (24, 29))
45465	25928810	A hypermethylated BCAT1 locus has been demonstrated for several pathologies including CRC and aberrant epigenetic regulation causes a ratio shift in three main BCAT1 mRNA transcripts differing only in the first exon, which harbors alternative untranslated regions.	('BCAT1', 'Gene', (160, 165))	('BCAT1', 'Gene', '586', (18, 23))	('hypermethylated', 'Var', (2, 17))	('mRNA transcripts', 'MPA', (166, 182))	('ratio shift', 'MPA', (134, 145))	('aberrant epigenetic regulation', 'Var', (94, 124))	('causes', 'Reg', (125, 131))	('BCAT1', 'Gene', (18, 23))	('BCAT1', 'Gene', '586', (160, 165))	('BCAT', 'molecular_function', 'GO:0043840', ('18', '22'))	('BCAT', 'molecular_function', 'GO:0043840', ('160', '164'))	('regulation', 'biological_process', 'GO:0065007', ('114', '124'))	('CRC', 'Disease', (86, 89))
45466	25928810	How the BCAT1 isoforms affect cell proliferation is unknown, but it is speculated that dysfunctional production of branched-chain amino acids may affect synthesis of macromolecules required for cell division, perhaps at the G1-to-S cell cycle control point.	('BCAT1', 'Gene', (8, 13))	('branched-chain amino acids', 'Chemical', 'MESH:D000597', (115, 141))	('affect', 'Reg', (146, 152))	('BCAT1', 'Gene', '586', (8, 13))	('dysfunctional', 'Var', (87, 100))
45471	25928810	Thus, loss of SEPT9 expression may play an active role in tumour invasion, where metastatic tumour cells through poorly understood mechanisms migrate to the vascular system.	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('loss', 'Var', (6, 10))	('play', 'Reg', (35, 39))	('tumour', 'Disease', (92, 98))	('SEPT9', 'Gene', '10801', (14, 19))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('SEPT9', 'Gene', (14, 19))	('tumour', 'Disease', (58, 64))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))
45473	25928810	We speculate if loss of IKZF1 activity due to hypermethylation, leads to constitutively active Notch signaling which inhibits differentiation of crypt progenitor cells and results in a large increase in undifferentiated transient amplifying cells as previously described.	('undifferentiated transient amplifying cells', 'CPA', (203, 246))	('IKZF1', 'Gene', '10320', (24, 29))	('differentiation of crypt progenitor cells', 'CPA', (126, 167))	('increase', 'PosReg', (191, 199))	('Notch signaling', 'MPA', (95, 110))	('inhibits', 'NegReg', (117, 125))	('loss', 'NegReg', (16, 20))	('IKZF1', 'Gene', (24, 29))	('hypermethylation', 'Var', (46, 62))	('activity', 'MPA', (30, 38))
45478	25928810	Our own dataset only included four Stage I cancers, and while two (50%) of these were detected, the sample numbers are presently too low to conclude whether the methylated BCAT1/IKZF1 test will give good detection of Stage I cancers.	('I cancers', 'Disease', 'MESH:D009369', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))	('IKZF1', 'Gene', '10320', (178, 183))	('BCAT1', 'Gene', '586', (172, 177))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('methylated', 'Var', (161, 171))	('I cancers', 'Disease', (223, 232))	('I cancers', 'Disease', (41, 50))	('BCAT1', 'Gene', (172, 177))	('IKZF1', 'Gene', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('I cancers', 'Disease', 'MESH:D009369', (223, 232))
45480	25928810	Unfortunately, we could not assess whether detectability of methylated BCAT1 and IKZF1 DNA in blood was associated with appearance of vasculature-related features, as these variables were not recorded in the histological reports for the cancers included in the dataset herein.	('IKZF1', 'Gene', '10320', (81, 86))	('BCAT1', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('DNA', 'cellular_component', 'GO:0005574', ('87', '90'))	('IKZF1', 'Gene', (81, 86))	('BCAT', 'molecular_function', 'GO:0043840', ('71', '75'))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('cancers', 'Disease', (237, 244))	('cancers', 'Disease', 'MESH:D009369', (237, 244))	('BCAT1', 'Gene', '586', (71, 76))	('methylated', 'Var', (60, 70))
45515	33946986	Increasing evidence also implicates a profound role for PPARs in stromal cellular behaviors and eventual consequences in cancer hallmarks.	('stromal cellular behaviors', 'CPA', (65, 91))	('consequences', 'Reg', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('PPARs', 'Var', (56, 61))	('cancer hallmarks', 'Disease', (121, 137))	('cancer hallmarks', 'Disease', 'MESH:D009369', (121, 137))
45523	33946986	In breast cancer stem cells, GW6471 (a PPARalpha antagonist) is anti-proliferative and pro-apoptotic, while Wy14643 (a PPARalpha agonist) induces the clonal expansion of breast cancer mammospheres by promoting the signaling activities of the nuclear receptor kappaB (NF-kappaB)/ interleukin-6 (IL-6) axis, SLUG, Notch3, and Jagged 1.	('interleukin-6', 'Gene', '16193', (279, 292))	('signaling activities', 'MPA', (214, 234))	('GW6471', 'Chemical', 'MESH:C449302', (29, 35))	('IL-6', 'Gene', '16193', (294, 298))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('Jagged 1', 'Gene', '16449', (324, 332))	('clonal expansion', 'CPA', (150, 166))	('Wy14643', 'Var', (108, 115))	('Notch3', 'Gene', '18131', (312, 318))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('SLUG', 'Gene', '20583', (306, 310))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('NF-kappaB', 'Gene', (267, 276))	('promoting', 'PosReg', (200, 209))	('Wy14643', 'Chemical', 'MESH:C006253', (108, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('interleukin-6', 'Gene', (279, 292))	('breast cancer', 'Disease', (170, 183))	('SLUG', 'Gene', (306, 310))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('IL-6', 'Gene', (294, 298))	('Notch3', 'Gene', (312, 318))	('breast cancer', 'Disease', (3, 16))	('Jagged 1', 'Gene', (324, 332))	('induces', 'PosReg', (138, 145))	('GW6471', 'Var', (29, 35))	('NF-kappaB', 'Gene', '18033', (267, 276))	('IL-6', 'molecular_function', 'GO:0005138', ('294', '298'))	('signaling', 'biological_process', 'GO:0023052', ('214', '223'))
45537	33946986	Separately, by suppressing matrix metalloproteinases and antagonizing Smad3-dependent transcriptional activity, PPARgamma also attenuates extracellular matrix (ECM) remodeling and epithelial-mesenchymal transition (EMT), which, in turn, leads to reduced tumor metastasis.	('matrix metalloproteinases', 'Protein', (27, 52))	('PPARgamma', 'Var', (112, 121))	('EMT', 'biological_process', 'GO:0001837', ('215', '218'))	('attenuates', 'NegReg', (127, 137))	('suppressing', 'NegReg', (15, 26))	('tumor metastasis', 'Disease', 'MESH:D009362', (254, 270))	('tumor metastasis', 'Disease', (254, 270))	('reduced', 'NegReg', (246, 253))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('180', '213'))	('Smad3', 'Gene', '17127', (70, 75))	('epithelial-mesenchymal transition', 'CPA', (180, 213))	('Smad3', 'Gene', (70, 75))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('138', '158'))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('antagonizing', 'NegReg', (57, 69))
45548	33946986	Notably, the genetic background could act as a strong modifier of the pro-tumor effect of PPARgamma, as examplified by the predisposition of certain PPARgamma polymorphisms (i.e., Pro12Ala and C161T) to breast cancer.	('Pro12Ala', 'Chemical', '-', (180, 188))	('PPARgamma', 'Gene', (149, 158))	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('breast cancer', 'Disease', (203, 216))	('C161T', 'Var', (193, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('C161T', 'Mutation', 'rs3856806', (193, 198))	('tumor', 'Disease', (74, 79))	('Pro12Ala', 'Var', (180, 188))
45557	33946986	In a nonmelanoma skin cancer mouse model, PPARbeta/delta activates the oncogene Src and the EGFR/Erk1/2 signaling pathways upon UV exposure, resulting in increased tumor burden and EMT.	('tumor', 'Disease', (164, 169))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('Erk1/2', 'Gene', (97, 103))	('Src', 'Gene', (80, 83))	('EMT', 'CPA', (181, 184))	('nonmelanoma skin cancer', 'Disease', 'MESH:D012878', (5, 28))	('mouse', 'Species', '10090', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('increased', 'PosReg', (154, 163))	('Erk1/2', 'Gene', '26417;26413', (97, 103))	('skin cancer', 'Phenotype', 'HP:0008069', (17, 28))	('PPARbeta/delta', 'Var', (42, 56))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('Src', 'Gene', '20779', (80, 83))	('activates', 'PosReg', (57, 66))	('nonmelanoma skin cancer', 'Disease', (5, 28))	('EGFR', 'Gene', (92, 96))	('EGFR', 'Gene', '13649', (92, 96))
45595	33946986	Cancer exosomes loaded with miRNA-144 and miRNA-155 facilitate the beige/brown differentiation of CAAs by modulating the MAP3K8-Erk1/2-PPARgamma axis, whereas those carrying miRNA-126 can disrupt IRS-GLUT4 signaling and promote AMPK- and HIF1alpha-mediated autophagy.	('CAAs', 'Chemical', '-', (98, 102))	('MAP3K8', 'Gene', (121, 127))	('facilitate', 'PosReg', (52, 62))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Erk1/2', 'Gene', (128, 134))	('GLUT4', 'Gene', (200, 205))	('modulating', 'Reg', (106, 116))	('GLUT4', 'Gene', '20528', (200, 205))	('Erk1/2', 'Gene', '26417;26413', (128, 134))	('MAP3K8', 'Gene', '26410', (121, 127))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('HIF1alpha', 'Gene', '15251', (238, 247))	('promote', 'PosReg', (220, 227))	('miRNA-144', 'Var', (28, 37))	('HIF1alpha', 'Gene', (238, 247))	('beige/brown differentiation of CAAs', 'CPA', (67, 102))	('miRNA-155', 'Var', (42, 51))	('IRS', 'Gene', (196, 199))	('Cancer', 'Disease', (0, 6))	('IRS', 'Gene', '105148', (196, 199))	('disrupt', 'NegReg', (188, 195))
45602	33946986	Consistent with these observations, the adipocyte-specific deletion of PPARgamma in a chemically induced breast cancer model impaired BRCA1 expression in CAAs and subsequently accelerated tumor formation and progression.	('tumor', 'Disease', (188, 193))	('BRCA1', 'Gene', (134, 139))	('impaired', 'NegReg', (125, 133))	('expression', 'MPA', (140, 150))	('progression', 'CPA', (208, 219))	('PPARgamma', 'Gene', (71, 80))	('CAAs', 'Chemical', '-', (154, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('formation', 'biological_process', 'GO:0009058', ('194', '203'))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('deletion', 'Var', (59, 67))	('breast cancer', 'Disease', (105, 118))	('BRCA1', 'Gene', '12189', (134, 139))	('accelerated', 'PosReg', (176, 187))
45610	33946986	Interestingly, mice with fibroblast-selective PPARbeta/delta deletion developed fewer and smaller skin tumors than wild-type mice exposed to topical carcinogens.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('skin tumors', 'Disease', 'MESH:D012878', (98, 109))	('PPARbeta/delta', 'Gene', (46, 60))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('deletion', 'Var', (61, 69))	('fewer', 'NegReg', (80, 85))	('smaller', 'NegReg', (90, 97))	('mice', 'Species', '10090', (125, 129))	('mice', 'Species', '10090', (15, 19))	('skin tumors', 'Phenotype', 'HP:0008069', (98, 109))	('topical', 'molecular_function', 'GO:0003809', ('141', '148'))	('skin tumors', 'Disease', (98, 109))
45611	33946986	Similar results were recapitulated using chemically and genetically induced intestinal carcinogenesis in these mutant mice, indicating that PPARbeta/delta activity in stromal fibroblasts promotes tumor initiation.	('PPARbeta/delta', 'Var', (140, 154))	('tumor initiation', 'Disease', (196, 212))	('intestinal carcinogenesis', 'Disease', (76, 101))	('intestinal carcinogenesis', 'Disease', 'MESH:D063646', (76, 101))	('promotes', 'PosReg', (187, 195))	('mice', 'Species', '10090', (118, 122))	('tumor initiation', 'Disease', 'MESH:D009369', (196, 212))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
45612	33946986	The delayed tumor emergence in the mutant mice was due to an enhanced antioxidant response in the epithelium.	('enhanced', 'PosReg', (61, 69))	('antioxidant response', 'MPA', (70, 90))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('mice', 'Species', '10090', (42, 46))	('mutant', 'Var', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
45617	33946986	PPARbeta/delta in fibroblasts upregulates the expression of LRG1, which blunts the epidermal response to TGFbeta1.	('PPARbeta/delta', 'Var', (0, 14))	('TGFbeta1', 'Gene', (105, 113))	('epidermal response', 'MPA', (83, 101))	('TGFbeta1', 'Gene', '21803', (105, 113))	('blunts', 'NegReg', (72, 78))	('upregulates', 'PosReg', (30, 41))	('LRG1', 'Gene', (60, 64))	('expression', 'MPA', (46, 56))
45618	33946986	Furthermore, exogenous LRG1 can also ablate the influence of TGFbeta1 on ROS generation and NRF2 activity.	('ROS generation', 'biological_process', 'GO:1903409', ('73', '87'))	('ROS', 'Chemical', 'MESH:D000077154', (73, 76))	('ablate', 'NegReg', (37, 43))	('TGFbeta1', 'Gene', (61, 69))	('NRF2', 'Gene', '18024', (92, 96))	('TGFbeta1', 'Gene', '21803', (61, 69))	('NRF2', 'Gene', (92, 96))	('ROS generation', 'MPA', (73, 87))	('exogenous', 'Var', (13, 22))	('LRG1', 'Protein', (23, 27))
45621	33946986	The expression of LRG1 is increased by a PPARbeta/delta agonist, GW501516, which strongly suggests that LRG1 is a direct target of PPARbeta/delta.	('LRG1', 'Gene', (18, 22))	('expression', 'MPA', (4, 14))	('GW501516', 'Chemical', 'MESH:C425931', (65, 73))	('increased', 'PosReg', (26, 35))	('GW501516', 'Var', (65, 73))
45622	33946986	Therefore, during the early stage of tumorigenesis, CAF PPARbeta/delta may stimulate LRG1 expression, which interferes with TGFbeta1-dependent redox homeostasis, to support a sustained oncogenic transformation in the surrounding tumor epithelium.	('TGFbeta1', 'Gene', '21803', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('CAF', 'Gene', '104272', (52, 55))	('stimulate', 'PosReg', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('oncogenic transformation', 'CPA', (185, 209))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('PPARbeta/delta', 'Var', (56, 70))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', (37, 42))	('expression', 'MPA', (90, 100))	('support', 'PosReg', (165, 172))	('TGFbeta1', 'Gene', (124, 132))	('CAF', 'Gene', (52, 55))	('LRG1', 'Gene', (85, 89))
45631	33946986	Furthermore, by transcriptionally suppressing the expression of endothelial P450 CYP2C epoxygenase, whose function is to catalyze arachidonic acid epoxidation, PPARalpha also diminishes the epoxygenase products, epoxyeicosatrienoic acids, which are pro-angiogenic.	('epoxyeicosatrienoic acids', 'MPA', (212, 237))	('oxygen', 'Chemical', 'MESH:D010100', (192, 198))	('oxygen', 'Chemical', 'MESH:D010100', (89, 95))	('epoxygenase products', 'MPA', (190, 210))	('suppressing', 'NegReg', (34, 45))	('endothelial P450 CYP2C epoxygenase', 'Enzyme', (64, 98))	('epoxyeicosatrienoic acids', 'Chemical', '-', (212, 237))	('diminishes', 'NegReg', (175, 185))	('arachidonic acid', 'Chemical', 'MESH:D016718', (130, 146))	('PPARalpha', 'Var', (160, 169))	('expression', 'MPA', (50, 60))
45642	33946986	Mechanistically, abolishing PPARgamma in the endothelial cells disrupts E2F1-mediated Wnt signaling and GSK3B interacting protein activity, resulting in suppressed endothelial proliferation.	('E2F1', 'Gene', (72, 76))	('E2F1', 'Gene', '13555', (72, 76))	('Wnt', 'Gene', '22418', (86, 89))	('disrupts', 'NegReg', (63, 71))	('GSK3B interacting protein', 'Protein', (104, 129))	('Wnt', 'Gene', (86, 89))	('abolishing', 'Var', (17, 27))	('suppressed', 'NegReg', (153, 163))	('activity', 'MPA', (130, 138))	('PPARgamma', 'Protein', (28, 37))	('endothelial proliferation', 'CPA', (164, 189))
45650	33946986	For instance, 15d-PGJ2 activates PPARgamma and suppresses the proliferation of CAFs and expression of the ECM remodeling enzyme, MMP2.	('MMP2', 'molecular_function', 'GO:0004228', ('129', '133'))	('15d-PGJ2', 'Var', (14, 22))	('CAF', 'Gene', '104272', (79, 82))	('MMP2', 'Gene', '17390', (129, 133))	('suppresses', 'NegReg', (47, 57))	('PPARgamma', 'Protein', (33, 42))	('activates', 'PosReg', (23, 32))	('CAF', 'Gene', (79, 82))	('MMP2', 'Gene', (129, 133))	('expression', 'MPA', (88, 98))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (14, 22))
45652	33946986	The repression of PPARgamma activity also disturbs the quiescent state of hepatic and pancreatic stellate cells, compelling their differentiation into CAFs with highly aggressive phenotypes and inducing desmoplasia in the TME.	('disturbs', 'Reg', (42, 50))	('desmoplasia', 'Disease', (203, 214))	('compelling', 'Reg', (113, 123))	('CAF', 'Gene', (151, 154))	('quiescent state', 'MPA', (55, 70))	('inducing', 'Reg', (194, 202))	('CAF', 'Gene', '104272', (151, 154))	('PPARgamma activity', 'Gene', (18, 36))	('repression', 'Var', (4, 14))
45653	33946986	Despite some conflicting results, PPARgamma in CAFs can disrupt pro-tumorigenic paracrine signaling by suppressing the liberation of cytokines and chemokines.	('tumor', 'Disease', (68, 73))	('PPARgamma', 'Var', (34, 43))	('CAF', 'Gene', (47, 50))	('disrupt', 'NegReg', (56, 63))	('CAF', 'Gene', '104272', (47, 50))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('suppressing', 'NegReg', (103, 114))
45655	33946986	Classical PPARgamma ligands, namely rosiglitazone, N-docosahexaenoyl ethanolamide, and N-docosahexaenoyl serotonin, effectively block paracrine signals from cancer cells to sway the fate of macrophages to adopt alternative activation and reduce their STAT3-mediated pro-inflammatory response.	('STAT3', 'Gene', (251, 256))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('N-docosahexaenoyl ethanolamide', 'Chemical', 'MESH:C561061', (51, 81))	('fat', 'Gene', (182, 185))	('fat', 'Gene', '12491', (182, 185))	('N-docosahexaenoyl serotonin', 'Chemical', '-', (87, 114))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('N-docosahexaenoyl', 'Var', (87, 104))	('block', 'NegReg', (128, 133))	('cancer', 'Disease', (157, 163))	('rosiglitazone', 'Chemical', 'MESH:D000077154', (36, 49))	('STAT3', 'Gene', '20848', (251, 256))	('reduce', 'NegReg', (238, 244))	('paracrine signals', 'MPA', (134, 151))
45656	33946986	In macrophages challenged with pathogens, WY14643 (PPARalpha agonist) and 15d-PGJ2 (PPARgamma agonist) tip the balance towards the M2 phenotype by enhancing the expression of arginase I, Ym1 (chitinase 3-like 3), mannose receptor, TGF-beta and increasing phagocytic capacity while diminishing M1 macrophage biomarkers.	('Ym1', 'Gene', '12655', (187, 190))	('phagocytic capacity', 'CPA', (255, 274))	('WY14643', 'Var', (42, 49))	('WY14643', 'Chemical', 'MESH:C006253', (42, 49))	('M1 macrophage biomarkers', 'MPA', (293, 317))	('expression', 'MPA', (161, 171))	('15d-PGJ2', 'Chemical', 'MESH:C097240', (74, 82))	('TGF-beta', 'Gene', (231, 239))	('enhancing', 'PosReg', (147, 156))	('15d-PGJ2', 'Var', (74, 82))	('Ym1', 'Gene', (187, 190))	('mannose receptor', 'Protein', (213, 229))	('increasing', 'PosReg', (244, 254))	('arginase I', 'Gene', '11846', (175, 185))	('TGF-beta', 'Gene', '21802', (231, 239))	('diminishing', 'NegReg', (281, 292))	('arginase I', 'Gene', (175, 185))
45657	33946986	PPARgamma antagonists and macrophage-specific PPARgamma ablation attenuate these effects, clearly outlining the dependency of TAM differentiation on PPARgamma.	('TAM', 'Chemical', '-', (126, 129))	('PPARgamma', 'Gene', (46, 55))	('attenuate', 'NegReg', (65, 74))	('ablation', 'Var', (56, 64))
45684	33946986	Our latest report showed that exogenous ANGPTL4 activates macrophages and induces hypercytokinemia via PI3K/Akt-mediated complement component 5a (C5a) activation.	('macrophages', 'CPA', (58, 69))	('induces', 'Reg', (74, 81))	('C5a', 'Gene', (146, 149))	('Akt', 'Gene', '11651', (108, 111))	('Akt', 'Gene', (108, 111))	('hypercytokinemia', 'Disease', (82, 98))	('PI3K', 'molecular_function', 'GO:0016303', ('103', '107'))	('exogenous', 'Var', (30, 39))	('ANGPTL4', 'Gene', '57875', (40, 47))	('ANGPTL4', 'Gene', (40, 47))	('activates', 'PosReg', (48, 57))	('hypercytokinemia', 'Disease', 'None', (82, 98))	('C5a', 'Gene', '15139', (146, 149))
45688	33946986	In myeloid-derived suppressor cells (MDSCs), deficiency of lysosomal acid lipase (lal-/-) impaired the production of PPARgamma ligands, which led to reduced PPARgamma activity, ROS accumulation, and mTOR-mediated tumor metastasis.	('impaired', 'NegReg', (90, 98))	('mTOR', 'Gene', (199, 203))	('PPARgamma', 'Enzyme', (157, 166))	('mTOR', 'Gene', '56717', (199, 203))	('tumor metastasis', 'Disease', 'MESH:D009362', (213, 229))	('PPARgamma', 'Protein', (117, 126))	('reduced', 'NegReg', (149, 156))	('tumor metastasis', 'Disease', (213, 229))	('production of', 'MPA', (103, 116))	('ROS', 'Protein', (177, 180))	('deficiency', 'Var', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('activity', 'MPA', (167, 175))	('ROS', 'Chemical', 'MESH:D000077154', (177, 180))
45689	33946986	Following intravenous injection of B16 melanoma cells, increased lung metastases were observed in mice with myeloid-specific PPARgamma knockout, further reinforcing the role of MDSCs' PPARgamma in metastasis.	('B16', 'CellLine', 'CVCL:N540', (35, 38))	('lung metastases', 'Disease', (65, 80))	('knockout', 'Var', (135, 143))	('lung metastases', 'Disease', 'MESH:D009362', (65, 80))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('increased', 'PosReg', (55, 64))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('mice', 'Species', '10090', (98, 102))	('PPARgamma', 'Gene', (125, 134))
45705	33946986	Yet, unlike PPARalpha and PPARgamma, PPARbeta/delta, which is ubiquitously expressed in almost all tissues, displays an apparent pro-tumor activity.	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('PPARbeta/delta', 'Var', (37, 51))	('tumor', 'Disease', 'MESH:D009369', (133, 138))
45729	33946986	We anticipate that the investigation of newer PPAR modulators and their anticancer effect in the TME will gain momentum in the years to come.	('PPAR', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('modulators', 'Var', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
45736	33863904	Cancer cells expressing higher DUSP16 are intrinsically more resistant to chemotherapy-induced cell death than cells with lower DUSP16 expression.	('DUSP16', 'Gene', (31, 37))	('higher', 'Var', (24, 30))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('resistant', 'CPA', (61, 70))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
45737	33863904	Overexpression of DUSP16 in cancer cells leads to increased resistance to cell death upon chemotherapy treatment.	('cell death', 'biological_process', 'GO:0008219', ('74', '84'))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('DUSP16', 'Gene', (18, 24))	('increased', 'PosReg', (50, 59))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', (28, 34))
45738	33863904	In contrast, knockdown of DUSP16 in cancer cells increases their sensitivity to treatment.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('sensitivity to treatment', 'MPA', (65, 89))	('increases', 'PosReg', (49, 58))	('DUSP16', 'Gene', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('knockdown', 'Var', (13, 22))
45743	33863904	Here, the authors show that dual-specificity phosphatase 16 (DUSP16) expression is associated with chemoresistance in several types of cancer through impairing mitochondria-associated apoptosis.	('dual-specificity phosphatase 16', 'Gene', (28, 59))	('cancer', 'Disease', (135, 141))	('dual-specificity phosphatase 16', 'Gene', '80824', (28, 59))	('mitochondria', 'cellular_component', 'GO:0005739', ('160', '172'))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('apoptosis', 'biological_process', 'GO:0097194', ('184', '193'))	('chemoresistance', 'Disease', (99, 114))	('DUSP16', 'Gene', (61, 67))	('impairing', 'NegReg', (150, 159))	('associated', 'Reg', (83, 93))	('apoptosis', 'biological_process', 'GO:0006915', ('184', '193'))	('phosphatase', 'molecular_function', 'GO:0016791', ('45', '56'))	('mitochondria-associated apoptosis', 'MPA', (160, 193))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('expression', 'Var', (69, 79))
45745	33863904	Drug resistance may arise intrinsically from host factors or may be acquired by genetic or epigenetic alterations in the cancer cells.	('Drug resistance', 'Phenotype', 'HP:0020174', (0, 15))	('Drug resistance', 'MPA', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('epigenetic alterations', 'Var', (91, 113))	('arise', 'Reg', (20, 25))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
45755	33863904	5-FU, on the other hand, is an apyrimidine analog that inhibits thymidylate synthase and can also misincorporate into DNA during polynucleotide biosynthesis, which leads to DNA damage and apoptosis.	('apyrimidine', 'Chemical', '-', (31, 42))	('DNA damage', 'MPA', (173, 183))	('leads to', 'Reg', (164, 172))	('thymidylate synthase', 'Gene', (64, 84))	('inhibits', 'NegReg', (55, 63))	('5-FU', 'Chemical', 'MESH:D005472', (0, 4))	('apoptosis', 'CPA', (188, 197))	('misincorporate', 'Var', (98, 112))	('polynucleotide', 'Chemical', 'MESH:D011119', (129, 143))	('thymidylate synthase', 'Gene', '7298', (64, 84))
45765	33863904	Inhibition of p38 suppressed cisplatin-induced apoptosis while prolonged p38 activation has been associated with increased sensitivity to cisplatin-induced apoptosis in cervical, ovarian, and breast cancers.	('p38', 'Gene', (14, 17))	('sensitivity', 'MPA', (123, 134))	('apoptosis', 'biological_process', 'GO:0097194', ('47', '56'))	('apoptosis', 'biological_process', 'GO:0006915', ('47', '56'))	('cisplatin-induced apoptosis', 'MPA', (29, 56))	('suppressed', 'NegReg', (18, 28))	('ovarian', 'Disease', (179, 186))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('p38', 'Gene', '1432', (14, 17))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('cervical', 'Disease', (169, 177))	('p38', 'Gene', (73, 76))	('breast cancers', 'Disease', 'MESH:D001943', (192, 206))	('breast cancers', 'Disease', (192, 206))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('Inhibition', 'Var', (0, 10))	('increased', 'PosReg', (113, 122))	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('breast cancers', 'Phenotype', 'HP:0003002', (192, 206))	('ovarian', 'Disease', 'MESH:D010049', (179, 186))	('activation', 'PosReg', (77, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('apoptosis', 'biological_process', 'GO:0097194', ('156', '165'))	('p38', 'Gene', '1432', (73, 76))	('apoptosis', 'biological_process', 'GO:0006915', ('156', '165'))
45768	33863904	Moreover, inhibition of cytokeratin 8 in NPC cell lines increased cancer cell sensitivity to cisplatin by activating the JNK pathway.	('cytokeratin 8', 'Gene', '3856', (24, 37))	('JNK', 'Gene', (121, 124))	('NPC', 'Gene', '4864', (41, 44))	('increased', 'PosReg', (56, 65))	('NPC', 'cellular_component', 'GO:0005643', ('41', '44'))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('activating', 'PosReg', (106, 116))	('JNK', 'Gene', '5599', (121, 124))	('JNK', 'molecular_function', 'GO:0004705', ('121', '124'))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cytokeratin 8', 'Gene', (24, 37))	('inhibition', 'Var', (10, 20))	('NPC', 'Phenotype', 'HP:0100630', (41, 44))	('NPC', 'Gene', (41, 44))	('cancer', 'Disease', (66, 72))
45772	33863904	Action of DUSP16 has been implicated in leukemia, NSCL cancer, prostate carcinoma, and Burkitt's lymphoma, possibly through inactivation of JNK.	('prostate carcinoma', 'Phenotype', 'HP:0012125', (63, 81))	('inactivation', 'Var', (124, 136))	('leukemia', 'Disease', (40, 48))	('leukemia', 'Disease', 'MESH:D007938', (40, 48))	('lymphoma', 'Phenotype', 'HP:0002665', (97, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('prostate carcinoma', 'Disease', (63, 81))	('implicated', 'Reg', (26, 36))	('NSCL cancer', 'Disease', (50, 61))	('DUSP16', 'Gene', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (87, 105))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (87, 105))	('JNK', 'Gene', (140, 143))	('NSCL cancer', 'Disease', 'MESH:D009369', (50, 61))	("Burkitt's lymphoma", 'Disease', (87, 105))	('JNK', 'Gene', '5599', (140, 143))	('JNK', 'molecular_function', 'GO:0004705', ('140', '143'))	('prostate carcinoma', 'Disease', 'MESH:D011471', (63, 81))	('leukemia', 'Phenotype', 'HP:0001909', (40, 48))
45773	33863904	Interestingly, silencing of DUSP16 in Burkitt's lymphoma cells has been shown to increase JNK activity and enhance sensitivity to doxorubicin, sorbitol, and cisplatin.	('DUSP16', 'Gene', (28, 34))	('JNK', 'Gene', (90, 93))	('JNK', 'Gene', '5599', (90, 93))	('doxorubicin', 'Chemical', 'MESH:D004317', (130, 141))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (38, 56))	('silencing', 'Var', (15, 24))	('enhance', 'PosReg', (107, 114))	("Burkitt's lymphoma", 'Disease', (38, 56))	('increase', 'PosReg', (81, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (157, 166))	('JNK', 'molecular_function', 'GO:0004705', ('90', '93'))	('sorbitol', 'MPA', (143, 151))	('sorbitol', 'Chemical', 'MESH:D013012', (143, 151))	('lymphoma', 'Phenotype', 'HP:0002665', (48, 56))	('sensitivity to doxorubicin', 'MPA', (115, 141))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (38, 56))
45776	33863904	Overexpression of DUSP16 in cancer cells, including NPC, CRC, breast and gastric cancer cells, resulted in reduced cell death upon treatment with chemotherapy drugs, including cisplatin, carboplatin, oxaliplatin, fluorouracil (5-FU), and epirubicin in vitro and in vivo; whereas CRISP/Cas9-mediated knockout of DUSP16 in cancer cells led to an increased sensitivity to these drugs.	('cisplatin', 'Chemical', 'MESH:D002945', (176, 185))	('reduced', 'NegReg', (107, 114))	('cancer', 'Disease', (81, 87))	('5-FU', 'Chemical', 'MESH:D005472', (227, 231))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('NPC', 'Phenotype', 'HP:0100630', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (321, 327))	('sensitivity to these drugs', 'MPA', (354, 380))	('DUSP16', 'Gene', (311, 317))	('NPC', 'Gene', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('DUSP16', 'Gene', (18, 24))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (200, 211))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('increased', 'PosReg', (344, 353))	('fluorouracil', 'Chemical', 'MESH:D005472', (213, 225))	('cancer', 'Disease', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', (321, 327))	('NPC', 'Gene', '4864', (52, 55))	('epirubicin', 'Chemical', 'MESH:D015251', (238, 248))	('cell death', 'CPA', (115, 125))	('carboplatin', 'Chemical', 'MESH:D016190', (187, 198))	('knockout', 'Var', (299, 307))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('gastric cancer', 'Disease', (73, 87))
45780	33863904	Protein expression of DUSP16 was only detected in C666-1 and HK-1 cells, but not in CNE-1 and HONE-1 cells (Fig.	('HONE-1', 'CellLine', 'CVCL:8706', (94, 100))	('DUSP16', 'Gene', (22, 28))	('C666-1', 'Var', (50, 56))	('CNE-1', 'CellLine', 'CVCL:6888', (84, 89))	('HK-1', 'molecular_function', 'GO:0004673', ('61', '65'))	('C666-1', 'CellLine', 'CVCL:7949', (50, 56))
45783	33863904	DUSP16 mRNA expression could be strongly induced by cisplatin in HK-1 cells, but was only weakly induced in C666-1 cells (Fig.	('DUSP16', 'Gene', (0, 6))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('mRNA expression', 'MPA', (7, 22))	('induced', 'Reg', (41, 48))	('C666-1', 'CellLine', 'CVCL:7949', (108, 114))	('cisplatin', 'Var', (52, 61))
45789	33863904	For instance, upon 5 mug/mL cisplatin treatment, the percentage of total apoptotic cells in HK-1 was 41.6% (including both AnnexinV single positive and AnnexinV/7AAD double-positive cells), but was only 19% in C666-1 (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('HK-1', 'Gene', (92, 96))	('C666-1', 'CellLine', 'CVCL:7949', (210, 216))	('apoptotic cells', 'CPA', (73, 88))	('cisplatin', 'Var', (28, 37))	('7AAD', 'Chemical', 'MESH:C025942', (161, 165))
45792	33863904	Therefore, C666-1 cells, which express a higher level of DUSP16, are more resistant to cisplatin treatment than HK-1 cells which express a much lower level of this molecule.	('C666-1', 'Var', (11, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('C666-1', 'CellLine', 'CVCL:7949', (11, 17))	('DUSP16', 'Gene', (57, 63))	('resistant', 'MPA', (74, 83))
45807	33863904	Conversely, the number of surviving (AnnexinV-7AAD-) cells was approximately twofold higher in DUSP16-expressing cells than that of vector-expressing cells (Vector-HK-1 vs DUSP16-HK-1: 35.85% vs 63.13%, p < 0.01, Fig.	('DUSP16-expressing', 'Var', (95, 112))	('higher', 'PosReg', (85, 91))	('7AAD', 'Chemical', 'MESH:C025942', (46, 50))	('HK-1', 'molecular_function', 'GO:0004673', ('164', '168'))	('HK-1', 'molecular_function', 'GO:0004673', ('179', '183'))
45823	33863904	Although a reduction in activation was observed at 24 and 48 h of treatment, higher levels of ERK activation were detected in the DUSP16-expressing cells compared to the vector-expressing cells from 12 h onward.	('ERK', 'Gene', (94, 97))	('higher', 'PosReg', (77, 83))	('DUSP16-expressing', 'Var', (130, 147))	('ERK', 'molecular_function', 'GO:0004707', ('94', '97'))	('activation', 'MPA', (98, 108))	('ERK', 'Gene', '5594', (94, 97))
45847	33863904	In contrast, reduced expression of cleaved caspase 9 and 3, the active form of these two proteins, were detected in DUSP16-expressing cells compared to vector-expressing cells in all four types of cancer cells (Fig.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('DUSP16-expressing', 'Var', (116, 133))	('cancer', 'Disease', (197, 203))	('caspase 9 and 3', 'Gene', '842;836', (43, 58))	('expression', 'MPA', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cleaved', 'MPA', (35, 42))	('reduced', 'NegReg', (13, 20))
45858	33863904	Furthermore, we found that cisplatin treatment resulted in increased accumulation of BAX which is a pro-apoptotic protein in the mitochondria, and the accumulation of BAX was reduced by the expression of DUSP16 in both HK-1 and DLD-1 cells (Fig.	('reduced', 'NegReg', (175, 182))	('expression', 'Var', (190, 200))	('BAX', 'Gene', '581', (85, 88))	('BAX', 'Gene', '581', (167, 170))	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('BAX', 'Gene', (167, 170))	('DUSP16', 'Gene', (204, 210))	('accumulation', 'MPA', (69, 81))	('increased', 'PosReg', (59, 68))	('BAX', 'Gene', (85, 88))
45860	33863904	To elucidate the role of BAX in DUSP16-mediated cisplatin resistance, we generated BAX knockout DLD-1 cells with or without DUSP16 overexpression using CRISP/cas9 technology.	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('BAX', 'Gene', (25, 28))	('BAX', 'Gene', '581', (25, 28))	('BAX', 'Gene', (83, 86))	('cas', 'cellular_component', 'GO:0005650', ('158', '161'))	('BAX', 'Gene', '581', (83, 86))	('knockout', 'Var', (87, 95))
45864	33863904	Knockout of BAX from vector-transfected cells resulted in a reduction of apoptosis to 26.3%, which was comparable to that of DUSP16-overexpression/ BAX knockout cells (27.5%), demonstrating that BAX is essential for DUSP16-mediated cisplatin resistance.	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('BAX', 'Gene', (195, 198))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('BAX', 'Gene', '581', (195, 198))	('reduction', 'NegReg', (60, 69))	('apoptosis', 'CPA', (73, 82))	('Knockout', 'Var', (0, 8))	('cisplatin', 'Chemical', 'MESH:D002945', (232, 241))	('BAX', 'Gene', (148, 151))	('BAX', 'Gene', (12, 15))	('BAX', 'Gene', '581', (148, 151))	('BAX', 'Gene', '581', (12, 15))
45868	33863904	Treatment of HK-1 cells with Peptide V5 successfully inhibited BAX accumulation in mitochondria at 48 h upon cisplatin treatment (Supplementary Fig.	('inhibited', 'NegReg', (53, 62))	('Peptide V5', 'Var', (29, 39))	('BAX', 'Gene', (63, 66))	('BAX', 'Gene', '581', (63, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))
45879	33863904	To further address the function of JNK and p38 in DUSP16-mediated response to chemotherapy drugs, we treated HK-1 cells with the JNK-specific inhibitor, SP600125, the p38-specific inhibitor, SB203580, or both combined, together with cisplatin.	('p38', 'Gene', '1432', (43, 46))	('JNK', 'molecular_function', 'GO:0004705', ('129', '132'))	('HK-1', 'molecular_function', 'GO:0004673', ('109', '113'))	('JNK', 'Gene', '5599', (35, 38))	('SP600125', 'Var', (153, 161))	('cisplatin', 'Chemical', 'MESH:D002945', (233, 242))	('SP600125', 'Chemical', 'MESH:C432165', (153, 161))	('p38', 'Gene', '1432', (167, 170))	('JNK', 'Gene', (129, 132))	('p38', 'Gene', (43, 46))	('JNK', 'Gene', '5599', (129, 132))	('SB203580', 'Chemical', 'MESH:C093642', (191, 199))	('p38', 'Gene', (167, 170))	('JNK', 'molecular_function', 'GO:0004705', ('35', '38'))	('JNK', 'Gene', (35, 38))
45880	33863904	Treatment with SP600125 alone blocked cisplatin-induced JNK activation (Supplementary Fig.	('JNK', 'Gene', (56, 59))	('SP600125', 'Chemical', 'MESH:C432165', (15, 23))	('blocked', 'NegReg', (30, 37))	('JNK', 'Gene', '5599', (56, 59))	('SP600125', 'Var', (15, 23))	('JNK', 'molecular_function', 'GO:0004705', ('56', '59'))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))
45881	33863904	SB203580 selectively blocks the p38 catalytic activity and the activation of downstream substrates such as the activating transcription factor 2 (ATF2).	('ATF2', 'Gene', (146, 150))	('transcription', 'biological_process', 'GO:0006351', ('122', '135'))	('transcription factor', 'molecular_function', 'GO:0000981', ('122', '142'))	('catalytic activity', 'molecular_function', 'GO:0003824', ('36', '54'))	('catalytic activity', 'MPA', (36, 54))	('p38', 'Gene', (32, 35))	('SB203580', 'Var', (0, 8))	('SB203580', 'Chemical', 'MESH:C093642', (0, 8))	('ATF2', 'Gene', '1386', (146, 150))	('blocks', 'NegReg', (21, 27))	('activating transcription factor 2', 'Gene', '1386', (111, 144))	('activating transcription factor 2', 'Gene', (111, 144))	('p38', 'Gene', '1432', (32, 35))	('activation', 'PosReg', (63, 73))
45882	33863904	Consistently, the activation of ATF2 was suppressed by SB203580 in HK-1 cells upon treatment (Supplementary Fig.	('ATF2', 'Gene', (32, 36))	('suppressed', 'NegReg', (41, 51))	('SB203580', 'Var', (55, 63))	('activation', 'MPA', (18, 28))	('SB203580', 'Chemical', 'MESH:C093642', (55, 63))	('ATF2', 'Gene', '1386', (32, 36))
45883	33863904	Combination of SP600125 and SB203580 resulted in the inhibition of both JNK and p38 activation in response to cisplatin (Supplementary Fig.	('inhibition', 'NegReg', (53, 63))	('JNK', 'Gene', (72, 75))	('SP600125', 'Chemical', 'MESH:C432165', (15, 23))	('activation', 'PosReg', (84, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (110, 119))	('SP600125', 'Var', (15, 23))	('p38', 'Gene', (80, 83))	('SB203580', 'Chemical', 'MESH:C093642', (28, 36))	('response to cisplatin', 'MPA', (98, 119))	('JNK', 'Gene', '5599', (72, 75))	('SB203580', 'Var', (28, 36))	('response to cisplatin', 'biological_process', 'GO:0072718', ('98', '119'))	('JNK', 'molecular_function', 'GO:0004705', ('72', '75'))	('p38', 'Gene', '1432', (80, 83))
45885	33863904	Interestingly, inhibition of both JNK and p38 resulted in sustained ERK activation (Supplementary Fig.	('activation', 'PosReg', (72, 82))	('p38', 'Gene', (42, 45))	('JNK', 'Gene', '5599', (34, 37))	('ERK', 'Gene', '5594', (68, 71))	('p38', 'Gene', '1432', (42, 45))	('ERK', 'Gene', (68, 71))	('JNK', 'Gene', (34, 37))	('inhibition', 'Var', (15, 25))
45887	33863904	Assessment of HK-1 cell death in cells co-treated with cisplatin and SP600125, SB203580, or both was conducted.	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('SB203580', 'Chemical', 'MESH:C093642', (79, 87))	('SB203580', 'Var', (79, 87))	('SP600125', 'Chemical', 'MESH:C432165', (69, 77))	('SP600125', 'Var', (69, 77))
45892	33863904	These results suggest that both JNK and p38 promote apoptosis in NPC cells in response to cisplatin and inhibition of both JNK and p38 results in cisplatin resistance.	('p38', 'Gene', '1432', (40, 43))	('NPC', 'Gene', '4864', (65, 68))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('JNK', 'Gene', (32, 35))	('JNK', 'molecular_function', 'GO:0004705', ('123', '126'))	('JNK', 'Gene', '5599', (32, 35))	('JNK', 'molecular_function', 'GO:0004705', ('32', '35'))	('p38', 'Gene', (131, 134))	('apoptosis', 'CPA', (52, 61))	('inhibition', 'Var', (104, 114))	('NPC', 'Phenotype', 'HP:0100630', (65, 68))	('results in', 'Reg', (135, 145))	('response to cisplatin', 'biological_process', 'GO:0072718', ('78', '99'))	('JNK', 'Gene', (123, 126))	('p38', 'Gene', (40, 43))	('JNK', 'Gene', '5599', (123, 126))	('p38', 'Gene', '1432', (131, 134))	('NPC', 'Gene', (65, 68))	('promote', 'PosReg', (44, 51))	('cisplatin', 'Chemical', 'MESH:D002945', (146, 155))	('response to cisplatin', 'MPA', (78, 99))	('apoptosis', 'biological_process', 'GO:0097194', ('52', '61'))	('cisplatin resistance', 'MPA', (146, 166))	('NPC', 'cellular_component', 'GO:0005643', ('65', '68'))	('apoptosis', 'biological_process', 'GO:0006915', ('52', '61'))
45896	33863904	Inhibition of JNK or p38 resulted in reduced levels of cleaved caspase 3 induced by cisplatin compared to cells treated with vehicle, with greater inhibition of cleaved caspase 3 in cells with JNK inhibition than with p38 inhibition (Supplementary Fig.	('caspase 3', 'Gene', (63, 72))	('JNK', 'Gene', (193, 196))	('JNK', 'Gene', (14, 17))	('caspase 3', 'Gene', '836', (63, 72))	('p38', 'Gene', '1432', (218, 221))	('inhibition', 'NegReg', (197, 207))	('JNK', 'Gene', '5599', (14, 17))	('p38', 'Gene', '1432', (21, 24))	('caspase 3', 'Gene', (169, 178))	('caspase 3', 'Gene', '836', (169, 178))	('JNK', 'Gene', '5599', (193, 196))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('Inhibition', 'Var', (0, 10))	('p38', 'Gene', (218, 221))	('inhibition', 'NegReg', (147, 157))	('reduced', 'NegReg', (37, 44))	('p38', 'Gene', (21, 24))
45900	33863904	To validate the role of DUSP16 in cancer cell response to chemotherapy in vivo, NOD SCID gamma (NSG) mice were inoculated with either vector-expressing, DUSP16-expressing HK-1, or DUSP16-expressing DLD-1 cells.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('SCID', 'Disease', 'MESH:D053632', (84, 88))	('SCID', 'Disease', (84, 88))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('mice', 'Species', '10090', (101, 105))	('cancer', 'Disease', (34, 40))	('DUSP16-expressing', 'Var', (153, 170))
45913	33863904	Conversely, Ki67 staining results demonstrated an increase in the number of proliferative cells in DUSP16-expressing xenografts treated with cisplatin compared to that in vector-expressing ones (Fig.	('DUSP16-expressing', 'Gene', (99, 116))	('Ki67', 'Gene', (12, 16))	('cisplatin', 'Chemical', 'MESH:D002945', (141, 150))	('increase', 'PosReg', (50, 58))	('Ki67', 'Gene', '17345', (12, 16))	('cisplatin', 'Var', (141, 150))
45923	33863904	These results demonstrate that DUSP16 expression in C666-1 cells promotes cisplatin resistance, confirming that DUSP16 inhibits cisplatin-mediated apoptosis in NPC.	('NPC', 'cellular_component', 'GO:0005643', ('160', '163'))	('DUSP16', 'Gene', (31, 37))	('DUSP16', 'Var', (112, 118))	('C666-1', 'CellLine', 'CVCL:7949', (52, 58))	('NPC', 'Phenotype', 'HP:0100630', (160, 163))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('apoptosis', 'biological_process', 'GO:0097194', ('147', '156'))	('NPC', 'Gene', (160, 163))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('promotes', 'PosReg', (65, 73))	('NPC', 'Gene', '4864', (160, 163))	('cisplatin-mediated apoptosis', 'CPA', (128, 156))	('apoptosis', 'biological_process', 'GO:0006915', ('147', '156'))	('cisplatin resistance', 'MPA', (74, 94))	('inhibits', 'NegReg', (119, 127))
45926	33863904	Interestingly, earlier induction of ERK activation was also noted in the DUSP16-KD cells compared to the Vector cells (Fig.	('ERK', 'molecular_function', 'GO:0004707', ('36', '39'))	('ERK', 'Gene', '5594', (36, 39))	('DUSP16-KD', 'Var', (73, 82))	('ERK', 'Gene', (36, 39))	('activation', 'PosReg', (40, 50))
45934	33863904	7A), indicating that DUSP16-KD C666-1 tumors were more sensitive to growth inhibition by cisplatin than Vector tumors.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('C666-1', 'Var', (31, 37))	('tumors', 'Disease', (38, 44))	('growth inhibition', 'MPA', (68, 85))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('C666-1', 'CellLine', 'CVCL:7949', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('DUSP16-KD C666-1', 'Var', (21, 37))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('Vector tumors', 'Disease', (104, 117))	('Vector tumors', 'Disease', 'MESH:D000079426', (104, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('sensitive', 'MPA', (55, 64))
45935	33863904	Cleaved caspase 3 staining of the tumor sections demonstrated that DUSP16-KD xenografts had 1.4-fold greater cleaved caspase 3 staining compared to that of Vector xenografts in response to cisplatin (Fig.	('response to cisplatin', 'biological_process', 'GO:0072718', ('177', '198'))	('caspase 3', 'Gene', (117, 126))	('tumor', 'Disease', (34, 39))	('caspase 3', 'Gene', '836', (117, 126))	('staining', 'MPA', (127, 135))	('caspase 3', 'Gene', (8, 17))	('greater', 'PosReg', (101, 108))	('caspase 3', 'Gene', '836', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('DUSP16-KD', 'Var', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (189, 198))
45938	33863904	To test our hypothesis that strong DUSP16 expression is associated with poor survival in a patient population, we performed clinicopathological analysis on locally advanced squamous cell carcinoma (SCC) of the head and neck (HNSCC) cohort where concurrent single-agent cisplatin treatment with radiotherapy is the standard first-line regime.	('SCC', 'Phenotype', 'HP:0002860', (198, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (173, 196))	('HNSCC', 'Disease', (225, 230))	('cisplatin', 'Chemical', 'MESH:D002945', (269, 278))	('DUSP16', 'Gene', (35, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (173, 196))	('SCC', 'Phenotype', 'HP:0002860', (227, 230))	('HNSCC', 'Disease', 'MESH:D000077195', (225, 230))	('squamous cell carcinoma', 'Disease', (173, 196))	('expression', 'Var', (42, 52))	('patient', 'Species', '9606', (91, 98))
45947	33863904	Analysis of DFS in association with DUSP16 expression levels demonstrated that patients (n = 45) with high DUSP16 protein expression in their tumors had significantly reduced survival probability compared to patients (n = 68) with low DUSP16 (p < 0.0001) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('DUSP16', 'Gene', (107, 113))	('patients', 'Species', '9606', (208, 216))	('high', 'Var', (102, 106))	('protein', 'Protein', (114, 121))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('patients', 'Species', '9606', (79, 87))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('reduced', 'NegReg', (167, 174))	('survival probability', 'CPA', (175, 195))
45951	33863904	As major negative regulators of the MAPKs, altered expression of DUSPs/MKPs may influence the outcome of chemotherapy in cancers.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('influence', 'Reg', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('DUSP', 'Gene', (65, 69))	('expression', 'MPA', (51, 61))	('DUSP', 'Gene', '1847', (65, 69))	('altered', 'Var', (43, 50))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
45952	33863904	While numerous studies have shown that loss of DUSP expression is correlated with progression of several cancers, others have associated the gain of DUSP expression with cancer progression, drug resistance, and poor prognosis.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancer', 'Disease', (170, 176))	('DUSP', 'Gene', '1847', (47, 51))	('cancers', 'Disease', (105, 112))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('gain', 'PosReg', (141, 145))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('DUSP', 'Gene', (149, 153))	('loss', 'Var', (39, 43))	('drug resistance', 'Disease', (190, 205))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('drug resistance', 'Phenotype', 'HP:0020174', (190, 205))	('DUSP', 'Gene', '1847', (149, 153))	('DUSP', 'Gene', (47, 51))	('expression', 'MPA', (154, 164))
45959	33863904	Nevertheless, we found that the DUSP16-higher C666-1 cells are more resistant to cisplatin-mediated cell death than the HK-1 cells which have minimal DUSP16 expression (Fig.	('HK-1', 'molecular_function', 'GO:0004673', ('120', '124'))	('cell death', 'biological_process', 'GO:0008219', ('100', '110'))	('C666-1', 'Var', (46, 52))	('DUSP16-higher C666-1', 'Var', (32, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('C666-1', 'CellLine', 'CVCL:7949', (46, 52))	('resistant', 'MPA', (68, 77))
45960	33863904	Furthermore, C666-1 cells are more resistant to carboplatin than HK-1 cells (Fig.	('C666-1', 'Var', (13, 19))	('carboplatin', 'Chemical', 'MESH:D016190', (48, 59))	('resistant', 'MPA', (35, 44))	('C666-1', 'CellLine', 'CVCL:7949', (13, 19))
45965	33863904	A CRISPR/Cas9-mediated approach was also used to knock down the expression of DUSP16 in C666-1 NPC cells.	('expression', 'MPA', (64, 74))	('NPC', 'Phenotype', 'HP:0100630', (95, 98))	('knock', 'Var', (49, 54))	('DUSP16', 'Gene', (78, 84))	('C666-1 NPC', 'CellLine', 'CVCL:7949', (88, 98))
45968	33863904	In addition, high DUSP16 expression was found to be associated with poorer disease-free survival in a cohort of HNSCC patients upon completion of chemoradiation therapy (Fig.	('disease-free survival', 'CPA', (75, 96))	('poorer', 'NegReg', (68, 74))	('high', 'Var', (13, 17))	('DUSP16', 'Gene', (18, 24))	('expression', 'MPA', (25, 35))	('HNSCC', 'Disease', (112, 117))	('SCC', 'Phenotype', 'HP:0002860', (114, 117))	('HNSCC', 'Disease', 'MESH:D000077195', (112, 117))	('patients', 'Species', '9606', (118, 126))
45975	33863904	Furthermore, knockdown of DUSP16 in C666-1 cells resulted in enhanced JNK and p38 activation associated with increased cell apoptosis upon cisplatin treatment (Fig.	('JNK', 'Gene', (70, 73))	('enhanced', 'PosReg', (61, 69))	('p38', 'Gene', '1432', (78, 81))	('JNK', 'Gene', '5599', (70, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('activation', 'PosReg', (82, 92))	('p38', 'Gene', (78, 81))	('DUSP16', 'Gene', (26, 32))	('knockdown', 'Var', (13, 22))	('C666-1', 'CellLine', 'CVCL:7949', (36, 42))
45982	33863904	Conversely, knockdown of DUSP16 in C666-1 resulted in increased JNK and p38 activation and increased apoptosis (Fig.	('DUSP16', 'Gene', (25, 31))	('C666-1', 'Var', (35, 41))	('p38', 'Gene', (72, 75))	('knockdown', 'Var', (12, 21))	('C666-1', 'CellLine', 'CVCL:7949', (35, 41))	('increased', 'PosReg', (54, 63))	('p38', 'Gene', '1432', (72, 75))	('JNK', 'Gene', (64, 67))	('apoptosis', 'CPA', (101, 110))	('activation', 'PosReg', (76, 86))	('JNK', 'Gene', '5599', (64, 67))
45983	33863904	Interestingly, C666-1 cells, which constitutively express a higher level of DUSP16, are intrinsically more resistant to cisplatin than HK-1 cells (Fig.	('C666-1', 'CellLine', 'CVCL:7949', (15, 21))	('more', 'PosReg', (102, 106))	('DUSP16', 'Gene', (76, 82))	('C666-1', 'Var', (15, 21))	('resistant to cisplatin', 'MPA', (107, 129))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))
45988	33863904	Similarly, inhibition of both JNK and p38 using their specific inhibitors also resulted in prolonged ERK activation in HK-1 cells (Supplementary Fig.	('ERK', 'Gene', '5594', (101, 104))	('ERK', 'Gene', (101, 104))	('JNK', 'Gene', (30, 33))	('activation', 'PosReg', (105, 115))	('p38', 'Gene', '1432', (38, 41))	('inhibition', 'Var', (11, 21))	('JNK', 'Gene', '5599', (30, 33))	('p38', 'Gene', (38, 41))
45996	33863904	Cancer cells have evolved multiple mechanisms such as expressing high levels of anti-apoptotic factors or inactivating pro-apoptotic molecules to escape the induction of apoptosis.	('Cancer', 'Disease', (0, 6))	('inactivating', 'Var', (106, 118))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
46000	33863904	DUSP16-mediated reduction of caspase 3 activation was further confirmed in DUSP16-expression HK-1 xenografts (Fig.	('caspase 3', 'Gene', (29, 38))	('reduction', 'NegReg', (16, 25))	('DUSP16-expression', 'Var', (75, 92))	('caspase 3', 'Gene', '836', (29, 38))	('activation', 'MPA', (39, 49))
46001	33863904	5C, D); whereas increased caspase 3 activation was detected in DUSP16 knockdown C666-1 tumors (Fig.	('DUSP16', 'Gene', (63, 69))	('knockdown', 'Var', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('activation', 'PosReg', (36, 46))	('C666-1', 'CellLine', 'CVCL:7949', (80, 86))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('caspase 3', 'Gene', (26, 35))	('caspase 3', 'Gene', '836', (26, 35))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
46005	33863904	These data suggest that caspase 3 is a downstream activator of JNK/p38 upon cisplatin treatment, and can be targeted by DUSP16 through inactivation of JNK and p38.	('caspase 3', 'Gene', (24, 33))	('p38', 'Gene', (159, 162))	('caspase 3', 'Gene', '836', (24, 33))	('JNK', 'molecular_function', 'GO:0004705', ('63', '66'))	('p38', 'Gene', (67, 70))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('JNK', 'Gene', '5599', (63, 66))	('JNK', 'molecular_function', 'GO:0004705', ('151', '154'))	('JNK', 'Gene', (151, 154))	('p38', 'Gene', '1432', (159, 162))	('inactivation', 'Var', (135, 147))	('p38', 'Gene', '1432', (67, 70))	('JNK', 'Gene', (63, 66))	('JNK', 'Gene', '5599', (151, 154))
46008	33863904	Studies using BAX knockout cells with or without DUSP16 overexpression provided definitive evidence on the essential role of BAX in DUSP16-mediated chemoresistance (Fig.	('chemoresistance', 'CPA', (148, 163))	('BAX', 'Gene', (14, 17))	('BAX', 'Gene', '581', (14, 17))	('BAX', 'Gene', (125, 128))	('BAX', 'Gene', '581', (125, 128))	('DUSP16-mediated', 'Var', (132, 147))
46013	33863904	We have analyzed the association of DUSP16 with patient survival in two cohorts of cancer patients, a small cohort of HNSCC patients and a cohort of 113 breast cancer patients, and found that high DUSP16 levels in tumors were associated with significantly lower patient survival.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Disease', (214, 220))	('HNSCC', 'Disease', 'MESH:D000077195', (118, 123))	('patients', 'Species', '9606', (124, 132))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('cancer', 'Disease', (160, 166))	('patient', 'Species', '9606', (167, 174))	('patient', 'Species', '9606', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('patient', 'Species', '9606', (262, 269))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('lower', 'NegReg', (256, 261))	('HNSCC', 'Disease', (118, 123))	('patient survival', 'CPA', (262, 278))	('patient', 'Species', '9606', (124, 131))	('patients', 'Species', '9606', (90, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('high', 'Var', (192, 196))	('patients', 'Species', '9606', (167, 175))	('DUSP16', 'Gene', (197, 203))	('patient', 'Species', '9606', (90, 97))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Disease', (83, 89))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('breast cancer', 'Disease', (153, 166))
46018	33863904	NPC cell lines, C666-1 and HK-1, were kindly provided by Professor Chan Soh Ha (NUS Immunology Center) and were maintained in RPM1 1640 (Gibco, USA) supplemented with 10% fetal bovine serum (FBS) in the presence of penicillin (100 IU/mL) and streptomycin (100 mug/mL) at 37  C under a humidified atmosphere of 95% air and 5% CO2.	('NPC', 'Gene', '4864', (0, 3))	('penicillin', 'Chemical', 'MESH:D010406', (215, 225))	('streptomycin', 'Chemical', 'MESH:D013307', (242, 254))	('NPC', 'cellular_component', 'GO:0005643', ('0', '3'))	('HK-1', 'molecular_function', 'GO:0004673', ('27', '31'))	('NPC', 'Gene', (0, 3))	('100 mug/mL', 'Var', (256, 266))	('NPC', 'Phenotype', 'HP:0100630', (0, 3))	('mug', 'molecular_function', 'GO:0043739', ('260', '263'))	('C666-1', 'CellLine', 'CVCL:7949', (16, 22))	('CO2', 'Chemical', 'MESH:D002245', (325, 328))
46019	33863904	C666-1 is an undifferentiated NPC cell line which stably maintains the EBV episomes while HK-1 is a well-differentiated, EBV-negative NPC cell line.	('C666-1', 'Var', (0, 6))	('C666-1', 'CellLine', 'CVCL:7949', (0, 6))	('NPC', 'Phenotype', 'HP:0100630', (30, 33))	('NPC', 'Gene', (30, 33))	('EBV episomes', 'MPA', (71, 83))	('NPC', 'Phenotype', 'HP:0100630', (134, 137))	('NPC', 'Gene', '4864', (30, 33))	('NPC', 'Gene', (134, 137))	('NPC', 'Gene', '4864', (134, 137))
46024	33863904	A 1-h pre-treatment with inhibitors of ERK (50 muM of PD98059), p38 (20 muM of SB203580), or JNK (20 muM of SP600125) was done prior to cisplatin treatment.	('JNK', 'Gene', (93, 96))	('PD98059', 'Chemical', 'MESH:C093973', (54, 61))	('20 muM of SB203580', 'Var', (69, 87))	('p38', 'Gene', '1432', (64, 67))	('pre', 'molecular_function', 'GO:0003904', ('6', '9'))	('ERK', 'Gene', '5594', (39, 42))	('50 muM', 'Var', (44, 50))	('JNK', 'Gene', '5599', (93, 96))	('SB203580', 'Chemical', 'MESH:C093642', (79, 87))	('JNK', 'molecular_function', 'GO:0004705', ('93', '96'))	('ERK', 'Gene', (39, 42))	('p38', 'Gene', (64, 67))	('ERK', 'molecular_function', 'GO:0004707', ('39', '42'))	('cisplatin', 'Chemical', 'MESH:D002945', (136, 145))	('PD98059', 'Var', (54, 61))	('SP600125', 'Chemical', 'MESH:C432165', (108, 116))
46106	33504012	Among them, six are used in cancer therapy: Cytarabine (Ara-C), eribulin mesylate (E7389), trabectedin (ET-743), brentuximab vedotin (SGN-35), polatuzamab vedotin and aplidin.	('polatuzamab vedotin', 'Chemical', '-', (143, 162))	('Cytarabine', 'Chemical', 'MESH:D003561', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('E7389', 'Chemical', 'MESH:C490954', (83, 88))	('eribulin mesylate', 'Chemical', 'MESH:C490954', (64, 81))	('trabectedin', 'Chemical', 'MESH:D000077606', (91, 102))	('aplidin', 'Chemical', 'MESH:C098980', (167, 174))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('E7389', 'Var', (83, 88))	('Ara-C', 'Chemical', 'MESH:D003561', (56, 61))	('ET-743', 'Chemical', 'MESH:D000077606', (104, 110))	('cancer', 'Disease', (28, 34))
46132	33504012	Studies on mouse models show that cyclophosphamide also promotes an antitumour immune response, inducing the delocalization of Gram-positive bacteria of the intestinal microbiota to secondary lymphoid organs, via gap junctions, in the intestinal epithelium, stimulating the production of Th17 cells and the secretion of IL-17 and IFNgamma.	('delocalization', 'MPA', (109, 123))	('production', 'MPA', (274, 284))	('cyclophosphamide', 'Var', (34, 50))	('mouse', 'Species', '10090', (11, 16))	('immune response', 'biological_process', 'GO:0006955', ('79', '94'))	('inducing', 'Reg', (96, 104))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('IL-17', 'Gene', (320, 325))	('promotes', 'PosReg', (56, 64))	('IL-17', 'molecular_function', 'GO:0030367', ('320', '325'))	('IL-17', 'Gene', '16171', (320, 325))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('stimulating', 'PosReg', (258, 269))	('secretion', 'biological_process', 'GO:0046903', ('307', '316'))	('secretion', 'MPA', (307, 316))	('tumour', 'Disease', (72, 78))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (34, 50))
46134	33504012	Oxaliplatin can also promote the activation of cytotoxic T lymphocytes in both transgenic and transplantable murine models of prostate cancers.	('cytotoxic T lymphocytes', 'CPA', (47, 70))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('activation', 'PosReg', (33, 43))	('prostate cancers', 'Disease', 'MESH:D011471', (126, 142))	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (0, 11))	('Oxaliplatin', 'Var', (0, 11))	('prostate cancers', 'Phenotype', 'HP:0012125', (126, 142))	('murine', 'Species', '10090', (109, 115))	('promote', 'PosReg', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('prostate cancers', 'Disease', (126, 142))
46141	33504012	This challenging aim is even more important, considering that ICD not only inhibits primary tumours, but dramatically suppresses distant metastatic tumours, thus exerting an abscopal effect ('ab scopus', away from the target), useful in cancer therapy.	('suppresses', 'NegReg', (118, 128))	('tumours', 'Disease', 'MESH:D009369', (148, 155))	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('tumours', 'Disease', (148, 155))	('ICD', 'Var', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('tumours', 'Disease', (92, 99))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('tumours', 'Phenotype', 'HP:0002664', (148, 155))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (237, 243))	('inhibits', 'NegReg', (75, 83))
46190	33504012	Similar activity is exerted by the exopolysaccharide, p-KG03, isolated from Gyrodinium impudicum, and by sulphated polysaccharides, from Tribonema sp.	('sulphated polysaccharides', 'Chemical', '-', (105, 130))	('activity', 'MPA', (8, 16))	('Gyrodinium impudicum', 'Species', '396600', (76, 96))	('exopolysaccharide', 'Chemical', '-', (35, 52))	('p-KG03', 'Chemical', '-', (54, 60))	('p-KG03', 'Var', (54, 60))
46191	33504012	In particular, the compound p-KG03 is able to induce IFN-gamma and IL-2 release, targeting preferentially NK cells with the specific activation against host neoplastic cells.	('p-KG03', 'Chemical', '-', (28, 34))	('p-KG03', 'Var', (28, 34))	('IFN-gamma', 'Gene', '3458', (53, 62))	('IFN-gamma', 'Gene', (53, 62))	('IL-2', 'Gene', '3558', (67, 71))	('induce', 'PosReg', (46, 52))	('IL-2', 'Gene', (67, 71))
46199	33504012	It was recently demonstrated that the modified pectin from Spirulina maxima modulates the gut microbiota in mice, inducing mucin, IFN-alpha and IL-6 release, key factors for ICD activation during an inflammatory cascade.	('Spirulina maxima', 'Species', '129910', (59, 75))	('inducing', 'PosReg', (114, 122))	('mucin', 'MPA', (123, 128))	('IFN-alpha', 'Gene', (130, 139))	('mice', 'Species', '10090', (108, 112))	('modulates', 'Reg', (76, 85))	('modified', 'Var', (38, 46))	('IFN-alpha', 'Gene', '111654', (130, 139))
46201	33504012	The polyunsaturated fatty acids from Schizochytrium induce microbiota stimulation and mucin release.	('microbiota stimulation', 'CPA', (59, 81))	('polyunsaturated', 'Var', (4, 19))	('Schizochytrium', 'Species', '1907177', (37, 51))	('polyunsaturated fatty acids', 'Chemical', 'MESH:D005231', (4, 31))	('mucin release', 'CPA', (86, 99))
46227	33329482	Colibactin-producing E. coli alkylates DNA at adenine residues and induces double-stranded breaks, anaphase bridges and chromosome aberrations.	('alkylates', 'Var', (29, 38))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('anaphase bridges', 'CPA', (99, 115))	('double-stranded breaks', 'MPA', (75, 97))	('adenine', 'Chemical', 'MESH:D000225', (46, 53))	('chromosome aberrations', 'CPA', (120, 142))	('E. coli', 'Species', '562', (21, 28))	('induces', 'Reg', (67, 74))	('anaphase', 'biological_process', 'GO:0051322', ('99', '107'))	('chromosome', 'cellular_component', 'GO:0005694', ('120', '130'))
46249	33329482	YL32 was significantly enriched in adenoma.	('adenoma', 'Disease', 'MESH:D000236', (35, 42))	('YL32', 'Var', (0, 4))	('adenoma', 'Disease', (35, 42))
46276	33329482	More than 80% CRC results from chromosomal instabilities, including mutation of the adenomatous polyposis coli (APC) gene and K-ras oncogene.	('APC', 'Phenotype', 'HP:0005227', (112, 115))	('adenomatous polyposis coli', 'Disease', (84, 110))	('APC', 'Disease', 'MESH:D011125', (112, 115))	('APC', 'Disease', (112, 115))	('mutation', 'Var', (68, 76))	('CRC', 'Phenotype', 'HP:0003003', (14, 17))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (84, 110))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (84, 110))	('results from', 'Reg', (18, 30))	('K-ras', 'Gene', (126, 131))	('K-ras', 'Gene', '3845', (126, 131))
46277	33329482	APC gene-deficient mice can spontaneously grow tumors in the intestine and patients carrying the KRAS mutation show chemotherapeutic resistance.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('APC', 'Phenotype', 'HP:0005227', (0, 3))	('KRAS', 'Gene', (97, 101))	('mutation', 'Var', (102, 110))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('KRAS', 'Gene', '3845', (97, 101))	('patients', 'Species', '9606', (75, 83))	('APC', 'Disease', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('mice', 'Species', '10090', (19, 23))
46279	33329482	Septin 9 gene methylation has been shown to be effective as a biomarker and approved by the FDA.	('Septin 9', 'Gene', '10801', (0, 8))	('Septin 9', 'Gene', (0, 8))	('methylation', 'Var', (14, 25))	('methylation', 'biological_process', 'GO:0032259', ('14', '25'))
46280	33329482	Meanwhile, methylation of bone morphogenic protein 3 and N-Myc downstream-regulated gene 4 displayed high specificity as an early and frequent event in colorectal tumors.	('colorectal tumors', 'Disease', 'MESH:D015179', (152, 169))	('N-Myc downstream-regulated gene 4', 'Gene', '65009', (57, 90))	('N-Myc downstream-regulated gene 4', 'Gene', (57, 90))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('colorectal tumors', 'Disease', (152, 169))	('methylation', 'Var', (11, 22))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('frequent event', 'Reg', (134, 148))
46298	33329482	A preliminary calculation showed that combination of FIT and bacterial markers would avert up to 30% of total colonoscopies as well as save an estimated 77 million $ per 100,000 participants.	('participants', 'Species', '9606', (178, 190))	('avert', 'NegReg', (85, 90))	('colonoscopies', 'Disease', (110, 123))	('save', 'NegReg', (135, 139))	('combination', 'Var', (38, 49))
46308	33066568	Further, Ru-1 significantly reduced the growth of primary heterotopic tumor in mice, similarly to oxaliplatin.	('reduced', 'NegReg', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('growth', 'MPA', (40, 46))	('heterotopic tumor', 'Disease', (58, 75))	('mice', 'Species', '10090', (79, 83))	('heterotopic tumor', 'Disease', 'MESH:D063192', (58, 75))	('Ru-1', 'Var', (9, 13))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (98, 109))
46309	33066568	Renal damage in Ru-1 treated mice was lower in comparison with oxaliplatin treated mice, as evaluated by serum levels of urea and creatinine and histological evaluation, but Ru-1 induced higher liver damage than oxaliplatin, evaluated by the serum levels of alanine aminotransferase.	('liver damage', 'Disease', (194, 206))	('Ru-1', 'Var', (174, 178))	('liver damage', 'Disease', 'MESH:D056486', (194, 206))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (63, 74))	('Renal damage', 'Disease', (0, 12))	('mice', 'Species', '10090', (83, 87))	('Renal damage', 'Disease', 'MESH:D007674', (0, 12))	('alanine aminotransferase', 'Gene', '76282', (258, 282))	('alanine aminotransferase', 'Gene', (258, 282))	('mice', 'Species', '10090', (29, 33))	('creatinine', 'Chemical', 'MESH:D003404', (130, 140))	('urea', 'Chemical', 'MESH:D014508', (121, 125))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (212, 223))
46312	33066568	Our data highlight the significant cytotoxic activity of [Ru(Cl-tpy)(en)Cl][Cl] against human and mouse colon carcinoma cells, as well as in vivo antitumor activity in CT26 tumor-bearing mice similar to standard chemotherapeutic oxaliplatin, accompanied with lower nephrotoxicity in comparison with oxaliplatin.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('[Ru', 'Var', (57, 60))	('mice', 'Species', '10090', (187, 191))	('colon carcinoma', 'Disease', (104, 119))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (229, 240))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('human', 'Species', '9606', (88, 93))	('nephrotoxicity', 'Disease', (265, 279))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (299, 310))	('cytotoxic', 'CPA', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('colon carcinoma', 'Disease', 'MESH:D003110', (104, 119))	('nephrotoxicity', 'Disease', 'MESH:D007674', (265, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('CT26', 'CellLine', 'CVCL:7254', (168, 172))	('mouse', 'Species', '10090', (98, 103))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', (173, 178))	('[Ru(Cl-tpy)(en)Cl][Cl', 'Chemical', '-', (57, 78))
46319	33066568	Three ruthenium compounds, NAMI-A ((ImH)[trans-RuCl4(dmso-S)(Im)], Im (imidazole), dmso (dimethylsulfoxide)), KP1019 (IndH)[trans-RuCl4(Ind)2], Ind (indazole)), and KP1339 (Na[trans-RuCl4(Ind)2]) have entered human clinical trials.	('human', 'Species', '9606', (209, 214))	('imidazole', 'Chemical', 'MESH:C029899', (71, 80))	('trans-RuCl4(Ind)', 'Chemical', '-', (176, 192))	('KP1019', 'Var', (110, 116))	('trans-RuCl4', 'Chemical', '-', (41, 52))	('Ind', 'Chemical', 'MESH:D007191', (136, 139))	('Ind', 'Chemical', 'MESH:D007191', (144, 147))	('indazole', 'Chemical', 'MESH:D007191', (149, 157))	('trans-RuCl4', 'Chemical', '-', (176, 187))	('Ind', 'Chemical', 'MESH:D007191', (118, 121))	('KP1339', 'Chemical', 'MESH:C551585', (165, 171))	('IndH', 'Chemical', '-', (118, 122))	('Ind', 'Chemical', 'MESH:D007191', (188, 191))	('KP1019', 'Chemical', 'MESH:C499292', (110, 116))	('dimethylsulfoxide', 'Chemical', 'MESH:D004121', (89, 106))	('dmso', 'Chemical', 'MESH:D004121', (53, 57))	('trans-RuCl4(Ind)', 'Chemical', '-', (124, 140))	('ruthenium compounds', 'Chemical', 'MESH:D017975', (6, 25))	('dmso', 'Chemical', 'MESH:D004121', (83, 87))	('KP1339', 'Var', (165, 171))	('trans-RuCl4', 'Chemical', '-', (124, 135))	('dmso-S', 'Chemical', 'MESH:D004121', (53, 59))	('ImH', 'Chemical', '-', (36, 39))	('NAMI-A', 'Chemical', 'MESH:C113661', (27, 33))
46320	33066568	Clinically investigated ruthenium complexes, KP1019 and its sodium salt analogue KP1339, which are active against colon carcinomas, were thought to exhibit tumor selectivity via HSA (Human Serum Albumin) mediated pathways based on increased permeability and the retention effect of tumor tissues.	('colon carcinomas', 'Disease', (114, 130))	('tumor', 'Disease', (282, 287))	('sodium salt', 'Chemical', '-', (60, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('tumor', 'Disease', (156, 161))	('Human', 'Species', '9606', (183, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('colon carcinomas', 'Disease', 'MESH:D003110', (114, 130))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('KP1019', 'Var', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('Serum Albumin', 'Gene', (189, 202))	('increased', 'PosReg', (231, 240))	('KP1019', 'Chemical', 'MESH:C499292', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('HSA', 'Pathway', (178, 181))	('permeability', 'MPA', (241, 253))	('KP1339', 'Chemical', 'MESH:C551585', (81, 87))	('ruthenium complexes', 'Chemical', '-', (24, 43))	('Serum Albumin', 'Gene', '213', (189, 202))
46346	33066568	The MTT assay procedures were used to evaluate the in vitro cytotoxicity of complexes Ru-1 and Ru-2 on a mouse carcinoma cell line (CT26) and two human carcinoma cell lines (HCT116 and SW480).	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('cytotoxicity', 'Disease', (60, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('HCT116', 'CellLine', 'CVCL:0291', (174, 180))	('SW480', 'CellLine', 'CVCL:0546', (185, 190))	('carcinoma', 'Disease', (111, 120))	('carcinoma', 'Disease', (152, 161))	('cytotoxicity', 'Disease', 'MESH:D064420', (60, 72))	('Ru-2', 'Var', (95, 99))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('CT26', 'CellLine', 'CVCL:7254', (132, 136))	('human', 'Species', '9606', (146, 151))	('carcinoma', 'Disease', 'MESH:D009369', (152, 161))	('carcinoma', 'Disease', 'MESH:D009369', (111, 120))	('mouse', 'Species', '10090', (105, 110))
46352	33066568	Interestingly, comparing the IC50 values obtained after 24 and 72 h of treatment it was noticed that Ru-1 exerts higher cytotoxicity toward CT26 and SW480 cells in comparison with oxaliplatin after 24 h of treatment, while the cytotoxicity of oxaliplatin is stronger 72 h after treatment, indicating that Ru-1 exerted its cytotoxicity faster than oxaliplatin (Figure 4 and Table 1).	('oxaliplatin', 'Chemical', 'MESH:D000077150', (347, 358))	('cytotoxicity', 'Disease', (322, 334))	('cytotoxicity', 'Disease', 'MESH:D064420', (227, 239))	('cytotoxicity', 'Disease', (120, 132))	('higher', 'PosReg', (113, 119))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (180, 191))	('cytotoxicity', 'Disease', 'MESH:D064420', (322, 334))	('CT26', 'CellLine', 'CVCL:7254', (140, 144))	('Ru-1', 'Var', (101, 105))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (243, 254))	('cytotoxicity', 'Disease', (227, 239))	('cytotoxicity', 'Disease', 'MESH:D064420', (120, 132))	('SW480', 'CellLine', 'CVCL:0546', (149, 154))
46356	33066568	The LDH levels increased from 8.37% (HCT116) to 36.43% (CT26) following Ru-1 treatment and from 2.35% (HCT116) to 33.07% (SW480) following Ru-2 treatment in comparison with 0% (HCT116) to 2.20% (SW480) after oxaliplatin treatment at a concentration of 300 muM (Figure 5).	('Ru-2', 'Var', (139, 143))	('SW480', 'CellLine', 'CVCL:0546', (122, 127))	('SW480', 'CellLine', 'CVCL:0546', (195, 200))	('HCT116', 'CellLine', 'CVCL:0291', (103, 109))	('increased', 'PosReg', (15, 24))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (208, 219))	('HCT116', 'CellLine', 'CVCL:0291', (177, 183))	('CT26', 'CellLine', 'CVCL:7254', (56, 60))	('LDH', 'MPA', (4, 7))	('HCT116', 'CellLine', 'CVCL:0291', (37, 43))
46357	33066568	To investigate the possible apoptotic death of tumor cells treated by complexes Ru-1 and Ru-2, an Annexin V/PI staining assay was performed (Figure 6).	('Annexin V', 'Gene', '11747', (98, 107))	('death', 'Disease', 'MESH:D003643', (38, 43))	('Ru-1', 'Var', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('death', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Ru-2', 'Var', (89, 93))	('tumor', 'Disease', (47, 52))	('Annexin V', 'Gene', (98, 107))
46361	33066568	Further, Ru-1 and oxaliplatin induced late apoptosis in HCT116 cells, more efficiently than Ru-2, while the percentage of early apoptotic HCT116 cells did not differ significantly between treated and untreated cells (Figure 6A,C).	('oxaliplatin', 'Chemical', 'MESH:D000077150', (18, 29))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('HCT116', 'CellLine', 'CVCL:0291', (56, 62))	('Ru-1', 'Var', (9, 13))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('HCT116', 'CellLine', 'CVCL:0291', (138, 144))	('late apoptosis', 'CPA', (38, 52))
46366	33066568	Ru-1 caused G2/M phase arrest of HCT116 cells (Figure 7B), and Ru-2 caused G2/M and S phase arrest in treated SW480 cells compared to respective untreated cells (Figure 7C).	('G2/M', 'CPA', (75, 79))	('arrest', 'Disease', (23, 29))	('Ru-1', 'Var', (0, 4))	('arrest', 'Disease', 'MESH:D006323', (92, 98))	('arrest', 'Disease', 'MESH:D006323', (23, 29))	('SW480', 'CellLine', 'CVCL:0546', (110, 115))	('arrest', 'Disease', (92, 98))	('HCT116', 'CellLine', 'CVCL:0291', (33, 39))	('Ru-2', 'Var', (63, 67))
46373	33066568	Furthermore, the tumor weights measured after necropsy, were markedly lower in mice treated with Ru-1 and oxaliplatin in comparison to vehicle-treated mice (p = 0.046; p = 0.039, Mann-Whitney U test) (Figure 8B), while tumors of mice treated with Ru-2 were slightly smaller than tumors from the control group, but without statistical significance (Figure 8).	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Disease', (219, 224))	('Ru-1', 'Var', (97, 101))	('tumors', 'Disease', (279, 285))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('tumors', 'Disease', 'MESH:D009369', (279, 285))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (17, 22))	('tumors', 'Disease', (219, 225))	('tumor', 'Disease', (279, 284))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (106, 117))	('mice', 'Species', '10090', (151, 155))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('mice', 'Species', '10090', (79, 83))	('lower', 'NegReg', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('mice', 'Species', '10090', (229, 233))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
46379	33066568	The group of mice treated with Ru-2 had slightly higher urea concentration (~3 units) compared to all other groups, but still statistically significant (significant difference from: Ru-1 group (p = 0.008); oxaliplatin group (p = 0.010); control group (p = 0.017); Figure 9C), while there was no significant difference in creatinine concentration between the groups (Figure 9C).	('urea', 'Chemical', 'MESH:D014508', (56, 60))	('mice', 'Species', '10090', (13, 17))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (206, 217))	('urea concentration', 'MPA', (56, 74))	('creatinine', 'Chemical', 'MESH:D003404', (321, 331))	('higher', 'PosReg', (49, 55))	('Ru-2', 'Var', (31, 35))
46381	33066568	The serum level of ALT was significantly higher in the group of Ru-1-treated tumor-bearing mice in comparison with Ru-2 and oxaliplatin-treated and control mice (significant difference from: Ru-2 group (p = 0.015); control group (p = 0.018); Figure 9C).	('mice', 'Species', '10090', (91, 95))	('ALT', 'Gene', (19, 22))	('Ru-1-treated', 'Var', (64, 76))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (124, 135))	('serum level', 'MPA', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('ALT', 'Gene', '76282', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('higher', 'PosReg', (41, 47))	('mice', 'Species', '10090', (156, 160))	('tumor', 'Disease', (77, 82))
46383	33066568	No significant histological changes in the heart tissue were observed in Ru-1 and Ru-2-treated mice in comparison with oxaliplatin and saline-treated mice (Figure 10A).	('mice', 'Species', '10090', (150, 154))	('mice', 'Species', '10090', (95, 99))	('Ru-2-treated', 'Gene', (82, 94))	('Ru-1', 'Var', (73, 77))	('saline', 'Chemical', 'MESH:D012965', (135, 141))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (119, 130))
46390	33066568	Fields of necrosis in the tumors of mice treated with Ru-2 were larger compared to necrosis fields in the tumors of untreated mice and oxaliplatin-treated mice, but were smaller compared to necrosis fields in the tumor of Ru-1-treated mice (Figure 10E).	('necrosis', 'Disease', (10, 18))	('mice', 'Species', '10090', (126, 130))	('tumors', 'Disease', (106, 112))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (135, 146))	('mice', 'Species', '10090', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('mice', 'Species', '10090', (235, 239))	('tumor', 'Disease', (106, 111))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('necrosis', 'Disease', 'MESH:D009336', (190, 198))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('mice', 'Species', '10090', (155, 159))	('necrosis', 'Disease', (190, 198))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('necrosis', 'Disease', 'MESH:D009336', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', (213, 218))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('necrosis', 'Disease', (83, 91))	('Ru-2', 'Var', (54, 58))	('necrosis', 'Disease', 'MESH:D009336', (10, 18))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
46392	33066568	Ru-1 exhibited similar cytotoxic capacity after 24 h exposure compared to oxaliplatin, especially against mouse colon carcinoma cell line (CT26) and human colon carcinoma cell line (SW480) (Table 1, Figure 4).	('Ru-1', 'Var', (0, 4))	('colon carcinoma', 'Disease', (112, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('colon carcinoma', 'Disease', (155, 170))	('SW480', 'CellLine', 'CVCL:0546', (182, 187))	('human', 'Species', '9606', (149, 154))	('colon carcinoma', 'Disease', 'MESH:D003110', (112, 127))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (74, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('CT26', 'CellLine', 'CVCL:7254', (139, 143))	('colon carcinoma', 'Disease', 'MESH:D003110', (155, 170))	('mouse', 'Species', '10090', (106, 111))
46397	33066568	The LDH levels increased up to 36.43% for CT26 cells following Ru-1 treatment, and up to 33.07% for SW480 cells following Ru-2 treatment at a concentration of 300 muM and only 2.20% for SW480 cells after 24 h treatment with oxaliplatin at the same concentration, which is in line with previous studies.	('oxaliplatin', 'Chemical', 'MESH:D000077150', (224, 235))	('Ru-1', 'Var', (63, 67))	('LDH levels', 'MPA', (4, 14))	('increased', 'PosReg', (15, 24))	('SW480', 'CellLine', 'CVCL:0546', (100, 105))	('CT26', 'CellLine', 'CVCL:7254', (42, 46))	('SW480', 'CellLine', 'CVCL:0546', (186, 191))
46405	33066568	Cells that are in late apoptosis, or already dead cells, are both Annexin V FITC and PI positive.	('FITC', 'Chemical', '-', (76, 80))	('apoptosis', 'biological_process', 'GO:0097194', ('23', '32'))	('PI positive', 'Var', (85, 96))	('Annexin V', 'Gene', (66, 75))	('Annexin V', 'Gene', '11747', (66, 75))	('apoptosis', 'biological_process', 'GO:0006915', ('23', '32'))
46406	33066568	The highest percentage of late apoptotic SW480 cells was observed upon oxaliplatin treatment relative to the untreated but also to the cells treated with ruthenium(II) terpyridine complexes (Figure 6).	('ruthenium(II) terpyridine complexes', 'Chemical', '-', (154, 189))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (71, 82))	('SW480', 'CellLine', 'CVCL:0546', (41, 46))	('late apoptotic SW480 cells', 'CPA', (26, 52))	('oxaliplatin', 'Var', (71, 82))
46408	33066568	In terms of the results related to the ability of ruthenium(II) complexes to induce apoptosis of HCT116 cells, there are results from the previous research that confirm that ruthenium(II) complexes increase the early and late apoptosis of HCT116 in a time- and concentration-dependent manners, but less than oxaliplatin, which is consistent with our results.	('complexes', 'Var', (188, 197))	('ruthenium(II)', 'Chemical', '-', (174, 187))	('HCT116', 'CellLine', 'CVCL:0291', (239, 245))	('increase', 'PosReg', (198, 206))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (308, 319))	('ruthenium(II)', 'Chemical', '-', (50, 63))	('HCT116', 'CellLine', 'CVCL:0291', (97, 103))	('HCT116', 'Gene', (239, 245))
46414	33066568	Ru-1 induced the arrest of CT26 and HCT116 cells in the G2/M phase, and Ru-2 caused G2/M phase arrest in SW480 cells, which is likely related to the molecular changes in the cancer cells (Figure 7).	('Ru-1', 'Gene', (0, 4))	('SW480', 'CellLine', 'CVCL:0546', (105, 110))	('HCT116', 'CellLine', 'CVCL:0291', (36, 42))	('arrest', 'Disease', (17, 23))	('G2/M phase', 'CPA', (56, 66))	('CT26', 'CellLine', 'CVCL:7254', (27, 31))	('G2/M', 'MPA', (84, 88))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('arrest', 'Disease', 'MESH:D006323', (95, 101))	('M phase', 'biological_process', 'GO:0000279', ('87', '94'))	('M phase', 'biological_process', 'GO:0000279', ('59', '66'))	('arrest', 'Disease', 'MESH:D006323', (17, 23))	('arrest', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('Ru-2', 'Var', (72, 76))
46419	33066568	Ru-1 reduced the colon carcinoma growth and progression as evaluated by significantly lower tumor volume and weight (Figure 8).	('Ru-1', 'Var', (0, 4))	('progression', 'CPA', (44, 55))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('lower', 'NegReg', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('reduced the colon carcinoma growth', 'Disease', (5, 39))	('reduced the colon carcinoma growth', 'Disease', 'MESH:D003110', (5, 39))	('tumor', 'Disease', (92, 97))
46421	33066568	Since it has been reported that oxaliplatin would cause liver damage, we tested ALT and AST levels in mice serum as indicators for liver function.	('cause', 'Reg', (50, 55))	('mice', 'Species', '10090', (102, 106))	('ALT', 'molecular_function', 'GO:0004021', ('80', '83'))	('ALT', 'Gene', '76282', (80, 83))	('AST', 'Gene', '235504', (88, 91))	('liver damage', 'Disease', (56, 68))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (32, 43))	('AST', 'Gene', (88, 91))	('ALT', 'Gene', (80, 83))	('liver damage', 'Disease', 'MESH:D056486', (56, 68))	('oxaliplatin', 'Var', (32, 43))
46478	33066568	In order to receive more information about the possible interactions of ruthenium(II) terpyridine complexes with biologically relevant ligands, we have studied the ligand substitution reactions of two Ru(II) terpyridine complexes, [Ru(Cl-tpy)(en)Cl][Cl] (Ru-1) and [Ru(Cl-tpy)(dach)Cl][Cl] (Ru-2), with reduced glutathione (GSH).	('reduced glutathione', 'MPA', (303, 322))	('[Ru(Cl-tpy)(', 'Var', (231, 243))	('[Ru(Cl-tpy)(', 'Var', (265, 277))	('GSH', 'Chemical', 'MESH:D005978', (324, 327))	('[Ru(Cl-tpy)(dach)Cl]', 'Chemical', '-', (265, 285))	('[Ru(Cl-tpy)(en)Cl][Cl', 'Chemical', '-', (231, 252))	('ruthenium(II) terpyridine complexes', 'Chemical', '-', (72, 107))	('Ru(II) terpyridine complexes', 'Chemical', '-', (201, 229))	('glutathione', 'Chemical', 'MESH:D005978', (311, 322))
46607	32599788	Particularly, as cytosolic Ca2+ begins to rise, Ca2+ activates various downstream partners such as calmodulin, calcineurin and protein kinase C (PKC) which, in turn, modulate important cellular processes and functions, including transcriptional regulation, intracellular protein trafficking, differentiation, proliferation, adhesion and invasion.	('differentiation', 'CPA', (292, 307))	('transcriptional regulation', 'MPA', (229, 255))	('calcineurin', 'Enzyme', (111, 122))	('cellular processes', 'CPA', (185, 203))	('Ca2+', 'Var', (48, 52))	('protein kinase C', 'Gene', (127, 143))	('PKC', 'Gene', (145, 148))	('calmodulin', 'Gene', (99, 109))	('modulate', 'Reg', (166, 174))	('proliferation', 'CPA', (309, 322))	('intracellular protein trafficking', 'MPA', (257, 290))	('Ca2+', 'Chemical', 'MESH:D000069285', (27, 31))	('calmodulin', 'Gene', '801', (99, 109))	('PKC', 'Gene', '112476', (145, 148))	('Ca2+', 'Chemical', 'MESH:D000069285', (48, 52))	('adhesion', 'CPA', (324, 332))	('protein kinase C', 'Gene', '112476', (127, 143))	('invasion', 'CPA', (337, 345))
46612	32599788	However, during prolonged stimulation and despite serving as the receptor's co-agonist along with IP3, Ca2+ can trigger IP3R ubiquitination and subsequent degradation as a preventative measure against toxic buildup of cytosolic Ca2+.	('IP3', 'Gene', (98, 101))	('Ca2+', 'Var', (103, 107))	('IP3', 'Gene', (120, 123))	('IP3R', 'Gene', '3710', (120, 124))	('ubiquitination', 'MPA', (125, 139))	('Ca2+', 'Chemical', 'MESH:D000069285', (103, 107))	('IP3R', 'Gene', (120, 124))	('IP3', 'Gene', '3710', (120, 123))	('IP3', 'Gene', '3710', (98, 101))	('Ca2+', 'Chemical', 'MESH:D000069285', (228, 232))	('degradation', 'MPA', (155, 166))
46622	32599788	As a result, the IP3Rs-mediated increase in the resting cytosolic Ca2+ concentration paves the way for RyRs to reach their maximum functional capacity.	('IP3Rs-mediated', 'Var', (17, 31))	('IP3Rs', 'Chemical', '-', (17, 22))	('increase', 'PosReg', (32, 40))	('Ca2+', 'Chemical', 'MESH:D000069285', (66, 70))	('resting cytosolic Ca2+ concentration', 'MPA', (48, 84))	('RyR', 'Gene', (103, 106))	('RyR', 'Gene', '6262', (103, 106))
46627	32599788	In cardiac myocytes, the opening of voltage-gated L-type Ca2+ channels caused by membrane depolarization increases intracellular Ca2+ level, triggering the opening of RyR2 and subsequent Ca2+ sparks, an essential element in maintaining excitation-contraction coupling in healthy cardiac functions.	('opening', 'MPA', (156, 163))	('RyR2', 'Gene', '6262', (167, 171))	('Ca2+ sparks', 'MPA', (187, 198))	('RyR2', 'Gene', (167, 171))	('Ca2+', 'Chemical', 'MESH:D000069285', (187, 191))	('increases intracellular Ca2+ level', 'Phenotype', 'HP:0003575', (105, 139))	('depolarization', 'Var', (90, 104))	('intracellular', 'cellular_component', 'GO:0005622', ('115', '128'))	('membrane depolarization', 'biological_process', 'GO:0051899', ('81', '104'))	('RyR', 'cellular_component', 'GO:1990425', ('167', '170'))	('Ca2+', 'Chemical', 'MESH:D000069285', (129, 133))	('intracellular Ca2+ level', 'MPA', (115, 139))	('triggering', 'Reg', (141, 151))	('membrane', 'cellular_component', 'GO:0016020', ('81', '89'))	('increases', 'PosReg', (105, 114))	('Ca2+', 'Chemical', 'MESH:D000069285', (57, 61))
46644	32599788	To prevent excessive Ca2+ entry, STIM2.1, a naturally occurring STIM2 variant, hinders STIM-Orai cross-linking and decreases clustering of CRAC channels at the plasma membrane.	('STIM2', 'Gene', (33, 38))	('Ca2+', 'Chemical', 'MESH:D000069285', (21, 25))	('STIM2', 'Gene', '57620', (64, 69))	('Ca2+ entry', 'MPA', (21, 31))	('clustering', 'MPA', (125, 135))	('STIM2', 'Gene', (64, 69))	('decreases', 'NegReg', (115, 124))	('variant', 'Var', (70, 77))	('STIM-Orai cross-linking', 'MPA', (87, 110))	('hinders', 'NegReg', (79, 86))	('STIM2', 'Gene', '57620', (33, 38))
46650	32599788	Post-transcriptional modifications, mainly alternative splicing, generate at least 14 SERCA variants with diverse species-dependent cellular and tissue distributions throughout various stages of development.	('Post', 'Gene', (0, 4))	('alternative splicing', 'Var', (43, 63))	('SERCA', 'Gene', '489', (86, 91))	('splicing', 'biological_process', 'GO:0045292', ('55', '63'))	('SERCA', 'Gene', (86, 91))	('Post', 'Gene', '159371', (0, 4))
46653	32599788	SERCA3 variants are often found co-expressed with the SERCA2b variant in a wide variety of tissues and cells, such as the salivary glands, lymphoid tissues, pancreatic cells and cerebellar Purkinje neurons.	('SERCA3', 'Gene', '489', (0, 6))	('SERCA2', 'Gene', (54, 60))	('variants', 'Var', (7, 15))	('SERCA3', 'Gene', (0, 6))	('SERCA2', 'Gene', '488', (54, 60))	('variant', 'Var', (62, 69))
46655	32599788	As there seems to be notable differences in Ca2+-binding affinities across SERCA isoforms and amongst variants within the same SERCA isoform, the tissue-specific expression equilibrium of SERCA variants transmits differential Ca2+ rhythms required for the survival and function of that specific tissue.	('Ca2+', 'Chemical', 'MESH:D000069285', (226, 230))	('SERCA', 'Gene', '489', (75, 80))	('SERCA', 'Gene', (75, 80))	('SERCA', 'Gene', '489', (188, 193))	('SERCA', 'Gene', (188, 193))	('SERCA', 'Gene', (127, 132))	('transmits differential Ca2+ rhythms', 'MPA', (203, 238))	('variants', 'Var', (194, 202))	('Ca2+-binding', 'Protein', (44, 56))	('SERCA', 'Gene', '489', (127, 132))	('Ca2+', 'Chemical', 'MESH:D000069285', (44, 48))	('binding', 'molecular_function', 'GO:0005488', ('49', '56'))
46656	32599788	Considering the crucial role of SERCA pumps in maintaining ER Ca2+ homeostasis, the intricate modulatory mechanisms and existence of various SERCA variants allow for a tight control of the molecular dynamics and kinetic behavior of this pump.	('variants', 'Var', (147, 155))	('SERCA', 'Gene', '489', (32, 37))	('SERCA', 'Gene', (32, 37))	('Ca2+', 'Chemical', 'MESH:D000069285', (62, 66))	('SERCA', 'Gene', '489', (141, 146))	('SERCA', 'Gene', (141, 146))	('ER Ca2+ homeostasis', 'MPA', (59, 78))
46687	32599788	Furthermore, in colorectal cancer cell lines, abrogation of oncogenic K-Ras unleashed IP3R3 activity, enhancing IP3R3-mediated Ca2+ release and inducing cellular sensitization to apoptosis.	('cellular sensitization to apoptosis', 'CPA', (153, 188))	('inducing', 'Reg', (144, 152))	('IP3R3', 'Gene', '3710', (112, 117))	('enhancing', 'PosReg', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('IP3R3', 'Gene', (112, 117))	('abrogation', 'Var', (46, 56))	('colorectal cancer', 'Disease', 'MESH:D015179', (16, 33))	('K-Ras', 'Gene', '3845', (70, 75))	('IP3R3', 'Gene', '3710', (86, 91))	('IP3R3', 'Gene', (86, 91))	('colorectal cancer', 'Phenotype', 'HP:0003003', (16, 33))	('colorectal cancer', 'Disease', (16, 33))	('K-Ras', 'Gene', (70, 75))	('Ca2+', 'Chemical', 'MESH:D000069285', (127, 131))
46702	32599788	Collectively, rampant manipulations of the IP3R expression profile throughout cancer development epitomize the notion that many malignancies have harbored the increasingly diversifying capacity to sabotage IP3R-mediated Ca2+ transients and therefore, global Ca2+ signaling to stimulate oncogenesis at the genetic level.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('IP3R', 'Gene', '3710', (43, 47))	('Ca2+', 'Chemical', 'MESH:D000069285', (220, 224))	('Ca2+', 'Chemical', 'MESH:D000069285', (258, 262))	('cancer', 'Disease', (78, 84))	('manipulations', 'Var', (22, 35))	('sabotage', 'NegReg', (197, 205))	('IP3R', 'Gene', (43, 47))	('global', 'MPA', (251, 257))	('malignancies', 'Disease', 'MESH:D009369', (128, 140))	('IP3R', 'Gene', '3710', (206, 210))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('IP3R', 'Gene', (206, 210))	('oncogenesis', 'CPA', (286, 297))	('malignancies', 'Disease', (128, 140))	('stimulate', 'PosReg', (276, 285))
46711	32599788	Besides aberrant RyR2 expression levels in giving rise to malignancy, several mutations of RyR2s have been linked to lung cancer.	('malignancy', 'Disease', 'MESH:D009369', (58, 68))	('linked', 'Reg', (107, 113))	('malignancy', 'Disease', (58, 68))	('RyR2', 'Gene', (91, 95))	('RyR2', 'Gene', '6262', (17, 21))	('lung cancer', 'Disease', (117, 128))	('RyR2', 'Gene', (17, 21))	('mutations', 'Var', (78, 87))	('RyR2', 'Gene', '6262', (91, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))
46721	32599788	The activity of these oncogenic pathways is often dictated by pathological modifications of Ca2+ release and influx channels, in particular, at the level of store operated Ca2+ entry (SOCE).	('oncogenic', 'CPA', (22, 31))	('SOCE', 'biological_process', 'GO:0002115', ('184', '188'))	('Ca2+ release', 'MPA', (92, 104))	('Ca2+', 'Chemical', 'MESH:D000069285', (172, 176))	('modifications', 'Var', (75, 88))	('dictated by', 'Reg', (50, 61))	('activity', 'MPA', (4, 12))	('Ca2+', 'Chemical', 'MESH:D000069285', (92, 96))
46724	32599788	In glioblastoma multiforme, STIM1 and Orai1 knockdown decreased cancer cell invasion and proliferation, respectively.	('proliferation', 'CPA', (89, 102))	('STIM1', 'Gene', '6786', (28, 33))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('glioblastoma multiforme', 'Disease', (3, 26))	('Orai1', 'Gene', (38, 43))	('decreased', 'NegReg', (54, 63))	('knockdown', 'Var', (44, 53))	('Orai1', 'Gene', '84876', (38, 43))	('STIM1', 'Gene', (28, 33))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (3, 26))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
46729	32599788	To corroborate this, McAndrew further demonstrated that Orai1 siRNA knockdown not only attenuated cytosolic Ca2+ influx in breast cancer MDA-MB-231 and MCF-7 cell lines in the presence of invasive stimulus PAR-2, but also reduced their viability.	('PAR-2', 'Gene', '2150', (206, 211))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (137, 147))	('Orai1', 'Gene', '84876', (56, 61))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('attenuated', 'NegReg', (87, 97))	('breast cancer', 'Disease', (123, 136))	('Ca2+', 'Chemical', 'MESH:D000069285', (108, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('MCF-7', 'CellLine', 'CVCL:0031', (152, 157))	('knockdown', 'Var', (68, 77))	('Orai1', 'Gene', (56, 61))	('PAR-2', 'Gene', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('reduced', 'NegReg', (222, 229))	('cytosolic Ca2+ influx', 'MPA', (98, 119))
46737	32599788	Conversely, Orai3 knockdown led to decreased ERalpha+ MCF7 cell proliferation and invasion.	('knockdown', 'Var', (18, 27))	('Orai3', 'Gene', (12, 17))	('ERalpha', 'Gene', (45, 52))	('invasion', 'CPA', (82, 90))	('ERalpha', 'Gene', '2099', (45, 52))	('decreased', 'NegReg', (35, 44))	('MCF7', 'CellLine', 'CVCL:0031', (54, 58))	('cell proliferation', 'biological_process', 'GO:0008283', ('59', '77'))	('Orai3', 'Gene', '93129', (12, 17))
46738	32599788	Another independent study led by Faouzi also demonstrated that Orai3 knockdown impaired breast cancer MCF-7 cell proliferation and arrested cell cycle progression at the G1 phase without affecting the proliferation and survival of wild-type mammary MCF-10A cells.	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('impaired breast cancer', 'Disease', (79, 101))	('MCF-7', 'CellLine', 'CVCL:0031', (102, 107))	('Orai3', 'Gene', '93129', (63, 68))	('cell cycle progression at the G1 phase', 'CPA', (140, 178))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Orai3', 'Gene', (63, 68))	('MCF-10A', 'CellLine', 'CVCL:0598', (249, 256))	('arrested', 'NegReg', (131, 139))	('knockdown', 'Var', (69, 78))	('impaired breast cancer', 'Disease', 'MESH:D001943', (79, 101))
46749	32599788	Additionally, highlighting the interplay between SERCA2 deficiency to malignancy came the finding of Prasad et al.	('SERCA2', 'Gene', (49, 55))	('malignancy', 'Disease', 'MESH:D009369', (70, 80))	('malignancy', 'Disease', (70, 80))	('SERCA2', 'Gene', '488', (49, 55))	('deficiency', 'Var', (56, 66))
46763	32599788	Moreover, SERCA2b is found over-expressed in epithelial prostate cancer cells and that knockdown of SERCA2b decreases prostate cancer proliferation.	('epithelial prostate cancer', 'Disease', 'MESH:D011471', (45, 71))	('decreases prostate', 'Phenotype', 'HP:0008687', (108, 126))	('SERCA2', 'Gene', '488', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('SERCA2', 'Gene', '488', (100, 106))	('epithelial prostate cancer', 'Disease', (45, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (118, 133))	('decreases prostate cancer', 'Disease', (108, 133))	('decreases prostate cancer', 'Disease', 'MESH:D011471', (108, 133))	('SERCA2', 'Gene', (10, 16))	('SERCA2', 'Gene', (100, 106))	('knockdown', 'Var', (87, 96))
46778	32599788	This depletion of the ER Ca2+ store, in and of itself, induces ER stress, and causes elevated cytoplasmic Ca2+ that can activate intrinsic apoptotic pathways through calmodulin/calcineurin-mediated signal transduction.	('Ca2+', 'Chemical', 'MESH:D000069285', (106, 110))	('depletion', 'Var', (5, 14))	('stress', 'Disease', 'MESH:D000079225', (66, 72))	('activate', 'PosReg', (120, 128))	('Ca2+', 'Chemical', 'MESH:D000069285', (25, 29))	('calmodulin', 'Gene', '801', (166, 176))	('calcineurin', 'molecular_function', 'GO:0004722', ('177', '188'))	('stress', 'Disease', (66, 72))	('induces', 'Reg', (55, 62))	('cytoplasmic Ca2+', 'MPA', (94, 110))	('elevated', 'PosReg', (85, 93))	('intrinsic apoptotic pathways', 'Pathway', (129, 157))	('signal transduction', 'biological_process', 'GO:0007165', ('198', '217'))	('calcineurin', 'molecular_function', 'GO:0004723', ('177', '188'))	('calmodulin', 'Gene', (166, 176))
46785	32599788	Through the use of in-silico models, such as molecular dynamic simulations and structure-based virtual screening, Sampath and Sankaranarayanan identified SB01990, SPB06836, and KM06293 as drug leads capable of disrupting Ca2+ binding to the active sites of Orai1, inhibiting ORAI-mediated Ca2+ influx with relatively ideal pharmacokinetics.	('SPB06836', 'Var', (163, 171))	('binding', 'Interaction', (226, 233))	('SB01990', 'Var', (154, 161))	('Ca2+', 'Chemical', 'MESH:D000069285', (289, 293))	('Ca2+', 'Protein', (221, 225))	('inhibiting', 'NegReg', (264, 274))	('ORAI-mediated Ca2+ influx', 'MPA', (275, 300))	('Ca2+', 'Chemical', 'MESH:D000069285', (221, 225))	('KM06293', 'Chemical', '-', (177, 184))	('disrupting', 'NegReg', (210, 220))	('SB01990', 'Chemical', '-', (154, 161))	('Orai1', 'Gene', (257, 262))	('Orai1', 'Gene', '84876', (257, 262))	('KM06293', 'Var', (177, 184))
46789	32599788	Indeed, loss-of-function mutations in human ORAI1 or STIM1 lead to increased susceptibility of developing tumors.	('mutations', 'Var', (25, 34))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('STIM1', 'Gene', (53, 58))	('human', 'Species', '9606', (38, 43))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('ORAI1', 'Gene', '84876', (44, 49))	('ORAI1', 'Gene', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('STIM1', 'Gene', '6786', (53, 58))	('loss-of-function', 'NegReg', (8, 24))
46804	31662984	Downregulation of TOP2alpha with siRNA or miR-494 transfection resulted in an increase of cytotoxicity and decrease of cell colonies to 5-FU for HCT-8/5-FU cells.	('cell colonies', 'CPA', (119, 132))	('5-FU', 'Chemical', 'MESH:D005472', (136, 140))	('miR-494', 'Gene', '574452', (42, 49))	('5-FU', 'Chemical', 'MESH:D005472', (151, 155))	('Downregulation', 'NegReg', (0, 14))	('miR-494', 'Gene', (42, 49))	('TOP2alpha', 'Gene', (18, 27))	('decrease', 'NegReg', (107, 115))	('increase of cytotoxicity', 'Disease', (78, 102))	('increase of cytotoxicity', 'Disease', 'MESH:D064420', (78, 102))	('TOP2alpha', 'Gene', '7153', (18, 27))	('transfection', 'Var', (50, 62))
46814	31662984	Treatment with 5-FU has been shown to reduce tumor size by approximately 50% in patients with advanced CRC and prolong their median survival by 5 months.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('patients', 'Species', '9606', (80, 88))	('tumor', 'Disease', (45, 50))	('prolong', 'PosReg', (111, 118))	('CRC', 'Phenotype', 'HP:0003003', (103, 106))	('reduce', 'NegReg', (38, 44))	('5-FU', 'Var', (15, 19))	('CRC', 'Disease', 'MESH:D015179', (103, 106))	('5-FU', 'Chemical', 'MESH:D005472', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('CRC', 'Disease', (103, 106))	('median', 'MPA', (125, 131))
46815	31662984	However, since the late 1990s, studies have revealed that 5-FU treatment can lead to therapy resistance accompanied by hand-foot syndrome, cardiotoxicity, and gastrointestinal side effects.	('lead to', 'Reg', (77, 84))	('5-FU', 'Var', (58, 62))	('therapy', 'Disease', (85, 92))	('hand-foot syndrome', 'Disease', (119, 137))	('cardiotoxicity', 'Disease', 'MESH:D066126', (139, 153))	('5-FU', 'Chemical', 'MESH:D005472', (58, 62))	('hand-foot syndrome', 'Disease', 'MESH:D060831', (119, 137))	('gastrointestinal', 'Disease', (159, 175))	('cardiotoxicity', 'Disease', (139, 153))
46822	31662984	Recently, as a novel herbal medicine, LA16001, which is composed of Prunella vulgaris L., was found to prevent cisplatin-induced anorexia.	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('herbal medicine', 'Species', '1407750', (21, 36))	('LA16001', 'Var', (38, 45))	('Prunella vulgaris L', 'Species', '39358', (68, 87))	('anorexia', 'Disease', 'MESH:D000855', (129, 137))	('prevent', 'NegReg', (103, 110))	('anorexia', 'Disease', (129, 137))	('anorexia', 'Phenotype', 'HP:0002039', (129, 137))
46871	31662984	To further confirm the role of TOP2alpha in 5-FU resistance, siRNA of TOP2alpha and miR-494 which was reported to target TOP2alpha was used to knock down the expression of TOP2alpha.	('expression', 'MPA', (158, 168))	('TOP2alpha', 'Gene', '7153', (70, 79))	('knock', 'Var', (143, 148))	('TOP2alpha', 'Gene', (172, 181))	('miR-494', 'Gene', '574452', (84, 91))	('TOP2alpha', 'Gene', (31, 40))	('TOP2alpha', 'Gene', (70, 79))	('TOP2alpha', 'Gene', (121, 130))	('TOP2alpha', 'Gene', '7153', (172, 181))	('miR-494', 'Gene', (84, 91))	('TOP2alpha', 'Gene', '7153', (31, 40))	('5-FU', 'Chemical', 'MESH:D005472', (44, 48))	('TOP2alpha', 'Gene', '7153', (121, 130))
46872	31662984	Compared to the negative control, siRNA or miR-494 transfection enhanced the 5-FU sensitive and cytotoxicity for HCT-8/5-FU cells (Figures 2(f) and 2(g)).	('miR-494', 'Gene', (43, 50))	('5-FU', 'Chemical', 'MESH:D005472', (77, 81))	('5-FU', 'Chemical', 'MESH:D005472', (119, 123))	('cytotoxicity', 'Disease', (96, 108))	('transfection', 'Var', (51, 63))	('miR-494', 'Gene', '574452', (43, 50))	('5-FU sensitive', 'MPA', (77, 91))	('cytotoxicity', 'Disease', 'MESH:D064420', (96, 108))	('enhanced', 'PosReg', (64, 72))
46873	31662984	Their transfection could also increase the cytotoxicity for HCT-8/5-FU cells, and miR-494 enhanced the 5-FU sensitivity for HCT-8/5-FU cells (Figures 2(h)-2(j)).	('miR-494', 'Gene', (82, 89))	('5-FU', 'Chemical', 'MESH:D005472', (130, 134))	('cytotoxicity', 'Disease', (43, 55))	('transfection', 'Var', (6, 18))	('5-FU', 'Chemical', 'MESH:D005472', (66, 70))	('5-FU', 'Chemical', 'MESH:D005472', (103, 107))	('enhanced', 'PosReg', (90, 98))	('increase', 'PosReg', (30, 38))	('cytotoxicity', 'Disease', 'MESH:D064420', (43, 55))	('miR-494', 'Gene', '574452', (82, 89))	('5-FU sensitivity', 'MPA', (103, 119))
46882	31662984	To study the effects of EESP on the 5-FU sensitivity of colon carcinoma cells, 5-FU-resistant HCT-8/5-FU cells were treated at 0.25 mg/mL and 0.5 mg/mL of EESP separately with 5-FU at 3.2 mM or 0.25 mg/mL and 0.5 mg/mL of EESP alone for 48 h. There was no significant difference in the number of cell colonies between the 5-FU group and the control group.	('5-FU', 'Chemical', 'MESH:D005472', (100, 104))	('5-FU', 'Chemical', 'MESH:D005472', (79, 83))	('5-FU', 'Chemical', 'MESH:D005472', (176, 180))	('colon carcinoma', 'Disease', 'MESH:D015179', (56, 71))	('5-FU', 'Chemical', 'MESH:D005472', (36, 40))	('colon carcinoma', 'Disease', (56, 71))	('5-FU', 'Var', (322, 326))	('5-FU', 'Chemical', 'MESH:D005472', (322, 326))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
46883	31662984	However, following treatment with 0.25 mg/mL and 0.5 mg/mL EESP combined with 5-FU, the number of cell colonies significantly decreased (Figures 3(a) and 3(c)).	('decreased', 'NegReg', (126, 135))	('5-FU', 'Chemical', 'MESH:D005472', (78, 82))	('0.5 mg/mL', 'Var', (49, 58))	('0.25 mg/mL', 'Var', (34, 44))
46888	31662984	These results together clearly implied that EESP enhanced 5-FU cell sensitivity in HCT-8/5-FU cells via suppression of cell colony formation and cell apoptosis induction.	('cell colony formation', 'CPA', (119, 140))	('suppression', 'NegReg', (104, 115))	('cell apoptosis induction', 'CPA', (145, 169))	('5-FU cell sensitivity', 'MPA', (58, 79))	('enhanced', 'PosReg', (49, 57))	('5-FU', 'Chemical', 'MESH:D005472', (89, 93))	('apoptosis', 'biological_process', 'GO:0097194', ('150', '159'))	('EESP', 'Var', (44, 48))	('5-FU', 'Chemical', 'MESH:D005472', (58, 62))	('apoptosis', 'biological_process', 'GO:0006915', ('150', '159'))	('formation', 'biological_process', 'GO:0009058', ('131', '140'))
46914	31662984	Mutation or overexpression of TOP2alpha was associated with chemotherapeutic resistance to some drugs, such as etoposide, irinotecan, and 5-FU.	('overexpression', 'PosReg', (12, 26))	('etoposide', 'Chemical', 'MESH:D005047', (111, 120))	('chemotherapeutic resistance to some drugs', 'MPA', (60, 101))	('Mutation', 'Var', (0, 8))	('TOP2alpha', 'Gene', (30, 39))	('5-FU', 'Chemical', 'MESH:D005472', (138, 142))	('TOP2alpha', 'Gene', '7153', (30, 39))	('irinotecan', 'Chemical', 'MESH:C051890', (122, 132))	('associated with', 'Reg', (44, 59))
46923	31662984	So there is a possibility for EESP being suppressed by the expression of TOP2alpha via YBX1.	('YBX1', 'Gene', (87, 91))	('YBX1', 'Gene', '4904', (87, 91))	('EESP', 'Disease', (30, 34))	('TOP2alpha', 'Gene', (73, 82))	('TOP2alpha', 'Gene', '7153', (73, 82))	('expression', 'Var', (59, 69))
46944	31624493	TKSE suppressed the growth of HT-29 and CT-26 cells (both colorectal cancer cell lines) and the cytotoxic effect of TKSE was greater than that of 5-fluorouracil (5-Fu) in HT-29 cells.	('5-fluorouracil', 'Chemical', 'MESH:D005472', (146, 160))	('colorectal cancer', 'Phenotype', 'HP:0003003', (58, 75))	('suppressed', 'NegReg', (5, 15))	('cytotoxic effect', 'CPA', (96, 112))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('5-Fu', 'Chemical', 'MESH:D005472', (162, 166))	('TKSE', 'Var', (116, 120))	('colorectal cancer', 'Disease', (58, 75))	('greater', 'PosReg', (125, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (58, 75))	('growth', 'CPA', (20, 26))
46945	31624493	Furthermore, TKSE dose-dependently inhibited activations of the Akt/mTOR and ERK pathways, and markedly induced the phosphorylation of AMPK.	('AMPK', 'Gene', (135, 139))	('Akt/mTOR', 'Pathway', (64, 72))	('phosphorylation', 'MPA', (116, 131))	('induced', 'PosReg', (104, 111))	('TKSE', 'Var', (13, 17))	('AMPK', 'Gene', '5563', (135, 139))	('inhibited', 'NegReg', (35, 44))	('ERK pathways', 'Pathway', (77, 89))
46947	31624493	In addition, TKSE attenuated the hypoxia-inducible factor-1alpha/vascular endothelial growth factor signaling pathway in HT-29 cells under hypoxic-mimic conditions and inhibited migration and invasion.	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('65', '99'))	('vascular endothelial growth factor', 'Gene', (65, 99))	('attenuated', 'NegReg', (18, 28))	('TKSE', 'Var', (13, 17))	('hypoxia-inducible factor-1alpha', 'Gene', '3091', (33, 64))	('inhibited', 'NegReg', (168, 177))	('hypoxia-inducible factor-1alpha', 'Gene', (33, 64))	('vascular endothelial growth factor', 'Gene', '7422', (65, 99))	('vascular endothelial growth factor signaling pathway', 'biological_process', 'GO:0038084', ('65', '117'))
46949	31624493	In the same model, 5-Fu caused significant body weight loss, but no such loss was observed in TKSE-treated mice.	('weight loss', 'Disease', 'MESH:D015431', (48, 59))	('5-Fu', 'Chemical', 'MESH:D005472', (19, 23))	('weight loss', 'Disease', (48, 59))	('mice', 'Species', '10090', (107, 111))	('weight loss', 'Phenotype', 'HP:0001824', (48, 59))	('5-Fu', 'Var', (19, 23))
46950	31624493	Taken together, these results suggest TKSE has potent anti-tumor effects which might be partly due to the activation of AMPK, and the induction mitochondrial-mediated apoptosis in colorectal cancer cells.	('induction', 'PosReg', (134, 143))	('AMPK', 'molecular_function', 'GO:0050405', ('120', '124'))	('AMPK', 'molecular_function', 'GO:0047322', ('120', '124'))	('tumor', 'Disease', (59, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (180, 197))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (180, 197))	('AMPK', 'Gene', (120, 124))	('apoptosis', 'biological_process', 'GO:0097194', ('167', '176'))	('apoptosis', 'biological_process', 'GO:0006915', ('167', '176'))	('colorectal cancer', 'Disease', (180, 197))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('activation', 'PosReg', (106, 116))	('mitochondrial-mediated apoptosis', 'CPA', (144, 176))	('TKSE', 'Var', (38, 42))	('AMPK', 'Gene', '5563', (120, 124))	('AMPK', 'molecular_function', 'GO:0004691', ('120', '124'))
46962	31624493	Donguibogam, which is a classical textbook of traditional Korean medicine, states trichosanthis semen reduces sputum production and swelling, and has detoxifying properties.	('reduces', 'NegReg', (102, 109))	('sputum production', 'MPA', (110, 127))	('trichosanthis', 'Var', (82, 95))	('swelling', 'Disease', (132, 140))	('swelling', 'Disease', 'MESH:D004487', (132, 140))	('detoxifying properties', 'CPA', (150, 172))
46964	31624493	In the scientific literature, trichosanthis semen has been reported to have anti-hepatocarcinogenic, anti-diabetic, anti-inflammatory, and anti-oxidative effects.	('anti-hepatocarcinogenic', 'CPA', (76, 99))	('diabetic', 'Disease', 'MESH:D003920', (106, 114))	('anti-inflammatory', 'MPA', (116, 133))	('diabetic', 'Disease', (106, 114))	('trichosanthis', 'Var', (30, 43))
47006	31624493	HT-29 and CT-26 cells were treated with various concentrations of TKSE (10-500 mug/mL) or 5-Fu (1-50 muM; positive control) for 24 and 48 h. Treatment with TKSE decreased the viabilities of HT-29 and CT-26 cells in a dose- and time-dependent manner as compared with vehicle-treated controls (Fig.	('decreased', 'NegReg', (161, 170))	('TKSE', 'Var', (156, 160))	('5-Fu', 'Chemical', 'MESH:D005472', (90, 94))	('viabilities', 'CPA', (175, 186))	('mug', 'molecular_function', 'GO:0043739', ('79', '82'))
47007	31624493	Notably, the cytotoxic effect of TKSE on HT-29 human colorectal cancer cells was also greater than that of 5-Fu.	('cytotoxic effect', 'CPA', (13, 29))	('greater', 'PosReg', (86, 93))	('TKSE', 'Var', (33, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (53, 70))	('5-Fu', 'Chemical', 'MESH:D005472', (107, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (53, 70))	('human', 'Species', '9606', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('colorectal cancer', 'Disease', (53, 70))
47010	31624493	Flow cytometer determined fluorescence intensity measurements showed that TKSE dose-dependently increased the proportion of rhodamine 123-negative cells, indicating loss of mitochondrial membrane potential in both HT-29 and CT-26 cells, though this loss was greater in HT-29 cells than in CT-26 cells (Fig.	('increased', 'PosReg', (96, 105))	('mitochondrial membrane potential', 'MPA', (173, 205))	('TKSE', 'Var', (74, 78))	('rhodamine 123', 'Chemical', 'MESH:C050316', (124, 137))	('loss', 'NegReg', (165, 169))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('173', '195'))
47013	31624493	In HT-29 cells treated with different concentrations of TKSE (50-300 microg/mL) for 6 h, TKSE dose-dependently reduced the expressions of p-Akt, p-mTOR, p-p70S6K1, p-4E-BP1, and p-ERK, without affecting their total levels (Fig.	('p-ERK', 'Gene', (178, 183))	('BP1', 'Gene', (169, 172))	('expressions', 'MPA', (123, 134))	('ERK', 'molecular_function', 'GO:0004707', ('180', '183'))	('BP1', 'Gene', '474256', (169, 172))	('reduced', 'NegReg', (111, 118))	('p-p70S6K1', 'Var', (153, 162))	('p-Akt', 'Protein', (138, 143))	('TKSE', 'Var', (89, 93))	('p-mTOR', 'Protein', (145, 151))	('p-ERK', 'Gene', '9451', (178, 183))
47023	31624493	Although slight cytotoxicity was observed at the highest concentration (300 mug/mL) of TKSE in the transwell invasion assays, TKSE markedly suppressed the invasiveness toward the FBS-attractant gradient in the dose-dependent manner (Fig.	('transwell invasion assays', 'CPA', (99, 124))	('suppressed', 'NegReg', (140, 150))	('cytotoxicity', 'Disease', 'MESH:D064420', (16, 28))	('invasiveness toward the', 'CPA', (155, 178))	('TKSE', 'Var', (126, 130))	('cytotoxicity', 'Disease', (16, 28))
47024	31624493	These results suggest TKSE suppresses the metastatic abilities of colorectal cancer cells.	('metastatic abilities of', 'CPA', (42, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('TKSE', 'Var', (22, 26))	('suppresses', 'NegReg', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal cancer', 'Disease', (66, 83))	('colorectal cancer', 'Disease', 'MESH:D015179', (66, 83))
47045	31624493	We report the following novel findings: (1) TKSE inhibited the proliferation of colorectal cancer cells by inhibiting the Akt/mTOR and ERK signaling pathways and activating AMPK, thus inducing apoptosis, (2) TKSE inhibited the metastatic abilities of colorectal cancer cells through the HIF-1alpha/VEGF pathway, and (3) TKSE exerted the anti-tumor effect without causing any observed toxic effects in our CT-26 tumor-bearing mouse model.	('proliferation', 'CPA', (63, 76))	('TKSE', 'Var', (44, 48))	('AMPK', 'Gene', (173, 177))	('inhibiting', 'NegReg', (107, 117))	('inducing', 'Reg', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (411, 416))	('metastatic abilities', 'CPA', (227, 247))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (251, 268))	('HIF-1alpha/VEGF pathway', 'Pathway', (287, 310))	('colorectal cancer', 'Disease', (80, 97))	('tumor', 'Disease', (342, 347))	('mouse', 'Species', '10090', (425, 430))	('activating', 'Reg', (162, 172))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('ERK signaling pathways', 'Pathway', (135, 157))	('AMPK', 'Gene', '5563', (173, 177))	('colorectal cancer', 'Disease', 'MESH:D015179', (251, 268))	('inhibited', 'NegReg', (49, 58))	('tumor', 'Disease', (411, 416))	('apoptosis', 'CPA', (193, 202))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('inhibited', 'NegReg', (213, 222))	('colorectal cancer', 'Disease', (251, 268))	('tumor', 'Disease', 'MESH:D009369', (411, 416))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
47046	31624493	Proliferation and survival related signaling pathways such as PI3K/AKT/mTOR and RAS/RAF/MEK/ERK play important roles in pathogeneses of solid tumors, and KRAS, BRAF, and PIK3CA (PI3K) mutations are the most common in colorectal cancer.	('RAF', 'Gene', '22882', (161, 164))	('BRAF', 'Gene', (160, 164))	('PIK3CA', 'Gene', '5290', (170, 176))	('BRAF', 'Gene', '673', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('mutations', 'Var', (184, 193))	('colorectal cancer', 'Disease', (217, 234))	('solid tumors', 'Disease', 'MESH:D009369', (136, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('RAF', 'Gene', (161, 164))	('KRAS', 'Gene', '3845', (154, 158))	('AKT', 'Gene', (67, 70))	('PIK3CA', 'Gene', (170, 176))	('KRAS', 'Gene', (154, 158))	('colorectal cancer', 'Phenotype', 'HP:0003003', (217, 234))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('RAF', 'Gene', '22882', (84, 87))	('AKT', 'Gene', '207', (67, 70))	('MEK', 'Gene', '5609', (88, 91))	('solid tumors', 'Disease', (136, 148))	('common', 'Reg', (207, 213))	('MEK', 'Gene', (88, 91))	('RAF', 'Gene', (84, 87))	('colorectal cancer', 'Disease', 'MESH:D015179', (217, 234))
47048	31624493	reported enhanced anti-tumor activities for the dual PI3K/mTOR inhibitor PF-502 and the MEK inhibitor PD-901 when used in combination in in vitro and in vivo models of colorectal cancer.	('MEK', 'Gene', '5609', (88, 91))	('PF-502', 'Var', (73, 79))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('PI3K', 'molecular_function', 'GO:0016303', ('53', '57'))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('colorectal cancer', 'Disease', (168, 185))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('MEK', 'Gene', (88, 91))	('tumor', 'Disease', (23, 28))	('enhanced', 'PosReg', (9, 17))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))
47051	31624493	Oral administration of quercetin reduced tumor volume and activated AMPK in HT-29 tumor xenograft mice, and berberine activated AMPK, decreased mTOR (a downstream target of AMPK) levels, and phosphorylated p53 in colorectal cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('activated', 'PosReg', (118, 127))	('AMPK', 'Gene', (173, 177))	('AMPK', 'Gene', (68, 72))	('AMPK', 'Gene', '5563', (128, 132))	('tumor', 'Disease', (82, 87))	('berberine', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('reduced', 'NegReg', (33, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (213, 230))	('activated', 'PosReg', (58, 67))	('AMPK', 'Gene', (128, 132))	('mice', 'Species', '10090', (98, 102))	('p53', 'Gene', (206, 209))	('decreased', 'NegReg', (134, 143))	('quercetin', 'Chemical', 'MESH:D011794', (23, 32))	('colorectal cancer', 'Disease', (213, 230))	('tumor', 'Disease', (41, 46))	('p53', 'Gene', '22060', (206, 209))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('AMPK', 'Gene', '5563', (173, 177))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('AMPK', 'Gene', '5563', (68, 72))	('phosphorylated', 'Var', (191, 205))	('berberine', 'Chemical', 'MESH:D001599', (108, 117))	('colorectal cancer', 'Phenotype', 'HP:0003003', (213, 230))
47053	31624493	Consistent with these observations, we observed TKSE activated AMPK and decreased mTOR activity in HT-29 cells.	('TKSE', 'Var', (48, 52))	('mTOR activity', 'MPA', (82, 95))	('activated', 'PosReg', (53, 62))	('AMPK', 'Gene', '5563', (63, 67))	('decreased', 'NegReg', (72, 81))	('AMPK', 'molecular_function', 'GO:0050405', ('63', '67'))	('AMPK', 'molecular_function', 'GO:0004691', ('63', '67'))	('AMPK', 'Gene', (63, 67))	('AMPK', 'molecular_function', 'GO:0047322', ('63', '67'))
47054	31624493	Furthermore, TKSE inhibited colorectal cancer cell proliferation by regulating these signaling pathways, disrupting mitochondrial membrane potentials, and inducing apoptosis.	('disrupting', 'NegReg', (105, 115))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('mitochondrial membrane potentials', 'MPA', (116, 149))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('inducing', 'Reg', (155, 163))	('regulating', 'Reg', (68, 78))	('colorectal cancer', 'Disease', (28, 45))	('apoptosis', 'CPA', (164, 173))	('TKSE', 'Var', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('inhibited', 'NegReg', (18, 27))	('apoptosis', 'biological_process', 'GO:0097194', ('164', '173'))	('apoptosis', 'biological_process', 'GO:0006915', ('164', '173'))	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('116', '138'))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))
47056	31624493	In addition, the present study shows TKSE suppresses the metastatic potential of colorectal cancer cells.	('colorectal cancer', 'Disease', (81, 98))	('metastatic potential of', 'CPA', (57, 80))	('TKSE', 'Var', (37, 41))	('suppresses', 'NegReg', (42, 52))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))
47057	31624493	As tumors grow, hypoxia develops as a result of uncontrolled rapid cell proliferation and nutrient supply becomes inadequate, and these deficiencies activate various intracellular signaling pathways including the major HIF-1/VEGF pathway and the PI3K/AKT/mTOR, ERK, and NF-kB pathways.	('AKT', 'Gene', (251, 254))	('deficiencies', 'Var', (136, 148))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('intracellular signaling pathways', 'Pathway', (166, 198))	('hypoxia', 'Disease', 'MESH:D000860', (16, 23))	('HIF-1', 'Gene', (219, 224))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('ERK', 'Pathway', (261, 264))	('NF-kB pathways', 'Pathway', (270, 284))	('activate', 'PosReg', (149, 157))	('AKT', 'Gene', '207', (251, 254))	('HIF-1', 'Gene', '3091', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('hypoxia', 'Disease', (16, 23))
47063	31624493	On the other hand, 5-Fu significantly reduced body weights indicating general toxicity, whereas TKSE did not.	('body weights', 'CPA', (46, 58))	('toxicity', 'Disease', 'MESH:D064420', (78, 86))	('toxicity', 'Disease', (78, 86))	('reduced', 'NegReg', (38, 45))	('reduced body weights', 'Phenotype', 'HP:0004325', (38, 58))	('5-Fu', 'Chemical', 'MESH:D005472', (19, 23))	('5-Fu', 'Var', (19, 23))
47065	31624493	Although 5-Fu is one of the most effective chemotherapeutics for the treatment of colorectal cancer, it frequently causes intestinal mucosal injury, and thus, abdominal pain and diarrhea.	('abdominal pain', 'Disease', 'MESH:D015746', (159, 173))	('intestinal mucosal injury', 'Disease', 'MESH:D007410', (122, 147))	('colorectal cancer', 'Disease', (82, 99))	('diarrhea', 'Disease', 'MESH:D003967', (178, 186))	('diarrhea', 'Phenotype', 'HP:0002014', (178, 186))	('diarrhea', 'Disease', (178, 186))	('pain', 'Phenotype', 'HP:0012531', (169, 173))	('abdominal pain', 'Phenotype', 'HP:0002027', (159, 173))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('intestinal mucosal injury', 'Disease', (122, 147))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('abdominal pain', 'Disease', (159, 173))	('5-Fu', 'Chemical', 'MESH:D005472', (9, 13))	('causes', 'Reg', (115, 121))	('5-Fu', 'Var', (9, 13))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))
47085	29761424	Phenolic acid intake, highly correlated with coffee consumption, was inversely associated with colon cancer in men (HRlog2 = 0.91, 95 % CI 0.85-0.97) and positively associated with rectal cancer in women (HRlog2 = 1.10, 95 % CI 1.02-1.19); although associations did not exceed the Bonferroni threshold for significance.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('rectal cancer', 'Disease', 'MESH:D012004', (181, 194))	('colon cancer', 'Disease', 'MESH:D015179', (95, 107))	('rectal cancer', 'Disease', (181, 194))	('associated', 'Reg', (165, 175))	('Phenolic', 'Var', (0, 8))	('women', 'Species', '9606', (198, 203))	('men', 'Species', '9606', (111, 114))	('associated', 'Interaction', (79, 89))	('colon cancer', 'Phenotype', 'HP:0003003', (95, 107))	('men', 'Species', '9606', (200, 203))	('rectal cancer', 'Phenotype', 'HP:0100743', (181, 194))	('colon cancer', 'Disease', (95, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('inversely', 'NegReg', (69, 78))	('Phenolic acid', 'Chemical', 'MESH:C017616', (0, 13))
47087	29761424	Our study suggests a possible inverse association between phenolic acid intake and colon cancer risk in men and positive with rectal cancer risk in women.	('rectal cancer', 'Disease', 'MESH:D012004', (126, 139))	('colon cancer', 'Disease', (83, 95))	('inverse', 'NegReg', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('men', 'Species', '9606', (104, 107))	('rectal cancer', 'Disease', (126, 139))	('phenolic acid', 'Chemical', 'MESH:C017616', (58, 71))	('rectal cancer', 'Phenotype', 'HP:0100743', (126, 139))	('men', 'Species', '9606', (150, 153))	('colon cancer', 'Phenotype', 'HP:0003003', (83, 95))	('colon cancer', 'Disease', 'MESH:D015179', (83, 95))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('phenolic', 'Var', (58, 66))	('women', 'Species', '9606', (148, 153))
47091	29761424	Experimental studies have shown anti-carcinogenic properties of polyphenols against CRC through several plausible biological mechanisms including modulation of nuclear factor (NF)-kappaB genes involved in inflammation and carcinogenesis, reduction of oxidative damage to lipids and DNA, induction of phase I and II enzymes, inhibition of angiogenesis, stimulation of DNA repair and apoptosis.	('carcinogenesis', 'Disease', 'MESH:D063646', (222, 236))	('inflammation', 'Disease', (205, 217))	('CRC', 'Disease', (84, 87))	('CRC', 'Phenotype', 'HP:0003003', (84, 87))	('induction', 'PosReg', (287, 296))	('inhibition', 'NegReg', (324, 334))	('inhibition of angiogenesis', 'biological_process', 'GO:0016525', ('324', '350'))	('modulation', 'Var', (146, 156))	('stimulation of DNA repair', 'biological_process', 'GO:0045739', ('352', '377'))	('CRC', 'Disease', 'MESH:D015179', (84, 87))	('oxidative damage to lipids', 'MPA', (251, 277))	('apoptosis', 'biological_process', 'GO:0097194', ('382', '391'))	('angiogenesis', 'CPA', (338, 350))	('apoptosis', 'biological_process', 'GO:0006915', ('382', '391'))	('apoptosis', 'CPA', (382, 391))	('men', 'Species', '9606', (6, 9))	('DNA', 'cellular_component', 'GO:0005574', ('282', '285'))	('inflammation', 'Disease', 'MESH:D007249', (205, 217))	('polyphenols', 'Chemical', 'MESH:D059808', (64, 75))	('DNA repair', 'CPA', (367, 377))	('reduction', 'NegReg', (238, 247))	('DNA', 'cellular_component', 'GO:0005574', ('367', '370'))	('carcinogenesis', 'Disease', (222, 236))	('stimulation', 'PosReg', (352, 363))	('inflammation', 'biological_process', 'GO:0006954', ('205', '217'))
47094	29761424	Furthermore, polyphenols can modulate gut microbiota, both in quantity and type of species.	('polyphenols', 'Chemical', 'MESH:D059808', (13, 24))	('modulate', 'Reg', (29, 37))	('gut microbiota', 'CPA', (38, 52))	('polyphenols', 'Var', (13, 24))
47204	31258757	This study investigated the clinicopathological significance of CK7 positivity in CRCs.	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('positivity', 'Var', (68, 78))	('CK7', 'Gene', (64, 67))	('CK7', 'Gene', '3855', (64, 67))	('CRCs', 'Disease', (82, 86))
47231	31258757	As the CK7 antigen is found in both healthy and neoplastic cells, antibodies against CK7 together with CK20 can be used for immunohistochemistry (IHC) staining to determine the origin of the tumor.	('CK20', 'Gene', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('CK20', 'Gene', '54474', (103, 107))	('CK7', 'Gene', (85, 88))	('CK7', 'Gene', (7, 10))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('antibodies', 'Var', (66, 76))	('CK7', 'Gene', '3855', (85, 88))	('CK7', 'Gene', '3855', (7, 10))
47275	31258757	CK7 positivity was correlated with the location, differentiation, lymph node metastasis, and the Dukes' stage.	('differentiation', 'CPA', (49, 64))	('positivity', 'Var', (4, 14))	('correlated', 'Reg', (19, 29))	("Dukes' stage", 'CPA', (97, 109))	('CK7', 'Gene', (0, 3))	('CK7', 'Gene', '3855', (0, 3))	('lymph node metastasis', 'CPA', (66, 87))
47276	31258757	There was no correlation between CK7 positivity and perineural invasion, intravascular tumor thrombus, and the depth of infiltration.	('perineural invasion', 'CPA', (52, 71))	('intravascular tumor', 'Phenotype', 'HP:0100742', (73, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('CK7', 'Gene', (33, 36))	('intravascular tumor thrombus', 'Disease', (73, 101))	('intravascular tumor thrombus', 'Disease', 'MESH:D013927', (73, 101))	('CK7', 'Gene', '3855', (33, 36))	('positivity', 'Var', (37, 47))
47279	31258757	The difference in the number of cases where the tumor occurred in the ascending colon between CK7 positive and negative CRCs was statistically significant (chi2 = 4.620, P = 0.032).	('CK7', 'Gene', (94, 97))	('CRC', 'Phenotype', 'HP:0003003', (120, 123))	('tumor', 'Disease', (48, 53))	('CK7', 'Gene', '3855', (94, 97))	('positive', 'Var', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
47292	31258757	Furthermore, in well and moderately differentiated CRCs with CK7 positivity, single cancer cells with a scattered distribution almost always yielded positive IHC staining results for CK7 and only some of the cells in the cancer nests yielded positive results for CK7 (Fig.	('CK7', 'Gene', (183, 186))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('CK7', 'Gene', '3855', (183, 186))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', (221, 227))	('CRCs', 'Disease', (51, 55))	('CK7', 'Gene', (263, 266))	('positivity', 'Var', (65, 75))	('CRC', 'Phenotype', 'HP:0003003', (51, 54))	('CK7', 'Gene', (61, 64))	('CK7', 'Gene', '3855', (263, 266))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('positive', 'PosReg', (149, 157))	('CK7', 'Gene', '3855', (61, 64))
47329	31258757	We provided evidence showing that CK7 positivity was associated with the location, differentiation, lymph node metastasis, and the Dukes' stage of CRCs.	('CRC', 'Phenotype', 'HP:0003003', (147, 150))	('differentiation', 'CPA', (83, 98))	('lymph node metastasis', 'CPA', (100, 121))	('positivity', 'Var', (38, 48))	("Dukes' stage", 'CPA', (131, 143))	('associated', 'Reg', (53, 63))	('CK7', 'Gene', (34, 37))	('CK7', 'Gene', '3855', (34, 37))
47332	31258757	Furthermore, CK7 positivity is associated with the anatomic site of the tumor and there were more CK7 positive cases in the ascending colon.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('positivity', 'Var', (17, 27))	('associated', 'Reg', (31, 41))	('CK7', 'Gene', (98, 101))	('CK7', 'Gene', (13, 16))	('CK7', 'Gene', '3855', (98, 101))	('CK7', 'Gene', '3855', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
47336	31258757	ICC and western blotting also confirmed that LoVo and HCT116 PGCCs and their daughter cells had higher CK7 expression than the control cells.	('CK7', 'Gene', (103, 106))	('PGCCs', 'Gene', (61, 66))	('HCT116', 'CellLine', 'CVCL:0291', (54, 60))	('CK7', 'Gene', '3855', (103, 106))	('expression', 'MPA', (107, 117))	('HCT116', 'Var', (54, 60))	('PGCCs', 'Chemical', '-', (61, 66))	('higher', 'PosReg', (96, 102))
47367	31258757	In serrated polyps from inflammatory bowel disease patients, dysplasia grade correlated with BRAF and KRAS mutation status, prevalent conventional neoplasia, and rates of advanced neoplasia development.	('mutation status', 'Var', (107, 122))	('neoplasia', 'Phenotype', 'HP:0002664', (147, 156))	('neoplasia', 'Disease', 'MESH:D009369', (180, 189))	('patients', 'Species', '9606', (51, 59))	('BRAF', 'Gene', '673', (93, 97))	('polyps', 'Disease', (12, 18))	('serrated polyps', 'Phenotype', 'HP:0032222', (3, 18))	('BRAF', 'Gene', (93, 97))	('neoplasia', 'Disease', (180, 189))	('men', 'Species', '9606', (197, 200))	('KRAS', 'Gene', '3845', (102, 106))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (24, 50))	('polyps', 'Disease', 'MESH:D011127', (12, 18))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (24, 50))	('neoplasia', 'Disease', 'MESH:D009369', (147, 156))	('inflammatory bowel disease', 'Disease', (24, 50))	('correlated', 'Reg', (77, 87))	('neoplasia', 'Phenotype', 'HP:0002664', (180, 189))	('dysplasia', 'Disease', (61, 70))	('dysplasia', 'Disease', 'MESH:D004476', (61, 70))	('neoplasia', 'Disease', (147, 156))	('KRAS', 'Gene', (102, 106))
47370	31258757	Our data demonstrated that CK7 positivity was associated with the location, differentiation, lymph node metastasis, and the Dukes' stage of CRCs.	('CK7', 'Gene', '3855', (27, 30))	('CRC', 'Phenotype', 'HP:0003003', (140, 143))	('differentiation', 'CPA', (76, 91))	("Dukes' stage", 'CPA', (124, 136))	('positivity', 'Var', (31, 41))	('CK7', 'Gene', (27, 30))	('associated', 'Reg', (46, 56))	('lymph node metastasis', 'CPA', (93, 114))
47372	31258757	However, further studies are required to elucidate the detailed molecular mechanisms of CK7 positivity and its association with tumor lymph node metastasis and regulation of signal pathways.	('tumor lymph node metastasis', 'Disease', (128, 155))	('regulation', 'biological_process', 'GO:0065007', ('160', '170'))	('tumor lymph node metastasis', 'Disease', 'MESH:D009362', (128, 155))	('CK7', 'Gene', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('association', 'Interaction', (111, 122))	('CK7', 'Gene', '3855', (88, 91))	('positivity', 'Var', (92, 102))
47396	29925227	Inaccurate assessment of adenomatous polyp size may lead to more frequent surveillance colonoscopies, exposing patients to undue risk and generating a significant cost.	('more', 'PosReg', (60, 64))	('surveillance colonoscopies', 'Disease', (74, 100))	('adenomatous polyp', 'Disease', (25, 42))	('adenomatous polyp', 'Disease', 'MESH:D018256', (25, 42))	('adenomatous polyp', 'Phenotype', 'HP:0005227', (25, 42))	('lead to', 'Reg', (52, 59))	('Inaccurate', 'Var', (0, 10))	('patients', 'Species', '9606', (111, 119))
47461	28422723	SAC morphology was observed in 38% of MACs, and was associated with proximal location (P=0.001), BRAF mutation (P=0.042), CIMP-positive status (P=0.023), and contiguous traditional serrated adenoma (P=0.019).	('SAC', 'Phenotype', 'HP:0032222', (0, 3))	('adenoma', 'Disease', (190, 197))	('MACs', 'Gene', (38, 42))	('mutation', 'Var', (102, 110))	('SAC', 'cellular_component', 'GO:0035003', ('0', '3'))	('associated', 'Reg', (52, 62))	('CIMP', 'Chemical', '-', (122, 126))	('adenoma', 'Disease', 'MESH:D000236', (190, 197))	('BRAF', 'Gene', '673', (97, 101))	('MACs', 'Gene', '54453', (38, 42))	('SAC', 'biological_process', 'GO:0071173', ('0', '3'))	('BRAF', 'Gene', (97, 101))	('serrated adenoma', 'Phenotype', 'HP:0032222', (181, 197))
47466	28422723	MACs exhibit a higher frequency of DNA mismatch repair (MMR) defects, microsatellite instability (MSI) and RAS/RAF/MAPK pathway mutations than non-MACs, and a lower incidence of p53 mutations.	('MACs', 'Gene', (147, 151))	('MACs', 'Gene', (0, 4))	('mutations', 'Var', (128, 137))	('RAF', 'Gene', '22882', (111, 114))	('defects', 'NegReg', (61, 68))	('RAF', 'Gene', (111, 114))	('microsatellite', 'MPA', (70, 84))	('DNA', 'MPA', (35, 38))	('MACs', 'Gene', '54453', (147, 151))	('MACs', 'Gene', '54453', (0, 4))	('p53', 'Gene', (178, 181))	('p53', 'Gene', '7157', (178, 181))
47474	28422723	In contrast with conventional colorectal adenocarcinoma resulting from a conventional adenoma-carcinoma sequence, SACs have a higher frequency of BRAF or KRAS mutations and higher levels of CIMP.	('BRAF', 'Gene', (146, 150))	('KRAS', 'Gene', '3845', (154, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('colorectal adenocarcinoma', 'Disease', (30, 55))	('CIMP', 'Chemical', '-', (190, 194))	('SAC', 'Phenotype', 'HP:0032222', (114, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('mutations', 'Var', (159, 168))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (86, 103))	('CIMP', 'MPA', (190, 194))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (30, 55))	('BRAF', 'Gene', '673', (146, 150))	('adenoma-carcinoma', 'Disease', (86, 103))	('KRAS', 'Gene', (154, 158))
47476	28422723	BRAF mutation might be an early event in CIMP tumors and might direct CIMP development.	('CIMP', 'Chemical', '-', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CIMP development', 'CPA', (70, 86))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('BRAF', 'Gene', '673', (0, 4))	('CIMP', 'Chemical', '-', (41, 45))	('BRAF', 'Gene', (0, 4))	('direct', 'Reg', (63, 69))	('tumors', 'Disease', (46, 52))	('men', 'Species', '9606', (82, 85))	('mutation', 'Var', (5, 13))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
47477	28422723	CIMP and BRAF mutations are associated with serrated CRC development, and these mutations occur frequently in MACs and SACs.	('MACs', 'Gene', '54453', (110, 114))	('BRAF', 'Gene', (9, 13))	('associated', 'Reg', (28, 38))	('MACs', 'Gene', (110, 114))	('men', 'Species', '9606', (64, 67))	('CIMP', 'Gene', (0, 4))	('CIMP', 'Chemical', '-', (0, 4))	('SAC', 'Phenotype', 'HP:0032222', (119, 122))	('serrated CRC', 'Disease', (44, 56))	('mutations', 'Var', (14, 23))	('BRAF', 'Gene', '673', (9, 13))
47487	28422723	MACs with SAC morphology were associated with proximal location (P=0.001), BRAF mutation (P=0.042), and CIMP-positive status (P=0.023) (Table 1).	('MACs', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (75, 79))	('SAC', 'Phenotype', 'HP:0032222', (10, 13))	('CIMP-positive status', 'Var', (104, 124))	('BRAF', 'Gene', (75, 79))	('MACs', 'Gene', '54453', (0, 4))	('CIMP', 'Chemical', '-', (104, 108))	('mutation', 'Var', (80, 88))
47495	28422723	The most common KRAS mutation in our samples was G12D (16.5%, 13/79); other mutations included G13D (13.9%, 11/79), G12V (6.3%, 5/79), G12A (2.5%, 2/79), G12C (1.3%, 1/79), G12R (1.3%, 1/79), and A18D (1.3%, 1/79) (Supplementary Table 2).	('G12R', 'Mutation', 'rs121913530', (173, 177))	('G12D', 'Mutation', 'rs121913529', (49, 53))	('G13D', 'Mutation', 'rs112445441', (95, 99))	('G12V', 'Var', (116, 120))	('A18D', 'Mutation', 'p.A18D', (196, 200))	('A18D', 'Var', (196, 200))	('G13D', 'Var', (95, 99))	('men', 'Species', '9606', (221, 224))	('G12A', 'Mutation', 'rs121913529', (135, 139))	('KRAS', 'Gene', (16, 20))	('G12V', 'Mutation', 'rs121913529', (116, 120))	('G12D', 'Var', (49, 53))	('G12R', 'Var', (173, 177))	('KRAS', 'Gene', '3845', (16, 20))	('G12C', 'Var', (154, 158))	('G12A', 'Var', (135, 139))	('G12C', 'Mutation', 'rs121913530', (154, 158))
47496	28422723	Analysis of BRAF mutations in codon 600 of exon 15 was successfully performed in 77 colorectal MACs, and 12 (15.6%) exhibited BRAF mutations.	('MACs', 'Gene', (95, 99))	('BRAF', 'Gene', '673', (12, 16))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('MACs', 'Gene', '54453', (95, 99))	('mutations', 'Var', (17, 26))
47497	28422723	The most common BRAF mutation in our series was V600E (13%, 10/77).	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('V600E', 'Mutation', 'rs113488022', (48, 53))	('V600E', 'Var', (48, 53))
47498	28422723	Other BRAF mutations included D594G (1.3%, 1/77) and D594N (1.3%, 1/77) in two MACs without SAC morphology.	('D594N', 'SUBSTITUTION', 'None', (53, 58))	('D594G', 'Var', (30, 35))	('MACs', 'Gene', '54453', (79, 83))	('MACs', 'Gene', (79, 83))	('BRAF', 'Gene', '673', (6, 10))	('SAC', 'Phenotype', 'HP:0032222', (92, 95))	('D594G', 'Mutation', 'rs121913338', (30, 35))	('BRAF', 'Gene', (6, 10))	('D594N', 'Var', (53, 58))
47499	28422723	BRAF mutation was associated with SAC morphology (P=0.042), poorer tumor differentiation (P=0.002), and CIMP-positive status (P=0.001) in colorectal MACs (Supplementary Table 3).	('SAC', 'Phenotype', 'HP:0032222', (34, 37))	('men', 'Species', '9606', (161, 164))	('MACs', 'Gene', '54453', (149, 153))	('SAC', 'Disease', (34, 37))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MACs', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (0, 4))	('tumor', 'Disease', (67, 72))	('BRAF', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('CIMP', 'Chemical', '-', (104, 108))
47502	28422723	Fifteen percent (12/81) of these MACs had at least three aberrantly methylated genes and were CIMP-positive.	('aberrantly methylated', 'Var', (57, 78))	('CIMP', 'Chemical', '-', (94, 98))	('MACs', 'Gene', (33, 37))	('MACs', 'Gene', '54453', (33, 37))
47504	28422723	BRAF mutation analysis was successfully performed in three of the four MACs with contiguous traditional serrated adenoma; all harbored BRAF mutations and were CIMP positive.	('serrated adenoma', 'Phenotype', 'HP:0032222', (104, 120))	('BRAF', 'Gene', '673', (135, 139))	('CIMP', 'Chemical', '-', (159, 163))	('harbored', 'Reg', (126, 134))	('BRAF', 'Gene', (135, 139))	('adenoma', 'Disease', (113, 120))	('MACs', 'Gene', '54453', (71, 75))	('adenoma', 'Disease', 'MESH:D000236', (113, 120))	('BRAF', 'Gene', '673', (0, 4))	('mutations', 'Var', (140, 149))	('BRAF', 'Gene', (0, 4))	('MACs', 'Gene', (71, 75))
47516	28422723	We showed that MAC with SAC morphology tended to grow in the proximal colon with a higher frequency of "serrated pathway carcinoma" molecular features, including BRAF mutations and CIMP-positivity than MACs without SAC morphology.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('MAC', 'cellular_component', 'GO:0005579', ('15', '18'))	('SAC', 'Phenotype', 'HP:0032222', (24, 27))	('MACs', 'Gene', (202, 206))	('SAC', 'cellular_component', 'GO:0035003', ('24', '27'))	('MAC', 'cellular_component', 'GO:0097423', ('15', '18'))	('carcinoma', 'Disease', 'MESH:D002277', (121, 130))	('mutations', 'Var', (167, 176))	('carcinoma', 'Disease', (121, 130))	('SAC', 'Phenotype', 'HP:0032222', (215, 218))	('MACs', 'Gene', '54453', (202, 206))	('CIMP', 'Chemical', '-', (181, 185))	('BRAF', 'Gene', '673', (162, 166))	('SAC', 'biological_process', 'GO:0071173', ('24', '27'))	('BRAF', 'Gene', (162, 166))
47517	28422723	SAC morphology was noted in 38% of MACs in our study, a result higher than previously reported (9.1%) for SAC in colorectal cancer, which might explain the high frequency of BRAF mutations and CIMP-positive status in MACs.	('SAC', 'Phenotype', 'HP:0032222', (0, 3))	('colorectal cancer', 'Disease', (113, 130))	('CIMP', 'Chemical', '-', (193, 197))	('SAC', 'Disease', (0, 3))	('MACs', 'Gene', (217, 221))	('MACs', 'Gene', '54453', (35, 39))	('rectal cancer', 'Phenotype', 'HP:0100743', (117, 130))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('BRAF', 'Gene', '673', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('MACs', 'Gene', (35, 39))	('BRAF', 'Gene', (174, 178))	('mutations', 'Var', (179, 188))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('SAC', 'Phenotype', 'HP:0032222', (106, 109))	('MACs', 'Gene', '54453', (217, 221))
47529	28422723	In previous studies using the Weisenberger panel, CIMP-positive status suggested good patient outcome in KRAS wild-type or MSI CRC, but a poor prognosis in rectal cancer or CRC with chromosomal instability.	('CIMP', 'Chemical', '-', (50, 54))	('chromosomal instability', 'Phenotype', 'HP:0040012', (182, 205))	('KRAS', 'Gene', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('patient', 'Species', '9606', (86, 93))	('MSI', 'Var', (123, 126))	('rectal cancer', 'Disease', 'MESH:D012004', (156, 169))	('KRAS', 'Gene', '3845', (105, 109))	('rectal cancer', 'Disease', (156, 169))	('rectal cancer', 'Phenotype', 'HP:0100743', (156, 169))
47534	28422723	The relatively high SAC incidence in MACs might explain the high frequency of BRAF mutations and CIMP-positive status in MACs.	('mutations', 'Var', (83, 92))	('CIMP', 'Chemical', '-', (97, 101))	('SAC', 'Phenotype', 'HP:0032222', (20, 23))	('BRAF', 'Gene', '673', (78, 82))	('BRAF', 'Gene', (78, 82))	('MACs', 'Gene', (121, 125))	('MACs', 'Gene', '54453', (37, 41))	('SAC', 'biological_process', 'GO:0071173', ('20', '23'))	('SAC', 'cellular_component', 'GO:0035003', ('20', '23'))	('MACs', 'Gene', (37, 41))	('MACs', 'Gene', '54453', (121, 125))
47551	28422723	Mutations covering KRAS codons 12 and 13, and BRAF codon 600 were assessed with direct sequencing of PCR-amplified DNA (Supplementary Methods).	('men', 'Species', '9606', (126, 129))	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('KRAS', 'Gene', (19, 23))	('KRAS', 'Gene', '3845', (19, 23))	('Mutations', 'Var', (0, 9))
47553	28422723	Tumor samples were categorized as CIMP positive if methylation was detected in >=3/5 genes, and CIMP negative if methylation was detected in <=2/5 genes.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('detected', 'Reg', (67, 75))	('methylation', 'Var', (51, 62))	('CIMP', 'Chemical', '-', (34, 38))	('CIMP', 'Chemical', '-', (96, 100))
47569	27513864	Additionally, the co-culture with macrophages increased the mRNA expression of metabolism- and survival-related genes more in SW1463 than in RKO.	('metabolism', 'biological_process', 'GO:0008152', ('79', '89'))	('mRNA expression', 'MPA', (60, 75))	('increased', 'PosReg', (46, 55))	('SW1463', 'CellLine', 'CVCL:1718', (126, 132))	('SW1463', 'Var', (126, 132))
47572	27513864	In the presence of RKO or SW1463, irradiated macrophages exhibit higher levels of pro-inflammatory TNF, IL6, CCL2 and CCR7, and of anti-inflammatory CCL18.	('levels', 'MPA', (72, 78))	('IL6', 'Gene', '3569', (104, 107))	('CCR', 'molecular_function', 'GO:0043880', ('118', '121'))	('SW1463', 'Var', (26, 32))	('CCL', 'molecular_function', 'GO:0044101', ('109', '112'))	('TNF', 'Gene', '7124', (99, 102))	('CCL18', 'Gene', (149, 154))	('CCL2', 'Gene', '6347', (109, 113))	('IL6', 'Gene', (104, 107))	('CCR7', 'Gene', (118, 122))	('RKO', 'Var', (19, 22))	('CCL18', 'Gene', '6362', (149, 154))	('SW1463', 'CellLine', 'CVCL:1718', (26, 32))	('CCR7', 'Gene', '1236', (118, 122))	('IL6', 'molecular_function', 'GO:0005138', ('104', '107'))	('CCL', 'molecular_function', 'GO:0044101', ('149', '152'))	('TNF', 'Gene', (99, 102))	('CCL2', 'Gene', (109, 113))	('higher', 'PosReg', (65, 71))
47582	27513864	In fact, in animal models, depletion of tumour-associated macrophages, either locally or systemically, prior to radiotherapy, decreases tumour regrowth, favouring the anti-tumour effects of ionizing radiation.	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('decreases tumour regrowth', 'Disease', (126, 151))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('tumour', 'Disease', (40, 46))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('tumour', 'Disease', (136, 142))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('tumour', 'Disease', (172, 178))	('depletion', 'Var', (27, 36))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('decreases tumour regrowth', 'Disease', 'MESH:D009369', (126, 151))
47587	27513864	Although macrophages may play a role in tumour cell radioresistance, this may also be intrinsically determined, namely by p53 mutations and chromosomal instability in tumour cells.	('chromosomal instability', 'Var', (140, 163))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('chromosomal instability', 'Phenotype', 'HP:0040012', (140, 163))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('tumour', 'Disease', (167, 173))	('tumour', 'Disease', (40, 46))	('p53', 'Gene', '7157', (122, 125))	('mutations', 'Var', (126, 135))	('radioresistance', 'CPA', (52, 67))	('p53', 'Gene', (122, 125))
47588	27513864	Additionally, alterations in DNA repair efficiency, upregulation of the pro-survival protein Bcl-xL, enhanced aerobic glycolysis, and altered mitochondrial function may also contribute to acquired resistance to radiation-induced apoptosis.	('alterations', 'Var', (14, 25))	('Bcl-xL', 'Gene', (93, 99))	('upregulation', 'PosReg', (52, 64))	('aerobic glycolysis', 'MPA', (110, 128))	('DNA repair', 'biological_process', 'GO:0006281', ('29', '39'))	('acquired resistance to radiation-induced apoptosis', 'CPA', (188, 238))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('apoptosis', 'biological_process', 'GO:0097194', ('229', '238'))	('pro-survival', 'biological_process', 'GO:0043066', ('72', '84'))	('apoptosis', 'biological_process', 'GO:0006915', ('229', '238'))	('contribute', 'Reg', (174, 184))	('mitochondrial function', 'MPA', (142, 164))	('altered', 'Reg', (134, 141))	('enhanced', 'PosReg', (101, 109))	('Bcl-xL', 'Gene', '598', (93, 99))	('glycolysis', 'biological_process', 'GO:0006096', ('118', '128'))	('DNA', 'Gene', (29, 32))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
47642	27513864	Our results demonstrated that both Chk2 and H2AX phosphorylation increased in SW1463 irradiated alone or in co-culture, when compared to the respective non-irradiated controls, indicating, as expected, higher DNA damage levels in irradiated cells.	('increased', 'PosReg', (65, 74))	('Chk2', 'Gene', (35, 39))	('H2AX', 'Gene', '3014', (44, 48))	('SW1463', 'CellLine', 'CVCL:1718', (78, 84))	('phosphorylation', 'MPA', (49, 64))	('DNA damage levels', 'MPA', (209, 226))	('H2AX', 'Gene', (44, 48))	('higher', 'PosReg', (202, 208))	('SW1463', 'Var', (78, 84))	('Chk2', 'Gene', '11200', (35, 39))
47643	27513864	However, no major alterations were found between Chk2 phosphorylation levels in SW1463 cells cultured alone or in combination with macrophages, suggesting that macrophages may increase SW1463 radioresistance through alternative mechanisms rather than DNA damage reduction, which requires further investigation.	('SW1463', 'CellLine', 'CVCL:1718', (185, 191))	('SW1463', 'CellLine', 'CVCL:1718', (80, 86))	('increase', 'PosReg', (176, 184))	('radioresistance', 'CPA', (192, 207))	('SW1463', 'Var', (185, 191))	('Chk2', 'Gene', '11200', (49, 53))	('phosphorylation', 'biological_process', 'GO:0016310', ('54', '69'))	('Chk2', 'Gene', (49, 53))	('DNA', 'cellular_component', 'GO:0005574', ('251', '254'))
47650	27513864	Contrarily, macrophages enhanced SW1463 SLC2A1 expression in both irradiated and non-irradiated conditions and LDHA without radiation exposure.	('SW1463', 'CellLine', 'CVCL:1718', (33, 39))	('LDHA', 'Gene', (111, 115))	('enhanced', 'PosReg', (24, 32))	('LDHA', 'Gene', '3939', (111, 115))	('SLC2A1', 'Gene', '6513', (40, 46))	('SW1463', 'Var', (33, 39))	('SLC2A1', 'Gene', (40, 46))	('expression', 'MPA', (47, 57))
47651	27513864	Additionally, an increase of LDHA expression in irradiated versus non-irradiated SW1463 co-cultures, but not in RKO co-cultures, was found, suggesting that SW1463 cells exhibit an adaptive metabolic response and a more radiation resistant profile, as indicated by the literature.	('more', 'PosReg', (214, 218))	('expression', 'MPA', (34, 44))	('SW1463', 'CellLine', 'CVCL:1718', (156, 162))	('SW1463', 'CellLine', 'CVCL:1718', (81, 87))	('LDHA', 'Gene', (29, 33))	('SW1463', 'Var', (156, 162))	('increase', 'PosReg', (17, 25))	('radiation resistant profile', 'CPA', (219, 246))	('LDHA', 'Gene', '3939', (29, 33))	('adaptive metabolic response', 'CPA', (180, 207))
47653	27513864	For SW1463, macrophages contribute to decrease apoptosis, which may be achieved through metabolic alterations induced by enhanced glucose transporter expression, which was also validated at the protein level (S2 Fig).	('SW1463', 'CellLine', 'CVCL:1718', (4, 10))	('SW1463', 'Var', (4, 10))	('glucose transporter expression', 'MPA', (130, 160))	('apoptosis', 'CPA', (47, 56))	('enhanced', 'PosReg', (121, 129))	('glucose', 'Chemical', 'MESH:D005947', (130, 137))	('decrease', 'NegReg', (38, 46))
47661	27513864	Additionally, SW1463, but not RKO cells, increased the expression of CXCL8 and CD80 pro-inflammatory (Fig 4), and of VCAN and IL10 anti-inflammatory markers (Fig 5).	('IL10', 'Gene', (126, 130))	('IL10', 'Gene', '3586', (126, 130))	('increased', 'PosReg', (41, 50))	('SW1463', 'CellLine', 'CVCL:1718', (14, 20))	('IL10', 'molecular_function', 'GO:0005141', ('126', '130'))	('CXCL8', 'Gene', '3576', (69, 74))	('CXCL8', 'Gene', (69, 74))	('CD80', 'Gene', (79, 83))	('SW1463', 'Var', (14, 20))	('expression', 'MPA', (55, 65))	('VCAN', 'Gene', (117, 121))	('CD80', 'Gene', '941', (79, 83))	('VCAN', 'Gene', '1462', (117, 121))
47663	27513864	Consistently, in the presence of either RKO or SW1463 cells, macrophages exhibited increased expression of IL6 and CCL2, while decreased the expression of CCL5 pro-inflammatory markers.	('SW1463 cells', 'Var', (47, 59))	('decreased', 'NegReg', (127, 136))	('increased', 'PosReg', (83, 92))	('IL6', 'molecular_function', 'GO:0005138', ('107', '110'))	('CCL2', 'Gene', '6347', (115, 119))	('CCL5', 'Gene', (155, 159))	('IL6', 'Gene', '3569', (107, 110))	('SW1463', 'CellLine', 'CVCL:1718', (47, 53))	('CCL2', 'Gene', (115, 119))	('expression', 'MPA', (93, 103))	('CCL5', 'Gene', '6352', (155, 159))	('IL6', 'Gene', (107, 110))	('CCL', 'molecular_function', 'GO:0044101', ('155', '158'))	('macrophages', 'CPA', (61, 72))	('CCL', 'molecular_function', 'GO:0044101', ('115', '118'))
47688	27513864	Briefly, radiosensitive RKO cells express mutated ATM, similarly to patients with a genetic disorder characterized by hypersensitivity to ionizing radiation.	('ATM', 'Gene', (50, 53))	('mutated', 'Var', (42, 49))	('genetic disorder', 'Disease', (84, 100))	('hypersensitivity', 'Disease', 'MESH:D004342', (118, 134))	('hypersensitivity', 'Disease', (118, 134))	('genetic disorder', 'Disease', 'MESH:D030342', (84, 100))	('patients', 'Species', '9606', (68, 76))	('ATM', 'Gene', '472', (50, 53))	('hypersensitivity', 'biological_process', 'GO:0002524', ('118', '134'))
47689	27513864	On the other hand, SW1463 cells express mutated TP53 and KRAS, which may delay apoptosis, enhance repair of DNA double-strand breaks or induce metabolic reprogramming, as a way of protecting cells from radiation-induced damage.	('TP53', 'Gene', '7157', (48, 52))	('enhance', 'PosReg', (90, 97))	('TP53', 'Gene', (48, 52))	('SW1463', 'CellLine', 'CVCL:1718', (19, 25))	('metabolic reprogramming', 'CPA', (143, 166))	('KRAS', 'Gene', (57, 61))	('delay apoptosis', 'CPA', (73, 88))	('mutated', 'Var', (40, 47))	('KRAS', 'Gene', '3845', (57, 61))	('repair', 'MPA', (98, 104))	('induce', 'Reg', (136, 142))
47690	27513864	Besides mutations, that intrinsically determine cancer cell response to radiation, other events, with which macrophages may interfere, can also modulate it.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('determine', 'Reg', (38, 47))	('mutations', 'Var', (8, 17))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('modulate', 'Reg', (144, 152))
47696	27513864	Accordingly, Mcl-1 targeting or depletion may sensitize cancer cells to radiation-induced apoptosis.	('radiation-induced apoptosis', 'CPA', (72, 99))	('sensitize', 'Reg', (46, 55))	('depletion', 'Var', (32, 41))	('Mcl-1', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('Mcl-1', 'Gene', '4170', (13, 18))
47701	27513864	On the other hand, increased levels of anti-inflammatory IL10 in irradiated macrophages upon co-culture with SW1463 cells may support survival and consequent macrophage-promoted SW1463 radioresistance, since high IL10 levels in tumour-associated macrophages may play a role in cancer progression and resistance to therapy.	('SW1463', 'Var', (178, 184))	('IL10', 'Gene', (213, 217))	('IL10', 'Gene', '3586', (213, 217))	('tumour', 'Disease', (228, 234))	('cancer', 'Disease', (277, 283))	('survival', 'CPA', (134, 142))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('SW1463', 'CellLine', 'CVCL:1718', (109, 115))	('radioresistance', 'CPA', (185, 200))	('tumour', 'Disease', 'MESH:D009369', (228, 234))	('IL10', 'Gene', (57, 61))	('support', 'PosReg', (126, 133))	('SW1463', 'CellLine', 'CVCL:1718', (178, 184))	('IL10', 'Gene', '3586', (57, 61))	('play', 'Reg', (262, 266))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))
47730	27091625	Chemoresistance associated with OXA is a complex and multifactorial process in which several mechanisms such as drug influx/efflux modifications, alterations in DNA damage repair, decrease of cell death activation, autocrine survival signalling or high detoxification activity could play a part.	('cell death activation', 'CPA', (192, 213))	('DNA damage repair', 'MPA', (161, 178))	('detoxification', 'biological_process', 'GO:0098754', ('253', '267'))	('alterations', 'Var', (146, 157))	('OXA', 'Chemical', 'MESH:D000077150', (32, 35))	('drug influx/efflux modifications', 'MPA', (112, 144))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('signalling', 'biological_process', 'GO:0023052', ('234', '244'))	('cell death', 'biological_process', 'GO:0008219', ('192', '202'))	('Chemoresistance', 'Disease', (0, 15))	('efflux', 'biological_process', 'GO:0140115', ('124', '130'))	('decrease', 'NegReg', (180, 188))	('efflux', 'biological_process', 'GO:0140352', ('124', '130'))
47741	27091625	Thus, the inhibition or modulation of NF-kappaB and its downstream targets has been proposed as an important target for the development of therapeutic approaches against this disease and the resistance to platinum agents.	('modulation', 'Var', (24, 34))	('inhibition', 'NegReg', (10, 20))	('platinum', 'Chemical', 'MESH:D010984', (205, 213))	('NF-kappaB', 'Gene', '4790', (38, 47))	('NF-kappaB', 'Gene', (38, 47))
47802	27091625	HT29 and HTOXAR3 cells were treated with Curcumin at 10 and 20 muM for 24 h. As expected, Curcumin decreased p65 phosphorylation and Survivin expression in a dose-dependent manner in both cell lines (Fig.	('decreased', 'NegReg', (99, 108))	('muM', 'Gene', '56925', (63, 66))	('Survivin', 'Protein', (133, 141))	('p65', 'Gene', (109, 112))	('phosphorylation', 'biological_process', 'GO:0016310', ('113', '128'))	('muM', 'Gene', (63, 66))	('HTOXAR3', 'CellLine', 'CVCL:8476', (9, 16))	('Curcumin', 'Chemical', 'MESH:D003474', (90, 98))	('Curcumin', 'Var', (90, 98))	('p65', 'Gene', '5970', (109, 112))	('expression', 'MPA', (142, 152))	('HT29', 'CellLine', 'CVCL:0320', (0, 4))	('Curcumin', 'Chemical', 'MESH:D003474', (41, 49))
47827	27091625	Forty-eight hours after gene silencing, cells were seeded in 96-well plates and treated for 24 h with doses of OXA ranging 0-100 muM.	('OXA', 'Chemical', 'MESH:D000077150', (111, 114))	('muM', 'Gene', (129, 132))	('gene silencing', 'Var', (24, 38))	('muM', 'Gene', '56925', (129, 132))	('gene silencing', 'biological_process', 'GO:0016458', ('24', '38'))
47840	27091625	8c, explants p93 and p141 were the only ones with a score = 2 when treated with Curcumin + OXA and interestingly, they had the highest CXCL1 basal levels as compared to explants with score 1 or 0.	('OXA', 'Chemical', 'MESH:D000077150', (91, 94))	('highest', 'Reg', (127, 134))	('Curcumin', 'Chemical', 'MESH:D003474', (80, 88))	('p93', 'Var', (13, 16))	('p141', 'Var', (21, 25))	('CXCL1', 'Gene', '2919', (135, 140))	('CXCL1', 'Gene', (135, 140))
47885	27091625	These results are not definitive yet they lead us to hypothesize that i) in some cases, the addition of Curcumin to OXA could lead to a more efficacious treatment, permitting dose reduction of the latter and avoiding toxicity; ii) combinations of Curcumin + OXA could be an effective treatment in metastatic CRC patients, including those that had progressed to an OXA-based first line.	('metastatic CRC patients', 'Disease', (297, 320))	('Curcumin', 'Chemical', 'MESH:D003474', (104, 112))	('patients', 'Species', '9606', (312, 320))	('toxicity', 'Disease', 'MESH:D064420', (217, 225))	('toxicity', 'Disease', (217, 225))	('OXA', 'Chemical', 'MESH:D000077150', (116, 119))	('combinations', 'Var', (231, 243))	('OXA', 'Chemical', 'MESH:D000077150', (364, 367))	('OXA', 'Chemical', 'MESH:D000077150', (258, 261))	('Curcumin', 'Chemical', 'MESH:D003474', (247, 255))
47915	27091625	Interfering RNA (siRNA) was used to generate specific knockdowns of CXCL8 and CXCL1 in the HTOXAR3 cell line.	('CXCL8', 'Gene', '3576', (68, 73))	('CXCL1', 'Gene', '2919', (78, 83))	('CXCL8', 'Gene', (68, 73))	('CXCL1', 'Gene', (78, 83))	('knockdowns', 'Var', (54, 64))	('HTOXAR3', 'CellLine', 'CVCL:8476', (91, 98))
47917	27091625	CXCL8 and CXCL1 were transiently silenced by using a pool of 4 different siRNAs (Smartpool On-target plus: CXCL8 siRNA, #L-004756; CXCL1 siRNA, #L-003898 ;Dhamacon, GE, respectively).	('CXCL1', 'Gene', (131, 136))	('CXCL8', 'Gene', (0, 5))	('CXCL8', 'Gene', '3576', (107, 112))	('CXCL1', 'Gene', '2919', (10, 15))	('#L-003898 ', 'Var', (144, 154))	('CXCL8', 'Gene', (107, 112))	('CXCL1', 'Gene', (10, 15))	('#L-004756', 'Var', (120, 129))	('CXCL1', 'Gene', '2919', (131, 136))	('CXCL8', 'Gene', '3576', (0, 5))
47930	27091625	A11105-01, Invitrogen) and resuspended in cold PBS with a PI concentration of 3 muM.	('PBS', 'Chemical', '-', (47, 50))	('muM', 'Gene', '56925', (80, 83))	('A11105-01', 'Var', (0, 9))	('muM', 'Gene', (80, 83))
47939	25621049	It has been suggested that D-erythrose may specifically inhibit the growth of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('D-erythrose', 'Var', (27, 38))	('inhibit', 'NegReg', (56, 63))	('tumor', 'Disease', (78, 83))	('D-erythrose', 'Chemical', 'MESH:C073321', (27, 38))
47946	25621049	The results revealed that D-erythrose significantly reduced the weight of the intraperitoneal tumor by 69.1%, markedly inhibited the development of ascites and increased tumor cell apoptosis, without any observed toxic effects.	('apoptosis', 'biological_process', 'GO:0097194', ('181', '190'))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('D-erythrose', 'Var', (26, 37))	('reduced', 'NegReg', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('increased', 'PosReg', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('apoptosis', 'biological_process', 'GO:0006915', ('181', '190'))	('tumor', 'Disease', (94, 99))	('inhibited', 'NegReg', (119, 128))	('tumor', 'Disease', (170, 175))	('D-erythrose', 'Chemical', 'MESH:C073321', (26, 37))	('ascites', 'Phenotype', 'HP:0001541', (148, 155))	('ascites', 'Disease', 'MESH:D001201', (148, 155))	('ascites', 'Disease', (148, 155))
47962	25621049	Based on the aforementioned findings, at the 101st Annual Meeting of the American Association for Cancer Research, Wang and Wei put forward the hypothesis that, in tumor tissues, the administered D-erythrose is oxidized in the cytosol or mitochondria to carbon dioxide, which is then converted to carbonic acid under the catalysis of carbonic anhydrase.	('tumor', 'Disease', (164, 169))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Cancer', 'Disease', (98, 104))	('D-erythrose', 'Var', (196, 207))	('carbon dioxide', 'Chemical', 'MESH:D002245', (254, 268))	('Cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('cytosol', 'cellular_component', 'GO:0005829', ('227', '234'))	('carbonic acid', 'Chemical', 'MESH:D002255', (297, 310))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('D-erythrose', 'Chemical', 'MESH:C073321', (196, 207))	('mitochondria', 'cellular_component', 'GO:0005739', ('238', '250'))
47964	25621049	In the previous study by Wang and Wei, D-erythrose was used as an antitumor agent, and it was found that D-erythrose could inhibit the viability of several cancer cell lines in vitro, and suppress the growth of lung cancer in a subcutaneous tumor model of LL-2 Lewis lung cells in vivo.	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('LL-2', 'Gene', '633295', (256, 260))	('D-erythrose', 'Var', (105, 116))	('growth', 'CPA', (201, 207))	('viability', 'CPA', (135, 144))	('cancer', 'Disease', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (241, 246))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('D-erythrose', 'Chemical', 'MESH:C073321', (105, 116))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('lung cancer', 'Disease', (211, 222))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (228, 246))	('inhibit', 'NegReg', (123, 130))	('suppress', 'NegReg', (188, 196))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('LL-2', 'Gene', (256, 260))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('cancer', 'Disease', (156, 162))	('tumor', 'Disease', (70, 75))	('lung cancer', 'Disease', 'MESH:D008175', (211, 222))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('D-erythrose', 'Chemical', 'MESH:C073321', (39, 50))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
47986	25621049	It is clear that mice treated with D-erythrose bore fewer intraperitoneal metastases than mice treated with NS.	('fewer', 'NegReg', (52, 57))	('mice', 'Species', '10090', (17, 21))	('D-erythrose', 'Chemical', 'MESH:C073321', (35, 46))	('metastases', 'Disease', (74, 84))	('mice', 'Species', '10090', (90, 94))	('metastases', 'Disease', 'MESH:D009362', (74, 84))	('D-erythrose', 'Var', (35, 46))
47995	25621049	In addition, the mean volume of ascites in the D-erythrose-treated group was significantly smaller compared with that of the NS group (P<0.05).	('ascites', 'Disease', (32, 39))	('ascites', 'Phenotype', 'HP:0001541', (32, 39))	('D-erythrose', 'Chemical', 'MESH:C073321', (47, 58))	('ascites', 'Disease', 'MESH:D001201', (32, 39))	('D-erythrose-treated', 'Var', (47, 66))	('smaller', 'NegReg', (91, 98))
47997	25621049	3, the percentage of TUNEL-positive cells (apoptotic cells) was significantly increased in the D-erythrose treated group compared with that in the NS group (P<0.01).	('D-erythrose', 'Var', (95, 106))	('increased', 'PosReg', (78, 87))	('D-erythrose', 'Chemical', 'MESH:C073321', (95, 106))
48003	25621049	Furthermore, in the present study, malignant ascites were markedly reduced in the D-erythrose-treated group (Fig.	('ascites', 'Disease', (45, 52))	('ascites', 'Phenotype', 'HP:0001541', (45, 52))	('reduced', 'NegReg', (67, 74))	('ascites', 'Disease', 'MESH:D001201', (45, 52))	('D-erythrose', 'Chemical', 'MESH:C073321', (82, 93))	('D-erythrose-treated', 'Var', (82, 101))
48004	25621049	2), indicating that D-erythrose may also inhibit tumor invasion.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('D-erythrose', 'Chemical', 'MESH:C073321', (20, 31))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('inhibit', 'NegReg', (41, 48))	('D-erythrose', 'Var', (20, 31))
48007	25621049	In the present study, TUNEL staining of the tumor tissue sections demonstrated that IP administration of D-erythrose resulted in increased apoptosis of colon cancer cells compared with the cells treated with the control agent (Fig.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('D-erythrose', 'Var', (105, 116))	('apoptosis', 'biological_process', 'GO:0097194', ('139', '148'))	('colon cancer', 'Disease', (152, 164))	('apoptosis', 'biological_process', 'GO:0006915', ('139', '148'))	('increased', 'PosReg', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('colon cancer', 'Phenotype', 'HP:0003003', (152, 164))	('D-erythrose', 'Chemical', 'MESH:C073321', (105, 116))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('apoptosis', 'CPA', (139, 148))	('colon cancer', 'Disease', 'MESH:D015179', (152, 164))
48008	25621049	3), indicating that D-erythrose may exert its antitumor effect by induction of apoptosis.	('D-erythrose', 'Chemical', 'MESH:C073321', (20, 31))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('apoptosis', 'CPA', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('D-erythrose', 'Var', (20, 31))	('tumor', 'Disease', (50, 55))
48015	25621049	The antitumor mechanism of D-erythrose may be associated with the unique bioenergetic metabolism of cancer cells.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('D-erythrose', 'Var', (27, 38))	('metabolism', 'biological_process', 'GO:0008152', ('86', '96'))	('tumor', 'Disease', (8, 13))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('D-erythrose', 'Chemical', 'MESH:C073321', (27, 38))
48026	25621049	Based on the high levels of glycolysis and lactate production in cancer cells, D-erythrose significantly inhibited the growth of colon cancer in vivo in the present study, without any observed effect on normal tissues, indicating that D-erythrose may become a potentially effective and specific antitumor agent against colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (129, 141))	('D-erythrose', 'Chemical', 'MESH:C073321', (235, 246))	('lactate production', 'MPA', (43, 61))	('cancer', 'Disease', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('cancer', 'Disease', (135, 141))	('colon cancer', 'Disease', 'MESH:D015179', (129, 141))	('cancer', 'Disease', (325, 331))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('colon cancer', 'Phenotype', 'HP:0003003', (319, 331))	('glycolysis', 'MPA', (28, 38))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('D-erythrose', 'Var', (79, 90))	('inhibited', 'NegReg', (105, 114))	('glycolysis', 'biological_process', 'GO:0006096', ('28', '38'))	('colon cancer', 'Disease', 'MESH:D015179', (319, 331))	('colon cancer', 'Disease', (129, 141))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('D-erythrose', 'Chemical', 'MESH:C073321', (79, 90))	('tumor', 'Disease', (299, 304))	('growth', 'MPA', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (325, 331))	('lactate', 'Chemical', 'MESH:D019344', (43, 50))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('colon cancer', 'Disease', (319, 331))
48028	25621049	In conclusion, the present data suggest that D-erythrose can markedly suppress the growth of colon carcinoma, inhibit tumor cell invasion and increase tumor cell apoptosis, without any observed toxic effects.	('D-erythrose', 'Chemical', 'MESH:C073321', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('suppress', 'NegReg', (70, 78))	('increase tumor', 'Disease', 'MESH:D009369', (142, 156))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (151, 156))	('growth', 'CPA', (83, 89))	('colon carcinoma', 'Disease', 'MESH:D015179', (93, 108))	('tumor', 'Disease', (118, 123))	('colon carcinoma', 'Disease', (93, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('D-erythrose', 'Var', (45, 56))	('inhibit', 'NegReg', (110, 117))	('increase tumor', 'Disease', (142, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
48106	25390042	AOM induction regimen has been reported to cause aberrant crypt foci in the colon, which was confirmed in our present study by the observation of crypt formation and mucosal damage.	('mucosal damage', 'Disease', 'MESH:D009059', (166, 180))	('cause', 'Reg', (43, 48))	('formation', 'biological_process', 'GO:0009058', ('152', '161'))	('AOM', 'Var', (0, 3))	('mucosal damage', 'Disease', (166, 180))	('crypt', 'Disease', (58, 63))
48110	25390042	Mutations and overexpression of beta-catenin are associated with many cancers, including colorectal carcinoma.	('colorectal carcinoma', 'Disease', 'MESH:D015179', (89, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('beta-catenin', 'Protein', (32, 44))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('associated', 'Reg', (49, 59))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('colorectal carcinoma', 'Disease', (89, 109))	('cancers', 'Disease', (70, 77))	('overexpression', 'PosReg', (14, 28))
48122	25216868	Out of 32 mutations, 16 were located at hMLH1 and 16 at hMSH2.	('hMLH1', 'Gene', '4292', (40, 45))	('hMSH', 'molecular_function', 'GO:0018775', ('56', '60'))	('hMSH2', 'Gene', '4436', (56, 61))	('mutations', 'Var', (10, 19))	('hMSH2', 'Gene', (56, 61))	('hMLH1', 'Gene', (40, 45))
48123	25216868	Among all the 32 families with mutations, families with hMSH2 mutation had a higher ratio of synchronous and metachronous colon cancers than families with hMLH1 mutation (33 vs. 6 %, P = 0.04).	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('synchronous and metachronous colon cancers', 'Disease', 'MESH:D015179', (93, 135))	('colon cancer', 'Phenotype', 'HP:0003003', (122, 134))	('hMSH', 'molecular_function', 'GO:0018775', ('56', '60'))	('hMLH1', 'Gene', (155, 160))	('mutation', 'Var', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('hMLH1', 'Gene', '4292', (155, 160))	('hMSH2', 'Gene', '4436', (56, 61))	('hMSH2', 'Gene', (56, 61))	('colon cancers', 'Phenotype', 'HP:0003003', (122, 135))
48124	25216868	Patients with hMSH2 mutation more frequently harbour synchronous and metachronous colon cancers.	('colon cancer', 'Phenotype', 'HP:0003003', (82, 94))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('mutation', 'Var', (20, 28))	('hMSH2', 'Gene', '4436', (14, 19))	('Patients', 'Species', '9606', (0, 8))	('synchronous and metachronous colon cancers', 'Disease', 'MESH:D015179', (53, 95))	('hMSH2', 'Gene', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('colon cancers', 'Phenotype', 'HP:0003003', (82, 95))	('harbour', 'Reg', (45, 52))
48128	25216868	Most (90 %) of the mutations locate in two MMR genes, MLH1 (50 %) and MSH2 (40 %).	('locate', 'Reg', (29, 35))	('MLH1', 'Gene', '4292', (54, 58))	('MLH1', 'Gene', (54, 58))	('mutations', 'Var', (19, 28))	('MSH2', 'Gene', (70, 74))	('MSH2', 'Gene', '4436', (70, 74))
48133	25216868	Studies of families meeting the Amsterdam criteria have identified germline MSH2 and MLH1 mutations with a relatively high sensitivity (~60 %) and specificity (~70 %).	('mutations', 'Var', (90, 99))	('MLH1', 'Gene', '4292', (85, 89))	('MLH1', 'Gene', (85, 89))	('MSH2', 'Gene', (76, 80))	('MSH2', 'Gene', '4436', (76, 80))
48134	25216868	In contrast, germline MSH2 and MLH1 mutations were found with a higher sensitivity (~94 %) and a lower specificity (~30 %) when families meeting the Bethesda criteria were studied.	('MSH2', 'Gene', (22, 26))	('MSH2', 'Gene', '4436', (22, 26))	('mutations', 'Var', (36, 45))	('MLH1', 'Gene', '4292', (31, 35))	('lower', 'NegReg', (97, 102))	('MLH1', 'Gene', (31, 35))
48142	25216868	The golden standard for diagnostic of HNPCC is germline mutation in MMR genes.	('germline mutation', 'Var', (47, 64))	('HNPCC', 'Gene', (38, 43))	('MMR', 'Gene', (68, 71))	('HNPCC', 'Phenotype', 'HP:0006716', (38, 43))	('HNPCC', 'Gene', '4436', (38, 43))
48146	25216868	In patients with endometrial cancer, MMR gene mutations are most prevalent in the MSH2 gene (5.2-7.0 %).	('mutations', 'Var', (46, 55))	('MSH2', 'Gene', (82, 86))	('endometrial cancer', 'Phenotype', 'HP:0012114', (17, 35))	('MSH2', 'Gene', '4436', (82, 86))	('endometrial cancer', 'Disease', 'MESH:D016889', (17, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('patients', 'Species', '9606', (3, 11))	('endometrial cancer', 'Disease', (17, 35))	('prevalent', 'Reg', (65, 74))
48155	25216868	Sequence variants that would obviously impact the function of MLH1 or MSH2 proteins, such as nonsense and frameshift mutations, were considered pathogenic.	('nonsense', 'Var', (93, 101))	('impact', 'NegReg', (39, 45))	('MLH1', 'Gene', '4292', (62, 66))	('MSH2', 'Gene', (70, 74))	('proteins', 'Protein', (75, 83))	('MLH1', 'Gene', (62, 66))	('MSH2', 'Gene', '4436', (70, 74))	('frameshift mutations', 'Var', (106, 126))	('function', 'MPA', (50, 58))
48158	25216868	Sixteen mutations were located at hMLH1, and 16 were located at hMSH2.	('hMSH2', 'Gene', '4436', (64, 69))	('hMLH1', 'Gene', (34, 39))	('hMLH1', 'Gene', '4292', (34, 39))	('mutations', 'Var', (8, 17))	('hMSH2', 'Gene', (64, 69))	('hMSH', 'molecular_function', 'GO:0018775', ('64', '68'))
48159	25216868	Among the 16 mutations of hMLH1, exon12 and exon15 both occupied three mutations.	('hMLH1', 'Gene', '4292', (26, 31))	('exon12', 'Var', (33, 39))	('hMLH1', 'Gene', (26, 31))	('exon15', 'Var', (44, 50))
48160	25216868	Among the 16 mutations of hMLH2, exon7 had six.	('mutations', 'Var', (13, 22))	('hMLH2', 'Gene', (26, 31))	('hMLH2', 'Gene', '5378', (26, 31))	('exon7', 'Var', (33, 38))
48163	25216868	Among all the 32 families with mutations, those with hMSH2 mutation had a higher ratio of synchronous and metachronous colon cancers than families with hMLH1 mutation (33 vs. 6 %, P = 0.04) (Table 3).	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('colon cancers', 'Phenotype', 'HP:0003003', (119, 132))	('hMSH2', 'Gene', '4436', (53, 58))	('colon cancer', 'Phenotype', 'HP:0003003', (119, 131))	('hMSH2', 'Gene', (53, 58))	('synchronous and metachronous colon cancers', 'Disease', 'MESH:D015179', (90, 132))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('hMLH1', 'Gene', (152, 157))	('mutation', 'Var', (59, 67))	('hMLH1', 'Gene', '4292', (152, 157))
48170	25216868	Timm Goecke also reported rectal cancers were remarkably frequent in 281 MLH1/MSH2 mutation carriers in German.	('MSH2', 'Gene', (78, 82))	('MSH2', 'Gene', '4436', (78, 82))	('rectal cancers', 'Disease', 'MESH:D012004', (26, 40))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('frequent', 'Reg', (57, 65))	('mutation', 'Var', (83, 91))	('rectal cancers', 'Disease', (26, 40))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('MLH1', 'Gene', '4292', (73, 77))	('MLH1', 'Gene', (73, 77))
48180	25216868	Some studies also show the relative risk of gastric cancer in HNPCC mutation carriers compared with the general population has been reported to be higher by 4-19-fold in populations of the Western world and at least by twofold in endemic areas in Asia.	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('HNPCC', 'Phenotype', 'HP:0006716', (62, 67))	('mutation', 'Var', (68, 76))	('gastric cancer', 'Disease', (44, 58))	('HNPCC', 'Gene', (62, 67))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('higher', 'PosReg', (147, 153))	('HNPCC', 'Gene', '4436', (62, 67))
48181	25216868	calculated the lifetime risk of gastric cancer in mutation carriers of the HNPCC gene as 19 % in the Finnish population.	('HNPCC', 'Gene', (75, 80))	('gastric cancer', 'Disease', (32, 46))	('gastric cancer', 'Disease', 'MESH:D013274', (32, 46))	('HNPCC', 'Gene', '4436', (75, 80))	('HNPCC', 'Phenotype', 'HP:0006716', (75, 80))	('gastric cancer', 'Phenotype', 'HP:0012126', (32, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('mutation', 'Var', (50, 58))
48185	25216868	Their limited sensitivity for identifying families with MSH2 and MLH1 mutations make it inappropriate to use the Amsterdam criteria as the sole criteria in choosing which patients should undergo genetic testing.	('mutations', 'Var', (70, 79))	('MLH1', 'Gene', '4292', (65, 69))	('patients', 'Species', '9606', (171, 179))	('MLH1', 'Gene', (65, 69))	('MSH2', 'Gene', (56, 60))	('MSH2', 'Gene', '4436', (56, 60))
48197	25216868	Approximately 85 % of genetically defined HNPCC patients have germline mutations in MLH1 and MSH2.	('germline mutations', 'Var', (62, 80))	('MLH1', 'Gene', '4292', (84, 88))	('MLH1', 'Gene', (84, 88))	('HNPCC', 'Gene', (42, 47))	('HNPCC', 'Gene', '4436', (42, 47))	('MSH2', 'Gene', (93, 97))	('HNPCC', 'Phenotype', 'HP:0006716', (42, 47))	('patients', 'Species', '9606', (48, 56))	('MSH2', 'Gene', '4436', (93, 97))
48198	25216868	reported that MLH1 carriers (n = 112) had a higher prevalence of colorectal cancer (79 vs. 69 %, P = 0.08) and younger age of diagnosis (42.2 vs. 44.8 years, P = 0.03) when compared to MSH2 carriers (n = 173).	('colorectal cancer', 'Phenotype', 'HP:0003003', (65, 82))	('MSH2', 'Gene', (185, 189))	('MLH1', 'Gene', '4292', (14, 18))	('MSH2', 'Gene', '4436', (185, 189))	('colorectal cancer', 'Disease', (65, 82))	('MLH1', 'Gene', (14, 18))	('carriers', 'Var', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (65, 82))
48199	25216868	While the prevalence of endometrial cancer in women (68/167, 41 %) was similar in both groups (36 vs. 44 %), other extracolonic cancers were more frequent in MSH2 carriers compared to MLH1 carriers (24 vs. 9 %; OR 3.2; 95 % CI 1.5-6.6; P = 0.001) and their families (P<0.001).	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('endometrial cancer', 'Phenotype', 'HP:0012114', (24, 42))	('colonic cancers', 'Disease', (120, 135))	('MSH2', 'Gene', (158, 162))	('carriers', 'Var', (163, 171))	('endometrial cancer', 'Disease', 'MESH:D016889', (24, 42))	('colonic cancers', 'Disease', 'MESH:D015179', (120, 135))	('MSH2', 'Gene', '4436', (158, 162))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('MLH1', 'Gene', '4292', (184, 188))	('women', 'Species', '9606', (46, 51))	('MLH1', 'Gene', (184, 188))	('endometrial cancer', 'Disease', (24, 42))	('frequent', 'Reg', (146, 154))
48201	25216868	Males with MLH1 mutations exhibited a significantly higher CRC risk than females (67 vs. 35 % by age 70, P = 0.02), while the risk was similar in MSH2 carriers (about 54 %).	('mutations', 'Var', (16, 25))	('MSH2', 'Gene', (146, 150))	('MLH1', 'Gene', '4292', (11, 15))	('MSH2', 'Gene', '4436', (146, 150))	('higher', 'PosReg', (52, 58))	('MLH1', 'Gene', (11, 15))	('CRC', 'Disease', (59, 62))
48202	25216868	The relative risk was constant with age (hazard ratio; between 5.5 and 5.1 over age 30-70) in MLH1 carriers, while the harzard ratio in MSH2 carriers decreased with age (from 13.1 at age 30 to 5.4 at age 70).	('MSH2', 'Gene', (136, 140))	('MSH2', 'Gene', '4436', (136, 140))	('MLH1', 'Gene', '4292', (94, 98))	('carriers', 'Var', (99, 107))	('MLH1', 'Gene', (94, 98))
48203	25216868	In our study, families with hMSH2 mutation had a higher ratio of synchronous and metachronous colon cancers than families with hMLH1 mutation (33 vs. 6 %, P = 0.04).	('synchronous and metachronous colon cancers', 'Disease', 'MESH:D015179', (65, 107))	('hMLH1', 'Gene', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mutation', 'Var', (34, 42))	('colon cancers', 'Phenotype', 'HP:0003003', (94, 107))	('hMSH2', 'Gene', '4436', (28, 33))	('hMLH1', 'Gene', '4292', (127, 132))	('hMSH2', 'Gene', (28, 33))	('hMSH', 'molecular_function', 'GO:0018775', ('28', '32'))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))
48204	25216868	So, we suggest patient with hMSH2 mutation need more frequent colonoscopy during follow-up.	('patient', 'Species', '9606', (15, 22))	('hMSH2', 'Gene', (28, 33))	('mutation', 'Var', (34, 42))	('hMSH2', 'Gene', '4436', (28, 33))
48205	25216868	It has been recently reported that pathogenic PMS2 mutation is more frequently identified (4 %) than originally expected.	('PMS2', 'Gene', '5395', (46, 50))	('PMS2', 'Gene', (46, 50))	('pathogenic', 'Reg', (35, 45))	('mutation', 'Var', (51, 59))
48206	25216868	reported that the cumulative risk for Lynch associated tumours was significantly lower in MSH6 carriers when compared to MLH1 or MSH2 mutation carriers (P = 0.002).	('MSH2', 'Gene', '4436', (129, 133))	('tumours', 'Disease', (55, 62))	('lower', 'NegReg', (81, 86))	('MSH6', 'Gene', (90, 94))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('carriers', 'Var', (95, 103))	('MSH6', 'Gene', '2956', (90, 94))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('MLH1', 'Gene', '4292', (121, 125))	('MLH1', 'Gene', (121, 125))	('MSH2', 'Gene', (129, 133))	('tumours', 'Disease', 'MESH:D009369', (55, 62))
48207	25216868	reported the risk of colorectal cancer in MSH6 carriers in the Dutch HNPCC database.	('MSH6', 'Gene', (42, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (21, 38))	('MSH6', 'Gene', '2956', (42, 46))	('HNPCC', 'Gene', (69, 74))	('colorectal cancer', 'Disease', (21, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('carriers', 'Var', (47, 55))	('HNPCC', 'Gene', '4436', (69, 74))	('colorectal cancer', 'Disease', 'MESH:D015179', (21, 38))	('HNPCC', 'Phenotype', 'HP:0006716', (69, 74))
48208	25216868	The median age of onset of colorectal cancer in putative mutation carriers was 10 years higher for MSH6 (54 years; 95 % CI 51-56) compared with MLH1 and MSH2 carriers (44 years; 95 % CI 43-45).	('higher', 'PosReg', (88, 94))	('mutation', 'Var', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (27, 44))	('MSH6', 'Gene', '2956', (99, 103))	('MLH1', 'Gene', '4292', (144, 148))	('MLH1', 'Gene', (144, 148))	('colorectal cancer', 'Disease', (27, 44))	('MSH6', 'Gene', (99, 103))	('MSH2', 'Gene', (153, 157))	('MSH2', 'Gene', '4436', (153, 157))	('colorectal cancer', 'Disease', 'MESH:D015179', (27, 44))
48219	24723943	Although the potential of several molecular markers, including the TP53 or KRAS mutational status and loss of heterozygosity in chromosome 18q, has been investigated to identify patients with a greater likelihood of recurrence after curative resection, the results are conflicting.	('chromosome', 'cellular_component', 'GO:0005694', ('128', '138'))	('KRAS', 'Gene', (75, 79))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('loss of heterozygosity', 'Var', (102, 124))	('KRAS', 'Gene', '3845', (75, 79))
48242	24723943	In colorectal adenocarcinoma, perinuclear LC3A expression, indicative of a basal level of autophagic function, has been shown to be an independent marker of good prognosis, but high SLS counts, presumably reflecting an excessive autophagic response, were associated with tumor hypoxia, metastases, and poor prognosis.	('metastases', 'Disease', (286, 296))	('tumor hypoxia', 'Disease', 'MESH:D000860', (271, 284))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('metastases', 'Disease', 'MESH:D009362', (286, 296))	('colorectal adenocarcinoma', 'Disease', (3, 28))	('high', 'Var', (177, 181))	('tumor hypoxia', 'Disease', (271, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))
48243	24723943	demonstrated that patients with low LC3 expression had a higher objective response rate among advanced colorectal cancer patients treated with cetuximab-containing chemotherapy.	('expression', 'MPA', (40, 50))	('objective response', 'CPA', (64, 82))	('low', 'Var', (32, 35))	('higher', 'PosReg', (57, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('colorectal cancer', 'Disease', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('LC3', 'Gene', (36, 39))	('cetuximab', 'Chemical', 'MESH:D000068818', (143, 152))
48244	24723943	reported that high BECN1 expression was associated with favorable outcomes in resected stage IIIB colon cancers treated with 5-FU-based adjuvant chemotherapy after surgery.	('BECN1', 'Gene', (19, 24))	('colon cancer', 'Phenotype', 'HP:0003003', (98, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('expression', 'MPA', (25, 35))	('colon cancers', 'Disease', (98, 111))	('high', 'Var', (14, 18))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('colon cancers', 'Phenotype', 'HP:0003003', (98, 111))	('colon cancers', 'Disease', 'MESH:D015179', (98, 111))
48249	24723943	This protective effect of estrogens is mediated by interaction with estrogen receptor beta (ER beta), microsatellite status, and progressive hypermethylation of the CpG islands of the promoter region of the ER.	('interaction', 'Interaction', (51, 62))	('hypermethylation', 'Var', (141, 157))	('ER beta', 'Gene', '2100', (92, 99))	('ER beta', 'Gene', (92, 99))	('estrogen receptor beta', 'Gene', (68, 90))	('estrogen receptor beta', 'Gene', '2100', (68, 90))
48256	23807509	Normal colonocytes faced with this unfavourable environment can transform into CRC cells for survival through epigenetic reprogramming to express genes which increase mobility to allow migration and proliferation.	('proliferation', 'CPA', (199, 212))	('CRC', 'Phenotype', 'HP:0003003', (79, 82))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('mobility', 'MPA', (167, 175))	('epigenetic reprogramming', 'Var', (110, 134))	('increase', 'PosReg', (158, 166))
48276	23807509	In this paper, known models of colorectal carcinogenesis are reviewed in the context of documented risk factors, and how modification of these risk factors might act to promote or diminish oncogenesis.	('diminish', 'NegReg', (180, 188))	('oncogenesis', 'CPA', (189, 200))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (31, 56))	('modification', 'Var', (121, 133))	('oncogenesis', 'biological_process', 'GO:0007048', ('189', '200'))	('colorectal carcinogenesis', 'Disease', (31, 56))	('promote', 'PosReg', (169, 176))
48283	23807509	provided a molecular basis for the adenoma to carcinoma sequence by describing the complex multi-step process in which cells accumulate genetic changes (especially gene deletions and activations) that control cell growth and differentiation.	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('adenoma to carcinoma', 'Disease', (35, 55))	('adenoma to carcinoma', 'Disease', 'MESH:D000236', (35, 55))	('gene deletions', 'Var', (164, 178))
48284	23807509	In contrast to the lesions of the conventional pathway which harbour mutations in the APC gene, adenomas and tumours of the serrated pathway are characterised by mutation in the BRAF gene.	('BRAF', 'Gene', (178, 182))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))	('APC', 'Gene', (86, 89))	('APC', 'Gene', '324', (86, 89))	('APC', 'cellular_component', 'GO:0005680', ('86', '89'))	('BRAF', 'Gene', '673', (178, 182))	('mutation', 'Var', (162, 170))	('adenomas and tumours', 'Disease', 'MESH:D000236', (96, 116))
48357	23807509	Models of tumorigenesis suggest that mutations acquired by tumour cells are not a direct impact of external DNA damaging agents but are generated by the cell itself as a result of a mutation response.	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('N', 'Chemical', 'MESH:D009584', (109, 110))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (37, 46))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('tumour', 'Disease', (59, 65))
48359	23807509	Epigenetically reprogrammed and transformed CRC cells faced with altered environments such as shortage of oxygen and nutrients, in this case butyrate as the energy source, can easily express genes to increase mobility to allow migration and proliferation into new environments.	('genes', 'Var', (191, 196))	('mobility', 'CPA', (209, 217))	('oxygen', 'Chemical', 'MESH:D010100', (106, 112))	('increase', 'PosReg', (200, 208))	('proliferation', 'CPA', (241, 254))	('butyrate', 'Chemical', 'MESH:D002087', (141, 149))	('express', 'Reg', (183, 190))	('CRC', 'Phenotype', 'HP:0003003', (44, 47))
48364	23807509	High ammonia has been shown to increase inflammatory lesions in rats, which are established precursors in animal models and humans to the development of CRC.	('rats', 'Species', '10116', (64, 68))	('humans', 'Species', '9606', (124, 130))	('High ammonia', 'Var', (0, 12))	('inflammatory', 'CPA', (40, 52))	('ammonia', 'Chemical', 'MESH:D000641', (5, 12))	('High ammonia', 'Phenotype', 'HP:0001987', (0, 12))	('CRC', 'Phenotype', 'HP:0003003', (153, 156))	('increase', 'PosReg', (31, 39))
48382	23807509	If these and other related adducts are formed but not repaired, and cause mutation in key oncogenes and/or tumour suppressor genes, these events may explain the association of red meat with CRC.	('mutation', 'Var', (74, 82))	('association', 'Interaction', (161, 172))	('CRC', 'Disease', (190, 193))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('CRC', 'Phenotype', 'HP:0003003', (190, 193))	('tumour', 'Disease', (107, 113))
48387	23807509	In a "high risk" environment, these cells have the potential to accumulate genetic and epigenetic changes that may contribute to tumorigenesis, especially if these result in somatic mutations of oncogenes or silencing of key tumour suppressor genes.	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('tumour', 'Disease', (225, 231))	('silencing', 'NegReg', (208, 217))	('tumorigenesis', 'CPA', (129, 142))	('result', 'Reg', (164, 170))	('contribute', 'Reg', (115, 125))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('oncogenes', 'Protein', (195, 204))	('mutations', 'Var', (182, 191))
48388	23807509	In vitro studies have also shown that in the presence of butyrate, colon carcinoma cells (e.g., HT-29 cells) acquire a differentiated phenotype through replacement of glucose for butyrate as the main carbon source with alterations in the transporter expression.	('butyrate', 'Chemical', 'MESH:D002087', (57, 65))	('glucose', 'MPA', (167, 174))	('transporter expression', 'MPA', (238, 260))	('carbon', 'Chemical', 'MESH:D002244', (200, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('replacement', 'Var', (152, 163))	('colon carcinoma', 'Disease', 'MESH:D015179', (67, 82))	('glucose', 'Chemical', 'MESH:D005947', (167, 174))	('colon carcinoma', 'Disease', (67, 82))	('alterations', 'Reg', (219, 230))	('butyrate', 'Chemical', 'MESH:D002087', (179, 187))	('butyrate', 'MPA', (179, 187))	('HT-29 cells', 'CellLine', 'CVCL:0320', (96, 107))
48412	33676027	Loss of mitochondrial aconitase promotes colorectal cancer progression via SCD1-mediated lipid remodeling Mitochondrial aconitase (ACO2) is an essential enzyme that bridges the TCA cycle and lipid metabolism.	('colorectal cancer', 'Phenotype', 'HP:0003003', (41, 58))	('SCD1', 'Gene', '6319', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('TCA cycle', 'biological_process', 'GO:0006099', ('177', '186'))	('mitochondrial aconitase', 'Gene', (8, 31))	('lipid', 'Chemical', 'MESH:D008055', (89, 94))	('mitochondrial aconitase', 'Gene', '50', (8, 31))	('lipid metabolism', 'biological_process', 'GO:0006629', ('191', '207'))	('colorectal cancer', 'Disease', (41, 58))	('Mitochondrial aconitase', 'Gene', '50', (106, 129))	('SCD1', 'Gene', (75, 79))	('colorectal cancer', 'Disease', 'MESH:D015179', (41, 58))	('Mitochondrial aconitase', 'Gene', (106, 129))	('promotes', 'PosReg', (32, 40))	('Loss', 'Var', (0, 4))	('TCA', 'Chemical', 'MESH:D014238', (177, 180))	('lipid', 'Chemical', 'MESH:D008055', (191, 196))
48420	33676027	Specifically, blockade of ACO2 caused a reduction in TCA cycle intermediates and suppression of mitochondrial oxidative phosphorylation, resulting in an increase in glycolysis and elevated citrate flux for fatty acid and lipid synthesis.	('TCA', 'Chemical', 'MESH:D014238', (53, 56))	('citrate', 'Chemical', 'MESH:D019343', (189, 196))	('elevated citrate', 'Phenotype', 'HP:0012406', (180, 196))	('TCA cycle intermediates', 'MPA', (53, 76))	('mitochondrial oxidative phosphorylation', 'MPA', (96, 135))	('ACO2', 'Gene', (26, 30))	('reduction', 'NegReg', (40, 49))	('blockade', 'Var', (14, 22))	('increase', 'PosReg', (153, 161))	('suppression', 'NegReg', (81, 92))	('lipid', 'Chemical', 'MESH:D008055', (221, 226))	('lipid synthesis', 'biological_process', 'GO:0008610', ('221', '236'))	('glycolysis', 'biological_process', 'GO:0006096', ('165', '175'))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('110', '135'))	('fatty acid', 'Chemical', 'MESH:D005227', (206, 216))	('glycolysis', 'MPA', (165, 175))	('elevated', 'PosReg', (180, 188))	('TCA cycle', 'biological_process', 'GO:0006099', ('53', '62'))
48422	33676027	Pharmacological inhibition of SCD selectively reduced tumor formation of CRC with ACO2 deficiency.	('CRC', 'Disease', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('CRC', 'Phenotype', 'HP:0003003', (73, 76))	('ACO2', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('reduced', 'NegReg', (46, 53))	('deficiency', 'Var', (87, 97))	('SCD', 'Gene', '6319', (30, 33))	('tumor', 'Disease', (54, 59))	('formation', 'biological_process', 'GO:0009058', ('60', '69'))	('SCD', 'Gene', (30, 33))
48425	33676027	Knockdown of ACO2 promotes colorectal cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('Knockdown', 'Var', (0, 9))	('colorectal cancer', 'Phenotype', 'HP:0003003', (27, 44))	('colorectal cancer', 'Disease', (27, 44))	('ACO2', 'Gene', (13, 17))	('promotes', 'PosReg', (18, 26))	('colorectal cancer', 'Disease', 'MESH:D015179', (27, 44))
48426	33676027	Knockdown of ACO2 leads to a perturbed TCA cycle and attenuates oxidative phosphorylation.	('TCA cycle', 'MPA', (39, 48))	('TCA', 'Chemical', 'MESH:D014238', (39, 42))	('Knockdown', 'Var', (0, 9))	('perturbed', 'Reg', (29, 38))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('64', '89'))	('TCA cycle', 'biological_process', 'GO:0006099', ('39', '48'))	('ACO2', 'Gene', (13, 17))	('oxidative phosphorylation', 'MPA', (64, 89))	('attenuates', 'NegReg', (53, 63))
48428	33676027	Knockdown of ACO2 promotes fatty acid synthesis and lipid desaturation.	('fatty acid', 'Chemical', 'MESH:D005227', (27, 37))	('fatty acid synthesis', 'MPA', (27, 47))	('Knockdown', 'Var', (0, 9))	('lipid desaturation', 'MPA', (52, 70))	('ACO2', 'Gene', (13, 17))	('lipid', 'Chemical', 'MESH:D008055', (52, 57))	('promotes', 'PosReg', (18, 26))
48429	33676027	Accumulating evidence has suggested a link between abnormalities of TCA cycle enzymes and tumorigenesis.	('TCA cycle enzymes', 'Enzyme', (68, 85))	('TCA', 'Chemical', 'MESH:D014238', (68, 71))	('abnormalities', 'Var', (51, 64))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('abnormalities of TCA cycle enzymes', 'Phenotype', 'HP:0000816', (51, 85))	('TCA cycle', 'biological_process', 'GO:0006099', ('68', '77'))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
48435	33676027	A genomic sequencing study of 23 CRC patients indicated deletion of the ACO2 gene located in 22q13.	('deletion', 'Var', (56, 64))	('CRC', 'Phenotype', 'HP:0003003', (33, 36))	('patients', 'Species', '9606', (37, 45))	('ACO2', 'Gene', (72, 76))
48442	33676027	Herein, we attempted to identify the metabolic alterations that are critical for the growth and survival of CRC cells in metabolic stress induced by ACO2 deficiency.	('ACO2', 'Gene', (149, 153))	('deficiency', 'Var', (154, 164))	('stress', 'Disease', 'MESH:D000079225', (131, 137))	('stress', 'Disease', (131, 137))	('CRC', 'Phenotype', 'HP:0003003', (108, 111))
48466	33676027	The culture medium was replaced with glucose-free RPMI-1640 medium with 10% FBS supplemented with [U-13C6]-glucose or [U-13C5]-glutamine (>99%; Cambridge Isotope Laboratories).	('13C', 'Chemical', 'MESH:C000615229', (121, 124))	('RPMI-1640 medium', 'Chemical', '-', (50, 66))	('glucose', 'Chemical', 'MESH:D005947', (107, 114))	('13C', 'Chemical', 'MESH:C000615229', (101, 104))	('[U-13C5]-glutamine', 'Var', (118, 136))	('[U-13C5]-glutamine', 'Chemical', '-', (118, 136))	('glucose', 'Chemical', 'MESH:D005947', (37, 44))	('[U-13C6]-glucose', 'Var', (98, 114))
48498	33676027	Although deletion of the ACO2 gene in chromosome 22q has been previously reported, to investigate other possibility that may contribute to the frequent downregulation in CRC, we performed a methylation analysis of colorectal adenocarcinoma (COAD) from TCGA.	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (214, 239))	('deletion', 'Var', (9, 17))	('COAD', 'Disease', (241, 245))	('ACO2', 'Gene', (25, 29))	('colorectal adenocarcinoma', 'Disease', (214, 239))	('CRC', 'Phenotype', 'HP:0003003', (170, 173))	('COAD', 'Disease', 'MESH:D029424', (241, 245))
48504	33676027	Ki-67 staining of LoVo-derived tumors also indicated cell proliferation promoted by knockdown of ACO2 (Figure 2E).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('knockdown', 'Var', (84, 93))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('cell proliferation', 'CPA', (53, 71))	('promoted', 'PosReg', (72, 80))	('LoVo', 'CellLine', 'CVCL:0399', (18, 22))	('ACO2', 'Gene', (97, 101))
48508	33676027	Because ACO2 catalyzes the isomerization of citrate to isocitrate in the TCA cycle, we reasoned that the impaired ACO2 activity perturbed the flow of TCA cycle intermediates and therefore inhibits the electron transport chain (ETC) coupled with oxidative phosphorylation (OXPHOS).	('TCA', 'Chemical', 'MESH:D014238', (150, 153))	('ACO2', 'Gene', (114, 118))	('oxidative phosphorylation', 'MPA', (245, 270))	('perturbed', 'NegReg', (128, 137))	('electron transport chain', 'MPA', (201, 225))	('isocitrate', 'Chemical', 'MESH:C034219', (55, 65))	('TCA cycle', 'biological_process', 'GO:0006099', ('73', '82'))	('electron transport chain', 'biological_process', 'GO:0022900', ('201', '225'))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('245', '270'))	('citrate', 'Chemical', 'MESH:D019343', (44, 51))	('TCA cycle', 'biological_process', 'GO:0006099', ('150', '159'))	('activity', 'MPA', (119, 127))	('OXPHOS', 'biological_process', 'GO:0002082', ('272', '278'))	('citrate', 'Chemical', 'MESH:D019343', (58, 65))	('TCA', 'Chemical', 'MESH:D014238', (73, 76))	('inhibits', 'NegReg', (188, 196))	('flow of TCA cycle intermediates', 'MPA', (142, 173))	('impaired', 'Var', (105, 113))
48509	33676027	First, we performed targeted metabolomics with a gas chromatography-mass spectrometry analysis and demonstrated that LoVo cells stably expressing shACO2 showed significantly reduced levels of TCA cycle intermediates, including isocitrate, succinate, fumarate, and malate (Figure 3A).	('LoVo', 'CellLine', 'CVCL:0399', (117, 121))	('fumarate', 'Chemical', 'MESH:D005650', (250, 258))	('succinate', 'MPA', (239, 248))	('isocitrate', 'Chemical', 'MESH:C034219', (227, 237))	('isocitrate', 'MPA', (227, 237))	('TCA', 'Enzyme', (192, 195))	('fumarate', 'MPA', (250, 258))	('TCA', 'Chemical', 'MESH:D014238', (192, 195))	('levels', 'MPA', (182, 188))	('succinate', 'Chemical', 'MESH:D019802', (239, 248))	('shACO2', 'Chemical', '-', (146, 152))	('reduced', 'NegReg', (174, 181))	('TCA cycle', 'biological_process', 'GO:0006099', ('192', '201'))	('malate', 'MPA', (264, 270))	('malate', 'Chemical', 'MESH:C030298', (264, 270))	('shACO2', 'Var', (146, 152))
48510	33676027	Moreover, ACO2 knockdown caused a significant increase in glycolysis intermediates including glycerol 3-phosphate, phosphoenolpyruvate, 3-phosphoglyceric acid, pyruvate, and lactate (Figure 3B).	('knockdown', 'Var', (15, 24))	('increase', 'PosReg', (46, 54))	('pyruvate', 'Chemical', 'MESH:D019289', (126, 134))	('glycerol 3-phosphate', 'MPA', (93, 113))	('glycolysis intermediates', 'MPA', (58, 82))	('pyruvate', 'MPA', (160, 168))	('lactate', 'Chemical', 'MESH:D019344', (174, 181))	('glycolysis', 'biological_process', 'GO:0006096', ('58', '68'))	('ACO2', 'Gene', (10, 14))	('glycerol 3-phosphate', 'Chemical', 'MESH:C029620', (93, 113))	('lactate', 'MPA', (174, 181))	('phosphoenolpyruvate', 'MPA', (115, 134))	('3-phosphoglyceric acid', 'Chemical', '-', (136, 158))	('3-phosphoglyceric acid', 'MPA', (136, 158))	('pyruvate', 'Chemical', 'MESH:D019289', (160, 168))	('phosphoenolpyruvate', 'Chemical', 'MESH:D010728', (115, 134))
48512	33676027	We observed attenuated mitochondrial OXPHOS coupled with increased glycolytic activity in LoVo cells after ACO2 knockdown (Figure 3C-D).	('LoVo', 'CellLine', 'CVCL:0399', (90, 94))	('knockdown', 'Var', (112, 121))	('attenuated', 'NegReg', (12, 22))	('increased', 'PosReg', (57, 66))	('mitochondrial OXPHOS coupled', 'MPA', (23, 51))	('ACO2', 'Gene', (107, 111))	('glycolytic activity', 'MPA', (67, 86))
48514	33676027	The attenuated mitochondrial OXPHOS and increase in glycolysis was also confirmed in HCT116 and HCT15 cells with ACO2 knockdown (Supplementary Fig.	('knockdown', 'Var', (118, 127))	('attenuated', 'NegReg', (4, 14))	('HCT116', 'CellLine', 'CVCL:0291', (85, 91))	('ACO2', 'Gene', (113, 117))	('mitochondrial OXPHOS', 'MPA', (15, 35))	('increase', 'PosReg', (40, 48))	('glycolysis', 'MPA', (52, 62))	('HCT15', 'CellLine', 'CVCL:0292', (96, 101))
48515	33676027	Calculation from OCR demonstrated that ATP production from mitochondria decreased by approximately 25% in the ACO2 knockdown cells.	('ATP production from mitochondria', 'MPA', (39, 71))	('ATP', 'Chemical', 'MESH:D000255', (39, 42))	('decreased', 'NegReg', (72, 81))	('mitochondria', 'cellular_component', 'GO:0005739', ('59', '71'))	('ACO2', 'Gene', (110, 114))	('knockdown', 'Var', (115, 124))
48516	33676027	However, we observed an approximately 10% decrease in total ATP levels after ACO2 knockdown (Figure 3F).	('ATP', 'Chemical', 'MESH:D000255', (60, 63))	('ACO2', 'Gene', (77, 81))	('knockdown', 'Var', (82, 91))	('decrease', 'NegReg', (42, 50))	('total ATP levels', 'MPA', (54, 70))
48521	33676027	However, glucose oxidation decreased to 20% and glutamine oxidation increased to 38% after ACO2 knockdown, indicating the activation of the glutaminolysis pathway.	('knockdown', 'Var', (96, 105))	('glucose oxidation', 'MPA', (9, 26))	('glutamine oxidation', 'MPA', (48, 67))	('decreased', 'NegReg', (27, 36))	('glucose', 'Chemical', 'MESH:D005947', (9, 16))	('ACO2', 'Gene', (91, 95))	('activation', 'PosReg', (122, 132))	('increased', 'PosReg', (68, 77))	('glutamine', 'Chemical', 'MESH:D005973', (48, 57))	('glutaminolysis pathway', 'Pathway', (140, 162))
48522	33676027	To further characterize the metabolic routes, we cultured the LoVo cells with [U-13C]-glucose or [U-13C]-glutamine and examined the carbon source as demonstrated by the atom transition map shown in Figure 4B.	('LoVo', 'CellLine', 'CVCL:0399', (62, 66))	('[U-13C]-glutamine', 'Var', (97, 114))	('13C', 'Chemical', 'MESH:C000615229', (81, 84))	('[U-13C]-glutamine', 'Chemical', '-', (97, 114))	('carbon', 'Chemical', 'MESH:D002244', (132, 138))	('13C', 'Chemical', 'MESH:C000615229', (100, 103))	('[U-13C]-glucose', 'Var', (78, 93))	('glucose', 'Chemical', 'MESH:D005947', (86, 93))
48523	33676027	The TCA intermediates including succinate, fumarate, malate, and citrate labeled with [U-13C]-glucose (M+2) decreased after ACO2 knockdown (Figure 4C).	('citrate labeled with [U-13C]-glucose', 'MPA', (65, 101))	('malate', 'MPA', (53, 59))	('glucose', 'Chemical', 'MESH:D005947', (94, 101))	('malate', 'Chemical', 'MESH:C030298', (53, 59))	('citrate', 'Chemical', 'MESH:D019343', (65, 72))	('fumarate', 'Chemical', 'MESH:D005650', (43, 51))	('succinate', 'MPA', (32, 41))	('fumarate', 'MPA', (43, 51))	('13C', 'Chemical', 'MESH:C000615229', (89, 92))	('knockdown', 'Var', (129, 138))	('TCA intermediates', 'MPA', (4, 21))	('TCA', 'Chemical', 'MESH:D014238', (4, 7))	('succinate', 'Chemical', 'MESH:D019802', (32, 41))	('decreased', 'NegReg', (108, 117))	('ACO2', 'Gene', (124, 128))
48525	33676027	These data collectively indicated that blockade of ACO2 prevented glucose flow and activated anaplerosis from glutamine oxidation in the TCA cycle.	('blockade', 'Var', (39, 47))	('glutamine', 'Chemical', 'MESH:D005973', (110, 119))	('TCA', 'Chemical', 'MESH:D014238', (137, 140))	('anaplerosis from glutamine oxidation', 'MPA', (93, 129))	('prevented', 'NegReg', (56, 65))	('glucose', 'Chemical', 'MESH:D005947', (66, 73))	('TCA cycle', 'biological_process', 'GO:0006099', ('137', '146'))	('ACO2', 'Gene', (51, 55))	('activated', 'PosReg', (83, 92))	('glucose flow', 'MPA', (66, 78))
48526	33676027	To further characterized the alteration of glutamine metabolism in the TCA cycle after ACO2 knockdown, we measured both the oxidative metabolism and reductive carboxylation of [U-13C]-glutamine.	('reductive carboxylation', 'MPA', (149, 172))	('TCA', 'Chemical', 'MESH:D014238', (71, 74))	('glutamine', 'Chemical', 'MESH:D005973', (184, 193))	('knockdown', 'Var', (92, 101))	('alteration', 'Reg', (29, 39))	('[U-13C]-glutamine', 'Chemical', '-', (176, 193))	('glutamine', 'Chemical', 'MESH:D005973', (43, 52))	('oxidative metabolism', 'MPA', (124, 144))	('ACO2', 'Gene', (87, 91))
48528	33676027	Loss of ACO2 caused a significant increase in the metabolites that flow from glutamine oxidation including pyruvate (M + 3), alanine (M + 3), aspartate (M + 4), and citrate (M + 4).	('citrate', 'MPA', (165, 172))	('ACO2', 'Gene', (8, 12))	('glutamine oxidation', 'MPA', (77, 96))	('aspartate', 'MPA', (142, 151))	('alanine', 'Chemical', 'MESH:D000409', (125, 132))	('glutamine', 'Chemical', 'MESH:D005973', (77, 86))	('pyruvate', 'Chemical', 'MESH:D019289', (107, 115))	('aspartate', 'Chemical', 'MESH:D001224', (142, 151))	('increase', 'PosReg', (34, 42))	('metabolites', 'MPA', (50, 61))	('Loss', 'Var', (0, 4))	('citrate', 'Chemical', 'MESH:D019343', (165, 172))
48530	33676027	Overall, our data demonstrated the critical role of glutamine-dependent anaplerosis to maintain the TCA cycle and produce citrate upon loss of ACO2.	('produce citrate', 'MPA', (114, 129))	('ACO2', 'Gene', (143, 147))	('TCA', 'Chemical', 'MESH:D014238', (100, 103))	('TCA cycle', 'MPA', (100, 109))	('loss', 'Var', (135, 139))	('maintain', 'PosReg', (87, 95))	('citrate', 'Chemical', 'MESH:D019343', (122, 129))	('glutamine', 'Chemical', 'MESH:D005973', (52, 61))
48533	33676027	We reasoned that ACO2 deficiency may direct citrate flux into the cytosol for acetyl-CoA pools, thus promoting fatty acid synthesis.	('fatty acid', 'Chemical', 'MESH:D005227', (111, 121))	('direct', 'PosReg', (37, 43))	('citrate flux into the cytosol for acetyl-CoA pools', 'MPA', (44, 94))	('ACO2', 'Gene', (17, 21))	('promoting', 'PosReg', (101, 110))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (78, 88))	('fatty acid synthesis', 'MPA', (111, 131))	('citrate', 'Chemical', 'MESH:D019343', (44, 51))	('deficiency', 'Var', (22, 32))
48534	33676027	We indeed found a significant increase in acetyl-CoA, newly synthesized palmitate (14%-26%), and stearate (10%-14%) after ACO2 knockdown (Figure 5A-B).	('stearate', 'Chemical', 'MESH:D013228', (97, 105))	('acetyl-CoA', 'MPA', (42, 52))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (42, 52))	('palmitate', 'Chemical', 'MESH:D010168', (72, 81))	('ACO2', 'Gene', (122, 126))	('increase', 'PosReg', (30, 38))	('stearate', 'MPA', (97, 105))	('knockdown', 'Var', (127, 136))
48535	33676027	Consistently, we found increased palmitoylcarnitine (fold change = 3.1, P < 0.05), acetylcarnitine (fold change = 3.3, P < 0.001), and hexanoylcarnitine (fold change = 21.2, P < 0.01) in ACO2 knockdown cells (Figure 5C).	('hexanoylcarnitine', 'MPA', (135, 152))	('ACO2', 'Gene', (187, 191))	('acetylcarnitine', 'MPA', (83, 98))	('palmitoylcarnitine', 'MPA', (33, 51))	('hexanoylcarnitine', 'Chemical', 'MESH:C061301', (135, 152))	('increased', 'PosReg', (23, 32))	('palmitoylcarnitine', 'Chemical', 'MESH:D010172', (33, 51))	('acetylcarnitine', 'Chemical', 'MESH:D000108', (83, 98))	('knockdown', 'Var', (192, 201))
48536	33676027	We only observed a marginal increase in carnitine in CRC cells with ACO2 knockdown (fold change = 1.196, P < 0.01), which along with a higher level of carnitine derivatives may suggest enhanced transport of fatty acids through mitochondrial membranes.	('enhanced', 'PosReg', (185, 193))	('ACO2', 'Gene', (68, 72))	('fatty acids', 'Chemical', 'MESH:D005227', (207, 218))	('carnitine derivatives', 'MPA', (151, 172))	('carnitine', 'Chemical', 'MESH:D002331', (40, 49))	('carnitine', 'MPA', (40, 49))	('CRC', 'Phenotype', 'HP:0003003', (53, 56))	('higher', 'PosReg', (135, 141))	('carnitine', 'Chemical', 'MESH:D002331', (151, 160))	('increase', 'PosReg', (28, 36))	('knockdown', 'Var', (73, 82))
48538	33676027	Therefore, decreased malonyl-coA levels after ACO2 knockdown may also contribute to enhanced beta-oxidation by releasing the inhibition of CPT (Figure 5D).	('CPT', 'molecular_function', 'GO:0004142', ('139', '142'))	('ACO2', 'Gene', (46, 50))	('beta-oxidation', 'MPA', (93, 107))	('CPT', 'molecular_function', 'GO:0004095', ('139', '142'))	('inhibition', 'MPA', (125, 135))	('decreased', 'NegReg', (11, 20))	('releasing', 'PosReg', (111, 120))	('malonyl-coA levels', 'MPA', (21, 39))	('malonyl-coA', 'Chemical', 'MESH:D008316', (21, 32))	('enhanced', 'PosReg', (84, 92))	('CPT', 'Enzyme', (139, 142))	('knockdown', 'Var', (51, 60))
48540	33676027	The ratio of fatty acid oxidation to the total fuel oxidation substantially enhanced after knockdown of ACO2 in LoVo cells (4.4-fold increase, P < 0.01) (Figure 5E).	('ratio', 'MPA', (4, 9))	('knockdown', 'Var', (91, 100))	('enhanced', 'PosReg', (76, 84))	('ACO2', 'Gene', (104, 108))	('LoVo', 'CellLine', 'CVCL:0399', (112, 116))	('fatty acid oxidation', 'biological_process', 'GO:0019395', ('13', '33'))	('fatty acid', 'Chemical', 'MESH:D005227', (13, 23))	('fatty acid oxidation', 'MPA', (13, 33))
48541	33676027	Taken together, our findings suggested that upregulation of de novo fatty acid synthesis from acetyl-CoA along with reduced inhibition of carnitine palmitoyltransferase (CPT) by malonyl-CoA promoted mitochondrial-driven oxidation under metabolically stressed conditions induced by loss of ACO2 (Figure 5F).	('stress', 'Disease', (250, 256))	('CPT', 'Gene', (170, 173))	('de novo fatty acid synthesis', 'MPA', (60, 88))	('carnitine', 'Chemical', 'MESH:D002331', (138, 147))	('malonyl-CoA', 'Chemical', 'MESH:D008316', (178, 189))	('upregulation', 'PosReg', (44, 56))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (94, 104))	('stress', 'Disease', 'MESH:D000079225', (250, 256))	('mitochondrial-driven oxidation', 'MPA', (199, 229))	('reduced inhibition', 'NegReg', (116, 134))	('ACO2', 'Gene', (289, 293))	('fatty acid', 'Chemical', 'MESH:D005227', (68, 78))	('loss', 'Var', (281, 285))	('promoted', 'PosReg', (190, 198))
48543	33676027	We performed a global lipidomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the effect of loss of ACO2 on lipid metabolism.	('loss', 'Var', (132, 136))	('lipid', 'Chemical', 'MESH:D008055', (148, 153))	('ACO2', 'Gene', (140, 144))	('lipid metabolism', 'MPA', (148, 164))	('lipid', 'Chemical', 'MESH:D008055', (22, 27))
48545	33676027	Moreover, a differential analysis showed a total of 799 altered lipids after knockdown of ACO2 (log2fold change > 1 or < -1, P < 0.05) (Supplementary Fig.	('ACO2', 'Gene', (90, 94))	('lipids', 'MPA', (64, 70))	('altered', 'Reg', (56, 63))	('knockdown', 'Var', (77, 86))	('lipids', 'Chemical', 'MESH:D008055', (64, 70))
48549	33676027	The quantitative analysis further demonstrated that loss of ACO2 was closely associated with increased levels of glycerophospholipids including phosphatidylcholine (PC, fold change = 1.3, P < 0.01), phosphatidylethanolamine (PE, fold change = 1.4, P < 0.01), phosphatidylinositol (PI, fold change = 1.3, P < 0.001), phosphatidylserine (PS, fold change = 1.3, P < 0.01), cardiolipin (CL, fold change = 2.2, P < 0.001), and sphingolipids including ceramide (Cer, fold change = 2.4, P < 0.001) and sphingomyelin (SM, fold change = 1.6, P < 0.001) (Figure 6A).	('PC', 'Chemical', 'MESH:D010713', (165, 167))	('phosphatidylethanolamine', 'MPA', (199, 223))	('loss', 'Var', (52, 56))	('increased', 'PosReg', (93, 102))	('ACO2', 'Gene', (60, 64))	('glycerophospholipids', 'MPA', (113, 133))	('glycerophospholipids', 'Chemical', 'MESH:D020404', (113, 133))	('phosphatidylserine', 'MPA', (316, 334))	('sphingolipids', 'Chemical', 'MESH:D013107', (422, 435))	('phosphatidylinositol', 'MPA', (259, 279))	('amide', 'Chemical', 'MESH:D000577', (449, 454))	('sphingomyelin', 'MPA', (495, 508))	('cardiolipin', 'MPA', (370, 381))	('levels', 'MPA', (103, 109))
48551	33676027	Because TGs are stored in lipid droplets, we reasoned that loss of ACO2 may activate lipolysis and release of free fatty acids.	('lipid', 'Chemical', 'MESH:D008055', (26, 31))	('ACO2', 'Gene', (67, 71))	('lipolysis', 'MPA', (85, 94))	('activate', 'PosReg', (76, 84))	('TG', 'Chemical', 'MESH:D014280', (8, 10))	('free fatty acids', 'Chemical', 'MESH:D005230', (110, 126))	('release of free fatty acids', 'MPA', (99, 126))	('loss', 'Var', (59, 63))
48553	33676027	We next examined the lipid composition (saturated vs unsaturated bonds) after ACO2 knockdown.	('examined', 'Reg', (8, 16))	('lipid', 'Chemical', 'MESH:D008055', (21, 26))	('knockdown', 'Var', (83, 92))	('ACO2', 'Gene', (78, 82))
48554	33676027	As shown in Figure 6B, the ratio of unsaturated fatty acids (16:1 and 18:1) to saturated fatty acids (16:0 and 18:0) significantly increased after ACO2 knockdown in LoVo cells.	('knockdown', 'Var', (152, 161))	('saturated fatty acids', 'Chemical', 'MESH:D005227', (79, 100))	('increased', 'PosReg', (131, 140))	('unsaturated fatty acids', 'Chemical', 'MESH:D005231', (36, 59))	('ratio', 'MPA', (27, 32))	('ACO2', 'Gene', (147, 151))	('LoVo', 'CellLine', 'CVCL:0399', (165, 169))	('saturated fatty acids', 'Chemical', 'MESH:D005227', (38, 59))
48559	33676027	Importantly, a substantial increase in unsaturated PC species containing one or more double bonds was detected in LoVo-shACO2 compared to LoVo-nc cells.	('LoVo', 'CellLine', 'CVCL:0399', (138, 142))	('unsaturated PC', 'Chemical', '-', (39, 53))	('unsaturated PC species containing', 'MPA', (39, 72))	('LoVo', 'CellLine', 'CVCL:0399', (114, 118))	('LoVo-shACO2', 'Var', (114, 125))	('shACO2', 'Chemical', '-', (119, 125))	('increase', 'PosReg', (27, 35))
48562	33676027	We showed a significant increase in the ratio of unsaturated FA to saturated FA in the ACO2 knockdown cells (Figure 6B).	('increase', 'PosReg', (24, 32))	('knockdown', 'Var', (92, 101))	('unsaturated FA', 'MPA', (49, 63))	('unsaturated FA', 'Chemical', '-', (49, 63))	('ACO2', 'Gene', (87, 91))	('ratio', 'MPA', (40, 45))
48563	33676027	Importantly, the immunoblotting analysis revealed markedly enhanced SCD1 expression upon loss of ACO2 in CRC cells (LoVo, HCT116), while no significant change was detected in other enzymes (Figure 6E) such as FASN, ACLY, and SLC25A1.	('HCT116', 'CellLine', 'CVCL:0291', (122, 128))	('loss', 'Var', (89, 93))	('FASN', 'Gene', (209, 213))	('SLC25A1', 'Gene', (225, 232))	('enhanced', 'PosReg', (59, 67))	('SLC25A1', 'Gene', '6576', (225, 232))	('FASN', 'Gene', '2194', (209, 213))	('SCD1', 'Gene', (68, 72))	('ACLY', 'Gene', '47', (215, 219))	('expression', 'MPA', (73, 83))	('ACLY', 'Gene', (215, 219))	('LoVo', 'CellLine', 'CVCL:0399', (116, 120))	('CRC', 'Phenotype', 'HP:0003003', (105, 108))	('SCD1', 'Gene', '6319', (68, 72))	('ACO2', 'Gene', (97, 101))
48566	33676027	We also showed that citrate supplementation caused a significant increase in intracellular acetyl-CoA levels and concomitant upregulation of acetyl-histone H3 (Supplementary Fig.	('increase', 'PosReg', (65, 73))	('intracellular', 'cellular_component', 'GO:0005622', ('77', '90'))	('citrate', 'Chemical', 'MESH:D019343', (20, 27))	('upregulation', 'PosReg', (125, 137))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (91, 101))	('acetyl-histone H3', 'MPA', (141, 158))	('intracellular acetyl-CoA levels', 'MPA', (77, 108))	('acetyl-histone', 'Chemical', '-', (141, 155))	('supplementation', 'Var', (28, 43))
48567	33676027	Our data suggested that loss of ACO2 may promote SCD1 expression through histone acetylation.	('loss', 'Var', (24, 28))	('expression', 'MPA', (54, 64))	('ACO2', 'Gene', (32, 36))	('histone acetylation', 'MPA', (73, 92))	('SCD1', 'Gene', '6319', (49, 53))	('promote', 'PosReg', (41, 48))	('SCD1', 'Gene', (49, 53))
48568	33676027	A939572, a small molecule inhibitor that specifically targets SCD1 enzymatic activity, was then used to test the functional significance of lipid desaturation to cell survival of CRC cells with ACO2 deficiency.	('A939572', 'Chemical', '-', (0, 7))	('lipid', 'Chemical', 'MESH:D008055', (140, 145))	('SCD1', 'Gene', (62, 66))	('ACO2', 'Gene', (194, 198))	('CRC', 'Phenotype', 'HP:0003003', (179, 182))	('test', 'Reg', (104, 108))	('deficiency', 'Var', (199, 209))	('mole', 'Phenotype', 'HP:0003764', (17, 21))	('SCD1', 'Gene', '6319', (62, 66))
48569	33676027	The MTS assay demonstrated that A939572 effectively reduced the cell viability of the ACO2 knockdown cells, whereas the LoVo-nc cells were less sensitive (Supplementary Fig.	('A939572', 'Var', (32, 39))	('reduced', 'NegReg', (52, 59))	('knockdown', 'Var', (91, 100))	('A939572', 'Chemical', '-', (32, 39))	('LoVo', 'CellLine', 'CVCL:0399', (120, 124))	('cell viability', 'CPA', (64, 78))	('ACO2', 'Gene', (86, 90))
48573	33676027	In contrast, A939572 significantly decreased growth rates and final weights of LoVo-shACO2-derived tumors (Figure 6G-H).	('growth rates', 'CPA', (45, 57))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('LoVo', 'CellLine', 'CVCL:0399', (79, 83))	('decreased', 'NegReg', (35, 44))	('A939572', 'Var', (13, 20))	('shACO2', 'Chemical', '-', (84, 90))	('decreased growth', 'Phenotype', 'HP:0001510', (35, 51))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('final weights', 'CPA', (62, 75))	('A939572', 'Chemical', '-', (13, 20))	('tumors', 'Disease', (99, 105))
48574	33676027	Our data suggested that inhibition of lipid desaturation selectively suppressed CRC cell growth under metabolic stress induced by loss of ACO2.	('lipid desaturation', 'MPA', (38, 56))	('lipid', 'Chemical', 'MESH:D008055', (38, 43))	('CRC cell growth', 'CPA', (80, 95))	('inhibition', 'Var', (24, 34))	('suppressed', 'NegReg', (69, 79))	('stress', 'Disease', 'MESH:D000079225', (112, 118))	('CRC', 'Phenotype', 'HP:0003003', (80, 83))	('loss', 'Var', (130, 134))	('stress', 'Disease', (112, 118))	('ACO2', 'Gene', (138, 142))
48576	33676027	ACO2 knockdown promoted CRC cell growth in vitro and tumorigenicity in vivo.	('promoted', 'PosReg', (15, 23))	('CRC', 'Phenotype', 'HP:0003003', (24, 27))	('knockdown', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('CRC cell growth', 'CPA', (24, 39))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cell growth', 'biological_process', 'GO:0016049', ('28', '39'))	('ACO2', 'Gene', (0, 4))	('tumor', 'Disease', (53, 58))
48578	33676027	Our results demonstrated that CRC cells activated metabolic adaptations to enhance survival under stress induced by loss of ACO2.	('stress', 'Disease', (98, 104))	('stress', 'Disease', 'MESH:D000079225', (98, 104))	('survival', 'CPA', (83, 91))	('metabolic adaptations', 'CPA', (50, 71))	('loss', 'Var', (116, 120))	('enhance', 'PosReg', (75, 82))	('CRC', 'Phenotype', 'HP:0003003', (30, 33))	('ACO2', 'Gene', (124, 128))
48584	33676027	Therefore, blockade of ACO2 hindered the oxidative metabolism of glucose carbon and activate glutamine supply for anaplerosis in the TCA cycle.	('TCA', 'Chemical', 'MESH:D014238', (133, 136))	('glutamine', 'Chemical', 'MESH:D005973', (93, 102))	('ACO2', 'Gene', (23, 27))	('hindered', 'NegReg', (28, 36))	('carbon', 'Chemical', 'MESH:D002244', (73, 79))	('glutamine supply', 'MPA', (93, 109))	('blockade', 'Var', (11, 19))	('activate', 'PosReg', (84, 92))	('anaplerosis', 'MPA', (114, 125))	('oxidative metabolism of glucose carbon', 'MPA', (41, 79))	('glucose', 'Chemical', 'MESH:D005947', (65, 72))
48585	33676027	Indeed, knockdown of ACO2 caused elevated glutamine-derived citrate and decreased glucose-derived citrate in CRC cells.	('elevated', 'PosReg', (33, 41))	('knockdown', 'Var', (8, 17))	('decreased', 'NegReg', (72, 81))	('elevated glutamine', 'Phenotype', 'HP:0003217', (33, 51))	('ACO2', 'Gene', (21, 25))	('citrate', 'Chemical', 'MESH:D019343', (60, 67))	('glucose', 'Chemical', 'MESH:D005947', (82, 89))	('glucose-derived citrate', 'MPA', (82, 105))	('glutamine-derived citrate', 'MPA', (42, 67))	('citrate', 'Chemical', 'MESH:D019343', (98, 105))	('glutamine', 'Chemical', 'MESH:D005973', (42, 51))	('CRC', 'Phenotype', 'HP:0003003', (109, 112))
48588	33676027	We observed an increased ratio of citrate/isocitrate, although no significant accumulation of citrate was detected after ACO2 knockdown in the CRC cells.	('citrate/isocitrate', 'MPA', (34, 52))	('citrate', 'Chemical', 'MESH:D019343', (45, 52))	('citrate', 'Chemical', 'MESH:D019343', (34, 41))	('citrate', 'Chemical', 'MESH:D019343', (94, 101))	('isocitrate', 'Chemical', 'MESH:C034219', (42, 52))	('ratio', 'MPA', (25, 30))	('increased', 'PosReg', (15, 24))	('knockdown', 'Var', (126, 135))	('ACO2', 'Gene', (121, 125))	('CRC', 'Phenotype', 'HP:0003003', (143, 146))
48592	33676027	Moreover, the upregulation of glycolysis and fatty acid oxidation contributed a considerable fraction of the energy supply in CRC cells with defective mitochondria caused by loss of ACO2.	('fatty acid', 'Chemical', 'MESH:D005227', (45, 55))	('CRC', 'Phenotype', 'HP:0003003', (126, 129))	('fatty acid oxidation', 'MPA', (45, 65))	('glycolysis', 'MPA', (30, 40))	('ACO2', 'Gene', (182, 186))	('energy supply', 'MPA', (109, 122))	('upregulation', 'PosReg', (14, 26))	('loss', 'Var', (174, 178))
48593	33676027	Importantly, we demonstrated that loss of ACO2 induced major alterations in lipid metabolism characterized by enhanced lipid abundance and unsaturation.	('unsaturation', 'MPA', (139, 151))	('loss', 'Var', (34, 38))	('lipid', 'Chemical', 'MESH:D008055', (119, 124))	('lipid metabolism', 'biological_process', 'GO:0006629', ('76', '92'))	('alterations', 'Reg', (61, 72))	('enhanced', 'PosReg', (110, 118))	('lipid', 'Chemical', 'MESH:D008055', (76, 81))	('lipid abundance', 'MPA', (119, 134))	('ACO2', 'Gene', (42, 46))	('lipid metabolism', 'MPA', (76, 92))
48595	33676027	The role of acetate in the contribution to FA synthesis in the context of CRC with ACO2 deficiency is worth further investigation.	('ACO2', 'Gene', (83, 87))	('CRC', 'Phenotype', 'HP:0003003', (74, 77))	('acetate', 'Chemical', 'MESH:D000085', (12, 19))	('deficiency', 'Var', (88, 98))
48596	33676027	Furthermore, the lipidomic analysis demonstrated that glycerophospholipid was the most significantly altered pathway in the ACO2 knockdown cells.	('glycerophospholipid', 'MPA', (54, 73))	('lipid', 'Chemical', 'MESH:D008055', (68, 73))	('lipid', 'Chemical', 'MESH:D008055', (17, 22))	('knockdown', 'Var', (129, 138))	('altered', 'Reg', (101, 108))	('ACO2', 'Gene', (124, 128))	('glycerophospholipid', 'Chemical', 'MESH:D020404', (54, 73))
48598	33676027	Beyond its effect on lipid synthesis, we uncovered the enhanced lipid unsaturation caused by ACO2 knockdown in CRC cells.	('lipid', 'Chemical', 'MESH:D008055', (64, 69))	('lipid unsaturation', 'MPA', (64, 82))	('lipid', 'Chemical', 'MESH:D008055', (21, 26))	('enhanced', 'PosReg', (55, 63))	('knockdown', 'Var', (98, 107))	('CRC', 'Phenotype', 'HP:0003003', (111, 114))	('ACO2', 'Gene', (93, 97))
48599	33676027	The ACO2 knockdown cells exhibited a higher ratio of unsaturated fatty acids to saturated fatty acids (16C and 18C) compared with the control cells.	('ratio', 'MPA', (44, 49))	('knockdown', 'Var', (9, 18))	('higher', 'PosReg', (37, 43))	('saturated fatty acids', 'Chemical', 'MESH:D005227', (55, 76))	('unsaturated fatty acids', 'MPA', (53, 76))	('unsaturated fatty acids', 'Chemical', 'MESH:D005231', (53, 76))	('saturated fatty acids', 'Chemical', 'MESH:D005227', (80, 101))	('ACO2', 'Gene', (4, 8))
48600	33676027	The conversion of saturated fatty acid to monounsaturated fatty acid is known to be mediated by SCD1, which was upregulated in the ACO2 knockdown cells in this study.	('ACO2', 'Gene', (131, 135))	('monounsaturated fatty acid', 'Chemical', 'MESH:D005229', (42, 68))	('SCD1', 'Gene', '6319', (96, 100))	('upregulated', 'PosReg', (112, 123))	('saturated fatty acid', 'Chemical', 'MESH:D005227', (48, 68))	('saturated fatty acid', 'Chemical', 'MESH:D005227', (18, 38))	('knockdown', 'Var', (136, 145))	('monounsaturated fatty acid', 'MPA', (42, 68))	('conversion', 'MPA', (4, 14))	('SCD1', 'Gene', (96, 100))
48601	33676027	Therefore, upregulation of SCD may be crucial for membrane synthesis to compensate for the defect of mitochondrial metabolism in CRC cells with ACO2 deficiency.	('SCD', 'Gene', (27, 30))	('SCD', 'Gene', '6319', (27, 30))	('mitochondrial metabolism', 'MPA', (101, 125))	('membrane', 'cellular_component', 'GO:0016020', ('50', '58'))	('ACO2', 'Gene', (144, 148))	('synthesis', 'biological_process', 'GO:0009058', ('59', '68'))	('metabolism', 'biological_process', 'GO:0008152', ('115', '125'))	('deficiency', 'Var', (149, 159))	('upregulation', 'PosReg', (11, 23))	('CRC', 'Phenotype', 'HP:0003003', (129, 132))
48603	33676027	We demonstrated that pharmacological inhibition of SCD selectively suppressed the in vivo growth of CRC with ACO2 knockdown.	('in vivo growth of CRC', 'CPA', (82, 103))	('ACO2', 'Gene', (109, 113))	('CRC', 'Phenotype', 'HP:0003003', (100, 103))	('knockdown', 'Var', (114, 123))	('SCD', 'Gene', (51, 54))	('SCD', 'Gene', '6319', (51, 54))	('suppressed', 'NegReg', (67, 77))
48605	33676027	The perturbation of the TCA cycle and attenuated OXPHOS induced by loss of ACO2 provide direct evidence of dysfunctional mitochondria in colorectal cancer.	('attenuated', 'NegReg', (38, 48))	('dysfunctional mitochondria', 'Disease', (107, 133))	('colorectal cancer', 'Disease', (137, 154))	('OXPHOS', 'MPA', (49, 55))	('ACO2', 'Gene', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('TCA cycle', 'Enzyme', (24, 33))	('colorectal cancer', 'Disease', 'MESH:D015179', (137, 154))	('TCA', 'Chemical', 'MESH:D014238', (24, 27))	('dysfunctional mitochondria', 'Disease', 'MESH:C564925', (107, 133))	('loss', 'Var', (67, 71))	('OXPHOS', 'biological_process', 'GO:0002082', ('49', '55'))	('TCA cycle', 'biological_process', 'GO:0006099', ('24', '33'))	('mitochondria', 'cellular_component', 'GO:0005739', ('121', '133'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (137, 154))
48606	33676027	Our study highlights the metabolomic roadmap of metabolic rewiring to override stress induced by ACO2 deficiency.	('stress', 'Disease', 'MESH:D000079225', (79, 85))	('deficiency', 'Var', (102, 112))	('stress', 'Disease', (79, 85))	('ACO2', 'Gene', (97, 101))
48607	33676027	For the first time, we report that decreasing ACO2 enhances fatty acid synthesis and lipid desaturation, leading to a lipogenic phenotype to promote CRC growth.	('ACO2', 'Gene', (46, 50))	('lipid', 'Chemical', 'MESH:D008055', (85, 90))	('lipogenic phenotype', 'MPA', (118, 137))	('CRC growth', 'CPA', (149, 159))	('CRC', 'Phenotype', 'HP:0003003', (149, 152))	('fatty acid', 'Chemical', 'MESH:D005227', (60, 70))	('promote', 'PosReg', (141, 148))	('enhances', 'PosReg', (51, 59))	('lipid desaturation', 'MPA', (85, 103))	('decreasing', 'Var', (35, 45))	('fatty acid synthesis', 'MPA', (60, 80))
48715	31139021	Furthermore, knockdown of UTX significantly inhibited tumour growth in vivo.	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('inhibited', 'NegReg', (44, 53))	('tumour', 'Disease', (54, 60))	('UTX', 'Gene', (26, 29))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('knockdown', 'Var', (13, 22))
48716	31139021	In addition, knockdown of UTX decreased the expression of KIF14 and pAKT and increased the expression of P21.	('expression', 'MPA', (91, 101))	('expression', 'MPA', (44, 54))	('P21', 'Gene', '644914', (105, 108))	('AKT', 'Gene', (69, 72))	('KIF14', 'Gene', (58, 63))	('KIF14', 'Gene', '9928', (58, 63))	('P21', 'Gene', (105, 108))	('increased', 'PosReg', (77, 86))	('AKT', 'Gene', '207', (69, 72))	('knockdown', 'Var', (13, 22))	('decreased', 'NegReg', (30, 39))
48722	31139021	Generally, the trimethylation of histone H3 lysine 27 (H3K27me3) suppresses gene expression, while the trimethylation of histone H3 lysine 4 (H3K4me3) activates genes expression.	('H3', 'Chemical', 'MESH:C012616', (142, 144))	('activates', 'PosReg', (151, 160))	('trimethylation', 'Var', (15, 29))	('lysine', 'Chemical', 'MESH:D008239', (132, 138))	('H3', 'Chemical', 'MESH:C012616', (129, 131))	('lysine', 'Chemical', 'MESH:D008239', (44, 50))	('gene expression', 'MPA', (76, 91))	('lysine 4', 'Chemical', '-', (132, 140))	('H3', 'Chemical', 'MESH:C012616', (41, 43))	('suppresses', 'NegReg', (65, 75))	('genes expression', 'MPA', (161, 177))	('H3', 'Chemical', 'MESH:C012616', (55, 57))
48731	31139021	The cell cycle is altered when KIF14 is silenced, thus explaining the role of KIF14 in oncogenesis.	('cell cycle', 'CPA', (4, 14))	('altered', 'Reg', (18, 25))	('cell cycle', 'biological_process', 'GO:0007049', ('4', '14'))	('KIF14', 'Gene', (31, 36))	('oncogenesis', 'biological_process', 'GO:0007048', ('87', '98'))	('KIF14', 'Gene', '9928', (31, 36))	('silenced', 'Var', (40, 48))	('KIF14', 'Gene', (78, 83))	('KIF14', 'Gene', '9928', (78, 83))
48742	31139021	In brief, the slides were incubated in UTX (33510, CST) and KIF14 antibody (ab71155, Abcam) and diluted 1:200 at 4  C overnight.	('KIF14', 'Gene', '9928', (60, 65))	('CST', 'Gene', '106478911', (51, 54))	('antibody', 'cellular_component', 'GO:0042571', ('66', '74'))	('33510', 'Var', (44, 49))	('CST', 'Gene', (51, 54))	('antibody', 'cellular_component', 'GO:0019815', ('66', '74'))	('antibody', 'cellular_component', 'GO:0019814', ('66', '74'))	('antibody', 'molecular_function', 'GO:0003823', ('66', '74'))	('KIF14', 'Gene', (60, 65))
48761	31139021	To examine the effect of UTX in CRC cell lines, we generated UTX knockdown HCT116, SW620 and normal epithelial NCM460 cells by two shRNAs.	('HCT116', 'CellLine', 'CVCL:0291', (75, 81))	('SW620', 'CellLine', 'CVCL:0547', (83, 88))	('CRC', 'Phenotype', 'HP:0003003', (32, 35))	('UTX', 'Gene', (61, 64))	('knockdown', 'Var', (65, 74))	('HCT116', 'Gene', (75, 81))
48770	31139021	In addition, we found that knockdown of UTX was associated with a reduction in both tumour volume and weight (Fig.	('weight', 'CPA', (102, 108))	('knockdown', 'Var', (27, 36))	('tumour volume', 'Disease', 'MESH:D009369', (84, 97))	('UTX', 'Gene', (40, 43))	('tumour volume', 'Disease', (84, 97))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('reduction', 'NegReg', (66, 75))
48771	31139021	In addition, there were fewer Ki67-positive cells in UTX knockdown tumours compared to the control group (Fig.	('tumours', 'Disease', 'MESH:D009369', (67, 74))	('tumours', 'Disease', (67, 74))	('knockdown', 'Var', (57, 66))	('UTX', 'Gene', (53, 56))	('Ki67-positive', 'Protein', (30, 43))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))	('fewer', 'NegReg', (24, 29))
48778	31139021	We also confirmed the protein expression levels of KIF14 and its downstream proteins pAKT (phosphorylated AKT, S473 and T308) and P21 in UTX-KD and control CRC cell lines using WB (Fig.	('AKT', 'Gene', (106, 109))	('AKT', 'Gene', (86, 89))	('S473', 'Var', (111, 115))	('P21', 'Gene', '644914', (130, 133))	('CRC', 'Phenotype', 'HP:0003003', (156, 159))	('KIF14', 'Gene', (51, 56))	('KIF14', 'Gene', '9928', (51, 56))	('AKT', 'Gene', '207', (106, 109))	('T308', 'Var', (120, 124))	('AKT', 'Gene', '207', (86, 89))	('P21', 'Gene', (130, 133))
48782	31139021	We then overexpressed KIF14 after knocking down UTX, and we found that overexpression of KIF14 could significantly rescue the cell proliferation defects caused by UTX knockdown (Fig.	('KIF14', 'Gene', (89, 94))	('KIF14', 'Gene', '9928', (89, 94))	('cell proliferation defects', 'CPA', (126, 152))	('UTX', 'Gene', (163, 166))	('rescue', 'PosReg', (115, 121))	('knockdown', 'Var', (167, 176))	('KIF14', 'Gene', (22, 27))	('KIF14', 'Gene', '9928', (22, 27))
48812	28710943	Factors associated with shorter survival for selected cancers included: distant/regional recurrence for BC and CRC; current/former smoker for LC; high grade for CRC; and <4-year time-to-recurrence for BC.	('distant/regional recurrence', 'CPA', (72, 99))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('CRC', 'Disease', (111, 114))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('shorter', 'NegReg', (24, 31))	('high', 'Var', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
48947	28774330	The postoperative histology revealed pT3, pN2b (11/17), pM1, L0, V1, G2, and R0 resection margin.	('pM1', 'Gene', '8834', (56, 59))	('pM1', 'Gene', (56, 59))	('L0, V1, G2, and R0', 'Gene', '28299', (61, 79))	('pN2b', 'Var', (42, 46))	('pT3', 'Var', (37, 40))
48966	28774330	There is growing evidence that PVE not only does stimulate the growth of FLR but also induces significant tumor growth in patients with CRLM.	('PVE', 'Phenotype', 'HP:0030242', (31, 34))	('induces', 'Reg', (86, 93))	('FLR', 'Protein', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('PVE', 'Var', (31, 34))	('patients', 'Species', '9606', (122, 130))	('PVE', 'Chemical', '-', (31, 34))	('growth', 'MPA', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('stimulate', 'PosReg', (49, 58))	('tumor', 'Disease', (106, 111))
48980	28774330	found that short CFI is closely associated with significantly better prognosis in terms of overall survival and disease-free survival based on 74 patients suffering from CRLM who received operations.	('patients', 'Species', '9606', (146, 154))	('better', 'PosReg', (62, 68))	('short', 'Var', (11, 16))	('disease-free survival', 'CPA', (112, 133))
49072	27479195	DNA mutations, DNA methylation, non-coding RNAs, etc) which may provide additional molecular evidence to clarify the potential tumorigenic differences between proximal and distal adenomas.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('methylation', 'Var', (19, 30))	('tumor', 'Disease', (127, 132))	('adenomas', 'Disease', 'MESH:D000236', (179, 187))	('mutations', 'Var', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('adenomas', 'Disease', (179, 187))
49089	27479195	Our observations provide data to support the importance of the dysregulation of the TGFbeta pathway in colorectal carcinogenesis in humans.	('TGFbeta', 'Gene', (84, 91))	('colorectal carcinogenesis', 'Disease', (103, 128))	('humans', 'Species', '9606', (132, 138))	('TGFbeta', 'Gene', '7040', (84, 91))	('dysregulation', 'Var', (63, 76))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (103, 128))
49095	27479195	Individuals with a high deep stromal expression of COX-2 developed significantly more recurrent adenomas (65%) than those with a low deep stromal expression (47%, p=0.04).	('COX-2', 'Gene', (51, 56))	('high', 'Var', (19, 23))	('COX-2', 'Gene', '5743', (51, 56))	('adenomas', 'Disease', 'MESH:D000236', (96, 104))	('adenomas', 'Disease', (96, 104))
49099	27479195	In addition to evaluating the individual markers within a pathway, it is also important to consider their relationship to each other because cancer development is a long-term, complex process requiring an accumulation of alterations in multiple genes and signaling pathways to form a complex cross-talk network.	('alterations', 'Var', (221, 232))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('signaling', 'biological_process', 'GO:0023052', ('255', '264'))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
49111	27479195	This can result from direct mutations within cyclin D1, cancer-specific alternative splicing or mutations that target the upstream signaling pathway that regulate the phosphorylation-dependent nuclear export of cyclin D1 complexes.	('result from', 'Reg', (9, 20))	('cyclin D1', 'Gene', (45, 54))	('cyclin D1', 'Gene', '595', (211, 220))	('regulate', 'Reg', (154, 162))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('upstream signaling pathway', 'Pathway', (122, 148))	('cyclin D1', 'Gene', (211, 220))	('cyclin D1', 'Gene', '595', (45, 54))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('mutations', 'Var', (28, 37))	('mutations', 'Var', (96, 105))	('alternative splicing', 'Var', (72, 92))
49128	28356122	Aberrant expression of hsa-miRNA-195 (miR-195) which is distinguished as a clinically noteworthy miRNA has previously been observed in multiple cancers, yet its role in CRC remains unclear.	('hsa-miRNA-195', 'Gene', (23, 36))	('Aberrant', 'Var', (0, 8))	('miR-195', 'Gene', (38, 45))	('miR-195', 'Gene', '406971', (38, 45))	('hsa-miRNA-195', 'Gene', '406971', (23, 36))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('CRC', 'Phenotype', 'HP:0003003', (169, 172))	('observed', 'Reg', (123, 131))	('miR', 'Gene', '220972', (38, 41))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('miR', 'Gene', (38, 41))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('miR', 'Gene', '220972', (97, 100))	('miR', 'Gene', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
49133	28356122	Four downregulated miRNAs (hsa-let-7a, hsa-miR-125b, hsa-miR-145, and hsa-miR-195) were demonstrated to be potentially useful diagnostic markers in the clinical setting.	('miR', 'Gene', (74, 77))	('hsa-miR-195', 'Gene', '406971', (70, 81))	('miR', 'Gene', (19, 22))	('miR', 'Gene', '220972', (19, 22))	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', '220972', (74, 77))	('miR', 'Gene', (57, 60))	('miR', 'Gene', (43, 46))	('miR', 'Gene', '220972', (57, 60))	('rat', 'Species', '10116', (95, 98))	('hsa-miR-195', 'Gene', (70, 81))	('hsa-miR-145', 'Gene', '406937', (53, 64))	('hsa-let-7a', 'Var', (27, 37))	('let-7', 'Chemical', '-', (31, 36))	('downregulated', 'NegReg', (5, 18))	('hsa-miR-145', 'Gene', (53, 64))
49202	28356122	Twenty-five miRNAs were retained after filtering by the mean and SD (10%) to filter small expression intensities and small variation genes.	('small variation', 'Var', (117, 132))	('miR', 'Gene', '220972', (12, 15))	('miR', 'Gene', (12, 15))
49214	28356122	In contrast, low levels of let-7, miR-125b, or miR-145 in TCGA CRC tissues were correlated with improved overall survivals (Additional file 10: Figure S1b).	('improved', 'PosReg', (96, 104))	('miR', 'Gene', '220972', (47, 50))	('CRC', 'Phenotype', 'HP:0003003', (63, 66))	('miR', 'Gene', (47, 50))	('overall survivals', 'CPA', (105, 122))	('miR', 'Gene', '220972', (34, 37))	('miR-145', 'Gene', (47, 54))	('miR', 'Gene', (34, 37))	('miR-145', 'Gene', '406937', (47, 54))	('let-7', 'Chemical', '-', (27, 32))	('let-7', 'Var', (27, 32))
49221	28356122	Taken together, these results indicate that deregulated miR-195 expression plays a critical role in human CRC.	('expression', 'MPA', (64, 74))	('CRC', 'Phenotype', 'HP:0003003', (106, 109))	('deregulated', 'Var', (44, 55))	('human', 'Species', '9606', (100, 105))	('miR-195', 'Gene', (56, 63))	('human CRC', 'Disease', (100, 109))	('miR-195', 'Gene', '406971', (56, 63))
49234	28356122	Of note, Kaplan-Meier and Cox's proportional hazards regression model also revealed that patients with high levels of YAP1 had shorter overall survivals (Fig.	('shorter', 'NegReg', (127, 134))	('overall survivals', 'MPA', (135, 152))	('high levels', 'Var', (103, 114))	('patients', 'Species', '9606', (89, 97))	('YAP1', 'Gene', (118, 122))	('Cox', 'Gene', '1351', (26, 29))	('Cox', 'Gene', (26, 29))
49251	28356122	YAP1, which harbors two conserved miR-195-5p cognate sites, namely, 162-168 and 1857-1862 of YAP1 3'-UTR (Fig.	('miR-195-5p', 'Gene', (34, 44))	('1857-1862', 'Var', (80, 89))	('miR-195-5p', 'Gene', '100316756', (34, 44))	('YAP1', 'Gene', (93, 97))
49253	28356122	The luciferase reporter plasmid pmiR-RB-REPORTTM-YAP1-3'-UTR or mutant reporter plasmid carrying point mutations in the putative miR-195-5p binding sites was co-transfected with miR-195-5p mimics or miR mimic NC and inhibitors, separately.	('miR', 'Gene', '220972', (33, 36))	('miR', 'Gene', (33, 36))	('miR', 'Gene', '220972', (129, 132))	('miR', 'Gene', (129, 132))	('rat', 'Species', '10116', (232, 235))	('miR', 'Gene', '220972', (178, 181))	('miR-195-5p', 'Gene', '100316756', (129, 139))	('miR', 'Gene', (178, 181))	('binding', 'molecular_function', 'GO:0005488', ('140', '147'))	('miR-195-5p', 'Gene', '100316756', (178, 188))	('miR', 'Gene', '220972', (199, 202))	('miR-195-5p', 'Gene', (129, 139))	('miR', 'Gene', (199, 202))	('miR-195-5p', 'Gene', (178, 188))	('point mutations', 'Var', (97, 112))
49255	28356122	6c, P < 0.05), but no significant effects were observed for the reporter plasmid carrying mutant YAP1 3'-UTR (i.e., pmiR-RB-REPORTTM-mut-YAP1-3'-UTR).	('YAP1', 'Gene', (97, 101))	('mutant', 'Var', (90, 96))	('miR', 'Gene', '220972', (117, 120))	('miR', 'Gene', (117, 120))
49293	28356122	found aberrant expression of miR-195 could indicate a poorer prognosis in adrenocortical carcinoma.	('adrenocortical carcinoma', 'Disease', (74, 98))	('miR-195', 'Gene', (29, 36))	('aberrant expression', 'Var', (6, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (74, 98))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (74, 98))	('miR-195', 'Gene', '406971', (29, 36))
49300	28356122	To our knowledge, this is the first meta-analysis that reveals the detailed mechanism where loss of miR-195-5p leads to malignant progression of CRC via unleashed expression of YAP1.	('CRC', 'Phenotype', 'HP:0003003', (145, 148))	('malignant progression', 'CPA', (120, 141))	('leads to', 'Reg', (111, 119))	('miR-195-5p', 'Gene', '100316756', (100, 110))	('loss', 'Var', (92, 96))	('YAP1', 'Gene', (177, 181))	('miR-195-5p', 'Gene', (100, 110))	('CRC', 'Disease', (145, 148))
49301	28356122	In several tumors, aberrant activation of the Hippo/YAP signaling pathway represents one of the most important mechanisms accounting for oncogenic progression and invasiveness, and has been recognized as a prognostic factor of poor outcome.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('YAP', 'Gene', (52, 55))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('activation', 'PosReg', (28, 38))	('aberrant', 'Var', (19, 27))	('YAP', 'Gene', '10413', (52, 55))
49305	28356122	Interestingly, we also found that loss of miR-195-5p accelerated YAP expression and promoted nuclear accumulation of YAP and EMT in vitro.	('YAP', 'Gene', '10413', (117, 120))	('loss', 'Var', (34, 38))	('YAP', 'Gene', (65, 68))	('nuclear accumulation', 'CPA', (93, 113))	('accelerated', 'PosReg', (53, 64))	('promoted', 'PosReg', (84, 92))	('YAP', 'Gene', (117, 120))	('EMT', 'CPA', (125, 128))	('miR-195-5p', 'Gene', '100316756', (42, 52))	('expression', 'MPA', (69, 79))	('rat', 'Species', '10116', (59, 62))	('miR-195-5p', 'Gene', (42, 52))	('YAP', 'Gene', '10413', (65, 68))	('EMT', 'biological_process', 'GO:0001837', ('125', '128'))
49310	28356122	Four downregulated miRNAs (hsa-let-7a, hsa-miR-125b, hsa-miR-145, and hsa-miR-195) can be potentially useful diagnostic markers in the clinic.	('miR', 'Gene', (74, 77))	('hsa-miR-195', 'Gene', '406971', (70, 81))	('miR', 'Gene', (19, 22))	('miR', 'Gene', '220972', (19, 22))	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', '220972', (74, 77))	('miR', 'Gene', (57, 60))	('miR', 'Gene', (43, 46))	('miR', 'Gene', '220972', (57, 60))	('hsa-miR-195', 'Gene', (70, 81))	('hsa-miR-145', 'Gene', '406937', (53, 64))	('hsa-let-7a', 'Var', (27, 37))	('let-7', 'Chemical', '-', (31, 36))	('downregulated', 'NegReg', (5, 18))	('hsa-miR-145', 'Gene', (53, 64))
49333	27464589	The approved multi-target sDNA test, commercialized as Cologuard  (Exact Sciences, Madison WI), assays mutant KRAS, methylated BMP3, methylated NDRG4 and a fecal immunochemical test (FIT).	('BMP3', 'Gene', (127, 131))	('methylated', 'Var', (133, 143))	('mutant', 'Var', (103, 109))	('NDRG4', 'Gene', (144, 149))	('KRAS', 'Gene', '3845', (110, 114))	('sDNA', 'Chemical', '-', (26, 30))	('NDRG4', 'Gene', '65009', (144, 149))	('BMP3', 'Gene', '651', (127, 131))	('KRAS', 'Gene', (110, 114))	('methylated', 'Var', (116, 126))
49334	27464589	However, recent case-control data show that stool assay of aberrant DNA methylation markers, achieved >90% sensitivity at 90% specificity for CRC in patients with IBD.	('patients', 'Species', '9606', (149, 157))	('IBD', 'Phenotype', 'HP:0002037', (163, 166))	('IBD', 'Disease', (163, 166))	('aberrant', 'Var', (59, 67))	('CRC', 'Phenotype', 'HP:0003003', (142, 145))	('DNA methylation markers', 'Gene', (68, 91))	('CRC', 'Disease', (142, 145))
49429	23725603	These observations suggested that GUCY2C could have utility as a biomarker for metastatic colorectal cancer, a hypothesis that has been supported by several retrospective and prospective clinical trials.	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('GUCY2C', 'Var', (34, 40))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('colorectal cancer', 'Disease', (90, 107))
49430	23725603	Additionally, immune compartmentalization separates the mucosal and systemic immune systems, and limits their cross-talk suggesting that GUCY2C-specific systemic immunity is unlikely to cause autoimmunity in intestinal mucosa.	('GUCY2C-specific', 'Var', (137, 152))	('men', 'Species', '9606', (28, 31))	('autoimmunity', 'Phenotype', 'HP:0002960', (192, 204))	('autoimmunity', 'Disease', (192, 204))	('autoimmunity', 'Disease', 'MESH:D001327', (192, 204))
49446	23725603	In stage II colon cancer patients, OncoVAX increased the 5-year survival rate by 15% and 5-year disease-free survival rate by 16% compared to control treatment.	('men', 'Species', '9606', (155, 158))	('OncoVAX', 'Chemical', '-', (35, 42))	('disease-free survival', 'CPA', (96, 117))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('patients', 'Species', '9606', (25, 33))	('II colon cancer', 'Disease', (9, 24))	('increased', 'PosReg', (43, 52))	('OncoVAX', 'Var', (35, 42))	('II colon cancer', 'Disease', 'MESH:D015179', (9, 24))	('colon cancer', 'Phenotype', 'HP:0003003', (12, 24))
49509	23725603	These results have led to the design of a phase I clinical trial examining Ad5-GUCY2C in early-stage colorectal cancer patients.	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('Ad5-GUCY2C', 'Var', (75, 85))	('patients', 'Species', '9606', (119, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal cancer', 'Disease', (101, 118))
49591	33923277	We previously showed that deficiency of autophagy in intestinal epithelial cells (IECs) enhances CoPEC-induced colorectal carcinogenesis in ApcMin/+ mice.	('colorectal carcinogenesis', 'Disease', (111, 136))	('deficiency', 'Var', (26, 36))	('colorectal carcinogenesis', 'Disease', 'MESH:D015179', (111, 136))	('enhances', 'PosReg', (88, 96))	('mice', 'Species', '10090', (149, 153))	('autophagy', 'CPA', (40, 49))	('Apc', 'Gene', '11789', (140, 143))	('autophagy', 'biological_process', 'GO:0016236', ('40', '49'))	('Apc', 'Gene', (140, 143))	('CoPEC', 'Chemical', '-', (97, 102))	('autophagy', 'biological_process', 'GO:0006914', ('40', '49'))
49593	33923277	Methods: Mice with autophagy deficiency in IECs (Atg16l1 IEC) or wild-type mice (Atg16l1flox/flox) were infected with the CoPEC 11G5 strain or the mutant 11G5 clbQ incapable of producing colibactin and subjected to 12 cycles of DSS treatment to induce chronic colitis.	('mutant', 'Var', (147, 153))	('colitis', 'Phenotype', 'HP:0002583', (260, 267))	('Atg16l1', 'Gene', (81, 88))	('CoPEC', 'Chemical', '-', (122, 127))	('Mice', 'Species', '10090', (9, 13))	('chronic colitis', 'Phenotype', 'HP:0100281', (252, 267))	('Atg16l1', 'Gene', (49, 56))	('autophagy', 'biological_process', 'GO:0006914', ('19', '28'))	('DSS', 'Chemical', '-', (228, 231))	('autophagy deficiency in IECs', 'Disease', 'MESH:C564093', (19, 47))	('Atg16l1', 'Gene', '77040', (81, 88))	('Atg16l1', 'Gene', '77040', (49, 56))	('colitis', 'Disease', (260, 267))	('mice', 'Species', '10090', (75, 79))	('colibactin', 'Chemical', 'MESH:C569566', (187, 197))	('infected', 'Disease', 'MESH:D007239', (104, 112))	('colitis', 'Disease', 'MESH:D003092', (260, 267))	('infected', 'Disease', (104, 112))	('autophagy', 'biological_process', 'GO:0016236', ('19', '28'))	('clbQ', 'Gene', (159, 163))	('autophagy deficiency in IECs', 'Disease', (19, 47))	('11G5 clbQ', 'Gene', (154, 163))
49595	33923277	Results: 11G5 or 11G5 clbQ infection increased clinical and histological inflammation scores, and these were further enhanced by IEC-specific autophagy deficiency.	('inflammation', 'Disease', 'MESH:D007249', (73, 85))	('inflammation', 'Disease', (73, 85))	('11G5', 'Var', (9, 13))	('clbQ infection', 'Disease', (22, 36))	('autophagy deficiency', 'Disease', (142, 162))	('11G5', 'Var', (17, 21))	('clbQ infection', 'Disease', 'MESH:D007239', (22, 36))	('enhanced', 'PosReg', (117, 125))	('autophagy deficiency', 'Disease', 'MESH:C564093', (142, 162))	('increased', 'PosReg', (37, 46))
49596	33923277	11G5 infection, but not 11G5 clbQ infection, triggered the formation of invasive carcinomas, and this was further increased by autophagy deficiency.	('clbQ infection', 'Disease', (29, 43))	('infection', 'Disease', (34, 43))	('autophagy deficiency', 'Disease', 'MESH:C564093', (127, 147))	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('infection', 'Disease', 'MESH:D007239', (34, 43))	('clbQ infection', 'Disease', 'MESH:D007239', (29, 43))	('invasive carcinomas', 'Disease', (72, 91))	('invasive carcinomas', 'Disease', 'MESH:D009361', (72, 91))	('increased', 'PosReg', (114, 123))	('triggered', 'Reg', (45, 54))	('autophagy', 'biological_process', 'GO:0006914', ('127', '136'))	('autophagy', 'biological_process', 'GO:0016236', ('127', '136'))	('11G5', 'Var', (0, 4))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('infection', 'Disease', (5, 14))	('infection', 'Disease', 'MESH:D007239', (5, 14))	('autophagy deficiency', 'Disease', (127, 147))
49604	33923277	One of the most common genetically susceptible mouse models of CRC is ApcMin/+ mice, which carry a loss-of-function germinal mutation in the Apc gene, leading to spontaneous formation of multiple adenomas in the intestine and the colon.	('Apc', 'Gene', '11789', (141, 144))	('Apc', 'Gene', (70, 73))	('Apc', 'Gene', '11789', (70, 73))	('CRC', 'Phenotype', 'HP:0003003', (63, 66))	('formation', 'biological_process', 'GO:0009058', ('174', '183'))	('mouse', 'Species', '10090', (47, 52))	('mice', 'Species', '10090', (79, 83))	('adenomas', 'Disease', 'MESH:D000236', (196, 204))	('Apc', 'cellular_component', 'GO:0005680', ('141', '144'))	('adenomas', 'Disease', (196, 204))	('multiple adenomas in the intestine', 'Phenotype', 'HP:0200008', (187, 221))	('Apc', 'Gene', (141, 144))	('loss-of-function', 'NegReg', (99, 115))	('mutation', 'Var', (125, 133))
49605	33923277	ApcMin/+ mice bearing microbiota develop more intestinal and colorectal tumors compared with germ-free ApcMin/+ mice.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('intestinal', 'Disease', (46, 56))	('Apc', 'Gene', (103, 106))	('Apc', 'Gene', '11789', (103, 106))	('microbiota', 'Var', (22, 32))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('colorectal tumors', 'Disease', 'MESH:D015179', (61, 78))	('mice', 'Species', '10090', (112, 116))	('Apc', 'Gene', (0, 3))	('mice', 'Species', '10090', (9, 13))	('colorectal tumors', 'Disease', (61, 78))	('Apc', 'Gene', '11789', (0, 3))
49616	33923277	Importantly, a direct link between a distinct mutational signature caused by exposure of human intestinal epithelial cells (IECs) to CoPEC and known CRC driver mutations was shown.	('CRC driver', 'Gene', (149, 159))	('CoPEC', 'Chemical', '-', (133, 138))	('human', 'Species', '9606', (89, 94))	('mutations', 'Var', (160, 169))	('CRC', 'Phenotype', 'HP:0003003', (149, 152))
49633	33923277	Furthermore, during the chronic DSS treatment, a significant increase in mortality was observed for 11G5- or 11G5 clbQ-infected Atg16l1 IEC mice compared to + PBS groups (Figure 1c).	('Atg16l1', 'Gene', '77040', (128, 135))	('clbQ-infected', 'Disease', 'MESH:D007239', (114, 127))	('mice', 'Species', '10090', (140, 144))	('11G5-', 'Var', (100, 105))	('Atg16l1', 'Gene', (128, 135))	('clbQ-infected', 'Disease', (114, 127))	('mortality', 'Disease', 'MESH:D003643', (73, 82))	('PBS', 'Chemical', 'MESH:D007854', (159, 162))	('DSS', 'Chemical', '-', (32, 35))	('increase', 'PosReg', (61, 69))	('mortality', 'Disease', (73, 82))
49636	33923277	Importantly, infection with 11G5, but not the mutant 11G5 clbQ, triggered the formation of adenocarcinomas as shown by representative images of the colons of mice at sacrifice (Figure 2) and histological examination (Figure 3).	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('infection', 'Disease', (13, 22))	('mice', 'Species', '10090', (158, 162))	('infection', 'Disease', 'MESH:D007239', (13, 22))	('11G5', 'Var', (28, 32))	('adenocarcinomas', 'Disease', 'MESH:D000230', (91, 106))	('adenocarcinomas', 'Disease', (91, 106))
49639	33923277	Infection with 11G5 was associated with significantly increased neoplasia score, determined based on the criteria in Table 1, compared to +PBS and 11G5 clbQ-infected conditions for both Atg16l1flox/flox and Atg16l1 IEC mice (Figure 3 and Figure 4a).	('Atg16l1', 'Gene', (207, 214))	('Infection', 'Disease', (0, 9))	('clbQ-infected', 'Disease', 'MESH:D007239', (152, 165))	('Atg16l1', 'Gene', '77040', (207, 214))	('11G5', 'Var', (15, 19))	('mice', 'Species', '10090', (219, 223))	('Atg16l1', 'Gene', '77040', (186, 193))	('clbQ-infected', 'Disease', (152, 165))	('increased', 'PosReg', (54, 63))	('neoplasia', 'Disease', (64, 73))	('Infection', 'Disease', 'MESH:D007239', (0, 9))	('Atg16l1', 'Gene', (186, 193))	('neoplasia', 'Phenotype', 'HP:0002664', (64, 73))	('neoplasia', 'Disease', 'MESH:D009369', (64, 73))	('PBS', 'Chemical', 'MESH:D007854', (139, 142))
49646	33923277	Histological examination showed that infection with 11G5 or 11G5 clbQ was associated with enhanced histological inflammation score, determined based on the criteria in Table 2 (Figure 4d).	('11G5', 'Var', (60, 64))	('inflammation', 'Disease', 'MESH:D007249', (112, 124))	('enhanced histological inflammation score', 'Phenotype', 'HP:0012649', (90, 130))	('enhanced', 'PosReg', (90, 98))	('inflammation', 'Disease', (112, 124))	('infection', 'Disease', (37, 46))	('11G5', 'Var', (52, 56))	('infection', 'Disease', 'MESH:D007239', (37, 46))	('clbQ', 'Gene', (65, 69))
49663	33923277	Mutations in core autophagy-related genes are associated with numerous diseases, such as neurological disorders, inflammatory diseases or cancers.	('autophagy-related genes', 'Gene', (18, 41))	('inflammatory diseases', 'Disease', (113, 134))	('numerous diseases', 'Disease', (62, 79))	('autophagy', 'biological_process', 'GO:0016236', ('18', '27'))	('core', 'cellular_component', 'GO:0019013', ('13', '17'))	('neurological disorders', 'Disease', 'MESH:D009422', (89, 111))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Mutations', 'Var', (0, 9))	('numerous diseases', 'Disease', 'MESH:D003141', (62, 79))	('associated', 'Reg', (46, 56))	('neurological disorders', 'Disease', (89, 111))	('autophagy', 'biological_process', 'GO:0006914', ('18', '27'))	('inflammatory diseases', 'Disease', 'MESH:D007249', (113, 134))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
49669	33923277	Nevertheless, the role of autophagy in host defense against Fusobacterium nucleatum, a bacterium associated with colorectal carcinogenesis, has been investigated.	('colorectal carcinogenesis', 'Disease', 'MESH:D015179', (113, 138))	('Fusobacterium nucleatum', 'Species', '851', (60, 83))	('colorectal carcinogenesis', 'Disease', (113, 138))	('Fusobacterium', 'Var', (60, 73))
49684	33923277	Thus, autophagy deficiency in IECs may lead to the appearance of mutations in the genes implicated in carcinogenesis, enhancing the formation of adenomatous lesions.	('carcinogenesis', 'Disease', 'MESH:D063646', (102, 116))	('autophagy deficiency in IECs', 'Disease', (6, 34))	('lead', 'Reg', (39, 43))	('autophagy', 'biological_process', 'GO:0016236', ('6', '15'))	('carcinogenesis', 'Disease', (102, 116))	('adenomatous lesions', 'Disease', (145, 164))	('formation', 'biological_process', 'GO:0009058', ('132', '141'))	('autophagy', 'biological_process', 'GO:0006914', ('6', '15'))	('autophagy deficiency in IECs', 'Disease', 'MESH:C564093', (6, 34))	('adenomatous lesions', 'Disease', 'MESH:D011125', (145, 164))	('formation', 'MPA', (132, 141))	('enhancing', 'PosReg', (118, 127))	('mutations', 'Var', (65, 74))
49689	33923277	Another study showed that mutant mice that inducibly express UVRAG, a tumor suppressor gene involved in autophagy process, display increased inflammatory response in colitis-associated cancer development and promote spontaneous tumorigenesis associated to age-related autophagy suppression.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('increased inflammatory response', 'Phenotype', 'HP:0012649', (131, 162))	('autophagy', 'biological_process', 'GO:0006914', ('104', '113'))	('mutant', 'Var', (26, 32))	('promote', 'PosReg', (208, 215))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('inflammatory response', 'biological_process', 'GO:0006954', ('141', '162'))	('increased', 'PosReg', (131, 140))	('autophagy', 'biological_process', 'GO:0016236', ('268', '277'))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('colitis-associated cancer', 'Disease', 'MESH:D009369', (166, 191))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('UVRAG', 'Gene', (61, 66))	('UVRAG', 'Gene', '78610', (61, 66))	('autophagy', 'biological_process', 'GO:0006914', ('268', '277'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('mice', 'Species', '10090', (33, 37))	('autophagy', 'biological_process', 'GO:0016236', ('104', '113'))	('colitis-associated cancer', 'Disease', (166, 191))	('inflammatory response', 'CPA', (141, 162))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (228, 233))	('colitis', 'Phenotype', 'HP:0002583', (166, 173))
49692	33923277	In the current study, we showed that compared to the uninfected condition, 11G5 or 11G5 clbQ infection increased clinical and histological inflammation scores.	('clbQ infection', 'Disease', (88, 102))	('increased', 'PosReg', (103, 112))	('inflammation', 'Disease', 'MESH:D007249', (139, 151))	('infected', 'Disease', 'MESH:D007239', (55, 63))	('11G5', 'Var', (75, 79))	('clbQ infection', 'Disease', 'MESH:D007239', (88, 102))	('inflammation', 'Disease', (139, 151))	('inflammation', 'biological_process', 'GO:0006954', ('139', '151'))	('11G5', 'Var', (83, 87))	('infected', 'Disease', (55, 63))
49696	33923277	No difference in clinical and histological inflammation score was observed between 11G5- and 11G5DeltaclbQ-infected conditions either in wild-type mice or mice with IEC-specific autophagy deficiency.	('mice', 'Species', '10090', (147, 151))	('autophagy deficiency', 'Disease', 'MESH:C564093', (178, 198))	('11G5-', 'Var', (83, 88))	('inflammation', 'Disease', 'MESH:D007249', (43, 55))	('clbQ-infected', 'Disease', 'MESH:D007239', (102, 115))	('mice', 'Species', '10090', (155, 159))	('clbQ-infected', 'Disease', (102, 115))	('inflammation', 'Disease', (43, 55))	('autophagy deficiency', 'Disease', (178, 198))
49704	33923277	Mice deficient for Atg16l1 specifically in IECs (Atg16l1flox/floxCreVillin mice, hereafter termed Atg16l1DeltaIEC) and their littermates Atg16l1flox/flox were housed in specific pathogen-free conditions.	('Atg16l1', 'Gene', (19, 26))	('mice', 'Species', '10090', (75, 79))	('Atg16l1', 'Gene', (98, 105))	('Atg16l1', 'Gene', (137, 144))	('Atg16l1DeltaIEC', 'Gene', (98, 113))	('Atg16l1', 'Gene', '77040', (19, 26))	('Atg16l1', 'Gene', '77040', (98, 105))	('Atg16l1', 'Gene', '77040', (137, 144))	('IECs', 'Disease', (43, 47))	('Atg16l1DeltaIEC', 'Gene', '77040', (98, 113))	('Atg16l1', 'Gene', (49, 56))	('Mice', 'Species', '10090', (0, 4))	('Atg16l1', 'Gene', '77040', (49, 56))	('deficient', 'Var', (5, 14))
49705	33923277	Mice were uninfected or infected with the 11G5 strain or the mutant 11G5DeltaclbQ as previously described.	('infected', 'Disease', 'MESH:D007239', (24, 32))	('11G5DeltaclbQ', 'Gene', (68, 81))	('infected', 'Disease', 'MESH:D007239', (12, 20))	('mutant', 'Var', (61, 67))	('Mice', 'Species', '10090', (0, 4))	('infected', 'Disease', (24, 32))	('infected', 'Disease', (12, 20))
49723	33923277	The primary antibodies used were anti-LC3 (#L8918, Sigma-Aldrich, Saint-Louis, MO, USA), anti-phospho-H2AX (#2577, Cell Signaling) and anti-alpha-tubulin (#2144, Cell Signaling).	('LC3', 'Gene', '66734', (38, 41))	('Signaling', 'biological_process', 'GO:0023052', ('120', '129'))	('#2144', 'Var', (155, 160))	('Signaling', 'biological_process', 'GO:0023052', ('167', '176'))	('LC3', 'Gene', (38, 41))	('#L8918', 'Var', (43, 49))	('#2577', 'Var', (108, 113))	('H2AX', 'Gene', (102, 106))	('H2AX', 'Gene', '15270', (102, 106))
49748	32322269	In univariate analysis of potential factors, presence of hypertension, stages II-III disease, neoadjuvant treatment (either chemotherapy or radiochemotherapy), adjuvant treatment (either chemotherapy or radiochemotherapy), and longer duration of ileostomy (>3 months) were associated with more frequent combined outcome of "any ileostomy-related complication during ileostomy."	('hypertension', 'Phenotype', 'HP:0000822', (57, 69))	('II-III disease', 'Disease', 'MESH:D005776', (78, 92))	('II-III disease', 'Disease', (78, 92))	('presence', 'Var', (45, 53))
49768	31388510	KLF5 was significantly associated with the presence of KRAS mutations, and KLF5 was an independent poor response predictor of CRT in rectal cancer.	('KRAS', 'Gene', (55, 59))	('rectal cancer', 'Disease', (133, 146))	('KLF5', 'Gene', (0, 4))	('KLF5', 'Gene', '688', (0, 4))	('rectal cancer', 'Phenotype', 'HP:0100743', (133, 146))	('KRAS', 'Gene', '3845', (55, 59))	('associated', 'Reg', (23, 33))	('mutations', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('KLF5', 'Gene', (75, 79))	('KLF5', 'Gene', '688', (75, 79))	('rectal cancer', 'Disease', 'MESH:D012004', (133, 146))
49778	31388510	From March 2015 to January 2016, four multicenter 60 consecutive patients who received neoadjuvant chemoradiation for locally advanced (radiological T3-4 or N+ and/or clinically bulky) rectal cancer were enrolled in this study.	('rectal cancer', 'Disease', 'MESH:D012004', (185, 198))	('rectal cancer', 'Disease', (185, 198))	('rectal cancer', 'Phenotype', 'HP:0100743', (185, 198))	('patients', 'Species', '9606', (65, 73))	('T3-4', 'Var', (149, 153))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
49815	31388510	High KLF5 expression and p53 mutation were significantly associated with poor response of CRT (TRG 1 or 2) (P = 0.004, P = 0.021, respectfully) (Table 2).	('p53', 'Gene', (25, 28))	('mutation', 'Var', (29, 37))	('p53', 'Gene', '7157', (25, 28))	('TRG 1', 'Gene', '7195', (95, 100))	('TRG 1', 'Gene', (95, 100))	('KLF5', 'Gene', (5, 9))	('KLF5', 'Gene', '688', (5, 9))
49816	31388510	Additionally, a trend towards an association between KRAS mutation status and tumor regression was observed but was not statistically significant (P = 0.062).	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('KRAS', 'Gene', (53, 57))	('tumor', 'Disease', (78, 83))	('KRAS', 'Gene', '3845', (53, 57))	('mutation status', 'Var', (58, 73))
49821	31388510	We examined 6 different human colorectal cancer cell lines for mutated KRAS, mutated BRAF and KLF5 expression.	('mutated', 'Var', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('colorectal cancer', 'Disease', (30, 47))	('human', 'Species', '9606', (24, 29))	('BRAF', 'Gene', (85, 89))	('mutated', 'Var', (77, 84))	('KLF5', 'Gene', (94, 98))	('KRAS', 'Gene', (71, 75))	('BRAF', 'Gene', '673', (85, 89))	('colorectal cancer', 'Disease', 'MESH:D015179', (30, 47))	('KLF5', 'Gene', '688', (94, 98))	('KRAS', 'Gene', '3845', (71, 75))	('rectal cancer', 'Phenotype', 'HP:0100743', (34, 47))	('colorectal cancer', 'Phenotype', 'HP:0003003', (30, 47))
49823	31388510	Only HT-29 contained a BRAF mutation.	('mutation', 'Var', (28, 36))	('HT-29', 'CellLine', 'CVCL:0320', (5, 10))	('BRAF', 'Gene', (23, 27))	('BRAF', 'Gene', '673', (23, 27))
49824	31388510	The level of KLF5 expression in the 6 cell lines correlated with KRAS genotype, with those containing mutated KRAS having higher levels.	('correlated', 'Reg', (49, 59))	('KRAS', 'Gene', '3845', (65, 69))	('KRAS', 'Gene', '3845', (110, 114))	('KLF5', 'Gene', (13, 17))	('mutated', 'Var', (102, 109))	('KLF5', 'Gene', '688', (13, 17))	('KRAS', 'Gene', (65, 69))	('KRAS', 'Gene', (110, 114))
49825	31388510	It is of interest to note that HT-29, which contains a mutated BRAF gene, exhibited higher levels of KLF5, similar to those cell lines harboring KRAS mutations.	('KRAS', 'Gene', (145, 149))	('mutated', 'Var', (55, 62))	('KLF5', 'Gene', (101, 105))	('KRAS', 'Gene', '3845', (145, 149))	('KLF5', 'Gene', '688', (101, 105))	('BRAF', 'Gene', '673', (63, 67))	('HT-29', 'CellLine', 'CVCL:0320', (31, 36))	('BRAF', 'Gene', (63, 67))	('higher', 'PosReg', (84, 90))
49827	31388510	Conversely, HCT116 p53+/+ and HCT116 p53-/-, cell lines with activating KRASG13D mutations, exhibited higher levels of KLF5, cyclin D1 and b-catenin (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (30, 36))	('HCT116', 'CellLine', 'CVCL:0291', (12, 18))	('b-catenin', 'Gene', (139, 148))	('cyclin D1', 'Gene', (125, 134))	('KRAS', 'Gene', (72, 76))	('KRAS', 'Gene', '3845', (72, 76))	('higher', 'PosReg', (102, 108))	('KLF5', 'Gene', '688', (119, 123))	('p53', 'Gene', (19, 22))	('levels', 'MPA', (109, 115))	('b-catenin', 'Gene', '1499', (139, 148))	('p53', 'Gene', (37, 40))	('mutations', 'Var', (81, 90))	('p53', 'Gene', '7157', (19, 22))	('p53', 'Gene', '7157', (37, 40))	('KLF5', 'Gene', (119, 123))	('activating', 'PosReg', (61, 71))	('cyclin D1', 'Gene', '595', (125, 134))
49829	31388510	The cell line with KRAS mutation such as HCT116+/+ or HCT116-/-, high KLF5 expression, high cyclin D1 and high b-catenin expression was shown sequentially.	('HCT116+/+', 'Var', (41, 50))	('cyclin D1', 'Gene', '595', (92, 101))	('HCT116', 'CellLine', 'CVCL:0291', (54, 60))	('KLF5', 'Gene', (70, 74))	('cyclin', 'molecular_function', 'GO:0016538', ('92', '98'))	('KRAS', 'Gene', (19, 23))	('HCT116', 'CellLine', 'CVCL:0291', (41, 47))	('b-catenin', 'Gene', '1499', (111, 120))	('KRAS', 'Gene', '3845', (19, 23))	('cyclin D1', 'Gene', (92, 101))	('KLF5', 'Gene', '688', (70, 74))	('high', 'PosReg', (87, 91))	('high', 'PosReg', (65, 69))	('HCT116-/-', 'Var', (54, 63))	('b-catenin', 'Gene', (111, 120))
49830	31388510	However, the cell line without KRAS mutation such SW480, CaC02 showed low KLF5 expression and cyclin D1 and b-catenin expressed in proportion to KLF5 expression (Fig.	('KRAS', 'Gene', (31, 35))	('cyclin D1', 'Gene', (94, 103))	('KRAS', 'Gene', '3845', (31, 35))	('KLF5', 'Gene', (145, 149))	('SW480', 'Var', (50, 55))	('KLF5', 'Gene', (74, 78))	('KLF5', 'Gene', '688', (145, 149))	('SW480', 'CellLine', 'CVCL:0546', (50, 55))	('b-catenin', 'Gene', '1499', (108, 117))	('b-catenin', 'Gene', (108, 117))	('KLF5', 'Gene', '688', (74, 78))	('cyclin D1', 'Gene', '595', (94, 103))	('low', 'NegReg', (70, 73))
49838	31388510	The level of KLF5 was increased in SNU-C4 5-FU compared to SNU-C4.	('SNU-C4', 'Var', (35, 41))	('5-FU', 'Chemical', 'MESH:D005472', (42, 46))	('increased', 'PosReg', (22, 31))	('KLF5', 'Gene', (13, 17))	('KLF5', 'Gene', '688', (13, 17))
49852	31388510	In vitro, we found that the KLF5 is located downstream of the KRAS mutation and protein KLF5 is stabilized by chemo or radiation therapy, increasing the cell cycling protein such as cyclin D1 or cell proliferation protein such as b-catenin, which is predicted to be related to cell survival.	('KRAS', 'Gene', (62, 66))	('protein', 'cellular_component', 'GO:0003675', ('166', '173'))	('b-catenin', 'Gene', '1499', (230, 239))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('KLF5', 'Gene', '688', (28, 32))	('b-catenin', 'Gene', (230, 239))	('mutation', 'Var', (67, 75))	('KLF5', 'Gene', (28, 32))	('KLF5', 'Gene', '688', (88, 92))	('cyclin D1', 'Gene', (182, 191))	('cell proliferation', 'biological_process', 'GO:0008283', ('195', '213'))	('KLF5', 'Gene', (88, 92))	('cyclin D1', 'Gene', '595', (182, 191))	('increasing', 'PosReg', (138, 148))	('cell cycling protein', 'CPA', (153, 173))	('cell proliferation', 'CPA', (195, 213))	('KRAS', 'Gene', '3845', (62, 66))	('protein', 'cellular_component', 'GO:0003675', ('214', '221'))	('cyclin', 'molecular_function', 'GO:0016538', ('182', '188'))
49859	31388510	As our data demonstrated, KRAS mutation tended to predict tumor regression grade but not has significance.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mutation', 'Var', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('KRAS', 'Gene', (26, 30))	('KRAS', 'Gene', '3845', (26, 30))
49864	31388510	Here, we made a hypothesis that each mutation of RAS, RAF, MER, ERK also influence the results of chemoradiation response, so, molecule of downstream such like KLF5 would be more specific to predict CRT response.	('results', 'MPA', (87, 94))	('mutation', 'Var', (37, 45))	('MER', 'Gene', (59, 62))	('RAS', 'Gene', (49, 52))	('ERK', 'Gene', '5594', (64, 67))	('RAF', 'Gene', '22882', (54, 57))	('ERK', 'Gene', (64, 67))	('RAF', 'Gene', (54, 57))	('KLF5', 'Gene', (160, 164))	('KLF5', 'Gene', '688', (160, 164))	('influence', 'Reg', (73, 82))	('MER', 'Gene', '10461', (59, 62))
49875	31388510	We thought that KLF5 expression would trigger cell cycle activation via cyclin D1 or cyclin B1/CdC and maintain bonding each other or adhesion another site via b-catenin.	('b-catenin', 'Gene', (160, 169))	('cyclin D1', 'Gene', (72, 81))	('cyclin B1', 'Gene', '891', (85, 94))	('cell cycle activation', 'CPA', (46, 67))	('bonding', 'MPA', (112, 119))	('cyclin D1', 'Gene', '595', (72, 81))	('b-catenin', 'Gene', '1499', (160, 169))	('trigger', 'Reg', (38, 45))	('expression', 'Var', (21, 31))	('maintain', 'PosReg', (103, 111))	('KLF5', 'Gene', (16, 20))	('cyclin B1', 'Gene', (85, 94))	('KLF5', 'Gene', '688', (16, 20))	('adhesion', 'MPA', (134, 142))
49893	31388510	We found that protein of KLF5 which related with KRAS, BRAF mutation is a potential mediator to resist CRT in rectal cancer.	('rectal cancer', 'Phenotype', 'HP:0100743', (110, 123))	('mutation', 'Var', (60, 68))	('KLF5', 'Gene', (25, 29))	('KRAS', 'Gene', '3845', (49, 53))	('KLF5', 'Gene', '688', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('BRAF', 'Gene', '673', (55, 59))	('rectal cancer', 'Disease', 'MESH:D012004', (110, 123))	('rectal cancer', 'Disease', (110, 123))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('BRAF', 'Gene', (55, 59))	('KRAS', 'Gene', (49, 53))
49897	31388510	KLF5 was significantly related with KRAS mutation but, KLF5 has an independent role to get resistance from preoperative CRT.	('KLF5', 'Gene', (0, 4))	('KLF5', 'Gene', '688', (0, 4))	('KLF5', 'Gene', (55, 59))	('KLF5', 'Gene', '688', (55, 59))	('KRAS', 'Gene', (36, 40))	('mutation', 'Var', (41, 49))	('KRAS', 'Gene', '3845', (36, 40))
49900	30103475	Despite the accumulating evidence of the role of dysregulated microRNAs in malignancies, the therapeutic efficacy of pharmacological-targeting of CRC-SC-associated microRNAs is relatively under-explored.	('CRC-SC-associated', 'Disease', (146, 163))	('malignancies', 'Disease', 'MESH:D009369', (75, 87))	('dysregulated', 'Var', (49, 61))	('malignancies', 'Disease', (75, 87))
49904	30103475	We also showed that 4-AAQB-induced re-expression of hsa-miR-324-5p, akin to short-interfering RNA, reduced SOD2 expression, correlates with the concurrent down-regulation of SOD2, N-cadherin, vimentin, c-Myc, and BcL-xL2, with concomitant up-regulation of E-cadherin and BAX2 proteins.	('SOD', 'Gene', (107, 110))	('hsa-miR-324-5p', 'Var', (52, 66))	('c-Myc', 'Gene', (202, 207))	('BAX', 'Gene', (271, 274))	('BAX', 'Gene', '581', (271, 274))	('up-regulation', 'PosReg', (239, 252))	('SOD', 'Gene', '6647;6648;6649', (174, 177))	('SOD2', 'molecular_function', 'GO:0004784', ('174', '178'))	('c-Myc', 'Gene', '4609', (202, 207))	('expression', 'MPA', (112, 122))	('vimentin', 'cellular_component', 'GO:0045098', ('192', '200'))	('BcL-xL2', 'Protein', (213, 220))	('cadherin', 'molecular_function', 'GO:0008014', ('258', '266'))	('SOD', 'Gene', (174, 177))	('down-regulation', 'NegReg', (155, 170))	('E-cadherin', 'Gene', (256, 266))	('E-cadherin', 'Gene', '999', (256, 266))	('SOD2', 'molecular_function', 'GO:0004784', ('107', '111'))	('SOD', 'Gene', '6647;6648;6649', (107, 110))	('down-regulation of SOD2', 'biological_process', 'GO:1901670', ('155', '178'))	('4-AAQB', 'Chemical', 'MESH:C555021', (20, 26))	('vimentin', 'cellular_component', 'GO:0045099', ('192', '200'))	('N-cadherin', 'Gene', (180, 190))	('regulation', 'biological_process', 'GO:0065007', ('242', '252'))	('vimentin', 'Protein', (192, 200))	('RNA', 'cellular_component', 'GO:0005562', ('94', '97'))	('N-cadherin', 'Gene', '1000', (180, 190))	('cadherin', 'molecular_function', 'GO:0008014', ('182', '190'))	('reduced', 'NegReg', (99, 106))
49905	30103475	Enhanced expression of hsa-miR-324-5p in the CRC cells suppressed their tumorigenicity in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('hsa-miR-324-5p', 'Var', (23, 37))	('expression', 'MPA', (9, 19))	('suppressed', 'NegReg', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('Enhanced', 'PosReg', (0, 8))
49907	30103475	Conclusion: Our findings highlight the pre-clinical anti-CSC efficacy of 4-AAQB, with or without FOLFOX in CRC, and suggest a potential novel therapeutic strategy for CRC patients.	('CRC', 'Disease', (107, 110))	('pre', 'molecular_function', 'GO:0003904', ('39', '42'))	('4-AAQB', 'Var', (73, 79))	('anti-CSC', 'MPA', (52, 60))	('patients', 'Species', '9606', (171, 179))	('FOLFOX', 'Chemical', '-', (97, 103))	('CRC', 'Disease', (167, 170))	('4-AAQB', 'Chemical', 'MESH:C555021', (73, 79))
49912	30103475	In an earlier work by our team, we demonstrated that 4-acetylantroquinonol B (4-AAQB), a mycelial isolate of Antrodia camphorata, a common Taiwanese camphor tree mushroom with a broad range of documented bioactivities, effectively disrupts essential oncogenic signaling pathways such as the Lgr5/Wnt/beta-catenin, JAK-STAT, and non-transmembrane receptor tyrosine kinase signaling pathways, inhibits the acquisition of the CRC-stem cell (SC) phenotype, down-regulates the expression and/or activities of stemness-associated genes including ALDH1, attenuates tumor aggression, and accentuates chemosensitivity in CRC cells.	('Antrodia camphorata', 'Species', '196114', (109, 128))	('chemosensitivity in CRC cells', 'CPA', (592, 621))	('oncogenic signaling pathways', 'Pathway', (250, 278))	('4-acetylantroquinonol B', 'Chemical', 'MESH:C555021', (53, 76))	('camphor tree', 'Species', '13429', (149, 161))	('mushroom', 'Species', '5341', (162, 170))	('acquisition', 'CPA', (404, 415))	('aggression', 'Phenotype', 'HP:0000718', (564, 574))	('expression', 'MPA', (472, 482))	('accentuates', 'PosReg', (580, 591))	('ALDH1', 'Gene', (540, 545))	('4-acetylantroquinonol', 'Var', (53, 74))	('disrupts', 'NegReg', (231, 239))	('attenuates tumor aggression', 'Disease', 'MESH:C538265', (547, 574))	('4-AAQB', 'Chemical', 'MESH:C555021', (78, 84))	('attenuates tumor aggression', 'Disease', (547, 574))	('inhibits', 'NegReg', (391, 399))	('tumor', 'Phenotype', 'HP:0002664', (558, 563))	('down-regulates', 'NegReg', (453, 467))	('Lgr5/Wnt/beta-catenin', 'Pathway', (291, 312))	('activities', 'MPA', (490, 500))
49919	30103475	Despite documented association between mutations in the SOD2 gene and several pathologies, including sporadic motor neuron disease, idiopathic dilated cardiomyopathy (IDC), premature aging (progeria), and cancer, the role of SOD2 in cancer cells, such as in CRC cells, is not fully understood.	('SOD', 'Gene', '6647;6648;6649', (56, 59))	('sporadic motor neuron disease', 'Disease', (101, 130))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('SOD', 'Gene', '6647;6648;6649', (225, 228))	('cancer', 'Disease', (205, 211))	('SOD', 'Gene', (56, 59))	('premature aging', 'Disease', (173, 188))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (143, 165))	('mutations', 'Var', (39, 48))	('cancer', 'Disease', (233, 239))	('SOD', 'Gene', (225, 228))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('idiopathic dilated cardiomyopathy', 'Disease', 'MESH:C536277', (132, 165))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (151, 165))	('idiopathic dilated cardiomyopathy', 'Disease', (132, 165))	('association', 'Interaction', (19, 30))
49922	30103475	Deregulation of epigenetic factors and patterns, such as aberrant DNA methylation, histone tail modification, and non-coding RNA (ncRNA) regulation, are implicated in loss of cell identity and contribute to several human pathologies, including cancer.	('DNA', 'Protein', (66, 69))	('contribute', 'Reg', (193, 203))	('epigenetic', 'Var', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('DNA methylation', 'biological_process', 'GO:0006306', ('66', '81'))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('regulation', 'biological_process', 'GO:0065007', ('137', '147'))	('RNA', 'cellular_component', 'GO:0005562', ('125', '128'))	('loss', 'NegReg', (167, 171))	('histone', 'Protein', (83, 90))	('cell identity', 'CPA', (175, 188))	('human', 'Species', '9606', (215, 220))	('cancer', 'Disease', (244, 250))	('aberrant', 'Var', (57, 65))
49923	30103475	There is documented correlation or association between down-regulated miRNA expression, and tumor initiation or metastatic disease progression, however, there is a dearth of information regarding SOD2-regulated miRNA(s) in CRC, and regarding how the epigenetic modulation of SOD2 contributes to the CSC-like and metastatic phenotype of CRC cells.	('SOD', 'Gene', (196, 199))	('SOD', 'Gene', (275, 278))	('CSC-like', 'Disease', (299, 307))	('SOD', 'Gene', '6647;6648;6649', (275, 278))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('epigenetic modulation', 'Var', (250, 271))	('tumor initiation', 'Disease', 'MESH:D009369', (92, 108))	('SOD2', 'molecular_function', 'GO:0004784', ('196', '200'))	('down-regulated', 'NegReg', (55, 69))	('CRC', 'Disease', (336, 339))	('SOD', 'Gene', '6647;6648;6649', (196, 199))	('SOD2', 'molecular_function', 'GO:0004784', ('275', '279'))	('contributes', 'Reg', (280, 291))	('tumor initiation', 'Disease', (92, 108))
49926	30103475	Consequently, herein, we provide evidence that hsa-miR-324 interacts with SOD2, and that the aberrant expression of SOD2 enhances the oncogenicity and cancer stem cell-like phenotype of CRC cells and the therapeutic effect of 4-AAQB in these cells is mediated by inducing re-expression of SOD2-suppressed hsa-miR-324.	('4-AAQB', 'Chemical', 'MESH:C555021', (226, 232))	('SOD', 'Gene', (289, 292))	('SOD', 'Gene', (74, 77))	('enhances', 'PosReg', (121, 129))	('SOD2', 'molecular_function', 'GO:0004784', ('116', '120'))	('hsa-miR-324', 'Gene', '442898', (47, 58))	('cancer', 'Disease', (151, 157))	('oncogenicity', 'CPA', (134, 146))	('hsa-miR-324', 'Gene', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('hsa-miR-324', 'Gene', '442898', (305, 316))	('SOD', 'Gene', '6647;6648;6649', (116, 119))	('SOD2', 'molecular_function', 'GO:0004784', ('289', '293'))	('aberrant expression', 'Var', (93, 112))	('SOD2', 'molecular_function', 'GO:0004784', ('74', '78'))	('hsa-miR-324', 'Gene', (305, 316))	('SOD', 'Gene', '6647;6648;6649', (289, 292))	('SOD', 'Gene', '6647;6648;6649', (74, 77))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('SOD', 'Gene', (116, 119))
49948	30103475	Taken together, those findings do indicate that aberrant expression of SOD2 correlates with disease progression, and the SOD2-induced down-regulation of hsa-miR-324 facilitates poor prognosis, while suggesting the molecular targetability of SOD2 and potential therapeutic utility of hsa-miR-324-5p in advanced stage and metastatic CRC patients.	('SOD', 'Gene', (241, 244))	('expression', 'MPA', (57, 67))	('facilitates', 'PosReg', (165, 176))	('SOD', 'Gene', (121, 124))	('hsa-miR-324', 'Gene', '442898', (153, 164))	('metastatic CRC', 'Disease', (320, 334))	('hsa-miR-324', 'Gene', (153, 164))	('hsa-miR-324', 'Gene', '442898', (283, 294))	('SOD', 'Gene', '6647;6648;6649', (71, 74))	('down-regulation', 'NegReg', (134, 149))	('aberrant', 'Var', (48, 56))	('poor prognosis', 'CPA', (177, 191))	('SOD', 'Gene', (71, 74))	('hsa-miR-324', 'Gene', (283, 294))	('patients', 'Species', '9606', (335, 343))	('SOD', 'Gene', '6647;6648;6649', (241, 244))	('SOD', 'Gene', '6647;6648;6649', (121, 124))
49951	30103475	More importantly, considering the clinical relevance of CSC targeting in effective anticancer therapies, we demonstrated that exposure to 2.5 muM, 5 muM, 7.5 muM, or 10 muM 4-AAQB reduced the proportion of DLD-1 SP cells by 4.2% (p < 0.01), 7.4% (p < 0.001), 8.4% (p < 0.001), or 8.9% (p < 0.001), compared to 6.4% by 100 muM verapamil, which specifically inhibits the Hoechst dye-extruding potential of the ATP-binding cassette (ABC) membrane transporter.	('muM', 'Gene', (322, 325))	('muM', 'Gene', '56925', (169, 172))	('muM', 'Gene', (169, 172))	('inhibits', 'NegReg', (356, 364))	('muM', 'Gene', '56925', (158, 161))	('cancer', 'Disease', (87, 93))	('membrane', 'cellular_component', 'GO:0016020', ('435', '443'))	('muM', 'Gene', (158, 161))	('muM', 'Gene', '56925', (149, 152))	('muM', 'Gene', '56925', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('muM', 'Gene', (149, 152))	('4-AAQB', 'Chemical', 'MESH:C555021', (173, 179))	('muM', 'Gene', (142, 145))	('SP', 'Chemical', '-', (212, 214))	('4-AAQB', 'Var', (173, 179))	('reduced', 'NegReg', (180, 187))	('ATP-binding', 'molecular_function', 'GO:0005524', ('408', '419'))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('muM', 'Gene', '56925', (322, 325))	('verapamil', 'Chemical', 'MESH:D014700', (326, 335))
49952	30103475	For the HCT116 SP cells treated with 2.5 muM, 5 muM, 7.5 muM, or 10 muM 4-AAQB, we observed 3.1% (p < 0.001), 3.6% (p < 0.001), 4.1% (p < 0.001), or 4.4% (p < 0.001) reduction, respectively, in comparison with 1.8% by 100 muM verapamil (Figure 4C).	('muM', 'Gene', (222, 225))	('4-AAQB', 'Var', (72, 78))	('muM', 'Gene', '56925', (41, 44))	('muM', 'Gene', (68, 71))	('muM', 'Gene', (41, 44))	('muM', 'Gene', (57, 60))	('muM', 'Gene', '56925', (48, 51))	('4-AAQB', 'Chemical', 'MESH:C555021', (72, 78))	('muM', 'Gene', (48, 51))	('muM', 'Gene', '56925', (222, 225))	('SP', 'Chemical', '-', (15, 17))	('HCT116', 'CellLine', 'CVCL:0291', (8, 14))	('muM', 'Gene', '56925', (68, 71))	('muM', 'Gene', '56925', (57, 60))	('verapamil', 'Chemical', 'MESH:D014700', (226, 235))
49953	30103475	Additionally, we observed a marked reduction in the SP cell number (Figure 4D), as well as significant cell death and dysmorphism in cultured DLD-1 or HCT116 SP cells exposed to 10 muM 4-AAQB compared to the untreated control group; interestingly, 4-AAQB exhibited no significant inhibitory effect on the viability and/or proliferation of the non-tumor colon cell line, CRL-1831 (Figure 4E).	('tumor colon', 'Disease', 'MESH:D015179', (347, 358))	('dysmorphism', 'Disease', 'None', (118, 129))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('CRL', 'Gene', (370, 373))	('4-AAQB', 'Chemical', 'MESH:C555021', (185, 191))	('SP cell number', 'CPA', (52, 66))	('4-AAQB', 'Chemical', 'MESH:C555021', (248, 254))	('tumor colon', 'Phenotype', 'HP:0100273', (347, 358))	('proliferation', 'CPA', (322, 335))	('SP', 'Chemical', '-', (158, 160))	('reduction', 'NegReg', (35, 44))	('tumor colon', 'Disease', (347, 358))	('4-AAQB', 'Var', (248, 254))	('HCT116', 'CellLine', 'CVCL:0291', (151, 157))	('CRL', 'Gene', '133396', (370, 373))	('SP', 'Chemical', '-', (52, 54))	('muM', 'Gene', '56925', (181, 184))	('muM', 'Gene', (181, 184))	('dysmorphism', 'Disease', (118, 129))
49954	30103475	This data indicates that 4-AAQB inhibits the viability and/or proliferation of human colorectal carcinoma wide-type and side-population cells, as well as corroborating the findings of our previously published work.	('colorectal carcinoma', 'Disease', 'MESH:D015179', (85, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('human', 'Species', '9606', (79, 84))	('4-AAQB', 'Chemical', 'MESH:C555021', (25, 31))	('proliferation', 'CPA', (62, 75))	('viability', 'CPA', (45, 54))	('colorectal carcinoma', 'Disease', (85, 105))	('inhibits', 'NegReg', (32, 40))	('4-AAQB', 'Var', (25, 31))
49955	30103475	Investigating the molecular mechanism underlying the observed inhibitory effect of 4-AAQB in the SOD2-rich CRC SP cells, which serve as in vitro CRC-SC models, the results of our Western blot analyses demonstrate that exposure to 5-10 muM 4-AAQB significantly down-regulates the expression level of SOD2, N-cadherin, vimentin, c-Myc, and Bcl-xL proteins, while up-regulating the expression of E-cadherin and Bax in the DLD-1 or HCT116 SP cells (Figure 5A,B).	('muM', 'Gene', (235, 238))	('Bax', 'Gene', '581', (408, 411))	('up-regulating', 'PosReg', (361, 374))	('expression level', 'MPA', (279, 295))	('4-AAQB', 'Chemical', 'MESH:C555021', (83, 89))	('Bcl-xL', 'Gene', '598', (338, 344))	('c-Myc', 'Gene', (327, 332))	('N-cadherin', 'Gene', (305, 315))	('down-regulates', 'NegReg', (260, 274))	('c-Myc', 'Gene', '4609', (327, 332))	('E-cadherin', 'Gene', (393, 403))	('E-cadherin', 'Gene', '999', (393, 403))	('SOD', 'Gene', (97, 100))	('N-cadherin', 'Gene', '1000', (305, 315))	('vimentin', 'MPA', (317, 325))	('HCT116', 'CellLine', 'CVCL:0291', (428, 434))	('SOD', 'Gene', '6647;6648;6649', (299, 302))	('4-AAQB', 'Chemical', 'MESH:C555021', (239, 245))	('SP', 'Chemical', '-', (111, 113))	('4-AAQB', 'Var', (239, 245))	('SP', 'Chemical', '-', (435, 437))	('expression', 'MPA', (379, 389))	('SOD', 'Gene', (299, 302))	('Bax', 'Gene', (408, 411))	('muM', 'Gene', '56925', (235, 238))	('Bcl-xL', 'Gene', (338, 344))	('SOD', 'Gene', '6647;6648;6649', (97, 100))
49959	30103475	Furthermore, using the RT-PCR, we demonstrated that DLD-1 SP cells treated with 10 muM 4-AAQB exhibited significantly suppressed SOD2 mRNA expression, and conversely up-regulated hsa-miR-324-5p expression.	('SP', 'Chemical', '-', (58, 60))	('4-AAQB', 'Var', (87, 93))	('muM', 'Gene', '56925', (83, 86))	('up-regulated', 'PosReg', (166, 178))	('SOD', 'Gene', '6647;6648;6649', (129, 132))	('SOD2', 'molecular_function', 'GO:0004784', ('129', '133'))	('hsa-miR-324-5p expression', 'MPA', (179, 204))	('4-AAQB', 'Chemical', 'MESH:C555021', (87, 93))	('muM', 'Gene', (83, 86))	('SOD', 'Gene', (129, 132))	('suppressed', 'NegReg', (118, 128))
49960	30103475	These data suggest that the anticancer effect of 4-AAQB, akin to SOD2-silencing, is mediated by hsa-miR-324 and it is associated with EMT- and cell-death-related molecular changes in the colorectal cancer SP cells, at both the transcript and protein levels.	('colorectal cancer', 'Disease', (187, 204))	('4-AAQB', 'Var', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('hsa-miR-324', 'Gene', (96, 107))	('cancer', 'Disease', (198, 204))	('SOD', 'Gene', (65, 68))	('cancer', 'Disease', (32, 38))	('colorectal cancer', 'Disease', 'MESH:D015179', (187, 204))	('4-AAQB', 'Chemical', 'MESH:C555021', (49, 55))	('SOD', 'Gene', '6647;6648;6649', (65, 68))	('SP', 'Chemical', '-', (205, 207))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('colorectal cancer', 'Phenotype', 'HP:0003003', (187, 204))	('hsa-miR-324', 'Gene', '442898', (96, 107))
49961	30103475	Having established that 4-AAQB effectively elicits the up-regulation of hsa-miR-324 while down-regulating SOD2 expression, we further investigated the effect of 4-AAQB treatment on the motility and oncogenicity of CRC-SCs using the sorted DLD-1 or HCT116 SP cells.	('down-regulating', 'NegReg', (90, 105))	('4-AAQB', 'Chemical', 'MESH:C555021', (24, 30))	('4-AAQB', 'Chemical', 'MESH:C555021', (161, 167))	('SP', 'Chemical', '-', (255, 257))	('hsa-miR-324', 'Gene', '442898', (72, 83))	('up-regulation', 'PosReg', (55, 68))	('hsa-miR-324', 'Gene', (72, 83))	('regulation', 'biological_process', 'GO:0065007', ('58', '68'))	('SCs', 'molecular_function', 'GO:0004776', ('218', '221'))	('expression', 'MPA', (111, 121))	('SOD', 'Gene', '6647;6648;6649', (106, 109))	('4-AAQB', 'Var', (24, 30))	('HCT116', 'CellLine', 'CVCL:0291', (248, 254))	('SOD2', 'molecular_function', 'GO:0004784', ('106', '110'))	('investigated', 'Reg', (134, 146))	('SOD', 'Gene', (106, 109))
49962	30103475	We demonstrated that compared to the observed migration by the untreated cells, exposure to 5-10 muM 4-AAQB significantly attenuates the ability of the SP cells to migrate in a dose-dependent manner over a 24 h time-course (Figure 6A).	('muM', 'Gene', '56925', (97, 100))	('4-AAQB', 'Var', (101, 107))	('SP', 'Chemical', '-', (152, 154))	('4-AAQB', 'Chemical', 'MESH:C555021', (101, 107))	('muM', 'Gene', (97, 100))	('attenuates', 'NegReg', (122, 132))
49963	30103475	At the 24 h time-point, the DLD-1 SP cells treated with 5-10 muM 4-AAQB had lost ~20-29% migratory potential, while the HCT116 SP cells recorded a 41-59% lag in migration, in comparison to observed migration by their untreated counterparts (Figure 6B).	('SP', 'Chemical', '-', (127, 129))	('HCT116', 'CellLine', 'CVCL:0291', (120, 126))	('muM', 'Gene', (61, 64))	('muM', 'Gene', '56925', (61, 64))	('migratory potential', 'CPA', (89, 108))	('4-AAQB', 'Chemical', 'MESH:C555021', (65, 71))	('lost', 'NegReg', (76, 80))	('migration', 'CPA', (161, 170))	('SP', 'Chemical', '-', (34, 36))	('4-AAQB', 'Var', (65, 71))
49965	30103475	Moreover, we observed that there was a significantly attenuated capacity to form colonies in the 4-AAQB-treated SP cells, in comparison to the untreated SP cells (Figure 6E,F).	('SP', 'Chemical', '-', (153, 155))	('attenuated', 'NegReg', (53, 63))	('4-AAQB', 'Chemical', 'MESH:C555021', (97, 103))	('4-AAQB-treated', 'Var', (97, 111))	('SP', 'Chemical', '-', (112, 114))
49966	30103475	These results indicate that 4-AAQB effectively inhibits the SOD2-mediated motility, invasiveness, and the clonogenicity of CRC-SC cells.	('4-AAQB', 'Chemical', 'MESH:C555021', (28, 34))	('SOD', 'Gene', '6647;6648;6649', (60, 63))	('invasiveness', 'CPA', (84, 96))	('clonogenicity of CRC-SC cells', 'CPA', (106, 135))	('SOD', 'Gene', (60, 63))	('4-AAQB', 'Var', (28, 34))	('inhibits', 'NegReg', (47, 55))
49969	30103475	We demonstrated that 4-AAQB significantly inhibited the self-renewal capacity of the DLD-1 (5 muM: 69% inhibition, p < 0.01; 10 muM: 90% inhibition, p < 0.01) or HCT116 (5 muM: 61% inhibition, p < 0.05; 10 muM: 80% inhibition, p < 0.01) primary colonospheres (Figure 7B).	('muM', 'Gene', '56925', (172, 175))	('self-renewal capacity', 'CPA', (56, 77))	('muM', 'Gene', '56925', (206, 209))	('muM', 'Gene', (206, 209))	('4-AAQB', 'Chemical', 'MESH:C555021', (21, 27))	('muM', 'Gene', '56925', (94, 97))	('muM', 'Gene', '56925', (128, 131))	('muM', 'Gene', (172, 175))	('inhibited', 'NegReg', (42, 51))	('HCT116', 'Gene', (162, 168))	('muM', 'Gene', (94, 97))	('muM', 'Gene', (128, 131))	('4-AAQB', 'Var', (21, 27))	('HCT116', 'CellLine', 'CVCL:0291', (162, 168))
49971	30103475	These data indicate that 4-AAQB efficaciously suppresses the CSC-like phenotype, including the proliferation and self-renewal of CRC cells, in vitro.	('4-AAQB', 'Chemical', 'MESH:C555021', (25, 31))	('suppresses', 'NegReg', (46, 56))	('self-renewal of CRC cells', 'CPA', (113, 138))	('CSC-like', 'Disease', (61, 69))	('4-AAQB', 'Var', (25, 31))
49974	30103475	Macro-anatomically, the average weights of the tumors that were resected from the 4-AAQB- and combination-treated mice were significantly lesser than that of the FOLFOX- treated or untreated control mice (4-AAQB vs. control: 334.3  +-  79.4 mg vs. 3674.1  +-  593.1  mg, p  <  0.001; Combination vs. control: 282.6  +-  46.8 mg vs. 3674.1  +-  593.1 mg, p  <  0.001; FOLFOX vs. control: 459.3  +-  57.9 mg vs. 3674.1  +-  593.1 mg, p  <  0.01) (Figure 8A,B), indicating that the xenograft tumor growth was significantly inhibited by 4-AAQB alone or in combination with FOLFOX, compared with the FOLFOX- treated or untreated group.	('tumor', 'Disease', 'MESH:D009369', (489, 494))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('inhibited', 'NegReg', (520, 529))	('tumors', 'Disease', (47, 53))	('4-AAQB', 'Chemical', 'MESH:C555021', (82, 88))	('FOLFOX', 'Chemical', '-', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (489, 494))	('4-AAQB', 'Chemical', 'MESH:C555021', (533, 539))	('FOLFOX', 'Chemical', '-', (367, 373))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('4-AAQB', 'Var', (533, 539))	('FOLFOX', 'Chemical', '-', (595, 601))	('mice', 'Species', '10090', (114, 118))	('4-AAQB', 'Chemical', 'MESH:C555021', (205, 211))	('tumor', 'Disease', (47, 52))	('mice', 'Species', '10090', (199, 203))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', (489, 494))	('FOLFOX', 'Chemical', '-', (569, 575))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
49979	30103475	Those results indicate that 4-AAQB is non-toxic to non-cancerous tissues (also see Supplementary Figure S2), and that alone or in synergism with FOLFOX, 4-AAQB significantly inhibits CRC xenograft tumor growth in vivo.	('cancerous', 'Disease', (55, 64))	('4-AAQB', 'Chemical', 'MESH:C555021', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('4-AAQB', 'Var', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('inhibits', 'NegReg', (174, 182))	('FOLFOX', 'Chemical', '-', (145, 151))	('4-AAQB', 'Chemical', 'MESH:C555021', (153, 159))	('cancerous', 'Disease', 'MESH:D009369', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))
49980	30103475	In our previous work on the role of 4-AAQB in CRC, we provided evidence that 4-AAQB exhibits potent antiproliferative and anti-CSC therapeutic effects in CRC.	('antiproliferative', 'CPA', (100, 117))	('CRC', 'Disease', (154, 157))	('4-AAQB', 'Var', (77, 83))	('4-AAQB', 'Chemical', 'MESH:C555021', (36, 42))	('anti-CSC therapeutic effects', 'CPA', (122, 150))	('4-AAQB', 'Chemical', 'MESH:C555021', (77, 83))
49981	30103475	We showed that 4-AAQB effectively reverses or attenuates the resistance of cancer cells to 5-FU or FOLFOX anticancer therapy, thus, enhancing chemosensitivity both in vitro and in vivo.	('5-FU', 'Chemical', 'MESH:D005472', (91, 95))	('reverses', 'NegReg', (34, 42))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('chemosensitivity', 'CPA', (142, 158))	('4-AAQB', 'Chemical', 'MESH:C555021', (15, 21))	('4-AAQB', 'Var', (15, 21))	('cancer', 'Disease', (75, 81))	('resistance', 'MPA', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('attenuates', 'NegReg', (46, 56))	('FOLFOX', 'Chemical', '-', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('enhancing', 'PosReg', (132, 141))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
49986	30103475	This negative epigenetic modulation of SOD2 was shown to be associated with the converse enrichment of hsa-miR-324 and through the interaction of the 3'-UTR of SOD2 mRNA to the 5'-UTR of hsa-miR-324 (Figure 1 and Figure 2).	('epigenetic modulation', 'Var', (14, 35))	('SOD2', 'molecular_function', 'GO:0004784', ('39', '43'))	('hsa-miR-324', 'Gene', '442898', (103, 114))	('hsa-miR-324', 'Gene', '442898', (187, 198))	('SOD', 'Gene', '6647;6648;6649', (160, 163))	('SOD', 'Gene', '6647;6648;6649', (39, 42))	('hsa-miR-324', 'Gene', (103, 114))	('hsa-miR-324', 'Gene', (187, 198))	('SOD', 'Gene', (160, 163))	('interaction', 'Interaction', (131, 142))	('SOD', 'Gene', (39, 42))	('negative', 'NegReg', (5, 13))	('SOD2', 'molecular_function', 'GO:0004784', ('160', '164'))
49989	30103475	Consistent with the latter, in this study we demonstrated the oncogenic role of the aberrant expression of SOD2 in CRC, as evidenced by its ability to facilitate metastatic disease progression through the repression of hsa-miR-324 (Figure 3).	('hsa-miR-324', 'Gene', (219, 230))	('facilitate', 'PosReg', (151, 161))	('SOD', 'Gene', (107, 110))	('CRC', 'Disease', (115, 118))	('metastatic disease progression', 'CPA', (162, 192))	('SOD2', 'molecular_function', 'GO:0004784', ('107', '111'))	('hsa-miR-324', 'Gene', '442898', (219, 230))	('SOD', 'Gene', '6647;6648;6649', (107, 110))	('aberrant', 'Var', (84, 92))
49990	30103475	In addition, we also showed that 4-AAQB inhibits the viability and/or proliferation of human CRC SP cells in a hsa-miR-324-mediated manner, with associated attenuation of the SOD2-facilitated EMT and enhanced cell-death in the SP cells (Figure 4 and Figure 5; Supplementary Figure S1).	('hsa-miR-324', 'Gene', '442898', (111, 122))	('SP', 'Chemical', '-', (227, 229))	('attenuation', 'NegReg', (156, 167))	('4-AAQB', 'Var', (33, 39))	('human', 'Species', '9606', (87, 92))	('proliferation', 'CPA', (70, 83))	('hsa-miR-324', 'Gene', (111, 122))	('SP', 'Chemical', '-', (97, 99))	('SOD', 'Gene', '6647;6648;6649', (175, 178))	('4-AAQB', 'Chemical', 'MESH:C555021', (33, 39))	('cell-death', 'CPA', (209, 219))	('inhibits', 'NegReg', (40, 48))	('enhanced', 'PosReg', (200, 208))	('EMT', 'CPA', (192, 195))	('SOD', 'Gene', (175, 178))	('viability', 'CPA', (53, 62))
49994	30103475	The targeting and killing of these CSC-like SP cells by 4-AAQB is posited as a rational and efficacious therapeutic approach, as it eliminates the quiescent, slowly-dividing, and characteristically therapy-resistant tumor-initiating (and maintaining-) cells, alongside the sensitive rapidly-dividing non-SP cells.	('tumor', 'Disease', (216, 221))	('slowly-dividing', 'CPA', (158, 173))	('4-AAQB', 'Chemical', 'MESH:C555021', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('SP', 'Chemical', '-', (304, 306))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('SP', 'Chemical', '-', (44, 46))	('eliminates', 'NegReg', (132, 142))	('4-AAQB', 'Var', (56, 62))	('quiescent', 'MPA', (147, 156))
49995	30103475	Consistent with this, we provided evidence that 4-AAQB, in a dose-dependent manner, effectively targets the primary colonospheres and subsequent generations of colonospheres, recapitulating the pharmacological inhibition of CRC-SC-related self-renewal or propagation, with associated attenuation of the expression of critical pluripotency transcription factors (Figure 7).	('self-renewal', 'CPA', (239, 251))	('attenuation', 'NegReg', (284, 295))	('4-AAQB', 'Chemical', 'MESH:C555021', (48, 54))	('transcription', 'biological_process', 'GO:0006351', ('339', '352'))	('pluripotency', 'Disease', (326, 338))	('expression', 'MPA', (303, 313))	('4-AAQB', 'Var', (48, 54))	('pluripotency', 'Disease', 'None', (326, 338))	('propagation', 'CPA', (255, 266))
49996	30103475	Understanding that self-renewal, a vital property of the CSC-like SP cells, is associated with the facilitation and maintenance of the proliferative capacity of cancerous cells, makes the clinical implication of our data apparent, as it highlights the putative ability of 4-AAQB to negatively modulate oncogenic self-renewal signaling, thus enhancing the sensitivity of malignant cells to chemotherapeutics, altering their survival strategies, limiting tumorigenesis and/or oncogenicity, and apparently impeding disease recurrence.	('SP', 'Chemical', '-', (66, 68))	('cancerous', 'Disease', 'MESH:D009369', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (453, 458))	('4-AAQB', 'Chemical', 'MESH:C555021', (272, 278))	('negatively', 'NegReg', (282, 292))	('disease recurrence', 'CPA', (512, 530))	('impeding', 'NegReg', (503, 511))	('survival strategies', 'CPA', (423, 442))	('enhancing', 'PosReg', (341, 350))	('oncogenic self-renewal', 'MPA', (302, 324))	('4-AAQB', 'Var', (272, 278))	('altering', 'Reg', (408, 416))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('signaling', 'biological_process', 'GO:0023052', ('325', '334'))	('cancerous', 'Disease', (161, 170))	('limiting', 'NegReg', (444, 452))	('oncogenicity', 'CPA', (474, 486))	('tumor', 'Disease', (453, 458))	('tumor', 'Disease', 'MESH:D009369', (453, 458))	('modulate', 'Reg', (293, 301))	('sensitivity', 'MPA', (355, 366))
49997	30103475	From in vivo validation of our in vitro findings, we confirmed that 4-AAQB alone or in synergism with FOLFOX reduces the tumorigenicity of CRC cells by suppressing SOD and up-regulating hsa-miR-324 expression, in vivo (Figure 8).	('suppressing', 'NegReg', (152, 163))	('4-AAQB', 'Chemical', 'MESH:C555021', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('hsa-miR-324', 'Gene', '442898', (186, 197))	('SOD', 'Gene', (164, 167))	('tumor', 'Disease', (121, 126))	('SOD', 'Gene', '6647;6648;6649', (164, 167))	('4-AAQB', 'Var', (68, 74))	('hsa-miR-324', 'Gene', (186, 197))	('expression', 'MPA', (198, 208))	('up-regulating', 'PosReg', (172, 185))	('FOLFOX', 'Chemical', '-', (102, 108))	('reduces', 'NegReg', (109, 116))	('SOD', 'molecular_function', 'GO:0004784', ('164', '167'))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
50000	30103475	In the light of this, we showed in addition that 4-AAQB enhances the sensitivity of CRC cells to the standard of care FOLFOX, and significantly potentiates the anticancer effect of FOLFOX in the murine CRC xenograft models (Figure 8; Supplementary Figure S2).	('4-AAQB', 'Var', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('4-AAQB', 'Chemical', 'MESH:C555021', (49, 55))	('FOLFOX', 'Chemical', '-', (181, 187))	('sensitivity', 'MPA', (69, 80))	('murine', 'Species', '10090', (195, 201))	('FOLFOX', 'Chemical', '-', (118, 124))	('potentiates', 'PosReg', (144, 155))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('enhances', 'PosReg', (56, 64))
50003	30103475	This present study provides evidence that 4-AAQB alone or by synergistically interacting with FOLFOX, exhibits an enhanced ability to kill CRC cells, inducing marked apoptosis via an epigenetically modulated pathway.	('inducing', 'Reg', (150, 158))	('4-AAQB', 'Chemical', 'MESH:C555021', (42, 48))	('FOLFOX', 'Chemical', '-', (94, 100))	('enhanced', 'PosReg', (114, 122))	('4-AAQB', 'Var', (42, 48))	('apoptosis', 'CPA', (166, 175))	('epigenetically modulated pathway', 'Pathway', (183, 215))
50009	30103475	We propose that SOD2-enrichment in the CRC cells accentuates mitochondrial biogenesis, activates the intracellular anti-oxidative machinery, alleviates oxidative stress, and enhances the maintenance of the CSC-like phenotype, as well as acquisition of resistance to chemotherapeutic agents, by functional suppression of hsa-miR-324-5p expression and/or activity; however, exposure to 4-AAQB induces the re-expression of hsa-miR-324-5p, attenuates SOD2 expression, and sensitizes the CSC-like SP cells in CRC to FOLFOX therapy.	('SOD', 'Gene', '6647;6648;6649', (16, 19))	('SOD2', 'molecular_function', 'GO:0004784', ('16', '20'))	('SOD2', 'molecular_function', 'GO:0004784', ('447', '451'))	('4-AAQB', 'Var', (384, 390))	('hsa-miR-324-5p', 'Protein', (420, 434))	('FOLFOX', 'Chemical', '-', (511, 517))	('mitochondrial biogenesis', 'MPA', (61, 85))	('SOD', 'Gene', (447, 450))	('SOD', 'Gene', '6647;6648;6649', (447, 450))	('enhances', 'PosReg', (174, 182))	('SOD', 'Gene', (16, 19))	('accentuates', 'PosReg', (49, 60))	('expression', 'MPA', (452, 462))	('re-expression', 'MPA', (403, 416))	('sensitizes', 'Reg', (468, 478))	('intracellular anti-oxidative machinery', 'MPA', (101, 139))	('intracellular', 'cellular_component', 'GO:0005622', ('101', '114'))	('oxidative stress', 'MPA', (152, 168))	('SP', 'Chemical', '-', (492, 494))	('attenuates', 'NegReg', (436, 446))	('oxidative stress', 'Phenotype', 'HP:0025464', (152, 168))	('alleviates', 'NegReg', (141, 151))	('activates', 'PosReg', (87, 96))	('4-AAQB', 'Chemical', 'MESH:C555021', (384, 390))
50010	30103475	Thus, we propound a novel perspective on the putative roles of 4-AAQB as a hsa-miR-324-mediated CSC-targeting small molecule inhibitor of SOD2 in CRC, in vitro and in vivo.	('4-AAQB', 'Var', (63, 69))	('SOD', 'Gene', (138, 141))	('4-AAQB', 'Chemical', 'MESH:C555021', (63, 69))	('hsa-miR-324', 'Gene', '442898', (75, 86))	('hsa-miR-324', 'Gene', (75, 86))	('SOD', 'Gene', '6647;6648;6649', (138, 141))
50029	30103475	Blots were blocked for 1 h with 5% skimmed milk in Tris Buffered Saline with Tween 20 (TBST), incubated overnight at 4  C with specific primary antibodies against SOD2 (1:1000), E-cadherin (1:2000), N-cadherin (1:2000), vimentin (1:1000), c-Myc (1:1000), BAX (1:1000), BCL-xL (1:1000), and beta-actin (1:500).	('BAX', 'Gene', '581', (255, 258))	('BAX', 'Gene', (255, 258))	('c-Myc', 'Gene', (239, 244))	('Tween 20', 'Chemical', 'MESH:D011136', (77, 85))	('c-Myc', 'Gene', '4609', (239, 244))	('beta-actin', 'Gene', (290, 300))	('BCL-xL', 'Gene', '598', (269, 275))	('E-cadherin', 'Gene', (178, 188))	('E-cadherin', 'Gene', '999', (178, 188))	('vimentin', 'Protein', (220, 228))	('SOD', 'Gene', '6647;6648;6649', (163, 166))	('1:2000', 'Var', (211, 217))	('N-cadherin', 'Gene', (199, 209))	('BCL-xL', 'Gene', (269, 275))	('N-cadherin', 'Gene', '1000', (199, 209))	('TBST', 'Chemical', '-', (87, 91))	('SOD', 'Gene', (163, 166))	('beta-actin', 'Gene', '728378', (290, 300))	('Tris Buffered Saline', 'Chemical', '-', (51, 71))	('1:2000', 'Var', (190, 196))
50062	30103475	In conclusion, this present study demonstrates that 4-AAQB inhibits the aberrant expression of SOD2 through the re-expression of hsa-miR-324-5p, the negative modulation of pluripotency transcription factors, the augmentation of the BAX/BCL-xL ratios, and the reprogramming of malignant colorectal cancer cells from the aggressive mesenchymal phenotype to a relatively benign epithelial phenotype, subsequently enhancing the sensitivity of the cancer cells to conventional chemotherapy and facilitating better prognosis, as depicted in our Schematic abstract.	('augmentation', 'PosReg', (212, 224))	('SOD', 'Gene', '6647;6648;6649', (95, 98))	('BAX', 'Gene', '581', (232, 235))	('negative', 'NegReg', (149, 157))	('sensitivity', 'MPA', (424, 435))	('aberrant', 'MPA', (72, 80))	('expression', 'MPA', (81, 91))	('colorectal cancer', 'Disease', 'MESH:D015179', (286, 303))	('pluripotency', 'Disease', (172, 184))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('SOD', 'Gene', (95, 98))	('cancer', 'Disease', (443, 449))	('hsa-miR-324-5p', 'Gene', (129, 143))	('colorectal cancer', 'Disease', (286, 303))	('BCL-xL', 'Gene', '598', (236, 242))	('enhancing', 'PosReg', (410, 419))	('cancer', 'Phenotype', 'HP:0002664', (443, 449))	('inhibits', 'NegReg', (59, 67))	('pluripotency', 'Disease', 'None', (172, 184))	('BCL-xL', 'Gene', (236, 242))	('cancer', 'Disease', (297, 303))	('4-AAQB', 'Chemical', 'MESH:C555021', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (443, 449))	('reprogramming', 'CPA', (259, 272))	('colorectal cancer', 'Phenotype', 'HP:0003003', (286, 303))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('BAX', 'Gene', (232, 235))	('4-AAQB', 'Var', (52, 58))
50073	28966729	We previously reported that ATO is cytotoxic and causes DNA damage in HT-29 human colorectal adenocarcinoma cells.	('colorectal adenocarcinoma', 'Disease', (82, 107))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (82, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('human', 'Species', '9606', (76, 81))	('ATO', 'Chemical', 'MESH:D000077237', (28, 31))	('ATO', 'Var', (28, 31))	('causes', 'Reg', (49, 55))	('HT-29', 'CellLine', 'CVCL:0320', (70, 75))	('DNA damage', 'MPA', (56, 66))
50085	28966729	Multiple risk factors including smoking, alcohol consumption, dietary factors, family history, lifestyle, ethnicity, and genetic alterations have been associated with colon cancer.	('genetic alterations', 'Var', (121, 140))	('colon cancer', 'Phenotype', 'HP:0003003', (167, 179))	('associated', 'Reg', (151, 161))	('colon cancer', 'Disease', 'MESH:D015179', (167, 179))	('alcohol', 'Chemical', 'MESH:D000438', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('colon cancer', 'Disease', (167, 179))
50106	28966729	Published research has reported that ATO influences multiple pathways, which may result in the induction of apoptosis, genotoxicity, enhanced cell proliferation, promotion of differentiation, oxidative stress and activation or inhibition of a variety of cellular signal transduction pathways.	('differentiation', 'CPA', (175, 190))	('signal transduction', 'biological_process', 'GO:0007165', ('263', '282'))	('promotion', 'PosReg', (162, 171))	('oxidative', 'MPA', (192, 201))	('toxicity', 'Disease', (123, 131))	('ATO', 'Chemical', 'MESH:D000077237', (37, 40))	('oxidative stress', 'Phenotype', 'HP:0025464', (192, 208))	('cellular signal transduction pathways', 'Pathway', (254, 291))	('ATO', 'Var', (37, 40))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('95', '117'))	('cell proliferation', 'biological_process', 'GO:0008283', ('142', '160'))	('cell proliferation', 'CPA', (142, 160))	('toxicity', 'Disease', 'MESH:D064420', (123, 131))	('apoptosis', 'CPA', (108, 117))	('inhibition', 'NegReg', (227, 237))	('enhanced', 'PosReg', (133, 141))
50115	28966729	Recent studies conducted in our laboratory have demonstrated that ATO is cytotoxic and genotoxic as revealed by the significant increase in DNA damage in HT-29 cells.	('increase', 'PosReg', (128, 136))	('ATO', 'Chemical', 'MESH:D000077237', (66, 69))	('HT-29 cells', 'CellLine', 'CVCL:0320', (154, 165))	('DNA damage', 'MPA', (140, 150))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('ATO', 'Var', (66, 69))
50182	28966729	Published studies have shown that arsenic induces the generation of reactive oxygen species.	('arsenic', 'Chemical', 'MESH:D001151', (34, 41))	('generation of reactive oxygen species', 'MPA', (54, 91))	('arsenic', 'Var', (34, 41))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (68, 91))
50188	28966729	Being highly reactive by nature, ROS can directly or indirectly modulate the functions of many enzymes through a multitude of signaling cascades which can influence cell survival or death.	('cell survival', 'CPA', (165, 178))	('OS', 'Phenotype', 'HP:0025464', (34, 36))	('modulate', 'Reg', (64, 72))	('enzymes', 'Enzyme', (95, 102))	('functions', 'MPA', (77, 86))	('ROS', 'Chemical', 'MESH:D017382', (33, 36))	('influence', 'Reg', (155, 164))	('ROS', 'Var', (33, 36))
50202	28966729	In the present study, we demonstrated that a dose-dependent effect of ATO in the induction of sub G1 phase was observed and clearly demonstrated that ATO induced apoptosis in HT-29 cells.	('sub G1 phase', 'CPA', (94, 106))	('ATO', 'Chemical', 'MESH:D000077237', (150, 153))	('ATO', 'Var', (150, 153))	('apoptosis', 'CPA', (162, 171))	('ATO', 'Chemical', 'MESH:D000077237', (70, 73))	('HT-29 cells', 'CellLine', 'CVCL:0320', (175, 186))
50249	28931402	Moreover, BsAb not only offers an effective linkage between therapeutics (e.g., immune effector cells, radionuclides) and targets (e.g., tumor cells) but also simultaneously blocks two different oncogenic mediators such as anti-epidermal growth factor receptor (EGFR) x anti-HER2 and anti- EGFR x anti-c-MET.	('EGFR', 'Gene', '1956', (262, 266))	('BsAb', 'Chemical', 'MESH:D018033', (10, 14))	('tumor', 'Disease', (137, 142))	('ide', 'Gene', (230, 233))	('ide', 'Gene', '3416', (112, 115))	('blocks', 'NegReg', (174, 180))	('anti-', 'Var', (284, 289))	('EGFR', 'Gene', (262, 266))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('ide', 'Gene', '3416', (230, 233))	('EGFR', 'Gene', '1956', (290, 294))	('linkage', 'Interaction', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('EGFR', 'Gene', (290, 294))	('ide', 'Gene', (112, 115))
50252	28931402	The IgG-like molecules containing Fc domain retain Fc-mediated effector functions such as antibody-dependent cell mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular phagocytosis (ADCP), mainly including quandroma, knobs-into-holes, scFv-IgG, and (IgG)2.	('quandroma', 'Disease', 'None', (255, 264))	('antibody-dependent cellular phagocytosis', 'CPA', (189, 229))	('knobs-into-holes', 'Disease', (266, 282))	('cytotoxicity', 'Disease', (123, 135))	('Fc domain', 'Var', (34, 43))	('cytotoxicity', 'Disease', (165, 177))	('cytotoxicity', 'Disease', 'MESH:D064420', (123, 135))	('quandroma', 'Disease', (255, 264))	('cytotoxicity', 'Disease', 'MESH:D064420', (165, 177))
50275	28931402	A study demonstrated that high expression of EpCAM was a poor prognostic indicator of breast cancer with node-positive.	('rat', 'Species', '10116', (15, 18))	('high', 'Var', (26, 30))	('EpCAM', 'Protein', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))
50286	28931402	In their studies, opsonization with catumaxomab caused the activation of PBMCs and destroyed EpCAM-positive tumor cells.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('EpCAM-positive', 'MPA', (93, 107))	('catumaxomab', 'Chemical', 'MESH:C522419', (36, 47))	('tumor', 'Disease', (108, 113))	('PBMCs', 'Protein', (73, 78))	('catumaxomab', 'Var', (36, 47))	('destroyed', 'NegReg', (83, 92))	('activation', 'PosReg', (59, 69))
50317	28931402	Via MT110, T cells could potently recognize and lyse target tumor cells.	('MT110', 'Chemical', 'MESH:C000607229', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('MT110', 'Var', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('lyse', 'CPA', (48, 52))
50323	28931402	Their results indicated that 1H8/CD3 effectively eradicated CD133+ EpCAM+ HCC CSCs and EpCAM+ HCC cells in vitro and in vivo.	('HCC', 'Phenotype', 'HP:0001402', (94, 97))	('CD133+', 'Var', (60, 66))	('eradicated', 'NegReg', (49, 59))	('HCC', 'Phenotype', 'HP:0001402', (74, 77))	('1H8', 'Chemical', '-', (29, 32))
50325	28931402	Another study showed that MT110 eliminated colorectal cancer cells and stem cells.	('MT110', 'Chemical', 'MESH:C000607229', (26, 31))	('colorectal cancer', 'Disease', (43, 60))	('MT110', 'Var', (26, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (43, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('eliminated', 'NegReg', (32, 42))
50326	28931402	Some studies also demonstrated that MT110 could eradicate the primary cancer cells and the CSCs of pancreatic cancer in vivo and in vitro.	('pancreatic cancer', 'Disease', (99, 116))	('cancer', 'Disease', (110, 116))	('MT110', 'Chemical', 'MESH:C000607229', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('MT110', 'Var', (36, 41))	('CSCs', 'CPA', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (99, 116))	('eradicate', 'NegReg', (48, 57))	('rat', 'Species', '10116', (25, 28))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('pancreatic cancer', 'Disease', 'MESH:D010190', (99, 116))
50335	28931402	Besides, a novel recombinant antibody E3Bi enhanced the specific cytotoxicity of activated T cell (ATC) in tumor cell lines with high EpCAM expression and significantly inhibited tumor growth in mice model.	('enhanced', 'PosReg', (43, 51))	('ide', 'Gene', (3, 6))	('mice', 'Species', '10090', (195, 199))	('cytotoxicity', 'Disease', 'MESH:D064420', (65, 77))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('E3Bi', 'Var', (38, 42))	('ide', 'Gene', '3416', (3, 6))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('cytotoxicity', 'Disease', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('inhibited', 'NegReg', (169, 178))	('tumor', 'Disease', (179, 184))
50344	28931402	However, there are studies demonstrated that the therapeutic outcome of anti-EGFR mAbs is not well satisfying in patients with KRAS and BRAF genes mutated CRC.	('CRC', 'Phenotype', 'HP:0003003', (155, 158))	('CRC', 'Gene', (155, 158))	('BRAF', 'Gene', '673', (136, 140))	('patients', 'Species', '9606', (113, 121))	('BRAF', 'Gene', (136, 140))	('KRAS', 'Gene', (127, 131))	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'Gene', (77, 81))	('rat', 'Species', '10116', (34, 37))	('EGFR', 'molecular_function', 'GO:0005006', ('77', '81'))	('mutated', 'Var', (147, 154))
50345	28931402	T cell engaged BiTE antibodies using the binding domains of cetuximab, and panitumumab remained potent antitumor activity in KRAS and BRAF mutation of CRC cell lines and in xenograft models.	('mutation', 'Var', (139, 147))	('tumor', 'Disease', (107, 112))	('CRC', 'Phenotype', 'HP:0003003', (151, 154))	('panitumumab', 'Chemical', 'MESH:D000077544', (75, 86))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('BRAF', 'Gene', '673', (134, 138))	('BRAF', 'Gene', (134, 138))	('cell engaged BiTE', 'Phenotype', 'HP:0020122', (2, 19))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cetuximab', 'Chemical', 'MESH:D000068818', (60, 69))	('KRAS', 'Disease', (125, 129))
50348	28931402	A group examined the antitumor activity of the ATC armed with chemically heteroconjugated anti-CD3 x anti-HER2 (HER2Bi) and/or anti-CD3 x anti-EGFR (EGFRBi).	('EGFR', 'Gene', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('EGFR', 'Gene', '1956', (149, 153))	('anti-CD3', 'Var', (90, 98))	('EGFR', 'Gene', (149, 153))	('EGFR', 'Gene', '1956', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
50389	28931402	The phosphorylation of EGFR and HER3 activated the downstream Ras/MAPK and (PI3K)/AKT signaling pathways which contributed to the cell growth and proliferation.	('activated', 'PosReg', (37, 46))	('rat', 'Species', '10116', (153, 156))	('HER3', 'Protein', (32, 36))	('contributed', 'Reg', (111, 122))	('cell growth', 'CPA', (130, 141))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (23, 27))	('phosphorylation', 'Var', (4, 19))
50392	28931402	The study results showed that MEHD7945A not only potently inhibited receptor phosphorylation of EGFR and HER3 but also enhanced gemcitabine-mediated cytotoxicity in vitro and in vivo.	('MEHD7945A', 'Var', (30, 39))	('cytotoxicity', 'Disease', (149, 161))	('EGFR', 'Gene', (96, 100))	('HER3', 'Protein', (105, 109))	('phosphorylation', 'biological_process', 'GO:0016310', ('77', '92'))	('gemcitabine', 'Chemical', 'MESH:C056507', (128, 139))	('cytotoxicity', 'Disease', 'MESH:D064420', (149, 161))	('EGFR', 'molecular_function', 'GO:0005006', ('96', '100'))	('inhibited', 'NegReg', (58, 67))	('receptor phosphorylation', 'MPA', (68, 92))	('enhanced', 'PosReg', (119, 127))	('EGFR', 'Gene', '1956', (96, 100))
50393	28931402	Besides, the dermatologic toxicity of MEHD7945A was significantly less than monospecific antibody in xenograft models.	('MEHD7945A', 'Var', (38, 47))	('ide', 'Gene', (3, 6))	('toxicity', 'Disease', 'MESH:D064420', (26, 34))	('toxicity', 'Disease', (26, 34))	('ide', 'Gene', '3416', (3, 6))	('less', 'NegReg', (66, 70))
50394	28931402	For instance, EGFR x c-MET bispecific antibody JNJ-61186372 enhanced the killing of EGFR mutant lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('EGFR', 'Gene', '1956', (14, 18))	('antibody', 'cellular_component', 'GO:0019815', ('38', '46'))	('EGFR', 'Gene', (14, 18))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('antibody', 'cellular_component', 'GO:0019814', ('38', '46'))	('EGFR', 'molecular_function', 'GO:0005006', ('14', '18'))	('lung cancer', 'Disease', (96, 107))	('EGFR', 'Gene', '1956', (84, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('antibody', 'molecular_function', 'GO:0003823', ('38', '46'))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutant', 'Var', (89, 95))	('EGFR', 'Gene', (84, 88))	('killing', 'CPA', (73, 80))	('enhanced', 'PosReg', (60, 68))	('antibody', 'cellular_component', 'GO:0042571', ('38', '46'))
50412	28931402	The CEA splice variant neither affected the binding of MEDI-565 and full-length CEA nor inhibited MEDI-565-induced T-cell activation and cytotoxicity.	('inhibited', 'NegReg', (88, 97))	('MEDI-565', 'Chemical', '-', (98, 106))	('T-cell activation', 'biological_process', 'GO:0042110', ('115', '132'))	('cytotoxicity', 'Disease', (137, 149))	('variant', 'Var', (15, 22))	('MEDI-565', 'Chemical', '-', (55, 63))	('cytotoxicity', 'Disease', 'MESH:D064420', (137, 149))	('binding', 'molecular_function', 'GO:0005488', ('44', '51'))
50434	28931402	Compared with single-chain tandem scFvs (e.g., BiTE), two-chain diabodies induced T cell-activated proliferation in a target cell-dependent manner, which could reduce the toxicity to normal tissues.	('two-chain diabodies', 'Var', (54, 73))	('toxicity', 'Disease', 'MESH:D064420', (171, 179))	('toxicity', 'Disease', (171, 179))	('T cell-activated proliferation', 'CPA', (82, 112))	('rat', 'Species', '10116', (106, 109))
50448	28931402	The anti-CEA/anti-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) bispecific antibody exhibited low tumor targeting and rapid blood clearance in a xenograft mouse model, but the specific tumor uptake and low normal tissue accumulation of the BsAb still improved the efficacy of RIT.	('uptake', 'biological_process', 'GO:0098657', ('215', '221'))	('anti-CEA/anti-1', 'Var', (4, 19))	('tumor', 'Disease', (122, 127))	('uptake', 'biological_process', 'GO:0098739', ('215', '221'))	('antibody', 'cellular_component', 'GO:0019814', ('99', '107'))	('tumor', 'Disease', (209, 214))	('BsAb', 'Chemical', 'MESH:D018033', (264, 268))	('efficacy', 'MPA', (288, 296))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('DOTA', 'Chemical', 'MESH:C071349', (82, 86))	('mouse', 'Species', '10090', (179, 184))	('antibody', 'molecular_function', 'GO:0003823', ('99', '107'))	('blood clearance', 'CPA', (148, 163))	('improved', 'PosReg', (275, 283))	('low tumor', 'Disease', 'MESH:D009800', (118, 127))	('antibody', 'cellular_component', 'GO:0042571', ('99', '107'))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('low tumor', 'Disease', (118, 127))	('1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid', 'Chemical', 'MESH:C071349', (18, 80))	('antibody', 'cellular_component', 'GO:0019815', ('99', '107'))
50465	28931402	In another phase I/II trial (NCT01221675) by Centre Rene Gauducheau, nine patients with CEA-expressing advanced lung cancer were treated with TF2 and the IMP288 bivalent HSG peptide.	('ide', 'Gene', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('patients', 'Species', '9606', (74, 82))	('ide', 'Gene', '3416', (178, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('Ga', 'Chemical', 'MESH:D005708', (57, 59))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('CEA-', 'Gene', (88, 92))	('IMP288 bivalent', 'Var', (154, 169))	('CEA-', 'Gene', '1048', (88, 92))	('HSG', 'Chemical', '-', (170, 173))
50472	28931402	Furthermore, the BsAb pre-targeting showed rapid clearance from normal tissues and clear visualization of tumor within 1-2 h. TF2 pre-targeting CEA on the surface of tumor cells followed by the addition of Ga-labeled hapten could be obviously sensitive in the visualization of CEA.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('Ga', 'Chemical', 'MESH:D005708', (206, 208))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('pre-targeting', 'Var', (130, 143))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('BsAb', 'Chemical', 'MESH:D018033', (17, 21))	('TF2', 'Gene', (126, 129))	('tumor', 'Disease', (106, 111))
50485	28931402	BAY2010112 (AMG212, MT112), as a PSMA/CD3-bispecific BiTE antibody, bound to PSMA which was expressed in prostate cancer cell lines and PSMA cDNA transfected cell lines, and mediated T cells to eliminate target cells in vitro.	('bound', 'Interaction', (68, 73))	('prostate cancer', 'Disease', (105, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('prostate cancer', 'Disease', 'MESH:D011471', (105, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))	('BAY2010112', 'Var', (0, 10))	('BAY2010112', 'Chemical', '-', (0, 10))
50489	28931402	administration, subcutaneous (s.c.) injection of BAY2010112 significantly inhibited tumor formation and induced tumor regression in the subcutaneous xenograft immunodeficient NOD/SCID mice.	('BAY2010112', 'Var', (49, 59))	('inhibited', 'NegReg', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('rat', 'Species', '10116', (8, 11))	('BAY2010112', 'Chemical', '-', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('immunodeficient NOD', 'Disease', 'MESH:D020191', (159, 178))	('SCID', 'Disease', (179, 183))	('formation', 'biological_process', 'GO:0009058', ('90', '99'))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (84, 89))	('SCID', 'Disease', 'MESH:D053632', (179, 183))	('mice', 'Species', '10090', (184, 188))	('immunodeficient NOD', 'Disease', (159, 178))	('tumor', 'Disease', (112, 117))
50490	28931402	In addition, the bioavailability of BAY2010112 was approximately 18% after s.c. administration in mice.	('bioavailability', 'MPA', (17, 32))	('rat', 'Species', '10116', (88, 91))	('BAY2010112', 'Var', (36, 46))	('BAY2010112', 'Chemical', '-', (36, 46))	('mice', 'Species', '10090', (98, 102))
50492	28931402	Patients with castration resistant prostate cancer will be recruited and treated with different dosages of BAY2010112.	('BAY2010112', 'Var', (107, 117))	('rat', 'Species', '10116', (18, 21))	('BAY2010112', 'Chemical', '-', (107, 117))	('prostate cancer', 'Disease', 'MESH:D011471', (35, 50))	('prostate cancer', 'Phenotype', 'HP:0012125', (35, 50))	('Patients', 'Species', '9606', (0, 8))	('prostate cancer', 'Disease', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
50495	28931402	MOR209/ES414 is a novel humanized BsAb which is designed to treat metastatic castration-resistant prostate cancer (mCRPC) by redirecting T cell cytotoxicity against prostate cancer cells expressing PSMA.	('BsAb', 'Chemical', 'MESH:D018033', (34, 38))	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('human', 'Species', '9606', (24, 29))	('ES414', 'Chemical', '-', (7, 12))	('prostate cancer', 'Disease', 'MESH:D011471', (165, 180))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('rat', 'Species', '10116', (81, 84))	('prostate cancer', 'Phenotype', 'HP:0012125', (165, 180))	('MOR209/ES414', 'Var', (0, 12))	('prostate cancer', 'Disease', (98, 113))	('cytotoxicity', 'Disease', (144, 156))	('prostate cancer', 'Disease', (165, 180))	('MOR209', 'Chemical', '-', (0, 6))	('prostate cancer', 'Disease', 'MESH:D011471', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('redirecting', 'PosReg', (125, 136))	('cytotoxicity', 'Disease', 'MESH:D064420', (144, 156))
50496	28931402	MOR209/ES414 induced T cell activation and proliferation, and lysed tumor cells in vitro.	('tumor', 'Disease', (68, 73))	('T cell activation', 'CPA', (21, 38))	('ES414', 'Chemical', '-', (7, 12))	('T cell activation', 'biological_process', 'GO:0042110', ('21', '38'))	('rat', 'Species', '10116', (50, 53))	('MOR209/ES414', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('MOR209', 'Chemical', '-', (0, 6))	('proliferation', 'CPA', (43, 56))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
50497	28931402	In murine xenograft models, MOR209/ES414 also showed significant inhibitory effect on tumor and prolonged the survival time.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('ES414', 'Chemical', '-', (35, 40))	('prolonged', 'PosReg', (96, 105))	('MOR209', 'Chemical', '-', (28, 34))	('inhibitory effect', 'NegReg', (65, 82))	('MOR209/ES414', 'Var', (28, 40))	('murine', 'Species', '10090', (3, 9))	('survival time', 'CPA', (110, 123))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
50498	28931402	The half-life period of MOR209/ES414 was 4 days in the peripheral blood of NOD/SCIDgamma (NSG) mice.	('mice', 'Species', '10090', (95, 99))	('ES414', 'Chemical', '-', (31, 36))	('MOR209', 'Chemical', '-', (24, 30))	('MOR209/ES414', 'Var', (24, 36))	('SCID', 'Disease', 'MESH:D053632', (79, 83))	('SCID', 'Disease', (79, 83))
50503	28931402	After activation, CD4+ and CD8+ T cells expanded and killed prostate cancer cells mainly through the perforin-granzyme-based pathway, while the FasL pathway acted as a supplementary part.	('prostate cancer', 'Phenotype', 'HP:0012125', (60, 75))	('prostate cancer', 'Disease', (60, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('killed', 'CPA', (53, 59))	('CD4+', 'Var', (18, 22))	('prostate cancer', 'Disease', 'MESH:D011471', (60, 75))	('perforin-granzyme-based pathway', 'Pathway', (101, 132))	('CD8+ T', 'Var', (27, 33))
50539	27902460	Lymph node metastasis was found in 34 (15.6%) patients in this cohort (NET G1 in 1 patient, NET G2 in 3 patients, NEC G3 in 23 patients, and MANEC in 7 patients).	('patient', 'Species', '9606', (46, 53))	('patients', 'Species', '9606', (46, 54))	('NET', 'Phenotype', 'HP:0100634', (71, 74))	('patient', 'Species', '9606', (127, 134))	('NET', 'Phenotype', 'HP:0100634', (92, 95))	('found', 'Reg', (26, 31))	('patients', 'Species', '9606', (127, 135))	('patient', 'Species', '9606', (104, 111))	('patients', 'Species', '9606', (152, 160))	('NET G2', 'Var', (92, 98))	('patient', 'Species', '9606', (83, 90))	('patient', 'Species', '9606', (152, 159))	('patients', 'Species', '9606', (104, 112))	('Lymph node metastasis', 'CPA', (0, 21))
50568	27902460	In addition, 9.2% of lymph node metastases were found in tumors smaller than 10 mm and that lymph node metastases were more frequent in NET G2 than in NET G1.	('metastases', 'Disease', 'MESH:D009362', (103, 113))	('metastases', 'Disease', (32, 42))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('NET', 'Phenotype', 'HP:0100634', (151, 154))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('NET', 'Phenotype', 'HP:0100634', (136, 139))	('metastases', 'Disease', 'MESH:D009362', (32, 42))	('tumors', 'Disease', (57, 63))	('NET G2', 'Var', (136, 142))	('metastases', 'Disease', (103, 113))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
50603	28030802	Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies.	('translocation', 'Var', (134, 147))	('gene amplification', 'Var', (89, 107))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('oncogenesis', 'biological_process', 'GO:0007048', ('73', '84'))	('activating', 'MPA', (109, 119))
50604	28030802	With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (55, 58))	('tied', 'Reg', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('FGFR', 'molecular_function', 'GO:0005007', ('55', '59'))	('cell proliferation', 'biological_process', 'GO:0008283', ('117', '135'))	('FGF', 'Gene', (55, 58))	('aberrations', 'Var', (60, 71))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
50605	28030802	Inhibition of FGFR signaling appears promising in preclinical studies, suggesting a pathway of clinical interest in the development of targeted therapy.	('FGF', 'Gene', (14, 17))	('Inhibition', 'Var', (0, 10))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (14, 17))
50608	28030802	As we progress from the first generation of non-selective drugs to the second generation of selective FGFR inhibitors, it is clear that FGFR aberrations do not behave uniformly across cancer types; thus, a deeper understanding of biomarker strategies is undoubtedly warranted.	('cancer', 'Disease', (184, 190))	('FGFR', 'molecular_function', 'GO:0005007', ('102', '106'))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('FGFR', 'molecular_function', 'GO:0005007', ('136', '140'))	('FGF', 'Gene', (102, 105))	('FGF', 'Gene', (136, 139))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (102, 105))	('inhibitors', 'Var', (107, 117))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (136, 139))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
50611	28030802	We will also discuss qualities that may be desirable in future generations of FGFR inhibitors, with the hope that overcoming these current barriers will expedite the availability of this novel class of medications.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (78, 81))	('FGF', 'Gene', (78, 81))	('inhibitors', 'Var', (83, 93))
50613	28030802	Many prior studies indicate that alterations in FGFR signaling are associated with a broad range of congenital craniofacial developmental disorders.	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('congenital craniofacial developmental disorders', 'Disease', 'MESH:D019465', (100, 147))	('congenital craniofacial developmental disorders', 'Disease', (100, 147))	('alterations', 'Var', (33, 44))	('associated', 'Reg', (67, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('48', '52'))	('FGF', 'Gene', (48, 51))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (48, 51))
50614	28030802	Relatively recently, we have come to understand that somatic mutations of FGFR also have a role in oncologic evolution which makes this pathway of interest when exploring the realm of cancer-directed therapy.	('cancer', 'Disease', (184, 190))	('FGF', 'Gene', (74, 77))	('oncologic evolution', 'Disease', (99, 118))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutations', 'Var', (61, 70))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (74, 77))	('role', 'Reg', (91, 95))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
50617	28030802	We ultimately need to re-evaluate how we can better develop strategies to bring direct FGFR inhibitors into the clinical setting.	('FGF', 'Gene', (87, 90))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (87, 90))	('inhibitors', 'Var', (92, 102))
50621	28030802	The members differ from one another in their ligand affinities and tissue distribution with variations in splicing of FGFR1-3 accounting for some additional diversity.	('FGFR1', 'Gene', '2260', (118, 123))	('FGFR', 'molecular_function', 'GO:0005007', ('118', '122'))	('FGFR1', 'Gene', (118, 123))	('splicing', 'biological_process', 'GO:0045292', ('106', '114'))	('ligand', 'molecular_function', 'GO:0005488', ('45', '51'))	('ligand affinities', 'Interaction', (45, 62))	('variations', 'Var', (92, 102))
50624	28030802	Upon ligand binding, FGFRs dimerize and trigger a cascade of downstream signaling pathways, including the mitogen activated protein kinase (MAPK), signal transducer and activator of transcription (STAT), the phosphoinositide-3-kinase (PI3K)/Akt pathways, and DAG-PKC and IP3-Ca2+ signaling branches via PLCgamma activation.	('dimerize', 'Var', (27, 35))	('MAPK', 'Gene', (140, 144))	('ligand', 'molecular_function', 'GO:0005488', ('5', '11'))	('PLCgamma', 'Enzyme', (303, 311))	('binding', 'Interaction', (12, 19))	('MAPK', 'Gene', '5594', (140, 144))	('binding', 'molecular_function', 'GO:0005488', ('12', '19'))	('FGF', 'Gene', (21, 24))	('PKC', 'molecular_function', 'GO:0004697', ('263', '266'))	('activation', 'PosReg', (312, 322))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('Akt', 'Gene', (241, 244))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))	('Akt', 'Gene', '207', (241, 244))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (21, 24))	('mitogen activated protein kinase', 'Pathway', (106, 138))	('IP3', 'Chemical', 'MESH:D015544', (271, 274))	('Ca2+', 'Chemical', 'MESH:D000069285', (275, 279))	('trigger', 'Reg', (40, 47))	('signaling', 'biological_process', 'GO:0023052', ('280', '289'))	('PI3K', 'molecular_function', 'GO:0016303', ('235', '239'))	('MAPK', 'molecular_function', 'GO:0004707', ('140', '144'))	('transcription', 'biological_process', 'GO:0006351', ('182', '195'))
50626	28030802	There are several proposed mechanisms for FGFR related oncogenesis including: (i) activating or "driver" mutations resulting in cell growth and survival; (ii) neo-angiogenesis; and (iii) acquired resistance to other cancer therapy.	('cell growth', 'CPA', (128, 139))	('oncogenesis', 'Disease', (55, 66))	('activating', 'PosReg', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('neo-angiogenesis', 'CPA', (159, 175))	('mutations', 'Var', (105, 114))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('FGF', 'Gene', (42, 45))	('acquired resistance', 'CPA', (187, 206))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (42, 45))
50628	28030802	Receptor overexpression can be a result of gene amplification or changes in post-transcriptional processing; point mutations may result in constitutive receptor activation or decreased sensitivity to ligand binding; translocations can produce fusion proteins with constitutive activity; and isoform switching and alternative splicing can reduce specificity to FGFs.	('point mutations', 'Var', (109, 124))	('sensitivity to ligand binding', 'MPA', (185, 214))	('result', 'Reg', (129, 135))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (360, 363))	('specificity', 'MPA', (345, 356))	('translocations', 'Var', (216, 230))	('post-transcriptional processing', 'MPA', (76, 107))	('alternative splicing', 'Var', (313, 333))	('decreased', 'NegReg', (175, 184))	('ligand', 'molecular_function', 'GO:0005488', ('200', '206'))	('activation', 'PosReg', (161, 171))	('reduce', 'NegReg', (338, 344))	('overexpression', 'PosReg', (9, 23))	('fusion proteins', 'Protein', (243, 258))	('constitutive', 'Protein', (139, 151))	('splicing', 'biological_process', 'GO:0045292', ('325', '333'))	('changes', 'Reg', (65, 72))	('FGF', 'Gene', (360, 363))	('binding', 'molecular_function', 'GO:0005488', ('207', '214'))
50630	28030802	Using next generation sequencing (NGS) to detect FGFR anomalies, a comprehensive review of a cohort of nearly 5,000 cancer patients found aberrations in 7.1% of malignancies.	('anomalies', 'Disease', 'MESH:D000014', (54, 63))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (49, 52))	('cancer', 'Disease', (116, 122))	('aberrations', 'Var', (138, 149))	('malignancies', 'Disease', (161, 173))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('patients', 'Species', '9606', (123, 131))	('anomalies', 'Disease', (54, 63))	('FGF', 'Gene', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('malignancies', 'Disease', 'MESH:D009369', (161, 173))
50632	28030802	Amplification of the chromosomal region 8p11-12, the genomic location of FGFR1, has been detected in 10% of breast cancers (predominantly in estrogen receptor (ER) positive cancers) and this finding has been related to higher FGFR1 expression levels correlating to worse prognosis.	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('FGFR1', 'Gene', '2260', (226, 231))	('estrogen receptor', 'Gene', (141, 158))	('ER', 'Gene', '2099', (160, 162))	('breast cancers', 'Disease', 'MESH:D001943', (108, 122))	('breast cancers', 'Disease', (108, 122))	('expression', 'MPA', (232, 242))	('FGFR1', 'Gene', (73, 78))	('breast cancers', 'Phenotype', 'HP:0003002', (108, 122))	('FGFR', 'molecular_function', 'GO:0005007', ('226', '230'))	('higher', 'PosReg', (219, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Disease', (173, 180))	('FGFR1', 'Gene', (226, 231))	('FGFR', 'molecular_function', 'GO:0005007', ('73', '77'))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('estrogen receptor', 'Gene', '2099', (141, 158))	('detected', 'Reg', (89, 97))	('Amplification', 'Var', (0, 13))	('FGFR1', 'Gene', '2260', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('chromosomal region', 'cellular_component', 'GO:0098687', ('21', '39'))
50633	28030802	Recently, it has also been reported that FGFR1 is amplified in as many as 19% of squamous non-small cell lung cancers (SqCLC).	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('lung cancers', 'Phenotype', 'HP:0100526', (105, 117))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (94, 117))	('FGFR', 'molecular_function', 'GO:0005007', ('41', '45'))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (94, 116))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (90, 117))	('squamous non-small cell lung cancers', 'Disease', (81, 117))	('squamous non-small cell lung cancers', 'Disease', 'MESH:D002289', (81, 117))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (90, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('amplified', 'Var', (50, 59))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('FGFR1', 'Gene', (41, 46))	('FGFR1', 'Gene', '2260', (41, 46))
50634	28030802	Moreover, preclinical studies have shown that a subset of FGFR1-amplified small cell lung cancer is extremely sensitive to FGFR inhibition by PD173074, a specific FGFR1 inhibitor.	('inhibition', 'NegReg', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (74, 96))	('PD173074', 'Var', (142, 150))	('FGFR1', 'Gene', '2260', (163, 168))	('FGFR1', 'Gene', '2260', (58, 63))	('FGF', 'Gene', (163, 166))	('FGF', 'Gene', (123, 126))	('small cell lung cancer', 'Disease', 'MESH:D055752', (74, 96))	('FGF', 'Gene', (58, 61))	('small cell lung cancer', 'Disease', (74, 96))	('FGFR1', 'Gene', (163, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (163, 166))	('FGFR1', 'Gene', (58, 63))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (123, 126))	('PD173074', 'Chemical', 'MESH:C115711', (142, 150))	('sensitive', 'Reg', (110, 119))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (58, 61))
50635	28030802	FGFR1 amplifications have also been reported in oral squamous cell carcinoma, ovarian cancer, bladder cancer and rhabdomyosarcoma.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('rhabdomyosarcoma', 'Disease', (113, 129))	('FGFR1', 'Gene', (0, 5))	('ovarian cancer', 'Disease', (78, 92))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (48, 76))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (113, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (113, 129))	('oral squamous cell carcinoma', 'Disease', (48, 76))	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('bladder cancer', 'Disease', (94, 108))	('amplifications', 'Var', (6, 20))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('FGFR1', 'Gene', '2260', (0, 5))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ovarian cancer', 'Disease', 'MESH:D010051', (78, 92))	('reported', 'Reg', (36, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))
50639	28030802	Amplification and activating mutations in FGFR4 have been identified in 7-8% of rhabdomyosarcoma patients and FGFR inhibitors are potentially effective in a rhabdomyosarcoma mouse model expressing mutated FGFR4.	('FGFR', 'molecular_function', 'GO:0005007', ('110', '114'))	('mutated', 'Var', (197, 204))	('activating', 'PosReg', (18, 28))	('FGF', 'Gene', (110, 113))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (42, 45))	('mouse', 'Species', '10090', (174, 179))	('FGF', 'Gene', (205, 208))	('FGFR', 'molecular_function', 'GO:0005007', ('205', '209'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (110, 113))	('rhabdomyosarcoma', 'Disease', (80, 96))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (205, 208))	('mutations', 'Var', (29, 38))	('rhabdomyosarcoma', 'Disease', (157, 173))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))	('patients', 'Species', '9606', (97, 105))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (80, 96))	('Amplification', 'Var', (0, 13))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (157, 173))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (80, 96))	('FGF', 'Gene', (42, 45))	('identified', 'Reg', (58, 68))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (157, 173))
50644	28030802	Inhibition of this axis is thus hypothesized to result in a disruption of bile acid homeostasis.	('bile acid homeostasis', 'MPA', (74, 95))	('result', 'Reg', (48, 54))	('bile acid', 'Chemical', 'MESH:D001647', (74, 83))	('Inhibition', 'Var', (0, 10))	('disruption', 'MPA', (60, 70))	('homeostasis', 'biological_process', 'GO:0042592', ('84', '95'))
50645	28030802	The same review mentioned above also noted that gene mutations and rearrangements affecting FGF/FGFR signaling were less common than amplification.	('FGF', 'Gene', (92, 95))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (92, 95))	('FGF', 'Gene', (96, 99))	('rearrangements', 'Var', (67, 81))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (96, 99))	('signaling', 'biological_process', 'GO:0023052', ('101', '110'))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))
50646	28030802	Mutations in FGFR 2 are implicated in a broad spectrum of malignant disease.	('FGFR 2', 'Gene', '2263', (13, 19))	('FGFR 2', 'Gene', (13, 19))	('malignant disease', 'Disease', 'MESH:D009369', (58, 75))	('malignant disease', 'Disease', (58, 75))	('Mutations', 'Var', (0, 9))	('implicated', 'Reg', (24, 34))
50647	28030802	Mutations are present in 12% of endometrial carcinomas and FGFR2 mutant endometrial cancer cell lines are highly sensitive to FGFR tyrosine kinase inhibitors, implicating FGFR2 as an innovative therapeutic target in endometrial carcinoma.	('FGFR2', 'Gene', (59, 64))	('endometrial cancer', 'Disease', (72, 90))	('sensitive', 'MPA', (113, 122))	('endometrial cancer', 'Disease', 'MESH:D016889', (72, 90))	('FGFR2', 'Gene', '2263', (171, 176))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (32, 54))	('endometrial carcinoma', 'Disease', (216, 237))	('FGFR2', 'Gene', '2263', (59, 64))	('mutant', 'Var', (65, 71))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (32, 54))	('FGF', 'Gene', (126, 129))	('FGFR', 'molecular_function', 'GO:0005007', ('126', '130'))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (216, 237))	('tyrosine', 'Chemical', 'MESH:D014443', (131, 139))	('FGF', 'Gene', (171, 174))	('FGF', 'Gene', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (126, 129))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (32, 53))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (216, 237))	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('endometrial cancer', 'Phenotype', 'HP:0012114', (72, 90))	('endometrial carcinomas', 'Disease', (32, 54))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (32, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('171', '175'))	('FGFR2', 'Gene', (171, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (171, 174))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (59, 62))
50648	28030802	Also, approximately 10% of cases of gastric cancer are associated with FGFR2 amplification and/or mutation; in particular amplification is suggestive of a poor prognosis and more widespread disease.	('mutation', 'Var', (98, 106))	('gastric cancer', 'Disease', (36, 50))	('associated', 'Reg', (55, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (36, 50))	('amplification', 'Var', (77, 90))	('amplification', 'Var', (122, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('FGFR2', 'Gene', (71, 76))	('FGFR2', 'Gene', '2263', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
50649	28030802	Gastric cancer cell lines with FGFR2 amplifications show evidence of ligand-independent signaling and are highly sensitive to FGFR inhibitors.	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (126, 129))	('cancer', 'Disease', (8, 14))	('signaling', 'biological_process', 'GO:0023052', ('88', '97'))	('FGFR2', 'Gene', (31, 36))	('FGFR2', 'Gene', '2263', (31, 36))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (31, 34))	('ligand-independent signaling', 'MPA', (69, 97))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('FGF', 'Gene', (126, 129))	('Gastric cancer', 'Phenotype', 'HP:0012126', (0, 14))	('FGFR', 'molecular_function', 'GO:0005007', ('126', '130'))	('FGF', 'Gene', (31, 34))	('ligand', 'molecular_function', 'GO:0005488', ('69', '75'))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('amplifications', 'Var', (37, 51))
50650	28030802	In breast cancer, single nucleotide polymorphisms (SNPs) in FGFR2 were found to be strongly associated with evidence of postmenopausal disease.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('postmenopausal disease', 'Phenotype', 'HP:0008209', (120, 142))	('postmenopausal disease', 'Disease', (120, 142))	('single nucleotide polymorphisms', 'Var', (18, 49))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('FGFR', 'molecular_function', 'GO:0005007', ('60', '64'))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('FGFR2', 'Gene', (60, 65))	('FGFR2', 'Gene', '2263', (60, 65))	('associated', 'Reg', (92, 102))
50651	28030802	FGFR2 amplification is also detected in 5% of triple-negative breast cancers, providing the possibility of specific targeted therapy when many other options are less efficacious by the nature of the disease profile.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('detected', 'Reg', (28, 36))	('breast cancers', 'Phenotype', 'HP:0003002', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancers', 'Disease', 'MESH:D001943', (62, 76))	('breast cancers', 'Disease', (62, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('FGFR2', 'Gene', '2263', (0, 5))	('amplification', 'Var', (6, 19))	('FGFR2', 'Gene', (0, 5))	('triple-negative', 'Disease', (46, 61))
50652	28030802	Recently, several novel FGFR2 mutations have been identified in lung cancer, both in cases of adenocarcinoma and squamous cell carcinoma.	('lung cancer', 'Disease', (64, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('FGFR2', 'Gene', '2263', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('mutations', 'Var', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('identified', 'Reg', (50, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('FGFR2', 'Gene', (24, 29))
50655	28030802	As aforementioned, FGFR mutations do not always result in "driver" mutations alone.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (19, 22))	('mutations', 'Var', (24, 33))	('FGF', 'Gene', (19, 22))	('result', 'Reg', (48, 54))
50656	28030802	As seen 10% of melanoma, missense mutations of FGFR2 have been identified in BRAF-inhibitor treatment resistance.	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('BRAF', 'Gene', '673', (77, 81))	('identified', 'Reg', (63, 73))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('BRAF', 'Gene', (77, 81))	('treatment resistance', 'MPA', (92, 112))	('missense mutations', 'Var', (25, 43))	('FGFR2', 'Gene', (47, 52))	('FGFR2', 'Gene', '2263', (47, 52))
50657	28030802	FGFR3 mutations are found in approximately 70% of non-muscle-invasive bladder cancers and 10-20% of invasive bladder cancers.	('invasive bladder', 'Phenotype', 'HP:0100645', (61, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('invasive bladder cancers', 'Disease', (100, 124))	('invasive bladder cancers', 'Disease', (61, 85))	('non-muscle-invasive bladder', 'Phenotype', 'HP:0000011', (50, 77))	('mutations', 'Var', (6, 15))	('bladder cancers', 'Phenotype', 'HP:0009725', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('invasive bladder cancers', 'Disease', 'MESH:D001749', (100, 124))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('bladder cancers', 'Phenotype', 'HP:0009725', (109, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))	('invasive bladder cancers', 'Disease', 'MESH:D001749', (61, 85))	('FGFR3', 'Gene', (0, 5))	('invasive bladder', 'Phenotype', 'HP:0100645', (100, 116))	('found', 'Reg', (20, 25))
50658	28030802	The presence of an FGFR3 mutation strongly relates to low-grade, non-muscle-invasive tumors with a better prognosis, however the clinical viability of FGFR3 as a target for cancer directed therapy in this population is unclear and remains controversial.	('relates', 'Reg', (43, 50))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('low-grade', 'Disease', (54, 63))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (173, 179))	('mutation', 'Var', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('FGFR3', 'Gene', (19, 24))	('tumors', 'Disease', (85, 91))
50659	28030802	Interestingly, in patients with non-invasive bladder cancer after resection, the presence of an FGFR3 mutation in cells obtained from urinalysis at routine follow-up was predictive of disease recurrence.	('mutation', 'Var', (102, 110))	('bladder cancer', 'Phenotype', 'HP:0009725', (45, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('FGFR3', 'Gene', (96, 101))	('patients', 'Species', '9606', (18, 26))	('presence', 'Var', (81, 89))	('invasive bladder', 'Phenotype', 'HP:0100645', (36, 52))	('bladder cancer', 'Disease', 'MESH:D001749', (45, 59))	('bladder cancer', 'Disease', (45, 59))
50660	28030802	FGFR3 mutations have also been identified in many other cancer types, including 3% of squamous cell lung carcinoma, cervical cancers, multiple myeloma, prostate cancer and spermatocytic seminomas.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('spermatocytic seminomas', 'Phenotype', 'HP:0100617', (172, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('squamous cell lung carcinoma', 'Disease', (86, 114))	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', (56, 62))	('spermatocytic seminomas', 'Disease', 'MESH:C563236', (172, 195))	('multiple myeloma', 'Disease', 'MESH:D009101', (134, 150))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (86, 114))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('prostate cancer', 'Disease', 'MESH:D011471', (152, 167))	('prostate cancer', 'Phenotype', 'HP:0012125', (152, 167))	('cancer', 'Disease', (125, 131))	('mutations', 'Var', (6, 15))	('spermatocytic seminomas', 'Disease', (172, 195))	('multiple myeloma', 'Disease', (134, 150))	('prostate cancer', 'Disease', (152, 167))	('identified', 'Reg', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cervical cancers', 'Disease', (116, 132))	('cervical cancers', 'Disease', 'MESH:D002583', (116, 132))	('FGFR3', 'Gene', (0, 5))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (86, 114))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('multiple myeloma', 'Phenotype', 'HP:0006775', (134, 150))
50661	28030802	In head and neck squamous cell carcinoma (HNSCC) that was positive for human papilloma virus (HPV, 42.5% of 120 tumor samples), genomic analysis using parallel sequencing technology revealed nearly 18% of tumors with mutations in FGFR2 or FGFR 3, which was notably different than in HPV negative samples.	('FGFR', 'molecular_function', 'GO:0005007', ('239', '243'))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('HPV', 'Species', '10566', (283, 286))	('FGFR', 'molecular_function', 'GO:0005007', ('230', '234'))	('neck', 'cellular_component', 'GO:0044326', ('12', '16'))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('HNSCC', 'Phenotype', 'HP:0012288', (42, 47))	('papilloma', 'Phenotype', 'HP:0012740', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (112, 117))	('tumors', 'Disease', (205, 211))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (3, 40))	('FGFR2', 'Gene', (230, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('human papilloma virus', 'Species', '10566', (71, 92))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('neck squamous cell carcinoma', 'Disease', (12, 40))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (12, 40))	('FGFR 3', 'Gene', '2261', (239, 245))	('FGFR2', 'Gene', '2263', (230, 235))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('FGFR 3', 'Gene', (239, 245))	('HPV', 'Species', '10566', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (205, 210))	('mutations', 'Var', (217, 226))
50662	28030802	Interestingly, HPV negative cases that had FGFR3 mutations were not as responsive to FGFR inhibition as the single HPV positive case studied, suggesting further need for study in HNSCC based on HPV status.	('mutations', 'Var', (49, 58))	('FGF', 'Gene', (43, 46))	('FGF', 'Gene', (85, 88))	('HPV', 'Species', '10566', (115, 118))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (43, 46))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (85, 88))	('HPV', 'Species', '10566', (15, 18))	('HPV', 'Species', '10566', (194, 197))	('FGFR', 'molecular_function', 'GO:0005007', ('43', '47'))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))	('HNSCC', 'Phenotype', 'HP:0012288', (179, 184))
50663	28030802	FGFR3-activating mutations are also found at a high frequency in epidermal nevi and seborrhoeic keratosis, which are benign skin conditions and do not progress to malignancy.	('FGFR', 'molecular_function', 'GO:0005007', ('0', '4'))	('seborrhoeic keratosis', 'Phenotype', 'HP:0031287', (84, 105))	('seborrhoeic keratosis', 'Disease', 'MESH:D007642', (84, 105))	('FGFR3-activating', 'Gene', (0, 16))	('epidermal nevi', 'Phenotype', 'HP:0010816', (65, 79))	('malignancy', 'Disease', 'MESH:D009369', (163, 173))	('epidermal nevi', 'Disease', (65, 79))	('malignancy', 'Disease', (163, 173))	('seborrhoeic keratosis', 'Disease', (84, 105))	('nevi', 'Phenotype', 'HP:0003764', (75, 79))	('mutations', 'Var', (17, 26))
50666	28030802	In a comprehensive survey of gene fusions across different solid tumor histologies, the authors described a wide-ranging distribution of FGFR1, FGFR2, and FGFR3 fusions across 8 of 20 tumor types analyzed.	('FGFR2', 'Gene', '2263', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('FGFR1', 'Gene', (137, 142))	('tumor', 'Disease', (184, 189))	('FGFR3', 'Gene', (155, 160))	('FGFR1', 'Gene', '2260', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('fusions', 'Var', (161, 168))	('FGFR2', 'Gene', (144, 149))
50671	28030802	Pre-clinical evidence suggests that FGFR inhibitors are able to reduce growth and induce apoptosis in cell lines harboring FGFR1 gene rearrangements.	('rearrangements', 'Var', (134, 148))	('induce', 'Reg', (82, 88))	('FGF', 'Gene', (36, 39))	('reduce', 'NegReg', (64, 70))	('apoptosis', 'CPA', (89, 98))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (36, 39))	('FGF', 'Gene', (123, 126))	('FGFR1', 'Gene', (123, 128))	('growth', 'CPA', (71, 77))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (123, 126))	('reduce growth', 'Phenotype', 'HP:0001510', (64, 77))	('FGFR1', 'Gene', '2260', (123, 128))
50672	28030802	Intrahepatic cholangiocarcinoma demonstrates FGFR2 fusions in 13.6% of cases that are mutually exclusive with KRAS/BRAF mutations, and in vivo cellular studies confirm the oncogenic potential of this aberration.	('BRAF', 'Gene', '673', (115, 119))	('Intrahepatic cholangiocarcinoma', 'Disease', (0, 31))	('Intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (0, 31))	('FGFR2', 'Gene', (45, 50))	('FGFR2', 'Gene', '2263', (45, 50))	('BRAF', 'Gene', (115, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (13, 31))	('fusions', 'Var', (51, 58))
50677	28030802	The TACC3 gene (transforming acidic coiled-coil containing protein) was first identified as a component of FGFR3-TACC3 fusion in glioblastoma multiforme (GBM) and bladder urothelial tumors, this fusion protein is constitutively active and has been shown to affect mitosis by altering chromosomal segregation patterns.	('affect', 'Reg', (257, 263))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('glioblastoma multiforme', 'Disease', (129, 152))	('bladder urothelial tumors', 'Disease', (163, 188))	('altering', 'Reg', (275, 283))	('fusion', 'Var', (119, 125))	('bladder urothelial tumors', 'Disease', 'MESH:D001749', (163, 188))	('mitosis', 'Disease', 'None', (264, 271))	('chromosomal segregation patterns', 'CPA', (284, 316))	('glioblastoma', 'Phenotype', 'HP:0012174', (129, 141))	('FGFR3-TACC3', 'Gene', (107, 118))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (129, 152))	('bladder urothelial tumors', 'Phenotype', 'HP:0009725', (163, 188))	('mitosis', 'Disease', (264, 271))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
50678	28030802	In an analysis of nearly 600 cases of lung adenocarcinoma patients without any smoking history, investigators found an FGFR3-TACC3 fusion in a tissue sample from a patient that previously did not have any known oncogenic alteration.	('FGFR3-TACC3', 'Gene', (119, 130))	('patients', 'Species', '9606', (58, 66))	('patient', 'Species', '9606', (58, 65))	('patient', 'Species', '9606', (164, 171))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (38, 57))	('FGFR', 'molecular_function', 'GO:0005007', ('119', '123'))	('fusion', 'Var', (131, 137))	('lung adenocarcinoma', 'Disease', (38, 57))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (38, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
50680	28030802	In vitro, these cells with an FGFR3-TACC3 fusion demonstrated sensitivity to pan-FGFR inhibitors, suggesting a possible subset of lung adenocarcinoma patients that may benefit from targeting this pathway.	('FGF', 'Gene', (81, 84))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (130, 149))	('FGF', 'Gene', (30, 33))	('fusion', 'Var', (42, 48))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (30, 33))	('patients', 'Species', '9606', (150, 158))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (81, 84))	('lung adenocarcinoma', 'Disease', (130, 149))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (130, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))
50681	28030802	It is also worth mentioning that we described the first 3 cases of cervical cancer harboring the FGFR-TACC3 fusion, noting that one patient received treatment with FGFR targeted therapy and achieved stable disease for 4 cycles.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('FGF', 'Gene', (164, 167))	('fusion', 'Var', (108, 114))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (164, 167))	('patient', 'Species', '9606', (132, 139))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('FGF', 'Gene', (97, 100))
50682	28030802	However, ligand-dependent signaling may also occur and would suggest that ectopic expression of FGFs can promote cancer.	('promote', 'PosReg', (105, 112))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('ectopic expression', 'Var', (74, 92))	('FGF', 'Gene', (96, 99))	('signaling', 'biological_process', 'GO:0023052', ('26', '35'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (96, 99))	('ligand', 'molecular_function', 'GO:0005488', ('9', '15'))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
50687	28030802	Early development of FGFR inhibitors exhibits antitumor activity and present very specific toxicity profiles.	('inhibitors', 'Var', (26, 36))	('FGFR', 'molecular_function', 'GO:0005007', ('21', '25'))	('FGF', 'Gene', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('toxicity', 'Disease', 'MESH:D064420', (91, 99))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (21, 24))	('toxicity', 'Disease', (91, 99))	('tumor', 'Disease', (50, 55))
50688	28030802	Prior studies also indicate that FGFR inhibitors enhance tumor sensitivity to conventional anticancer drugs such as 5-fluorouracil, irinotecan, paclitaxel, and etoposide in human cancer cells acquiring anti-apoptotic potential based on aberrant FGFR activation.	('irinotecan', 'Chemical', 'MESH:D000077146', (132, 142))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('FGF', 'Gene', (33, 36))	('activation', 'PosReg', (250, 260))	('FGF', 'Gene', (245, 248))	('cancer', 'Disease', (95, 101))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (33, 36))	('inhibitors', 'Var', (38, 48))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', (57, 62))	('paclitaxel', 'Chemical', 'MESH:D017239', (144, 154))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (245, 248))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('human', 'Species', '9606', (173, 178))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('etoposide', 'Chemical', 'MESH:D005047', (160, 169))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (116, 130))	('enhance', 'PosReg', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Disease', (179, 185))
50697	28030802	Pan-FGFR inhibitors such as lenvatinib (E7080), ponatinib (AP24534), regorafenib (BAY 73-4506), dovitinib (TKI258), lucitanib (E3810), cediranib (AZD2171), intedanib (BIBF 1120), brivanib (BMS-540215), and others are currently being studied in clinical trials.	('intedanib', 'Chemical', 'MESH:C530716', (156, 165))	('AP24534', 'Chemical', 'MESH:C545373', (59, 66))	('BAY 73-4506', 'Chemical', 'MESH:C559147', (82, 93))	('lucitanib', 'Chemical', 'MESH:C000595232', (116, 125))	('AZD2171', 'Chemical', 'MESH:C500926', (146, 153))	('cediranib', 'Chemical', 'MESH:C500926', (135, 144))	('TKI258', 'Chemical', 'MESH:C500007', (107, 113))	('E7080', 'Chemical', 'MESH:C531958', (40, 45))	('regorafenib', 'Chemical', 'MESH:C559147', (69, 80))	('brivanib', 'Chemical', 'MESH:C509922', (179, 187))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (4, 7))	('FGF', 'Gene', (4, 7))	('dovitinib', 'Chemical', 'MESH:C500007', (96, 105))	('lenvatinib', 'Chemical', 'MESH:C531958', (28, 38))	('E7080', 'Var', (40, 45))	('E3810', 'Var', (127, 132))	('ponatinib', 'Chemical', 'MESH:C545373', (48, 57))	('BIBF', 'Chemical', '-', (167, 171))
50704	28030802	Interestingly, despite the high potency against FGFRs, one Phase II trial in advanced urothelial carcinoma using dovitinib to treat FGFR3 mutated versus FGFR wild-type cancer failed to show a meaningful overall response rate and the study was terminated after concluding that dovitinib has limited single-agent activity in this population.	('FGF', 'Gene', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('dovitinib', 'Chemical', 'MESH:C500007', (276, 285))	('FGF', 'Gene', (153, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('mutated', 'Var', (138, 145))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (132, 135))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (86, 106))	('dovitinib', 'Chemical', 'MESH:C500007', (113, 122))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (153, 156))	('cancer', 'Disease', (168, 174))	('FGF', 'Gene', (48, 51))	('urothelial carcinoma', 'Disease', (86, 106))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (48, 51))
50707	28030802	Lenvatinib (E7080, Eisai) is another multikinase inhibitor, inhibiting FGFR1-4 as well as VEGFR1-3, RET, KIT and PDGFR-beta.	('inhibiting', 'NegReg', (60, 70))	('RET', 'Gene', '5979', (100, 103))	('FGFR1', 'Gene', (71, 76))	('PDGFR-beta', 'Gene', (113, 123))	('VEGFR1', 'Gene', '2321', (90, 96))	('KIT', 'Gene', (105, 108))	('FGFR1', 'Gene', '2260', (71, 76))	('E7080', 'Chemical', 'MESH:C531958', (12, 17))	('VEGFR1', 'Gene', (90, 96))	('RET', 'Gene', (100, 103))	('Lenvatinib', 'Chemical', 'MESH:C531958', (0, 10))	('E7080', 'Var', (12, 17))	('PDGFR-beta', 'Gene', '5159', (113, 123))
50720	28030802	Ongoing Phase II/III clinical trials include a comparison of lenvatinib with sorafenib in hepatocellular carcinoma (NCT01761266), lenvatinib with everolimus in renal cell carcinoma (NCT02454478), and as monotherapy in unresectable biliary cancer (NCT02579616).	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (90, 114))	('biliary cancer', 'Disease', (231, 245))	('lenvatinib', 'Chemical', 'MESH:C531958', (61, 71))	('hepatocellular carcinoma', 'Disease', (90, 114))	('renal cell carcinoma', 'Disease', (160, 180))	('NCT01761266', 'Var', (116, 127))	('everolimus', 'Chemical', 'MESH:D000068338', (146, 156))	('lenvatinib', 'Chemical', 'MESH:C531958', (130, 140))	('biliary cancer', 'Disease', 'MESH:D001661', (231, 245))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (90, 114))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (160, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (160, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('sorafenib', 'Chemical', 'MESH:D000077157', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
50725	28030802	These include compounds like AZD4547, BGJ398, JNJ42756493, and PD173074.	('BGJ398', 'Var', (38, 44))	('JNJ42756493', 'Var', (46, 57))	('PD173074', 'Var', (63, 71))	('AZD4547', 'Var', (29, 36))	('PD173074', 'Chemical', 'MESH:C115711', (63, 71))	('AZD4547', 'Chemical', 'MESH:C572463', (29, 36))	('JNJ42756493', 'Chemical', 'MESH:C000604580', (46, 57))	('BGJ398', 'Chemical', 'MESH:C568950', (38, 44))
50726	28030802	AZD4547 is a small-molecule compound that is a selective FGFR (FGFR 1-3) inhibitor, delivered orally in capsule form.	('FGFR 1', 'Gene', '2260', (63, 69))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (63, 66))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('FGFR', 'molecular_function', 'GO:0005007', ('63', '67'))	('FGF', 'Gene', (57, 60))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (57, 60))	('FGF', 'Gene', (63, 66))	('FGFR', 'molecular_function', 'GO:0005007', ('57', '61'))	('FGFR 1', 'Gene', (63, 69))	('AZD4547', 'Var', (0, 7))	('capsule', 'cellular_component', 'GO:0042603', ('104', '111'))
50728	28030802	Oral administration of AZD4547 has also resulted in prolonged survival of FGFR3-TACC3-transformed glioma xenografts by 28 days compared with mice treated with the vehicle control.	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('prolonged', 'PosReg', (52, 61))	('survival', 'CPA', (62, 70))	('FGFR3-TACC3-transformed', 'Gene', (74, 97))	('mice', 'Species', '10090', (141, 145))	('AZD4547', 'Var', (23, 30))	('glioma', 'Disease', (98, 104))	('AZD4547', 'Chemical', 'MESH:C572463', (23, 30))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))
50729	28030802	Furthermore, inhibition with AZD4547 resulted in a significant dose-dependent tumor growth inhibition and survival of gastric cancer carrying an FGFR2 gene amplification both in vitro and in vivo.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('FGFR2', 'Gene', (145, 150))	('gastric cancer', 'Disease', (118, 132))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('survival', 'CPA', (106, 114))	('gastric cancer', 'Disease', 'MESH:D013274', (118, 132))	('FGFR2', 'Gene', '2263', (145, 150))	('AZD4547', 'Var', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('tumor', 'Disease', (78, 83))	('AZD4547', 'Chemical', 'MESH:C572463', (29, 36))	('FGFR', 'molecular_function', 'GO:0005007', ('145', '149'))
50730	28030802	Other pre-clinical studies on xenograft models transplanted with transformed cells derived from FGFR1 amplified NSCLC cancer patients have shown that AZD4547 stops tumor growth and promotes regression.	('tumor', 'Disease', (164, 169))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('stops', 'NegReg', (158, 163))	('regression', 'CPA', (190, 200))	('AZD4547', 'Var', (150, 157))	('promotes', 'PosReg', (181, 189))	('NSCLC cancer', 'Disease', (112, 124))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('FGFR1', 'Gene', (96, 101))	('FGFR1', 'Gene', '2260', (96, 101))	('NSCLC cancer', 'Disease', 'MESH:D009369', (112, 124))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('AZD4547', 'Chemical', 'MESH:C572463', (150, 157))	('patients', 'Species', '9606', (125, 133))
50733	28030802	The increase in serum phosphate concentration observed in this phase I study provides evidence that AZD4547 at this dose leads to pharmacologic target inhibition.	('pharmacologic target inhibition', 'MPA', (130, 161))	('AZD4547', 'Var', (100, 107))	('AZD4547', 'Chemical', 'MESH:C572463', (100, 107))	('increase in serum phosphate concentration', 'Phenotype', 'HP:0002905', (4, 45))	('serum phosphate concentration', 'MPA', (16, 45))	('phosphate', 'Chemical', 'MESH:D010710', (22, 31))	('increase', 'PosReg', (4, 12))	('increase in serum phosphate', 'Phenotype', 'HP:0002905', (4, 31))
50735	28030802	Expansion cohorts to further assess safety and tolerability required tumors with FGFR 1 amplification as confirmed through FISH (FGFR: Centromeric ratio >= 2).	('FGFR', 'molecular_function', 'GO:0005007', ('81', '85'))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('FGF', 'Gene', (81, 84))	('FGF', 'Gene', (129, 132))	('amplification', 'Var', (88, 101))	('FGFR 1', 'Gene', (81, 87))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('FGFR 1', 'Gene', '2260', (81, 87))	('FGFR', 'molecular_function', 'GO:0005007', ('129', '133'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (81, 84))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (129, 132))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))
50736	28030802	In a cohort of 15 patients with FGFR1 amplified SqCLC, the most common adverse events (AEs) were dermatologic and GI related.	('amplified', 'Var', (38, 47))	('FGFR', 'molecular_function', 'GO:0005007', ('32', '36'))	('FGFR1', 'Gene', (32, 37))	('SqCLC', 'MPA', (48, 53))	('FGFR1', 'Gene', '2260', (32, 37))	('patients', 'Species', '9606', (18, 26))	('AEs', 'Chemical', '-', (87, 90))
50741	28030802	Of note, partial response (PR, by RECIST criteria) was observed in tumors with a high burden of FGFR aberration including one SqCLC patient with FGFR1 amplification and another patient with FGFR2 amplified gastroesophageal cancer.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (145, 148))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (96, 99))	('gastroesophageal cancer', 'Disease', (206, 229))	('gastroesophageal cancer', 'Disease', 'MESH:D009369', (206, 229))	('FGF', 'Gene', (190, 193))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('FGFR1', 'Gene', '2260', (145, 150))	('FGFR', 'molecular_function', 'GO:0005007', ('145', '149'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (190, 193))	('FGFR2', 'Gene', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('FGF', 'Gene', (145, 148))	('patient', 'Species', '9606', (132, 139))	('tumors', 'Disease', (67, 73))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))	('FGFR2', 'Gene', '2263', (190, 195))	('FGF', 'Gene', (96, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('190', '194'))	('FGFR1', 'Gene', (145, 150))	('patient', 'Species', '9606', (177, 184))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('amplification', 'Var', (151, 164))
50743	28030802	AZD4547 is currently under a Phase II clinical trial to assess its activity in patients with FGFR1 or FGFR2 amplified breast, squamous lung, and stomach cancer whose cancers have progressed following previous chemotherapy (NCT01795768).	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('amplified', 'Var', (108, 117))	('breast', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('FGFR', 'molecular_function', 'GO:0005007', ('102', '106'))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('stomach cancer', 'Disease', (145, 159))	('FGFR1', 'Gene', (93, 98))	('squamous lung', 'Disease', 'MESH:D002294', (126, 139))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancers', 'Disease', (166, 173))	('squamous lung', 'Disease', (126, 139))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('FGFR2', 'Gene', (102, 107))	('stomach cancer', 'Disease', 'MESH:D013274', (145, 159))	('stomach cancer', 'Phenotype', 'HP:0012126', (145, 159))	('FGFR', 'molecular_function', 'GO:0005007', ('93', '97'))	('patients', 'Species', '9606', (79, 87))	('FGFR2', 'Gene', '2263', (102, 107))	('FGFR1', 'Gene', '2260', (93, 98))
50744	28030802	285 patients with advanced cancer were screened, identifying FGFR1 amplification in 18% (20/111) HER2 negative breast cancer, 9.5% (4/42) NSCLC, and FGFR2 amplification in 7.6% (10/132) gastroesophageal (GC).	('negative', 'NegReg', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('HER2', 'Gene', '2064', (97, 101))	('FGFR1', 'Gene', '2260', (61, 66))	('gastroesophageal', 'Disease', 'MESH:D005764', (186, 202))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('FGFR2', 'Gene', '2263', (149, 154))	('breast cancer', 'Disease', (111, 124))	('gastroesophageal', 'Disease', (186, 202))	('amplification', 'Var', (155, 168))	('amplification', 'Var', (67, 80))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('patients', 'Species', '9606', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('HER2', 'Gene', (97, 101))	('cancer', 'Disease', (118, 124))	('NSCLC', 'Disease', (138, 143))	('FGFR1', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('FGFR2', 'Gene', (149, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
50750	28030802	A recently completed Phase II trial aimed to evaluate the safety and efficacy of AZD4547 versus paclitaxel in advanced gastric or gastro-oesophageal junction cancer; no results have been reported (NTC01457846).	('paclitaxel', 'Chemical', 'MESH:D017239', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('gastro-oesophageal junction cancer', 'Disease', (130, 164))	('AZD4547', 'Var', (81, 88))	('gastro-oesophageal junction cancer', 'Disease', 'MESH:D005764', (130, 164))	('AZD4547', 'Chemical', 'MESH:C572463', (81, 88))	('advanced gastric', 'Disease', (110, 126))
50751	28030802	AZD4547 is also undergoing a Phase I/II clinical trial in combination with fulvestrant versus fulvestrant alone in ER+ breast cancer patients with FGFR1 amplification (NTC01202591).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('breast cancer', 'Disease', (119, 132))	('amplification', 'Var', (153, 166))	('patients', 'Species', '9606', (133, 141))	('fulvestrant', 'Chemical', 'MESH:D000077267', (94, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('ER', 'Gene', '2099', (115, 117))	('FGFR1', 'Gene', (147, 152))	('FGFR1', 'Gene', '2260', (147, 152))	('fulvestrant', 'Chemical', 'MESH:D000077267', (75, 86))
50753	28030802	Of the 94 enrolled patients initially, partial responses were seen in 4 FGFR3 mutated bladder cancers, 2 FGFR1 amplified SqCLC, and a reduction in tumor burden was seen in FGFR2 fusion cholangiocarcinoma as well as in FGFR1 amplified breast cancer.	('FGFR1', 'Gene', (105, 110))	('FGFR2', 'Gene', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (185, 203))	('mutated', 'Var', (78, 85))	('tumor', 'Disease', (147, 152))	('FGFR2', 'Gene', '2263', (172, 177))	('cholangiocarcinoma', 'Disease', (185, 203))	('FGFR1', 'Gene', '2260', (218, 223))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (185, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('patients', 'Species', '9606', (19, 27))	('bladder cancers', 'Phenotype', 'HP:0009725', (86, 101))	('breast cancer', 'Disease', (234, 247))	('FGFR1', 'Gene', '2260', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('FGFR1', 'Gene', (218, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('reduction', 'NegReg', (134, 143))	('bladder cancers', 'Disease', 'MESH:D001749', (86, 101))	('FGFR3', 'Gene', (72, 77))	('bladder cancers', 'Disease', (86, 101))
50754	28030802	Investigators used FISH to screen for FGFR1 amplification, and in the cohort of 17 SqCLC (expansion arm) patients there were 4/17 PRs (2 after data cutoff date) and 3 patients with SD.	('patients', 'Species', '9606', (105, 113))	('patients', 'Species', '9606', (167, 175))	('PRs', 'Disease', (130, 133))	('amplification', 'Var', (44, 57))	('FGFR1', 'Gene', (38, 43))	('FGFR1', 'Gene', '2260', (38, 43))	('SD', 'Chemical', '-', (181, 183))
50758	28030802	Trials that are actively recruiting for study of BGJ398 alone exist for non-muscle invasive urothelial carcinoma (NCT02657486), recurrent glioblastoma (NCT01975701), and advanced cholangiocarcinoma (NCT02150967).	('NCT02657486', 'Var', (114, 125))	('BGJ398', 'Chemical', 'MESH:C568950', (49, 55))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (179, 197))	('invasive urothelial carcinoma', 'Disease', (83, 112))	('BGJ398', 'Gene', (49, 55))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (179, 197))	('glioblastoma', 'Phenotype', 'HP:0012174', (138, 150))	('NCT02150967', 'Var', (199, 210))	('glioblastoma', 'Disease', (138, 150))	('glioblastoma', 'Disease', 'MESH:D005909', (138, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('NCT01975701', 'Var', (152, 163))	('invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (83, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cholangiocarcinoma', 'Disease', (179, 197))
50760	28030802	JNJ-42756493 (Janssen) is another pan-FGFR inhibitor that is orally bioavailable.	('JNJ-42756493', 'Var', (0, 12))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (38, 41))	('JNJ-42756493', 'Chemical', 'MESH:C000604580', (0, 12))	('FGF', 'Gene', (38, 41))
50765	28030802	All patients that responded demonstrated FGFR2 or FGFR3 translocations, and of the responses identified, 3 of the patients with partial responses harbored an FGFR3-TACC3 fusion alteration.	('FGFR3-TACC3', 'Gene', (158, 169))	('FGFR2', 'Gene', (41, 46))	('FGFR3', 'Gene', (50, 55))	('FGFR2', 'Gene', '2263', (41, 46))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (114, 122))	('translocations', 'Var', (56, 70))
50771	28030802	An FGFR2-IIIb-specific antibody, GP369, has been shown to inhibit the proliferation of human cancer cell lines and tumor xenografts with amplified or activated FGFR2 signaling.	('FGFR2', 'Gene', (3, 8))	('FGFR2', 'Gene', '2263', (3, 8))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('human', 'Species', '9606', (87, 92))	('tumor', 'Disease', (115, 120))	('proliferation', 'CPA', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('FGFR2', 'Gene', (160, 165))	('inhibit', 'NegReg', (58, 65))	('FGFR2', 'Gene', '2263', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('GP369', 'Var', (33, 38))
50772	28030802	BAY1187982 (Bayer) also falls under the spectrum of exploiting the antibody/antigen relationship as a human anti-FGFR2-Ab that is conjugated to a cytotoxic agent (antibody-drug conjugate).	('antibody', 'cellular_component', 'GO:0042571', ('163', '171'))	('antibody', 'cellular_component', 'GO:0019815', ('67', '75'))	('FGFR', 'molecular_function', 'GO:0005007', ('113', '117'))	('FGFR2', 'Gene', (113, 118))	('BAY1187982', 'Chemical', 'MESH:C000621819', (0, 10))	('antibody', 'cellular_component', 'GO:0019814', ('67', '75'))	('falls', 'Phenotype', 'HP:0002527', (24, 29))	('antibody', 'molecular_function', 'GO:0003823', ('67', '75'))	('fall', 'Phenotype', 'HP:0002527', (24, 28))	('antibody', 'cellular_component', 'GO:0019815', ('163', '171'))	('antibody', 'cellular_component', 'GO:0019814', ('163', '171'))	('antibody', 'molecular_function', 'GO:0003823', ('163', '171'))	('antibody', 'cellular_component', 'GO:0042571', ('67', '75'))	('BAY1187982', 'Var', (0, 10))	('FGFR2', 'Gene', '2263', (113, 118))	('human', 'Species', '9606', (102, 107))
50775	28030802	Antibodies targeting FGFR3 have also been shown to have significant inhibitory effect on cell proliferation in bladder cancer cells and t (4; 14)-positive multiple myeloma.	('multiple myeloma', 'Disease', 'MESH:D009101', (155, 171))	('inhibitory effect', 'NegReg', (68, 85))	('Antibodies', 'Var', (0, 10))	('bladder cancer', 'Disease', (111, 125))	('multiple myeloma', 'Disease', (155, 171))	('FGFR3', 'Gene', (21, 26))	('bladder cancer', 'Phenotype', 'HP:0009725', (111, 125))	('bladder cancer', 'Disease', 'MESH:D001749', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('multiple myeloma', 'Phenotype', 'HP:0006775', (155, 171))
50776	28030802	MFGR1877S (Genentech) is a human anti-FGFR3 monoclonal antibody that demonstrated activity in preclinical models of urothelial carcinoma harboring FGFR3 overexpression.	('overexpression', 'PosReg', (153, 167))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (116, 136))	('MFGR1877S', 'Var', (0, 9))	('anti-FGFR3', 'Gene', (33, 43))	('human', 'Species', '9606', (27, 32))	('FGFR3', 'Gene', (147, 152))	('urothelial carcinoma', 'Disease', (116, 136))	('activity', 'MPA', (82, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
50777	28030802	Subsequently there have been two Phase I trials completed, one in solid tumors (NCT01363024) and one in t(4; 14)-positive multiple myeloma (NCT01122875).	('solid tumors', 'Disease', 'MESH:D009369', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('solid tumors', 'Disease', (66, 78))	('NCT01363024', 'Var', (80, 91))	('multiple myeloma', 'Phenotype', 'HP:0006775', (122, 138))	('multiple myeloma', 'Disease', 'MESH:D009101', (122, 138))	('multiple myeloma', 'Disease', (122, 138))
50783	28030802	A subsequent Phase II trial is currently recruiting and is looking to evaluate FP-1039 in solid tumors alone, or in combination with docetaxel, or paclitaxel and carboplatin (NCT01868022).	('solid tumors', 'Disease', 'MESH:D009369', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('docetaxel', 'Chemical', 'MESH:D000077143', (133, 142))	('solid tumors', 'Disease', (90, 102))	('carboplatin', 'Chemical', 'MESH:D016190', (162, 173))	('paclitaxel', 'Chemical', 'MESH:D017239', (147, 157))	('FP-1039', 'Var', (79, 86))
50784	28030802	Given the broad scope of malignancies with FGF/FGFR pathway aberrations, proof of concept has been demonstrated for its role as a driver for oncogenesis, as a downstream key player in angiogenesis, and as a pathway responsible for acquired resistance to other anti-cancer therapies.	('FGFR', 'molecular_function', 'GO:0005007', ('47', '51'))	('FGF', 'Gene', (43, 46))	('malignancies', 'Disease', 'MESH:D009369', (25, 37))	('FGF', 'Gene', (47, 50))	('oncogenesis', 'biological_process', 'GO:0007048', ('141', '152'))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('oncogenesis', 'CPA', (141, 152))	('malignancies', 'Disease', (25, 37))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (43, 46))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (47, 50))	('aberrations', 'Var', (60, 71))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('angiogenesis', 'biological_process', 'GO:0001525', ('184', '196'))
50785	28030802	Pre-clinical and clinical studies have shown that cancers harboring FGF/FGFR pathway aberrations are likely to be sensitive to FGFR inhibitors across various histologies.	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (72, 75))	('cancers', 'Disease', (50, 57))	('FGF', 'Gene', (68, 71))	('FGF', 'Gene', (127, 130))	('aberrations', 'Var', (85, 96))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (68, 71))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (127, 130))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('sensitive', 'Reg', (114, 123))	('FGF', 'Gene', (72, 75))
50789	28030802	As aforementioned, a recent study used next generation sequencing (NGS) to characterize frequencies of FGFR aberrations in nearly 5,000 solid tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('FGFR', 'molecular_function', 'GO:0005007', ('103', '107'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (103, 106))	('aberrations', 'Var', (108, 119))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('FGF', 'Gene', (103, 106))
50790	28030802	They found that 7.1% of malignancies demonstrated detectable abnormalities with the most common being gene amplification, followed by mutations, then rearrangements.	('gene amplification', 'Var', (102, 120))	('malignancies', 'Disease', 'MESH:D009369', (24, 36))	('mutations', 'Var', (134, 143))	('malignancies', 'Disease', (24, 36))
50792	28030802	Within the cohort of malignancies analyzed, urothelial carcinoma exhibited the highest percentage of FGFR aberrancy (largely mutation, then amplification, followed by fusion) at 32%.	('FGF', 'Gene', (101, 104))	('malignancies', 'Disease', 'MESH:D009369', (21, 33))	('aberrancy', 'Var', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (101, 104))	('urothelial carcinoma', 'Disease', (44, 64))	('malignancies', 'Disease', (21, 33))	('amplification', 'Var', (140, 153))	('FGFR', 'molecular_function', 'GO:0005007', ('101', '105'))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (44, 64))	('mutation', 'Var', (125, 133))
50794	28030802	Notably there was no evaluation of FGF ligand dependent signaling, highlighting that a subset of patients with FGF/FGFR pathway aberrations may still benefit from FGFR targeted therapy but were not characterized in this study.	('FGF', 'Gene', (115, 118))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (35, 38))	('aberrations', 'Var', (128, 139))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (163, 166))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (111, 114))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (115, 118))	('FGF', 'Gene', (35, 38))	('benefit', 'PosReg', (150, 157))	('FGF', 'Gene', (163, 166))	('FGF', 'Gene', (111, 114))	('patients', 'Species', '9606', (97, 105))
50796	28030802	Ultimately, when evaluating all FGF/FGFR aberrations (mutations, amplifications, rearrangements, etc.)	('rearrangements', 'Var', (81, 95))	('FGF', 'Gene', (32, 35))	('FGF', 'Gene', (36, 39))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (36, 39))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (32, 35))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))
50798	28030802	Much of the pre-clinical and early clinical data come from trials in patient populations unselected for FGF/FGFR pathway abnormalities.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (104, 107))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (108, 111))	('abnormalities', 'Var', (121, 134))	('patient', 'Species', '9606', (69, 76))	('FGF', 'Gene', (108, 111))	('FGF', 'Gene', (104, 107))
50799	28030802	The true response rates or clinical benefits for those whose cancers harbor FGF/FGFR abnormalities may be higher than observed in unselected patient populations.	('FGF', 'Gene', (76, 79))	('FGF', 'Gene', (80, 83))	('response', 'CPA', (9, 17))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (76, 79))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (80, 83))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('patient', 'Species', '9606', (141, 148))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('higher', 'PosReg', (106, 112))	('cancers', 'Disease', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('clinical benefits', 'CPA', (27, 44))	('abnormalities', 'Var', (85, 98))
50800	28030802	Many ongoing Phase I/II trials can be commended for aiming to select patients with specific FGF/FGFR alterations, and at this stage (appropriately so) there exist a variety in the methods including FISH, chromogenic in situ hybridization (CISH), quantitative real-time PCR, and NGS.	('alterations', 'Var', (101, 112))	('FGF', 'Gene', (92, 95))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (92, 95))	('FGF', 'Gene', (96, 99))	('patients', 'Species', '9606', (69, 77))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (96, 99))	('FGFR', 'molecular_function', 'GO:0005007', ('96', '100'))
50804	28030802	We must additionally consider that FGF/FGFR pathway alterations likely vary in their role depending on tumor histology and interactions with other oncogenic pathways.	('interactions', 'Interaction', (123, 135))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('alterations', 'Var', (52, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('39', '43'))	('tumor', 'Disease', (103, 108))	('FGF', 'Gene', (39, 42))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (39, 42))	('FGF', 'Gene', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
50807	28030802	It was later found out that EGFR expression by IHC in colorectal cancer did not correlate with response to therapy, and subsequent investigation led to the identification of the KRAS mutation conferring resistance.	('KRAS', 'Gene', (178, 182))	('EGFR', 'Gene', '1956', (28, 32))	('colorectal cancer', 'Disease', 'MESH:D015179', (54, 71))	('EGFR', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (54, 71))	('mutation', 'Var', (183, 191))	('EGFR', 'molecular_function', 'GO:0005006', ('28', '32'))	('colorectal cancer', 'Disease', (54, 71))
50813	28030802	As further studies unfold, we need to utilize multiplex molecular testing such as NGS to screen tumors harboring specific molecular aberrations of interest and increase the likelihood of detecting actionable FGF/FGFR alterations in each patient.	('FGF', 'Gene', (208, 211))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('patient', 'Species', '9606', (237, 244))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (208, 211))	('FGF', 'Gene', (212, 215))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('212', '216'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (212, 215))	('alterations', 'Var', (217, 228))
50816	28030802	There are some studies that have identified a high concordance for actionable mutations between paired plasma and tumor specimens, especially for metastatic disease in non-small cell lung cancer, breast cancer, and colorectal cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (172, 194))	('colorectal cancer', 'Disease', 'MESH:D015179', (215, 232))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (168, 194))	('colorectal cancer', 'Disease', (215, 232))	('metastatic disease', 'Disease', (146, 164))	('mutations', 'Var', (78, 87))	('tumor', 'Disease', (114, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('non-small cell lung cancer', 'Disease', (168, 194))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('breast cancer', 'Disease', (196, 209))	('colorectal cancer', 'Phenotype', 'HP:0003003', (215, 232))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (168, 194))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
50821	28030802	The accessibility of testing would likely allow for frequent monitoring of tumor evolution, and the presence of novel molecular alterations while actively receiving anti-cancer treatment may predict upcoming resistance to therapy.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('alterations', 'Var', (128, 139))	('predict', 'Reg', (191, 198))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('resistance to', 'CPA', (208, 221))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
50822	28030802	Already this has been described in a small cohort of patients with colorectal cancer initially demonstrating KRAS wild-type tumors, which subsequently were noted to have molecular alterations (via serum analysis) including KRAS, NRAS, EGFR, and BRAF after treatment with anti-EGFR therapies.	('EGFR', 'Gene', '1956', (276, 280))	('NRAS', 'Gene', '4893', (229, 233))	('BRAF', 'Gene', (245, 249))	('BRAF', 'Gene', '673', (245, 249))	('patients', 'Species', '9606', (53, 61))	('EGFR', 'Gene', '1956', (235, 239))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('KRAS', 'Disease', (223, 227))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('NRAS', 'Gene', (229, 233))	('tumors', 'Disease', (124, 130))	('EGFR', 'Gene', (276, 280))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('KRAS', 'Var', (109, 113))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('EGFR', 'Gene', (235, 239))	('colorectal cancer', 'Disease', (67, 84))
50825	28030802	Ideally, we could use this approach to monitor treatment response, disease recurrence, as well as pick up resistant clones in patients that have an FGFR alteration being treated with an FGFR inhibitor.	('alteration', 'Var', (153, 163))	('FGF', 'Gene', (186, 189))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (148, 151))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (186, 189))	('patients', 'Species', '9606', (126, 134))	('FGF', 'Gene', (148, 151))
50826	28030802	New trial designs and approaches are being developed in order to capture the many malignancies that may harbor an FGF/FGFR aberration.	('FGF', 'Gene', (118, 121))	('aberration', 'Var', (123, 133))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (114, 117))	('FGFR', 'molecular_function', 'GO:0005007', ('118', '122'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (118, 121))	('malignancies', 'Disease', (82, 94))	('FGF', 'Gene', (114, 117))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))
50832	28030802	Thus far we have discussed the use of FGFR inhibitors assuming that FGF/FGFR is the primary driver for oncogenesis in certain histologies or in certain molecular aberrations such as FGFR3 fusion in bladder cancer.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (38, 41))	('bladder cancer', 'Disease', 'MESH:D001749', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('fusion', 'Var', (188, 194))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (72, 75))	('bladder cancer', 'Disease', (198, 212))	('FGF', 'Gene', (182, 185))	('FGF', 'Gene', (68, 71))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (68, 71))	('FGF', 'Gene', (38, 41))	('bladder cancer', 'Phenotype', 'HP:0009725', (198, 212))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (182, 185))	('FGF', 'Gene', (72, 75))
50834	28030802	Additionally we must appreciate the evolving nature of cancer cells and the likelihood of resistance to FGFR inhibitors directly either by (i) compensatory signaling or (ii) via intrinsic gatekeeper mutations in the FGFR receptors themselves.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (104, 107))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('gatekeeper', 'Species', '111938', (188, 198))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (216, 219))	('FGF', 'Gene', (216, 219))	('mutations', 'Var', (199, 208))	('FGF', 'Gene', (104, 107))	('compensatory signaling', 'MPA', (143, 165))	('cancer', 'Disease', (55, 61))
50835	28030802	Recently, acquired resistance to EGFR specific inhibitors in NSCLC mutant cell lines has been hypothesized to relate to the activation of the FGFR1-FGF2 autocrine loop.	('FGF2', 'Gene', '2247', (148, 152))	('activation', 'PosReg', (124, 134))	('FGFR', 'molecular_function', 'GO:0005007', ('142', '146'))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('EGFR', 'Gene', '1956', (33, 37))	('FGFR1', 'Gene', '2260', (142, 147))	('FGF2', 'Gene', (148, 152))	('EGFR', 'molecular_function', 'GO:0005006', ('33', '37'))	('FGFR1', 'Gene', (142, 147))	('NSCLC', 'Disease', (61, 66))	('mutant', 'Var', (67, 73))	('EGFR', 'Gene', (33, 37))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))
50842	28030802	This effect was appreciated in cell lines and xenograft mouse models of KRAS-mutant lung adenocarcinoma and KRAS-mutant pancreatic carcinoma, but was not as significant in KRAS wild-type lung cancer cells or KRAS mutant colon cancer.	('KRAS-mutant', 'Var', (108, 119))	('KRAS-mutant', 'Var', (72, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (120, 140))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('mouse', 'Species', '10090', (56, 61))	('colon cancer', 'Phenotype', 'HP:0003003', (220, 232))	('lung adenocarcinoma', 'Disease', (84, 103))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (84, 103))	('pancreatic carcinoma', 'Disease', (120, 140))	('colon cancer', 'Disease', 'MESH:D015179', (220, 232))	('colon cancer', 'Disease', (220, 232))	('lung cancer', 'Disease', (187, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
50846	28030802	Secondly, they hypothesize that a combination of MEK and FGFR inhibition would likely be a valid approach in the treatment of KRAS-mutant lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('MEK', 'Gene', (49, 52))	('FGF', 'Gene', (57, 60))	('MEK', 'Gene', '5609', (49, 52))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (57, 60))	('lung cancer', 'Disease', (138, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('inhibition', 'NegReg', (62, 72))	('KRAS-mutant', 'Var', (126, 137))
50851	28030802	In breast cancer, FGFR1 amplification has been associated with endocrine resistance and poor prognosis.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('endocrine resistance', 'MPA', (63, 83))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('FGFR1', 'Gene', (18, 23))	('amplification', 'Var', (24, 37))	('FGFR1', 'Gene', '2260', (18, 23))	('associated', 'Reg', (47, 57))
50854	28030802	In the development of a novel targeted therapy, we must also recognize the inevitability of acquiring resistance to the drug - either from up-regulation of compensatory pathways or innate mutations rendering the FGFR receptor resistant.	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (212, 215))	('nevi', 'Phenotype', 'HP:0003764', (76, 80))	('up-regulation', 'PosReg', (139, 152))	('FGF', 'Gene', (212, 215))	('mutations', 'Var', (188, 197))
50855	28030802	In a study using FGFR3-mutant cell lines, the investigators identified EGFR signaling as a key mechanism in limiting FGFR3 inhibition.	('FGFR3-mutant', 'Var', (17, 29))	('FGFR3', 'Gene', (117, 122))	('EGFR', 'Gene', '1956', (71, 75))	('inhibition', 'NegReg', (123, 133))	('EGFR', 'Gene', (71, 75))
50856	28030802	In partially dependent FGFR3 cell lines, inhibiting FGFR3 resulted in a temporary down regulation of MAPK signaling that was bypassed by a prompt up regulation in EGFR signaling.	('inhibiting', 'Var', (41, 51))	('MAPK', 'Gene', '5594', (101, 105))	('EGFR', 'Gene', '1956', (163, 167))	('MAPK', 'Gene', (101, 105))	('EGFR', 'Gene', (163, 167))	('FGFR3', 'Gene', (52, 57))	('down regulation', 'NegReg', (82, 97))
50857	28030802	In EGFR dependent cell lines, they also identified that EGFR downstream signaling dominated, even in the presence of an activating FGFR3 mutation.	('EGFR', 'Gene', '1956', (3, 7))	('EGFR', 'molecular_function', 'GO:0005006', ('3', '7'))	('EGFR', 'Gene', (3, 7))	('mutation', 'Var', (137, 145))	('EGFR', 'Gene', '1956', (56, 60))	('FGFR', 'molecular_function', 'GO:0005007', ('131', '135'))	('EGFR', 'Gene', (56, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('FGFR3', 'Gene', (131, 136))	('activating', 'PosReg', (120, 130))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))
50858	28030802	More recently, in SqCLC cell lines with FGFR1 amplification, investigators identified clonal cell populations that were resistant to treatment with AZD4547 or BAY1163877.	('BAY1163877', 'Chemical', '-', (159, 169))	('amplification', 'Var', (46, 59))	('AZD4547', 'Var', (148, 155))	('FGFR1', 'Gene', (40, 45))	('FGFR1', 'Gene', '2260', (40, 45))	('BAY1163877', 'Var', (159, 169))	('AZD4547', 'Chemical', 'MESH:C572463', (148, 155))
50860	28030802	In these AZD4547 treated cells, MET amplification was thought to lead to resistance through ErbB3 activation.	('resistance', 'MPA', (73, 83))	('activation', 'PosReg', (98, 108))	('lead to', 'Reg', (65, 72))	('AZD4547', 'Chemical', 'MESH:C572463', (9, 16))	('MET amplification', 'Var', (32, 49))	('ErbB3', 'Gene', (92, 97))	('ErbB3', 'Gene', '2065', (92, 97))
50864	28030802	In discussing innate mutations, the "gatekeeper" mutation is responsible for the most common type of kinase inhibitor resistance, these are mutations of a residue located in the ATP binding pocket of the RTK.	('ATP', 'Chemical', 'MESH:D000255', (178, 181))	('gatekeeper', 'Species', '111938', (37, 47))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('99', '115'))	('RTK', 'Gene', (204, 207))	('mutations', 'Var', (140, 149))	('ATP binding', 'molecular_function', 'GO:0005524', ('176', '187'))	('RTK', 'Gene', '5979', (204, 207))
50872	28030802	A similar pattern of drug development and understanding has unfolded in the targeted treatment of EGFR mutant NSCLC or ALK-rearranged NSCLC.	('EGFR', 'Gene', (98, 102))	('NSCLC', 'Disease', 'MESH:D002289', (134, 139))	('mutant', 'Var', (103, 109))	('ALK', 'Gene', (119, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (134, 139))	('NSCLC', 'Disease', (110, 115))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('ALK', 'Gene', '238', (119, 122))	('EGFR', 'Gene', '1956', (98, 102))	('NSCLC', 'Disease', (134, 139))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
50873	28030802	In treating EGFR mutant NSCLC, the first generation EGFR tyrosine kinase inhibitors gefinitib and erlotinib (approved in 2003 and 2004 respectively), followed by the second-generation afatinib, have been widely used in treatment of advanced disease.	('NSCLC', 'Disease', (24, 29))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('erlotinib', 'Chemical', 'MESH:D000069347', (98, 107))	('EGFR', 'Gene', '1956', (12, 16))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))	('afatinib', 'Chemical', 'MESH:D000077716', (184, 192))	('tyrosine', 'Chemical', 'MESH:D014443', (57, 65))	('gefinitib', 'Chemical', '-', (84, 93))	('EGFR', 'Gene', (12, 16))	('mutant', 'Var', (17, 23))
50874	28030802	In fact, the most common acquired EGFR mutation leading to decreased survival has been found to be the "gatekeeper" mutation T790M, with nearly 50-60% of resistant cases demonstrating this anomaly.	('gatekeeper', 'Species', '111938', (104, 114))	('anomaly', 'Disease', (189, 196))	('mutation', 'Var', (39, 47))	('EGFR', 'Gene', (34, 38))	('decreased', 'NegReg', (59, 68))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('anomaly', 'Disease', 'MESH:D000014', (189, 196))	('T790M', 'Mutation', 'rs121434569', (125, 130))	('EGFR', 'Gene', '1956', (34, 38))	('survival', 'MPA', (69, 77))
50876	28030802	Continued development of EGFR inhibitor therapy led to the accelerated approval of the third generation EGFR inhibitor osimertinib for patients with metastatic EGFR T790M mutation-positive NSCLC that have progressed on or after previous EGFR inhibitor therapy.	('T790M mutation-positive', 'Var', (165, 188))	('NSCLC', 'Disease', (189, 194))	('patients', 'Species', '9606', (135, 143))	('EGFR', 'Gene', '1956', (237, 241))	('EGFR', 'Gene', (25, 29))	('osimertinib', 'Chemical', 'MESH:C000603933', (119, 130))	('EGFR', 'Gene', (104, 108))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('EGFR', 'Gene', (237, 241))	('EGFR', 'Gene', '1956', (160, 164))	('T790M', 'Mutation', 'rs121434569', (165, 170))	('EGFR', 'Gene', (160, 164))	('NSCLC', 'Phenotype', 'HP:0030358', (189, 194))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'Gene', '1956', (104, 108))
50879	28030802	As observed in the aforementioned stories, resistance to ALK blockade also emerges in time by multiple mechanisms including: ALK kinase mutations (30%) at L1196M (gatekeeper), F1174L, and G1202R, as well as activation of alternate oncogenes with resulting bypass signaling.	('gatekeeper', 'Species', '111938', (163, 173))	('F1174L', 'Var', (176, 182))	('ALK', 'Gene', (57, 60))	('ALK', 'Gene', '238', (125, 128))	('G1202R', 'Var', (188, 194))	('F1174L', 'Mutation', 'rs863225281', (176, 182))	('G1202R', 'Mutation', 'rs1057519783', (188, 194))	('mutations', 'Var', (136, 145))	('L1196M', 'Mutation', 'rs1057519784', (155, 161))	('signaling', 'biological_process', 'GO:0023052', ('263', '272'))	('ALK', 'Gene', '238', (57, 60))	('ALK', 'Gene', (125, 128))
50881	28030802	With ceritinib, there already exists some emerging data that ALK-G1202R and F1174V/C mutations confer some resistance to therapy.	('resistance to therapy', 'MPA', (107, 128))	('F1174V', 'Var', (76, 82))	('ALK', 'Gene', (61, 64))	('F1174V', 'SUBSTITUTION', 'None', (76, 82))	('ceritinib', 'Chemical', 'MESH:C586847', (5, 14))	('ALK', 'Gene', '238', (61, 64))	('G1202R', 'Mutation', 'rs1057519783', (65, 71))
50884	28030802	Several pre-clinical studies have highlighted a significant gatekeeper mutation (FGFR1 V561M, FGFR2 V564I, FGFR3 V555M, FGFR4 V550M) that renders targeted therapy ineffective.	('V561M', 'Mutation', 'p.V561M', (87, 92))	('FGFR1', 'Gene', (81, 86))	('FGFR2', 'Gene', (94, 99))	('V564I', 'Var', (100, 105))	('gatekeeper', 'Species', '111938', (60, 70))	('FGFR2', 'Gene', '2263', (94, 99))	('V550M', 'Mutation', 'rs774571806', (126, 131))	('FGFR1', 'Gene', '2260', (81, 86))	('V555M', 'Mutation', 'rs199544087', (113, 118))	('FGFR3', 'Gene', (107, 112))	('V555M', 'Var', (113, 118))	('V561M', 'Var', (87, 92))	('V564I', 'Mutation', 'rs1057519797', (100, 105))
50885	28030802	Preclinical cellular models harboring the FGFR3 V555M mutation have demonstrated resistance to AZD4547.	('resistance', 'MPA', (81, 91))	('FGFR3', 'Gene', (42, 47))	('V555M', 'Mutation', 'rs199544087', (48, 53))	('AZD4547', 'Chemical', 'MESH:C572463', (95, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('42', '46'))	('V555M', 'Var', (48, 53))
50886	28030802	Recently, the FGFR1 V561M gatekeeper mutation was characterized at a structural and kinetic level where a 38-fold increase in autophosphorylation of the receptor was demonstrated.	('increase', 'PosReg', (114, 122))	('gatekeeper', 'Species', '111938', (26, 36))	('V561M', 'Var', (20, 25))	('FGFR1', 'Gene', (14, 19))	('autophosphorylation', 'MPA', (126, 145))	('FGFR1', 'Gene', '2260', (14, 19))	('V561M', 'Mutation', 'p.V561M', (20, 25))
50887	28030802	Interestingly, the mutated receptor still maintained affinity for AZD4547.	('affinity', 'MPA', (53, 61))	('AZD4547', 'Chemical', 'MESH:C572463', (66, 73))	('AZD4547', 'Var', (66, 73))	('mutated', 'Var', (19, 26))
50888	28030802	Subsequent generations of FGFR inhibitors will need to be able to circumvent these cellular defense mechanisms, and there exist two compounds FIIN-2 and FIIN-3 developed in preclinical studies that have demonstrated potency against wild type FGFR1-4 as well as receptors with gatekeeper mutations.	('FGF', 'Gene', (26, 29))	('FGFR1', 'Gene', '2260', (242, 247))	('gatekeeper', 'Species', '111938', (276, 286))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (242, 245))	('FGFR', 'molecular_function', 'GO:0005007', ('242', '246'))	('potency', 'MPA', (216, 223))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (26, 29))	('mutations', 'Var', (287, 296))	('FGFR', 'molecular_function', 'GO:0005007', ('26', '30'))	('FGF', 'Gene', (242, 245))	('FGFR1', 'Gene', (242, 247))
50891	28030802	When designing clinical trials, we should exclude tumors with the aforementioned gatekeeper mutations of FGFR known to confer possible resistance to currently available selective FGFR inhibitors.	('FGF', 'Gene', (105, 108))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('gatekeeper', 'Species', '111938', (81, 91))	('mutations', 'Var', (92, 101))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (105, 108))	('FGFR', 'molecular_function', 'GO:0005007', ('179', '183'))	('FGF', 'Gene', (179, 182))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (179, 182))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('FGFR', 'molecular_function', 'GO:0005007', ('105', '109'))
50910	28030802	Already in other known targetable mutations discussed above, such as EGFR in colorectal cancer or BCR-ABL1 in CML, the use of next generation sequencing (NGS) has proved invaluable in identifying not only actionable mutations, but also for screening "gatekeeper" mutations that may confer resistance to therapy.	('EGFR', 'Gene', '1956', (69, 73))	('colorectal cancer', 'Disease', (77, 94))	('EGFR', 'Gene', (69, 73))	('BCR-ABL1', 'Gene', (98, 106))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('CML', 'Disease', 'MESH:D015464', (110, 113))	('CML', 'Phenotype', 'HP:0005506', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('gatekeeper', 'Species', '111938', (251, 261))	('mutations', 'Var', (216, 225))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('CML', 'Disease', (110, 113))
50911	28030802	As selective FGFR inhibitors get closer to routine clinical use, we can learn from the past especially with regards to patient selection as it predicts response to therapy.	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('patient', 'Species', '9606', (119, 126))	('FGF', 'Gene', (13, 16))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (13, 16))	('inhibitors', 'Var', (18, 28))
50915	28030802	The use of massive parallel DNA sequencing technology allows for noting differences in disease response based on FGFR mutation or fusion in lung, which may be important in a minority of lung cancers and this detail would be easily missed with FISH or IHC.	('fusion', 'Var', (130, 136))	('lung cancers', 'Phenotype', 'HP:0100526', (186, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('FGF', 'Gene', (113, 116))	('lung cancers', 'Disease', (186, 198))	('mutation', 'Var', (118, 126))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('lung cancers', 'Disease', 'MESH:D008175', (186, 198))
50917	28030802	This is an ideal platform to discover unusual responders to FGFR inhibitor therapy with the goal of identifying new and relevant FGF/FGFR alterations, especially with the addition of rare tumors that might otherwise not have enrolled in a clinical trial.	('tumors', 'Disease', (188, 194))	('FGF', 'Gene', (129, 132))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('FGF', 'Gene', (60, 63))	('FGF', 'Gene', (133, 136))	('alterations', 'Var', (138, 149))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (60, 63))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (129, 132))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (133, 136))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))
50918	28030802	Despite the advances in drug design to include the second-generation selective FGFR inhibitors, the biology of FGF/FGFR signaling is complex and we have seen that response to therapy is dependent on a multitude of factors.	('FGF', 'Gene', (115, 118))	('inhibitors', 'Var', (84, 94))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (79, 82))	('FGFR', 'molecular_function', 'GO:0005007', ('115', '119'))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (111, 114))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (115, 118))	('FGF', 'Gene', (79, 82))	('signaling', 'biological_process', 'GO:0023052', ('120', '129'))	('FGF', 'Gene', (111, 114))
50919	28030802	At the present time, targeting FGFR fusion aberrations has demonstrated the best response; we see this in bladder cancer with encouraging results.	('bladder cancer', 'Disease', 'MESH:D001749', (106, 120))	('bladder cancer', 'Disease', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('aberrations', 'Var', (43, 54))	('FGF', 'Gene', (31, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (106, 120))	('FGF', 'Gene', '2246;2247;54250;2249;2252;9965;8074', (31, 34))
50921	28030802	This is of interest given that the tumors in which FGFR3-TACC3 mutations have been identified (2.6% of urothelial carcinoma cases, 1.2-8.3% of GBM) are on the more aggressive end of the spectrum with overall limited treatment options.	('mutations', 'Var', (63, 72))	('urothelial carcinoma', 'Disease', (103, 123))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('FGFR', 'molecular_function', 'GO:0005007', ('51', '55'))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('FGFR3-TACC3', 'Gene', (51, 62))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (103, 123))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
50928	26289647	He was diagnosed with hyperhomocysteinemia associated with a homozygous C677T mutation of the gene encoding the enzyme methylenetetrahydrofolate reductase.	('methylenetetrahydrofolate reductase', 'Gene', (119, 154))	('hyperhomocysteinemia', 'Disease', (22, 42))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (119, 154))	('C677T', 'Mutation', 'rs1801133', (72, 77))	('hyperhomocysteinemia', 'Disease', 'MESH:D020138', (22, 42))	('associated', 'Reg', (43, 53))	('C677T', 'Var', (72, 77))
50943	26289647	MTHF is formed from folic acid by the enzyme N5, N10 methylenetetrahydrofolate reductase (MTHFR).This MET recovery pathway contributes to regulating the serum Hcy concentration, and alterations therein underlie the development of Hcy-related atherosclerosis.	('MET', 'Chemical', 'MESH:D008715', (102, 105))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (53, 88))	('atherosclerosis', 'Disease', 'MESH:D050197', (242, 257))	('atherosclerosis', 'Phenotype', 'HP:0002621', (242, 257))	('methylenetetrahydrofolate reductase', 'Gene', (53, 88))	('folic acid', 'Chemical', 'MESH:D005492', (20, 30))	('atherosclerosis', 'Disease', (242, 257))	('MET recovery pathway', 'Pathway', (102, 122))	('MTHF', 'Chemical', 'MESH:C005984', (0, 4))	('Hcy', 'Chemical', 'MESH:D006710', (230, 233))	('MTHFR', 'Gene', '4524', (90, 95))	('Hcy', 'Chemical', 'MESH:D006710', (159, 162))	('serum Hcy concentration', 'MPA', (153, 176))	('underlie', 'Reg', (202, 210))	('alterations', 'Var', (182, 193))	('MTHF', 'Chemical', 'MESH:C005984', (90, 94))	('MTHFR', 'Gene', (90, 95))
50948	26289647	Two known MTHFR polymorphisms are associated with the reduced activity of the enzyme and therefore with increased levels of Hcy: the C677T polymorphism and the A1298C polymorphism.	('C677T', 'Mutation', 'rs1801133', (133, 138))	('C677T', 'Var', (133, 138))	('activity', 'MPA', (62, 70))	('increased', 'PosReg', (104, 113))	('MTHFR', 'Gene', '4524', (10, 15))	('A1298C', 'Mutation', 'rs1801131', (160, 166))	('levels of Hcy', 'MPA', (114, 127))	('A1298C polymorphism', 'Var', (160, 179))	('reduced', 'NegReg', (54, 61))	('MTHFR', 'Gene', (10, 15))	('Hcy', 'Chemical', 'MESH:D006710', (124, 127))
50950	26289647	MTHFR mutations are relatively common.	('MTHFR', 'Gene', (0, 5))	('MTHFR', 'Gene', '4524', (0, 5))	('mutations', 'Var', (6, 15))
50951	26289647	For example, homozygosity for MTHFR C677T is present in 0-3% of African Americans and in 9-11% of Caucasian Americans.	('C677T', 'Mutation', 'rs1801133', (36, 41))	('MTHFR', 'Gene', '4524', (30, 35))	('C677T', 'Var', (36, 41))	('MTHFR', 'Gene', (30, 35))
50953	26289647	However, in rare cases defects in MTHFR cause severe increases in plasma Hcy, leading to gait abnormalities, seizures, and psychiatric manifestations.	('psychiatric', 'Disease', 'MESH:D001523', (123, 134))	('seizures', 'Phenotype', 'HP:0001250', (109, 117))	('MTHFR', 'Gene', '4524', (34, 39))	('seizures', 'Disease', (109, 117))	('plasma Hcy', 'MPA', (66, 76))	('psychiatric manifestations', 'Phenotype', 'HP:0000708', (123, 149))	('gait abnormalities', 'Disease', (89, 107))	('Hcy', 'Chemical', 'MESH:D006710', (73, 76))	('defects', 'Var', (23, 30))	('MTHFR', 'Gene', (34, 39))	('leading to', 'Reg', (78, 88))	('seizures', 'Disease', 'MESH:D012640', (109, 117))	('increases', 'PosReg', (53, 62))	('man', 'Species', '9606', (135, 138))	('psychiatric', 'Disease', (123, 134))	('gait abnormalities', 'Disease', 'MESH:D020233', (89, 107))	('gait abnormalities', 'Phenotype', 'HP:0001288', (89, 107))
50965	26289647	A subsequent molecular analysis showed homozygosity for the MTHFR C677T mutation.	('MTHFR', 'Gene', '4524', (60, 65))	('C677T', 'Mutation', 'rs1801133', (66, 71))	('MTHFR', 'Gene', (60, 65))	('C677T', 'Var', (66, 71))
50981	26289647	This association is supported by the high frequency of homozygosity for the C677T MTHFR gene polymorphism in patients with RVO.	('MTHFR', 'Gene', (82, 87))	('patients', 'Species', '9606', (109, 117))	('RVO', 'Disease', (123, 126))	('RVO', 'Phenotype', 'HP:0012636', (123, 126))	('C677T', 'Mutation', 'rs1801133', (76, 81))	('MTHFR', 'Gene', '4524', (82, 87))	('C677T', 'Var', (76, 81))
50985	26289647	Chemotherapy enhances the risk of thrombosis by causing endothelial damage.	('endothelial', 'MPA', (56, 67))	('thrombosis', 'Disease', 'MESH:D013927', (34, 44))	('causing', 'Reg', (48, 55))	('Chemotherapy', 'Var', (0, 12))	('thrombosis', 'Disease', (34, 44))
50988	26289647	The anesthetic agent with the greatest impact on folate metabolism is N2O, which deactivates cobalamin via an oxidation reaction and causes an irreversible block of MET synthase, located at the confluence of Hcy methylation and the folate cycle.	('cobalamin', 'Protein', (93, 102))	('deactivates', 'NegReg', (81, 92))	('MET synthase', 'Enzyme', (165, 177))	('Hcy', 'Chemical', 'MESH:D006710', (208, 211))	('MET', 'Chemical', 'MESH:D008715', (165, 168))	('folate', 'Chemical', 'MESH:D005492', (49, 55))	('block', 'NegReg', (156, 161))	('oxidation reaction', 'MPA', (110, 128))	('cobalamin', 'Chemical', 'MESH:D014805', (93, 102))	('folate', 'Chemical', 'MESH:D005492', (232, 238))	('N2O', 'Var', (70, 73))	('N2O', 'Chemical', 'MESH:D009609', (70, 73))
50990	26289647	Therefore, N2O-induced MET synthase inhibition in patients with MTFR mutations can cause severe hematological and neurological effects and the use of N2O during anesthesia should therefore be avoided in this cohort.	('mutations', 'Var', (69, 78))	('patients', 'Species', '9606', (50, 58))	('N2O', 'Chemical', 'MESH:D009609', (150, 153))	('inhibition', 'NegReg', (36, 46))	('MET synthase', 'MPA', (23, 35))	('N2O', 'Chemical', 'MESH:D009609', (11, 14))	('MTFR', 'Gene', (64, 68))	('MET', 'Chemical', 'MESH:D008715', (23, 26))
50991	26289647	Over the last 30 years, more than a dozen clinical cases have been published in which N2O anesthesia led to neurological complications, including myelopathy, peripheral neuropathy, and hemiparesis, caused by a lack of MET in the brain.	('neurological complications', 'Disease', 'MESH:D002493', (108, 134))	('myelopathy', 'Disease', 'MESH:D013118', (146, 156))	('lack', 'NegReg', (210, 214))	('myelopathy', 'Disease', (146, 156))	('peripheral neuropathy', 'Disease', (158, 179))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (158, 179))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (158, 179))	('hemiparesis', 'Disease', 'MESH:D010291', (185, 196))	('N2O', 'Var', (86, 89))	('led to', 'Reg', (101, 107))	('hemiparesis', 'Phenotype', 'HP:0001269', (185, 196))	('neurological complications', 'Disease', (108, 134))	('hemiparesis', 'Disease', (185, 196))	('N2O', 'Chemical', 'MESH:D009609', (86, 89))	('myelopathy', 'Phenotype', 'HP:0002196', (146, 156))	('MET', 'Chemical', 'MESH:D008715', (218, 221))
50992	26289647	The neurological damage caused by N2O is often accompanied by hematological abnormalities, such as megaloblastic anemia and bone marrow disorders.	('megaloblastic anemia', 'Phenotype', 'HP:0001889', (99, 119))	('bone marrow disorders', 'Disease', 'MESH:D001855', (124, 145))	('megaloblastic anemia', 'Disease', (99, 119))	('N2O', 'Var', (34, 37))	('hematological abnormalities', 'Disease', (62, 89))	('hematological abnormalities', 'Disease', 'MESH:D006402', (62, 89))	('bone marrow disorders', 'Disease', (124, 145))	('N2O', 'Chemical', 'MESH:D009609', (34, 37))	('megaloblastic anemia', 'Disease', 'MESH:D000749', (99, 119))	('hematological abnormalities', 'Phenotype', 'HP:0001871', (62, 89))	('neurological damage', 'Disease', (4, 23))	('bone marrow disorders', 'Phenotype', 'HP:0005561', (124, 145))	('anemia', 'Phenotype', 'HP:0001903', (113, 119))	('neurological damage', 'Disease', 'MESH:D009422', (4, 23))
50994	26289647	This hypothesis links HHcy and the N2O-induced inhibition of folate metabolism with a defect in the MTHFR gene.	('defect', 'Var', (86, 92))	('folate metabolism', 'MPA', (61, 78))	('MTHFR', 'Gene', '4524', (100, 105))	('Hcy', 'Chemical', 'MESH:D006710', (23, 26))	('inhibition', 'NegReg', (47, 57))	('folate', 'Chemical', 'MESH:D005492', (61, 67))	('N2O', 'Chemical', 'MESH:D009609', (35, 38))	('MTHFR', 'Gene', (100, 105))
50998	26289647	Although the inhibition of cobalamin and HHcy after N2O administration is transient, lasting only for a few days, the effect coincides with the postoperative period, during which the patient is particularly vulnerable, as evidenced by the very high risk of serious cardiovascular complications on postoperative days 2 and 3.	('cardiovascular complications', 'Disease', (265, 293))	('N2O', 'Chemical', 'MESH:D009609', (52, 55))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (265, 293))	('cardiovascular complications', 'Disease', 'MESH:D002318', (265, 293))	('cobalamin', 'Chemical', 'MESH:D014805', (27, 36))	('Hcy', 'Chemical', 'MESH:D006710', (42, 45))	('patient', 'Species', '9606', (183, 190))	('inhibition', 'NegReg', (13, 23))	('N2O', 'Var', (52, 55))	('cobalamin', 'Protein', (27, 36))	('HHcy', 'Gene', (41, 45))
51002	26289647	Recent studies have also shown that patients homozygous for the MTHFR mutation who receive N2O anesthesia have higher postoperative plasma Hcy levels than patients who are heterozygous for the mutation or carry the wild-type gene.	('MTHFR', 'Gene', '4524', (64, 69))	('plasma Hcy levels', 'MPA', (132, 149))	('patients', 'Species', '9606', (36, 44))	('Hcy', 'Chemical', 'MESH:D006710', (139, 142))	('N2O', 'Chemical', 'MESH:D009609', (91, 94))	('MTHFR', 'Gene', (64, 69))	('higher', 'PosReg', (111, 117))	('patients', 'Species', '9606', (155, 163))	('mutation', 'Var', (70, 78))	('postoperative', 'MPA', (118, 131))
51007	26289647	Another consideration related to the MTHFR mutation is its association with colorectal cancer and its interference with chemotherapy.	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('MTHFR', 'Gene', (37, 42))	('association', 'Interaction', (59, 70))	('mutation', 'Var', (43, 51))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('colorectal cancer', 'Disease', (76, 93))	('MTHFR', 'Gene', '4524', (37, 42))
51009	26289647	In previous work, we analyzed the relationship between C677T and A1298C MTHFR gene polymorphisms and the biological, pathological, genetic, and epigenetic characteristics of several different tumor types and their response to chemotherapy with 5-fluorouracil.	('A1298C', 'Mutation', 'rs1801131', (65, 71))	('tumor', 'Disease', (192, 197))	('A1298C', 'Var', (65, 71))	('MTHFR', 'Gene', '4524', (72, 77))	('C677T', 'Mutation', 'rs1801133', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('C677T', 'Var', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('MTHFR', 'Gene', (72, 77))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (244, 258))
51011	26289647	While some authors have reported the protective effect of the allelic variant C677T in the development of several cancers, the meta-analysis of Pu et al.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('C677T', 'Mutation', 'rs1801133', (78, 83))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('C677T', 'Var', (78, 83))	('cancers', 'Disease', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))
51014	26289647	both the MTHFR 677T and the 1298C alleles are associated with a low risk of colorectal cancer.	('1298C', 'Var', (28, 33))	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('MTHFR', 'Gene', '4524', (9, 14))	('colorectal cancer', 'Disease', (76, 93))	('MTHFR', 'Gene', (9, 14))
51022	26289647	The ENIGMA II study showed that N2O does not increase the risk of death and cardiovascular complications or surgical site infection in patients undergoing major noncardiac surgery.	('N2O', 'Chemical', 'MESH:D009609', (32, 35))	('patients', 'Species', '9606', (135, 143))	('infection', 'Disease', (122, 131))	('infection', 'Disease', 'MESH:D007239', (122, 131))	('death and cardiovascular complications', 'Disease', 'MESH:D002318', (66, 104))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (76, 104))	('N2O', 'Var', (32, 35))
51024	26289647	Whether MTHFR gene polymorphisms are associated with an increased risk of N2O-induced cardiac events remains to be determined.	('MTHFR', 'Gene', (8, 13))	('polymorphisms', 'Var', (19, 32))	('N2O', 'Chemical', 'MESH:D009609', (74, 77))	('MTHFR', 'Gene', '4524', (8, 13))	('associated', 'Reg', (37, 47))	('N2O-induced cardiac events', 'Disease', (74, 100))
51026	26289647	Finally, our results have oncological implications, as they suggest that MTHFR polymorphisms influence the susceptibility to colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (125, 142))	('polymorphisms', 'Var', (79, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (125, 142))	('MTHFR', 'Gene', '4524', (73, 78))	('colorectal cancer', 'Disease', (125, 142))	('influence', 'Reg', (93, 102))	('MTHFR', 'Gene', (73, 78))
51139	25091112	It should be noted that significant differences (e.g., PC(34:1) at m/z 798.5426, PC(38:4) at m/z 832.5818, and C18:1 at m/z 281.2484) were observed between the cancerous area and the adjacent normal area in the positive and negative ion modes, respectively.	('C18:1 at m/z 281.2484', 'Var', (111, 132))	('cancerous', 'Disease', (160, 169))	('m/z 832.5818', 'Var', (93, 105))	('cancerous', 'Disease', 'MESH:D009369', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
51145	25091112	MUFAs (i.e., C16:1 at m/z 253.2174 and C18:1 at m/z 281.2484) in the cancerous area presented high intensities compared with those in the adjacent normal area, whereas PUFAs, PE and PI with polyunsaturated acyl chains (i.e., C22:4 at m/z 331.2645, [PE(38:4)-H]- at m/z 750.5441, and [PI(38:4)-H]- at m/z 885.5499) in the cancerous area had a lower level than those in the adjacent normal area.	('cancerous', 'Disease', (69, 78))	('cancerous', 'Disease', 'MESH:D009369', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('C18:1', 'Var', (39, 44))	('cancerous', 'Disease', (321, 330))	('FAs', 'Chemical', 'MESH:D005227', (2, 5))	('FAs', 'Chemical', 'MESH:D005227', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('C22:4', 'Var', (225, 230))	('cancerous', 'Disease', 'MESH:D009369', (321, 330))
51146	25091112	However, some exceptions were also observed for the alteration in the levels of these lipids, for example, the levels of C20:4 and PI(38:4) were increased in thyroid cancer, whereas no difference in their levels was detected between the cancerous area and the adjacent normal area for esophageal and gastric cancer.	('C20:4', 'Var', (121, 126))	('thyroid cancer', 'Disease', 'MESH:D013964', (158, 172))	('levels', 'MPA', (111, 117))	('lipids', 'Chemical', 'MESH:D008055', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancerous', 'Disease', 'MESH:D009369', (237, 246))	('gastric cancer', 'Phenotype', 'HP:0012126', (300, 314))	('thyroid cancer', 'Phenotype', 'HP:0002890', (158, 172))	('increased', 'PosReg', (145, 154))	('thyroid cancer', 'Disease', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('gastric cancer', 'Disease', (300, 314))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('cancerous', 'Disease', (237, 246))	('gastric cancer', 'Disease', 'MESH:D013274', (300, 314))
51150	25091112	PLS-DA score plot revealed the obvious differences between the cancerous area and the adjacent normal area from the patients with breast, colorectal, esophageal, lung, gastric, and thyroid cancer, with the predicted residual sum of square (PRESS) of 0.4603, 0.5379, 0.3757, 0.5069, 0.4125 and 0.4018, respectively (Fig.	('esophageal', 'Disease', (150, 160))	('colorectal', 'Disease', (138, 148))	('0.4018', 'Var', (293, 299))	('0.3757', 'Var', (266, 272))	('gastric', 'Disease', (168, 175))	('0.5069', 'Var', (274, 280))	('cancerous', 'Disease', 'MESH:D009369', (63, 72))	('thyroid cancer', 'Disease', 'MESH:D013964', (181, 195))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung', 'Disease', (162, 166))	('patients', 'Species', '9606', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('0.4125', 'Var', (282, 288))	('thyroid cancer', 'Phenotype', 'HP:0002890', (181, 195))	('thyroid cancer', 'Disease', (181, 195))	('breast', 'Disease', (130, 136))	('cancerous', 'Disease', (63, 72))	('0.5379', 'Var', (258, 264))
51155	25091112	Finally, 18 common variables labeled in blue were extracted, which were strongly associated with six types of cancer, and they are C16:1, C18:1, C20:1, PC(32:1), PC(34:1), PC(36:1), C20:4, C22:4, C22:5, PC(38:4), PC(38:6), PA(36:2), PA(38:3), PA(40:5), PE(38:4), PI(38:4), SM(22:0), and SM(24:1).	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('C22:5', 'Var', (196, 201))	('cancer', 'Disease', (110, 116))	('PC(34:1', 'Var', (162, 169))	('C20:1', 'Var', (145, 150))	('C22:4', 'Var', (189, 194))	('associated', 'Reg', (81, 91))	('C16:1', 'Var', (131, 136))	('PI(38:4', 'Var', (263, 270))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('C18:1', 'Var', (138, 143))	('PC(32:1', 'Var', (152, 159))	('PC(36:1', 'Var', (172, 179))	('C20:4', 'Var', (182, 187))	('PA(38:3', 'Var', (233, 240))	('PC(38:6', 'Var', (213, 220))	('PC(38:4', 'Var', (203, 210))
51157	25091112	It is worth noting that the levels of MUPCs (i.e., PC(32:1), PC(34:1), and PC(36:1)) and MUFAs (i.e., C16:1, C18:1, and C20:1) in the cancerous area were significantly increased compared with those in the adjacent normal area (Wilcoxon-Mann-Whitney test, p <0.05), whereas polyunsaturated lipids (i.e., PC(38:4), PC(38:6), PA(38:3), PA(40:5), PE(38:4), and PI(38:4)) and PUFAs (i.e., C20:4, C22:4, and C22:5) in the cancerous area were remarkably decreased compared with those in the adjacent normal area (Wilcoxon-Mann-Whitney test, p <0.05) except thyroid cancer.	('C22:5', 'Var', (402, 407))	('cancer', 'Phenotype', 'HP:0002664', (416, 422))	('decreased', 'NegReg', (447, 456))	('cancerous', 'Disease', 'MESH:D009369', (416, 425))	('C22:4', 'Var', (391, 396))	('PCs', 'Chemical', 'MESH:D010713', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (558, 564))	('thyroid cancer', 'Disease', (550, 564))	('FAs', 'Chemical', 'MESH:D005227', (373, 376))	('cancerous', 'Disease', (416, 425))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancerous', 'Disease', 'MESH:D009369', (134, 143))	('polyunsaturated lipids', 'Chemical', '-', (273, 295))	('C20:1', 'Var', (120, 125))	('C18:1', 'Var', (109, 114))	('thyroid cancer', 'Disease', 'MESH:D013964', (550, 564))	('FAs', 'Chemical', 'MESH:D005227', (91, 94))	('C16:1', 'Var', (102, 107))	('increased', 'PosReg', (168, 177))	('thyroid cancer', 'Phenotype', 'HP:0002890', (550, 564))	('cancerous', 'Disease', (134, 143))	('polyunsaturated lipids', 'MPA', (273, 295))
51161	25091112	S2, for breast, colorectal, and esophageal cancer, MUFAs (i.e., C16:1, C18:1, and C20:1) were strongly and positively correlated with MUPCs (i.e., PC(32:1), PC(34:1), and PC(36:1)), whereas both were negatively correlated with polyunsaturated lipids.	('esophageal cancer', 'Disease', 'MESH:D004938', (32, 49))	('C20:1', 'Var', (82, 87))	('C18:1', 'Var', (71, 76))	('colorectal', 'Disease', (16, 26))	('PCs', 'Chemical', 'MESH:D010713', (136, 139))	('correlated', 'Reg', (118, 128))	('breast', 'Disease', (8, 14))	('FAs', 'Chemical', 'MESH:D005227', (53, 56))	('MUPCs', 'Disease', (134, 139))	('polyunsaturated lipids', 'Chemical', '-', (227, 249))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('esophageal cancer', 'Disease', (32, 49))	('C16:1', 'Var', (64, 69))
51162	25091112	PUFAs (i.e., C20:4, C22:4, and C22:5) were strongly and positively correlated with polyunsaturated lipids (i.e., PC(38:4), PC(38:6), PA(38:3), PA(40:5), PE(38:4), and PI(38:4)); for lung and gastric cancer, the above-mentioned correlations became slightly lower; and for thyroid cancer, there were no obvious correlations among the above-mentioned lipids in the cancerous area.	('gastric cancer', 'Disease', (191, 205))	('correlated', 'Reg', (67, 77))	('lipids', 'Chemical', 'MESH:D008055', (348, 354))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancerous', 'Disease', (362, 371))	('gastric cancer', 'Disease', 'MESH:D013274', (191, 205))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('polyunsaturated lipids', 'Chemical', '-', (83, 105))	('lipids', 'Chemical', 'MESH:D008055', (99, 105))	('thyroid cancer', 'Disease', (271, 285))	('lower', 'NegReg', (256, 261))	('lung', 'Disease', (182, 186))	('gastric cancer', 'Phenotype', 'HP:0012126', (191, 205))	('C22:5', 'Var', (31, 36))	('polyunsaturated lipids', 'MPA', (83, 105))	('C22:4', 'Var', (20, 25))	('thyroid cancer', 'Disease', 'MESH:D013964', (271, 285))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('cancerous', 'Disease', 'MESH:D009369', (362, 371))	('FAs', 'Chemical', 'MESH:D005227', (2, 5))	('thyroid cancer', 'Phenotype', 'HP:0002890', (271, 285))
51165	25091112	S3, most ratios of MUFAs/SFAs in the cancerous area were significantly higher than those in the adjacent normal area except the ratio of C16:1/C16:0 in thyroid cancer.	('higher', 'PosReg', (71, 77))	('thyroid cancer', 'Disease', (152, 166))	('FAs', 'Chemical', 'MESH:D005227', (21, 24))	('cancerous', 'Disease', (37, 46))	('thyroid cancer', 'Phenotype', 'HP:0002890', (152, 166))	('thyroid cancer', 'Disease', 'MESH:D013964', (152, 166))	('C16:1/C16:0', 'Var', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancerous', 'Disease', 'MESH:D009369', (37, 46))	('FAs', 'Chemical', 'MESH:D005227', (26, 29))
51167	25091112	The ratio of PC(34:1)/PC(34:0) in lung or thyroid cancerous area was significantly increased or decreased compared with that in their individual corresponding adjacent normal area, whereas no difference in this ratio was detected between the cancerous area and the adjacent normal area for breast, colorectal, esophageal, and gastric cancer.	('lung', 'Disease', (34, 38))	('gastric cancer', 'Disease', 'MESH:D013274', (326, 340))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('increased', 'PosReg', (83, 92))	('decreased', 'NegReg', (96, 105))	('cancerous', 'Disease', (242, 251))	('thyroid cancerous', 'Disease', (42, 59))	('cancerous', 'Disease', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('colorectal', 'Disease', (298, 308))	('gastric cancer', 'Phenotype', 'HP:0012126', (326, 340))	('breast', 'Disease', (290, 296))	('thyroid cancer', 'Phenotype', 'HP:0002890', (42, 56))	('PC(34:1)/PC(', 'Var', (13, 25))	('gastric cancer', 'Disease', (326, 340))	('cancerous', 'Disease', 'MESH:D009369', (242, 251))	('cancerous', 'Disease', 'MESH:D009369', (50, 59))	('thyroid cancerous', 'Disease', 'MESH:D013964', (42, 59))	('esophageal', 'Disease', (310, 320))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
51179	25091112	For breast cancer, the levels of PC(38:3), PC(38:4), C22:4, C20:2, C20:3, PC(36:0), PC(38:5), and PC(36:1) were increased.	('C20:3', 'Var', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('C20:2', 'Var', (60, 65))	('C22:4', 'Var', (53, 58))
51180	25091112	The lipids of PC(38:2) and PC(34:1) in lung cancer and lipids of C22:3, PA(40:5), SM(36:2), PA(36:3), and PA(38:5) in thyroid cancer were also up-regulated.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('up-regulated', 'PosReg', (143, 155))	('lipids', 'Chemical', 'MESH:D008055', (4, 10))	('thyroid cancer', 'Disease', (118, 132))	('lung cancer', 'Disease', (39, 50))	('lipids', 'Chemical', 'MESH:D008055', (55, 61))	('thyroid cancer', 'Phenotype', 'HP:0002890', (118, 132))	('lipids', 'MPA', (4, 10))	('PA(40:5', 'Var', (72, 79))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('thyroid cancer', 'Disease', 'MESH:D013964', (118, 132))	('C22:3', 'Var', (65, 70))	('SM(36:2', 'Var', (82, 89))	('PC(34:1', 'Var', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
51189	25091112	1, MUPCs (i.e., PC(32:1), PC(34:1), and PC(36:1)) and MUFAs (i.e., C16:1 and C18:1) were significantly up-regulated and species with polyunsaturated fatty acyl chains (i.e., PC(38:4), PA(40:5), PE(38:4), PI(38:4)) and PUFAs (i.e., C20:4 and C22:4) were down-regulated in the cancerous area of six different types of cancer compared with those in the adjacent normal area.	('cancerous', 'Disease', (275, 284))	('C20:4', 'Var', (231, 236))	('FAs', 'Chemical', 'MESH:D005227', (220, 223))	('up-regulated', 'PosReg', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('PCs', 'Chemical', 'MESH:D010713', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('C22:4', 'Var', (241, 246))	('cancerous', 'Disease', 'MESH:D009369', (275, 284))	('FAs', 'Chemical', 'MESH:D005227', (56, 59))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', (316, 322))	('down-regulated', 'NegReg', (253, 267))	('cancer', 'Disease', (275, 281))
51197	25091112	S2, increase in the sum of FAs (C16:1, C16:0, C18:1, and C18:0) was positively correlated with the up-regulation of FASN in six types of cancer, indicating that FAs synthesis may play an important role in cancer pathogenesis.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('FASN', 'Gene', (116, 120))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('FASN', 'Gene', '2194', (116, 120))	('FAs', 'Chemical', 'MESH:D005227', (161, 164))	('cancer', 'Disease', (205, 211))	('FAs', 'Chemical', 'MESH:D005227', (27, 30))	('increase', 'PosReg', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('C16:0', 'Var', (39, 44))	('C18:0', 'Var', (57, 62))	('cancer', 'Disease', (137, 143))	('C16:1', 'Var', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('C18:1', 'Var', (46, 51))	('up-regulation', 'PosReg', (99, 112))
51207	25091112	This alteration of membrane fluidity may promote the carcinogenesis in six types of cancer.	('carcinogenesis', 'Disease', 'MESH:D063646', (53, 67))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('alteration', 'Var', (5, 15))	('carcinogenesis', 'Disease', (53, 67))	('cancer', 'Disease', (84, 90))	('promote', 'PosReg', (41, 48))	('membrane', 'cellular_component', 'GO:0016020', ('19', '27'))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
51208	25091112	On the other hand, polyunsaturated acyl chains are more susceptible to peroxidation, and oxidized lipid species may be ultimately degraded into smaller reactive products such as 4-hydroxyalkenal and malondialdehyde, which can cause cell damage, which are consistent with our observation that modulation of de novo lipogenesis has increased the ratio of monounsaturated lipids to polyunsaturated lipids in the cancerous tissue compared with that in the adjacent normal tissue, cancer cells are protected from oxidative stress-induced cell death.	('cancer', 'Phenotype', 'HP:0002664', (409, 415))	('malondialdehyde', 'Chemical', 'MESH:D008315', (199, 214))	('oxidative stress', 'Phenotype', 'HP:0025464', (508, 524))	('cancerous', 'Disease', (409, 418))	('lipid', 'Chemical', 'MESH:D008055', (369, 374))	('cell death', 'biological_process', 'GO:0008219', ('533', '543'))	('lipid', 'Chemical', 'MESH:D008055', (98, 103))	('polyunsaturated lipids', 'Chemical', '-', (379, 401))	('lipids', 'Chemical', 'MESH:D008055', (395, 401))	('cancer', 'Disease', (476, 482))	('increased', 'PosReg', (330, 339))	('lipids', 'Chemical', 'MESH:D008055', (369, 375))	('cancer', 'Phenotype', 'HP:0002664', (476, 482))	('cancer', 'Disease', 'MESH:D009369', (409, 415))	('cancerous', 'Disease', 'MESH:D009369', (409, 418))	('modulation', 'Var', (292, 302))	('lipid', 'Chemical', 'MESH:D008055', (395, 400))	('cancer', 'Disease', 'MESH:D009369', (476, 482))	('ratio', 'MPA', (344, 349))	('cancer', 'Disease', (409, 415))	('lipogenesis', 'biological_process', 'GO:0008610', ('314', '325'))	('degraded', 'NegReg', (130, 138))
51217	25091112	The alteration in the degree of lipid unsaturation generated by de novo lipogenic enzymes in the cancer microenvironment may related to carcinogenesis.	('related', 'Reg', (125, 132))	('cancer', 'Disease', (97, 103))	('carcinogenesis', 'Disease', 'MESH:D063646', (136, 150))	('carcinogenesis', 'Disease', (136, 150))	('alteration', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lipid', 'Chemical', 'MESH:D008055', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
51228	25091112	External calibration was performed using a lipid mixture (m/z 622.44423, m/z 734.56943, m/z 790.63203, and m/z 898.72593, which were from Avanti Polar Lipids, Inc., and identified by mass spectrometry) in positive ion mode and a tuning mixture (Part No.	('m/z 790.63203', 'Var', (88, 101))	('m/z 734.56943', 'Var', (73, 86))	('m/z 622.44423', 'Var', (58, 71))	('Lipids', 'Chemical', 'MESH:D008055', (151, 157))	('m/z 898.72593', 'Var', (107, 120))	('lipid', 'Chemical', 'MESH:D008055', (43, 48))
51236	25091112	These resulting sections were first incubated at room temperature with antibodies against FASN (1:250, Abcam, Cambridge, MA), SCD1 (1:200, Abcam), and CKalpha (1:200, Abcam), respectively, and then stored at 4 C overnight followed by rewarming at 37 C for 45 min.	('1:250', 'Var', (96, 101))	('SCD1', 'Gene', '6319', (126, 130))	('FASN', 'Gene', (90, 94))	('FASN', 'Gene', '2194', (90, 94))	('SCD1', 'Gene', (126, 130))
51334	22059907	Epigenetic changes in colorectal cancer Epigenetic changes frequently occur in human colorectal cancer.	('human', 'Species', '9606', (79, 84))	('colorectal cancer', 'Disease', (22, 39))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal cancer', 'Disease', (85, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (22, 39))	('occur', 'Reg', (70, 75))	('Epigenetic changes', 'Var', (40, 58))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (22, 39))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
51335	22059907	Genomic global hypomethylation, gene promoter region hypermethylation, histone modifications, and alteration of miRNA patterns are major epigenetic changes in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (159, 176))	('gene promoter region', 'MPA', (32, 52))	('colorectal cancer', 'Phenotype', 'HP:0003003', (159, 176))	('miRNA patterns', 'MPA', (112, 126))	('alteration', 'Reg', (98, 108))	('global hypomethylation', 'Var', (8, 30))	('histone', 'MPA', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('colorectal cancer', 'Disease', (159, 176))
51336	22059907	Loss of imprinting (LOI) is associated with colorectal neoplasia.	('Loss of', 'Var', (0, 7))	('associated', 'Reg', (28, 38))	('colorectal neoplasia', 'Disease', (44, 64))	('neoplasia', 'Phenotype', 'HP:0002664', (55, 64))	('imprinting', 'Protein', (8, 18))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (44, 64))
51339	22059907	Non-coding RNA is regarded as another kind of epigenetic marker in colorectal cancer.	('Non-coding RNA', 'Var', (0, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colorectal cancer', 'Disease', (67, 84))
51342	22059907	The accumulation of gene mutations and epigenetic alterations may drive the initiation and progression of benign adenoma to malignant adenocarcinoma.	('epigenetic alterations', 'Var', (39, 61))	('benign adenoma to malignant adenocarcinoma', 'Disease', 'MESH:D000230', (106, 148))	('benign adenoma to malignant adenocarcinoma', 'Disease', (106, 148))	('drive', 'PosReg', (66, 71))	('gene mutations', 'Var', (20, 34))
51343	22059907	Increasing evidence shows that aberrant epigenetic changes play important roles in human cancer.	('roles', 'Reg', (74, 79))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('human', 'Species', '9606', (83, 88))	('aberrant epigenetic changes', 'Var', (31, 58))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
51354	22059907	Promoter region hypermethylation is found in a variety of cancers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('found', 'Reg', (36, 41))	('hypermethylation', 'Var', (16, 32))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))
51357	22059907	Epigenetic silencing of numerous tumor suppressor genes by promoter region hypermethylation has been found in a variety of cancers, including CRC.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('found', 'Reg', (101, 106))	('numerous tumor', 'Disease', (24, 38))	('CRC', 'Phenotype', 'HP:0003003', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('tumor suppressor', 'biological_process', 'GO:0051726', ('33', '49'))	('Epigenetic silencing', 'Var', (0, 20))	('cancers', 'Disease', (123, 130))	('numerous tumor', 'Disease', 'MESH:D009369', (24, 38))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('33', '49'))	('CRC', 'Disease', (142, 145))
51358	22059907	Epigenetic changes were frequently found in precancerous lesions and adjacent tissues of CRC.	('precancerous lesions', 'Disease', 'MESH:D011230', (44, 64))	('precancerous lesions', 'Disease', (44, 64))	('CRC', 'Disease', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Epigenetic changes', 'Var', (0, 18))	('CRC', 'Phenotype', 'HP:0003003', (89, 92))	('found', 'Reg', (35, 40))
51359	22059907	Growth-regulatory genes have been found to be epigenetically silenced in colonic mucosa in elder individuals, which may increase risk of cancer associated with aging.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('epigenetically silenced', 'Var', (46, 69))	('Growth-regulatory genes', 'Gene', (0, 23))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('increase', 'PosReg', (120, 128))
51360	22059907	Methylation of ASC/TMS1 was reported to be a late-stage event in CRC, whereas hypermethylation of SOX17 is an early event of CRC.	('ASC', 'Gene', '29108', (15, 18))	('TMS1', 'Gene', (19, 23))	('TMS1', 'Gene', '29108', (19, 23))	('SOX17', 'Gene', '64321', (98, 103))	('Methylation', 'Var', (0, 11))	('CRC', 'Phenotype', 'HP:0003003', (65, 68))	('CRC', 'Phenotype', 'HP:0003003', (125, 128))	('ASC', 'Gene', (15, 18))	('SOX17', 'Gene', (98, 103))	('CRC', 'Disease', (65, 68))
51364	22059907	Gefitinib-sensitizing mutation is one of the examples.	('mutation', 'Var', (22, 30))	('Gefitinib-sensitizing', 'Disease', (0, 21))	('Gefitinib', 'Chemical', 'MESH:D000077156', (0, 9))
51371	22059907	It appears that cancers with high degrees of methylation (CIMP) represent a clinically and etiologically distinct group, one constituting "epigenetic instability," and seem to have distinct epidemiological, histological, and molecular features.	('cancers', 'Disease', (16, 23))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('methylation', 'Var', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('CIMP', 'Chemical', '-', (58, 62))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
51373	22059907	Recently, hypomethylation of CDH3 (P-cadherin) promoter was found in aberrant crypt foci (ACF) and CRC, with a potential field defect of CDH3 hypomethylation in the adjacent epithelium of cancer.	('CDH3', 'Gene', '1001', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('hypomethylation', 'Var', (10, 25))	('CDH3', 'Gene', (137, 141))	('CDH3', 'Gene', '1001', (137, 141))	('CRC', 'Disease', (99, 102))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('aberrant', 'Disease', (69, 77))	('found', 'Reg', (60, 65))	('cancer', 'Disease', (188, 194))	('CRC', 'Phenotype', 'HP:0003003', (99, 102))	('CDH3', 'Gene', (29, 33))
51374	22059907	In another study, a significant association was found between aberrant demethylation of CDH3 and tumor site or Dukes stage.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('CDH3', 'Gene', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CDH3', 'Gene', '1001', (88, 92))	('demethylation', 'biological_process', 'GO:0070988', ('71', '84'))	('tumor', 'Disease', (97, 102))	('aberrant demethylation', 'Var', (62, 84))	('Dukes stage', 'CPA', (111, 122))
51375	22059907	Promoter region hypomethylation is associated with induction of CDH3 expression in CRC.	('CDH3', 'Gene', (64, 68))	('CDH3', 'Gene', '1001', (64, 68))	('expression', 'MPA', (69, 79))	('CRC', 'Phenotype', 'HP:0003003', (83, 86))	('hypomethylation', 'Var', (16, 31))	('induction', 'PosReg', (51, 60))
51388	22059907	In general, methylation of H3K4, H3K36, and H3K79 are linked to gene expression activation, whereas H3K9me2, H3K9me3, H3K27me3 and H4K20 are associated with gene repression.	('H3', 'Gene', '126961', (109, 111))	('gene expression', 'MPA', (64, 79))	('methylation', 'biological_process', 'GO:0032259', ('12', '23'))	('H3', 'Gene', '126961', (44, 46))	('gene expression', 'biological_process', 'GO:0010467', ('64', '79'))	('H3', 'Gene', '126961', (27, 29))	('H3', 'Gene', '126961', (100, 102))	('H4K20', 'Var', (131, 136))	('H3', 'Gene', '126961', (118, 120))	('H3', 'Gene', '126961', (33, 35))	('methylation', 'Var', (12, 23))	('activation', 'PosReg', (80, 90))
51389	22059907	The global pattern of histone modifications has been considered a predictor for the risk of recurrence of human cancers.	('human', 'Species', '9606', (106, 111))	('histone', 'Protein', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('modifications', 'Var', (30, 43))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
51391	22059907	In cancer cells, disruption of the balance between HATs and HDACs contributes to transcriptional inactivation of tumor suppressor genes (TSGs).	('tumor', 'Disease', (113, 118))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('113', '129'))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('inactivation', 'NegReg', (97, 109))	('HDAC', 'Gene', (60, 64))	('transcriptional', 'MPA', (81, 96))	('cancer', 'Disease', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('disruption', 'Var', (17, 27))	('HDAC', 'Gene', '9734', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor suppressor', 'biological_process', 'GO:0051726', ('113', '129'))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
51392	22059907	Cyclin-dependent kinase inhibitor p21WAF1 is repressed by promoter hypoacetylation in the absence of CpG island hypermethylation, and expression can be reactivated by inhibition of HDAC activity.	('Cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('0', '33'))	('HDAC', 'Gene', '9734', (181, 185))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('17', '33'))	('HDAC', 'Gene', (181, 185))	('p21WAF1', 'Var', (34, 41))
51393	22059907	Interestingly, some TSGs with CpG island hypermethylation can also be re-expressed through inhibition of SIRT1, a class III HDAC that increases H4K16 and H3K9 acetylation at promoters, without affecting the hypermethylation status.	('H4K16', 'Protein', (144, 149))	('hypermethylation', 'Var', (41, 57))	('SIRT1', 'Gene', '23411', (105, 110))	('HDAC', 'Gene', (124, 128))	('HDAC', 'Gene', '9734', (124, 128))	('H3', 'Gene', '126961', (154, 156))	('SIRT1', 'Gene', (105, 110))	('inhibition', 'NegReg', (91, 101))	('increases', 'PosReg', (134, 143))	('acetylation', 'MPA', (159, 170))
51395	22059907	Methylation takes place on both lysine and arginine residues and has different degrees, including mono-, di-, and trimethylation.	('arginine', 'Chemical', 'MESH:D001120', (43, 51))	('di-', 'MPA', (105, 108))	('Methylation', 'Var', (0, 11))	('lysine', 'Chemical', 'MESH:D008239', (32, 38))	('mono-', 'MPA', (98, 103))	('trimethylation', 'MPA', (114, 128))	('arginine', 'Protein', (43, 51))
51401	22059907	DNA methylation maintains key repressive elements of the histone code at a hypermethylated gene promoter in RKO colon cancer cells.	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('men', 'Species', '9606', (44, 47))	('colon cancer', 'Disease', 'MESH:D015179', (112, 124))	('colon cancer', 'Phenotype', 'HP:0003003', (112, 124))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('methylation', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('colon cancer', 'Disease', (112, 124))	('RKO', 'CellLine', 'CVCL:0504', (108, 111))
51402	22059907	hMLH1, a mismatch repair gene, is often silenced by aberrant CpG island hypermethylation in colorectal cancers.	('hMLH1', 'Gene', (0, 5))	('colorectal cancers', 'Disease', (92, 110))	('mismatch repair', 'biological_process', 'GO:0006298', ('9', '24'))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('hMLH1', 'Gene', '4292', (0, 5))	('silenced', 'NegReg', (40, 48))	('hypermethylation', 'Var', (72, 88))	('aberrant', 'Var', (52, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('colorectal cancers', 'Disease', 'MESH:D015179', (92, 110))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))
51405	22059907	Alterations in HDACs are found in many human cancers including CRC.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('CRC', 'Phenotype', 'HP:0003003', (63, 66))	('human', 'Species', '9606', (39, 44))	('Alterations', 'Var', (0, 11))	('HDAC', 'Gene', (15, 19))	('HDAC', 'Gene', '9734', (15, 19))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))	('found', 'Reg', (25, 30))	('CRC', 'Disease', (63, 66))
51410	22059907	Histone deacetylase inhibitors (HDACi), such as short chain fatty acid and butyrate, have been recognized and utilized to induce growth arrest, differentiation, and apoptosis for several decades.	('induce', 'PosReg', (122, 128))	('short chain', 'Var', (48, 59))	('apoptosis', 'biological_process', 'GO:0097194', ('165', '174'))	('apoptosis', 'biological_process', 'GO:0006915', ('165', '174'))	('short chain fatty acid', 'Chemical', 'MESH:D005232', (48, 70))	('growth arrest', 'Disease', 'MESH:D006323', (129, 142))	('HDAC', 'Gene', (32, 36))	('growth arrest', 'Disease', (129, 142))	('apoptosis', 'CPA', (165, 174))	('HDAC', 'Gene', '9734', (32, 36))	('Histone deacetylase', 'Gene', '9734', (0, 19))	('growth arrest', 'Phenotype', 'HP:0001510', (129, 142))	('differentiation', 'CPA', (144, 159))	('butyrate', 'Chemical', 'MESH:D002087', (75, 83))	('Histone deacetylase', 'Gene', (0, 19))
51418	22059907	Two such agents, 5-azacytidine (Vidaza) and 5-aza-2'deoxycytidine (decitabine), have been approved for both myelodysplastic syndrome and leukemia.	('leukemia', 'Disease', (137, 145))	('leukemia', 'Phenotype', 'HP:0001909', (137, 145))	('leukemia', 'Disease', 'MESH:D007938', (137, 145))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (108, 132))	('myelodysplastic syndrome', 'Disease', (108, 132))	("5-aza-2'deoxycytidine", 'Var', (44, 65))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (108, 132))
51428	22059907	In stage II colon cancer, high level of miR-320 and/or miR-498 is correlated with progression-free survival.	('miR-498', 'Gene', '574460', (55, 62))	('correlated', 'Reg', (66, 76))	('miR-320', 'Var', (40, 47))	('miR-498', 'Gene', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('II colon cancer', 'Disease', (9, 24))	('II colon cancer', 'Disease', 'MESH:D015179', (9, 24))	('colon cancer', 'Phenotype', 'HP:0003003', (12, 24))
51432	22059907	Methylation of miR-9-1 was more frequent in advanced cancer and was significantly associated with regional nodal invasion, vascular invasion, and metastasis.	('vascular invasion', 'CPA', (123, 140))	('associated', 'Reg', (82, 92))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('metastasis', 'CPA', (146, 156))	('Methylation', 'Var', (0, 11))	('miR-9-1', 'Gene', '407046', (15, 22))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('regional nodal invasion', 'CPA', (98, 121))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('miR-9-1', 'Gene', (15, 22))	('frequent', 'Reg', (32, 40))
51436	22059907	The reversibility of epigenetic changes makes it possible to treat CRC with DNA methyltransferase inhibitors and histone deacetylase inhibitors.	('CRC', 'Disease', (67, 70))	('histone deacetylase', 'Gene', (113, 132))	('CRC', 'Phenotype', 'HP:0003003', (67, 70))	('DNA methyltransferase', 'Gene', (76, 97))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('epigenetic', 'Var', (21, 31))	('histone deacetylase', 'Gene', '9734', (113, 132))	('DNA methyltransferase', 'Gene', '1786', (76, 97))
51457	33858433	The antioxidant activity of chrysin is related to the presence of the double bond between C2-C3 and the carbonyl group on the C4 atom.	('antioxidant activity', 'MPA', (4, 24))	('chrysin', 'Chemical', 'MESH:C043561', (28, 35))	('C2-C3', 'Var', (90, 95))	('presence', 'Var', (54, 62))	('double bond', 'MPA', (70, 81))	('antioxidant activity', 'molecular_function', 'GO:0016209', ('4', '24'))
51463	33858433	The C30, C40-dichloro substituent in the chrysin molecule was responsible for the suppression of prostaglandin (PG) production.	('PG', 'Chemical', 'MESH:D011453', (112, 114))	('chrysin', 'Chemical', 'MESH:C043561', (41, 48))	('C40-dichloro', 'Var', (9, 21))	('C30', 'Var', (4, 7))	('mole', 'Phenotype', 'HP:0003764', (49, 53))	('prostaglandin', 'Chemical', 'MESH:D011453', (97, 110))	('C40-dichloro', 'Chemical', '-', (9, 21))	('suppression', 'NegReg', (82, 93))
51468	33858433	Methylation of both C5 and C7 resulted in higher effectiveness of this chrysin analog as a feasible chemotherapeutic agent for acute lymphoblastic leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('acute lymphoblastic leukemia', 'Disease', (127, 155))	('Methylation', 'Var', (0, 11))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (127, 155))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (133, 155))	('higher', 'PosReg', (42, 48))	('chrysin', 'Chemical', 'MESH:C043561', (71, 78))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (127, 155))	('effectiveness', 'MPA', (49, 62))
51470	33858433	By in silico screening, a series of C7-hydroxyproton substituted chrysin derivatives exhibited EGFR inhibiting possessions against breast cancer.	('chrysin', 'Chemical', 'MESH:C043561', (65, 72))	('inhibiting', 'NegReg', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('C7-hydroxyproton', 'Chemical', '-', (36, 52))	('EGFR', 'Gene', '1956', (95, 99))	('breast cancer', 'Disease', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('C7-hydroxyproton substituted', 'Var', (36, 64))	('EGFR', 'Gene', (95, 99))
51488	33858433	Doxorubicin loaded mPEG-PCL-chrysin micelles could significantly show potent anticancer activities in vitro, regarding the pi-pi stacking interactions among the mentioned micelles and doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (184, 195))	('pi-pi', 'Var', (123, 128))	('mice', 'Species', '10090', (171, 175))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('chrysin', 'Chemical', 'MESH:C043561', (28, 35))	('cancer', 'Disease', (81, 87))	('mPEG-PCL', 'Chemical', 'MESH:C439611', (19, 27))	('Doxorubicin', 'Chemical', 'MESH:D004317', (0, 11))	('mice', 'Species', '10090', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('men', 'Species', '9606', (161, 164))
51524	33858433	By substitution of benzyloxy, dimethylamino, nitro, and fluoro on chrysin structure, potent cytotoxic agents were synthetized that displayed considerable cytotoxicity against MDA-MB-231 and MCF-7.	('chrysin', 'Chemical', 'MESH:C043561', (66, 73))	('nitro', 'Chemical', '-', (45, 50))	('cytotoxicity', 'Disease', (154, 166))	('dimethylamino', 'Chemical', '-', (30, 43))	('MCF-7', 'CellLine', 'CVCL:0031', (190, 195))	('fluoro', 'Chemical', '-', (56, 62))	('substitution', 'Var', (3, 15))	('benzyloxy', 'Chemical', '-', (19, 28))	('cytotoxicity', 'Disease', 'MESH:D064420', (154, 166))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (175, 185))
51528	33858433	Various etiologies have participated in the initializations and progressions of gastric cancer including gene-environment dealings with Helicobacter pylori as the most prevailing reasons for the pathogenesis of gastric cancer, numerous genetic and epigenetic changes have been connected with its carcinogenesis moreover.	('genetic', 'Var', (236, 243))	('gastric cancer', 'Disease', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('gastric cancer', 'Disease', (211, 225))	('connected', 'Reg', (277, 286))	('men', 'Species', '9606', (117, 120))	('gastric cancer', 'Disease', 'MESH:D013274', (211, 225))	('carcinogenesis', 'Disease', 'MESH:D063646', (296, 310))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('Helicobacter pylori', 'Species', '210', (136, 155))	('gastric cancer', 'Phenotype', 'HP:0012126', (211, 225))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('epigenetic changes', 'Var', (248, 266))	('carcinogenesis', 'Disease', (296, 310))	('pathogenesis', 'biological_process', 'GO:0009405', ('195', '207'))
51533	33858433	Cell apoptosis (Bax and Bcl2) and cell cycle altered by G0/G1 arrest and decline in the number of cells in the S phase.	('arrest', 'Disease', 'MESH:D006323', (62, 68))	('Bcl2', 'Gene', (24, 28))	('arrest', 'Disease', (62, 68))	('decline', 'NegReg', (73, 80))	('G0/G1', 'Var', (56, 61))	('Bcl2', 'Gene', '596', (24, 28))	('cell cycle altered', 'CPA', (34, 52))
51535	33858433	CRISPR/Cas9 system was used to generate the TET1 gene knocked out.	('TET1', 'Gene', (44, 48))	('rat', 'Species', '10116', (35, 38))	('knocked out', 'Var', (54, 65))	('TET1', 'Gene', '80312', (44, 48))
51597	33858433	Chrysin pretreatment led to an increase in mitochondrial ROS creation, swelling in isolated mitochondria from hepatocytes, collapse in MMP, and release cytochrome c. Furthermore, Chrysin could elevate caspase-3 activity in the HCC rats group.	('swelling', 'Disease', 'MESH:D004487', (71, 79))	('cytochrome c', 'Gene', '54205', (152, 164))	('ROS', 'Chemical', 'MESH:D017382', (57, 60))	('caspase-3 activity', 'molecular_function', 'GO:0030693', ('201', '219'))	('cytochrome c', 'molecular_function', 'GO:0009461', ('152', '164'))	('MMP', 'Gene', '4312;4313;17390;4318;17395;4319', (135, 138))	('men', 'Species', '9606', (16, 19))	('Chrysin', 'Chemical', 'MESH:C043561', (0, 7))	('MMP', 'molecular_function', 'GO:0004235', ('135', '138'))	('mitochondria', 'cellular_component', 'GO:0005739', ('92', '104'))	('rats', 'Species', '10116', (231, 235))	('caspase-3', 'Enzyme', (201, 210))	('cytochrome c', 'Gene', (152, 164))	('activity', 'MPA', (211, 219))	('Chrysin', 'Var', (179, 186))	('elevate', 'PosReg', (193, 200))	('caspase-3 activity', 'molecular_function', 'GO:0004208', ('201', '219'))	('mitochondrial ROS creation', 'MPA', (43, 69))	('MMP', 'Gene', (135, 138))	('Chrysin', 'Chemical', 'MESH:C043561', (179, 186))	('cytochrome c', 'molecular_function', 'GO:0045155', ('152', '164'))	('swelling', 'Disease', (71, 79))
51634	33858433	One of the main markers indicated the poor prognosis in patients with urinary bladder tumor that is mutation in tumor protein p53 (TP53) gene.	('patients', 'Species', '9606', (56, 64))	('p53', 'Gene', '7157', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('p53', 'Gene', (126, 129))	('urinary bladder tumor', 'Disease', 'MESH:D001749', (70, 91))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('mutation', 'Var', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('bladder tumor', 'Phenotype', 'HP:0009725', (78, 91))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('urinary bladder tumor', 'Disease', (70, 91))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))
51635	33858433	It was found that the progression of bladder tumor cell was inhibited by chrysin at doses 10-100 microM in mutated and wild type TP53 in grade 1-3.	('progression', 'CPA', (22, 33))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('chrysin', 'Chemical', 'MESH:C043561', (73, 80))	('bladder tumor', 'Disease', 'MESH:D001749', (37, 50))	('mutated', 'Var', (107, 114))	('inhibited', 'NegReg', (60, 69))	('TP53', 'Gene', '7157', (129, 133))	('bladder tumor', 'Phenotype', 'HP:0009725', (37, 50))	('TP53', 'Gene', (129, 133))	('bladder tumor', 'Disease', (37, 50))
51637	33858433	Chrysin could affect cell cycle at G2 and M phases and cell morphology following decrease in the expression of PLK1, HOXB3 and SRC genes in mutated TP53 cells,.	('PLK1', 'Gene', (111, 115))	('decrease', 'NegReg', (81, 89))	('affect', 'Reg', (14, 20))	('TP53', 'Gene', '7157', (148, 152))	('HOXB3', 'Gene', '3213', (117, 122))	('TP53', 'Gene', (148, 152))	('PLK1', 'Gene', '5347', (111, 115))	('cell morphology', 'CPA', (55, 70))	('SRC', 'Gene', '6714', (127, 130))	('SRC', 'Gene', (127, 130))	('HOXB3', 'Gene', (117, 122))	('Chrysin', 'Chemical', 'MESH:C043561', (0, 7))	('cell cycle', 'biological_process', 'GO:0007049', ('21', '31'))	('expression', 'MPA', (97, 107))	('mutated', 'Var', (140, 147))
51661	33858433	8-bromo-7-methoxychrysin led to cell fate in cisplatin-sensitive/resistant A2780 and A2780/DDP cells happened via the regulation of Akt/FOXO3a, resulting in transcription of Bim.	('transcription', 'MPA', (157, 170))	('FOXO3a', 'Gene', '2309', (136, 142))	('FOXO3a', 'Gene', (136, 142))	('8-bromo-7-methoxychrysin', 'Chemical', 'MESH:C552860', (0, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('transcription', 'biological_process', 'GO:0006351', ('157', '170'))	('regulation', 'biological_process', 'GO:0065007', ('118', '128'))	('Akt', 'Gene', (132, 135))	('Bim', 'MPA', (174, 177))	('A2780/DDP', 'Var', (85, 94))	('cell fate', 'CPA', (32, 41))	('Akt', 'Gene', '207', (132, 135))
51696	33858433	Any abnormality in the production and secretion of mucins causes a pathological condition in the airway such as mucoepidermoid carcinoma.	('mucoepidermoid carcinoma', 'Disease', (112, 136))	('mucin', 'Gene', '100508689', (51, 56))	('production', 'MPA', (23, 33))	('abnormality', 'Var', (4, 15))	('causes', 'Reg', (58, 64))	('secretion', 'MPA', (38, 47))	('mucin', 'Gene', (51, 56))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (112, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
51757	33858433	Pretreatment with chrysin exposed S/G2 phase arrest and apoptosis.	('S/G2', 'SUBSTITUTION', 'None', (34, 38))	('arrest', 'Disease', (45, 51))	('men', 'Species', '9606', (8, 11))	('chrysin', 'Chemical', 'MESH:C043561', (18, 25))	('G2 phase', 'biological_process', 'GO:0051319', ('36', '44'))	('S/G2', 'Var', (34, 38))	('apoptosis', 'CPA', (56, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('56', '65'))	('apoptosis', 'biological_process', 'GO:0097194', ('56', '65'))	('arrest', 'Disease', 'MESH:D006323', (45, 51))
51760	33858433	The findings suggested that inhibitory effect of chrysin on ASCL1 was effective for carcinoid management.	('carcinoid', 'Phenotype', 'HP:0100570', (84, 93))	('carcinoid', 'Disease', 'MESH:D002276', (84, 93))	('men', 'Species', '9606', (100, 103))	('chrysin', 'Chemical', 'MESH:C043561', (49, 56))	('inhibitory effect', 'Var', (28, 45))	('ASCL1', 'Gene', (60, 65))	('ASCL1', 'Gene', '429', (60, 65))	('carcinoid', 'Disease', (84, 93))
51776	33858433	Moreover due to this co-treatment declined Akt phosphorylation in addition to intracellular GSH content.	('Akt', 'Gene', '207', (43, 46))	('intracellular', 'cellular_component', 'GO:0005622', ('78', '91'))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('Akt', 'Gene', (43, 46))	('men', 'Species', '9606', (29, 32))	('GSH', 'Chemical', 'MESH:D005978', (92, 95))	('declined', 'NegReg', (34, 42))	('co-treatment', 'Var', (21, 33))
51822	33486908	We included the data of patients from 2007 to 2016 with "Korean Standard Classification of Diseases Diagnostic Code" of C18, C19, or C20, which indicate malignancy of the colon and rectum.	('malignancy of the colon', 'Phenotype', 'HP:0100273', (153, 176))	('C18', 'Gene', '27241', (120, 123))	('malignancy of the colon', 'Disease', (153, 176))	('C19', 'Var', (125, 128))	('C20', 'Var', (133, 136))	('indicate', 'Reg', (144, 152))	('malignancy of the colon', 'Disease', 'MESH:D015179', (153, 176))	('Classification of Diseases', 'Disease', (73, 99))	('C18', 'Gene', (120, 123))	('Classification of Diseases', 'Disease', 'MESH:D008310', (73, 99))
51888	31078251	Given the not insignificant risk of metachronous or synchronous neoplasia, the presence of several of the above factors should lower threshold to recommend definitive total proctocolectomy when dysplasia that is otherwise resectable is diagnosed (see below).	('dysplasia', 'Disease', 'MESH:C536170', (194, 203))	('synchronous neoplasia', 'Disease', (52, 73))	('lower', 'NegReg', (127, 132))	('dysplasia', 'Disease', (194, 203))	('synchronous neoplasia', 'Disease', 'MESH:D009378', (52, 73))	('neoplasia', 'Phenotype', 'HP:0002664', (64, 73))	('presence', 'Var', (79, 87))
51893	31078251	For example, IBD-associated CRCs less often have APC and KRAS mutations and more often have TP53, IDH1, and MYC mutations compared to sporadic tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('APC', 'Gene', (49, 52))	('TP53', 'Gene', (92, 96))	('IDH1', 'Gene', '3417', (98, 102))	('MYC', 'Gene', '4609', (108, 111))	('less', 'NegReg', (33, 37))	('CRC', 'Phenotype', 'HP:0003003', (28, 31))	('tumors', 'Disease', (143, 149))	('KRAS', 'Gene', '3845', (57, 61))	('mutations', 'Var', (62, 71))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('KRAS', 'Gene', (57, 61))	('TP53', 'Gene', '7157', (92, 96))	('APC', 'Gene', '324', (49, 52))	('IBD', 'Disease', 'MESH:D015212', (13, 16))	('APC', 'cellular_component', 'GO:0005680', ('49', '52'))	('MYC', 'Gene', (108, 111))	('IBD', 'Phenotype', 'HP:0002037', (13, 16))	('IDH1', 'Gene', (98, 102))	('IBD', 'Disease', (13, 16))
52010	32144630	NECs and high-grade NETs (G3) confer a poor prognosis, demanding novel treatment strategies such as immune checkpoint inhibition in tumors with microsatellite instability (MSI).	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('NETs', 'Phenotype', 'HP:0100634', (20, 24))	('NET', 'Gene', '2004', (20, 23))	('NET', 'Gene', (20, 23))	('NECs', 'Phenotype', 'HP:0100634', (0, 4))	('tumors', 'Disease', (132, 138))	('microsatellite instability', 'Var', (144, 170))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
52024	32144630	Recent studies have found tumors with MSI among neuroendocrine carcinomas (some combined with a conventional adenocarcinoma component, MINEN) of the stomach, small intestine, and colorectum.	('MSI', 'Var', (38, 41))	('neuroendocrine carcinomas', 'Disease', (48, 73))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (48, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (48, 73))	('adenocarcinoma component', 'Disease', (109, 133))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('adenocarcinoma component', 'Disease', 'MESH:D000230', (109, 133))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
52041	32144630	For all cases with suspected MSI based on TMA screening, a fluorescent PCR-based assay was performed (MSI Analysis System; Promega, Madison, WI), incorporating the five microsatellite loci of the "Bethesda Panel" which includes two mononucleotide repeats (BAT25, BAT26) and three dinucleotides repeats (D2S123, D5S346, and D17S250).	('D2S123', 'Var', (303, 309))	('mononucleotide', 'Chemical', '-', (232, 246))	('BAT25', 'Var', (256, 261))	('TMA', 'Disease', (42, 45))	('D5S346', 'Var', (311, 317))	('BAT26', 'Var', (263, 268))	('TMA', 'Disease', 'MESH:D000783', (42, 45))	('D17S250', 'Var', (323, 330))
52063	32144630	For example, earlier studies identified 42 tumors harboring IDH1 mutations by screening 15,531 prostate cancers (0.3%) or 43 tumors exhibiting CD117 overexpression in a cohort of 1654 breast carcinomas (2.6%).	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('breast carcinomas', 'Disease', 'MESH:D001943', (184, 201))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('breast carcinomas', 'Disease', (184, 201))	('prostate cancers', 'Disease', 'MESH:D011471', (95, 111))	('CD117', 'Gene', '3815', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', (125, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (191, 201))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('breast carcinomas', 'Phenotype', 'HP:0003002', (184, 201))	('prostate cancers', 'Phenotype', 'HP:0012125', (95, 111))	('IDH1', 'Gene', (60, 64))	('CD117', 'Gene', (143, 148))	('prostate cancers', 'Disease', (95, 111))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('IDH1', 'Gene', '3417', (60, 64))	('mutations', 'Var', (65, 74))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
52068	32144630	Among the 239 analyzed neuroendocrine neoplasms, MSI was confirmed in 3 cases (1.3%), all representing NECs of the cecum, suggesting a considerable prevalence of MSI (30%; 3/10) in colorectal NECs, although this may not reflect the true MSI rate in colorectal NECs due to the small tumor cohort.	('colorectal NECs', 'Disease', (181, 196))	('MSI', 'Var', (162, 165))	('small tumor', 'Disease', 'MESH:D058405', (276, 287))	('neuroendocrine neoplasms', 'Disease', 'MESH:D018358', (23, 47))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('small tumor', 'Disease', (276, 287))	('neoplasm', 'Phenotype', 'HP:0002664', (38, 46))	('NECs', 'Phenotype', 'HP:0100634', (103, 107))	('colorectal NECs', 'Disease', 'MESH:D015179', (249, 264))	('neuroendocrine neoplasms', 'Disease', (23, 47))	('neuroendocrine neoplasm', 'Phenotype', 'HP:0100634', (23, 46))	('NECs', 'Phenotype', 'HP:0100634', (192, 196))	('neoplasms', 'Phenotype', 'HP:0002664', (38, 47))	('colorectal NECs', 'Disease', (249, 264))	('colorectal NECs', 'Disease', 'MESH:D015179', (181, 196))	('neuroendocrine neoplasms', 'Phenotype', 'HP:0100634', (23, 47))	('NECs', 'Phenotype', 'HP:0100634', (260, 264))
52083	32144630	reported MSI in 5 of 48 (10%) pancreatic NETs using the "Bethesda Panel," but status of MSI was already given when merely the mononucleotide repeat locus BAT-25 was instable, contrasting the current cut-off requiring instability in 40% of loci to justify MSI.	('mononucleotide', 'Chemical', '-', (126, 140))	('MSI', 'Var', (9, 12))	('pancreatic NETs', 'Disease', (30, 45))	('pancreatic NETs', 'Disease', 'MESH:D010195', (30, 45))	('NETs', 'Phenotype', 'HP:0100634', (41, 45))
52084	32144630	reported MSI-high, defined as instability of at least 4 loci of an extended panel of 12 microsatellites, in 18 of 55 (33%) insulinomas.	('insulinomas', 'Disease', 'MESH:D007340', (123, 134))	('MSI-high', 'Var', (9, 17))	('insulinomas', 'Disease', (123, 134))
52090	32144630	Regarding treatment purposes, homogeneity of MSI reduces the risk that molecular parameters obtained from small biopsies may not be representative for the entire cancer mass, a potential strong confounder for individualized therapies.	('homogeneity', 'Var', (30, 41))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('reduces', 'NegReg', (49, 56))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('MSI', 'Gene', (45, 48))
52092	32144630	PCR analysis revealed MSI-high in all 3 cases of MMR deficiency.	('MMR deficiency', 'Disease', (49, 63))	('MSI-high', 'Var', (22, 30))	('MMR deficiency', 'Disease', 'MESH:C536928', (49, 63))	('MMR', 'biological_process', 'GO:0006298', ('49', '52'))
52095	32144630	In summary, the detection of MSI in 3 of 10 colorectal NECs but not in other neuroendocrine neoplasm suggests that MSI affects NECs of the colorectum in a relevant manner, similar to colorectal adenocarcinomas.	('neuroendocrine neoplasm', 'Phenotype', 'HP:0100634', (77, 100))	('MSI', 'Var', (115, 118))	('neuroendocrine neoplasm', 'Disease', 'MESH:D018358', (77, 100))	('affects', 'Reg', (119, 126))	('colorectal NECs', 'Disease', 'MESH:D015179', (44, 59))	('neuroendocrine neoplasm', 'Disease', (77, 100))	('colorectal adenocarcinomas', 'Disease', (183, 209))	('NECs', 'Phenotype', 'HP:0100634', (55, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('NECs', 'Phenotype', 'HP:0100634', (127, 131))	('colorectal NECs', 'Disease', (44, 59))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (183, 209))	('neoplasm', 'Phenotype', 'HP:0002664', (92, 100))
52141	31795079	Conversely, the disruption of COX2 PGE (2) feedback by COX2 inhibitors suppressed the production of MDSC-associated suppressive factors and the cytotoxic T lymphocytes (CTL)-inhibitory function of fully developed MDSCs from cancer patients.	('disruption', 'Var', (16, 26))	('PGE (2)', 'Chemical', 'MESH:D015232', (35, 42))	('patients', 'Species', '9606', (231, 239))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('production of MDSC-associated suppressive factors', 'MPA', (86, 135))	('COX2', 'Gene', '5743', (30, 34))	('COX2', 'Gene', (30, 34))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('COX2', 'Gene', (55, 59))	('cancer', 'Disease', (224, 230))	('COX2', 'Gene', '5743', (55, 59))	('suppressed', 'NegReg', (71, 81))
52153	31795079	In particular, in experimental studies, ATRA improved the differentiation of myeloid cells and the immune response in cancer patients, and 13-cis-retinoic acid and beta-carotene increased both the number of IL-2 receptors and the percentage of peripheral blood lymphoid cells that express surface markers for T-helper cells.	('patients', 'Species', '9606', (125, 133))	('cancer', 'Disease', (118, 124))	('ATRA', 'Chemical', 'MESH:D014212', (40, 44))	('improved', 'PosReg', (45, 53))	('immune response', 'CPA', (99, 114))	('IL-2', 'Gene', '3558', (207, 211))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('13-cis-retinoic', 'Var', (139, 154))	('13-cis-retinoic acid', 'Chemical', 'MESH:D015474', (139, 159))	('differentiation of myeloid cells', 'CPA', (58, 90))	('IL-2', 'Gene', (207, 211))	('IL-2', 'molecular_function', 'GO:0005134', ('207', '211'))	('beta-carotene', 'Chemical', 'MESH:D019207', (164, 177))	('immune response', 'biological_process', 'GO:0006955', ('99', '114'))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('increased', 'PosReg', (178, 187))
52159	31795079	Moreover, the anti-tumoral action of Dl alpha tocopheryl is synergistic with that of some common antiblastics.	('tumoral', 'Disease', (19, 26))	('tumoral', 'Disease', 'MESH:D009369', (19, 26))	('Dl alpha', 'Var', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Dl alpha tocopheryl', 'Chemical', '-', (37, 56))
52232	31795079	pT2 No Mo was the post-operative TNM classification, G3, ER+ (30%) Pr+ (10%), Ki67 90%, and HER2 negative.	('TNM', 'Gene', (33, 36))	('HER2', 'Gene', '2064', (92, 96))	('rat', 'Species', '10116', (26, 29))	('HER2', 'Gene', (92, 96))	('TNM', 'Gene', '10178', (33, 36))	('pT2 No Mo', 'Var', (0, 9))
52251	31795079	pT2 N0 M0 was the post-operative TNM classification, and cells were HER2 negative.	('TNM', 'Gene', (33, 36))	('HER2', 'Gene', (68, 72))	('rat', 'Species', '10116', (26, 29))	('HER2', 'Gene', '2064', (68, 72))	('pT2 N0 M0', 'Var', (0, 9))	('TNM', 'Gene', '10178', (33, 36))
52287	31795079	pT3 N2a (6 regional lymph-nodes involved of 22 examined) M1 was the post-operative TNM classification.	('rat', 'Species', '10116', (76, 79))	('TNM', 'Gene', (83, 86))	('pT3 N2a', 'Var', (0, 7))	('TNM', 'Gene', '10178', (83, 86))
52366	31795079	From 10 August 2019 to 10 October 2019, he was again given cycles of IT and the mean daily PSA increase was 0.00065 ng/mL, 2 and 2.77 times lower than 0.013 ng/mL and 0.018 ng/mL, respectively.	('0.00065 ng/mL', 'Var', (108, 121))	('PSA', 'Gene', '354', (91, 94))	('PSA', 'Gene', (91, 94))
52385	31430887	The Intricate Interplay between Epigenetic Events, Alternative Splicing and Noncoding RNA Deregulation in Colorectal Cancer Colorectal cancer (CRC) results from a transformation of colonic epithelial cells into adenocarcinoma cells due to genetic and epigenetic instabilities, alongside remodelling of the surrounding stromal tumour microenvironment.	('Colorectal Cancer', 'Disease', 'MESH:D015179', (106, 123))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('Colorectal Cancer', 'Disease', (106, 123))	('stromal tumour', 'Disease', (318, 332))	('epigenetic instabilities', 'Var', (251, 275))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))	('adenocarcinoma', 'Disease', (211, 225))	('Alternative Splicing', 'Var', (51, 71))	('transformation', 'Reg', (163, 177))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (106, 123))	('Cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Colorectal cancer', 'Disease', (124, 141))	('results from', 'Reg', (148, 160))	('CRC', 'Phenotype', 'HP:0003003', (143, 146))	('stromal tumour', 'Disease', 'MESH:D046152', (318, 332))	('adenocarcinoma', 'Disease', 'MESH:D000230', (211, 225))	('tumour', 'Phenotype', 'HP:0002664', (326, 332))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))
52390	31430887	Epigenetically induced activation of proto-oncogenes and silencing of tumour-suppressors play a central role in the complexity of cancer emergence, progression and response to treatment.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('Epigenetically induced', 'Var', (0, 22))	('cancer', 'Disease', (130, 136))	('silencing', 'NegReg', (57, 66))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('activation', 'PosReg', (23, 33))	('proto-oncogenes', 'Protein', (37, 52))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('tumour', 'Disease', (70, 76))
52393	31430887	Mediators dynamically change through feedback loops that target epigenetic modifiers, thereby shaping the Waddington landscape of cancer development in which mediators bring about a cellular transition towards a cancer stem cell state favouring tumour progression.	('tumour', 'Disease', 'MESH:D009369', (245, 251))	('bring about', 'Reg', (168, 179))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('tumour', 'Disease', (245, 251))	('cancer', 'Disease', (130, 136))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('mediators', 'Var', (158, 167))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
52394	31430887	A deregulated epigenome often caused by environmental factors and facilitated by the interplay between modulators, modifiers and mediators can result in the intra-tumoural cellular heterogeneity that enables tumour evolution.	('intra-tumoural', 'Disease', (157, 171))	('deregulated', 'Var', (2, 13))	('tumour', 'Disease', (208, 214))	('intra-tumoural', 'Disease', 'MESH:D009369', (157, 171))	('enables', 'PosReg', (200, 207))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('epigenome', 'Protein', (14, 23))	('result in', 'Reg', (143, 152))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('tumour', 'Disease', 'MESH:D009369', (208, 214))	('tumour', 'Disease', (163, 169))
52395	31430887	During the early stages of CRC development, the normal colorectal epithelium is transformed into a benign adenoma by inactivation mutations in tumour suppressor genes (e.g., APC, TP53, SMAD4) and activating mutations in proto-oncogenes (KRAS, BRAF, PIK3CA).	('CRC', 'Phenotype', 'HP:0003003', (27, 30))	('KRAS', 'Gene', (237, 241))	('PIK3CA', 'Gene', (249, 255))	('APC', 'Disease', 'MESH:D011125', (174, 177))	('adenoma', 'Disease', 'MESH:D000236', (106, 113))	('inactivation', 'NegReg', (117, 129))	('APC', 'Disease', (174, 177))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('adenoma', 'Disease', (106, 113))	('activating', 'PosReg', (196, 206))	('APC', 'cellular_component', 'GO:0005680', ('174', '177'))	('SMAD4', 'Gene', (185, 190))	('mutations', 'Var', (207, 216))	('mutations', 'Var', (130, 139))	('tumour', 'Disease', (143, 149))	('TP53', 'Gene', (179, 183))
52398	31430887	created CRC organoids with loss of function mutations in APC, SMAD4 and TP53, and gain-of-function mutations in KRAS and/or PIK3CA that grew independent from niche factors in vitro, and formed tumours after implantation under the kidney sub-capsule in mice.	('mice', 'Species', '10090', (252, 256))	('tumours', 'Disease', 'MESH:D009369', (193, 200))	('APC', 'Disease', 'MESH:D011125', (57, 60))	('APC', 'Disease', (57, 60))	('gain-of-function', 'PosReg', (82, 98))	('tumours', 'Disease', (193, 200))	('loss of function', 'NegReg', (27, 43))	('CRC', 'Phenotype', 'HP:0003003', (8, 11))	('TP53', 'Gene', (72, 76))	('PIK3CA', 'Gene', (124, 130))	('mutations', 'Var', (99, 108))	('mutations', 'Var', (44, 53))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('KRAS', 'Gene', (112, 116))	('SMAD4', 'Gene', (62, 67))	('tumours', 'Phenotype', 'HP:0002664', (193, 200))
52399	31430887	They suggested that driver pathway mutations in epigenetic modulators facilitate the preservation of stem cells in the tumour microenvironment.	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('facilitate', 'PosReg', (70, 80))	('tumour', 'Disease', (119, 125))	('preservation', 'CPA', (85, 97))	('driver pathway', 'Pathway', (20, 34))	('mutations', 'Var', (35, 44))
52400	31430887	Another study sequentially introduced both inactivation mutations in tumour suppressor genes (APC, TP53, and SMAD4) and an oncogenic mutation in the KRAS oncogene to create CRC organoids from intestinal stem cells.	('tumour', 'Disease', (69, 75))	('TP53', 'Gene', (99, 103))	('APC', 'cellular_component', 'GO:0005680', ('94', '97'))	('SMAD4', 'Gene', (109, 114))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('inactivation mutations', 'Var', (43, 65))	('CRC', 'Phenotype', 'HP:0003003', (173, 176))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('APC', 'Disease', 'MESH:D011125', (94, 97))	('APC', 'Disease', (94, 97))
52401	31430887	By studying this CRISPR-mutated organoid containing four of the most frequently mutated CRC genes, they have demonstrated that quadruple mutants grow independent from niche factors as invasive carcinomas and combined loss of APC and P53 is sufficient for acquiring CIN.	('CIN', 'Phenotype', 'HP:0040012', (265, 268))	('APC', 'Disease', (225, 228))	('quadruple mutants', 'Var', (127, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('CIN', 'Disease', (265, 268))	('P53', 'Gene', (233, 236))	('CRC', 'Gene', (88, 91))	('P53', 'Gene', '7157', (233, 236))	('carcinomas', 'Phenotype', 'HP:0030731', (193, 203))	('CIN', 'Disease', 'MESH:D007674', (265, 268))	('invasive carcinomas', 'Disease', (184, 203))	('invasive carcinomas', 'Disease', 'MESH:D009361', (184, 203))	('CRC', 'Phenotype', 'HP:0003003', (88, 91))	('APC', 'Disease', 'MESH:D011125', (225, 228))	('loss', 'NegReg', (217, 221))
52402	31430887	Another group has genetically dissected CRC progression (adenoma-carcinoma sequence) by orthotopic transplantation of CRISPR-engineered CRC organoids to study the contribution of common CRC key mutations (in Wnt, EGFR, P53, and TGF-beta signalling pathways) to metastasis.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('CRC', 'Phenotype', 'HP:0003003', (136, 139))	('adenoma-carcinoma', 'Disease', (57, 74))	('EGFR', 'Gene', (213, 217))	('mutations', 'Var', (194, 203))	('CRC', 'Disease', (40, 43))	('P53', 'Gene', (219, 222))	('CRC', 'Gene', (186, 189))	('CRC', 'Phenotype', 'HP:0003003', (186, 189))	('CRC', 'Phenotype', 'HP:0003003', (40, 43))	('P53', 'Gene', '7157', (219, 222))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (57, 74))	('EGFR', 'Gene', '1956', (213, 217))
52403	31430887	generated complex preclinical models of serrated CRC by serial introduction of inactivation mutations in five genes (MLH1, TGFBR2, RNF43, ZNRF3, and p16Ink4a) in BRAFV600E organoids.	('RNF43', 'Gene', (131, 136))	('inactivation', 'NegReg', (79, 91))	('BRAFV600E', 'Mutation', 'rs113488022', (162, 171))	('CRC', 'Phenotype', 'HP:0003003', (49, 52))	('p16Ink4a', 'Gene', (149, 157))	('mutations', 'Var', (92, 101))	('TGFBR2', 'Gene', '7048', (123, 129))	('ZNRF3', 'Gene', '84133', (138, 143))	('TGFBR2', 'Gene', (123, 129))	('ZNRF3', 'Gene', (138, 143))	('MLH1', 'Gene', (117, 121))	('p16Ink4a', 'Gene', '1029', (149, 157))	('MLH1', 'Gene', '4292', (117, 121))	('clinical', 'Species', '191496', (21, 29))	('serrated CRC', 'Disease', (40, 52))	('RNF43', 'Gene', '54894', (131, 136))
52404	31430887	Although these studies have validated the critical role of mutations in epigenetic modulators in CRC development, emerging studies have shown that mutations in epigenetic modulators such as BRAFV600E and KRASG13D are tightly connected with the CpG island methylator phenotype (CIMP), which is generated by epigenetic modifiers.	('mutations', 'Var', (147, 156))	('CIMP', 'Chemical', '-', (277, 281))	('BRAFV600E', 'Mutation', 'rs113488022', (190, 199))	('G13D', 'Mutation', 'rs112445441', (208, 212))	('CRC', 'Phenotype', 'HP:0003003', (97, 100))	('KRASG13D', 'Gene', (204, 212))	('mutations', 'Var', (59, 68))	('CpG island methylator phenotype', 'Disease', (244, 275))	('BRAFV600E', 'Gene', (190, 199))	('connected', 'Reg', (225, 234))
52405	31430887	Although the role of BRAF and KRAS mutations in the development of CRC is well documented, the chicken-or-egg problem for CRC is to definitively prove whether mutations in epigenetic modulators eventually lead to CIMP or CIMP appears first and creates an environment that facilitates mutations in epigenetic modulators.	('lead to', 'Reg', (205, 212))	('CRC', 'Phenotype', 'HP:0003003', (122, 125))	('CIMP', 'Chemical', '-', (221, 225))	('mutations', 'Var', (159, 168))	('CIMP', 'Disease', (213, 217))	('facilitates', 'PosReg', (272, 283))	('mutations', 'Var', (284, 293))	('CRC', 'Phenotype', 'HP:0003003', (67, 70))	('-egg problem', 'Phenotype', 'HP:0410328', (105, 117))	('CIMP', 'Disease', (221, 225))	('CIMP', 'Chemical', '-', (213, 217))	('chicken', 'Species', '9031', (95, 102))
52407	31430887	The BRAFV600E mutation has been shown to result in CIMP development via increased BRAF/MEK/ERK signalling, which causes MAFG upregulation and phosphorylation.	('BRAFV600E', 'Var', (4, 13))	('MAFG', 'Gene', (120, 124))	('upregulation', 'PosReg', (125, 137))	('BRAFV600E', 'Mutation', 'rs113488022', (4, 13))	('increased', 'PosReg', (72, 81))	('ERK', 'Gene', '5594', (91, 94))	('phosphorylation', 'biological_process', 'GO:0016310', ('142', '157'))	('MEK', 'Gene', (87, 90))	('ERK', 'Gene', (91, 94))	('result', 'Reg', (41, 47))	('MEK', 'Gene', '5609', (87, 90))	('MAFG', 'Gene', '4097', (120, 124))	('signalling', 'biological_process', 'GO:0023052', ('95', '105'))	('phosphorylation', 'MPA', (142, 157))	('CIMP', 'Chemical', '-', (51, 55))	('CIMP development', 'CPA', (51, 67))	('ERK', 'molecular_function', 'GO:0004707', ('91', '94'))
52411	31430887	Conversely, other studies have shown that aberrant DNA hypermethylation and CIMP provides a permissive context for mutations in the BRAF gene.	('BRAF', 'Gene', (132, 136))	('mutations', 'Var', (115, 124))	('CIMP', 'Chemical', '-', (76, 80))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('51', '71'))	('aberrant', 'Var', (42, 50))
52413	31430887	Impaired epithelial balance can contribute to the acquisition of a cancerous state, e.g., through the deregulation of epigenetic control mechanisms, the transcriptional machinery, alternative splicing, the expression of non-coding RNAs or alterations in translation and protein stability.	('epigenetic control mechanisms', 'MPA', (118, 147))	('non-coding RNAs', 'Protein', (220, 235))	('alternative splicing', 'Var', (180, 200))	('contribute', 'Reg', (32, 42))	('splicing', 'biological_process', 'GO:0045292', ('192', '200'))	('cancerous', 'Disease', (67, 76))	('protein', 'cellular_component', 'GO:0003675', ('270', '277'))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('alterations', 'Reg', (239, 250))	('deregulation', 'MPA', (102, 114))	('protein', 'Protein', (270, 277))	('translation', 'biological_process', 'GO:0006412', ('254', '265'))	('RNAs', 'Protein', (231, 235))	('translation', 'MPA', (254, 265))	('cancerous', 'Disease', 'MESH:D009369', (67, 76))
52414	31430887	showed that cancers may have a stem cell origin in which reversible gene repression normally imposed by an epigenetic modifier (e.g., Polycomb group proteins) is replaced by constant silencing, locking cells into a permanent state of self-renewal that predisposes them to malignant transformation.	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('malignant transformation', 'CPA', (272, 296))	('cancers', 'Disease', (12, 19))	('predisposes', 'Reg', (252, 263))	('Polycomb', 'Var', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
52415	31430887	Another study demonstrated that driver mutations are significantly associated with aberrant DNA methylation in many cancer types, including CRC, and that these epigenetic changes contribute to carcinogenesis.	('DNA methylation', 'biological_process', 'GO:0006306', ('92', '107'))	('CRC', 'Phenotype', 'HP:0003003', (140, 143))	('DNA', 'cellular_component', 'GO:0005574', ('92', '95'))	('carcinogenesis', 'Disease', (193, 207))	('cancer', 'Disease', (116, 122))	('DNA', 'MPA', (92, 95))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('aberrant', 'Var', (83, 91))	('contribute', 'Reg', (179, 189))	('CRC', 'Disease', (140, 143))	('associated', 'Reg', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('carcinogenesis', 'Disease', 'MESH:D063646', (193, 207))
52418	31430887	Besides genetic instability and mutations, epigenomic disruption can contribute to transformation and the development of cancer-associated phenotypes.	('transformation', 'CPA', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('epigenomic disruption', 'Var', (43, 64))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('contribute', 'Reg', (69, 79))	('cancer', 'Disease', (121, 127))
52419	31430887	Defects in epigenetic effectors (readers, writers and erasers) mediate the development of cancers, including CRC.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Defects', 'Var', (0, 7))	('CRC', 'Disease', (109, 112))	('mediate', 'Reg', (63, 70))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('CRC', 'Phenotype', 'HP:0003003', (109, 112))	('epigenetic', 'Protein', (11, 21))
52422	31430887	DNA methylation, in combination with other epigenetic events, has been associated with different phenotypes of CRC including CIN, MSI and CIMP.	('CIMP', 'Chemical', '-', (138, 142))	('CIN', 'Disease', 'MESH:D007674', (125, 128))	('CRC', 'Disease', (111, 114))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('CIN', 'Phenotype', 'HP:0040012', (125, 128))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('MSI', 'Disease', (130, 133))	('methylation', 'Var', (4, 15))	('CRC', 'Phenotype', 'HP:0003003', (111, 114))	('CIMP', 'Disease', (138, 142))	('MSI', 'Disease', 'None', (130, 133))	('CIN', 'Disease', (125, 128))	('associated', 'Reg', (71, 81))
52423	31430887	For example, a recent study has shown that global hypomethylation is significantly associated with CIN in sporadic CRC.	('CIN', 'Disease', 'MESH:D007674', (99, 102))	('CRC', 'Phenotype', 'HP:0003003', (115, 118))	('CIN', 'Phenotype', 'HP:0040012', (99, 102))	('associated', 'Reg', (83, 93))	('global hypomethylation', 'Var', (43, 65))	('CIN', 'Disease', (99, 102))
52427	31430887	Aberrant DNA methylation also contributes to later stages of CRC, for example by establishing a CIMP phenotype through global genome hypermethylation, which results in silencing of tumour suppressor genes, such as CDKN2A/p16.	('CDKN2A', 'Gene', (214, 220))	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('Aberrant', 'Var', (0, 8))	('CDKN2A', 'Gene', '1029', (214, 220))	('CRC', 'Phenotype', 'HP:0003003', (61, 64))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('tumour', 'Disease', 'MESH:D009369', (181, 187))	('p16', 'Gene', '1029', (221, 224))	('CRC', 'Disease', (61, 64))	('tumour', 'Disease', (181, 187))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('silencing', 'NegReg', (168, 177))	('p16', 'Gene', (221, 224))	('hypermethylation', 'Var', (133, 149))	('CIMP', 'Chemical', '-', (96, 100))	('contributes', 'Reg', (30, 41))
52429	31430887	The association of driver mutations, including BRAFV600E and KRASG13D with methylation patterns can be used to stratify the heterogeneous cell population of a tumour into homogeneous subtypes.	('methylation', 'biological_process', 'GO:0032259', ('75', '86'))	('tumour', 'Disease', (159, 165))	('G13D', 'Mutation', 'rs112445441', (65, 69))	('KRASG13D', 'Var', (61, 69))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumour', 'Disease', 'MESH:D009369', (159, 165))	('BRAFV600E', 'Var', (47, 56))	('BRAFV600E', 'Mutation', 'rs113488022', (47, 56))
52430	31430887	Epigenomic and transcriptomic profiling of the colon cancer cell line DLD1 showed that a signature of mRNAs, miRNA, lncRNAs, and epigenetic alterations are associated with CRC metastasis.	('CRC', 'Phenotype', 'HP:0003003', (172, 175))	('miRNA', 'MPA', (109, 114))	('colon cancer', 'Phenotype', 'HP:0003003', (47, 59))	('colon cancer', 'Disease', 'MESH:D015179', (47, 59))	('epigenetic alterations', 'Var', (129, 151))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('associated', 'Reg', (156, 166))	('CRC', 'Disease', (172, 175))	('colon cancer', 'Disease', (47, 59))	('mRNAs', 'MPA', (102, 107))
52432	31430887	Due to promoter demethylation, the expression of H19 was elevated, a lncRNA which is associated with poor survival.	('H19', 'Gene', '283120', (49, 52))	('H19', 'Gene', (49, 52))	('promoter demethylation', 'Var', (7, 29))	('elevated', 'PosReg', (57, 65))	('expression', 'MPA', (35, 45))	('demethylation', 'biological_process', 'GO:0070988', ('16', '29'))
52445	31430887	Another study has identified that miR-133b is markedly downregulated through promoter hypermethylation in human CRC tissues compared to healthy colon cells.	('miR-133b', 'Gene', '442890', (34, 42))	('human', 'Species', '9606', (106, 111))	('miR-133b', 'Gene', (34, 42))	('promoter hypermethylation', 'Var', (77, 102))	('downregulated', 'NegReg', (55, 68))	('CRC', 'Phenotype', 'HP:0003003', (112, 115))
52446	31430887	Low miR-203 expression in CRC, for example, indirectly causes ABCG2 promoter methylation lowering the expression of this important efflux transporter and thereby CRC development.	('methylation', 'Var', (77, 88))	('ABCG2', 'Gene', (62, 67))	('ABCG2', 'Gene', '9429', (62, 67))	('expression of this important efflux transporter', 'MPA', (102, 149))	('CRC development', 'CPA', (162, 177))	('CRC', 'Phenotype', 'HP:0003003', (162, 165))	('lowering', 'NegReg', (89, 97))	('causes', 'Reg', (55, 61))	('CRC', 'Phenotype', 'HP:0003003', (26, 29))	('miR-203', 'Gene', '406986', (4, 11))	('miR-203', 'Gene', (4, 11))	('Low', 'Var', (0, 3))
52447	31430887	MiR-203 targets DNA Methyltransferase 3 Beta (DNMT3B), which is relieved from post-transcriptional repression in CRC and can, therefore, methylate the ABCG2 promoter.	('ABCG2', 'Gene', (151, 156))	('DNMT3B', 'Gene', (46, 52))	('DNMT3B', 'Gene', '1789', (46, 52))	('ABCG2', 'Gene', '9429', (151, 156))	('CRC', 'Phenotype', 'HP:0003003', (113, 116))	('methylate', 'Var', (137, 146))	('DNA', 'cellular_component', 'GO:0005574', ('16', '19'))	('DNA Methyltransferase 3 Beta', 'Gene', '1789', (16, 44))	('MiR-203', 'Gene', (0, 7))	('MiR-203', 'Gene', '406986', (0, 7))	('DNA Methyltransferase 3 Beta', 'Gene', (16, 44))
52450	31430887	Several studies have shown that three lncRNAs (CCAT1-l, CCAT1 and CCAT2), located upstream of the proto-oncogene MYC, are highly expressed in microsatellite-stable CRC and have been implicated in CRC predisposition by different mechanisms of action.	('CCAT1', 'Gene', '100507056', (56, 61))	('CRC', 'Phenotype', 'HP:0003003', (164, 167))	('CRC', 'Phenotype', 'HP:0003003', (196, 199))	('CCAT2', 'Gene', (66, 71))	('CCAT1', 'Gene', (56, 61))	('microsatellite-stable', 'Var', (142, 163))	('MYC', 'Gene', '4609', (113, 116))	('CCAT1', 'Gene', '100507056', (47, 52))	('CRC', 'Disease', (196, 199))	('CCAT1', 'Gene', (47, 52))	('implicated', 'Reg', (182, 192))	('MYC', 'Gene', (113, 116))	('CCAT2', 'Gene', '101805488', (66, 71))
52453	31430887	It was shown that upregulation of c-MYC facilitated by a large chromatin loop is linked to a cancer risk-associated single-nucleotide polymorphism (SNP, rs6983267) in CRC cells.	('upregulation', 'PosReg', (18, 30))	('cancer', 'Disease', (93, 99))	('c-MYC', 'Gene', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('CRC', 'Phenotype', 'HP:0003003', (167, 170))	('c-MYC', 'Gene', '4609', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('single-nucleotide polymorphism', 'Var', (116, 146))	('chromatin', 'cellular_component', 'GO:0000785', ('63', '72'))	('rs6983267', 'Mutation', 'rs6983267', (153, 162))
52455	31430887	demonstrated that the same SNP affects CCAT2 expression and the risk allele of SNP rs6983267 produces more lncRNA CCAT2 transcript, which in turn up-regulates MYC, miR-17-5p, and miR-20a through physical interaction with transcription factor TCF7L2.	('rs6983267', 'Var', (83, 92))	('lncRNA', 'MPA', (107, 113))	('CCAT2', 'Gene', '101805488', (114, 119))	('MYC', 'Gene', (159, 162))	('miR-20a', 'Gene', (179, 186))	('more', 'PosReg', (102, 106))	('SNP', 'Var', (79, 82))	('up-regulates', 'PosReg', (146, 158))	('CCAT2', 'Gene', '101805488', (39, 44))	('rs6983267', 'Mutation', 'rs6983267', (83, 92))	('interaction', 'Interaction', (204, 215))	('CCAT2', 'Gene', (114, 119))	('expression', 'MPA', (45, 55))	('MYC', 'Gene', '4609', (159, 162))	('CCAT2', 'Gene', (39, 44))	('miR-1', 'Gene', (164, 169))	('miR-1', 'Gene', '83856', (164, 169))
52464	31430887	revealed that lncRNA CRNDE (Colorectal Neoplasia Differentially Expressed) epigenetically silences DUSP5 and CDKN1A expression by binding to EZH2, a key component of the PRC2 complex.	('epigenetically', 'Var', (75, 89))	('Colorectal Neoplasia Differentially Expressed', 'Gene', '643911', (28, 73))	('expression', 'MPA', (116, 126))	('DUSP5', 'Gene', '1847', (99, 104))	('Neoplasia', 'Phenotype', 'HP:0002664', (39, 48))	('CDKN1A', 'Gene', (109, 115))	('binding', 'molecular_function', 'GO:0005488', ('130', '137'))	('CDKN1A', 'Gene', '1026', (109, 115))	('EZH2', 'Gene', '2146', (141, 145))	('PRC2 complex', 'cellular_component', 'GO:0035098', ('170', '182'))	('EZH2', 'Gene', (141, 145))	('silences', 'NegReg', (90, 98))	('DUSP5', 'Gene', (99, 104))	('CRNDE', 'Gene', '643911', (21, 26))	('CRNDE', 'Gene', (21, 26))	('Colorectal Neoplasia Differentially Expressed', 'Gene', (28, 73))	('binding', 'Interaction', (130, 137))
52466	31430887	DNA methylation and histone modifications appear to mutually reinforce silencing of tumour-suppressor genes in CRCs.	('modifications', 'Var', (28, 41))	('tumour', 'Disease', (84, 90))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('methylation', 'Var', (4, 15))	('reinforce', 'PosReg', (61, 70))	('CRC', 'Phenotype', 'HP:0003003', (111, 114))	('CRCs', 'Disease', (111, 115))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('silencing', 'MPA', (71, 80))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
52472	31430887	These transcriptome variations can be a result of either mutations in or aberrant expression of trans-acting splicing factors such as hnRNPL, SRSF1 (alias ASF/SF2), and SRSF6 or mutations in cis-regulatory sequences.	('SRSF1', 'Gene', (142, 147))	('result', 'Reg', (40, 46))	('ASF/SF2', 'Gene', '6426', (155, 162))	('splicing factor', 'Gene', '10569', (109, 124))	('transcriptome', 'MPA', (6, 19))	('expression', 'MPA', (82, 92))	('SRSF1', 'Gene', '6426', (142, 147))	('splicing', 'biological_process', 'GO:0045292', ('109', '117'))	('mutations in', 'Var', (57, 69))	('splicing factor', 'Gene', (109, 124))	('ASF/SF2', 'Gene', (155, 162))	('SRSF6', 'Gene', (169, 174))	('mutations', 'Var', (178, 187))	('hnRNPL', 'Gene', '3191', (134, 140))	('hnRNPL', 'Gene', (134, 140))
52478	31430887	Epigenetic splicing regulation works through different modes including (1) the modulation of the RNA Pol II elongation rate inducing either exon skipping or inclusion, (2) splicing factor recruitment or sequestration and (3) adaptor/scaffolding function.	('splicing factor', 'Gene', (172, 187))	('sequestration', 'MPA', (203, 216))	('modulation', 'Var', (79, 89))	('splicing factor', 'Gene', '10569', (172, 187))	('inclusion', 'MPA', (157, 166))	('RNA', 'cellular_component', 'GO:0005562', ('97', '100'))	('splicing', 'biological_process', 'GO:0045292', ('172', '180'))	('splicing', 'biological_process', 'GO:0045292', ('11', '19'))	('regulation', 'biological_process', 'GO:0065007', ('20', '30'))	('exon skipping', 'Var', (140, 153))	('RNA', 'Gene', (97, 100))
52479	31430887	Modes of epigenetic regulation can lead to changes in splicing factor concentration both spatially and temporally.	('lead to changes', 'Reg', (35, 50))	('epigenetic regulation', 'Var', (9, 30))	('splicing factor', 'Gene', (54, 69))	('splicing factor', 'Gene', '10569', (54, 69))
52482	31430887	demonstrated in a CRC mouse model that mutation of the histone methyltransferase SETD2 slows down transcription elongation and thereby facilitates the removal of intron 2 of dishevelled segment polarity protein 2 (DVL2) pre-mRNA; thereby augmenting Wnt/beta-catenin signalling and tumorigenesis.	('beta-catenin', 'Gene', '12387', (253, 265))	('mutation', 'Var', (39, 47))	('slows down', 'NegReg', (87, 97))	('dishevelled segment polarity protein 2', 'Gene', '13543', (174, 212))	('SETD2', 'Gene', (81, 86))	('removal', 'MPA', (151, 158))	('augmenting', 'PosReg', (238, 248))	('tumorigenesis', 'CPA', (281, 294))	('dishevelled segment polarity protein 2', 'Gene', (174, 212))	('CRC', 'Phenotype', 'HP:0003003', (18, 21))	('beta-catenin', 'Gene', (253, 265))	('mouse', 'Species', '10090', (22, 27))	('facilitates', 'PosReg', (135, 146))	('transcription', 'MPA', (98, 111))
52483	31430887	Epigenetic events can also help to recruit splicing factors to a specific locus.	('splicing factor', 'Gene', '10569', (43, 58))	('recruit', 'Reg', (35, 42))	('splicing', 'biological_process', 'GO:0045292', ('43', '51'))	('Epigenetic events', 'Var', (0, 17))	('splicing factor', 'Gene', (43, 58))
52484	31430887	revealed that SF3B1, an essential component of the U2 snRNP complex, specifically binds nucleosomes positioned at short exons flanked by long intronic sequences, suggesting that differences in chromatin organization between exons and introns pinpoint splicing factors to their pre-mRNA targets and determine splicing decisions.	('splicing', 'biological_process', 'GO:0045292', ('251', '259'))	('chromatin organization', 'biological_process', 'GO:0006325', ('193', '215'))	('differences', 'Var', (178, 189))	('snRNP', 'molecular_function', 'GO:0003734', ('54', '59'))	('determine', 'Reg', (298, 307))	('U2 snRNP', 'cellular_component', 'GO:0005686', ('51', '59'))	('chromatin', 'cellular_component', 'GO:0000785', ('193', '202'))	('splicing', 'biological_process', 'GO:0045292', ('308', '316'))	('splicing', 'MPA', (308, 316))	('SF3B1', 'Gene', (14, 19))	('splicing factor', 'Gene', '10569', (251, 266))	('SF3B1', 'Gene', '23451', (14, 19))	('pre', 'molecular_function', 'GO:0003904', ('277', '280'))	('splicing factor', 'Gene', (251, 266))
52485	31430887	confirmed that splicing factors specifically bind to post-translationally modified histone residues near exons that are targets of AS.	('post-translationally modified', 'Var', (53, 82))	('splicing factor', 'Gene', (15, 30))	('histone', 'Protein', (83, 90))	('bind', 'Interaction', (45, 49))	('splicing factor', 'Gene', '10569', (15, 30))
52486	31430887	revealed that alternatively spliced exons are enriched in DNA methylation and that DNA methylation in the gene body can enhance exon recognition by recruitment of the methyl-CpG binding protein 2 (MeCP2).	('MeCP2', 'Gene', '4204', (197, 202))	('enhance', 'PosReg', (120, 127))	('methyl-CpG binding protein 2', 'Gene', (167, 195))	('MeCP2', 'Gene', (197, 202))	('exon recognition', 'MPA', (128, 144))	('methyl-CpG binding protein 2', 'Gene', '4204', (167, 195))	('DNA methylation', 'Var', (83, 98))
52492	31430887	Several studies have shown that active cellular mechanisms and mutations can dynamically change histone marks and preferential association of splicing factors with exons.	('mutations', 'Var', (63, 72))	('association', 'Interaction', (127, 138))	('exons', 'Protein', (164, 169))	('histone', 'MPA', (96, 103))	('change', 'Reg', (89, 95))	('preferential', 'PosReg', (114, 126))	('splicing factor', 'Gene', (142, 157))	('splicing factor', 'Gene', '10569', (142, 157))
52493	31430887	For example, the G13D mutation in KRAS impacts on the epigenetic modification of heterogeneous nuclear ribonucleoproteins (hnRNPs) that is involved in pre-mRNA splicing.	('impacts', 'Reg', (39, 46))	('G13D', 'Var', (17, 21))	('epigenetic modification', 'MPA', (54, 77))	('G13D', 'Mutation', 'rs112445441', (17, 21))	('heterogeneous nuclear ribonucleoproteins', 'MPA', (81, 121))	('KRAS', 'Gene', (34, 38))
52494	31430887	suggest that KRAS mutations affect AS of EPDR1 and ZNF518B in CRC cells leading to differential isoform expression in these genes.	('affect', 'Reg', (28, 34))	('ZNF518B', 'Gene', '85460', (51, 58))	('CRC', 'Phenotype', 'HP:0003003', (62, 65))	('EPDR1', 'Gene', (41, 46))	('differential', 'Reg', (83, 95))	('isoform expression', 'MPA', (96, 114))	('KRAS', 'Gene', (13, 17))	('ZNF518B', 'Gene', (51, 58))	('EPDR1', 'Gene', '54749', (41, 46))	('mutations', 'Var', (18, 27))
52495	31430887	The oncogenic miRNAs miR-1298 and miR-92a downregulate the expression of SFQ and RBM4 in CRC.	('miR-92a', 'Var', (34, 41))	('RBM4', 'Gene', (81, 85))	('SFQ', 'Gene', (73, 76))	('expression', 'MPA', (59, 69))	('RBM4', 'Gene', '5936', (81, 85))	('downregulate', 'NegReg', (42, 54))	('miR-1298', 'Gene', (21, 29))	('CRC', 'Phenotype', 'HP:0003003', (89, 92))	('miR-1298', 'Gene', '100302153', (21, 29))
52517	31430887	Although MIRX34 showed antitumour activity in a subset of patients, the project was terminated because of immune-related serious adverse events reported in five patients treated with MIRX34.	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('patients', 'Species', '9606', (161, 169))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('patients', 'Species', '9606', (58, 66))	('tumour', 'Disease', (27, 33))	('MIRX34', 'Gene', (9, 15))	('MIRX34', 'Var', (183, 189))
52520	31430887	Therefore, certain small molecule compounds such as AC1Q3QWB (AQB) are used in cancer therapy for selectively blocking HOTAIR-EZH2 interaction.	('AQB', 'Chemical', '-', (62, 65))	('EZH2', 'Gene', '2146', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('blocking', 'NegReg', (110, 118))	('EZH2', 'Gene', (126, 130))	('HOTAIR', 'Gene', (119, 125))	('AC1Q3QWB', 'Var', (52, 60))	('HOTAIR', 'Gene', '100124700', (119, 125))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
52522	31430887	Another study has reported the use of an antisense oligonucleotide (ASO) to displace lncRNA XIST, the initiator of X-chromosome inactivation, from inactive X.	('XIST', 'Gene', '7503', (92, 96))	('X-chromosome', 'cellular_component', 'GO:0000805', ('115', '127'))	('XIST', 'Gene', (92, 96))	('oligonucleotide', 'Chemical', 'MESH:D009841', (51, 66))	('ASO', 'Chemical', 'MESH:D016376', (68, 71))	('X-chromosome inactivation', 'biological_process', 'GO:0009048', ('115', '140'))	('displace', 'NegReg', (76, 84))	('antisense', 'Var', (41, 50))
52526	31430887	Colorectal cancer arises in a stepwise mode from either discrete genetic alterations or epigenetic perturbations.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('discrete genetic alterations', 'Var', (56, 84))	('epigenetic perturbations', 'Var', (88, 112))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('Colorectal cancer', 'Disease', (0, 17))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('arises', 'Reg', (18, 24))
52527	31430887	Of note, recent findings reveal that epitranscriptomic modifications of lncRNAs, such as N6-methyladenosine (m6A), pseudouridine (Psi), and 5-methylcytosine (m5C), can regulate the diverse functions of lncRNAs.	('diverse', 'MPA', (181, 188))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (140, 156))	('m6A', 'Chemical', 'MESH:C010223', (109, 112))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (89, 107))	('N6-methyladenosine', 'Var', (89, 107))	('Psi', 'Chemical', 'MESH:D011560', (130, 133))	('regulate', 'Reg', (168, 176))	('m5C', 'Chemical', '-', (158, 161))	('pseudouridine', 'Chemical', 'MESH:D011560', (115, 128))
52531	31430887	Recently, a computational model was developed, linking cell surface receptor (EGFR) activation, the MAPK signalling pathway and tumour growth to determine whether ERK inhibitor drugs may be of benefit for CRC patients with the frequently occurring BRAFV600E mutation.	('MAPK', 'Gene', '5594', (100, 104))	('ERK', 'Gene', '5594', (163, 166))	('ERK', 'Gene', (163, 166))	('BRAFV600E', 'Var', (248, 257))	('BRAFV600E', 'Mutation', 'rs113488022', (248, 257))	('MAPK', 'Gene', (100, 104))	('CRC', 'Disease', (205, 208))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('patients', 'Species', '9606', (209, 217))	('tumour growth', 'Disease', (128, 141))	('CRC', 'Phenotype', 'HP:0003003', (205, 208))	('EGFR', 'Gene', '1956', (78, 82))	('cell surface receptor', 'Gene', (55, 76))	('EGFR', 'Gene', (78, 82))	('tumour growth', 'Disease', 'MESH:D006130', (128, 141))	('cell surface receptor', 'Gene', '57126', (55, 76))
52558	30453669	Tobacco use, alcohol abuse, an unhealthy diet, and physical inactivity are described as major cancer risk factors worldwide and modifying or avoiding these key risk factors can significantly reduce (30%-50%) the burden of cancer.	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('alcohol abuse', 'Disease', 'MESH:D000437', (13, 26))	('cancer', 'Disease', (222, 228))	('alcohol abuse', 'Phenotype', 'HP:0030955', (13, 26))	('Tobacco', 'Species', '4097', (0, 7))	('burden', 'MPA', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('modifying', 'Var', (128, 137))	('reduce', 'NegReg', (191, 197))	('cancer', 'Disease', (94, 100))	('alcohol abuse', 'Disease', (13, 26))
52574	30453669	The presence of (+)-catechin reduces the synergism effect between resveratrol and quercetin, which could explain the differences studies have shown in colon cancer risk reduction with moderate red wine consumption in humans, or in animal models, while others showed no effect.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('reduction', 'NegReg', (169, 178))	('resveratrol', 'Chemical', 'MESH:D000077185', (66, 77))	('quercetin', 'Chemical', 'MESH:D011794', (82, 91))	('synergism effect', 'MPA', (41, 57))	('red wine', 'Chemical', '-', (193, 201))	('colon cancer', 'Phenotype', 'HP:0003003', (151, 163))	('+)-catechin', 'Var', (17, 28))	('(+)-catechin', 'Chemical', 'MESH:D002392', (16, 28))	('humans', 'Species', '9606', (217, 223))	('colon cancer', 'Disease', 'MESH:D015179', (151, 163))	('reduces', 'NegReg', (29, 36))	('presence', 'Var', (4, 12))	('colon cancer', 'Disease', (151, 163))
52620	30453669	The activation of activator protein-1 (AP1) and nuclear factor-kappa B (NFkappaB), induced by TPA, was dose-dependently inhibited by RWE treatment.	('AP1', 'Gene', (39, 42))	('men', 'Species', '9606', (142, 145))	('nuclear factor-kappa B', 'Gene', (48, 70))	('activator protein-1', 'Gene', '3726', (18, 37))	('TPA', 'Var', (94, 97))	('inhibited', 'NegReg', (120, 129))	('AP1', 'Gene', '3726', (39, 42))	('NFkappaB', 'Gene', '4790', (72, 80))	('nuclear factor-kappa B', 'Gene', '4790', (48, 70))	('TPA', 'Chemical', 'MESH:D013755', (94, 97))	('NFkappaB', 'Gene', (72, 80))	('activation', 'PosReg', (4, 14))	('activator protein-1', 'Gene', (18, 37))
52647	30534533	- A mitomycin-c prodrug delivered by pegylated liposomes (Promitil) is activated by thiol groups, which are produced in excess by radiation-damaged cells, thus potentiating the radio-sensitizing effect of Promitil.	('thiol', 'Chemical', 'MESH:D013438', (84, 89))	('radio-sensitizing effect', 'MPA', (177, 201))	('potentiating', 'PosReg', (160, 172))	('activated', 'PosReg', (71, 80))	('Promitil', 'Chemical', '-', (205, 213))	('mitomycin-c', 'Gene', (4, 15))	('thiol', 'Var', (84, 89))	('mitomycin', 'Chemical', 'MESH:D016685', (4, 13))	('Promitil', 'Chemical', '-', (58, 66))
52680	30534533	The second patient is a 67-year old male, diagnosed in February 2013 with T3N1 colon cancer, RAS wild-type, who underwent Lt. hemicolectomy (March 2013), and had adjuvant capecitabine and oxaliplatin.	('colon cancer', 'Disease', (79, 91))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('patient', 'Species', '9606', (11, 18))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (188, 199))	('T3N1', 'Var', (74, 78))	('capecitabine', 'Chemical', 'MESH:D000069287', (171, 183))
52701	30534533	A landmark phase-III trial showed that adding MMC to radiation in the treatment of anal cancer led to better colostomy-free survival and disease-free survival and was also associated with improved 5-year overall survival (78.3 vs. 70.7%, p = 0.026) over neoadjuvant cisplatin and 5-FU followed by chemoradiation with cisplatin.	('anal cancer', 'Phenotype', 'HP:0032186', (83, 94))	('colostomy-free survival', 'CPA', (109, 132))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('MMC', 'Chemical', 'MESH:D016685', (46, 49))	('disease-free survival', 'CPA', (137, 158))	('better', 'PosReg', (102, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (317, 326))	('MMC', 'Var', (46, 49))	('overall survival', 'CPA', (204, 220))	('cisplatin', 'Chemical', 'MESH:D002945', (266, 275))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('5-FU', 'Chemical', 'MESH:D005472', (280, 284))	('improved', 'PosReg', (188, 196))
52716	30534533	While the presence of any type of metastases from most solid tumors are generally regarded as being representative of disseminated cancer and are not considered to be curable, evidence has emerged that the subgroup of patients with oligometastases can be cured or at least palliated for long periods of time by resection or ablation of these lesions.	('cancer', 'Disease', (131, 137))	('metastases', 'Disease', 'MESH:D009362', (237, 247))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('ablation', 'Var', (324, 332))	('patients', 'Species', '9606', (218, 226))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('metastases', 'Disease', (34, 44))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('metastases', 'Disease', 'MESH:D009362', (34, 44))	('metastases', 'Disease', (237, 247))
52772	29883385	Since organoids can be genetically engineered, this flexible system enables observation of how specific cancer-associated mutations change the nature of the immune interaction.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mutations', 'Var', (122, 131))	('change', 'Reg', (132, 138))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
52798	29883385	The latter is particularly relevant to understanding mechanisms of tumor-induced immune suppression since many of the tactics used by cancer cells to inactivate tumor infiltrating lymphocytes require direct contact via checkpoint proteins such as PD-1/PD-L1.	('inactivate', 'Var', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('PD-L1', 'Gene', (252, 257))	('cancer', 'Disease', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (67, 72))	('PD-L1', 'Gene', '29126', (252, 257))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', (161, 166))
52808	29883385	One of the few cancer-related organoid models where the influence of microbiota on carcinogenesis has been directly studied involves injection of Helicobacter pylori into the lumen of gastric organoids.	('Helicobacter pylori', 'Var', (146, 165))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('Helicobacter pylori', 'Species', '210', (146, 165))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
52812	29883385	Short chain fatty acids (SCFAs) such as butyrate, propionate and acetate are proinflammatory byproducts of microbial carbohydrate metabolism that induce proliferation and epigenetic alterations in intestinal organoids.	('carbohydrate', 'Chemical', 'MESH:D002241', (117, 129))	('Short chain fatty acids', 'Chemical', 'MESH:D005232', (0, 23))	('acetate', 'Chemical', 'MESH:D000085', (65, 72))	('butyrate', 'Chemical', 'MESH:D002087', (40, 48))	('epigenetic alterations', 'Var', (171, 193))	('proliferation', 'CPA', (153, 166))	('induce', 'Reg', (146, 152))	('carbohydrate metabolism', 'biological_process', 'GO:0005975', ('117', '140'))	('propionate', 'Chemical', 'MESH:D011422', (50, 60))
52827	29883385	Inflammation also increases the invasiveness of intestinal epithelial organoid cells deficient in TGFbR2, a gene frequently lost in a subset of colorectal cancer patients deficient in DNA mismatch repair.	('colorectal cancer', 'Phenotype', 'HP:0003003', (144, 161))	('patients', 'Species', '9606', (162, 170))	('increases', 'PosReg', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('colorectal cancer', 'Disease', (144, 161))	('deficient', 'Var', (85, 94))	('DNA', 'cellular_component', 'GO:0005574', ('184', '187'))	('TGFbR2', 'Gene', '7048', (98, 104))	('TGFbR2', 'Gene', (98, 104))	('mismatch repair', 'biological_process', 'GO:0006298', ('188', '203'))	('Inflammation', 'biological_process', 'GO:0006954', ('0', '12'))	('colorectal cancer', 'Disease', 'MESH:D015179', (144, 161))	('invasiveness of intestinal epithelial organoid', 'CPA', (32, 78))
52828	29883385	Similarly, loss of the IBD susceptibility gene ATG16L1 by intestinal epithelial cells promotes barrier disruption as a result of increased TNF-induced epithelial apoptosis.	('epithelial', 'CPA', (151, 161))	('barrier disruption', 'CPA', (95, 113))	('loss', 'Var', (11, 15))	('increased', 'PosReg', (129, 138))	('IBD', 'Phenotype', 'HP:0002037', (23, 26))	('TNF', 'Gene', (139, 142))	('ATG16L1', 'Gene', '55054', (47, 54))	('promotes', 'PosReg', (86, 94))	('apoptosis', 'biological_process', 'GO:0097194', ('162', '171'))	('apoptosis', 'biological_process', 'GO:0006915', ('162', '171'))	('TNF', 'Gene', '7124', (139, 142))	('ATG16L1', 'Gene', (47, 54))
52840	29883385	IL-6 in particular activates STAT3 signaling in tumor cells and high STAT3 phosphorylation is associated with a poor prognosis in many types of cancers.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('IL-6', 'molecular_function', 'GO:0005138', ('0', '4'))	('high', 'Var', (64, 68))	('tumor', 'Disease', (48, 53))	('STAT3', 'Gene', (69, 74))	('STAT3', 'Gene', '6774', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('signaling', 'biological_process', 'GO:0023052', ('35', '44'))	('phosphorylation', 'biological_process', 'GO:0016310', ('75', '90'))	('activates', 'PosReg', (19, 28))	('STAT3', 'Gene', (29, 34))	('IL-6', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('IL-6', 'Gene', '3569', (0, 4))	('STAT3', 'Gene', '6774', (69, 74))
52857	29883385	Furthermore, there is a positive feedback loop between JMJD3 and inflammation since removal of H3K27 methylation marks upregulates specific pro-inflammatory genes.	('inflammation', 'Disease', (65, 77))	('JMJD3', 'Gene', '23135', (55, 60))	('upregulates', 'PosReg', (119, 130))	('H3K27', 'Protein', (95, 100))	('removal', 'Var', (84, 91))	('methylation', 'Var', (101, 112))	('inflammation', 'Disease', 'MESH:D007249', (65, 77))	('JMJD3', 'Gene', (55, 60))
52860	29883385	The importance of this link between inflammation, cancer stem cells and epigenetic modification has been demonstrated in a model of colorectal cancer (CRC).	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('colorectal cancer', 'Disease', 'MESH:D015179', (132, 149))	('cancer', 'Disease', (50, 56))	('inflammation', 'Disease', 'MESH:D007249', (36, 48))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('CRC', 'Phenotype', 'HP:0003003', (151, 154))	('colorectal cancer', 'Phenotype', 'HP:0003003', (132, 149))	('inflammation', 'Disease', (36, 48))	('cancer', 'Disease', (143, 149))	('colorectal cancer', 'Disease', (132, 149))	('epigenetic modification', 'Var', (72, 95))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
52861	29883385	Chronic intestinal inflammation was found to hypermethylate DNA regions enriched in transcription factors and developmental genes and this pattern persisted in subsequently developing adenomas and adenoma-derived organoids made from intestinal stem cells.	('adenoma', 'Disease', (184, 191))	('adenomas', 'Disease', 'MESH:D000236', (184, 192))	('transcription', 'biological_process', 'GO:0006351', ('84', '97'))	('adenomas', 'Disease', (184, 192))	('adenoma', 'Disease', (197, 204))	('Chronic intestinal inflammation', 'Disease', (0, 31))	('developmental genes', 'Gene', (110, 129))	('adenoma', 'Disease', 'MESH:D000236', (197, 204))	('adenoma', 'Disease', 'MESH:D000236', (184, 191))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('transcription factors', 'Gene', (84, 105))	('inflammation', 'biological_process', 'GO:0006954', ('19', '31'))	('Chronic intestinal inflammation', 'Disease', 'MESH:D007249', (0, 31))	('hypermethylate', 'Var', (45, 59))
52866	29883385	For example, lentiviral delivery of shRNA against anti-inflammatory TGFbR2 in gastric cancer organoids led to metastatic differentiation and the acquisition of genetic heterogeneity, indicating that cancer-associated mutations in Tgfbr2 drive tumor progression.	('cancer', 'Disease', (199, 205))	('tumor', 'Disease', (243, 248))	('Tgfbr2', 'Gene', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('led to', 'Reg', (103, 109))	('TGFbR2', 'Gene', '7048', (68, 74))	('gastric cancer', 'Disease', (78, 92))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('cancer', 'Disease', (86, 92))	('Tgfbr2', 'Gene', '7048', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('TGFbR2', 'Gene', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('drive', 'PosReg', (237, 242))	('gastric cancer', 'Disease', 'MESH:D013274', (78, 92))	('metastatic differentiation', 'CPA', (110, 136))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('mutations', 'Var', (217, 226))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))
52868	29883385	In addition, genetic engineering of pancreatic cancer organoids using electroporation to deliver sgRNA for CRISPR/Cas9-mediated deletion of multiple oncogenes has revealed that stem cell niche factors are only needed during the initial stages of tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (36, 53))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (246, 251))	('pancreatic cancer', 'Disease', 'MESH:D010190', (36, 53))	('pancreatic cancer', 'Disease', (36, 53))	('deletion', 'Var', (128, 136))
52869	29883385	Combining genetic engineering of organoids with the coculture methods described above provides an extremely valuable system for studying the impact of inflammation both on the induction of driver gene mutations and on the evolution of established cancers in a proinflammatory TME.	('mutations', 'Var', (201, 210))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('inflammation', 'biological_process', 'GO:0006954', ('151', '163'))	('cancers', 'Disease', 'MESH:D009369', (247, 254))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('inflammation', 'Disease', 'MESH:D007249', (151, 163))	('cancers', 'Disease', (247, 254))	('inflammation', 'Disease', (151, 163))
52873	29883385	Organoids are essential for the study of driver mutations in cancer since they permit the long-term culture of normal primary cells that can be genetically engineered in order to determine the earliest events in tumor initiation.	('tumor initiation', 'Disease', (212, 228))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor initiation', 'Disease', 'MESH:D009369', (212, 228))	('mutations', 'Var', (48, 57))
52874	29883385	For example, several research groups have used sequential introduction of driver gene mutations to identify the individual roles of each in the tumorigenic cascade.	('mutations', 'Var', (86, 95))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
52875	29883385	By using CRISPR/Cas9 to sequentially introduce mutations in Apc, Tp53, Kras and Smad4 in intestinal epithelial organoids, Drost et al.	('Tp53', 'Gene', (65, 69))	('Kras', 'Gene', (71, 75))	('Smad4', 'Gene', (80, 85))	('Smad4', 'Gene', '4089', (80, 85))	('mutations', 'Var', (47, 56))	('Apc', 'Gene', (60, 63))	('Kras', 'Gene', '3845', (71, 75))	('Tp53', 'Gene', '7157', (65, 69))	('Apc', 'Gene', '324', (60, 63))
52876	29883385	determined that while simultaneous mutation of Apc and Tp53 was sufficient to induce chromosome missegregation and aneuploidy, mutation of all four genes was necessary for full invasive growth of the tumors in vivo.	('Apc', 'Gene', '324', (47, 50))	('aneuploidy', 'Disease', (115, 125))	('chromosome', 'cellular_component', 'GO:0005694', ('85', '95'))	('chromosome missegregation', 'CPA', (85, 110))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('mutation', 'Var', (35, 43))	('invasive growth', 'biological_process', 'GO:0007125', ('177', '192'))	('Tp53', 'Gene', (55, 59))	('invasive growth', 'biological_process', 'GO:0036267', ('177', '192'))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('Tp53', 'Gene', '7157', (55, 59))	('invasive growth', 'biological_process', 'GO:0044409', ('177', '192'))	('aneuploidy', 'Disease', 'MESH:D000782', (115, 125))	('induce', 'Reg', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('invasive growth', 'biological_process', 'GO:0001404', ('177', '192'))	('invasive growth', 'biological_process', 'GO:0044412', ('177', '192'))	('Apc', 'Gene', (47, 50))	('Apc', 'cellular_component', 'GO:0005680', ('47', '50'))	('tumors', 'Disease', (200, 206))	('invasive growth', 'biological_process', 'GO:0051831', ('177', '192'))
52878	29883385	This technique has also been used to identify new driver mutations in breast cancer organoids, identifying Mll3 and Ptpn22 as novel drivers in tumor progression.	('Mll3', 'Gene', '58508', (107, 111))	('Ptpn22', 'Gene', '26191', (116, 122))	('Ptpn22', 'Gene', (116, 122))	('tumor', 'Disease', (143, 148))	('Mll3', 'Gene', (107, 111))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('mutations', 'Var', (57, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
52879	29883385	Similarly, in pancreatic organoids, dual mutations in Kras and Cdkn2a led to non-tumorigenic clones, dual mutations in Kras and Tp53 only produced tumorigenesis in the presence of cancer-associated fibroblasts and quadruple mutations in Kras, Cdkn2a, Tp53 and Smad4 led to rapid tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('produced', 'Reg', (138, 146))	('Tp53', 'Gene', (128, 132))	('Kras', 'Gene', '3845', (119, 123))	('Smad4', 'Gene', (260, 265))	('Cdkn2a', 'Gene', (63, 69))	('tumor', 'Disease', (147, 152))	('Cdkn2a', 'Gene', '1029', (63, 69))	('Kras', 'Gene', '3845', (54, 58))	('Kras', 'Gene', (119, 123))	('non-tumor', 'Disease', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('pancreatic organoids', 'Disease', (14, 34))	('Tp53', 'Gene', '7157', (128, 132))	('pancreatic organoids', 'Disease', 'MESH:D010195', (14, 34))	('cancer', 'Disease', (180, 186))	('tumor', 'Disease', (81, 86))	('non-tumor', 'Disease', 'MESH:D009369', (77, 86))	('Kras', 'Gene', (54, 58))	('Kras', 'Gene', '3845', (237, 241))	('Tp53', 'Gene', (251, 255))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('tumor', 'Disease', (279, 284))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('Cdkn2a', 'Gene', (243, 249))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('Smad4', 'Gene', '4089', (260, 265))	('Cdkn2a', 'Gene', '1029', (243, 249))	('Kras', 'Gene', (237, 241))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('quadruple mutations', 'Var', (214, 233))	('Tp53', 'Gene', '7157', (251, 255))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('dual mutations', 'Var', (101, 115))
52880	29883385	Collectively, these studies illustrate the potential of using organoids to study how specific gene mutations alter a cancer cell's interactions with inflammatory cells in the TME.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('alter', 'Reg', (109, 114))	('interactions', 'Interaction', (131, 143))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('mutations', 'Var', (99, 108))	('cancer', 'Disease', (117, 123))
52881	29883385	There is increasing recognition that the mutation profile of each cancer has specific immunological consequences for how the tumor interacts with neighboring immune cells.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Disease', (125, 130))	('mutation', 'Var', (41, 49))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))	('interacts', 'Interaction', (131, 140))
52882	29883385	While this is epitomized by the well-documented relationship between mutational load and CD8+ tumor infiltrating lymphocyte numbers in cancers, the relationship between a tumor's genotype and immune phenotype extends far beyond this.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('CD8+', 'Gene', (89, 93))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('mutational', 'Var', (69, 79))	('CD8', 'Species', '1151253', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))
52883	29883385	Specific oncogene and tumor suppressor mutations are correlated with specific immunological parameters in the TME both within and across cancer types.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('22', '38'))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('mutations', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('cancer', 'Disease', (137, 143))	('tumor', 'Disease', (22, 27))	('tumor suppressor', 'biological_process', 'GO:0051726', ('22', '38'))
52884	29883385	For example, loss of Tp53 is consistently associated with high macrophage and monocyte infiltration in cancers situated in tissues as divergent as the colon, lung, prostate and pancreas.	('lung', 'Disease', (158, 162))	('Tp53', 'Gene', (21, 25))	('pancreas', 'Disease', (177, 185))	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('associated', 'Reg', (42, 52))	('pancreas', 'Disease', 'MESH:D010190', (177, 185))	('Tp53', 'Gene', '7157', (21, 25))	('colon', 'Disease', (151, 156))	('prostate', 'Disease', (164, 172))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('loss', 'Var', (13, 17))	('cancers', 'Disease', (103, 110))
52885	29883385	In contrast, Ctnnb1 (beta-catenin), Egfr and Pten mutations are associated with decreased CD8+ T cell infiltration in melanoma, non-small cell lung carcinoma and prostate cancer, respectively.	('decreased CD8+ T cell', 'Phenotype', 'HP:0005415', (80, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (162, 177))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('CD8+ T cell infiltration', 'MPA', (90, 114))	('decreased', 'NegReg', (80, 89))	('beta-catenin', 'Gene', (21, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('Ctnnb1', 'Gene', (13, 19))	('non-small cell lung carcinoma and prostate cancer', 'Disease', 'MESH:D002289', (128, 177))	('beta-catenin', 'Gene', '1499', (21, 33))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (128, 157))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (132, 157))	('CD8', 'Species', '1151253', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('Egfr', 'Gene', (36, 40))	('mutations', 'Var', (50, 59))	('Pten', 'Gene', (45, 49))
52888	29883385	This will undoubtedly identify many more promising genomic alterations that might regulate anti-tumor immunity and thus affect a patient's response rates to immunotherapies.	('alterations', 'Var', (59, 70))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('regulate', 'Reg', (82, 90))	('tumor', 'Disease', (96, 101))	('affect', 'Reg', (120, 126))	('response rates', 'CPA', (139, 153))	('patient', 'Species', '9606', (129, 136))
52889	29883385	Organoid coculture systems promise to shed light on the mechanisms regulating the immune effects of cancer mutations since they allow different cell populations to be cultured together for extended periods of time and can be set up from normal, untransformed cells.	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mutations', 'Var', (107, 116))
52892	29883385	Since each genotoxic agent leaves a permanent signature pattern of mutations in exposed cells, it is possible to trace back the exposure history of a given tumor using established methodology.	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('mutations', 'Var', (67, 76))
52906	29883385	Besides the extremely high cost of this model, its major limitation is an immune mismatch between the tumor and immune cells since each come from a different donor, meaning that even though CD4+ and CD8+ T cells are present in the engrafted host, they cannot be effectively recognize or kill the MHC mismatched tumor cells.	('CD4', 'Species', '1151252', (190, 193))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('CD8', 'Species', '1151253', (199, 202))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('donor', 'Species', '9606', (158, 163))	('CD4+', 'Var', (190, 194))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (311, 316))	('CD8+', 'Var', (199, 203))
52913	29883385	Giving our increasing understanding of the molecular variations in each cancer type and how significantly this affects patient prognosis, it is obvious that pre-clinical testing in as many primary human tumors as possible is necessary to identify patient subpopulations in which new drugs are effective, thereby increasing the overall clinical trial success rates.	('patient', 'Species', '9606', (119, 126))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('patient', 'Species', '9606', (247, 254))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('increasing', 'PosReg', (312, 322))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('variations', 'Var', (53, 63))	('human', 'Species', '9606', (197, 202))	('affects', 'Reg', (111, 118))	('cancer', 'Disease', (72, 78))
52921	29883385	Organoids can also be used to establish firm causative links between genetic alterations and drug responsiveness, as has been done in ovarian organoids with homologous recombination deficiencies and in liver cancer organoids with Kras and Arid1a mutations.	('liver cancer', 'Phenotype', 'HP:0002896', (202, 214))	('Kras', 'Gene', (230, 234))	('Arid1a', 'Gene', '8289', (239, 245))	('mutations', 'Var', (246, 255))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('deficiencies and in liver cancer', 'Disease', 'MESH:D006528', (182, 214))	('Arid1a', 'Gene', (239, 245))	('Kras', 'Gene', '3845', (230, 234))
52950	29662489	Immunological Approaches Towards Cancer and Inflammation: A Cross Talk The inflammation is the protective response of the body against various harmful stimuli; however, the aberrant and inappropriate activation tends to become harmful.	('Cancer', 'Disease', 'MESH:D009369', (33, 39))	('Cancer', 'Phenotype', 'HP:0002664', (33, 39))	('inflammation', 'biological_process', 'GO:0006954', ('75', '87'))	('Inflammation', 'biological_process', 'GO:0006954', ('44', '56'))	('inflammation', 'Disease', 'MESH:D007249', (75, 87))	('inflammation', 'Disease', (75, 87))	('aberrant', 'Var', (173, 181))	('Cancer', 'Disease', (33, 39))
52964	29662489	Monoclonal antibodies directed against TNF-alpha, VEGF, and IL-6 has shown promising results to ameliorate inflammation and cancer, while direct administration of IL-2 has been shown to cause tumor regression.	('IL-6', 'molecular_function', 'GO:0005138', ('60', '64'))	('IL-6', 'Gene', '3569', (60, 64))	('IL-2', 'Gene', (163, 167))	('VEGF', 'Gene', '7422', (50, 54))	('inflammation', 'Disease', 'MESH:D007249', (107, 119))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('IL-2', 'molecular_function', 'GO:0005134', ('163', '167'))	('VEGF', 'Gene', (50, 54))	('IL-6', 'Gene', (60, 64))	('tumor', 'Disease', (192, 197))	('inflammation', 'Disease', (107, 119))	('IL-2', 'Gene', '3558', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Disease', (124, 130))	('Monoclonal', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('inflammation', 'biological_process', 'GO:0006954', ('107', '119'))	('ameliorate', 'PosReg', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('TNF-alpha', 'Gene', (39, 48))
53017	29662489	Similarly, chronic inflammatory environment can drive tumor progression, because such a hostile environment is associated with increased growth factor secretion by inflammatory cells, and such proliferating cells are more prone to acquire genetic mutation and DNA damage, with resultant cell progression toward cancer.	('DNA', 'cellular_component', 'GO:0005574', ('260', '263'))	('cancer', 'Disease', (311, 317))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('secretion', 'biological_process', 'GO:0046903', ('151', '160'))	('genetic mutation', 'Var', (239, 255))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cell progression', 'CPA', (287, 303))	('growth factor secretion', 'MPA', (137, 160))	('tumor', 'Disease', (54, 59))	('increased', 'PosReg', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
53036	29662489	NF-kappaB makes the cell more resistant to apoptosis and necrosis by amplification of c-Jun-N-terminal kinase (JNK); this gene not only inhibits apoptosis protein 1 and 2 but also inhibits caretaker gene P53.	('NF-kappaB', 'Gene', (0, 9))	('apoptosis', 'Protein', (145, 154))	('necrosis', 'Disease', (57, 65))	('necrosis', 'biological_process', 'GO:0008219', ('57', '65'))	('JNK', 'molecular_function', 'GO:0004705', ('111', '114'))	('gene', 'Var', (122, 126))	('JNK', 'Gene', (111, 114))	('NF-kappaB', 'Gene', '4790', (0, 9))	('apoptosis', 'biological_process', 'GO:0097194', ('43', '52'))	('JNK', 'Gene', '5599', (111, 114))	('inhibits', 'NegReg', (180, 188))	('apoptosis', 'biological_process', 'GO:0006915', ('43', '52'))	('apoptosis', 'biological_process', 'GO:0097194', ('145', '154'))	('apoptosis', 'biological_process', 'GO:0006915', ('145', '154'))	('P53', 'Gene', (204, 207))	('c-Jun-N-terminal kinase', 'Gene', '5599', (86, 109))	('necrosis', 'biological_process', 'GO:0008220', ('57', '65'))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('necrosis', 'biological_process', 'GO:0070265', ('57', '65'))	('necrosis', 'biological_process', 'GO:0019835', ('57', '65'))	('necrosis', 'biological_process', 'GO:0001906', ('57', '65'))	('c-Jun-N-terminal kinase', 'Gene', (86, 109))	('inhibits', 'NegReg', (136, 144))	('necrosis', 'Disease', 'MESH:D009336', (57, 65))
53041	29662489	Thus, phosphorylated ikappaB undergoes subsequent proteasomal degradation.	('ikappaB', 'Protein', (21, 28))	('phosphorylated', 'Var', (6, 20))	('undergoes', 'Reg', (29, 38))	('ikappaB', 'Chemical', '-', (21, 28))	('proteasomal degradation', 'MPA', (50, 73))
53047	29662489	Alternative pathway involvement in carcinogenesis has been focused on in recent years, and its dysfunction has been implicated in several cancers.	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Disease', (138, 145))	('implicated', 'Reg', (116, 126))	('cancers', 'Disease', 'MESH:D009369', (138, 145))	('carcinogenesis', 'Disease', 'MESH:D063646', (35, 49))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('Alternative pathway', 'Pathway', (0, 19))	('dysfunction', 'Var', (95, 106))	('carcinogenesis', 'Disease', (35, 49))
53060	29662489	Keap1-Nrf2 dysregulation via mutation in either Nrf2 or its inhibitor Keap1 has been associated with the initiation of various tumors, including adenocarcinoma, and gall bladder and liver cancers.	('Keap1', 'Gene', (0, 5))	('mutation', 'Var', (29, 37))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('Keap1', 'Gene', '9817', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('Nrf2', 'Gene', '4780', (48, 52))	('Keap1', 'Gene', (70, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('dysregulation', 'Var', (11, 24))	('associated', 'Reg', (85, 95))	('Nrf2', 'Gene', '4780', (6, 10))	('gall bladder and liver cancers', 'Disease', 'MESH:D005706', (165, 195))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('adenocarcinoma', 'Disease', (145, 159))	('Nrf2', 'Gene', (48, 52))	('Keap1', 'Gene', '9817', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('liver cancers', 'Phenotype', 'HP:0002896', (182, 195))	('Nrf2', 'Gene', (6, 10))	('adenocarcinoma', 'Disease', 'MESH:D000230', (145, 159))
53061	29662489	Keap1 mutation stabilizes Nrf2, which in turn, causes increased synthesis of cytoprotective antioxidant proteins in normal body cells and transformed cells.	('Keap1', 'Gene', (0, 5))	('synthesis of cytoprotective antioxidant proteins', 'MPA', (64, 112))	('synthesis', 'biological_process', 'GO:0009058', ('64', '73'))	('Nrf2', 'Gene', (26, 30))	('mutation', 'Var', (6, 14))	('increased', 'PosReg', (54, 63))	('Nrf2', 'Gene', '4780', (26, 30))	('stabilizes', 'PosReg', (15, 25))	('Keap1', 'Gene', '9817', (0, 5))
53080	29662489	This signal-specific P53 modification activates different sets of genes, such as expression of Puma genes (P53-upregulated modulator of apoptosis), Bax (Bcl-2 associated x-protein), Noxa, and Apaf-1 (apoptotic protease activating factor-1) to induce apoptosis.	('Bax', 'Gene', (148, 151))	('induce', 'PosReg', (243, 249))	('apoptosis', 'CPA', (250, 259))	('Puma genes', 'Gene', (95, 105))	('Bcl-2', 'Gene', (153, 158))	('Bcl-2', 'Gene', '596', (153, 158))	('P53', 'Gene', (21, 24))	('modification', 'Var', (25, 37))	('Bax', 'Gene', '581', (148, 151))	('activates', 'PosReg', (38, 47))	('Apaf-1', 'Gene', (192, 198))
53082	29662489	A National Institute of Health study reported that 61% of bladder cancer cases showed P53 mutation, and its mutation was associated with invasive types of tumors.	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('associated', 'Reg', (121, 131))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('P53', 'Gene', (86, 89))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('bladder cancer', 'Disease', 'MESH:D001749', (58, 72))	('bladder cancer', 'Disease', (58, 72))	('mutation', 'Var', (90, 98))
53083	29662489	Several studies demonstrated that P53 nullifies the activation of the major inflammatory NF-kappaB signaling cascade by competing with cyclic AMP response element binding protein (CREB) and P300 coactivator protein.	('P53', 'Var', (34, 37))	('NF-kappaB', 'Gene', '4790', (89, 98))	('NF-kappaB', 'Gene', (89, 98))	('nullifies', 'NegReg', (38, 47))	('CREB', 'Gene', (180, 184))	('cyclic AMP response element binding protein', 'Gene', '1385', (135, 178))	('cyclic AMP response element binding protein', 'Gene', (135, 178))	('CREB', 'Gene', '1385', (180, 184))
53084	29662489	P53 directly inhibits the P65 NF-kappaB unit, and indirectly suppresses the IKKalpha-mediated activation of NF-kappaB.	('IKKalpha', 'Gene', '1147', (76, 84))	('P53', 'Var', (0, 3))	('NF-kappaB', 'Gene', '4790', (30, 39))	('IKKalpha', 'Gene', (76, 84))	('suppresses', 'NegReg', (61, 71))	('NF-kappaB', 'Gene', (30, 39))	('NF-kappaB', 'Gene', '4790', (108, 117))	('activation of NF-kappaB', 'biological_process', 'GO:0051092', ('94', '117'))	('inhibits', 'NegReg', (13, 21))	('P65', 'Gene', '5970', (26, 29))	('NF-kappaB', 'Gene', (108, 117))	('P65', 'Gene', (26, 29))
53085	29662489	This P53-mediated NF-kappaB suppression inhibits the synthesis of pro-inflammatory mediators such as COX-2, IL-6, and iNOS (Figure 2).	('IL-6', 'Gene', '3569', (108, 112))	('synthesis of pro-inflammatory mediators', 'MPA', (53, 92))	('P53-mediated', 'Var', (5, 17))	('COX-2', 'Gene', (101, 106))	('COX-2', 'Gene', '5743', (101, 106))	('iNOS', 'MPA', (118, 122))	('synthesis', 'biological_process', 'GO:0009058', ('53', '62'))	('NF-kappaB', 'Gene', '4790', (18, 27))	('IL-6', 'molecular_function', 'GO:0005138', ('108', '112'))	('NF-kappaB', 'Gene', (18, 27))	('suppression inhibits', 'NegReg', (28, 48))	('IL-6', 'Gene', (108, 112))
53093	29662489	JAK2 gain-of-function mutation has been observed in thrombocytopenia, polycythemia vera, and myelofibrosis neoplasia.	('thrombocytopenia', 'Disease', 'MESH:D013921', (52, 68))	('mutation', 'Var', (22, 30))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (52, 68))	('gain-of-function', 'PosReg', (5, 21))	('myelofibrosis neoplasia', 'Disease', (93, 116))	('neoplasia', 'Phenotype', 'HP:0002664', (107, 116))	('JAK2', 'Gene', '3717', (0, 4))	('polycythemia vera', 'Disease', 'MESH:D011087', (70, 87))	('myelofibrosis', 'Phenotype', 'HP:0011974', (93, 106))	('thrombocytopenia', 'Disease', (52, 68))	('JAK2', 'Gene', (0, 4))	('polycythemia vera', 'Disease', (70, 87))	('myelofibrosis neoplasia', 'Disease', 'MESH:D055728', (93, 116))	('polycythemia', 'Phenotype', 'HP:0001901', (70, 82))
53094	29662489	The JAK/STAT pathway is dephosphorylated and downregulated by protein tyrosine phosphatases (PTPs) such as PTP1B (PTPN1) and TC-PTP (PTPN2).	('JAK', 'molecular_function', 'GO:0004713', ('4', '7'))	('tyrosine', 'Chemical', 'MESH:D014443', (70, 78))	('PTP1B', 'Var', (107, 112))	('PTPs', 'Gene', '5805', (93, 97))	('downregulated', 'NegReg', (45, 58))	('PTPN1', 'Gene', '5770', (114, 119))	('TC-PTP', 'Gene', (125, 131))	('PTPN1', 'Gene', (114, 119))	('PTPs', 'Gene', (93, 97))	('TC-PTP', 'Gene', '5771', (125, 131))	('JAK/STAT pathway', 'Pathway', (4, 20))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
53097	29662489	In contrast with this, PTP1B counteracts IL-10-mediated STAT3 downstream anti-inflammatory responses.	('IL-10', 'molecular_function', 'GO:0005141', ('41', '46'))	('STAT3', 'Gene', '6774', (56, 61))	('PTP1B', 'Var', (23, 28))	('STAT3', 'Gene', (56, 61))
53098	29662489	PTP1B has demonstrated both tumorigenic and antitumor behavior in various studies, since mice lacking PTP1B were tumor resistant; however, PTP1B deficiency has also been observed in colon, breast, gastric, and prostate tumor development.	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', (219, 224))	('prostate tumor', 'Disease', 'MESH:D011471', (210, 224))	('gastric', 'CPA', (197, 204))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('prostate tumor', 'Phenotype', 'HP:0100787', (210, 224))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (113, 118))	('PTP1B', 'Gene', (139, 144))	('tumor', 'Disease', (48, 53))	('deficiency', 'Var', (145, 155))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('observed', 'Reg', (170, 178))	('breast', 'CPA', (189, 195))	('mice', 'Species', '10090', (89, 93))	('colon', 'Disease', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('prostate tumor', 'Disease', (210, 224))
53099	29662489	Mice with deficiency of CT-PTP (PTPN2) within 1-2 weeks of birth not only developed an inflammatory state, characterized by mononuclear infiltrates, but also showed increased synthesis of TNF-alpha, IFN-gamma, and NO.	('synthesis', 'MPA', (175, 184))	('TNF-alpha', 'MPA', (188, 197))	('Mice', 'Species', '10090', (0, 4))	('deficiency', 'Var', (10, 20))	('developed', 'Reg', (74, 83))	('CT-PTP', 'Gene', (24, 30))	('increased', 'PosReg', (165, 174))
53102	29662489	PI3K acts upon phosphatidylinositol-4,5-biphosphate substrate and phosphorylates it to phosphatidylinositol-3,4,5-triphosphate (PIP3), and the reaction is negatively regulated by phosphatase and tensin homolog (PTEN) tumor suppressor phosphatase, SHIP1/2, and INPP4B.	('INPP4B', 'Gene', (260, 266))	('negatively', 'NegReg', (155, 165))	('PTEN', 'Gene', (211, 215))	('tumor suppressor', 'biological_process', 'GO:0051726', ('217', '233'))	('PIP3', 'Chemical', '-', (128, 132))	('phosphatidylinositol-3,4,5-triphosphate', 'Chemical', 'MESH:C060974', (87, 126))	('tumor', 'Disease', (217, 222))	('phosphatase', 'molecular_function', 'GO:0016791', ('234', '245'))	('phosphatase', 'molecular_function', 'GO:0016791', ('179', '190'))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('PI3K', 'Var', (0, 4))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('179', '209'))	('SHIP1/2', 'Gene', '3635;3636', (247, 254))	('INPP4B', 'Gene', '8821', (260, 266))	('phosphatidylinositol-4,5-biphosphate', 'Chemical', 'MESH:D019269', (15, 51))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('SHIP1/2', 'Gene', (247, 254))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('217', '233'))
53104	29662489	Akt undergoes phosphorylation-dependent activation by PDK1 at threonine 308 residues and mTORC2 complex at serine 473.	('PDK1', 'Gene', '5170', (54, 58))	('PDK1', 'Gene', (54, 58))	('threonine', 'Chemical', 'MESH:D013912', (62, 71))	('mTORC2', 'cellular_component', 'GO:0031932', ('89', '95'))	('mTORC2', 'Gene', (89, 95))	('threonine 308', 'Var', (62, 75))	('PDK1', 'molecular_function', 'GO:0004740', ('54', '58'))	('activation', 'PosReg', (40, 50))	('serine', 'Chemical', 'MESH:D012694', (107, 113))	('Akt', 'Gene', '207', (0, 3))	('mTORC2', 'Gene', '74343', (89, 95))	('phosphorylation', 'biological_process', 'GO:0016310', ('14', '29'))	('Akt', 'Gene', (0, 3))
53106	29662489	PI3K mutations have been observed in various tumors, and its alteration may take place at several steps including gain-of-function mutations in genes encoding the P110alpha catalytic unit and rarely the P110beta catalytic unit.	('mutations', 'Var', (131, 140))	('PI3K', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('PI3K', 'molecular_function', 'GO:0016303', ('0', '4'))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('P110alpha', 'Gene', (163, 172))	('mutations', 'Var', (5, 14))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('P110alpha', 'Gene', '5290', (163, 172))	('P110beta', 'Gene', '5291', (203, 211))	('P110beta', 'Gene', (203, 211))	('gain-of-function', 'PosReg', (114, 130))
53107	29662489	The P85alpha regulatory subunit and loss-of-function mutations in PI3K inhibitor phosphatases such as PTEN and INDP4B are implicated in various tumors.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('loss-of-function', 'NegReg', (36, 52))	('INDP4B', 'Gene', (111, 117))	('PI3K', 'molecular_function', 'GO:0016303', ('66', '70'))	('mutations', 'Var', (53, 62))	('PI3K', 'Gene', (66, 70))	('PTEN', 'Gene', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
53108	29662489	PTEN loss-of-function mutation followed by increased activity of PI3K elevates programmed death ligand 1 (PD-1), an immune cell suppressant factor, whereas PI3K inhibitors increase the immune cell response to tumors.	('programmed death ligand 1', 'Gene', '574058', (79, 104))	('tumors', 'Disease', (209, 215))	('increase', 'PosReg', (172, 180))	('mutation', 'Var', (22, 30))	('PD-1', 'Gene', '5133', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('PD-1', 'Gene', (106, 110))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('PI3K', 'molecular_function', 'GO:0016303', ('65', '69'))	('ligand', 'molecular_function', 'GO:0005488', ('96', '102'))	('activity', 'MPA', (53, 61))	('PI3K', 'molecular_function', 'GO:0016303', ('156', '160'))	('programmed death ligand 1', 'Gene', (79, 104))	('increased', 'PosReg', (43, 52))	('PTEN', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('loss-of-function', 'NegReg', (5, 21))
53112	29662489	The role of CREB in cell survival has also been described in a number of tissues, such as nerve growth factor (NGF)-induced phosphorylation of CREB, and it was proposed that phosphorylated CREB induces genes that confer specificity to NGF signals that are associated with increased survival and differentiation of neurons.	('induces', 'Reg', (194, 201))	('increased', 'PosReg', (272, 281))	('phosphorylated', 'Var', (174, 188))	('CREB', 'Gene', (143, 147))	('CREB', 'Gene', '1385', (12, 16))	('CREB', 'Gene', '1385', (189, 193))	('specificity', 'MPA', (220, 231))	('CREB', 'Gene', (189, 193))	('CREB', 'Gene', '1385', (143, 147))	('genes', 'Gene', (202, 207))	('survival', 'CPA', (282, 290))	('phosphorylation', 'biological_process', 'GO:0016310', ('124', '139'))	('CREB', 'Gene', (12, 16))
53115	29662489	Thus, it is apparent that activation of CREB induces the survival of neurons via activating downstream target genes that encode prosurvival factors.	('CREB', 'Gene', '1385', (40, 44))	('induces', 'PosReg', (45, 52))	('survival of neurons', 'CPA', (57, 76))	('CREB', 'Gene', (40, 44))	('activation', 'Var', (26, 36))	('activating', 'PosReg', (81, 91))
53137	29662489	Alterations in genes encoding APC have been described in sporadic colorectal cancer development.	('APC', 'Disease', 'MESH:D011125', (30, 33))	('APC', 'Disease', (30, 33))	('Alterations', 'Var', (0, 11))	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal cancer', 'Disease', (66, 83))	('described', 'Reg', (44, 53))	('APC', 'cellular_component', 'GO:0005680', ('30', '33'))	('colorectal cancer', 'Disease', 'MESH:D015179', (66, 83))
53138	29662489	On the other hand, alteration in the porcupine enzyme-encoding gene, which resides in the endoplasmic reticulum (ER) and facilitates the process of Wnt secretion, has also been demonstrated in focal dermal hypoplasia.	('alteration', 'Var', (19, 29))	('facilitates', 'PosReg', (121, 132))	('demonstrated', 'Reg', (177, 189))	('focal dermal hypoplasia', 'Phenotype', 'HP:0007510', (193, 216))	('focal dermal hypoplasia', 'Disease', (193, 216))	('focal dermal hypoplasia', 'Disease', 'MESH:D005489', (193, 216))	('porcupine enzyme-encoding gene', 'Gene', (37, 67))
53144	29662489	PAMPs induce innate immune responses and increase the expression of inflammatory cytokines such as IFNs, ILs, and TNFs.	('innate immune responses', 'CPA', (13, 36))	('TNF', 'Gene', (114, 117))	('ILs', 'Disease', (105, 108))	('induce', 'PosReg', (6, 12))	('TNF', 'Gene', '7124', (114, 117))	('PAMPs', 'Var', (0, 5))	('expression of inflammatory cytokines', 'MPA', (54, 90))	('increase', 'PosReg', (41, 49))	('increase the expression of inflammatory cytokines', 'Phenotype', 'HP:0012649', (41, 90))
53166	29662489	The presence of INF-gamma cytokines at the tumor microenvironment has a positive impact on tumor prognosis.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('presence', 'Var', (4, 12))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (91, 96))
53171	29662489	TANs are shown to be involved in primary tumor progression; however, inhibition of the TGF-beta signal recruits antitumor TAN cells.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('TGF-beta', 'Gene', (87, 95))	('tumor', 'Disease', (41, 46))	('TANs', 'Chemical', '-', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('inhibition', 'Var', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (116, 121))	('TGF-beta', 'Gene', '7040', (87, 95))
53180	29662489	Similarly, high NLR has been correlated with poor cell differentiation, advanced stage tumors, worse prognosis, metastasis, and relapses.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('high', 'Var', (11, 15))	('metastasis', 'CPA', (112, 122))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('NLR', 'Gene', (16, 19))	('poor cell differentiation', 'CPA', (45, 70))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
53201	29662489	In a study of CD8+ T cell differentiation into long-lived memory precursor effector cells (MPECs), T cells expressing CD127hi and KLRG1lo and short-lived effector cells (SLECs) expressing KLRGhi and CD127lo are regulated by B-lymphocyte-induced maturation protein 1 (Blimp-1).	('KLRG1', 'Gene', '10219', (130, 135))	('B-lymphocyte-induced maturation protein 1', 'Gene', '639', (224, 265))	('CD127lo', 'Var', (199, 206))	('B-lymphocyte-induced maturation protein 1', 'Gene', (224, 265))	('CD8', 'Gene', (14, 17))	('Blimp-1', 'Gene', (267, 274))	('SLE', 'Disease', (170, 173))	('KLRG1', 'Gene', (130, 135))	('SLE', 'Disease', 'MESH:D008180', (170, 173))	('CD127hi', 'Var', (118, 125))	('SLE', 'Phenotype', 'HP:0002725', (170, 173))	('CD8', 'Gene', '925', (14, 17))	('Blimp-1', 'Gene', '639', (267, 274))
53214	29662489	Lack of IL-10 has been shown to predispose individuals to various pro-inflammatory conditions such as IBD, while exogenous IL-10 administration in vitro resolved the inflammation and also inhibited autoimmune responses.	('inflammation', 'Disease', 'MESH:D007249', (166, 178))	('IL-10', 'molecular_function', 'GO:0005141', ('8', '13'))	('IL-10', 'Gene', (8, 13))	('pro-inflammatory', 'MPA', (66, 82))	('Lack', 'Var', (0, 4))	('inflammation', 'Disease', (166, 178))	('predispose', 'Reg', (32, 42))	('inhibited', 'NegReg', (188, 197))	('IBD', 'Phenotype', 'HP:0002037', (102, 105))	('inflammation', 'biological_process', 'GO:0006954', ('166', '178'))	('IL-10', 'molecular_function', 'GO:0005141', ('123', '128'))	('IBD', 'Disease', (102, 105))	('autoimmune responses', 'CPA', (198, 218))
53220	29662489	On the other hand, VEGF-targeted therapies have been shown to inhibit tumor growth, angiogenesis, and permeability.	('angiogenesis', 'CPA', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('permeability', 'MPA', (102, 114))	('VEGF', 'Gene', (19, 23))	('inhibit', 'NegReg', (62, 69))	('VEGF', 'Gene', '7422', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('therapies', 'Var', (33, 42))
53239	29662489	It was previously reported that TCRalpha subunit constant (TRAC) mutation trigger the loss of alphabeta TCR on T-cell surface and beta-2 microglobulin (B2M) is necessary for the HLA-I heterodimers expression on cell surface.	('beta-2 microglobulin', 'Gene', (130, 150))	('loss', 'NegReg', (86, 90))	('RA', 'Phenotype', 'HP:0001370', (60, 62))	('cell surface', 'cellular_component', 'GO:0009986', ('113', '125'))	('cell surface', 'cellular_component', 'GO:0009986', ('211', '223'))	('TCR', 'cellular_component', 'GO:0042101', ('104', '107'))	('TCRalpha', 'Gene', (32, 40))	('alphabeta TCR', 'Protein', (94, 107))	('TCR', 'biological_process', 'GO:0006283', ('104', '107'))	('TRAC', 'Gene', (59, 63))	('B2M', 'Gene', '12010', (152, 155))	('mutation', 'Var', (65, 73))	('beta-2 microglobulin', 'Gene', '567', (130, 150))	('B2M', 'Gene', (152, 155))	('TCRalpha', 'Gene', '28755', (32, 40))
53248	29662489	The monoclonal anti-CD1d antibodies directed against the CD1d in vitro induced apoptosis via increasing the expression of Bax pro-apoptotic genes.	('Bax', 'Gene', '581', (122, 125))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('CD1d', 'Gene', '912', (57, 61))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('Bax', 'Gene', (122, 125))	('antibodies', 'Var', (25, 35))	('apoptosis', 'CPA', (79, 88))	('CD1d', 'Gene', (57, 61))	('CD1d', 'Gene', '912', (20, 24))	('expression', 'MPA', (108, 118))	('CD1d', 'Gene', (20, 24))	('increasing', 'PosReg', (93, 103))
53250	29662489	Similarly, a vaccine composed of alpha-GalCer-loaded MOPC315BM myeloma cells significantly reduced tumor growth and proliferation.	('tumor', 'Disease', (99, 104))	('myeloma', 'Disease', 'MESH:D009101', (63, 70))	('MOPC315BM', 'CellLine', 'CVCL:2616', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('reduced', 'NegReg', (91, 98))	('MOPC315BM', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('myeloma', 'Disease', (63, 70))
53263	29662489	A study reported that antagonists that target the A2AR and A2BR, on one hand, enhance the T cells effector function against the tumors, while on the other hand, also induce apoptosis in the cancerous cells and INF-gamma, which further prevented angiogenesis.	('enhance', 'PosReg', (78, 85))	('cancerous', 'Disease', (190, 199))	('A2BR', 'Var', (59, 63))	('apoptosis', 'CPA', (173, 182))	('angiogenesis', 'CPA', (245, 257))	('A2AR', 'Gene', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancerous', 'Disease', 'MESH:D009369', (190, 199))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('induce', 'Reg', (166, 172))	('A2AR', 'Gene', '135', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('prevented', 'NegReg', (235, 244))
53265	29662489	CD28 molecules expressed by T cells give out a costimulatory signal to APC B7 molecules, while CDLA-4 interrupts this costimulatory signal between activated T cells and APCs, thus suppressing the immune system.	('suppressing', 'NegReg', (180, 191))	('APC', 'Disease', 'MESH:D011125', (71, 74))	('APC', 'Disease', (71, 74))	('immune system', 'MPA', (196, 209))	('CD28', 'Gene', '940', (0, 4))	('suppressing the immune system', 'Phenotype', 'HP:0002721', (180, 209))	('costimulatory signal', 'MPA', (47, 67))	('CD28', 'Gene', (0, 4))	('interrupts', 'NegReg', (102, 112))	('APC', 'Disease', 'MESH:D011125', (169, 172))	('CDLA-4', 'Var', (95, 101))	('costimulatory signal', 'MPA', (118, 138))	('APC', 'Disease', (169, 172))
53266	29662489	Therefore, CTLA-4 inhibitors reverse the immune suppression and T cell responses against tumors cells.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('CTLA-4', 'Gene', (11, 17))	('immune suppression', 'CPA', (41, 59))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('CTLA-4', 'Gene', '1493', (11, 17))	('reverse', 'NegReg', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('inhibitors', 'Var', (18, 28))
53268	29662489	PD-1 interacts with stimulated cytotoxic CD8+ cells, rendering them unable to perform cytotoxicity, while PD-1 inhibitors activate CTLs to respond against the tumorigenic cells.	('activate', 'PosReg', (122, 130))	('PD-1', 'Gene', '5133', (106, 110))	('cytotoxicity', 'Disease', 'MESH:D064420', (86, 98))	('PD-1', 'Gene', (0, 4))	('PD-1', 'Gene', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('PD-1', 'Gene', '5133', (0, 4))	('CD8', 'Gene', (41, 44))	('CD8', 'Gene', '925', (41, 44))	('tumor', 'Disease', (159, 164))	('respond', 'MPA', (139, 146))	('cytotoxicity', 'Disease', (86, 98))	('inhibitors', 'Var', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
53271	29662489	CXCR2 promotes the migration of neutrophils from bone marrow to the circulation and recruits the neutrophils to the site of inflammation.	('inflammation', 'biological_process', 'GO:0006954', ('124', '136'))	('inflammation', 'Disease', (124, 136))	('promotes', 'PosReg', (6, 14))	('migration', 'CPA', (19, 28))	('CXCR2', 'Var', (0, 5))	('inflammation', 'Disease', 'MESH:D007249', (124, 136))
53272	29662489	CXCR2 is implicated not only in cancer development but also facilitates the process of metastasis.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('CXCR2', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('facilitates', 'PosReg', (60, 71))	('process of metastasis', 'CPA', (76, 97))
53296	29662489	Antibodies directed against TNF-alpha are considered as a first target and have proved clinically effective against RA.	('Antibodies', 'Var', (0, 10))	('effective', 'Reg', (98, 107))	('TNF-alpha', 'Gene', (28, 37))	('RA', 'Disease', 'MESH:D001172', (116, 118))	('RA', 'Phenotype', 'HP:0001370', (116, 118))
53298	29662489	Monoclonal antibody blockade of IL-6 proved effective in the treatment of RA and JIA.	('IL-6', 'Gene', (32, 36))	('IL-6', 'molecular_function', 'GO:0005138', ('32', '36'))	('Monoclonal', 'Var', (0, 10))	('RA', 'Phenotype', 'HP:0001370', (74, 76))	('antibody', 'cellular_component', 'GO:0042571', ('11', '19'))	('JIA', 'Disease', (81, 84))	('antibody', 'cellular_component', 'GO:0019815', ('11', '19'))	('IL-6', 'Gene', '3569', (32, 36))	('RA', 'Disease', 'MESH:D001172', (74, 76))	('JIA', 'Phenotype', 'HP:0005681', (81, 84))	('antibody', 'cellular_component', 'GO:0019814', ('11', '19'))	('antibody', 'molecular_function', 'GO:0003823', ('11', '19'))
53350	29662489	The microRNA-27b-3p (miR-27b) is a miRNA which is absent/deleted in the tissue of the patients with breast cancer and breast cancer cell lines which makes these cells chemoresistance, while its presence is related to the sensitization of the breast cancer cell to various chemotherapeutic agents.	('makes', 'Reg', (149, 154))	('miR-27b', 'Gene', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('patients', 'Species', '9606', (86, 94))	('miR-27b', 'Gene', '407019', (21, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (242, 255))	('microRNA-27b-3p', 'Var', (4, 19))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Disease', (100, 113))	('breast cancer', 'Disease', (242, 255))	('breast cancer', 'Disease', 'MESH:D001943', (242, 255))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('chemoresistance', 'CPA', (167, 182))	('sensitization', 'biological_process', 'GO:0046960', ('221', '234'))
53383	27982025	Further, we showed: 1) among all histologies, the not-otherwise-specified type had the lowest overall mutation count (p<.001 for entire cohort, p<.03 for the microsatellite instable group), and among the microsatellite instable tumors, this type also correlated with fewer frameshift mutations in coding mononucleotide repeats of a defined set of relevant genes (p<.01); 2) cytosine-phosphate-guanine-island-methylator-phenotype-high colorectal cancers with or without microsatellite instability tended to have different histological patterns: the former more often mucinous and the latter more often not-otherwise-specified; 3) mucinous histology was associated with more frequent alterations in BRAF, PIK3CA, and the transforming-growth-factor-beta pathway when compared to non-mucinous histologies (p<.001, p=.01, and p<0.001, respectively); and 4) few colorectal cancers (<9%) exhibited upregulation of immune inhibitory genes including major immune checkpoints; these tumors were primarily microsatellite instable (up to 43%, versus <3% in microsatellite-stable group) and had distinctly non-mucinous histologies with a solid growth.	('cancers', 'Phenotype', 'HP:0002664', (867, 874))	('mucin', 'Gene', (566, 571))	('mucin', 'Gene', (629, 634))	('alterations', 'Reg', (682, 693))	('transforming-growth-factor-beta', 'Gene', '7040', (719, 750))	('cancer', 'Phenotype', 'HP:0002664', (867, 873))	('colorectal cancer', 'Phenotype', 'HP:0003003', (434, 451))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('mucin', 'Gene', (780, 785))	('mucin', 'Gene', '100508689', (566, 571))	('colorectal cancers', 'Disease', (434, 452))	('mucin', 'Gene', '100508689', (629, 634))	('microsatellite', 'Var', (995, 1009))	('mucin', 'Gene', (1097, 1102))	('PIK3CA', 'Gene', (703, 709))	('cancers', 'Phenotype', 'HP:0002664', (445, 452))	('mononucleotide', 'Chemical', '-', (304, 318))	('mucin', 'Gene', '100508689', (780, 785))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('mucin', 'Gene', '100508689', (1097, 1102))	('tumors', 'Phenotype', 'HP:0002664', (973, 979))	('colorectal cancers', 'Disease', 'MESH:D015179', (856, 874))	('tumors', 'Disease', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (445, 451))	('BRAF', 'Gene', (697, 701))	('BRAF', 'Gene', '673', (697, 701))	('transforming-growth-factor-beta', 'Gene', (719, 750))	('tumor', 'Phenotype', 'HP:0002664', (973, 978))	('tumors', 'Disease', (973, 979))	('colorectal cancers', 'Disease', 'MESH:D015179', (434, 452))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('PIK3CA', 'Gene', '5290', (703, 709))	('tumors', 'Disease', 'MESH:D009369', (973, 979))	('colorectal cancer', 'Phenotype', 'HP:0003003', (856, 873))	('colorectal cancers', 'Disease', (856, 874))
53384	27982025	The morphological patterns associated with alterations of immune checkpoint genes bear the potential to guide patient selection for clinical trials that target immune checkpoints in colorectal cancer, and provide directions for future studies.	('colorectal cancer', 'Phenotype', 'HP:0003003', (182, 199))	('colorectal cancer', 'Disease', (182, 199))	('patient', 'Species', '9606', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('alterations', 'Var', (43, 54))	('immune checkpoint genes', 'Gene', (58, 81))	('colorectal cancer', 'Disease', 'MESH:D015179', (182, 199))
53398	27982025	The POLE-mutated group comprised the "ultra-mutated" tumors that did not show MSI-H. Molecular alterations evaluated included overall mutation rates, rates of frameshift mutations in coding mononucleotide repeats in 20 genes that have mononucleotides repeats of 6 nucleotides or longer (MSH3 [A8], MSH6 [C8], MLH3 [T9], TGFbetaR2 [A10], PRDM2 [A9], PTEN [A6], TCF7L2 [A9], AXIN2 [C7], ACVR2A [A8], ATR [A10], AIM2 [T10], RAD50 [A9], CHEK1 [A9], BLM [A9], CASP5 [T10], GRB14 [A9], MBD4 [T10], WISP3 [A9], SEC63 [T10]), methylation subtypes (CIMP-H, CIMP-L, cluster 3, and cluster 4), mutations or copy number alterations of genes (Suppl.	('mononucleotide', 'Chemical', '-', (235, 249))	('A10', 'Gene', '28870', (331, 334))	('A10', 'Gene', (403, 406))	('PRDM2', 'Gene', (337, 342))	('PRDM2', 'Gene', '7799', (337, 342))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('CIMP-L', 'Chemical', '-', (548, 554))	('AXIN2', 'Gene', (373, 378))	('MBD4', 'Gene', '8930', (480, 484))	('MLH3', 'Gene', '27030', (309, 313))	('TCF7L2', 'Gene', (360, 366))	('ATR', 'Gene', '545', (398, 401))	('TCF7L2', 'Gene', '6934', (360, 366))	('A10', 'Gene', (331, 334))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('MLH3', 'Gene', (309, 313))	('SEC63', 'Gene', (504, 509))	('MSH6', 'Gene', (298, 302))	('copy number alterations', 'Var', (596, 619))	('SEC63', 'Gene', '11231', (504, 509))	('RAD50', 'Gene', (421, 426))	('tumors', 'Disease', (53, 59))	('mononucleotide', 'Chemical', '-', (190, 204))	('GRB14', 'Gene', (468, 473))	('MSH6', 'Gene', '2956', (298, 302))	('MBD4', 'Gene', (480, 484))	('WISP3', 'Gene', (492, 497))	('CHEK1', 'Gene', '1111', (433, 438))	('CASP5', 'Gene', (455, 460))	('AIM2', 'Gene', '9447', (409, 413))	('CIMP-H', 'Chemical', '-', (540, 546))	('ACVR2A', 'Gene', '92', (385, 391))	('PTEN', 'Gene', (349, 353))	('CASP5', 'Gene', '838', (455, 460))	('RAD50', 'Gene', '10111', (421, 426))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('WISP3', 'Gene', '8838', (492, 497))	('ACVR2A', 'Gene', (385, 391))	('A10', 'Gene', '28870', (403, 406))	('MSH3', 'Gene', (287, 291))	('GRB14', 'Gene', '2888', (468, 473))	('AXIN2', 'Gene', '8313', (373, 378))	('CHEK1', 'Gene', (433, 438))	('ATR', 'Gene', (398, 401))	('MSH3', 'Gene', '4437', (287, 291))	('AIM2', 'Gene', (409, 413))	('mutations', 'Var', (583, 592))	('PTEN', 'Gene', '5728', (349, 353))
53400	27982025	In addition to the above major alteration patterns, we also evaluated morphological associations with alterations in genes associated with tumor immunity.	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('alterations', 'Var', (102, 113))
53415	27982025	As expected, the overall mutation count was highest in the POLE-mutated tumors (median, 3200) followed by MSI-H (median, 664) and non-MSI (median, 67) tumors.	('highest', 'Reg', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('mutation', 'Var', (25, 33))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))
53420	27982025	A slight tendency of poorly differentiated tumors having more mutations than the not-otherwise-specified type was noted in non-MSI-H/non-POLE cases (median, 78 vs. 67, p=0.8).	('non-MSI-H/non-POLE', 'Disease', (123, 141))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('mutations', 'Var', (62, 71))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
53421	27982025	Within the MSI-H tumors, analysis of mononucleotide frameshift mutations in the 20 genes that contain coding mononucleotide repeats of six nucleotides or longer showed that such mutations were lowest in the not-otherwise-specified type as well (median 2 vs 4-8 for other types, p<0.01).	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mononucleotide', 'Chemical', '-', (37, 51))	('MSI-H tumors', 'Disease', 'MESH:D009369', (11, 23))	('MSI-H tumors', 'Disease', (11, 23))	('mononucleotide', 'Chemical', '-', (109, 123))	('mononucleotide frameshift mutations', 'Var', (37, 72))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
53422	27982025	Poorly differentiated tumors with a solid growth tended to have the highest number of these mutations (Table 2).	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutations', 'Var', (92, 101))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', (22, 28))
53424	27982025	No association was detected between the lymphocyte count and frameshift mutation rate in any group of tumors.	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('frameshift mutation', 'Var', (61, 80))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
53433	27982025	When assessing the key genes involved in the major pathways evaluated by The Cancer Genome Atlas project (see Methods section), alterations in BRAF or PIK3CA emerged as patterns more frequently seen with mucinous histology.	('alterations', 'Var', (128, 139))	('Cancer', 'Phenotype', 'HP:0002664', (77, 83))	('PIK3CA', 'Gene', (151, 157))	('mucin', 'Gene', '100508689', (204, 209))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('PIK3CA', 'Gene', '5290', (151, 157))	('mucin', 'Gene', (204, 209))
53435	27982025	When assessing the non-MSI-H group, mucinous histology was significantly associated with BRAF mutations (p<0.02) whereas the association with PIK3CA did not reach statistical significance (p=0.13).	('PIK3CA', 'Gene', '5290', (142, 148))	('mucin', 'Gene', (36, 41))	('mutations', 'Var', (94, 103))	('associated', 'Reg', (73, 83))	('BRAF', 'Gene', '673', (89, 93))	('PIK3CA', 'Gene', (142, 148))	('mucin', 'Gene', '100508689', (36, 41))	('BRAF', 'Gene', (89, 93))
53436	27982025	Among the five major signaling pathways, alterations in TGF-beta pathway genes were particularly frequent in MSI-H tumors.	('TGF-beta', 'Gene', '7040', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('TGF-beta', 'Gene', (56, 64))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('MSI-H tumors', 'Disease', 'MESH:D009369', (109, 121))	('MSI-H tumors', 'Disease', (109, 121))	('frequent', 'Reg', (97, 105))	('alterations', 'Var', (41, 52))
53439	27982025	Figure 3 summarizes the frequencies of alterations in BRAF, PIK3CA, SMAD2 and SMAD4 in mucinous versus non-mucinous tumors throughout the entire cohort.	('mucinous tumor', 'Phenotype', 'HP:0031495', (107, 121))	('SMAD2', 'Gene', (68, 73))	('SMAD2', 'Gene', '4087', (68, 73))	('non-mucinous tumors', 'Disease', (103, 122))	('PIK3CA', 'Gene', (60, 66))	('SMAD4', 'Gene', (78, 83))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('PIK3CA', 'Gene', '5290', (60, 66))	('mucin', 'Gene', '100508689', (87, 92))	('mucin', 'Gene', '100508689', (107, 112))	('non-mucinous tumors', 'Disease', 'MESH:D002288', (103, 122))	('alterations', 'Var', (39, 50))	('mucin', 'Gene', (87, 92))	('mucin', 'Gene', (107, 112))	('SMAD4', 'Gene', '4089', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
53440	27982025	Altogether, 86% of mucinous tumors had alterations in at least one of these four genes, which was significantly higher than the 26% observed in non-mucinous tumors (p<0.0001).	('non-mucinous tumors', 'Disease', 'MESH:D002288', (144, 163))	('mucinous tumor', 'Phenotype', 'HP:0031495', (148, 162))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('mucinous tumor', 'Phenotype', 'HP:0031495', (19, 33))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('higher', 'Reg', (112, 118))	('mucinous tumors', 'Disease', (19, 34))	('alterations', 'Var', (39, 50))	('mucinous tumors', 'Disease', 'MESH:D002288', (148, 163))	('non-mucinous tumors', 'Disease', (144, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mucinous tumors', 'Disease', 'MESH:D002288', (19, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
53441	27982025	The BRAF and PIK3CA mutations observed in all tumors were predominantly recurrent hotspot mutations.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PIK3CA', 'Gene', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('PIK3CA', 'Gene', '5290', (13, 19))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('tumors', 'Disease', (46, 52))	('mutations', 'Var', (20, 29))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
53442	27982025	BRAF V600E accounted for 100% and 73% of the BRAF mutations in mucinous and non-mucinous tumors respectively.	('non-mucinous tumors', 'Disease', (76, 95))	('mucin', 'Gene', '100508689', (63, 68))	('mucinous tumor', 'Phenotype', 'HP:0031495', (80, 94))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('mutations', 'Var', (50, 59))	('mucin', 'Gene', '100508689', (80, 85))	('non-mucinous tumors', 'Disease', 'MESH:D002288', (76, 95))	('V600E', 'Var', (5, 10))	('mucin', 'Gene', (63, 68))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', '673', (45, 49))	('mucin', 'Gene', (80, 85))	('BRAF', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
53443	27982025	Recurrent hotspot mutations in PIK3CA accounted for 73% and 82% of the PIK3CA mutations in mucinous and non-mucinous tumors respectively.	('non-mucinous tumors', 'Disease', (104, 123))	('mucinous tumor', 'Phenotype', 'HP:0031495', (108, 122))	('mucin', 'Gene', (91, 96))	('mutations', 'Var', (18, 27))	('PIK3CA', 'Gene', '5290', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('mucin', 'Gene', '100508689', (108, 113))	('non-mucinous tumors', 'Disease', 'MESH:D002288', (104, 123))	('mutations', 'Var', (78, 87))	('PIK3CA', 'Gene', (31, 37))	('PIK3CA', 'Gene', '5290', (31, 37))	('mucin', 'Gene', '100508689', (91, 96))	('mucin', 'Gene', (108, 113))	('PIK3CA', 'Gene', (71, 77))
53445	27982025	Throughout the full cohort, mucinous tumor had a significantly reduced rate of TP53 mutation (37% vs. 58% in non-mucinous tumors, p<0.05).	('mucinous tumor', 'Disease', 'MESH:D002288', (113, 127))	('TP53', 'Gene', '7157', (79, 83))	('mucinous tumor', 'Disease', 'MESH:D002288', (28, 42))	('TP53', 'Gene', (79, 83))	('reduced', 'NegReg', (63, 70))	('mucinous tumor', 'Phenotype', 'HP:0031495', (113, 127))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('non-mucinous tumors', 'Disease', (109, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mucinous tumor', 'Phenotype', 'HP:0031495', (28, 42))	('mucinous tumor', 'Disease', (28, 42))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('non-mucinous tumors', 'Disease', 'MESH:D002288', (109, 128))	('mutation', 'Var', (84, 92))
53447	27982025	As expected, all 15 tumors were non-MSI-H. A trend was noted in which tumors of the not-otherwise-specified type with more complex architecture or solid growth were more likely to have chromosomal alterations; however, this did not reach statistical significance.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('chromosomal alterations', 'Var', (185, 208))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Disease', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
53461	27982025	In this analysis, we observed several interesting associations between tumor morphology and genetic alterations in the cohort of primary colorectal carcinomas studied by The Cancer Genome Atlas project.	('colorectal carcinomas', 'Disease', (137, 158))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (137, 158))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('Cancer', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('genetic alterations', 'Var', (92, 111))	('tumor', 'Disease', (71, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
53463	27982025	Second, while The Cancer Genome Atlas CIMP subtypes correlated tightly with MSI-H and "MSI-H histology", morphological differences were noted in CIMP-H tumors with or without MSI-H. Third, mucinous histology was associated with a specific molecular signature characterized by a higher rate of mutation or copy number alteration in BRAF, PIK3CA, SMAD2 and SMAD4, and a trend towards a lower rate of APC or TP53 mutations.	('CIMP-H tumors', 'Disease', 'MESH:D009369', (145, 158))	('PIK3CA', 'Gene', (337, 343))	('copy number alteration', 'Var', (305, 327))	('SMAD2', 'Gene', (345, 350))	('CIMP', 'Chemical', '-', (38, 42))	('SMAD4', 'Gene', (355, 360))	('TP53', 'Gene', '7157', (405, 409))	('Cancer', 'Phenotype', 'HP:0002664', (18, 24))	('BRAF', 'Gene', '673', (331, 335))	('BRAF', 'Gene', (331, 335))	('CIMP-H tumors', 'Disease', (145, 158))	('mucin', 'Gene', (189, 194))	('SMAD4', 'Gene', '4089', (355, 360))	('PIK3CA', 'Gene', '5290', (337, 343))	('mutation', 'Var', (293, 301))	('mucin', 'Gene', '100508689', (189, 194))	('TP53', 'Gene', (405, 409))	('CIMP', 'Chemical', '-', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('APC', 'Disease', 'MESH:D011125', (398, 401))	('APC', 'Disease', (398, 401))	('SMAD2', 'Gene', '4087', (345, 350))	('higher', 'PosReg', (278, 284))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
53466	27982025	Accumulating evidence has led to a firm belief that cancer is a genetic and epigenetic disease, and somatic mutations in specific genes are responsible for tumor initiation and progression.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (108, 117))	('tumor initiation', 'Disease', 'MESH:D009369', (156, 172))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cancer', 'Disease', (52, 58))	('tumor initiation', 'Disease', (156, 172))
53469	27982025	It remains to be elucidated whether and to what extent these additional seemingly "non-driver" mutations contribute to the progression of the tumor.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('contribute', 'Reg', (105, 115))	('mutations', 'Var', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
53470	27982025	In this context, it is intriguing to note that the mutation counts observed in colorectal carcinomas by The Cancer Genome Atlas project was significantly lower in tumors of conventional or not-otherwise-specified type when compared to tumors of other histologies.	('lower', 'NegReg', (154, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('tumors', 'Disease', (163, 169))	('mutation counts', 'Var', (51, 66))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('colorectal carcinomas', 'Disease', (79, 100))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (79, 100))	('tumors', 'Disease', (235, 241))	('Cancer', 'Phenotype', 'HP:0002664', (108, 114))
53472	27982025	This was also true with regard to mononucleotide frameshift mutations within MSI-H tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mononucleotide', 'Chemical', '-', (34, 48))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('MSI-H tumors', 'Disease', (77, 89))	('MSI-H tumors', 'Disease', 'MESH:D009369', (77, 89))	('mononucleotide frameshift mutations', 'Var', (34, 69))
53473	27982025	First, as the not-otherwise-specified type is the "simplest" form of all histologies and closest in appearance to normal colonic mucosa, are the more "complexed" or "specialized" forms of the other histologies a result of the excess mutation burden?	('colonic mucosa', 'Disease', (121, 135))	('mutation burden', 'Var', (233, 248))	('colonic mucosa', 'Disease', 'MESH:D015179', (121, 135))
53474	27982025	In MSI-H cancers, given that the degree of MSI - the number of mutations in the microsatellite repeats - is believed to be a "molecular clock" of how old the tumor is, are the not-otherwise-specified MSI-H cancers "younger" tumors?	('mutations', 'Var', (63, 72))	('tumor', 'Disease', (158, 163))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('MSI-H cancers', 'Disease', 'MESH:D009369', (3, 16))	('MSI-H cancers', 'Disease', (200, 213))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('tumor', 'Disease', (224, 229))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('MSI-H cancers', 'Disease', 'MESH:D009369', (200, 213))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('MSI-H cancers', 'Disease', (3, 16))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
53475	27982025	In addition, frameshift mutations at mononucleotide repeats have been shown to yield characteristic neo-antigenic peptides, and evidence exists that these peptides elicit immune responses; are tumors of the not-otherwise-specified type (a type with few frameshift mutations) less immunogenic than tumors with a solid growth that tend to have more frameshift mutations?	('mononucleotide', 'Chemical', '-', (37, 51))	('tumors', 'Disease', 'MESH:D009369', (297, 303))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('elicit', 'Reg', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('neo-antigenic peptides', 'MPA', (100, 122))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumors', 'Disease', (193, 199))	('frameshift mutations', 'Var', (13, 33))	('tumors', 'Disease', (297, 303))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))
53477	27982025	This is not surprising given that nearly all sporadic MSI-H tumors are molecularly based on the promoter CpG island hypermethylation-induced silencing of the MLH1 gene.	('silencing', 'NegReg', (141, 150))	('hypermethylation-induced', 'Var', (116, 140))	('MLH1', 'Gene', '4292', (158, 162))	('MSI-H tumors', 'Disease', 'MESH:D009369', (54, 66))	('MLH1', 'Gene', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('MSI-H tumors', 'Disease', (54, 66))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
53482	27982025	This pattern consisted of mutations and copy number alterations in BRAF (the MAPK/ERK pathway), PIK3CA (the PI3K pathway), and SMAD2 and SMAD4 (the TGF-beta pathway).	('MAPK', 'Gene', (77, 81))	('TGF-beta', 'Gene', '7040', (148, 156))	('BRAF', 'Gene', '673', (67, 71))	('SMAD2', 'Gene', '4087', (127, 132))	('SMAD4', 'Gene', '4089', (137, 142))	('BRAF', 'Gene', (67, 71))	('SMAD2', 'Gene', (127, 132))	('TGF-beta', 'Gene', (148, 156))	('ERK', 'Gene', '5594', (82, 85))	('mutations', 'Var', (26, 35))	('PIK3CA', 'Gene', (96, 102))	('SMAD4', 'Gene', (137, 142))	('ERK', 'Gene', (82, 85))	('PIK3CA', 'Gene', '5290', (96, 102))	('MAPK', 'Gene', '5594', (77, 81))	('copy number alterations', 'Var', (40, 63))
53485	27982025	In evaluating mutation frequencies of twelve genes in colorectal carcinoma, Chang et al also found a higher frequency of mutations in BRAF (8% vs 4%), PIK3CA (25% vs 13%) and SMAD4 (8% and 4%) in their mucinous carcinomas when compared to non-mucinous tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('mutations', 'Var', (121, 130))	('colorectal carcinoma', 'Disease', (54, 74))	('non-mucinous tumors', 'Disease', (239, 258))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (54, 74))	('SMAD4', 'Gene', '4089', (175, 180))	('mucinous carcinomas', 'Disease', (202, 221))	('BRAF', 'Gene', '673', (134, 138))	('BRAF', 'Gene', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('PIK3CA', 'Gene', '5290', (151, 157))	('non-mucinous tumors', 'Disease', 'MESH:D002288', (239, 258))	('mucinous carcinomas', 'Disease', 'MESH:D002288', (202, 221))	('PIK3CA', 'Gene', (151, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('carcinomas', 'Phenotype', 'HP:0030731', (211, 221))	('mucinous tumor', 'Phenotype', 'HP:0031495', (243, 257))	('SMAD4', 'Gene', (175, 180))
53487	27982025	Furthermore, animal studies have shown that mice expressing constitutively active PI3K in the intestinal epithelium developed colonic adenocarcinomas with mucinous histology.	('PI3K', 'Var', (82, 86))	('developed', 'Reg', (116, 125))	('mucin', 'Gene', '100508689', (155, 160))	('PI3K', 'molecular_function', 'GO:0016303', ('82', '86'))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('colonic adenocarcinomas', 'Disease', (126, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('mucin', 'Gene', (155, 160))	('mice', 'Species', '10090', (44, 48))	('colonic adenocarcinomas', 'Disease', 'MESH:D003110', (126, 149))
53488	27982025	Together, the data in the literature and our study indicate that alterations in BRAF, PIK3CA, SMAD2, and SMAD4 are more frequent in colorectal carcinomas with mucinous histology.	('alterations', 'Var', (65, 76))	('BRAF', 'Gene', (80, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (132, 153))	('SMAD4', 'Gene', (105, 110))	('mucin', 'Gene', '100508689', (159, 164))	('PIK3CA', 'Gene', (86, 92))	('frequent', 'Reg', (120, 128))	('SMAD2', 'Gene', (94, 99))	('SMAD2', 'Gene', '4087', (94, 99))	('PIK3CA', 'Gene', '5290', (86, 92))	('mucin', 'Gene', (159, 164))	('SMAD4', 'Gene', '4089', (105, 110))	('BRAF', 'Gene', '673', (80, 84))	('colorectal carcinomas', 'Disease', (132, 153))
53491	27982025	Clinically, the genetic alterations associated with mucinous histology bear practical relevance: BRAF V600E is associated with a poor prognosis and may also predict cetuximab resistance; PIK3CA mutations appear to be predictive of a benefit from aspirin; SMAD4 mutations have been shown to be an adverse prognostic marker.	('mutations', 'Var', (261, 270))	('PIK3CA', 'Gene', '5290', (187, 193))	('predict', 'Reg', (157, 164))	('SMAD4', 'Gene', (255, 260))	('mucin', 'Gene', '100508689', (52, 57))	('mutations', 'Var', (194, 203))	('cetuximab', 'Chemical', 'MESH:D000068818', (165, 174))	('SMAD4', 'Gene', '4089', (255, 260))	('V600E', 'Mutation', 'rs113488022', (102, 107))	('cetuximab resistance', 'MPA', (165, 185))	('mucin', 'Gene', (52, 57))	('PIK3CA', 'Gene', (187, 193))	('BRAF', 'Gene', '673', (97, 101))	('V600E', 'Var', (102, 107))	('BRAF', 'Gene', (97, 101))	('benefit', 'PosReg', (233, 240))	('aspirin', 'Chemical', 'MESH:D001241', (246, 253))
53495	27982025	Interestingly, clinical results thus far indicate that only a small subset of colorectal cancer patients responds to immune checkpoint inhibition, and almost all responders had MSI-H tumors; a recent phase II trial reported immune-related objective response to treatment with the anti-PD-1 agent, pembrolizumab, in 14% of 28 colorectal cancer patients enrolled, including 40% mismatch repair deficient cases and 0% mismatch repair proficient ones.	('colorectal cancer', 'Phenotype', 'HP:0003003', (325, 342))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('patients', 'Species', '9606', (343, 351))	('colorectal cancer', 'Disease', (325, 342))	('mismatch repair', 'biological_process', 'GO:0006298', ('376', '391'))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('mismatch repair', 'Var', (376, 391))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('pembrolizumab', 'Chemical', 'MESH:C582435', (297, 310))	('colorectal cancer', 'Disease', 'MESH:D015179', (325, 342))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('MSI-H tumors', 'Disease', (177, 189))	('patients', 'Species', '9606', (96, 104))	('MSI-H tumors', 'Disease', 'MESH:D009369', (177, 189))	('mismatch repair', 'biological_process', 'GO:0006298', ('415', '430'))	('colorectal cancer', 'Disease', (78, 95))
53509	27982025	5, mucinous histology, occurring in a minor but significant subset of colorectal cancers, is linked to relevant genetic traits such as alterations in BRAF, PIK3CA, and SMAD genes, all of which have been shown to have prognostic and/or predictive significance.	('mucin', 'Gene', '100508689', (3, 8))	('PIK3CA', 'Gene', '5290', (156, 162))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('linked', 'Reg', (93, 99))	('BRAF', 'Gene', (150, 154))	('alterations', 'Var', (135, 146))	('BRAF', 'Gene', '673', (150, 154))	('mucin', 'Gene', (3, 8))	('colorectal cancers', 'Disease', 'MESH:D015179', (70, 88))	('colorectal cancers', 'Disease', (70, 88))	('SMAD', 'Gene', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('PIK3CA', 'Gene', (156, 162))	('SMAD', 'Gene', '4089;4089', (168, 172))
53511	27982025	Of all the histologies, the not-otherwise-specified type is characterized by a relatively low mutation count, and in MSI-H cancers, a lower number of mononucleotide frameshift mutations.	('MSI-H cancers', 'Disease', (117, 130))	('not-otherwise-specified', 'Disease', (28, 51))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutation', 'MPA', (94, 102))	('mononucleotide', 'Chemical', '-', (150, 164))	('MSI-H cancers', 'Disease', 'MESH:D009369', (117, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('mononucleotide frameshift mutations', 'Var', (150, 185))	('low', 'NegReg', (90, 93))
53512	27982025	The latter may result in a lower generation of frameshift peptides or neo-antigens and thus a different degree of tumor immunogenicity.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('lower', 'NegReg', (27, 32))	('generation', 'MPA', (33, 43))	('frameshift', 'Var', (47, 57))	('tumor', 'Disease', (114, 119))	('neo-antigens', 'MPA', (70, 82))
53518	27451867	I3C has been identified as a ligand of the aryl hydrocarbon receptor (AHR), and we aimed to characterize this AHR activation in relation to its cytotoxic properties.	('aryl hydrocarbon receptor', 'Gene', (43, 68))	('AHR', 'Gene', (110, 113))	('AHR', 'Gene', '196', (70, 73))	('AHR', 'Gene', (70, 73))	('ligand', 'molecular_function', 'GO:0005488', ('29', '35'))	('aryl hydrocarbon receptor', 'Gene', '196', (43, 68))	('I3C', 'Var', (0, 3))	('AHR', 'Gene', '196', (110, 113))
53524	27451867	Further, using siRNA interference to knock down AHR responsiveness generated a significant resistance to the chemotherapeutic actions of indole-3-carbinol regarding both cell viability and apoptotic activity.	('knock', 'Var', (37, 42))	('resistance', 'MPA', (91, 101))	('cell viability', 'CPA', (170, 184))	('indole-3-carbinol', 'Chemical', 'MESH:C016517', (137, 154))	('apoptotic activity', 'CPA', (189, 207))	('AHR', 'Gene', '196', (48, 51))	('AHR', 'Gene', (48, 51))
53542	27451867	Due to its ability to bind various toxins and xenobiotics, stimulation of AHR is thought to provoke malignant transformation in certain tissues, while imparting a protective role in others.	('malignant transformation', 'CPA', (100, 124))	('AHR', 'Gene', '196', (74, 77))	('AHR', 'Gene', (74, 77))	('provoke', 'Reg', (92, 99))	('stimulation', 'Var', (59, 70))
53545	27451867	The effects of I3C have not been fully characterized as a result of canonical AHR signaling via CYP1A1, and this remains an important avenue of investigation going forward.	('CYP1A1', 'Gene', (96, 102))	('CYP1A1', 'Gene', '1543', (96, 102))	('I3C', 'Var', (15, 18))	('AHR', 'Gene', '196', (78, 81))	('AHR', 'Gene', (78, 81))
53558	27451867	Cells were treated with indole-3-carbinol (500 muM) or vehicle (DMSO) for 24 hours as previously described.	('DMSO', 'Chemical', 'MESH:D004121', (64, 68))	('500', 'Var', (43, 46))	('muM', 'Gene', (47, 50))	('indole-3-carbinol', 'Chemical', 'MESH:C016517', (24, 41))	('muM', 'Gene', '56925', (47, 50))
53560	27451867	The mRNA expression levels were assessed with TaqMan Universal PCR Master Mix (Applied Biosystems), custom-designed RT-PCR probes (Assay ID: CYP1A1; Hs01054797_g1, Ahr: Hs00169233_m1, beta-actin; Hs01060665_gl) and the automated gene expression protocol of the QuantStudio  7 Flex Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA).	('CYP1A1', 'Gene', (141, 147))	('beta-actin', 'Gene', '728378', (184, 194))	('gene expression', 'biological_process', 'GO:0010467', ('229', '244'))	('beta-actin', 'Gene', (184, 194))	('CYP1A1', 'Gene', '1543', (141, 147))	('Hs00169233_m1', 'Var', (169, 182))	('Ahr', 'Gene', '196', (164, 167))	('Ahr', 'Gene', (164, 167))	('Hs01060665_gl', 'Var', (196, 209))
53563	27451867	Si-AHR lines exhibit approximately 60% knockdown of AHR signaling.	('AHR', 'Gene', (52, 55))	('knockdown', 'Var', (39, 48))	('AHR', 'Gene', '196', (3, 6))	('AHR', 'Gene', (3, 6))	('signaling', 'biological_process', 'GO:0023052', ('56', '65'))	('AHR', 'Gene', '196', (52, 55))
53579	27451867	Additionally, at a dose of 1mM I3C, the si-Scramble cells exhibited a greater than 2-fold increase in caspase-3/7 apoptotic activity as compared to the si-AHR lines.	('AHR', 'Gene', (155, 158))	('AHR', 'Gene', '196', (155, 158))	('increase', 'PosReg', (90, 98))	('caspase-3', 'Gene', (102, 111))	('si-Scramble', 'Var', (40, 51))	('caspase-3', 'Gene', '836', (102, 111))
53585	27451867	To further examine the role that AHR activation plays in the cytotoxic effects of I3C, we established a model of AHR knock down with stable expression of siRNA interference.	('knock down', 'Var', (117, 127))	('AHR', 'Gene', '196', (113, 116))	('AHR', 'Gene', '196', (33, 36))	('AHR', 'Gene', (113, 116))	('AHR', 'Gene', (33, 36))
53588	27451867	I3C has long been recognized as an anticancer agent across various colorectal cancer cell lines.	('rectal cancer', 'Phenotype', 'HP:0100743', (71, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('I3C', 'Var', (0, 3))	('colorectal cancer', 'Disease', (67, 84))
53603	27451867	Another avenue to pursue would be to examine if any of the currently accepted mechanisms by which I3C affects colon cancer cell fate are modulated in any fashion by the AHR.	('colon cancer', 'Disease', (110, 122))	('AHR', 'Gene', (169, 172))	('affects', 'Reg', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('I3C', 'Var', (98, 101))	('colon cancer', 'Phenotype', 'HP:0003003', (110, 122))	('colon cancer', 'Disease', 'MESH:D015179', (110, 122))	('AHR', 'Gene', '196', (169, 172))
53608	27451867	Additionally, we have proven that I3C treatment in vitro upregulates AHR activity in five separate colorectal cancer cell lines, solidifying its agonist nature.	('activity', 'MPA', (73, 81))	('upregulates', 'PosReg', (57, 68))	('colorectal cancer', 'Disease', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('rectal cancer', 'Phenotype', 'HP:0100743', (103, 116))	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('AHR', 'Gene', '196', (69, 72))	('AHR', 'Gene', (69, 72))	('I3C', 'Var', (34, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))
53609	27451867	Further, we have demonstrated that siRNA knockdown of AHR levels corresponds to a relative resistance to I3C-induced decreases in cell viability and induction of apoptosis.	('decreases', 'NegReg', (117, 126))	('AHR', 'Gene', '196', (54, 57))	('AHR', 'Gene', (54, 57))	('apoptosis', 'CPA', (162, 171))	('knockdown', 'Var', (41, 50))	('cell viability', 'CPA', (130, 144))
53618	26075268	The Steinmetz Three-Grain and Steinmetz Country bread groups had higher scavenging rates of the DPPH free radical and lower serum levels of 8-OHdG and incidence of ACF, adenomas, and adenocarcinomas of colon than the White bread and MF group.	('ACF', 'Disease', (164, 167))	('rat', 'Species', '10116', (83, 86))	('adenomas', 'Disease', 'MESH:D000236', (169, 177))	('scavenging rates', 'MPA', (72, 88))	('adenomas', 'Disease', (169, 177))	('adenocarcinomas of colon', 'Phenotype', 'HP:0040276', (183, 207))	('adenocarcinomas of colon', 'Disease', (183, 207))	('DPPH free radical', 'Chemical', '-', (96, 113))	('adenocarcinomas of colon', 'Disease', 'MESH:D003110', (183, 207))	('serum levels of 8-OHdG', 'MPA', (124, 146))	('8-OHdG', 'Chemical', 'MESH:C067134', (140, 146))	('Steinmetz Three-Grain', 'Var', (4, 25))	('lower', 'NegReg', (118, 123))	('higher', 'PosReg', (65, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('Steinmetz', 'Var', (30, 39))
53632	26075268	DMH-induced colon cancer is a multistep process involving a series of pathological alterations, such as formation of aberrant cryptic foci.	('DMH-induced', 'Var', (0, 11))	('DMH', 'Chemical', 'MESH:D019813', (0, 3))	('colon cancer', 'Disease', (12, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('colon cancer', 'Phenotype', 'HP:0003003', (12, 24))	('colon cancer', 'Disease', 'MESH:D015179', (12, 24))	('rat', 'Species', '10116', (87, 90))	('formation', 'biological_process', 'GO:0009058', ('104', '113'))
53667	26075268	Steinmetz Three-Grain bread showed the strongest antioxidant activity (64.1 +- 3.8%), Steinmetz Country bread showed moderate antioxidant activity (46.9 +- 1.9%), and White bread showed the weakest antioxidant activity among the three kinds of bread (7.2 +- 0.4%).	('Steinmetz', 'Var', (86, 95))	('antioxidant activity', 'MPA', (126, 146))	('antioxidant activity', 'MPA', (49, 69))	('rat', 'Species', '10116', (121, 124))
53679	26075268	The number of mild and moderate-grade dysplasia adenomas was significantly smaller in the Steinmetz Three-Grain bread group compared with that in the White bread and MF group (Table 9).	('Steinmetz', 'Var', (90, 99))	('dysplasia adenomas', 'Disease', (38, 56))	('rat', 'Species', '10116', (27, 30))	('smaller', 'NegReg', (75, 82))	('dysplasia adenomas', 'Disease', 'MESH:D000236', (38, 56))
53692	26075268	DMH treatment induced oxidative stress and early inflammatory and tumour promotion response in the colons of Wistar rats.	('DMH', 'Chemical', 'MESH:D019813', (0, 3))	('DMH treatment', 'Var', (0, 13))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('Wistar rats', 'Species', '10116', (109, 120))	('oxidative stress', 'MPA', (22, 38))	('men', 'Species', '9606', (9, 12))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('induced', 'Reg', (14, 21))	('tumour', 'Disease', (66, 72))	('oxidative stress', 'Phenotype', 'HP:0025464', (22, 38))
53694	26075268	In our results, the Steinmetz Three-Grain and Steinmetz Country bread groups also had a lower incidence of ACF adenomas and adenocarcinomas in the colon than the White bread group.	('adenomas', 'Disease', 'MESH:D000236', (111, 119))	('adenomas', 'Disease', (111, 119))	('adenocarcinomas in the colon', 'Phenotype', 'HP:0040276', (124, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('Steinmetz', 'Var', (46, 55))	('adenocarcinomas in the colon', 'Disease', 'MESH:D003110', (124, 152))	('adenocarcinomas in the colon', 'Disease', (124, 152))	('Steinmetz Three-Grain', 'Var', (20, 41))	('lower', 'NegReg', (88, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))
53697	26075268	Moreover, the Steinmetz Three-Grain bread (A) group and the Steinmetz Country bread (B) group had a lower 8-OHdG serum level than that in the White bread (C) and MF (D) group.	('8-OHdG serum level', 'MPA', (106, 124))	('8-OHdG', 'Chemical', 'MESH:C067134', (106, 112))	('Steinmetz', 'Var', (14, 23))	('lower', 'NegReg', (100, 105))
53700	26075268	Inflammation-related processes have also been shown to be involved in the development of both human and DMH-induced colon carcinogenesis.	('colon carcinogenesis', 'Disease', 'MESH:D063646', (116, 136))	('colon carcinogenesis', 'Disease', (116, 136))	('Inflammation', 'biological_process', 'GO:0006954', ('0', '12'))	('DMH-induced', 'Var', (104, 115))	('DMH', 'Chemical', 'MESH:D019813', (104, 107))	('involved', 'Reg', (58, 66))	('men', 'Species', '9606', (81, 84))	('human', 'Species', '9606', (94, 99))
53702	26075268	Increased expression of Cox-2 has also frequently been observed in DMH-induced colon adenocarcinomas, adenomas, and ACF with dysplasia.	('Cox-2', 'Gene', (24, 29))	('dysplasia', 'Disease', (125, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('dysplasia', 'Disease', 'MESH:D004476', (125, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('adenomas', 'Disease', 'MESH:D000236', (102, 110))	('colon adenocarcinomas', 'Disease', (79, 100))	('expression', 'MPA', (10, 20))	('DMH-induced', 'Var', (67, 78))	('adenomas', 'Disease', (102, 110))	('Increased', 'PosReg', (0, 9))	('colon adenocarcinomas', 'Disease', 'MESH:D003110', (79, 100))	('DMH', 'Chemical', 'MESH:D019813', (67, 70))	('observed', 'Reg', (55, 63))	('ACF', 'Disease', (116, 119))
53703	26075268	The role of COX-2 in DMH/AOM-induced colon carcinogenesis and its involvement in different pathways of carcinogenesis is excellently described.	('DMH', 'Chemical', 'MESH:D019813', (21, 24))	('carcinogenesis', 'Disease', 'MESH:D063646', (43, 57))	('DMH/AOM-induced', 'Var', (21, 36))	('colon carcinogenesis', 'Disease', (37, 57))	('men', 'Species', '9606', (73, 76))	('carcinogenesis', 'Disease', (43, 57))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('COX-2', 'Gene', (12, 17))	('COX-2', 'Gene', '26198', (12, 17))	('carcinogenesis', 'Disease', (103, 117))	('AOM', 'Chemical', 'MESH:D001397', (25, 28))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (37, 57))
53717	25970424	MicroRNAs Induce Epigenetic Reprogramming and Suppress Malignant Phenotypes of Human Colon Cancer Cells Although cancer is a genetic disease, epigenetic alterations are involved in its initiation and progression.	('MicroRNAs', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Colon Cancer', 'Disease', (85, 97))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('Suppress', 'NegReg', (46, 54))	('Human', 'Species', '9606', (79, 84))	('genetic disease', 'Disease', (125, 140))	('Induce', 'Reg', (10, 16))	('cancer', 'Disease', (113, 119))	('Epigenetic Reprogramming', 'CPA', (17, 41))	('genetic disease', 'Disease', 'MESH:D030342', (125, 140))	('rat', 'Species', '10116', (157, 160))	('Colon Cancer', 'Phenotype', 'HP:0003003', (85, 97))	('Colon Cancer', 'Disease', 'MESH:D015179', (85, 97))
53724	25970424	Furthermore, in vivo administration of the ribonucleotides in mice elicited the induction of cancer cell apoptosis, which involves the mitochondrial Bcl2 protein family.	('ribonucleotides', 'Var', (43, 58))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('mice', 'Species', '10090', (62, 66))	('rat', 'Species', '10116', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Bcl2', 'Gene', '12043', (149, 153))	('Bcl2', 'Gene', (149, 153))
53726	25970424	Every cancer cell is largely derived from stem or progenitor cells of normal somatic tissue via genetic and epigenetic alterations.	('epigenetic alterations', 'Var', (108, 130))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('genetic', 'Var', (96, 103))	('rat', 'Species', '10116', (123, 126))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))
53727	25970424	These alterations inactivate growth-constraint tumor suppressor genes (TSGs) and activate growth-promoting oncogenes.	('alterations', 'Var', (6, 17))	('activate', 'PosReg', (81, 89))	('TSG', 'Gene', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('growth-promoting', 'CPA', (90, 106))	('inactivate', 'NegReg', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('rat', 'Species', '10116', (10, 13))	('TSG', 'Gene', '57045', (71, 74))	('tumor', 'Disease', (47, 52))
53729	25970424	We previously showed that the introduction of OSKM in epithelial cancer cells of gastrointestinal organs modulates the malignant phenotype.	('modulates', 'Reg', (105, 114))	('epithelial cancer', 'Phenotype', 'HP:0031492', (54, 71))	('OSKM', 'Gene', (46, 50))	('malignant phenotype', 'CPA', (119, 138))	('epithelial cancer', 'Disease', (54, 71))	('epithelial cancer', 'Disease', 'MESH:D000077216', (54, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('introduction', 'Var', (30, 42))
53730	25970424	Our findings suggested that reprogramming can suppress cancer invasion, drug resistance, and tumorigenicity through the re-activation of the tumor suppressor p16INK4A pathway by demethylation of the promoter sequence.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('reprogramming', 'CPA', (28, 41))	('tumor suppressor', 'biological_process', 'GO:0051726', ('141', '157'))	('drug resistance', 'CPA', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('demethylation', 'biological_process', 'GO:0070988', ('178', '191'))	('cancer', 'Disease', (55, 61))	('suppress', 'NegReg', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('drug resistance', 'Phenotype', 'HP:0020174', (72, 87))	('p16INK4A', 'Gene', (158, 166))	('drug resistance', 'biological_process', 'GO:0009315', ('72', '87'))	('p16INK4A', 'Gene', '1029', (158, 166))	('drug resistance', 'biological_process', 'GO:0042493', ('72', '87'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('141', '157'))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (141, 146))	('demethylation', 'Var', (178, 191))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
53731	25970424	Moreover, a recent mouse study of transgenic OSK factors showed that epigenetic modifications are involved in tumor initiation and development in vivo.	('involved', 'Reg', (98, 106))	('tumor initiation', 'Disease', 'MESH:D009369', (110, 126))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor initiation', 'Disease', (110, 126))	('epigenetic modifications', 'Var', (69, 93))	('mouse', 'Species', '10090', (19, 24))	('development', 'CPA', (131, 142))
53732	25970424	This study also demonstrated that, in combination with the inactivation of TSG signals such as mutant Apc, the modifications can orchestrate epigenetic alterations by the polycomb group complex to the core module of histone H3 at lysine-27.	('rat', 'Species', '10116', (156, 159))	('epigenetic alterations', 'MPA', (141, 163))	('modifications', 'Var', (111, 124))	('TSG', 'Gene', (75, 78))	('rat', 'Species', '10116', (23, 26))	('lysine', 'Chemical', 'MESH:D008239', (230, 236))	('rat', 'Species', '10116', (136, 139))	('mutant', 'Var', (95, 101))	('TSG', 'Gene', '57045', (75, 78))	('Apc', 'Disease', (102, 105))
53733	25970424	Taken together with previous findings, epigenetic alterations, regardless of the causes or results of the genetic changes, contribute to the occurrence and development of malignancies and may be attractive for the discovery of novel therapeutic targets against human cancer.	('malignancies', 'Disease', 'MESH:D009369', (171, 183))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('epigenetic alterations', 'Var', (39, 61))	('rat', 'Species', '10116', (54, 57))	('contribute', 'Reg', (123, 133))	('human', 'Species', '9606', (261, 266))	('malignancies', 'Disease', (171, 183))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))
53750	25970424	Cells were cultured in embryonal stem cell culture medium containing DMEM/F12 (Gibco Life Technologies, Tokyo, Japan), supplemented with 2 mM GlutaMAX, 20% knockout serum replacement (Gibco Life Technologies), 0.1 mM nonessential amino acids (NEAA, Gibco Life Technologies), 10 ng/ml basic fibroblast growth factor (bFGF, Wako, Tokyo, Japan), 55 muM 2-mercaptoethanol (Gibco Life Technologies), 1% penicillin-streptomycin, and chemical inhibitors, including 0.5 muM A83-01 (Stemgent, Cambridge, MA), 3 muM CHIR99021 (Stemgent), and 0.5 muM PD0325901 (Stemgent), at 37 C in a 5% CO2 incubator.	('ethanol', 'Chemical', 'MESH:D000431', (360, 367))	('PD0325901', 'Chemical', 'MESH:C506614', (540, 549))	('CO2', 'Chemical', '-', (578, 581))	('basic fibroblast growth factor', 'Gene', (284, 314))	('DMEM/F12', 'Gene', '2161', (69, 77))	('bFGF', 'Gene', '2247', (316, 320))	('penicillin', 'Chemical', 'MESH:D010406', (398, 408))	('DMEM/F12', 'Gene', (69, 77))	('PD0325901', 'Var', (540, 549))	('basic fibroblast growth factor', 'Gene', '2247', (284, 314))	('bFGF', 'Gene', (316, 320))	('streptomycin', 'Chemical', 'MESH:D013307', (409, 421))
53794	25970424	Serially transplanted HT29 xenografts had the most abundant vasculature, was uniformly distributed over the whole tumor, and had the least amount of central necrosis.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('necrosis', 'biological_process', 'GO:0001906', ('157', '165'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('HT29', 'Var', (22, 26))	('necrosis', 'Disease', 'MESH:D009336', (157, 165))	('necrosis', 'biological_process', 'GO:0070265', ('157', '165'))	('tumor', 'Disease', (114, 119))	('HT29', 'CellLine', 'CVCL:0320', (22, 26))	('necrosis', 'biological_process', 'GO:0008219', ('157', '165'))	('necrosis', 'biological_process', 'GO:0019835', ('157', '165'))	('necrosis', 'biological_process', 'GO:0008220', ('157', '165'))	('necrosis', 'Disease', (157, 165))
53833	25970424	HT29 xenografts had the most abundant vascularization, was uniformly distributed over the whole tumor, and the least amount of necrosis.	('HT29', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('necrosis', 'Disease', 'MESH:D009336', (127, 135))	('tumor', 'Disease', (96, 101))	('necrosis', 'biological_process', 'GO:0070265', ('127', '135'))	('necrosis', 'biological_process', 'GO:0008219', ('127', '135'))	('necrosis', 'biological_process', 'GO:0001906', ('127', '135'))	('necrosis', 'biological_process', 'GO:0019835', ('127', '135'))	('HT29', 'CellLine', 'CVCL:0320', (0, 4))	('necrosis', 'biological_process', 'GO:0008220', ('127', '135'))	('necrosis', 'Disease', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
53839	25970424	On day 6, the cells were gently trypsinized, transferred onto MEF feeder cells, and cultured for additional 21 days in ES medium with three chemical inhibitors (3i; 0.5 muM A83-01, an ALK4/5/7 receptor inhibitor; 3 muM CHIR99021, a GSK-3beta inhibitor; and 0.5 muM PD0325901, a MEK inhibitor) (Fig 2A).	('MEK', 'Gene', (278, 281))	('ES medium', 'Chemical', '-', (119, 128))	('MEK', 'Gene', '5609', (278, 281))	('GSK-3beta', 'Gene', '2932', (232, 241))	('GSK-3beta', 'Gene', (232, 241))	('PD0325901', 'Var', (265, 274))	('MEF', 'Disease', (62, 65))	('PD0325901', 'Chemical', 'MESH:C506614', (265, 274))	('MEF', 'Disease', 'None', (62, 65))
53840	25970424	Round colonies were induced upon transfection of HT29 with miR-302s.	('transfection', 'Var', (33, 45))	('miR-302', 'Gene', (59, 66))	('miR-302', 'Gene', '723920', (59, 66))	('induced', 'Reg', (20, 27))	('Round colonies', 'CPA', (0, 14))	('HT29', 'CellLine', 'CVCL:0320', (49, 53))
53877	25970424	Immunocytochemistry showed that transfection of miR-302s resulted in the reduction of Ki67-positive cells (Fig 7B).	('miR-302', 'Gene', '723920', (48, 55))	('miR-302', 'Gene', (48, 55))	('transfection', 'Var', (32, 44))	('Ki67-positive cells', 'CPA', (86, 105))	('reduction', 'NegReg', (73, 82))
53885	25970424	Data showed that transfection with the miRs induced the development of TUNEL-positive cells (A in S2 Fig).	('miR', 'Gene', '735281', (39, 42))	('miR', 'Gene', (39, 42))	('TUNEL-positive cells', 'CPA', (71, 91))	('induced', 'Reg', (44, 51))	('transfection', 'Var', (17, 29))	('development', 'CPA', (56, 67))
53909	25970424	Epigenetic events are critical in dictating cellular differentiation and reprogramming of somatic and cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('reprogramming', 'CPA', (73, 86))	('Epigenetic events', 'Var', (0, 17))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cellular differentiation', 'CPA', (44, 68))	('dictating', 'Reg', (34, 43))
53998	25383169	Semi-quantitative analysis of the phalloidin stain demonstrated a twofold increase in fluorescent intensity of HT29 cells in comparison to HCT116 cells (data not shown).	('HT29 cells', 'CellLine', 'CVCL:0320', (111, 121))	('increase', 'PosReg', (74, 82))	('HT29', 'Var', (111, 115))	('HCT116', 'CellLine', 'CVCL:0291', (139, 145))	('rat', 'Species', '10116', (58, 61))	('phalloidin', 'Chemical', 'MESH:D010590', (34, 44))	('fluorescent intensity', 'MPA', (86, 107))
54028	25383169	HT29 cultures exhibited a slightly lower, more heterogeneous level of expression of tubulin; however, this may have been an inability of the antibody to penetrate into the cellular aggregates (with HT29 appearing to form more tightly packed aggregates than HCT116).	('antibody', 'molecular_function', 'GO:0003823', ('141', '149'))	('heterogeneous level', 'MPA', (47, 66))	('tubulin', 'Protein', (84, 91))	('HT29', 'CellLine', 'CVCL:0320', (198, 202))	('antibody', 'cellular_component', 'GO:0042571', ('141', '149'))	('HCT116', 'CellLine', 'CVCL:0291', (257, 263))	('expression', 'MPA', (70, 80))	('lower', 'NegReg', (35, 40))	('antibody', 'cellular_component', 'GO:0019815', ('141', '149'))	('rat', 'Species', '10116', (158, 161))	('HT29', 'Var', (198, 202))	('HT29', 'CellLine', 'CVCL:0320', (0, 4))	('antibody', 'cellular_component', 'GO:0019814', ('141', '149'))
54030	25383169	treated a spheroid model of mesothelioma with a fluorescently labelled SS1P immunotoxin antibody and monitored penetration over 16 h. The authors reported that the penetration of SS1P was limited to the outer periphery of the spheroids following 4 h of treatment indicating inadequate penetration to the core of the spheroid.	('rat', 'Species', '10116', (169, 172))	('rat', 'Species', '10116', (290, 293))	('mesothelioma', 'Disease', (28, 40))	('SS1P', 'Var', (179, 183))	('rat', 'Species', '10116', (116, 119))	('mesothelioma', 'Disease', 'MESH:D008654', (28, 40))
54044	25383169	However, in recent years, it has emerged that KRAS mutant status is a much more effective indicator of response to anti-EGFR therapy.	('EGFR', 'molecular_function', 'GO:0005006', ('120', '124'))	('KRAS', 'Gene', (46, 50))	('mutant', 'Var', (51, 57))	('KRAS', 'Gene', '3845', (46, 50))	('EGFR', 'Gene', '1956', (120, 124))	('EGFR', 'Gene', (120, 124))
54083	24937668	Although HA fragments are normally rapidly cleared, increased synthesis and breakdown of HA in the tumour context could potentially lead to the accumulation of small HA oligosaccharides (sHA) in the interstitial fluid, usually defined as HA of 4-25 disaccharides.	('HA', 'Chemical', 'MESH:C034124', (9, 11))	('increased', 'PosReg', (52, 61))	('breakdown', 'Var', (76, 85))	('HA', 'Chemical', 'MESH:C034124', (166, 168))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('HA', 'Chemical', 'MESH:C034124', (89, 91))	('HA', 'Chemical', 'MESH:C034124', (188, 190))	('accumulation', 'PosReg', (144, 156))	('tumour', 'Disease', (99, 105))	('sHA', 'Chemical', '-', (187, 190))	('oligosaccharides', 'Chemical', 'MESH:D009844', (169, 185))	('synthesis', 'biological_process', 'GO:0009058', ('62', '71'))	('breakdown', 'biological_process', 'GO:0009056', ('76', '85'))	('lead to', 'Reg', (132, 139))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('HA', 'Chemical', 'MESH:C034124', (238, 240))	('4-25 disaccharides', 'Chemical', '-', (244, 262))
54086	24937668	Furthermore, sHA can promote migration and invasion of tumour cells, for example, by increasing the expression of matrix metalloproteases and cytokines, and by inducing proteolytic cleavage of CD44.	('tumour', 'Disease', (55, 61))	('CD44', 'Gene', '960', (193, 197))	('CD44', 'Gene', (193, 197))	('invasion', 'CPA', (43, 51))	('rat', 'Species', '10116', (32, 35))	('increasing', 'PosReg', (85, 95))	('matrix metalloproteases', 'Protein', (114, 137))	('migration', 'CPA', (29, 38))	('expression', 'MPA', (100, 110))	('sHA', 'Var', (13, 16))	('inducing', 'PosReg', (160, 168))	('proteolytic cleavage', 'MPA', (169, 189))	('promote', 'PosReg', (21, 28))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('sHA', 'Chemical', '-', (13, 16))
54161	24937668	However, patients whose TIF contained >500 ng ml-1 sHA had a statistically significant higher incidence of lymph node metastasis (Figure 6A and C).	('patients', 'Species', '9606', (9, 17))	('lymph node metastasis', 'CPA', (107, 128))	('sHA', 'Chemical', '-', (51, 54))	('sHA', 'Gene', (51, 54))	('>500 ng ml-1', 'Var', (38, 50))	('higher', 'PosReg', (87, 93))
54170	24937668	Furthermore, sHA can influence angiogenesis.	('angiogenesis', 'biological_process', 'GO:0001525', ('31', '43'))	('sHA', 'Var', (13, 16))	('influence', 'Reg', (21, 30))	('angiogenesis', 'CPA', (31, 43))	('sHA', 'Chemical', '-', (13, 16))
54192	24937668	On the other hand, sialylation of CD44 inhibits its ability to bind to HA through a mechanism thought to involve steric hinderance due to the negative charge on HA molecules.	('bind', 'Interaction', (63, 67))	('HA', 'Chemical', 'MESH:C034124', (71, 73))	('ability', 'MPA', (52, 59))	('CD44', 'Gene', '960', (34, 38))	('HA', 'Chemical', 'MESH:C034124', (161, 163))	('CD44', 'Gene', (34, 38))	('inhibits', 'NegReg', (39, 47))	('sialylation', 'Var', (19, 30))
54206	24937668	Furthermore, ectopic expression of Hyal-1 promoted lymph node metastasis, while inhibition of Hyal-1 activity in a prostate cancer model reduced tumour growth and angiogenesis.	('Hyal-1', 'Gene', (35, 41))	('Hyal-1', 'Gene', (94, 100))	('prostate cancer', 'Disease', (115, 130))	('angiogenesis', 'CPA', (163, 175))	('ectopic expression', 'Var', (13, 31))	('Hyal-1', 'Gene', '3373', (35, 41))	('activity', 'MPA', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Hyal-1', 'Gene', '3373', (94, 100))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('prostate cancer', 'Disease', 'MESH:D011471', (115, 130))	('reduced tumour growth', 'Disease', (137, 158))	('reduced tumour growth', 'Disease', 'MESH:D006130', (137, 158))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))	('promoted', 'PosReg', (42, 50))	('inhibition', 'Var', (80, 90))	('lymph node metastasis', 'CPA', (51, 72))
54211	24937668	Furthermore, as sHA has pro-inflammatory and immuno-stimulatory properties, sHA may influence wound healing and inflammatory processes, in addition to contributing to the inflammatory status of tumours.	('tumours', 'Phenotype', 'HP:0002664', (194, 201))	('sHA', 'Var', (76, 79))	('contributing', 'Reg', (151, 163))	('influence', 'Reg', (84, 93))	('wound healing', 'biological_process', 'GO:0042060', ('94', '107'))	('inflammatory', 'MPA', (171, 183))	('tumours', 'Disease', 'MESH:D009369', (194, 201))	('tumours', 'Disease', (194, 201))	('wound healing', 'CPA', (94, 107))	('sHA', 'Chemical', '-', (76, 79))	('sHA', 'Chemical', '-', (16, 19))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('inflammatory processes', 'CPA', (112, 134))
54311	22893202	Marnett and colleagues, for example, described a series of ester and amide modifications to the carboxylic acid moiety on various NSAIDs, such as indomethacin and meclofenamic acid that increased selectivity for COX-2.	('ester', 'Chemical', 'MESH:D004952', (59, 64))	('selectivity', 'MPA', (196, 207))	('meclofenamic acid', 'Chemical', 'MESH:D008469', (163, 180))	('increased', 'PosReg', (186, 195))	('carboxylic acid', 'Chemical', 'MESH:D002264', (96, 111))	('indomethacin', 'Chemical', 'MESH:D007213', (146, 158))	('modifications', 'Var', (75, 88))	('amide', 'Chemical', 'MESH:D000577', (69, 74))	('COX-2', 'Enzyme', (212, 217))
54312	22893202	The rational for this approach was based on molecular modeling studies whereby a more restrictive binding domain was noted within the catalytic region of the COX-1 compared with COX-2, which permitted specificity via substitution of the carboxylic acid with bulky neutral residues.	('binding', 'Interaction', (98, 105))	('COX-1', 'Gene', '4512', (158, 163))	('COX-1', 'Gene', (158, 163))	('carboxylic acid', 'Chemical', 'MESH:D002264', (237, 252))	('restrictive', 'NegReg', (86, 97))	('substitution', 'Var', (217, 229))
54330	22893202	MY5445) and non-selective cGMP PDE inhibitors (e.g.	('cGMP', 'Chemical', 'MESH:D006152', (26, 30))	('cGMP PDE', 'molecular_function', 'GO:0047555', ('26', '34'))	('cGMP PDE', 'Protein', (26, 34))	('MY5445', 'CellLine', 'CVCL:3034', (0, 6))	('MY5445', 'Var', (0, 6))
54331	22893202	MY5445, trequinsin) could also suppress tumor cell growth, as well as knockdown of PDE5 by siRNA or antisense.	('antisense', 'Var', (100, 109))	('PDE', 'molecular_function', 'GO:0004114', ('83', '86'))	('knockdown', 'Var', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('MY5445', 'CellLine', 'CVCL:3034', (0, 6))	('PDE5', 'Gene', '8654', (83, 87))	('MY5445', 'Var', (0, 6))	('PDE5', 'Gene', (83, 87))	('cell growth', 'biological_process', 'GO:0016049', ('46', '57'))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('suppress', 'NegReg', (31, 39))	('trequinsin', 'Chemical', 'MESH:C035964', (8, 18))
54336	22893202	Initial efforts to synthesize sulindac derivatives that lack COX inhibitory activity, but have improved cGMP PDE inhibitory activity focused on modifications to either the sulfonyl or the carboxylic acid moieties.	('cGMP', 'Chemical', 'MESH:D006152', (104, 108))	('sulfonyl', 'Chemical', '-', (172, 180))	('carboxylic acid', 'Chemical', 'MESH:D002264', (188, 203))	('sulindac', 'Chemical', 'MESH:D013467', (30, 38))	('improved', 'PosReg', (95, 103))	('cGMP PDE inhibitory activity', 'MPA', (104, 132))	('COX inhibitory activity', 'MPA', (61, 84))	('modifications', 'Var', (144, 157))
54338	22893202	In light of information gained from molecular modeling docking sulindac sulfide into the COX active site, our laboratory has focused on chemically modifying the carboxylic acid moiety of sulindac sulfide and substituting with a positive-charged amide to interfere with COX binding.	('binding', 'Interaction', (273, 280))	('substituting', 'Var', (208, 220))	('amide', 'Chemical', 'MESH:D000577', (245, 250))	('carboxylic acid', 'Chemical', 'MESH:D002264', (161, 176))	('interfere', 'NegReg', (254, 263))	('sulindac sulfide', 'Chemical', 'MESH:C025462', (63, 79))	('COX', 'Protein', (269, 272))	('sulindac sulfide', 'Chemical', 'MESH:C025462', (187, 203))	('modifying', 'Reg', (147, 156))
54357	22893202	A number of NSAIDs and COX-2 selective inhibitors have been shown to reduce survivin expression and/or activity in cancer cells, but the best studied of these is celecoxib.	('inhibitors', 'Var', (39, 49))	('expression', 'MPA', (85, 95))	('cancer', 'Disease', (115, 121))	('activity', 'MPA', (103, 111))	('survivin', 'Protein', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('celecoxib', 'Chemical', 'MESH:D000068579', (162, 171))	('reduce', 'NegReg', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
54359	22893202	Even more promising, DMC has shown in vivo chemopreventive efficacy in various models of human cancer.	('human', 'Species', '9606', (89, 94))	('DMC', 'Var', (21, 24))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('DMC', 'Chemical', '-', (21, 24))	('cancer', 'Disease', (95, 101))	('chemopreventive efficacy', 'CPA', (43, 67))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
54382	22893202	These associated inflammatory changes may lead to molecular changes in epithelial cells that result in the inhibition of enzymes that repair DNA to molecular changes in signaling pathways associated with the initiation of neoplasia as a result of genetic mutations.	('initiation of neoplasia', 'Disease', (208, 231))	('enzymes', 'Enzyme', (121, 128))	('initiation of neoplasia', 'Disease', 'MESH:D009369', (208, 231))	('genetic mutations', 'Var', (247, 264))	('lead', 'Reg', (42, 46))	('neoplasia', 'Phenotype', 'HP:0002664', (222, 231))	('inhibition', 'NegReg', (107, 117))
54387	22893202	Traditional NSAIDs and COX-2 selective inhibitors most likely inhibit tumorigenesis through a combination of COX-dependent and COX-independent mechanisms.	('inhibitors', 'Var', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('COX-2', 'Gene', (23, 28))	('inhibit', 'NegReg', (62, 69))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
54396	33482809	Patients with high levels of LIMK1 demonstrated significantly lower overall survival rates and exhibited greater lymph node metastatic potential in a clinical cohort.	('overall survival rates', 'CPA', (68, 90))	('high levels', 'Var', (14, 25))	('lymph node metastatic potential', 'CPA', (113, 144))	('LIMK1', 'Gene', '3984', (29, 34))	('lower', 'NegReg', (62, 67))	('Patients', 'Species', '9606', (0, 8))	('LIMK1', 'Gene', (29, 34))	('greater', 'PosReg', (105, 112))
54398	33482809	However, immunohistochemical analyses showed that patients with high protein levels of CFL-1 and SSH1 exhibited greater lymph node metastatic potential and greater depth of local invasion.	('high', 'Var', (64, 68))	('protein levels', 'MPA', (69, 83))	('patients', 'Species', '9606', (50, 58))	('lymph node metastatic potential', 'CPA', (120, 151))	('CFL-1', 'Gene', '1072', (87, 92))	('SSH1', 'Gene', (97, 101))	('SSH1', 'Gene', '54434', (97, 101))	('CFL-1', 'Gene', (87, 92))	('greater', 'PosReg', (112, 119))	('depth of local invasion', 'CPA', (164, 187))
54400	33482809	However, patients with high levels of LIMK1 also demonstrated significantly lower overall survival rates in canonical (CMS2), and metabolic (CMS3) subtypes.	('patients', 'Species', '9606', (9, 17))	('LIMK1', 'Gene', '3984', (38, 43))	('canonical', 'Disease', (108, 117))	('LIMK1', 'Gene', (38, 43))	('lower', 'NegReg', (76, 81))	('metabolic', 'CPA', (130, 139))	('high levels', 'Var', (23, 34))
54451	33482809	A significant worse overall survival rate was observed for patients with high levels of LIMK1 in all tumor stages, early stage, and late stage (P < 0.001, P < 0.01, and P < 0.01, respectively), indicating that high level LIMK1 was an unfavorable prognostic indicator in patients with CRC.	('patients', 'Species', '9606', (270, 278))	('worse', 'NegReg', (14, 19))	('high levels', 'Var', (73, 84))	('CRC', 'Disease', (284, 287))	('tumor', 'Disease', (101, 106))	('LIMK1', 'Gene', '3984', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('LIMK1', 'Gene', (221, 226))	('patients', 'Species', '9606', (59, 67))	('LIMK1', 'Gene', '3984', (88, 93))	('LIMK1', 'Gene', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('overall survival', 'CPA', (20, 36))
54453	33482809	Patients with low levels of CFL-1 (late-stage III-IV) exhibited lower overall survival (P < 0.05) (Additional file 2: Figure S2B).	('overall survival', 'MPA', (70, 86))	('lower', 'NegReg', (64, 69))	('CFL-1', 'Gene', '1072', (28, 33))	('Patients', 'Species', '9606', (0, 8))	('CFL-1', 'Gene', (28, 33))	('low', 'Var', (14, 17))
54457	33482809	These results suggest that high mRNA level of LIMK1 is associated with positive regional lymph node metastasis in CRC patients.	('LIMK1', 'Gene', '3984', (46, 51))	('associated', 'Reg', (55, 65))	('LIMK1', 'Gene', (46, 51))	('high', 'Var', (27, 31))	('mRNA level', 'MPA', (32, 42))	('positive regional lymph node metastasis', 'CPA', (71, 110))	('patients', 'Species', '9606', (118, 126))	('CRC', 'Disease', (114, 117))
54467	33482809	Furthermore, patients with lymph node metastasis also exhibited a higher CFL-1 score (73.7%).	('CFL-1', 'Gene', (73, 78))	('patients', 'Species', '9606', (13, 21))	('CFL-1', 'Gene', '1072', (73, 78))	('higher', 'PosReg', (66, 72))	('lymph node metastasis', 'Var', (27, 48))
54514	33482809	In according, we found increased methylation level of the CFL-1 and SSH1 promoter regions in colon and rectum adenocarcinoma tissues from the TCGA database, suggesting that differences in the expression of CFL-1 and SSH1 in CRC may be related to epigenetic modifications (Additional file 6: Figure S5).	('SSH1', 'Gene', (216, 220))	('SSH1', 'Gene', '54434', (216, 220))	('related', 'Reg', (235, 242))	('CFL-1', 'Gene', '1072', (58, 63))	('CFL-1', 'Gene', '1072', (206, 211))	('colon and rectum adenocarcinoma', 'Disease', 'MESH:D012004', (93, 124))	('methylation level', 'MPA', (33, 50))	('CFL-1', 'Gene', (58, 63))	('increased', 'PosReg', (23, 32))	('epigenetic modifications', 'Var', (246, 270))	('SSH1', 'Gene', (68, 72))	('CFL-1', 'Gene', (206, 211))	('SSH1', 'Gene', '54434', (68, 72))
54551	33260810	There was a significantly higher survival among patients with low CEA ratios than among those with high CEA ratios.	('higher', 'PosReg', (26, 32))	('CEA', 'Gene', '1084', (104, 107))	('survival', 'MPA', (33, 41))	('low', 'Var', (62, 65))	('CEA', 'Gene', (66, 69))	('patients', 'Species', '9606', (48, 56))	('CEA', 'Gene', (104, 107))	('CEA', 'Gene', '1084', (66, 69))
54665	31307428	In addition to the strong association between high CD8:Treg ratio and favorable clinical outcome in the entire study group, the association between high CD8:Treg ratio and longer overall survival was significantly higher in primary right-sided mCRC (Fig.	('CD8', 'Gene', (153, 156))	('higher', 'PosReg', (214, 220))	('overall', 'MPA', (179, 186))	('CD8', 'Gene', '925', (153, 156))	('longer', 'PosReg', (172, 178))	('CD8', 'Gene', (51, 54))	('CR', 'Chemical', 'MESH:D002857', (245, 247))	('CD8', 'Gene', '925', (51, 54))	('high', 'Var', (148, 152))
54674	31307428	Our hypothesis that immune characteristics in the TME are reflected in the circulation is further supported by the finding of an association of KRAS mutant status with reduction in both CD8+ T cell count and number of Tregs.	('KRAS', 'Gene', '3845', (144, 148))	('CD8', 'Gene', '925', (186, 189))	('mutant status', 'Var', (149, 162))	('KRAS', 'Gene', (144, 148))	('CD8', 'Gene', (186, 189))	('reduction', 'NegReg', (168, 177))
54685	30191522	Phase I Study Combining the Aurora Kinase A Inhibitor Alisertib with mFOLFOX in Gastrointestinal Cancer Overexpression and cellular miss-localization of aurora kinase A (AURKA) in gastrointestinal cancers results in chromosomal instability, activation of multiple oncogenic pathways, and inhibition of pro-apoptotic signaling.	('miss-localization', 'Var', (132, 149))	('gastrointestinal cancers', 'Disease', (180, 204))	('chromosomal instability', 'Phenotype', 'HP:0040012', (216, 239))	('Aurora Kinase A', 'Gene', '6790', (28, 43))	('AURKA', 'Gene', (170, 175))	('chromosomal instability', 'CPA', (216, 239))	('activation', 'PosReg', (241, 251))	('pro-apoptotic signaling', 'Pathway', (302, 325))	('Gastrointestinal Cancer', 'Disease', (80, 103))	('mFOLFOX', 'Chemical', '-', (69, 76))	('oncogenic pathways', 'Pathway', (264, 282))	('Aurora Kinase A', 'Gene', (28, 43))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (180, 203))	('Gastrointestinal Cancer', 'Disease', 'MESH:D004067', (80, 103))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('Gastrointestinal Cancer', 'Phenotype', 'HP:0007378', (80, 103))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Alisertib', 'Chemical', 'MESH:C550258', (54, 63))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (180, 204))	('inhibition', 'NegReg', (288, 298))	('aurora kinase A', 'Gene', (153, 168))	('aurora kinase A', 'Gene', '6790', (153, 168))	('localization', 'biological_process', 'GO:0051179', ('137', '149'))	('signaling', 'biological_process', 'GO:0023052', ('316', '325'))
54686	30191522	Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 leading to cell death.	('mitotic delays', 'CPA', (27, 41))	('p73', 'Gene', '7161', (96, 99))	('severe chromosome congression', 'CPA', (43, 72))	('p73', 'Gene', (96, 99))	('AURKA', 'Gene', (14, 19))	('p53', 'Gene', (92, 95))	('activation', 'PosReg', (78, 88))	('Inhibition', 'Var', (0, 10))	('cell death', 'CPA', (111, 121))	('p53', 'Gene', '7157', (92, 95))
54698	30191522	Because AURKA is required for cytokinesis, inhibition of AURKA causes spindle pole and chromosome congression defects leading to aneuploidy, which is then followed by cell death.	('leading to', 'Reg', (118, 128))	('inhibition', 'Var', (43, 53))	('chromosome congression defects', 'Disease', 'MESH:D002869', (87, 117))	('aneuploidy', 'Disease', 'MESH:D000782', (129, 139))	('cell death', 'biological_process', 'GO:0008219', ('167', '177'))	('chromosome congression', 'biological_process', 'GO:0051310', ('87', '109'))	('chromosome', 'cellular_component', 'GO:0005694', ('87', '97'))	('chromosome congression defects', 'Disease', (87, 117))	('cytokinesis', 'biological_process', 'GO:0000910', ('30', '41'))	('aneuploidy', 'Disease', (129, 139))	('AURKA', 'Gene', (57, 62))	('spindle pole', 'cellular_component', 'GO:0000922', ('70', '82'))
54699	30191522	Knockdown of AURKA was shown to suppress centrosome maturation; in mice, genetic ablation or null mutation of AURKA caused mitotic arrest and embryonic death.	('embryonic death', 'Disease', (142, 157))	('centrosome', 'cellular_component', 'GO:0005813', ('41', '51'))	('null mutation', 'Var', (93, 106))	('mitotic arrest', 'Disease', (123, 137))	('mitotic arrest', 'Disease', 'MESH:D006323', (123, 137))	('centrosome maturation', 'CPA', (41, 62))	('genetic ablation', 'Var', (73, 89))	('AURKA', 'Gene', (110, 115))	('embryonic death', 'Disease', 'MESH:D003643', (142, 157))	('mice', 'Species', '10090', (67, 71))
54702	30191522	Overexpression or amplification of AURKA has been identified in several solid malignancies, including colorectal, gastric, esophageal, liver, and pancreas cancers.	('malignancies', 'Disease', 'MESH:D009369', (78, 90))	('pancreas cancers', 'Disease', 'MESH:D010190', (146, 162))	('malignancies', 'Disease', (78, 90))	('esophageal', 'Disease', (123, 133))	('AURKA', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('colorectal', 'Disease', (102, 112))	('gastric', 'Disease', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('identified', 'Reg', (50, 60))	('amplification', 'Var', (18, 31))	('pancreas cancers', 'Disease', (146, 162))	('liver', 'Disease', (135, 140))
54768	30191522	Our preclinical data showed that inhibiting AURKA in combination with platinum-based chemotherapies significantly decreased cell viability and survival, as well as significantly inhibited xenograft tumor growth in multiple gastrointestinal cancer models compared to either single agent alone, thus, suggesting a potential synergistic treatment combination.	('platinum', 'Chemical', 'MESH:D010984', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('tumor growth in multiple gastrointestinal cancer', 'Phenotype', 'HP:0200008', (198, 246))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('inhibited', 'NegReg', (178, 187))	('inhibiting', 'Var', (33, 43))	('decreased', 'NegReg', (114, 123))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (223, 246))	('men', 'Species', '9606', (339, 342))	('tumor', 'Disease', (198, 203))	('cancer', 'Disease', (240, 246))	('AURKA', 'Gene', (44, 49))
54900	29405760	Venoms are commonly known for their negative effects and cause severe health problems for human; venoms carry a variety of toxins that can cause neurotoxicity, nephrotoxicity, cytotoxicity, respiratory arrest, dermatitis, allergic reactions, hemorrhage, and disseminated intravascular coagulation.	('allergic reactions', 'Phenotype', 'HP:0012393', (222, 240))	('dermatitis', 'Phenotype', 'HP:0011123', (210, 220))	('neurotoxicity', 'Disease', (145, 158))	('disseminated intravascular coagulation', 'Phenotype', 'HP:0005521', (258, 296))	('human', 'Species', '9606', (90, 95))	('cytotoxicity', 'Disease', (176, 188))	('hemorrhage', 'Disease', 'MESH:D006470', (242, 252))	('respiratory arrest', 'Phenotype', 'HP:0005943', (190, 208))	('neurotoxicity', 'Disease', 'MESH:D020258', (145, 158))	('allergic reactions', 'Disease', (222, 240))	('coagulation', 'biological_process', 'GO:0050817', ('285', '296'))	('cytotoxicity', 'Disease', 'MESH:D064420', (176, 188))	('intravascular coagulation', 'Disease', (271, 296))	('respiratory arrest', 'Disease', 'MESH:D012131', (190, 208))	('respiratory arrest', 'Disease', (190, 208))	('hemorrhage', 'Disease', (242, 252))	('nephrotoxicity', 'Disease', (160, 174))	('cause', 'Reg', (139, 144))	('intravascular coagulation', 'Disease', 'MESH:D004211', (271, 296))	('dermatitis', 'Disease', 'MESH:D003872', (210, 220))	('dermatitis', 'Disease', (210, 220))	('allergic reactions', 'Disease', 'MESH:D004342', (222, 240))	('nephrotoxicity', 'Disease', 'MESH:D007674', (160, 174))	('disseminated', 'Disease', (258, 270))	('venoms', 'Var', (97, 103))
54946	29405760	Modulating these important cancer survivals parameters using scorpion venoms is a positive approach toward inhibiting cancer progression.	('Modulating', 'Var', (0, 10))	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('inhibiting', 'NegReg', (107, 117))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
54962	29405760	In addition, ROS is also known to disrupt normal protein function, which leads to cell death.	('ROS', 'Var', (13, 16))	('normal', 'MPA', (42, 48))	('protein', 'Protein', (49, 56))	('disrupt', 'NegReg', (34, 41))	('cell death', 'CPA', (82, 92))	('leads to', 'Reg', (73, 81))	('ROS', 'Chemical', 'MESH:D017382', (13, 16))
54987	29123583	Medullary colonic carcinoma with microsatellite instability has lower survival compared with conventional colonic adenocarcinoma with microsatellite instability Colorectal medullary carcinoma (MC) is a rare subtype of poorly differentiated adenocarcinoma (PDA) with unclear prognostic significance.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('adenocarcinoma', 'Disease', 'MESH:D000230', (114, 128))	('adenocarcinoma', 'Disease', 'MESH:D000230', (240, 254))	('colonic adenocarcinoma', 'Disease', 'MESH:D003110', (106, 128))	('colonic adenocarcinoma', 'Disease', (106, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('microsatellite', 'Var', (33, 47))	('Colorectal medullary carcinoma', 'Disease', (161, 191))	('colonic carcinoma', 'Disease', 'MESH:D015179', (10, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('PDA', 'Chemical', '-', (256, 259))	('colonic carcinoma', 'Disease', (10, 27))	('adenocarcinoma', 'Disease', (114, 128))	('survival', 'MPA', (70, 78))	('lower', 'NegReg', (64, 69))	('adenocarcinoma', 'Disease', (240, 254))	('poorly differentiated', 'Disease', (218, 239))	('Colorectal medullary carcinoma', 'Disease', 'MESH:D015179', (161, 191))
54988	29123583	Microsatellite instable (MSI) colorectal carcinomas have demonstrated better prognosis in clinical stage II.	('MSI', 'Disease', 'None', (25, 28))	('Microsatellite', 'Var', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (30, 51))	('colorectal carcinomas', 'Disease', (30, 51))	('MSI', 'Disease', (25, 28))
55010	29123583	The adverse prognosis associated with the poor differentiation of most of these tumor subtypes contrasts with the positive prognosis associated with MSI.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('MSI', 'Disease', 'None', (149, 152))	('tumor', 'Disease', (80, 85))	('poor', 'Var', (42, 46))	('MSI', 'Disease', (149, 152))
55062	29123583	This heterogeneity of clinical behavior could be explained by the multitude of molecular heterogeneity underlying MSI tumors, because they also harbor BRAF mutations and KRAS mutations.	('MSI tumors', 'Disease', 'MESH:D009369', (114, 124))	('KRAS', 'Gene', (170, 174))	('mutations', 'Var', (156, 165))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('BRAF', 'Gene', '673', (151, 155))	('harbor', 'Reg', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('BRAF', 'Gene', (151, 155))	('KRAS', 'Gene', '3845', (170, 174))	('MSI tumors', 'Disease', (114, 124))
55073	28849164	We observed that ZZR enhanced the sensitivity of chemotherapeutic drugs and induced apoptosis in a dose- and time-dependent mannner in CRC MDR cells.	('ZZR', 'Var', (17, 20))	('MDR', 'Gene', (139, 142))	('apoptosis', 'CPA', (84, 93))	('enhanced', 'PosReg', (21, 29))	('CRC', 'Phenotype', 'HP:0003003', (135, 138))	('MDR', 'Gene', '18669', (139, 142))	('ZZR', 'Chemical', '-', (17, 20))	('induced', 'Reg', (76, 83))	('sensitivity of chemotherapeutic drugs', 'MPA', (34, 71))
55074	28849164	Interestingly, signaling of Hedgehog pathway, particularly Gli1, was also inhibited by ZZR.	('Gli1', 'Gene', (59, 63))	('inhibited', 'NegReg', (74, 83))	('Hedgehog', 'Gene', '42737', (28, 36))	('signaling', 'biological_process', 'GO:0023052', ('15', '24'))	('Hedgehog', 'Gene', (28, 36))	('ZZR', 'Var', (87, 90))	('signaling', 'MPA', (15, 24))	('ZZR', 'Chemical', '-', (87, 90))
55076	28849164	Furthermore, ZZR inhibited MDR CRC tumor growth in a xenograft mouse model as well as downregulated Gli1 levels.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('mouse', 'Species', '10090', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('MDR', 'Gene', '18669', (27, 30))	('Gli1 levels', 'MPA', (100, 111))	('CRC', 'Phenotype', 'HP:0003003', (31, 34))	('tumor', 'Disease', (35, 40))	('ZZR', 'Chemical', '-', (13, 16))	('MDR', 'Gene', (27, 30))	('downregulated', 'NegReg', (86, 99))	('inhibited', 'NegReg', (17, 26))	('ZZR', 'Var', (13, 16))
55077	28849164	This study provided the first direct evidence demonstrating ZZR can attenuate MDR by repressing Hedgehog signaling in human CRC.	('Hedgehog', 'Gene', '42737', (96, 104))	('attenuate', 'NegReg', (68, 77))	('Hedgehog', 'Gene', (96, 104))	('MDR', 'Gene', (78, 81))	('CRC', 'Phenotype', 'HP:0003003', (124, 127))	('human', 'Species', '9606', (118, 123))	('ZZR', 'Chemical', '-', (60, 63))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('MDR', 'molecular_function', 'GO:0004745', ('78', '81'))	('ZZR', 'Var', (60, 63))	('repressing', 'NegReg', (85, 95))	('MDR', 'Gene', '18669', (78, 81))
55110	28849164	When the tumors reach an average size of 100 mm3, the mice were randomized into 5 groups (n=6 per group) and received intragastric administration of vehicle control, L-OHP and amixture of ZZR and L-OHP.	('L-OHP', 'Chemical', 'MESH:D000077150', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('ZZR', 'Chemical', '-', (188, 191))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('mice', 'Species', '10090', (54, 58))	('L-OHP', 'Var', (166, 171))	('L-OHP', 'Chemical', 'MESH:D000077150', (196, 201))
55125	28849164	Our data revealed: the doses of IC10 and IC20 in HCT-116 cells were 103.44 and 212.57 microg/ml, 122.64 and 248.00 microg/ml in HCT-116/L-OHP cells, respectively (Fig.	('IC20', 'Var', (41, 45))	('HCT-116', 'CellLine', 'CVCL:0291', (128, 135))	('IC10', 'Var', (32, 36))	('L-OHP', 'Chemical', 'MESH:D000077150', (136, 141))	('HCT-116', 'CellLine', 'CVCL:0291', (49, 56))
55131	28849164	To explore the mechanisms of antiproliferative effect of ZZR, flow cytometry analysis was performed to determine if apoptosis was induced by L-OHP/ZZR combination.	('L-OHP', 'Chemical', 'MESH:D000077150', (141, 146))	('induced', 'Reg', (130, 137))	('ZZR', 'Chemical', '-', (57, 60))	('ZZR', 'Chemical', '-', (147, 150))	('L-OHP/ZZR', 'Var', (141, 150))
55133	28849164	This indicates that ZZR augmented L-OHP induced cell apoptosis in a dose-dependent manner.	('L-OHP', 'MPA', (34, 39))	('augmented', 'PosReg', (24, 33))	('ZZR', 'Var', (20, 23))	('ZZR', 'Chemical', '-', (20, 23))	('L-OHP', 'Chemical', 'MESH:D000077150', (34, 39))
55144	28849164	These data indicated that ZZR enhanced the inhibitory effect of L-OHP in vivo.	('L-OHP', 'MPA', (64, 69))	('enhanced', 'PosReg', (30, 38))	('ZZR', 'Chemical', '-', (26, 29))	('inhibitory effect', 'MPA', (43, 60))	('ZZR', 'Var', (26, 29))	('L-OHP', 'Chemical', 'MESH:D000077150', (64, 69))
55145	28849164	Immunohistochemistry analyses confirmed the lowered levels of Gli1 in tumors treated by ZZR (Fig.	('lowered', 'NegReg', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('ZZR', 'Chemical', '-', (88, 91))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Disease', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('ZZR', 'Var', (88, 91))	('levels', 'MPA', (52, 58))
55157	28849164	In our study, we found ZZR synergized with chemotherapeutic drugs to enhance cell apoptosis in a time-dependent manner, consistent with what several previous reports have shown with traditional Chinese prescriptions and formulae.	('cell apoptosis', 'CPA', (77, 91))	('ZZR', 'Chemical', '-', (23, 26))	('enhance', 'PosReg', (69, 76))	('apoptosis', 'biological_process', 'GO:0006915', ('82', '91'))	('apoptosis', 'biological_process', 'GO:0097194', ('82', '91'))	('ZZR', 'Var', (23, 26))
55161	28849164	Here we extended that study by using another two MDR colorectal cancer cell lines, and found ZZR perturbed the expression levels of Ptch1, Gli1 and Gli2.	('ZZR', 'Chemical', '-', (93, 96))	('Ptch1', 'Gene', '5727', (132, 137))	('perturbed', 'NegReg', (97, 106))	('Ptch1', 'Gene', (132, 137))	('MDR', 'Gene', '18669', (49, 52))	('Gli1', 'Gene', (139, 143))	('colorectal cancer', 'Disease', 'MESH:D015179', (53, 70))	('expression levels', 'MPA', (111, 128))	('ZZR', 'Var', (93, 96))	('Gli2', 'Gene', '2736', (148, 152))	('colorectal cancer', 'Phenotype', 'HP:0003003', (53, 70))	('MDR', 'Gene', (49, 52))	('Gli2', 'Gene', (148, 152))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('colorectal cancer', 'Disease', (53, 70))
55168	28849164	In conclusion, the present study for the first time demonstrated that ZZR suppresssed Gli1 protein levels in colorectal cancer through inhibiting Hedgehog signaling pathway.	('colorectal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('ZZR', 'Chemical', '-', (70, 73))	('ZZR', 'Var', (70, 73))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('Hedgehog', 'Gene', '42737', (146, 154))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('inhibiting', 'NegReg', (135, 145))	('Gli1', 'Protein', (86, 90))	('Hedgehog signaling pathway', 'biological_process', 'GO:0007224', ('146', '172'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('Hedgehog', 'Gene', (146, 154))	('suppresssed', 'NegReg', (74, 85))
55201	26537799	Then, additional glycan-derived traits for complex- and hybrid-type glycans were calculated (mono-fucosylation, multi-fucosylation, alpha2,6- and alpha2,3-sialylation, ratio Hex versus HexNAc, and number of antennae) and compared (Supplemental Table S5).	('Hex', 'Gene', '5657742', (185, 188))	('Hex', 'Gene', (174, 177))	('HexNAc', 'Chemical', '-', (185, 191))	('Hex', 'Gene', (185, 188))	('fucosylation', 'biological_process', 'GO:0036065', ('98', '110'))	('multi-fucosylation', 'Var', (112, 130))	('sialylation', 'biological_process', 'GO:0097503', ('155', '166'))	('fucosylation', 'biological_process', 'GO:0036065', ('118', '130'))	('Hex', 'Gene', '5657742', (174, 177))
55223	26537799	The characteristic fragment ion m/z 860 [M+H]+ was confirmed by MS3 (see Fig.	('MS3', 'Gene', (64, 67))	('MS3', 'Gene', '100271695', (64, 67))	('m/z 860 [M+H]+', 'Var', (32, 46))
55229	26537799	In accordance with their location in the PCA plots, SW1463 (30.8%), Co115 (29.0%), HCT116_VUmc (28.3%), and Colo320_VUmc (26.6%) exhibit the highest abundances of di-antennary glycans, while the highest levels of mono-antennary N-glycans were found in HCT15_VUmc (4.9%), SW948_VUmc (4.4%), HCT116_VUmc (4.3%), RKO_VUmc (4.3%), Colo205_VUmc (4.1%), and SW480_VUmc (3.8%) (Fig.	('di-antennary glycans', 'Protein', (163, 183))	('SW948', 'CellLine', 'CVCL:0632', (271, 276))	('SW480_VUmc', 'Var', (352, 362))
55243	26537799	S7C), as well as for fucosyltransferase (FUT) 4, the enzyme responsible for Lewis X epitopes on LacNAc repeats, with the trait multi-fucosylation (R2 = 0.2947, p value = .020; Supplemental Fig.	('fucosyltransferase (FUT) 4', 'Gene', (21, 47))	('Lewis X epitopes', 'Disease', 'MESH:D020961', (76, 92))	('fucosylation', 'biological_process', 'GO:0036065', ('133', '145'))	('Lewis X epitopes', 'Disease', (76, 92))	('fucosyltransferase (FUT) 4', 'Gene', '2526', (21, 47))	('multi-fucosylation', 'Var', (127, 145))
55246	26537799	However, FUT8, the enzyme responsible for alpha1,6-fucosylation of the N-glycan core, showed no correlation with the derived trait mono-fucosylation and instead showed the highest levels for SW48, SW480, SW620, and WiDr.	('SW620', 'Var', (204, 209))	('FUT8', 'Gene', (9, 13))	('levels', 'MPA', (180, 186))	('FUT8', 'Gene', '2530', (9, 13))	('mono-fucosylation', 'MPA', (131, 148))	('SW480', 'Var', (197, 202))	('SW48', 'Var', (191, 195))
55251	26537799	Moreover, the expression of MGAT3, the enzyme initiating bisection, was very low in SW620, suggesting that the suspected bisection is more likely to reflect terminal HexNAc on antennae.	('low', 'NegReg', (77, 80))	('expression', 'MPA', (14, 24))	('MGAT3', 'Gene', '4248', (28, 33))	('MGAT3', 'Gene', (28, 33))	('SW620', 'Var', (84, 89))
55252	26537799	Furthermore, cell line HCT116 has a mutation in the GDP-mannose-4,6-dehydratase (GMDS) and therefore very low fucose-levels and showed an aggressive phenotype, while restoration of the GMDS transcript and therefore enhanced fucosylation suppressed tumor formation and metastasis.	('fucose-levels', 'MPA', (110, 123))	('suppressed', 'NegReg', (237, 247))	('low', 'NegReg', (106, 109))	('GDP-mannose-4,6-dehydratase', 'Gene', '2762', (52, 79))	('fucosylation', 'MPA', (224, 236))	('enhanced', 'PosReg', (215, 223))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('mutation', 'Var', (36, 44))
55254	26537799	In contrast, high antenna fucosylation of TGF-beta was associated with poor prognosis and metastasis.	('TGF-beta', 'Gene', (42, 50))	('high', 'Var', (13, 17))	('metastasis', 'CPA', (90, 100))	('fucosylation', 'biological_process', 'GO:0036065', ('26', '38'))	('poor prognosis', 'CPA', (71, 85))	('TGF-beta', 'Gene', '7040', (42, 50))
55273	26871810	According to the cluster analysis of the TN scores, T1N1a was classified as stage I, and T2N1 and T1N1b-2a were classified as stage II for both colon and rectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('colon and rectal cancer', 'Disease', 'MESH:D012004', (144, 167))	('rectal cancer', 'Phenotype', 'HP:0100743', (154, 167))	('T1N1b-2a', 'Var', (98, 106))	('T1N1a', 'Var', (52, 57))	('T2N1', 'Var', (89, 93))
55274	26871810	However, T4bN0 was classified as IIIa in colon cancer, but as IIIb in rectal cancer (Table 1).	('rectal cancer', 'Disease', 'MESH:D012004', (70, 83))	('colon cancer', 'Phenotype', 'HP:0003003', (41, 53))	('colon cancer', 'Disease', 'MESH:D015179', (41, 53))	('T4bN0', 'Var', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('rectal cancer', 'Disease', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('rectal cancer', 'Phenotype', 'HP:0100743', (70, 83))	('colon cancer', 'Disease', (41, 53))
55300	26871810	For 2080 colorectal cancer patients, Cox regression analysis of multiple clinicopathological parameters against overall survival showed that independent risk factors included rectal cancer, older ages, non-R0 resection, mucinous adenocarcinoma or signet-ring cell carcinoma, fewer harvested lymph nodes, higher T stages, higher N stages, and higher preoperative carcinoembryonic antigen (CEA) level (Supplementary Table 1).	('non-R0 resection', 'Var', (202, 218))	('rectal cancer', 'Disease', 'MESH:D012004', (13, 26))	('rectal cancer', 'Disease', (175, 188))	('colorectal cancer', 'Disease', 'MESH:D015179', (9, 26))	('cell carcinoma', 'Disease', 'MESH:C538614', (259, 273))	('rectal cancer', 'Phenotype', 'HP:0100743', (175, 188))	('mucinous adenocarcinoma', 'Disease', (220, 243))	('colorectal cancer', 'Disease', (9, 26))	('fewer', 'NegReg', (275, 280))	('carcinoembryonic antigen', 'Gene', (362, 386))	('signet-ring', 'Disease', (247, 258))	('patients', 'Species', '9606', (27, 35))	('T stages', 'CPA', (311, 319))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('rectal cancer', 'Disease', 'MESH:D012004', (175, 188))	('colorectal cancer', 'Phenotype', 'HP:0003003', (9, 26))	('rectal cancer', 'Phenotype', 'HP:0100743', (13, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('carcinoembryonic antigen', 'Gene', '1084', (362, 386))	('CEA', 'Gene', (388, 391))	('cell carcinoma', 'Disease', (259, 273))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('higher', 'PosReg', (342, 348))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (220, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('CEA', 'Gene', '1084', (388, 391))
55328	26871810	Kim et al reported that the pT4 status was the most significant pathologic determinant of poor outcome, comparing to the other 25 histopathologic and immunohistochemical factors, in patients with stage II/III microsatellite instability-high colorectal cancer regardless of the regimens of adjuvant chemotherapy.	('microsatellite instability-high', 'Var', (209, 240))	('rectal cancer', 'Phenotype', 'HP:0100743', (245, 258))	('colorectal cancer', 'Phenotype', 'HP:0003003', (241, 258))	('colorectal cancer', 'Disease', (241, 258))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('patients', 'Species', '9606', (182, 190))	('colorectal cancer', 'Disease', 'MESH:D015179', (241, 258))
55329	26871810	The Iceland nationwide retrospective study also found that pT4 was a major indicator of poor prognosis in stage II/III colon carcinoma.	('pT4', 'Var', (59, 62))	('III colon carcinoma', 'Disease', (115, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('III colon carcinoma', 'Disease', 'MESH:D015179', (115, 134))
55330	26871810	For example, T1N1a is classified as stage I, and T2N1 and T1N1b-2a are classified as stage II for both colon and rectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('T2N1', 'Var', (49, 53))	('T1N1b-2a', 'Var', (58, 66))	('rectal cancer', 'Phenotype', 'HP:0100743', (113, 126))	('T1N1a', 'Var', (13, 18))	('colon and rectal cancer', 'Disease', 'MESH:D012004', (103, 126))
55331	26871810	However, T4bN0 is classified as IIIa in colon cancer, but as IIIb in rectal cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (40, 52))	('colon cancer', 'Disease', 'MESH:D015179', (40, 52))	('rectal cancer', 'Disease', 'MESH:D012004', (69, 82))	('colon cancer', 'Disease', (40, 52))	('rectal cancer', 'Disease', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('T4bN0', 'Var', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('rectal cancer', 'Phenotype', 'HP:0100743', (69, 82))
55365	26871810	In recent decades, more pathological factors, for example, venous or lymphatic invasion and perineural invasion; cellular factors, for example, poor differentiation, mucinous adenocarcinoma or signet-ring cell carcinoma, and high CEA level; and molecular factors, for example, ras gene mutation, B-raf gene mutation, microsatellite instability, and CpG island methylator phenotype, have been confirmed to be associated with the prognosis of colorectal cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('cell carcinoma', 'Disease', 'MESH:C538614', (205, 219))	('colorectal cancer', 'Phenotype', 'HP:0003003', (441, 458))	('rectal cancer', 'Phenotype', 'HP:0100743', (445, 458))	('high CEA level', 'Phenotype', 'HP:0031029', (225, 239))	('cancer', 'Phenotype', 'HP:0002664', (452, 458))	('ras', 'Gene', (277, 280))	('mucinous adenocarcinoma', 'Disease', (166, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('colorectal cancer', 'Disease', 'MESH:D015179', (441, 458))	('B-raf', 'Gene', (296, 301))	('CEA', 'Gene', (230, 233))	('colorectal cancer', 'Disease', (441, 458))	('microsatellite instability', 'Var', (317, 343))	('cell carcinoma', 'Disease', (205, 219))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (166, 189))	('associated', 'Reg', (408, 418))	('B-raf', 'Gene', '673', (296, 301))	('mutation', 'Var', (307, 315))	('CEA', 'Gene', '1084', (230, 233))
55373	26187947	From our previous studies in the vinegar fly, Drosophila melanogaster, we have identified a cooperative interaction between a mutation in the apico-basal cell polarity regulator Scribble (Scrib) and overexpression of the BTB-ZF protein Abrupt (Ab).	('Abrupt', 'Gene', '34560', (236, 242))	('Drosophila melanogaster', 'Species', '7227', (46, 69))	('Abrupt', 'Gene', (236, 242))	('Scribble', 'Gene', (178, 186))	('protein', 'cellular_component', 'GO:0003675', ('228', '235'))	('Scrib', 'Gene', (178, 183))	('mutation', 'Var', (126, 134))	('Ab', 'Gene', '34560', (244, 246))	('Scrib', 'Gene', (188, 193))	('cell polarity', 'biological_process', 'GO:0007163', ('154', '167'))	('Scrib', 'Gene', '44448', (178, 183))	('Scrib', 'Gene', '44448', (188, 193))	('Scribble', 'Gene', '44448', (178, 186))	('Ab', 'Gene', '34560', (236, 238))
55374	26187947	Herein, we show that co-expression of ab with actin cytoskeletal regulators, RhoGEF2 or Src64B, in the developing eye-antennal epithelial tissue results in the formation of overgrown amorphous tumours, whereas ab and DRac1 co-expression leads to non-cell autonomous overgrowth.	('actin', 'Gene', (46, 51))	('overgrowth', 'Phenotype', 'HP:0001548', (266, 276))	('actin', 'Gene', '35526', (46, 51))	('overgrown amorphous tumours', 'Disease', 'MESH:C567546', (173, 200))	('Src64B', 'Gene', (88, 94))	('RhoGEF2', 'Gene', '36915', (77, 84))	('overgrown amorphous tumours', 'Disease', (173, 200))	('DRac1', 'Gene', '38146', (217, 222))	('ab', 'Gene', '34560', (38, 40))	('ab', 'Gene', '34560', (210, 212))	('co-expression', 'Var', (21, 34))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('non-cell autonomous overgrowth', 'CPA', (246, 276))	('RhoGEF2', 'Gene', (77, 84))	('DRac1', 'Gene', (217, 222))	('Src64B', 'Gene', '48973', (88, 94))	('results in', 'Reg', (145, 155))	('tumours', 'Phenotype', 'HP:0002664', (193, 200))
55375	26187947	Together with ab, these genes affect the expression of differentiation genes, resulting in tumours locked in a progenitor cell fate.	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('tumours', 'Disease', 'MESH:D009369', (91, 98))	('expression', 'MPA', (41, 51))	('tumours', 'Disease', (91, 98))	('ab', 'Gene', '34560', (14, 16))	('genes', 'Var', (24, 29))	('differentiation genes', 'Gene', (55, 76))	('affect', 'Reg', (30, 36))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
55379	26187947	Cancer is a cooperative process involving many mutations that lead to the deregulation of the normal controls that regulate cell proliferation, survival, differentiation and migration, amongst other processes.	('survival', 'CPA', (144, 152))	('deregulation', 'MPA', (74, 86))	('mutations', 'Var', (47, 56))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('normal controls', 'MPA', (94, 109))	('lead to', 'Reg', (62, 69))	('differentiation', 'CPA', (154, 169))	('cell proliferation', 'CPA', (124, 142))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('migration', 'CPA', (174, 183))
55382	26187947	Recently, the disruption of apical-basal cell polarity, which affects cell adhesion and signalling pathways and leads to an epithelial to mesenchymal transition (EMT), has been realized as a new hallmark of cancer.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('signalling pathways', 'Pathway', (88, 107))	('affects', 'Reg', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('disruption', 'Var', (14, 24))	('cell', 'Pathway', (70, 74))	('apical-basal cell polarity', 'CPA', (28, 54))	('epithelial to mesenchymal transition', 'CPA', (124, 160))	('leads to', 'Reg', (112, 120))
55384	26187947	Whole organism or tissue-specific depletion of genes in the Scribble module lead to a loss of cell polarity and aberrant signalling, leading to the formation of neoplastic tumour in Drosophila epithelial tissues.	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('loss', 'NegReg', (86, 90))	('genes', 'Var', (47, 52))	('neoplastic tumour', 'Disease', 'MESH:D009369', (161, 178))	('neoplastic tumour', 'Phenotype', 'HP:0002664', (161, 178))	('formation', 'biological_process', 'GO:0009058', ('148', '157'))	('ab', 'Gene', '34560', (112, 114))	('neoplastic tumour', 'Disease', (161, 178))	('Scribble', 'Gene', '44448', (60, 68))	('cell polarity', 'CPA', (94, 107))	('signalling', 'biological_process', 'GO:0023052', ('121', '131'))	('depletion', 'Var', (34, 43))	('Drosophila', 'Species', '7227', (182, 192))	('cell polarity', 'biological_process', 'GO:0007163', ('94', '107'))	('Scribble', 'Gene', (60, 68))
55385	26187947	However, when scrib, dlg or lgl are mutated in patches of cells within the developing eye-antennal tissue, despite deregulation of signalling pathways and cell proliferation, tissue overgrowth does not ensue due to cell differentiation and Jun N-terminal Kinase (JNK)-mediated apoptosis.	('dlg', 'Gene', '32083', (21, 24))	('Jun N-terminal Kinase', 'Gene', '44801', (240, 261))	('dlg', 'Gene', (21, 24))	('lgl', 'Gene', (28, 31))	('overgrowth', 'Phenotype', 'HP:0001548', (182, 192))	('mutated', 'Var', (36, 43))	('cell proliferation', 'CPA', (155, 173))	('Jun N-terminal Kinase', 'Gene', (240, 261))	('signalling pathways', 'Pathway', (131, 150))	('lgl', 'Gene', '33156', (28, 31))	('deregulation', 'Reg', (115, 127))
55388	26187947	This mechanism is conserved in mammalian cells and mouse models, where depletion or knockout of scrib leads to hyperplasia, and additional expression of the Ras oncogene (Ha-RasV12) cooperates with scrib loss-of-function to promote tumorigenesis.	('hyperplasia', 'Disease', (111, 122))	('depletion', 'Var', (71, 80))	('mammalian', 'Species', '9606', (31, 40))	('tumorigenesis', 'CPA', (232, 245))	('knockout', 'Var', (84, 92))	('mouse', 'Species', '10090', (51, 56))	('scrib', 'Gene', (96, 101))	('promote', 'PosReg', (224, 231))	('hyperplasia', 'Disease', 'MESH:D006965', (111, 122))	('loss-of-function', 'NegReg', (204, 220))	('RasV12', 'Gene', (174, 180))	('RasV12', 'Gene', '41140', (174, 180))
55389	26187947	Moreover, similar to that observed in Drosophila, the expression of JNK is able to cooperate with Ha-RasV12 to promote invasive growth in 3D matrigel cultures.	('ab', 'Gene', '34560', (75, 77))	('expression', 'Var', (54, 64))	('Drosophila', 'Species', '7227', (38, 48))	('JNK', 'Gene', (68, 71))	('RasV12', 'Gene', (101, 107))	('RasV12', 'Gene', '41140', (101, 107))	('invasive growth', 'CPA', (119, 134))	('promote', 'PosReg', (111, 118))
55399	26187947	Indeed, constitutive activation of Rac1 during tube morphogenesis of the Drosophila salivary gland causes changes in epithelial cell morphology, resembling an epithelial to mesenchymal transition (EMT) by mislocalization or loss of expression of the apical polarity regulators, Crumbs and aPKC, and the adherens junction proteins E-cadherin and beta-catenin.	('mislocalization', 'Var', (205, 220))	('loss of', 'NegReg', (224, 231))	('apical polarity', 'Phenotype', 'HP:0032176', (250, 265))	('beta-catenin', 'Gene', '31151', (345, 357))	('E-cadherin', 'Gene', (330, 340))	('epithelial to mesenchymal transition', 'biological_process', 'GO:0001837', ('159', '195'))	('expression', 'MPA', (232, 242))	('E-cadherin', 'Gene', '37386', (330, 340))	('tube morphogenesis', 'biological_process', 'GO:0035239', ('47', '65'))	('Rac1', 'Gene', '38146', (35, 39))	('adherens junction', 'cellular_component', 'GO:0005912', ('303', '320'))	('epithelial cell morphology', 'CPA', (117, 143))	('aPKC', 'Gene', (289, 293))	('Drosophila salivary', 'Disease', (73, 92))	('aPKC', 'Gene', '47594', (289, 293))	('Drosophila salivary', 'Disease', 'MESH:D012466', (73, 92))	('Rac1', 'Gene', (35, 39))	('beta-catenin', 'Gene', (345, 357))	('cadherin', 'molecular_function', 'GO:0008014', ('332', '340'))	('changes', 'Reg', (106, 113))	('EMT', 'biological_process', 'GO:0001837', ('197', '200'))	('activation', 'PosReg', (21, 31))	('epithelial to mesenchymal transition', 'CPA', (159, 195))
55413	26187947	We show that co-expression of ab with RhoGEF2 or Src64B results in neoplastic tumour formation, whereas ab and DRac1 co-expression leads to non-cell autonomous overgrowth.	('RhoGEF2', 'Gene', (38, 45))	('overgrowth', 'Phenotype', 'HP:0001548', (160, 170))	('neoplastic tumour', 'Phenotype', 'HP:0002664', (67, 84))	('RhoGEF', 'molecular_function', 'GO:0005089', ('38', '44'))	('DRac1', 'Gene', (111, 116))	('formation', 'biological_process', 'GO:0009058', ('85', '94'))	('neoplastic tumour', 'Disease', (67, 84))	('ab', 'Gene', '34560', (30, 32))	('co-expression', 'Var', (13, 26))	('RhoGEF2', 'Gene', '36915', (38, 45))	('DRac1', 'Gene', '38146', (111, 116))	('Src64B', 'Gene', '48973', (49, 55))	('ab', 'Gene', '34560', (104, 106))	('neoplastic tumour', 'Disease', 'MESH:D009369', (67, 84))	('results in', 'Reg', (56, 66))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('Src64B', 'Gene', (49, 55))
55418	26187947	Mutation of scrib alone in clones results in cell morphology changes and disorganisation, but does not dramatically affect differentiation as revealed by Elav staining or lead to tissue overgrowth and larvae enter pupariation normally at day 5/6 after egg deposition (AED).	('scrib', 'Gene', (12, 17))	('changes', 'Reg', (61, 68))	('lead to', 'Reg', (171, 178))	('Mutation', 'Var', (0, 8))	('pupariation', 'CPA', (214, 225))	('results in', 'Reg', (34, 44))	('enter', 'Reg', (208, 213))	('cell morphology', 'CPA', (45, 60))	('overgrowth', 'Phenotype', 'HP:0001548', (186, 196))	('disorganisation', 'CPA', (73, 88))	('pupariation', 'biological_process', 'GO:0035073', ('214', '225'))	('Elav', 'Gene', (154, 158))	('Elav', 'Gene', '31000', (154, 158))
55445	26187947	In mosaic eye-antennal discs at day 5 AED, DRac1 over-expression produced small clones with cell morphology defects (although F-actin levels were only slightly increased, Fig.	('DRac1', 'Gene', '38146', (43, 48))	('increased', 'PosReg', (160, 169))	('cell morphology defects', 'CPA', (92, 115))	('DRac1', 'Gene', (43, 48))	('F-actin', 'Gene', (126, 133))	('F-actin', 'Gene', '35526', (126, 133))	('F-actin', 'cellular_component', 'GO:0031941', ('126', '133'))	('over-expression', 'Var', (49, 64))
55448	26187947	At later times (day 8/9 AED), DRac1 ab co-expression resulted in strong non-cell autonomous effects, as indicated by the highly folded wild-type tissue surrounding the clonal tissue and greater representation of GFP- tissue (Fig.	('co-expression', 'Var', (39, 52))	('non-cell autonomous effects', 'CPA', (72, 99))	('DRac1', 'Gene', '38146', (30, 35))	('ab', 'Gene', '34560', (36, 38))	('DRac1', 'Gene', (30, 35))
55449	26187947	DRac1 ab co-expression resulted in rounded clones with elevated F-actin levels at day 5 AED (white arrowheads, Fig.	('F-actin', 'cellular_component', 'GO:0031941', ('64', '71'))	('F-actin', 'Gene', (64, 71))	('DRac1', 'Gene', '38146', (0, 5))	('ab', 'Gene', '34560', (6, 8))	('F-actin', 'Gene', '35526', (64, 71))	('DRac1', 'Gene', (0, 5))	('elevated', 'PosReg', (55, 63))	('co-expression', 'Var', (9, 22))
55468	26187947	Altogether, these results show that increased cell proliferation of the mutant tissue and increased cell death of the wild-type tissue occurs in scrib- ab, RhoGEF2 ab, and Src64B ab mosaic discs, whilst the opposite occurs in DRac1 ab mosaic discs.	('ab', 'Gene', '34560', (152, 154))	('ab', 'Gene', '34560', (232, 234))	('mutant', 'Var', (72, 78))	('DRac1', 'Gene', '38146', (226, 231))	('cell death', 'biological_process', 'GO:0008219', ('100', '110'))	('RhoGEF2', 'Gene', (156, 163))	('cell death', 'CPA', (100, 110))	('increased', 'PosReg', (36, 45))	('scrib-', 'Gene', (145, 151))	('DRac1', 'Gene', (226, 231))	('ab', 'Gene', '34560', (164, 166))	('Src64B', 'Gene', '48973', (172, 178))	('ab', 'Gene', '34560', (179, 181))	('RhoGEF2', 'Gene', '36915', (156, 163))	('Src64B', 'Gene', (172, 178))	('cell proliferation', 'CPA', (46, 64))	('RhoGEF', 'molecular_function', 'GO:0005089', ('156', '162'))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))
55479	26187947	In RhoGEF2 ab clones in the eye disc, Dac expression was blocked (arrowheads, Fig.	('clones', 'Var', (14, 20))	('RhoGEF2', 'Gene', '36915', (3, 10))	('Dac', 'Gene', '34982', (38, 41))	('blocked', 'NegReg', (57, 64))	('RhoGEF', 'molecular_function', 'GO:0005089', ('3', '9'))	('ab', 'Gene', '34560', (11, 13))	('RhoGEF2', 'Gene', (3, 10))	('Dac', 'Gene', (38, 41))
55490	26187947	8C1-C4), probably due to a partial duplication of the antennae, which is sometimes observed in ab-expressing clones.	('antennae', 'Protein', (54, 62))	('ab', 'Gene', '34560', (95, 97))	('partial duplication', 'Var', (27, 46))	('ab', 'Gene', '34560', (13, 15))
55506	26187947	Stratification of the Rohrbeck Lung cancers dataset into different stages showed that there were several samples of lung adenocarcinoma or lung squamous cell carcinoma having high Bcl6 expression and high MAP2K4 expression relative to normal lung (No value), whereas high Bcl6 expression correlated with low Dlg2 or Llgl1 in some samples from all forms of lung cancers relative to normal lung (Fig.	('cancers', 'Disease', (361, 368))	('Lung cancers', 'Phenotype', 'HP:0100526', (31, 43))	('expression', 'MPA', (185, 195))	('Bcl6', 'Gene', (180, 184))	('Bcl6', 'Gene', '604', (272, 276))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (116, 135))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('MAP2K4', 'Gene', '6416', (205, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('MAP2K4', 'Gene', (205, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('Bcl6', 'Gene', (272, 276))	('cancers', 'Disease', 'MESH:D009369', (361, 368))	('MAP2K', 'molecular_function', 'GO:0004708', ('205', '210'))	('lung cancers', 'Disease', 'MESH:D008175', (356, 368))	('Llgl1', 'Gene', '3996', (316, 321))	('lung adenocarcinoma or lung squamous cell carcinoma', 'Disease', 'MESH:D000077192', (116, 167))	('lung cancers', 'Disease', (356, 368))	('Llgl1', 'Gene', (316, 321))	('Bcl6', 'Gene', '604', (180, 184))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('expression', 'MPA', (212, 222))	('cancers', 'Disease', (36, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (356, 367))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('lung cancers', 'Phenotype', 'HP:0100526', (356, 368))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('high', 'Var', (200, 204))	('cancers', 'Phenotype', 'HP:0002664', (361, 368))
55507	26187947	Also significantly positively correlated with a stronger trend compared with normal tissue were Bcl6 and MAP2K7 in the Boersma breast epithelial cancer dataset and ZBTB7A and MAP2K7 in the Zhai cervical squamous carcinoma dataset (Table 1).	('Boersma breast epithelial cancer', 'Disease', (119, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('ZBTB7A', 'Gene', '51341', (164, 170))	('positively', 'PosReg', (19, 29))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (203, 221))	('Bcl6', 'Gene', '604', (96, 100))	('ZBTB7A', 'Gene', (164, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('Bcl6', 'Gene', (96, 100))	('Zhai cervical squamous carcinoma', 'Disease', (189, 221))	('MAP2K', 'molecular_function', 'GO:0004708', ('105', '110'))	('Zhai cervical squamous carcinoma', 'Disease', 'MESH:D002294', (189, 221))	('MAP2K', 'molecular_function', 'GO:0004708', ('175', '180'))	('Boersma breast epithelial cancer', 'Disease', 'MESH:D001943', (119, 151))	('ab', 'Gene', '34560', (232, 234))	('correlated', 'Reg', (30, 40))	('epithelial cancer', 'Phenotype', 'HP:0031492', (134, 151))	('MAP2K7', 'Gene', (105, 111))	('MAP2K7', 'Var', (175, 181))
55538	26187947	scrib mutant cells also upregulate JNK, downregulate the E-cadherin/beta-catenin adhesion complex and repress Hippo signalling.	('mutant', 'Var', (6, 12))	('repress', 'NegReg', (102, 109))	('downregulate', 'NegReg', (40, 52))	('JNK', 'MPA', (35, 38))	('scrib', 'Gene', (0, 5))	('E-cadherin', 'Gene', (57, 67))	('E-cadherin', 'Gene', '37386', (57, 67))	('upregulate', 'PosReg', (24, 34))	('Hippo signalling', 'MPA', (110, 126))	('beta-catenin', 'Gene', (68, 80))	('beta-catenin', 'Gene', '31151', (68, 80))
55547	26187947	Interestingly, this study also found that in colon cancer xenografts, ZBTB7A represses the expression of genes in the glycolytic pathway, a metabolic pathway that is required for aggressive tumour growth, and that inhibition of this pathway reduces tumour growth.	('expression', 'MPA', (91, 101))	('reduces', 'NegReg', (241, 248))	('aggressive tumour growth', 'Disease', (179, 203))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('ZBTB7A', 'Gene', (70, 76))	('ab', 'Gene', '34560', (143, 145))	('represses', 'NegReg', (77, 86))	('colon cancer', 'Disease', (45, 57))	('tumour growth', 'Disease', 'MESH:D006130', (249, 262))	('aggressive tumour growth', 'Disease', 'MESH:D006130', (179, 203))	('inhibition', 'Var', (214, 224))	('tumour', 'Phenotype', 'HP:0002664', (249, 255))	('genes', 'Gene', (105, 110))	('colon cancer', 'Phenotype', 'HP:0003003', (45, 57))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('tumour growth', 'Disease', (249, 262))	('tumour growth', 'Disease', 'MESH:D006130', (190, 203))	('glycolytic pathway', 'Pathway', (118, 136))	('colon cancer', 'Disease', 'MESH:D015179', (45, 57))	('ZBTB7A', 'Gene', '51341', (70, 76))
55557	26187947	In summary, our functional studies in Drosophila and bioinformatics analysis of human cancers has shown that cooperative tumorigenic interactions occur between BTB-ZF genes and cell polarity or cytoskeletal genes, and warrants further investigation to determine whether restoring normal expression of these genes or downstream pathways in human cancer cells can reduce tumorigenesis.	('reduce', 'NegReg', (362, 368))	('tumorigenesis', 'CPA', (369, 382))	('human', 'Species', '9606', (339, 344))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('genes', 'Var', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Drosophila', 'Species', '7227', (38, 48))	('cancer', 'Disease', 'MESH:D009369', (345, 351))	('human', 'Species', '9606', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('BTB-ZF', 'Gene', (160, 166))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('cancer', 'Disease', (86, 92))	('cancer', 'Disease', (345, 351))
55662	25846868	Overexpressing Snail1 attenuated the upregulatory effects of silibinin on VDR levels, such that VDR levels were significantly lower (P < 0.01) in Snail1-overexpressing cells treated with silibinin vs. control (untransfected) cells treated with silibinin (Fig.	('Snail1-overexpressing', 'PosReg', (146, 167))	('VDR levels', 'MPA', (74, 84))	('lower', 'NegReg', (126, 131))	('Snail1', 'Gene', (15, 21))	('Snail1-overexpressing', 'Gene', (146, 167))	('silibinin', 'Chemical', 'MESH:D000077385', (244, 253))	('VDR levels', 'MPA', (96, 106))	('silibinin', 'Var', (187, 196))	('attenuated', 'NegReg', (22, 32))	('silibinin', 'Chemical', 'MESH:D000077385', (61, 70))	('silibinin', 'Chemical', 'MESH:D000077385', (187, 196))
55664	25846868	Overexpressing Snail1 also attenuated the anti-migratory effects of silibinin, such that migration of silibinin-treated Snail1-overexpressing cells was significantly higher (P < 0.01) than that of silibinin-treated untransfected cells (Fig.	('higher', 'PosReg', (166, 172))	('attenuated', 'NegReg', (27, 37))	('anti-migratory', 'CPA', (42, 56))	('silibinin', 'Chemical', 'MESH:D000077385', (102, 111))	('silibinin', 'Chemical', 'MESH:D000077385', (68, 77))	('Snail1', 'Gene', (15, 21))	('silibinin-treated', 'Var', (102, 119))	('migration', 'CPA', (89, 98))	('Snail1-overexpressing', 'Gene', (120, 141))	('silibinin', 'Chemical', 'MESH:D000077385', (197, 206))
55688	25846868	Vitamin D deficiency is associated with increased hospitalization and surgery in IBD patients.	('Vitamin D', 'Gene', (0, 9))	('IBD', 'Disease', 'MESH:C535541', (81, 84))	('IBD', 'Phenotype', 'HP:0002037', (81, 84))	('patients', 'Species', '9606', (85, 93))	('IBD', 'Disease', (81, 84))	('Vitamin D deficiency', 'Phenotype', 'HP:0100512', (0, 20))	('increased', 'PosReg', (40, 49))	('deficiency', 'Var', (10, 20))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))
55709	25846868	However, silibinin had no effect on RXRalpha levels in our system, indicating that the decrease in VDRE-mediated promoter activity by silibinin may predominantly occur via an effect on the VDR.	('silibinin', 'Chemical', 'MESH:D000077385', (134, 143))	('VDRE-mediated promoter activity', 'MPA', (99, 130))	('decrease', 'NegReg', (87, 95))	('silibinin', 'Chemical', 'MESH:D000077385', (9, 18))	('silibinin', 'Var', (134, 143))
55753	23737956	Some of its inhibitors even have been shown to be potentially attractive chemotherapeutic drugs in the treatment of colorectal cancer combined with other common chemotherapeutic agents.	('colorectal cancer', 'Phenotype', 'HP:0003003', (116, 133))	('inhibitors', 'Var', (12, 22))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('colorectal cancer', 'Disease', (116, 133))	('rectal cancer', 'Phenotype', 'HP:0100743', (120, 133))	('colorectal cancer', 'Disease', 'MESH:D015179', (116, 133))
55784	23737956	Pretreatment of cells with PI3K/Akt inhibitor LY294002 (LY) at 5microM (Fig.	('LY', 'Chemical', 'MESH:C085911', (46, 48))	('Akt', 'Gene', '207', (32, 35))	('PI3K', 'molecular_function', 'GO:0016303', ('27', '31'))	('Akt', 'Gene', (32, 35))	('LY294002', 'Var', (46, 54))	('LY', 'Chemical', 'MESH:C085911', (56, 58))	('LY294002', 'Chemical', 'MESH:C085911', (46, 54))
55925	26644411	Tumors were biopsied at the MTD for analysis of MEK pathway mutations and ERK phosphorylation.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('ERK', 'Gene', '5594', (74, 77))	('ERK', 'Gene', (74, 77))	('MEK', 'Gene', (48, 51))	('MEK', 'Gene', '5609', (48, 51))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('ERK', 'molecular_function', 'GO:0004707', ('74', '77'))	('phosphorylation', 'biological_process', 'GO:0016310', ('78', '93'))	('mutations', 'Var', (60, 69))
55931	26644411	The combination was associated with significantly reduced ERK phosphorylation in 5 out of 6 patients biopsied, with the greatest reductions in those with KRAS or BRAF mutations.	('KRAS', 'Gene', '3845', (154, 158))	('ERK', 'molecular_function', 'GO:0004707', ('58', '61'))	('reduced ERK', 'Phenotype', 'HP:0000654', (50, 61))	('patients', 'Species', '9606', (92, 100))	('mutations', 'Var', (167, 176))	('ERK', 'Gene', '5594', (58, 61))	('phosphorylation', 'biological_process', 'GO:0016310', ('62', '77'))	('reduced', 'NegReg', (50, 57))	('BRAF', 'Gene', '673', (162, 166))	('ERK', 'Gene', (58, 61))	('KRAS', 'Gene', (154, 158))	('BRAF', 'Gene', (162, 166))
55935	26644411	Mutations in receptor tyrosine kinases, or downstream intracellular MAPK signaling components (e.g., RAS), are common in various tumors and present a long-studied therapeutic target.	('common', 'Reg', (111, 117))	('MAPK signaling', 'biological_process', 'GO:0000165', ('68', '82'))	('tumors', 'Disease', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('intracellular', 'cellular_component', 'GO:0005622', ('54', '67'))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('Mutations', 'Var', (0, 9))	('MAPK', 'molecular_function', 'GO:0004707', ('68', '72'))
55940	26644411	Sorafenib (Nexavar ; Bayer Pharma AG) is an oral multikinase inhibitor with potent activity against Raf-1 and wild-type and mutant BRAF, and with antiangiogenic activity mediated by inhibition of vascular endothelial growth factor receptors and platelet-derived growth factors.	('activity', 'MPA', (83, 91))	('BRAF', 'Gene', (131, 135))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('196', '230'))	('Raf-1', 'Gene', '5894', (100, 105))	('vascular endothelial growth factor', 'Gene', (196, 230))	('mutant', 'Var', (124, 130))	('vascular endothelial growth factor', 'Gene', '7422', (196, 230))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))	('Nexavar', 'Chemical', 'MESH:D000077157', (11, 18))	('Raf-1', 'Gene', (100, 105))	('antiangiogenic', 'CPA', (146, 160))	('BRAF', 'Gene', '673', (131, 135))
55950	26644411	Other inclusion criteria for all cohorts were: amylase and lipase <=2 x upper limit of normal (ULN); hemoglobin >=8.5 g/L; absolute neutrophil count >=1500/mm3; platelet count >=75,000/mm3; total bilirubin <=1.5 x ULN; aspartate aminotransferase/alanine aminotransferase <=2.5 x ULN (or <= 5 x ULN for patients with liver involvement); pro-thrombin time international normalized ratio/partial thromboplastin time <=1.5 x ULN; and creatinine <=1.5 x ULN.	('>=1500/mm3', 'Var', (149, 159))	('creatinine', 'Chemical', 'MESH:D003404', (430, 440))	('partial thromboplastin time', 'Phenotype', 'HP:0003645', (385, 412))	('>=8.5', 'Var', (112, 117))	('thromboplastin', 'molecular_function', 'GO:0003804', ('393', '407'))	('hemoglobin', 'MPA', (101, 111))	('international normalized ratio/partial thromboplastin time', 'Phenotype', 'HP:0003645', (354, 412))	('patients', 'Species', '9606', (302, 310))	('creatinine', 'MPA', (430, 440))
55956	26644411	Protocol-defined DLTs included the following drug-related toxicities: grade 4 neutropenia lasting more than 7 days; febrile neutropenia (grade 3 or 4); grade 4 thrombocytopenia; grade >=3 laboratory or non-hematologic toxicity; grade >=3 lipase and/or amylase elevation; grade >=3 skin toxicity (not hand-foot skin reaction); grade 4 anemia; grade >=2 pulmonary hemorrhage/bleeding within 2 weeks of initial dose; grade >=3 diarrhea (if persists with anti-diarrheal medication); grade >=3 international normalized ratio or partial thromboplastin time with associated bleeding; grade >=3 hemorrhage/bleeding; and missing 7 or more consecutive refametinib daily doses because of drug-related toxicity.	('toxicity', 'Disease', (218, 226))	('neutropenia', 'Disease', (124, 135))	('febrile neutropenia', 'Disease', (116, 135))	('diarrhea', 'Phenotype', 'HP:0002014', (456, 464))	('pulmonary hemorrhage', 'Disease', 'MESH:D006470', (352, 372))	('anemia', 'Phenotype', 'HP:0001903', (334, 340))	('toxicities', 'Disease', 'MESH:D064420', (58, 68))	('toxicity', 'Disease', 'MESH:D064420', (690, 698))	('toxicity', 'Disease', 'MESH:D064420', (286, 294))	('hemorrhage', 'Disease', 'MESH:D006470', (362, 372))	('diarrhea', 'Phenotype', 'HP:0002014', (424, 432))	('anemia', 'Disease', (334, 340))	('toxicities', 'Disease', (58, 68))	('bleeding', 'Disease', (567, 575))	('neutropenia', 'Disease', 'MESH:D009503', (78, 89))	('hemorrhage', 'Disease', (587, 597))	('neutropenia', 'Phenotype', 'HP:0001875', (78, 89))	('pulmonary hemorrhage', 'Disease', (352, 372))	('bleeding', 'Disease', (598, 606))	('thrombocytopenia', 'Disease', 'MESH:D013921', (160, 176))	('diarrhea', 'Disease', (456, 464))	('amylase elevation', 'Phenotype', 'HP:0410288', (252, 269))	('grade', 'Disease', (577, 582))	('missing', 'NegReg', (612, 619))	('toxicity', 'Disease', (690, 698))	('bleeding', 'Disease', 'MESH:D006470', (373, 381))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (160, 176))	('partial thromboplastin time', 'Phenotype', 'HP:0003645', (523, 550))	('neutropenia', 'Phenotype', 'HP:0001875', (124, 135))	('toxicity', 'Disease', (286, 294))	('neutropenia', 'Disease', 'MESH:D009503', (124, 135))	('diarrhea', 'Disease', (424, 432))	('skin toxicity', 'Disease', 'MESH:D012871', (281, 294))	('refametinib', 'Chemical', 'MESH:C544830', (642, 653))	('grade >=3', 'Var', (479, 488))	('febrile neutropenia', 'Disease', 'MESH:D009503', (116, 135))	('international normalized ratio', 'MPA', (489, 519))	('diarrhea', 'Disease', 'MESH:D003967', (456, 464))	('hemorrhage', 'Disease', (362, 372))	('bleeding', 'Disease', (373, 381))	('partial', 'MPA', (523, 530))	('grade', 'Disease', (414, 419))	('skin reaction', 'Phenotype', 'HP:0011123', (310, 323))	('anemia', 'Disease', 'MESH:D000740', (334, 340))	('toxicity', 'Disease', 'MESH:D064420', (218, 226))	('diarrhea', 'Disease', 'MESH:D003967', (424, 432))	('pulmonary hemorrhage', 'Phenotype', 'HP:0040223', (352, 372))	('hemorrhage', 'Disease', 'MESH:D006470', (587, 597))	('grade', 'Disease', (271, 276))	('grade >', 'Disease', (342, 349))	('neutropenia', 'Disease', (78, 89))	('skin toxicity', 'Disease', (281, 294))	('bleeding', 'Disease', 'MESH:D006470', (567, 575))	('bleeding', 'Disease', 'MESH:D006470', (598, 606))	('thrombocytopenia', 'Disease', (160, 176))
56000	26644411	Two patients had KRAS-activating mutations (G12V and G13D), 1 had a BRAF-activating mutation (V600E), and 1 had a PIK3CA mutation.	('PIK3CA', 'Gene', '5290', (114, 120))	('G12V', 'Var', (44, 48))	('BRAF', 'Gene', '673', (68, 72))	('BRAF', 'Gene', (68, 72))	('G13D', 'Var', (53, 57))	('V600E', 'Var', (94, 99))	('G12V', 'Mutation', 'rs121913529', (44, 48))	('KRAS', 'Gene', (17, 21))	('PIK3CA', 'Gene', (114, 120))	('G13D', 'Mutation', 'rs112445441', (53, 57))	('patients', 'Species', '9606', (4, 12))	('KRAS', 'Gene', '3845', (17, 21))	('V600E', 'Mutation', 'rs113488022', (94, 99))
56001	26644411	Two further patients (1 with colorectal cancer and 1 with head and neck cancer) were wild-type for all mutations tested.	('patients', 'Species', '9606', (12, 20))	('mutations', 'Var', (103, 112))	('head and neck cancer', 'Phenotype', 'HP:0012288', (58, 78))	('colorectal cancer', 'Disease', 'MESH:D015179', (29, 46))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('colorectal cancer', 'Phenotype', 'HP:0003003', (29, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('colorectal cancer', 'Disease', (29, 46))	('head and neck cancer', 'Disease', 'MESH:D006258', (58, 78))
56003	26644411	Matched biopsies from the 3 patients with MAPK-activating mutations showed the largest reduction (average 80%); 1 patient with colorectal cancer (wild-type status) showed no reduction.	('mutations', 'Var', (58, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('MAPK-activating', 'Gene', (42, 57))	('MAPK', 'molecular_function', 'GO:0004707', ('42', '46'))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('colorectal cancer', 'Disease', (127, 144))	('patient', 'Species', '9606', (28, 35))	('patient', 'Species', '9606', (114, 121))	('colorectal cancer', 'Disease', 'MESH:D015179', (127, 144))	('patients', 'Species', '9606', (28, 36))	('reduction', 'NegReg', (87, 96))
56033	26644411	MAPK pathway-activating mutations were identified in 4 out of 6 patients and, although the sample size was small, those with activating mutations tended to show greater increases in the magnitude of pERK reduction.	('reduction', 'NegReg', (204, 213))	('ERK', 'Gene', '5594', (200, 203))	('patients', 'Species', '9606', (64, 72))	('MAPK', 'Gene', (0, 4))	('ERK', 'Gene', (200, 203))	('increases', 'PosReg', (169, 178))	('mutations', 'Var', (24, 33))
56048	26644411	Of note in this study, 4 patients had RAS mutations, of whom 3 had confirmed partial responses ranging from 128 to 382 days.	('RAS', 'Gene', (38, 41))	('patients', 'Species', '9606', (25, 33))	('mutations', 'Var', (42, 51))
56054	26644411	Further investigation into the safety and efficacy of refametinib plus sorafenib combination therapy is therefore warranted, and phase II studies of refametinib as monotherapy and in combination with sorafenib in HCC patients prospectively identified to have RAS-activating mutations are ongoing (NCT01915589 and NCT01915602, respectively).	('RAS-activating', 'Gene', (259, 273))	('sorafenib', 'Chemical', 'MESH:D000077157', (200, 209))	('refametinib', 'Chemical', 'MESH:C544830', (149, 160))	('NCT01915602', 'Var', (313, 324))	('sorafenib', 'Chemical', 'MESH:D000077157', (71, 80))	('HCC', 'Phenotype', 'HP:0001402', (213, 216))	('NCT01915589', 'Var', (297, 308))	('refametinib', 'Chemical', 'MESH:C544830', (54, 65))	('patients', 'Species', '9606', (217, 225))
56058	26644411	Refametinib plus sorafenib was associated with a reduction in ERK phosphorylation, tending to correlate with mutational status.	('reduction', 'NegReg', (49, 58))	('ERK', 'Gene', '5594', (62, 65))	('Refametinib', 'Chemical', 'MESH:C544830', (0, 11))	('phosphorylation', 'biological_process', 'GO:0016310', ('66', '81'))	('ERK', 'molecular_function', 'GO:0004707', ('62', '65'))	('Refametinib', 'Var', (0, 11))	('ERK', 'Gene', (62, 65))	('sorafenib', 'Chemical', 'MESH:D000077157', (17, 26))
56061	32184228	Prevalence of the BRAF p.v600e variant in patients with colorectal cancer from Mexico and its estimated frequency in Latin American and Caribbean populations This study aimed to investigate the frequency of the somatic BRAF p.V600E in patients with colorectal cancer (CRC) in Mexico and compare it with those estimated for Latin American and Caribbean populations.	('colorectal cancer', 'Disease', (249, 266))	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (249, 266))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('patients', 'Species', '9606', (235, 243))	('colorectal cancer', 'Disease', 'MESH:D015179', (249, 266))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', (56, 73))	('p.v600e', 'Var', (23, 30))	('BRAF', 'Gene', (219, 223))	('p.V600E', 'Mutation', 'rs113488022', (224, 231))	('BRAF', 'Gene', '673', (219, 223))	('BRAF', 'Gene', '673', (18, 22))	('CRC', 'Phenotype', 'HP:0003003', (268, 271))	('patients', 'Species', '9606', (42, 50))	('BRAF', 'Gene', (18, 22))	('p.V600E', 'Var', (224, 231))
56063	32184228	PCR-Sanger sequencing was used to identify the BRAF p.V600E variant.	('BRAF', 'Gene', (47, 51))	('p.V600E', 'Mutation', 'rs113488022', (52, 59))	('BRAF', 'Gene', '673', (47, 51))	('p.V600E', 'Var', (52, 59))
56064	32184228	In addition, a systematic literature search in PubMed/Medline database and Google of the 42 countries in Latin America and the Caribbean led to the collection of information on the BRAF p.V600E variant frequency of 17 population reports.	('BRAF', 'Gene', (181, 185))	('p.V600E', 'Mutation', 'rs113488022', (186, 193))	('BRAF', 'Gene', '673', (181, 185))	('p.V600E', 'Var', (186, 193))
56065	32184228	To compare the BRAF variant prevalence among populations, a statistical analysis was performed using GraphPad Prism V.6.0.	('BRAF', 'Gene', '673', (15, 19))	('variant', 'Var', (20, 27))	('BRAF', 'Gene', (15, 19))
56066	32184228	We found that 4% of patients with CRC were heterozygous for the p.V600E variant.	('CRC', 'Phenotype', 'HP:0003003', (34, 37))	('p.V600E', 'Mutation', 'rs113488022', (64, 71))	('p.V600E', 'Var', (64, 71))	('patients', 'Species', '9606', (20, 28))	('CRC', 'Disease', (34, 37))
56068	32184228	Our observational study provides the first evidence on the frequency of BRAF p.V600E in patients with CRC from Western Mexico, which is 4%, but increases to 7.8% for all of Latin America and the Caribbean.	('p.V600E', 'Mutation', 'rs113488022', (77, 84))	('CRC', 'Phenotype', 'HP:0003003', (102, 105))	('BRAF', 'Gene', (72, 76))	('patients', 'Species', '9606', (88, 96))	('p.V600E', 'Var', (77, 84))	('BRAF', 'Gene', '673', (72, 76))
56070	32184228	The BRAF p.V600E is an activating variant associated with several cancer types.	('cancer', 'Disease', (66, 72))	('p.V600E', 'Var', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('p.V600E', 'Mutation', 'rs113488022', (9, 16))
56072	32184228	The BRAF p.V600E variant frequency in patients with colorectal cancer is 4% for Western Mexican, and 7.8% for Latin American and Caribbean populations.	('p.V600E', 'Var', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('patients', 'Species', '9606', (38, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('colorectal cancer', 'Disease', (52, 69))	('p.V600E', 'Mutation', 'rs113488022', (9, 16))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))
56073	32184228	Variations in patient mean age and genetic characteristics in Latin American and Caribbean populations could underlie the significant differences in BRAF p.V600E variant frequency.	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('p.V600E', 'Mutation', 'rs113488022', (154, 161))	('p.V600E', 'Var', (154, 161))	('patient', 'Species', '9606', (14, 21))
56074	32184228	Determination of the BRAF p.V600E variant frequency in patients with colorectal cancer from Latin America and the Caribbean improves our understanding of the molecular characteristics of colorectal cancer, within this region, and provides an estimate of the need to increase molecular studies to support the treatment of the patient.	('colorectal cancer', 'Disease', (187, 204))	('patient', 'Species', '9606', (325, 332))	('p.V600E', 'Mutation', 'rs113488022', (26, 33))	('colorectal cancer', 'Phenotype', 'HP:0003003', (69, 86))	('colorectal cancer', 'Disease', 'MESH:D015179', (187, 204))	('p.V600E', 'Var', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('BRAF', 'Gene', '673', (21, 25))	('patients', 'Species', '9606', (55, 63))	('colorectal cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('BRAF', 'Gene', (21, 25))	('patient', 'Species', '9606', (55, 62))	('colorectal cancer', 'Phenotype', 'HP:0003003', (187, 204))	('improves', 'PosReg', (124, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (69, 86))
56079	32184228	Among the genetic changes encountered in CRC is the p.V600E pathogenic variant of the BRAF gene, which encodes a serine/threonine kinase involved in the EGFR-MAPK signaling pathway.	('CRC', 'Phenotype', 'HP:0003003', (41, 44))	('serine', 'Chemical', 'MESH:D012694', (113, 119))	('p.V600E', 'Var', (52, 59))	('BRAF', 'Gene', (86, 90))	('EGFR', 'Gene', '1956', (153, 157))	('signaling pathway', 'biological_process', 'GO:0007165', ('163', '180'))	('EGFR', 'molecular_function', 'GO:0005006', ('153', '157'))	('EGFR', 'Gene', (153, 157))	('MAPK', 'molecular_function', 'GO:0004707', ('158', '162'))	('p.V600E', 'Mutation', 'rs113488022', (52, 59))	('BRAF', 'Gene', '673', (86, 90))	('EGFR-MAPK signaling', 'biological_process', 'GO:0038029', ('153', '172'))
56081	32184228	The BRAF p.V600E variant (c.1799T>A, rs113488022, chr7:140 753 336 position in GRCh38.p12) causes a substitution of valine with glutamic acid at codon 600 (GTG GAG).	('causes', 'Reg', (91, 97))	('p.V600E', 'Var', (9, 16))	('p12', 'Gene', (86, 89))	('p.V600E', 'Mutation', 'rs113488022', (9, 16))	('c.1799T>A', 'Mutation', 'rs113488022', (26, 35))	('rs113488022', 'Mutation', 'rs113488022', (37, 48))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('substitution', 'Var', (100, 112))	('p12', 'Gene', '56655', (86, 89))	('GTG', 'Chemical', '-', (156, 159))	('valine', 'Protein', (116, 122))	('valine with glutamic acid at codon 600', 'Mutation', 'rs113488022', (116, 154))	('c.1799T>A', 'Var', (26, 35))
56082	32184228	This variant represents approximately 90% of all BRAF variants detected in CRC, with a prevalence of 2.5%-20% in this disease associated with a reduced survival of patients with metastases.	('metastases', 'Disease', 'MESH:D009362', (178, 188))	('reduced', 'NegReg', (144, 151))	('survival', 'MPA', (152, 160))	('patients', 'Species', '9606', (164, 172))	('metastases', 'Disease', (178, 188))	('BRAF', 'Gene', '673', (49, 53))	('CRC', 'Phenotype', 'HP:0003003', (75, 78))	('variants', 'Var', (54, 62))	('BRAF', 'Gene', (49, 53))
56085	32184228	However, it has been shown that pathogenic variants of the BRAF gene interfere with the treatment response; therefore, analyzing the occurrence of this variant in primary CRC tumors will benefit clinical treatment.	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('treatment response', 'CPA', (88, 106))	('CRC tumors', 'Disease', (171, 181))	('CRC tumors', 'Disease', 'MESH:D015179', (171, 181))	('interfere', 'NegReg', (69, 78))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('variants', 'Var', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('CRC', 'Phenotype', 'HP:0003003', (171, 174))
56086	32184228	Our goal in this study was to determine the prevalence of BRAF p.V600E variant in patients with primary CRC from Western Mexico and compare the rate of occurrence with that in Latin American and Caribbean populations estimated based on a systematic review of a collection of studies.	('patients', 'Species', '9606', (82, 90))	('CRC', 'Phenotype', 'HP:0003003', (104, 107))	('p.V600E', 'Mutation', 'rs113488022', (63, 70))	('BRAF', 'Gene', '673', (58, 62))	('BRAF', 'Gene', (58, 62))	('p.V600E', 'Var', (63, 70))
56094	32184228	Among the selected publications, six reports had been previously identified on PubMed, 12 were articles, four were published abstracts with no complete population data but reported the BRAF p.V600E frequency, and one study was a postgraduate dissertation.	('p.V600E', 'Var', (190, 197))	('BRAF', 'Gene', (185, 189))	('BRAF', 'Gene', '673', (185, 189))	('p.V600E', 'Mutation', 'rs113488022', (190, 197))
56095	32184228	From each study, we collected information on the BRAF p.V600E variant frequency, sex, mean and range of age of the study population, as well as pathological data, disease stage and tumor location.	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('p.V600E', 'Var', (54, 61))	('BRAF', 'Gene', '673', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('BRAF', 'Gene', (49, 53))	('p.V600E', 'Mutation', 'rs113488022', (54, 61))
56096	32184228	The BRAF p.V600E variant frequency was estimated by quantification of the instances of its detection in Western Mexicans.	('p.V600E', 'Var', (9, 16))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))	('p.V600E', 'Mutation', 'rs113488022', (9, 16))
56097	32184228	A statistical analysis was performed using GraphPad Prism V.6.0 to compare the BRAF variant prevalence between West Mexican to Latin American and the Caribbean populations.	('variant', 'Var', (84, 91))	('BRAF', 'Gene', (79, 83))	('BRAF', 'Gene', '673', (79, 83))
56099	32184228	Four subjects were found to be heterozygous for the BRAF p.V600E variant (figure 1): the neoplasms were always located in the right colon of patients aged 62-76 years, three of which were female.	('neoplasms', 'Disease', (89, 98))	('p.V600E', 'Mutation', 'rs113488022', (57, 64))	('p.V600E', 'Var', (57, 64))	('neoplasms', 'Phenotype', 'HP:0002664', (89, 98))	('BRAF', 'Gene', '673', (52, 56))	('BRAF', 'Gene', (52, 56))	('patients', 'Species', '9606', (141, 149))	('neoplasms', 'Disease', 'MESH:D009369', (89, 98))
56102	32184228	Of the 42 populations selected, reports on BRAF p.V600E prevalence were only found for Argentina, Brazil, Chile, Mexico, Paraguay, Peru and Puerto Rico for a total of 17 publications.	('p.V600E', 'Mutation', 'rs113488022', (48, 55))	('p.V600E', 'Var', (48, 55))	('BRAF', 'Gene', (43, 47))	('BRAF', 'Gene', '673', (43, 47))
56103	32184228	This pathogenic variant occurred in 0%-15% of the populations and, taken together, these data indicate that the BRAF p.V600E frequency for Latin America and the Caribbean equals 7.8% (117 positive findings out of 1492 analyzed patients).	('p.V600E', 'Var', (117, 124))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('p.V600E', 'Mutation', 'rs113488022', (117, 124))	('patients', 'Species', '9606', (227, 235))
56106	32184228	The presence of the most common pathogenic variant of the BRAF gene, p.V600E, is associated with reduced effectiveness of CRC monoclonal antibody treatment that targets the EGFR-MAPK pathway.	('CRC', 'Phenotype', 'HP:0003003', (122, 125))	('effectiveness', 'MPA', (105, 118))	('pathogenic', 'Reg', (32, 42))	('reduced', 'NegReg', (97, 104))	('EGFR', 'Gene', '1956', (173, 177))	('p.V600E', 'Mutation', 'rs113488022', (69, 76))	('BRAF', 'Gene', '673', (58, 62))	('EGFR', 'Gene', (173, 177))	('BRAF', 'Gene', (58, 62))	('p.V600E', 'Var', (69, 76))
56109	32184228	The four patients bearing the p.V600E variant were three women and a man, all older than 60 years, with tumors located in the proximal colon, three of which were at stages III-IV.	('patients', 'Species', '9606', (9, 17))	('p.V600E', 'Mutation', 'rs113488022', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('p.V600E', 'Var', (30, 37))	('women', 'Species', '9606', (57, 62))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))
56110	32184228	Although no statistical approach was possible due to the low number of patients positive for the pathogenic variant, the characteristics of these subjects are in agreement with the clinicopathological features associated with BRAF p.V600E described in three meta-analyses.	('p.V600E', 'Mutation', 'rs113488022', (231, 238))	('patients', 'Species', '9606', (71, 79))	('BRAF', 'Gene', '673', (226, 230))	('p.V600E', 'Var', (231, 238))	('BRAF', 'Gene', (226, 230))
56114	32184228	Given the overlap period in the selected studies, several reports used in these meta-analyses are shared, leading to similar results regarding the increased frequency of BRAF p.V600E in female patients, patients older than 60 years, the proximal colon tumor location, the TNM III-IV stage, poor differentiation of the tumor and poor outcome of CRC.	('patients', 'Species', '9606', (193, 201))	('BRAF', 'Gene', (170, 174))	('p.V600E', 'Var', (175, 182))	('TNM', 'Gene', '10178', (272, 275))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('CRC', 'Phenotype', 'HP:0003003', (344, 347))	('p.V600E', 'Mutation', 'rs113488022', (175, 182))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('colon tumor', 'Phenotype', 'HP:0100273', (246, 257))	('patients', 'Species', '9606', (203, 211))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('TNM', 'Gene', (272, 275))	('colon tumor', 'Disease', 'MESH:D003110', (246, 257))	('tumor', 'Disease', (318, 323))	('colon tumor', 'Disease', (246, 257))	('tumor', 'Disease', (252, 257))	('BRAF', 'Gene', '673', (170, 174))
56115	32184228	A comparison between the reported pathogenic variant frequencies of 10.8%, 11.1% and 11.38% showed no statistical differences, assuming a p=0.18, between the three meta-analyses, and the average estimate of the general frequency of BRAF p.V600E in patients with CRC is 11%.	('BRAF', 'Gene', '673', (232, 236))	('p.V600E', 'Mutation', 'rs113488022', (237, 244))	('CRC', 'Phenotype', 'HP:0003003', (262, 265))	('BRAF', 'Gene', (232, 236))	('p.V600E', 'Var', (237, 244))	('patients', 'Species', '9606', (248, 256))
56116	32184228	Since the three meta-analyses did not include studies on Latin American patients with CRC with the BRAF p.V600E, we conducted a search for publications with data from Latin American and Caribbean populations to compare the variant frequency.	('CRC', 'Phenotype', 'HP:0003003', (86, 89))	('BRAF', 'Gene', '673', (99, 103))	('BRAF', 'Gene', (99, 103))	('p.V600E', 'Mutation', 'rs113488022', (104, 111))	('p.V600E', 'Var', (104, 111))	('patients', 'Species', '9606', (72, 80))
56118	32184228	By comparing the selected populations, we only identified a significant difference in the frequency of BRAF p.V600E with one of the four Chilean populations included, the study of Wielandt et al,  with statistical significance (p=0.02).	('BRAF', 'Gene', '673', (103, 107))	('p.V600E', 'Mutation', 'rs113488022', (108, 115))	('BRAF', 'Gene', (103, 107))	('p.V600E', 'Var', (108, 115))
56121	32184228	Colomba et al,  Lopez-Rios et al  and Jurkowska et al  suggested that differences in methodologies could alter p.V600E frequencies, principally for patients with melanoma, but it was also for patients with CRC, as described by Loes et al  and Roma et al.	('patients', 'Species', '9606', (148, 156))	('CRC', 'Phenotype', 'HP:0003003', (206, 209))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('p.V600E', 'Var', (111, 118))	('alter', 'Reg', (105, 110))	('melanoma', 'Disease', (162, 170))	('patients', 'Species', '9606', (192, 200))	('Jurkowska', 'CellLine', 'None', (38, 47))	('CRC', 'Disease', (206, 209))	('p.V600E', 'Mutation', 'rs113488022', (111, 118))
56122	32184228	Yoon et al  studied the variant frequency in patients with stage III colon cancer, showing that BRAF p.V600E was detected half as often in black (6.4%) and Asian (5.6%) patients as compared with white patients (13.9%).	('patients', 'Species', '9606', (201, 209))	('patients', 'Species', '9606', (169, 177))	('p.V600E', 'Var', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('patients', 'Species', '9606', (45, 53))	('BRAF', 'Gene', (96, 100))	('stage III colon cancer', 'Disease', (59, 81))	('stage III colon cancer', 'Disease', 'MESH:D015179', (59, 81))	('BRAF', 'Gene', '673', (96, 100))	('colon cancer', 'Phenotype', 'HP:0003003', (69, 81))	('p.V600E', 'Mutation', 'rs113488022', (101, 108))
56123	32184228	Heath et al  reported similar results for patients with CRC with 1.7% BRAF p.V600E occurrence in African-American patients compared with 8.5% positive cases of Caucasians.	('p.V600E', 'Mutation', 'rs113488022', (75, 82))	('p.V600E', 'Var', (75, 82))	('CRC', 'Phenotype', 'HP:0003003', (56, 59))	('BRAF', 'Gene', '673', (70, 74))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (42, 50))	('BRAF', 'Gene', (70, 74))
56124	32184228	The genetic descent of patients with CRC from Western Mexico and Central Chile might be a crucial factor in producing the differences in frequency of BRAF p.V600E, which is further supported by the statistical discrepancy in the comparison of the whole variant frequency of 10.7%, considering the conclusive results for 28 of the 261 Central Chilean patients with CRC analyzed, in contrast to the 4% frequency estimated for Western Mexican patients with CRC (p=0.04).	('patients', 'Species', '9606', (23, 31))	('CRC', 'Phenotype', 'HP:0003003', (364, 367))	('CRC', 'Phenotype', 'HP:0003003', (454, 457))	('BRAF', 'Gene', (150, 154))	('patients', 'Species', '9606', (350, 358))	('BRAF', 'Gene', '673', (150, 154))	('patients', 'Species', '9606', (440, 448))	('p.V600E', 'Mutation', 'rs113488022', (155, 162))	('CRC', 'Phenotype', 'HP:0003003', (37, 40))	('p.V600E', 'Var', (155, 162))
56126	32184228	Altogether, a total of 1738 patients with CRC were included in the Latin American and Caribbean studies, but only 1492 of them were analyzed for the BRAF p.V600E, with 117 (7.8%) positive results.	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('p.V600E', 'Mutation', 'rs113488022', (154, 161))	('CRC', 'Phenotype', 'HP:0003003', (42, 45))	('p.V600E', 'Var', (154, 161))	('patients', 'Species', '9606', (28, 36))
56128	32184228	Nevertheless, investigations on the molecular profile of CRC tumors, exploring the prevalence of BRAF p.V600E and other variants, on Latin American and Caribbean patients are limited due to several factors, including economical and health infrastructure, that discourage research efforts.	('CRC', 'Phenotype', 'HP:0003003', (57, 60))	('patients', 'Species', '9606', (162, 170))	('p.V600E', 'Mutation', 'rs113488022', (102, 109))	('CRC tumors', 'Disease', (57, 67))	('CRC tumors', 'Disease', 'MESH:D015179', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('p.V600E', 'Var', (102, 109))	('BRAF', 'Gene', (97, 101))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('BRAF', 'Gene', '673', (97, 101))
56129	32184228	The reduced number of patients analyzed for BRAF p.V600E presence was also identified as a limitation of the estimate produced in this study, although most of the selected Latin American and Caribbean populations studies showed statistical similarity in variant frequency, regardless of the number of cases per study.	('BRAF', 'Gene', '673', (44, 48))	('BRAF', 'Gene', (44, 48))	('patients', 'Species', '9606', (22, 30))	('p.V600E', 'Mutation', 'rs113488022', (49, 56))	('p.V600E', 'Var', (49, 56))
56130	32184228	In conclusion, we found a 4% BRAF p.V600E prevalence among 101 CRC Western Mexican patients.	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('CRC', 'Phenotype', 'HP:0003003', (63, 66))	('p.V600E', 'Mutation', 'rs113488022', (34, 41))	('patients', 'Species', '9606', (83, 91))	('p.V600E', 'Var', (34, 41))
56132	32184228	As a whole, the BRAF p.V600E frequency in Latin America and the Caribbean was estimated to be 7.8%.	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('p.V600E', 'Mutation', 'rs113488022', (21, 28))	('p.V600E', 'Var', (21, 28))
56134	31356589	The impact of DNA methylation on the cancer proteome Aberrant DNA methylation disrupts normal gene expression in cancer and broadly contributes to oncogenesis.	('Aberrant', 'Var', (53, 61))	('disrupts', 'NegReg', (78, 86))	('DNA', 'Gene', (62, 65))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('oncogenesis', 'biological_process', 'GO:0007048', ('147', '158'))	('gene expression', 'biological_process', 'GO:0010467', ('94', '109'))	('cancer', 'Disease', (37, 43))	('DNA methylation', 'biological_process', 'GO:0006306', ('14', '29'))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('cancer', 'Disease', (113, 119))	('DNA methylation', 'biological_process', 'GO:0006306', ('62', '77'))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('contributes', 'Reg', (132, 143))	('DNA', 'cellular_component', 'GO:0005574', ('14', '17'))	('normal gene expression', 'MPA', (87, 109))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('oncogenesis', 'Disease', (147, 158))
56145	31356589	Toward this end a multi-institutional consortium, The Cancer Genome Atlas (TCGA), has extensively characterized numerous cancer sites producing genome wide data for mutations, copy number alterations (CNA), RNA expression, microRNA expression, and DNA methylation.	('Cancer Genome Atlas', 'Disease', (54, 73))	('RNA expression', 'MPA', (207, 221))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (54, 73))	('numerous cancer', 'Disease', 'MESH:D009369', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('copy number alterations', 'Var', (176, 199))	('DNA methylation', 'biological_process', 'GO:0006306', ('248', '263'))	('mutations', 'Var', (165, 174))	('DNA', 'cellular_component', 'GO:0005574', ('248', '251'))	('microRNA expression', 'MPA', (223, 242))	('numerous cancer', 'Disease', (112, 127))	('RNA', 'cellular_component', 'GO:0005562', ('207', '210'))
56151	31356589	Furthermore, DNA methylation has been numerously cited as a potentially causative event in cancer.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('DNA methylation', 'Var', (13, 28))
56152	31356589	Among potential DNA methylation drivers, silencing of tumor suppressors through promoter CpG island hypermethylation is best understood and linked to corresponding gene silencing.	('tumor', 'Disease', (54, 59))	('hypermethylation', 'Var', (100, 116))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))
56162	31356589	For each cohort both models identify genes that are 1) differentially methylated when compared to normal adjacent tissue and 2) functionally predictive of downstream effects at the level of RNA expression in the case of MethylMix-GE or protein abundance in the case of MethylMix-PA (Fig 2).	('are 1', 'Gene', '6293', (48, 53))	('RNA', 'Gene', (190, 193))	('MethylMix', 'Chemical', '-', (220, 229))	('effects', 'Reg', (166, 173))	('protein abundance', 'MPA', (236, 253))	('RNA', 'cellular_component', 'GO:0005562', ('190', '193'))	('MethylMix-GE', 'Var', (220, 232))	('MethylMix', 'Chemical', '-', (269, 278))	('protein', 'cellular_component', 'GO:0003675', ('236', '243'))	('are 1', 'Gene', (48, 53))	('MethylMix-PA', 'Chemical', '-', (269, 281))	('methylated', 'MPA', (70, 80))	('MethylMix-PA', 'Var', (269, 281))
56166	31356589	Therefore, MethylMix-PA better enriches for methylation-states that more likely execute functional roles in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('MethylMix-PA', 'Chemical', '-', (11, 23))	('methylation-states', 'Var', (44, 62))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
56168	31356589	In breast cancer we discovered 19 novel differentially methylated genes of diverse biological functions.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('differentially', 'Var', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))
56169	31356589	MethylMix-PA identified hyper-methylation of FSTL1, an autoantigen that promotes immune response.	('MethylMix-PA', 'Chemical', '-', (0, 12))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('immune response', 'biological_process', 'GO:0006955', ('81', '96'))	('FSTL1', 'Gene', (45, 50))	('FSTL1', 'Gene', '11167', (45, 50))	('promotes', 'PosReg', (72, 80))	('hyper-methylation', 'Var', (24, 41))
56172	31356589	Next, MethylMix-PA identified hypo-methylation of CEACAM5 (also known as CEA), a cell surface glycoprotein that is used as a clinical biomarker for gastrointestinal cancers and may promote tumor development through its role as a cell adhesion molecule.	('CEACAM5', 'Gene', (50, 57))	('cell adhesion', 'biological_process', 'GO:0007155', ('229', '242'))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))	('CEACAM5', 'Gene', '1048', (50, 57))	('cell surface', 'cellular_component', 'GO:0009986', ('81', '93'))	('MethylMix-PA', 'Chemical', '-', (6, 18))	('CEA', 'Gene', (50, 53))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('229', '251'))	('hypo-methylation', 'Var', (30, 46))	('CEA', 'Gene', (73, 76))	('promote', 'PosReg', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (148, 172))	('tumor', 'Disease', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('CEA', 'Gene', '1048', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('CEA', 'Gene', '1048', (73, 76))	('gastrointestinal cancers', 'Disease', (148, 172))
56174	31356589	Next, MethylMix-PA also identified hyper-methylation of FOXO1, a transcritionf factor where low expression has been associated with cancer.	('hyper-methylation', 'Var', (35, 52))	('cancer', 'Disease', (132, 138))	('MethylMix-PA', 'Chemical', '-', (6, 18))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('FOXO1', 'Gene', (56, 61))	('FOXO1', 'Gene', '2308', (56, 61))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('associated', 'Reg', (116, 126))
56176	31356589	We found that MethylMix-PA identifies a functional effect of UTR hypo-methylation of the PTPRC gene.	('methylation', 'biological_process', 'GO:0032259', ('70', '81'))	('PTPRC', 'Gene', '5788', (89, 94))	('hypo-methylation', 'Var', (65, 81))	('MethylMix-PA', 'Chemical', '-', (14, 26))	('PTPRC', 'Gene', (89, 94))
56181	31356589	Of note MethylMix-PA filtered out functional effects of a UTR hypo-methylation in S100A9 previously detected by MethylMix-GE.	('S100A9', 'Gene', (82, 88))	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('hypo-methylation', 'Var', (62, 78))	('MethylMix', 'Chemical', '-', (112, 121))	('MethylMix', 'Chemical', '-', (8, 17))	('MethylMix-PA', 'Chemical', '-', (8, 20))	('S100A9', 'Gene', '6280', (82, 88))
56182	31356589	Next, MethylMix-PA identified hyper-methylation across the promoter region of LTF, a likely tumor suppressor which is produced by neutrophils to regulate growth and differentiation.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('92', '108'))	('LTF', 'Gene', (78, 81))	('LTF', 'Gene', '4057', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('MethylMix-PA', 'Chemical', '-', (6, 18))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('hyper-methylation', 'Var', (30, 47))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('tumor', 'Disease', (92, 97))	('tumor suppressor', 'biological_process', 'GO:0051726', ('92', '108'))
56184	31356589	Additionally, gene expression of LTF has previously been shown to correlate with tumor size and survival in breast cancer.	('LTF', 'Gene', '4057', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('correlate', 'Reg', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('tumor', 'Disease', (81, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('breast cancer', 'Disease', (108, 121))	('LTF', 'Gene', (33, 36))	('gene expression', 'Var', (14, 29))
56185	31356589	MethylMix-PA picks up hypo-methylation states in 18 unique genes in ovarian cancer related to processes of invasion and proliferation.	('ovarian cancer', 'Phenotype', 'HP:0100615', (68, 82))	('hypo-methylation states', 'Var', (22, 45))	('ovarian cancer', 'Disease', 'MESH:D010051', (68, 82))	('MethylMix-PA', 'Chemical', '-', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('ovarian cancer', 'Disease', (68, 82))
56186	31356589	MethylMix-PA uniquely identifies hypo-methylation in the promoter region of EVL a key regulator of the actin cytoskeleton, associated with invasion and metastasis.	('invasion', 'CPA', (139, 147))	('associated', 'Reg', (123, 133))	('metastasis', 'CPA', (152, 162))	('MethylMix-PA', 'Chemical', '-', (0, 12))	('EVL', 'Gene', (76, 79))	('hypo-methylation', 'Var', (33, 49))	('EVL', 'Gene', '51466', (76, 79))
56187	31356589	Overexpression of EVL is also indicative of advanced stage in breast cancer and has been implicated in malignancies due to inappropriate recombination.	('EVL', 'Gene', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('malignancies', 'Disease', 'MESH:D009369', (103, 115))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('EVL', 'Gene', '51466', (18, 21))	('Overexpression', 'Var', (0, 14))	('malignancies', 'Disease', (103, 115))
56188	31356589	Next, MethylMix-PA identified hypo-methylation of CTSZ, also known as cathepsin Z, a a lysosomal cysteine proteinase that has been shown to be involved in many primary tumors.	('hypo-methylation', 'Var', (30, 46))	('CTSZ', 'Gene', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('cathepsin Z', 'Gene', (70, 81))	('involved', 'Reg', (143, 151))	('MethylMix-PA', 'Chemical', '-', (6, 18))	('CTSZ', 'Gene', '1522', (50, 54))	('cathepsin Z', 'Gene', '1522', (70, 81))	('primary tumors', 'Disease', (160, 174))	('primary tumors', 'Disease', 'MESH:D009369', (160, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
56190	31356589	We also found hypermethylation of GSTM2, a gene that is normally high expressed in ovary, but has been shown to be a hypermethylated in lung cancers and colorectal cancers, suggesting a tumor suppressor role for GSTM2 across tissues.	('GSTM2', 'Gene', (34, 39))	('tumor', 'Disease', (186, 191))	('colorectal cancers', 'Disease', 'MESH:D015179', (153, 171))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('lung cancers', 'Disease', 'MESH:D008175', (136, 148))	('GSTM2', 'Gene', '2946', (34, 39))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('lung cancers', 'Disease', (136, 148))	('hypermethylation', 'Var', (14, 30))	('GSTM2', 'Gene', (212, 217))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('186', '202'))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('lung cancers', 'Phenotype', 'HP:0100526', (136, 148))	('colorectal cancer', 'Phenotype', 'HP:0003003', (153, 170))	('colorectal cancers', 'Disease', (153, 171))	('tumor suppressor', 'biological_process', 'GO:0051726', ('186', '202'))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('ovary', 'Disease', (83, 88))	('GSTM2', 'Gene', '2946', (212, 217))	('ovary', 'Disease', 'MESH:D010051', (83, 88))
56191	31356589	Lastly, MethylMix-PA also identifies hypo-methylation in the mitochondrial genes SPG7, speculatively linked to cancer through metabolic function.	('SPG7', 'Gene', '6687', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('hypo-methylation', 'Var', (37, 53))	('SPG7', 'Gene', (81, 85))	('methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('MethylMix-PA', 'Chemical', '-', (8, 20))
56211	31356589	The CIMP subtype has known association with MLH1 silencing through hyper-methylation, which is reflected in our MethylMix-PA subtypes where we find cluster-1 to include the majority of samples with non-silenced MLH1.	('silencing', 'NegReg', (49, 58))	('MLH1', 'Gene', (44, 48))	('MLH1', 'Gene', (211, 215))	('MethylMix-PA', 'Chemical', '-', (112, 124))	('MLH1', 'Gene', '4292', (44, 48))	('methylation', 'biological_process', 'GO:0032259', ('73', '84'))	('hyper-methylation', 'Var', (67, 84))	('CIMP', 'Chemical', '-', (4, 8))	('MLH1', 'Gene', '4292', (211, 215))
56217	31356589	Epigenetic aberrations contribute to oncogenesis, where DNA hypermethylation inactivates tumor suppressor genes, while hypomethylation is known to promote genomic instability and activate oncogenes.	('hypomethylation', 'Var', (119, 134))	('activate', 'PosReg', (179, 187))	('genomic', 'MPA', (155, 162))	('promote', 'PosReg', (147, 154))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('inactivates', 'NegReg', (77, 88))	('hypermethylation', 'Var', (60, 76))	('oncogenesis', 'Disease', (37, 48))	('DNA hypermethylation', 'Var', (56, 76))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('oncogenes', 'CPA', (188, 197))
56218	31356589	Therefore, DNA methylation has potential to inform patient treatment and improve patient outcomes through new diagnostics and therapeutics.	('methylation', 'Var', (15, 26))	('patient', 'Species', '9606', (81, 88))	('DNA methylation', 'biological_process', 'GO:0006306', ('11', '26'))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('inform', 'Reg', (44, 50))	('patient', 'Species', '9606', (51, 58))	('improve', 'PosReg', (73, 80))
56226	31356589	Otherwise put, many abnormally methylated genes are likely only passengers and do not functionally contribute to cancer development.	('contribute', 'Reg', (99, 109))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('abnormally methylated genes', 'Var', (20, 47))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
56227	31356589	Identification of a reduced set of genes in our study has pragmatic benefits for cancer research, where narrowing nominations to fewer high-quality candidates increases the likelihood of finding true targets; strongest candidates include genes identified by both models that show negative correlation between DNA methylation and both gene expression and protein abundance, and therefore have clear biological interpretations amenable to validation in the laboratory.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('correlation', 'Interaction', (289, 300))	('methylation', 'Var', (313, 324))	('gene expression', 'MPA', (334, 349))	('negative', 'NegReg', (280, 288))	('protein abundance', 'MPA', (354, 371))
56240	31356589	More broadly our study supports using proteomic data to better understand how epigenetic deregulation promotes cancer.	('epigenetic deregulation', 'Var', (78, 101))	('promotes', 'PosReg', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
56336	31263250	FTIR spectroscopy for IO-MMMs clearly showed the distinctive characteristic absorption stretching bands of iron oxide Fe-O (~500-600 cm-1) and O-H (~3200-3600 cm-1), with the disappearance of peaks in the region 960-1100 cm-1 correspondingto Si-O (1100 cm-1) and Si-O-Fe (960 cm-1) stretching vibrations (Fig.	('IO-MMMs', 'Chemical', '-', (22, 29))	('Fe', 'Chemical', 'MESH:D007501', (268, 270))	('Si-O-Fe', 'Chemical', '-', (263, 270))	('Fe', 'Chemical', 'MESH:D007501', (118, 120))	('Si', 'Chemical', 'MESH:D012825', (263, 265))	('Si', 'Chemical', 'MESH:D012825', (242, 244))	('iron oxide', 'Chemical', 'MESH:C000499', (107, 117))	('Si-O-Fe', 'Var', (263, 270))	('~500-600', 'Var', (124, 132))
56389	31263250	Representative FTIR spectra clearly showed that for instance Dox@IO-MMMs has the same characteristic absorption bands as the free Dox with distinctive peaks at ~3400 cm-1and ~2900 cm-1 due to O-H/N-H stretching and C-H stretching vibrations of the incorporated Dox, respectively (Supplemental Fig.	('Dox@IO-MMMs', 'Var', (61, 72))	('C-H stretching', 'MPA', (215, 229))	('IO-MMMs', 'Chemical', '-', (65, 72))	('Dox', 'Chemical', 'MESH:D004317', (130, 133))	('O-H/N-H stretching', 'MPA', (192, 210))	('Dox', 'Chemical', 'MESH:D004317', (61, 64))	('Dox', 'Chemical', 'MESH:D004317', (261, 264))
56393	31263250	Average zeta potential values were found to be xi = -24.9 +- 1.55 mV for Dox@IO-MMMs, xi = -26 +- 1.01 mV for Daun@IO-MMMs, and xi = -7.57 +- 1.65 mV for Daun/Tam@IO-MMMs (Supplemental Fig.	('IO-MMMs', 'Chemical', '-', (77, 84))	('Dox', 'Chemical', 'MESH:D004317', (73, 76))	('Daun@', 'Var', (110, 115))	('Daun', 'Chemical', 'MESH:D003630', (154, 158))	('IO-MMMs', 'Chemical', '-', (163, 170))	('Tam', 'Chemical', 'MESH:D013629', (159, 162))	('Daun', 'Chemical', 'MESH:D003630', (110, 114))	('IO-MMMs', 'Chemical', '-', (115, 122))	('zeta potential', 'MPA', (8, 22))
56402	31263250	Meanwhile, hydrogen bonding between the hydroxyl groups of IO-MMM and the corresponding groups of Dox could be disrupted by adjusting proton amounts at different pH values.	('hydroxyl', 'Chemical', 'MESH:D017665', (40, 48))	('hydrogen', 'Interaction', (11, 19))	('IO-MMM', 'Var', (59, 65))	('IO-MMM', 'Chemical', '-', (59, 65))	('hydrogen', 'Chemical', 'MESH:D006859', (11, 19))	('Dox', 'Chemical', 'MESH:D004317', (98, 101))	('disrupted', 'NegReg', (111, 120))
56414	31263250	It is anticipated that upon internalization, IO-MMMs release both Daun and Tam inside the cells, and, hence, enhance the cytotoxic effect through exhibiting synergistic anti-proliferative activities on the different cancerous cell lines.	('release', 'MPA', (53, 60))	('Tam', 'Chemical', 'MESH:D013629', (75, 78))	('Tam', 'MPA', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cytotoxic effect', 'CPA', (121, 137))	('IO-MMMs', 'Chemical', '-', (45, 52))	('cancerous', 'Disease', (216, 225))	('IO-MMMs', 'Var', (45, 52))	('Daun', 'Chemical', 'MESH:D003630', (66, 70))	('anti-proliferative activities', 'CPA', (169, 198))	('Daun', 'MPA', (66, 70))	('enhance', 'PosReg', (109, 116))	('cancerous', 'Disease', 'MESH:D009369', (216, 225))
56422	31263250	In Daun/Tam@IO-MMMs-treated cancerous cells, confocal images confirmed that Daun delivered by Daun/Tam@IO-MMMs is entering the cells gradually as time elapses causing apoptotic cell death after 24 hrs (Fig.	('Daun', 'Chemical', 'MESH:D003630', (76, 80))	('Daun', 'Chemical', 'MESH:D003630', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancerous', 'Disease', 'MESH:D009369', (28, 37))	('causing', 'Reg', (159, 166))	('apoptotic cell death', 'CPA', (167, 187))	('Tam', 'Chemical', 'MESH:D013629', (99, 102))	('IO-MMMs', 'Chemical', '-', (12, 19))	('IO-MMMs', 'Chemical', '-', (103, 110))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('167', '187'))	('cancerous', 'Disease', (28, 37))	('Daun', 'Chemical', 'MESH:D003630', (3, 7))	('Daun/Tam@IO-MMMs', 'Var', (94, 110))	('Tam', 'Chemical', 'MESH:D013629', (8, 11))
56446	31263250	In order to investigate the penetration of Daun/Tam@IO-MMM formulation into tumor tissues, we treated primary breast tumor surgery sections derived directly from primary lesions with either Daun/Tam@IO-MMMs or free Daun/Tam at equivalent drug concentrations.	('Daun', 'Chemical', 'MESH:D003630', (215, 219))	('tumor', 'Disease', (76, 81))	('IO-MMMs', 'Chemical', '-', (199, 206))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('breast tumor', 'Disease', 'MESH:D001943', (110, 122))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('Daun/Tam', 'Var', (190, 198))	('Daun', 'Chemical', 'MESH:D003630', (190, 194))	('IO-MMM', 'Chemical', '-', (52, 58))	('breast tumor', 'Phenotype', 'HP:0100013', (110, 122))	('Tam', 'Chemical', 'MESH:D013629', (48, 51))	('breast tumor', 'Disease', (110, 122))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('Tam', 'Chemical', 'MESH:D013629', (220, 223))	('tumor', 'Disease', (117, 122))	('Daun', 'Chemical', 'MESH:D003630', (43, 47))	('IO-MMM', 'Chemical', '-', (199, 205))	('Tam', 'Chemical', 'MESH:D013629', (195, 198))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
56465	31263250	Even with the naked eye, the shrinkage of Daun/Tam@IO-MMMs-treated tumor tissue compared to free drug-treated tissue was obvious, confirming the potential of IO-MMMs as effective drug delivery vehicle penetrating inside the tumor via the EPR effect, and significantly improving the recognized limited tumor penetration of free drugs.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('IO-MMMs', 'Chemical', '-', (158, 165))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('IO-MMMs', 'Var', (158, 165))	('Tam', 'Chemical', 'MESH:D013629', (47, 50))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', (301, 306))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('IO-MMMs', 'Chemical', '-', (51, 58))	('tumor', 'Disease', (67, 72))	('Daun', 'Chemical', 'MESH:D003630', (42, 46))	('improving', 'PosReg', (268, 277))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
56550	30555542	Results: We found that among the examined 20 piRNAs, only piRNA-54265 was overexpressed in CRC compared with non-tumor tissues and higher levels in tumor or in serum were significantly associated with poor survival in patients.	('poor', 'NegReg', (201, 205))	('tumor', 'Disease', (113, 118))	('non-tumor', 'Disease', 'MESH:D009369', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('patients', 'Species', '9606', (218, 226))	('CRC', 'Disease', (91, 94))	('tumor', 'Disease', (148, 153))	('associated with', 'Reg', (185, 200))	('piRNA-54265', 'Var', (58, 69))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('non-tumor', 'Disease', (109, 118))	('overexpressed', 'PosReg', (74, 87))	('CRC', 'Phenotype', 'HP:0003003', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('higher', 'PosReg', (131, 137))
56565	30555542	We show that overexpressed piR-54265 prevents CRC cells from undergoing apoptosis and is correlated with resistance to anticancer agents and poor prognosis in CRC patients.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('piR-54265', 'Var', (27, 36))	('patients', 'Species', '9606', (163, 171))	('prevents', 'NegReg', (37, 45))	('CRC', 'Disease', (46, 49))	('CRC', 'Phenotype', 'HP:0003003', (159, 162))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('CRC', 'Phenotype', 'HP:0003003', (46, 49))	('cancer', 'Disease', (123, 129))
56566	30555542	Treatment targeting piR-54265 shows efficacy in inhibiting xenograft tumor growth and metastasis in mice.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mice', 'Species', '10090', (100, 104))	('inhibiting', 'NegReg', (48, 58))	('piR-54265', 'Var', (20, 29))	('xenograft tumor', 'Disease', (59, 74))	('men', 'Species', '9606', (5, 8))	('xenograft tumor', 'Disease', 'MESH:D009369', (59, 74))
56567	30555542	Serum piR-54265 levels are up-regulated in a stage-dependent manner, and high piR-54265 level is associated with poor response to chemotherapy and poor survival in CRC patients.	('up-regulated', 'PosReg', (27, 39))	('CRC', 'Phenotype', 'HP:0003003', (164, 167))	('Serum piR-54265', 'MPA', (0, 15))	('CRC', 'Disease', (164, 167))	('patients', 'Species', '9606', (168, 176))	('high', 'Var', (73, 77))
56592	30555542	DNA copy number alterations including deletion, neutral and amplification for piR-54265 were determined by the copy number of segments covering the gene.	('piR-54265', 'Gene', (78, 87))	('men', 'Species', '9606', (129, 132))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('deletion', 'Var', (38, 46))
56605	30555542	To establish CRC cells overexpressing piR-54265, HCT116 and LoVo cells were infected with recombinant lentiviruses designated piR-54265, which express pi-sno57 because of the insertion of SNORD57 precursor downstream of CMV promoter in pLent-Puro-GFP (Vigene Biosciences), a lentiviral vector or an empty pLent-Puro-GFP vector, which severs as control.	('CRC', 'Phenotype', 'HP:0003003', (13, 16))	('SNORD57', 'Gene', (188, 195))	('insertion', 'Var', (175, 184))	('LoVo', 'CellLine', 'CVCL:0399', (60, 64))	('HCT116', 'CellLine', 'CVCL:0291', (49, 55))	('pi-sno57', 'Var', (151, 159))	('SNORD57', 'Gene', '26792', (188, 195))
56618	30555542	Antibodies from Abcam against PIWIL1 (ab12337) or STAT3 (ab119352), from Santa Cruz against PIWIL2 (sc-67502), PIWIL3 (sc-398779) or PIWIL4 (sc-68932) and from Cell Signaling Technology against p-SRC (p-Tyr416, D4964) were used.	('Tyr416', 'Chemical', '-', (203, 209))	('gain', 'Disease', 'MESH:D015430', (187, 191))	('gain', 'Disease', (23, 27))	('STAT3', 'Gene', '6774', (50, 55))	('PIWIL1', 'Gene', (30, 36))	('gain', 'Disease', 'MESH:D015430', (85, 89))	('gain', 'Disease', (187, 191))	('PIWIL2', 'Gene', '55124', (92, 98))	('gain', 'Disease', (85, 89))	('PIWIL4', 'Gene', '143689', (133, 139))	('SRC', 'Gene', '6714', (196, 199))	('PIWIL3', 'Gene', '440822', (111, 117))	('SRC', 'Gene', (196, 199))	('PIWIL3', 'Gene', (111, 117))	('gain', 'Disease', 'MESH:D015430', (23, 27))	('STAT3', 'Gene', (50, 55))	('PIWIL4', 'Gene', (133, 139))	('p-Tyr416', 'Var', (201, 209))	('PIWIL1', 'Gene', '9271', (30, 36))	('PIWIL2', 'Gene', (92, 98))
56619	30555542	Briefly, commercially synthesized, biotinylated piR-54265 (Genepharma) or its antisense was incubated with cellular protein extracted from ordinary CRC cells or CRC cells transfected with whole-length PIWIL2 or truncated PIWIL2.	('CRC', 'Phenotype', 'HP:0003003', (161, 164))	('PIWIL2', 'Gene', '55124', (201, 207))	('PIWIL2', 'Gene', '55124', (221, 227))	('biotin', 'Chemical', 'MESH:D001710', (35, 41))	('CRC', 'Phenotype', 'HP:0003003', (148, 151))	('PIWIL2', 'Gene', (201, 207))	('truncated', 'Var', (211, 220))	('PIWIL2', 'Gene', (221, 227))
56622	30555542	Antibodies against STAT3 (ab119352), p-STAT3 (p-Y705, ab76315), SRC (ab109381), BCL-XL (ab32370), active CASPASE-3 (ab32351), MMP2 (ab86607) or MMP9 (ab58803) were from Abcam.	('MMP9', 'Gene', (144, 148))	('MMP9', 'Gene', '4318', (144, 148))	('SRC', 'Gene', '6714', (64, 67))	('BCL-XL', 'Gene', (80, 86))	('STAT3', 'Gene', (39, 44))	('MMP2', 'Gene', '4313', (126, 130))	('p-Y705', 'Var', (46, 52))	('ab32370', 'Var', (88, 95))	('gain', 'Disease', 'MESH:D015430', (12, 16))	('STAT3', 'Gene', '6774', (39, 44))	('SRC', 'Gene', (64, 67))	('CASPASE-3', 'Gene', (105, 114))	('BCL-XL', 'Gene', '598', (80, 86))	('gain', 'Disease', (12, 16))	('ab32351', 'Var', (116, 123))	('STAT3', 'Gene', (19, 24))	('ab76315', 'Var', (54, 61))	('ab86607', 'Var', (132, 139))	('ab119352', 'Var', (26, 34))	('MMP2', 'Gene', (126, 130))	('STAT3', 'Gene', '6774', (19, 24))	('CASPASE-3', 'Gene', '836', (105, 114))
56624	30555542	Antibodies against PIWIL2 (sc-67502) or p-SRC (p-Tyr416, D4964) were from Santa Cruz or Cell Signaling Technology, respectively.	('p-Tyr416, D4964', 'Var', (47, 62))	('D4964', 'Var', (57, 62))	('Tyr416', 'Chemical', '-', (49, 55))	('gain', 'Disease', (12, 16))	('gain', 'Disease', 'MESH:D015430', (12, 16))	('sc-67502', 'Var', (27, 35))	('PIWIL2', 'Gene', '55124', (19, 25))	('SRC', 'Gene', '6714', (42, 45))	('SRC', 'Gene', (42, 45))	('PIWIL2', 'Gene', (19, 25))	('Signaling', 'biological_process', 'GO:0023052', ('93', '102'))
56625	30555542	Antibody against FLAG tag (F1804) or 6xHIS tag (SAB2702218) was from Sigma, while antibody against beta-ACTIN (60008-1-Ig) was from Proteintech.	('beta-ACTIN', 'Gene', '728378', (99, 109))	('gain', 'Disease', (92, 96))	('HIS', 'Chemical', 'MESH:D006639', (39, 42))	('gain', 'Disease', 'MESH:D015430', (92, 96))	('F1804', 'Var', (27, 32))	('gain', 'Disease', 'MESH:D015430', (10, 14))	('gain', 'Disease', (10, 14))	('beta-ACTIN', 'Gene', (99, 109))
56633	30555542	We also treated subcutaneous xenografts with antagopiR54265, a synthesized piR-54265 inhibitor (Ribobio; Table S4) by intra-tumor injection.	('intra-tumor', 'Disease', 'MESH:D009369', (118, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('intra-tumor', 'Disease', (118, 129))	('antagopiR54265', 'Chemical', '-', (45, 59))	('antagopiR54265', 'Var', (45, 59))
56642	30555542	We also treated metastatic tumors with antagopiR54265.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('antagopiR54265', 'Chemical', '-', (39, 53))	('antagopiR54265', 'Var', (39, 53))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))
56643	30555542	When tumors reached 1x106 radiance (p/s/cm2/sr), antagopiR54265 (80 mg/kg body weight) only or antagopiR54265 plus 5-FU (100 mg/kg body weight) was intravenously given to mice one time per day in the first three days, and after that one time per week for 3 weeks.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('antagopiR54265', 'Chemical', '-', (49, 63))	('mice', 'Species', '10090', (171, 175))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('antagopiR54265', 'Chemical', '-', (95, 109))	('antagopiR54265', 'Var', (95, 109))	('5-FU', 'Chemical', 'MESH:D005472', (115, 119))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
56652	30555542	Chi-square test was used to examine the relationships between piR-54265 expression levels and chemotherapy efficacy in CRC patients.	('expression', 'Species', '29278', (72, 82))	('patients', 'Species', '9606', (123, 131))	('CRC', 'Disease', (119, 122))	('CRC', 'Phenotype', 'HP:0003003', (119, 122))	('piR-54265', 'Var', (62, 71))
56655	30555542	We found that, among these top 20 piRNAs, only piR-54265 was significantly overexpressed in tumor tissues compared with their non-tumor counterparts (Figure 1A) and this result was verified in another set of 108 samples consisting of paired CRC and non-tumor tissues from the AHSU (Suzhou; Figure S3B).	('non-tumor', 'Disease', 'MESH:D009369', (249, 258))	('CRC', 'Phenotype', 'HP:0003003', (241, 244))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('non-tumor', 'Disease', 'MESH:D009369', (126, 135))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('piR-54265', 'Var', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('non-tumor', 'Disease', (249, 258))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (253, 258))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (130, 135))	('non-tumor', 'Disease', (126, 135))	('overexpressed', 'PosReg', (75, 88))
56659	30555542	Kaplan-Meier estimate showed that CRC patients with high piR-54265 level had significantly shorter progression-free survival (PFS) time and overall survival (OS) time than patients with low piR-54265 level in both SYSUCC1 and AHSU patient sets and combined samples (Figure 1F-G).	('overall survival', 'CPA', (140, 156))	('progression-free survival', 'CPA', (99, 124))	('CRC', 'Phenotype', 'HP:0003003', (34, 37))	('patient', 'Species', '9606', (172, 179))	('patient', 'Species', '9606', (38, 45))	('high piR-54265 level', 'Var', (52, 72))	('patients', 'Species', '9606', (38, 46))	('patients', 'Species', '9606', (172, 180))	('shorter', 'NegReg', (91, 98))	('OS', 'Chemical', '-', (158, 160))	('patient', 'Species', '9606', (231, 238))
56660	30555542	Cox regression analysis with sex, age, smoking status, drinking status and family history as covariates further demonstrated piR-54265 level was an independent risk factor for PFS (HR=1.96, 95% CI=1.37-2.80) and OS (HR=1.99, 95% CI=1.35-2.93) in combined samples (Table 1 and Table 2).	('piR-54265 level', 'Var', (125, 140))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('PFS', 'Disease', (176, 179))	('OS', 'Chemical', '-', (212, 214))
56661	30555542	We further performed the analysis stratified by tumor location and TNM stage and found that higher level of piR-54265 was associated with shorter survival time in patients with either colon or rectal cancer (Figure S4A).	('colon or rectal cancer', 'Disease', 'MESH:D012004', (184, 206))	('piR-54265', 'Var', (108, 117))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('patients', 'Species', '9606', (163, 171))	('tumor', 'Disease', (48, 53))	('rectal cancer', 'Phenotype', 'HP:0100743', (193, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('shorter', 'NegReg', (138, 145))	('TNM', 'Gene', '10178', (67, 70))	('colon or rectal cancer', 'Disease', (184, 206))	('survival time', 'CPA', (146, 159))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('TNM', 'Gene', (67, 70))
56662	30555542	However, with respect to TNM stage, higher level of piR-54265 was only associated with shorter survival time in patients with advanced cancer (Figure S4B).	('piR-54265', 'Var', (52, 61))	('survival time', 'CPA', (95, 108))	('cancer', 'Disease', (135, 141))	('TNM', 'Gene', '10178', (25, 28))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('TNM', 'Gene', (25, 28))	('shorter', 'NegReg', (87, 94))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
56664	30555542	We next examined the effects of piR-54265 on malignant phenotypes of CRC cells by ectopic expression of piR-54265 or its antisense (Figure S5A-B).	('examined', 'Reg', (8, 16))	('CRC', 'Phenotype', 'HP:0003003', (69, 72))	('expression', 'Species', '29278', (90, 100))	('piR-54265', 'Var', (104, 113))
56665	30555542	We observed that overexpression of piR-54265 in CRC cells substantially increased the rate of cell proliferation (Figure 2A), whereas knockdown of piR-54265 had the reverse results (Figure 2B).	('piR-54265', 'Var', (35, 44))	('increased', 'PosReg', (72, 81))	('expression', 'Species', '29278', (21, 31))	('CRC', 'Phenotype', 'HP:0003003', (48, 51))	('cell proliferation', 'biological_process', 'GO:0008283', ('94', '112'))	('overexpression', 'PosReg', (17, 31))	('cell proliferation', 'CPA', (94, 112))
56666	30555542	The colony formation ability in both CRC cells was markedly enhanced by piR-54265 overexpression but substantially suppressed by piR-54265 knockdown (Figure 2C).	('expression', 'Species', '29278', (86, 96))	('colony formation ability', 'CPA', (4, 28))	('piR-54265 overexpression', 'Var', (72, 96))	('CRC', 'Phenotype', 'HP:0003003', (37, 40))	('formation', 'biological_process', 'GO:0009058', ('11', '20'))	('suppressed', 'NegReg', (115, 125))	('enhanced', 'PosReg', (60, 68))	('overexpression', 'Var', (82, 96))
56667	30555542	We injected CRC cells into the rear flank of nude mice and found that the growth rate of xenograft overexpressing piR-54265 was significantly higher than that of controls (Figure 2D).	('growth rate', 'CPA', (74, 85))	('piR-54265', 'Var', (114, 123))	('CRC', 'Phenotype', 'HP:0003003', (12, 15))	('nude mice', 'Species', '10090', (45, 54))	('higher', 'PosReg', (142, 148))
56668	30555542	Neither overexpression nor knockdown of piR-54265 had a significant effect on the cell cycle progression (Figure S5C), suggesting that the promoting effects of piR-54265 on CRC cell proliferation may be through inhibiting apoptosis.	('apoptosis', 'biological_process', 'GO:0006915', ('222', '231'))	('inhibiting', 'NegReg', (211, 221))	('cell proliferation', 'biological_process', 'GO:0008283', ('177', '195'))	('cell cycle', 'biological_process', 'GO:0007049', ('82', '92'))	('piR-54265', 'Var', (160, 169))	('apoptosis', 'CPA', (222, 231))	('CRC', 'Phenotype', 'HP:0003003', (173, 176))	('promoting', 'PosReg', (139, 148))	('expression', 'Species', '29278', (12, 22))	('CRC cell proliferation', 'CPA', (173, 195))	('apoptosis', 'biological_process', 'GO:0097194', ('222', '231'))
56669	30555542	We found that overexpression of piR-54265 significantly enhanced but knockdown of piR-54265 significantly suppressed the migration and invasion abilities of CRC cells in vitro (Figure 2G-H).	('piR-54265', 'Var', (82, 91))	('expression', 'Species', '29278', (18, 28))	('suppressed', 'NegReg', (106, 116))	('enhanced', 'PosReg', (56, 64))	('invasion abilities of CRC cells in vitro', 'CPA', (135, 175))	('knockdown', 'Var', (69, 78))	('CRC', 'Phenotype', 'HP:0003003', (157, 160))
56670	30555542	Furthermore, we found that CRC cells with stable piR-54265 overexpression had remarkably increased lung metastasis compared with control cells as measured by luminescence imaging.	('piR-54265', 'Var', (49, 58))	('CRC', 'Phenotype', 'HP:0003003', (27, 30))	('expression', 'Species', '29278', (63, 73))	('lung metastasis', 'Disease', (99, 114))	('lung metastasis', 'Disease', 'MESH:D009362', (99, 114))	('overexpression', 'PosReg', (59, 73))	('increased', 'PosReg', (89, 98))
56671	30555542	In contrast, cells with stable knockdown of piR-54265 expression had significantly reduced lung metastasis compared with control cells (Figure 2I-K and Figure S6).	('reduced', 'NegReg', (83, 90))	('lung metastasis', 'Disease', (91, 106))	('lung metastasis', 'Disease', 'MESH:D009362', (91, 106))	('piR-54265 expression', 'Var', (44, 64))	('expression', 'Species', '29278', (54, 64))	('knockdown', 'Var', (31, 40))
56672	30555542	In addition to lung metastasis, overexpression of piR-54265 promoted CRC cells localized in other organs and tissues such as brain and bone (Figure 2L).	('CRC cells localized', 'CPA', (69, 88))	('lung metastasis', 'Disease', (15, 30))	('promoted', 'PosReg', (60, 68))	('piR-54265', 'Var', (50, 59))	('lung metastasis', 'Disease', 'MESH:D009362', (15, 30))	('CRC', 'Phenotype', 'HP:0003003', (69, 72))	('expression', 'Species', '29278', (36, 46))
56673	30555542	Since ncRNAs may be involved in the cis regulation of target genes located at the nearby genomic locus, we first examined the mRNA levels of 9 genes within about 2 mega-bases centering the gene generating piR-54265 (Figure S7A) and found no significant difference when piR-54265 expression was knocked down as compared with controls (Figure S7B), suggesting that piR-54265 might not function in this way.	('knocked', 'Var', (294, 301))	('expression', 'Species', '29278', (279, 289))	('piR-54265', 'Var', (205, 214))	('piR-54265', 'Gene', (269, 278))
56674	30555542	Another possible function we conjectured might be that piR-54265 interacts with PIWI proteins to perform the function as its name defines.	('piR-54265', 'Var', (55, 64))	('interacts', 'Interaction', (65, 74))	('PIWI', 'Gene', '9271', (80, 84))	('PIWI', 'Gene', (80, 84))
56675	30555542	Indeed, by RIP-qPCR and pulldown assays, we demonstrated that piR-54265 specifically binds PIWIL2, a member of the PIWI family (Figure 3A-B).	('PIWI', 'Gene', (91, 95))	('PIWI', 'Gene', '9271', (115, 119))	('PIWI', 'Gene', (115, 119))	('PIWIL2', 'Gene', '55124', (91, 97))	('PIWI', 'Gene', '9271', (91, 95))	('PIWIL2', 'Gene', (91, 97))	('piR-54265', 'Var', (62, 71))	('binds', 'Interaction', (85, 90))
56677	30555542	We then investigated the molecular consequences of the interaction between piR-54265 and PIWIL2.	('PIWIL2', 'Gene', (89, 95))	('interaction', 'Interaction', (55, 66))	('investigated', 'Reg', (8, 20))	('piR-54265', 'Var', (75, 84))	('PIWIL2', 'Gene', '55124', (89, 95))
56681	30555542	However, what is important is that we found that the PIWIL2/STAT3/p-SRC interaction in CRC cells varied when the piR-54265 expression was perturbed, although the levels of both PIWIL2, total STAT3 and SRC proteins were roughly constant (Figure 3G-H); these results indicated that piR-54265 may facilitate the formation of PIWIL2/STAT3/p-SRC complex.	('SRC', 'Gene', (337, 340))	('SRC', 'Gene', (201, 204))	('STAT3', 'Gene', (191, 196))	('varied', 'Reg', (97, 103))	('STAT3', 'Gene', '6774', (191, 196))	('PIWIL2', 'Gene', '55124', (322, 328))	('PIWIL2', 'Gene', '55124', (53, 59))	('PIWIL2', 'Gene', (177, 183))	('perturbed', 'Reg', (138, 147))	('expression', 'Species', '29278', (123, 133))	('piR-54265', 'Var', (280, 289))	('SRC', 'Gene', '6714', (68, 71))	('STAT3', 'Gene', (60, 65))	('STAT3', 'Gene', (329, 334))	('SRC', 'Gene', '6714', (337, 340))	('SRC', 'Gene', '6714', (201, 204))	('facilitate', 'PosReg', (294, 304))	('CRC', 'Phenotype', 'HP:0003003', (87, 90))	('PIWIL2', 'Gene', '55124', (177, 183))	('STAT3', 'Gene', '6774', (60, 65))	('SRC', 'Gene', (68, 71))	('STAT3', 'Gene', '6774', (329, 334))	('PIWIL2', 'Gene', (53, 59))	('PIWIL2', 'Gene', (322, 328))
56682	30555542	Because piR-54265 overexpression or knockdown in CRC cells appeared to substantially affect only the level of phosphorylated STAT3 (p-STAT3) but no other proteins (Figure 3H), we postulated that piR-54265 may function via activating STAT3 signaling pathway.	('STAT3', 'Gene', (125, 130))	('piR-54265', 'Gene', (8, 17))	('expression', 'Species', '29278', (22, 32))	('CRC', 'Phenotype', 'HP:0003003', (49, 52))	('signaling pathway', 'biological_process', 'GO:0007165', ('239', '256'))	('knockdown', 'Var', (36, 45))	('STAT3', 'Gene', '6774', (134, 139))	('STAT3', 'Gene', '6774', (125, 130))	('STAT3', 'Gene', '6774', (233, 238))	('affect', 'Reg', (85, 91))	('piR-54265', 'Var', (195, 204))	('STAT3', 'Gene', (134, 139))	('activating', 'PosReg', (222, 232))	('STAT3', 'Gene', (233, 238))
56684	30555542	We found that CRC cells overexpressing piR-54265 had substantial up-regulation of p-STAT3 and BCL-XL but down-regulation of cleaved-CASP9, -CASP3 and -CASP7 compared with control cells; the reverse results were obtained in cells with piR-54265 knockdown (Figure 4A).	('CASP7', 'Gene', '840', (151, 156))	('STAT3', 'Gene', '6774', (84, 89))	('CASP3', 'Gene', (140, 145))	('BCL-XL', 'Gene', '598', (94, 100))	('down-regulation', 'NegReg', (105, 120))	('CRC', 'Phenotype', 'HP:0003003', (14, 17))	('STAT3', 'Gene', (84, 89))	('CASP9', 'Gene', (132, 137))	('piR-54265', 'Var', (39, 48))	('CASP7', 'Gene', (151, 156))	('BCL-XL', 'Gene', (94, 100))	('CASP9', 'Gene', '842', (132, 137))	('CASP3', 'Gene', '836', (140, 145))	('up-regulation', 'PosReg', (65, 78))
56688	30555542	We then performed rescue assays to verify that the effects of piR-54265 on CRC cell are via PIWIL2 and STAT3.	('STAT3', 'Gene', (103, 108))	('PIWIL2', 'Gene', (92, 98))	('PIWIL2', 'Gene', '55124', (92, 98))	('CRC', 'Phenotype', 'HP:0003003', (75, 78))	('STAT3', 'Gene', '6774', (103, 108))	('piR-54265', 'Var', (62, 71))
56690	30555542	Since overexpression of piR-54265 prevents CRC cells from undergoing apoptosis and was associated with prognosis of CRC patients who received postoperative chemotherapy, we thus investigated whether this piRNA is involved in chemo-sensitivity.	('CRC', 'Phenotype', 'HP:0003003', (116, 119))	('apoptosis', 'biological_process', 'GO:0006915', ('69', '78'))	('associated', 'Reg', (87, 97))	('expression', 'Species', '29278', (10, 20))	('prevents', 'NegReg', (34, 42))	('patients', 'Species', '9606', (120, 128))	('CRC', 'Disease', (116, 119))	('CRC', 'Phenotype', 'HP:0003003', (43, 46))	('piR-54265', 'Var', (24, 33))	('apoptosis', 'biological_process', 'GO:0097194', ('69', '78'))
56691	30555542	We observed that CRC cells overexpressing piR-54265 had significantly higher half maximal inhibitory concentrations (IC50) toward 5-FU and oxaliplatin, while cells with piR-54265 knockdown had significantly lower IC50 compared with their controls (Figure 5A-B).	('5-FU', 'Chemical', 'MESH:D005472', (130, 134))	('CRC', 'Phenotype', 'HP:0003003', (17, 20))	('half maximal inhibitory concentrations', 'MPA', (77, 115))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (139, 150))	('higher', 'PosReg', (70, 76))	('piR-54265', 'Var', (42, 51))
56693	30555542	We found that subcutaneous tumors formed from CRC cells overexpressing piR-54265 were more resistant to the chemotherapy than tumors derived from the cells without piR-54265 overexpression (Figure 5E), while subcutaneous tumors with knockdown of piR-54265 had a better response to these agents (Figure 5F).	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('piR-54265', 'Var', (71, 80))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumors', 'Disease', (126, 132))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (14, 33))	('tumors', 'Disease', (221, 227))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (14, 33))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('expression', 'Species', '29278', (178, 188))	('subcutaneous tumors', 'Disease', (14, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('resistant', 'CPA', (91, 100))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (208, 227))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (208, 227))	('tumors', 'Disease', (27, 33))	('CRC', 'Phenotype', 'HP:0003003', (46, 49))	('subcutaneous tumors', 'Disease', (208, 227))
56694	30555542	These results indicate that overexpression of piR-54265 plays an important role in conferring chemotherapy insensitivity to CRC cells, and targeting piR-54265 might provide a new approach for CRC treatment.	('chemotherapy insensitivity', 'MPA', (94, 120))	('CRC', 'Phenotype', 'HP:0003003', (192, 195))	('piR-54265', 'Var', (149, 158))	('piR-54265', 'Var', (46, 55))	('men', 'Species', '9606', (201, 204))	('CRC', 'Phenotype', 'HP:0003003', (124, 127))	('CRC', 'Disease', (192, 195))	('expression', 'Species', '29278', (32, 42))	('overexpression', 'PosReg', (28, 42))
56695	30555542	To test whether targeting piR-54265 might suppress tumor growth and metastasis, we conducted experimental therapy in mouse subcutaneous xenograft and metastatic tumor models using antagopiR54265, a specific chemically modified piR-54265 inhibitor with suitable pharmacokinetic properties for in vivo study.	('suppress', 'NegReg', (42, 50))	('antagopiR54265', 'Chemical', '-', (180, 194))	('antagopiR54265', 'Var', (180, 194))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mouse', 'Species', '10090', (117, 122))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('men', 'Species', '9606', (99, 102))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
56696	30555542	We injected antagopiR54265 or scramble sequence directly into subcutaneous tumors (Figure 5G) and observed that after 5-8 injections, subcutaneous tumors treated with antagopiR54265 had significantly reduced tumor volume compared with those treated with scramble controls (Figure 5H-I).	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (134, 153))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (134, 153))	('antagopiR54265', 'Chemical', '-', (167, 181))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (62, 81))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (62, 81))	('tumor', 'Disease', (75, 80))	('subcutaneous tumors', 'Disease', (134, 153))	('tumor', 'Disease', (147, 152))	('subcutaneous tumors', 'Disease', (62, 81))	('reduced', 'NegReg', (200, 207))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', (208, 213))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('antagopiR54265', 'Chemical', '-', (12, 26))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('antagopiR54265', 'Var', (167, 181))
56697	30555542	We also injected this antagopiR54265 or its control through the tail vein into blood to treat metastatic tumors when tumor sizes reached a certain threshold (Figure 5J) and similar results were obtained showing that mice treated with antagopiR54265 had significantly reduced tumor burdens and longer survival time compared with controls (Figure 5K-M).	('tumors', 'Disease', (105, 111))	('tumor', 'Disease', (275, 280))	('survival time', 'CPA', (300, 313))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (105, 110))	('mice', 'Species', '10090', (216, 220))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('antagopiR54265', 'Chemical', '-', (22, 36))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('antagopiR54265', 'Var', (234, 248))	('reduced', 'NegReg', (267, 274))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('longer', 'PosReg', (293, 299))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('antagopiR54265', 'Chemical', '-', (234, 248))
56698	30555542	Furthermore, combined treatment of antagopiR54265 with 5-FU had greater efficacy than treatment with each agent alone (Figure 5K-M).	('antagopiR54265', 'Chemical', '-', (35, 49))	('antagopiR54265', 'Var', (35, 49))	('men', 'Species', '9606', (91, 94))	('5-FU', 'Chemical', 'MESH:D005472', (55, 59))	('combined', 'Interaction', (13, 21))	('men', 'Species', '9606', (27, 30))	('efficacy', 'MPA', (72, 80))
56699	30555542	In addition, treatment of mice with antagopiR54265 showed no apparent side-effects because no significant differences in animal body-weight gain were seen over the course of intra-tumor (Figure S9B) or intravenous injection (Figure S9C), implying a low toxicity of this piRNA inhibitor.	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('men', 'Species', '9606', (18, 21))	('gain', 'Disease', 'MESH:D015430', (140, 144))	('intra-tumor', 'Disease', 'MESH:D009369', (174, 185))	('weight gain', 'Phenotype', 'HP:0004324', (133, 144))	('antagopiR54265', 'Chemical', '-', (36, 50))	('antagopiR54265', 'Var', (36, 50))	('gain', 'Disease', (140, 144))	('intra-tumor', 'Disease', (174, 185))	('toxicity', 'Disease', 'MESH:D064420', (253, 261))	('toxicity', 'Disease', (253, 261))	('mice', 'Species', '10090', (26, 30))
56705	30555542	We found that patients with low serum piR-54265 level had significantly better response to chemotherapy than those with high serum piR-54265 level in patients recruited at SYSUCC (SYSUCC2, N=215, P=0.010; Table S2 and Figure 6F) and at Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS, N=102, P=0.019; Table S3 and Figure 6G) and combined samples (N=317, P<0.0001; Figure 6H).	('Cancer', 'Phenotype', 'HP:0002664', (236, 242))	('better', 'PosReg', (72, 78))	('patients', 'Species', '9606', (150, 158))	('response to chemotherapy', 'CPA', (79, 103))	('patients', 'Species', '9606', (14, 22))	('low', 'Var', (28, 31))
56709	30555542	The overexpressed piR-54265 may function as an essential mediator to activate STAT3 signaling, consequently enhancing proliferation and promoting invasion and metastasis of CRC cells.	('piR-54265', 'Var', (18, 27))	('metastasis', 'CPA', (159, 169))	('activate', 'PosReg', (69, 77))	('STAT3', 'Gene', '6774', (78, 83))	('proliferation', 'CPA', (118, 131))	('CRC', 'Phenotype', 'HP:0003003', (173, 176))	('STAT3', 'Gene', (78, 83))	('promoting', 'PosReg', (136, 145))	('enhancing', 'PosReg', (108, 117))	('invasion', 'CPA', (146, 154))
56710	30555542	We have demonstrated in mice xenograft models that treatment with piR-54265 inhibitor is effective in suppressing tumor growth and metastasis.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('piR-54265 inhibitor', 'Var', (66, 85))	('mice', 'Species', '10090', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('men', 'Species', '9606', (56, 59))	('suppressing', 'NegReg', (102, 113))	('tumor', 'Disease', (114, 119))
56711	30555542	Remarkably, we have further found that the levels of piR-54265 in CRC tissues is correlated with the levels in serum of patients, both of which are highly associated with clinical outcomes such as resistance to chemotherapy and poor survival in CRC patients.	('CRC', 'Phenotype', 'HP:0003003', (66, 69))	('patients', 'Species', '9606', (249, 257))	('associated', 'Reg', (155, 165))	('resistance to chemotherapy', 'CPA', (197, 223))	('piR-54265', 'Var', (53, 62))	('patients', 'Species', '9606', (120, 128))	('CRC', 'Phenotype', 'HP:0003003', (245, 248))
56716	30555542	We have also investigated the biological functions of piR-54265 in CRC and demonstrated that piR-54265 is able to specifically interact with the PIWI domain of PIWIL2 protein and mediates the formation of PIWIL2/STAT3/p-SRC complex, in which STAT3 is phosphorylatively activated by p-SRC.	('PIWI', 'Gene', '9271', (205, 209))	('PIWIL2', 'Gene', '55124', (160, 166))	('PIWI', 'Gene', (145, 149))	('CRC', 'Phenotype', 'HP:0003003', (67, 70))	('PIWI', 'Gene', (160, 164))	('STAT3', 'Gene', (212, 217))	('piR-54265', 'Var', (93, 102))	('SRC', 'Gene', '6714', (284, 287))	('protein', 'cellular_component', 'GO:0003675', ('167', '174'))	('PIWI', 'Gene', (205, 209))	('PIWIL2', 'Gene', '55124', (205, 211))	('SRC', 'Gene', '6714', (220, 223))	('STAT3', 'Gene', '6774', (212, 217))	('formation', 'biological_process', 'GO:0009058', ('192', '201'))	('SRC', 'Gene', (284, 287))	('STAT3', 'Gene', (242, 247))	('SRC', 'Gene', (220, 223))	('PIWIL2', 'Gene', (160, 166))	('mediates', 'Reg', (179, 187))	('PIWI', 'Gene', '9271', (145, 149))	('PIWI', 'Gene', '9271', (160, 164))	('STAT3', 'Gene', '6774', (242, 247))	('interact', 'Interaction', (127, 135))	('PIWIL2', 'Gene', (205, 211))
56725	30555542	By carrying out experimental treatment in xenograft tumor models with a synthetic inhibitor of piR-54265, we found that administration of antagopiR54265 directly into the tumor or vein substantially reduced the growth and metastasis of xenografts in mice.	('antagopiR54265', 'Chemical', '-', (138, 152))	('antagopiR54265', 'Var', (138, 152))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('xenograft tumor', 'Disease', (42, 57))	('men', 'Species', '9606', (22, 25))	('men', 'Species', '9606', (34, 37))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('mice', 'Species', '10090', (250, 254))	('xenograft tumor', 'Disease', 'MESH:D009369', (42, 57))	('reduced', 'NegReg', (199, 206))
56726	30555542	Furthermore, combined administration of antagopiR54265 with 5-FU showed an increased anticancer effect.	('antagopiR54265', 'Chemical', '-', (40, 54))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('antagopiR54265', 'Var', (40, 54))	('cancer', 'Disease', (89, 95))	('combined', 'Interaction', (13, 21))	('increased', 'PosReg', (75, 84))	('5-FU', 'Chemical', 'MESH:D005472', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
56727	30555542	Interestingly, we observed that administration of antagopiR54265 to mice did not show apparent side-effects, which is reflected by the similar bodyweight gain compared with control mice treated with a scrambled sequence.	('mice', 'Species', '10090', (68, 72))	('mice', 'Species', '10090', (181, 185))	('bodyweight gain', 'Disease', 'MESH:D015430', (143, 158))	('bodyweight gain', 'Disease', (143, 158))	('antagopiR54265', 'Chemical', '-', (50, 64))	('antagopiR54265', 'Var', (50, 64))	('weight gain', 'Phenotype', 'HP:0004324', (147, 158))
56728	30555542	Although further investigations should be performed to systematically evaluate the potential toxicity caused by the inhibition of piR-54265, the results in the current study suggest that piR-54265 may be a druggable target for effective treatment of CRC.	('piR-54265', 'Var', (187, 196))	('CRC', 'Disease', (250, 253))	('men', 'Species', '9606', (242, 245))	('toxicity', 'Disease', 'MESH:D064420', (93, 101))	('toxicity', 'Disease', (93, 101))	('CRC', 'Phenotype', 'HP:0003003', (250, 253))
56731	30555542	Furthermore, serum piR-54265 may serve as a prediction marker for response to chemotherapy and prognosis in CRC patients.	('serum piR-54265', 'Var', (13, 28))	('CRC', 'Disease', (108, 111))	('patients', 'Species', '9606', (112, 120))	('CRC', 'Phenotype', 'HP:0003003', (108, 111))
56733	30555542	In addition, it would be interesting to explore whether piR-54265 also plays the same role in other types of human cancer.	('cancer', 'Disease', (115, 121))	('human', 'Species', '9606', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('piR-54265', 'Var', (56, 65))
56734	30555542	AUC area under the ROC curve CPM counts per million mapped reads CRC colorectal cancer 5-FU 5-fluorouracil IC50 half maximal inhibitory concentration OS overall survival Oxal oxaliplatin PFS progression-free survival piRNA PIWI-interacting RNA p-SRC phosphorylated SRC p-STAT3 phosphorylated STAT3 RECIST response evaluation criteria in solid tumors ROC receiver operating characteristic curve SCNA somatic copy number alteration TRG tumor regression grade.	('TRG', 'Disease', (430, 433))	('STAT3', 'Gene', (271, 276))	('PIWI', 'Gene', '9271', (223, 227))	('SRC', 'Gene', '6714', (246, 249))	('tumor', 'Disease', 'MESH:D009369', (434, 439))	('rectal cancer', 'Phenotype', 'HP:0100743', (73, 86))	('colorectal cancer', 'Phenotype', 'HP:0003003', (69, 86))	('alteration', 'Var', (419, 429))	('STAT3', 'Gene', '6774', (271, 276))	('SRC', 'Gene', (246, 249))	('Oxal', 'Chemical', '-', (170, 174))	('STAT3', 'Gene', (292, 297))	('tumor', 'Phenotype', 'HP:0002664', (434, 439))	('PIWI', 'Gene', (223, 227))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('copy number alteration', 'Var', (407, 429))	('solid tumors', 'Disease', (337, 349))	('OS', 'Chemical', '-', (150, 152))	('colorectal cancer', 'Disease', 'MESH:D015179', (69, 86))	('STAT3', 'Gene', '6774', (292, 297))	('tumor', 'Disease', (343, 348))	('5-FU', 'Chemical', 'MESH:D005472', (87, 91))	('CRC', 'Phenotype', 'HP:0003003', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (343, 348))	('colorectal cancer', 'Disease', (69, 86))	('SRC', 'Gene', '6714', (265, 268))	('solid tumors', 'Disease', 'MESH:D009369', (337, 349))	('tumors', 'Phenotype', 'HP:0002664', (343, 349))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (92, 106))	('tumor', 'Disease', (434, 439))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('TRG', 'Chemical', '-', (430, 433))	('SRC', 'Gene', (265, 268))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (175, 186))
56853	29751641	The detection of dopamine is an elusive, yet highly desirable, target due to the association between the loss of dopamine and Parkinson's disease.	('dopamine', 'MPA', (113, 121))	("Parkinson's disease", 'Disease', (126, 145))	('loss', 'Var', (105, 109))	('dopamine', 'Chemical', 'MESH:D004298', (113, 121))	("Parkinson's disease", 'Disease', 'MESH:D010300', (126, 145))	('dopamine', 'Chemical', 'MESH:D004298', (17, 25))
56855	29751641	Very low LODs for dopamine have been achieved using an AuNR dimer coated with an Ag shell (0.006 pM) and Au core-Ag shell NP-Au nanorod heterodimers (0.02 nM).	('Au', 'Chemical', 'MESH:D006046', (55, 57))	('dopamine', 'Chemical', 'MESH:D004298', (18, 26))	('Au', 'Chemical', 'MESH:D006046', (105, 107))	('core', 'cellular_component', 'GO:0019013', ('108', '112'))	('0.006', 'Var', (91, 96))	('LODs for dopamine', 'MPA', (9, 26))	('Au', 'Chemical', 'MESH:D006046', (125, 127))
56871	29751641	The results show that the NPY32-36 C-terminal fragments were involved in the adsorption process on the metal substrate where tyrosine and arginine are mainly responsible for the interaction with the Ag and Au surfaces.	('adsorption', 'MPA', (77, 87))	('interaction', 'Interaction', (178, 189))	('rat', 'Species', '10116', (114, 117))	('involved', 'Reg', (61, 69))	('NPY', 'Gene', (26, 29))	('tyrosine', 'Chemical', 'MESH:D014443', (125, 133))	('metal', 'Chemical', 'MESH:D008670', (103, 108))	('responsible', 'Reg', (158, 169))	('men', 'Species', '9606', (50, 53))	('tyrosine', 'Var', (125, 133))	('arginine', 'Chemical', 'MESH:D001120', (138, 146))	('Au', 'Chemical', 'MESH:D006046', (206, 208))	('NPY', 'Gene', '4852', (26, 29))
56952	29751641	LMG is not a strong Raman scattering molecule; however, when exposed to H2O2 through the conjugated HRP, it is reduced and converted to malachite green (MG), which exhibits a strong SERS signal.	('MG', 'Chemical', 'MESH:C005095', (1, 3))	('malachite', 'Species', '64457', (136, 145))	('H2O2', 'Chemical', 'MESH:D006861', (72, 76))	('H2O2', 'Var', (72, 76))	('SERS', 'Chemical', '-', (182, 186))	('LMG', 'Chemical', 'MESH:C015320', (0, 3))	('MG', 'Chemical', 'MESH:C005095', (153, 155))	('SERS signal', 'MPA', (182, 193))
56962	29751641	were able to directly identify a characteristic peak (1509 cm-1) corresponding to the presence of PDGF-BB, and using PCA-LDA, constructed a model for diagnosis that had 87.9% sensitivity and 87.0% specificity using the PDGF-BB peak, showing the great potential of SERS as a diagnostic clinical technique for CHD.	('SERS', 'Chemical', '-', (264, 268))	('CHD', 'Disease', (308, 311))	('PDGF-BB', 'Gene', (98, 105))	('presence', 'Var', (86, 94))	('CHD', 'Disease', 'None', (308, 311))
56976	29751641	While initially developed as a method for detecting drug delivery to tumors, the MTX-nanostar probes have also been applied to detection of cardiovascular diseases due to the non-specific accumulation of the MTX-nanostars in the hearts of healthy mice.	('cardiovascular diseases', 'Disease', (140, 163))	('accumulation', 'PosReg', (188, 200))	('mice', 'Species', '10090', (247, 251))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (140, 162))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (140, 163))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (140, 163))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('MTX-nanostars', 'Var', (208, 221))	('MTX', 'Chemical', 'MESH:D008942', (208, 211))	('MTX', 'Chemical', 'MESH:D008942', (81, 84))
56979	29751641	Vascular cell adhesion molecule-1 (VCAM-1) is believed to play a role in the development of atherosclerosis, so the detection of VCAM-1 could be used to diagnose atherosclerosis even before clinical symptoms arise.	('VCAM-1', 'Gene', '7412', (129, 135))	('VCAM-1', 'Gene', (35, 41))	('atherosclerosis', 'Disease', (162, 177))	('atherosclerosis', 'Disease', 'MESH:D050197', (92, 107))	('atherosclerosis', 'Phenotype', 'HP:0002621', (92, 107))	('detection', 'Var', (116, 125))	('atherosclerosis', 'Phenotype', 'HP:0002621', (162, 177))	('atherosclerosis', 'Disease', (92, 107))	('VCAM-1', 'Gene', (129, 135))	('VCAM-1', 'Gene', '7412', (35, 41))	('diagnose', 'Reg', (153, 161))	('men', 'Species', '9606', (84, 87))	('Vascular cell adhesion molecule-1', 'Gene', '7412', (0, 33))	('atherosclerosis', 'Disease', 'MESH:D050197', (162, 177))	('Vascular cell adhesion molecule-1', 'Gene', (0, 33))
57011	29751641	By coupling SERS measurements with PCA-LDA, a model was generated that could not only diagnose luminal A breast cancer but could also differentiate between cancers at different stages (pT1N0 and pTxN+), with improved performance at the detection of early stage cancers (pT1N0) than advanced cancers (pTxN+).	('improved', 'PosReg', (208, 216))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('stage cancers', 'Disease', 'MESH:D009369', (255, 268))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('diagnose', 'Reg', (86, 94))	('cancers', 'Disease', 'MESH:D009369', (291, 298))	('stage cancers', 'Disease', (255, 268))	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('cancers', 'Disease', (261, 268))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('men', 'Species', '9606', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('rat', 'Species', '10116', (60, 63))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('breast cancer', 'Disease', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', (156, 163))	('SERS', 'Chemical', '-', (12, 16))	('cancers', 'Phenotype', 'HP:0002664', (291, 298))	('cancers', 'Disease', (291, 298))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancers', 'Disease', 'MESH:D009369', (261, 268))	('pT1N0', 'Var', (270, 275))
57078	29751641	This SERS-based genotyping was also applied to mutant and wild type DNA obtained from three melanoma cell lines, with the results confirmed by droplet digital PCR (ddPCR).	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('SERS', 'Chemical', '-', (5, 9))	('melanoma', 'Disease', 'MESH:D008545', (92, 100))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('melanoma', 'Disease', (92, 100))	('mutant', 'Var', (47, 53))
57088	29751641	5'-thiolated single-stranded DNA oligonucleotides were immobilized on the surface of the AgNR substrates for the detection of synthetic RNA sequence coding for genetic mutation N665, a mutation of the PB1-F2 protein which codes for increased virulence of the flu.	('N665', 'Var', (177, 181))	('virulence', 'MPA', (242, 251))	('PB1-F2', 'Gene', (201, 207))	('synthetic RNA', 'Species', '2086595', (126, 139))	('rat', 'Species', '10116', (99, 102))	('increased', 'PosReg', (232, 241))	("5'-thiolated single-stranded DNA oligonucleotides", 'Chemical', '-', (0, 49))
57273	28053678	Samples of adenocarcinoma with G2 and G3 grade showed significantly higher levels of immunohistochemical expression of this antioxidant enzyme.	('higher', 'PosReg', (68, 74))	('immunohistochemical expression', 'MPA', (85, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('levels', 'MPA', (75, 81))	('adenocarcinoma', 'Disease', (11, 25))	('G3 grade', 'Var', (38, 46))	('adenocarcinoma', 'Disease', 'MESH:D000230', (11, 25))
57319	28053678	Moreover, it has been reported that intrinsic antioxidant enzymes are vital to the regulation of oxidative stress within cells, and alterations of these enzymes are connected with cancer pathogenesis as well.	('alterations', 'Var', (132, 143))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('connected', 'Reg', (165, 174))	('intrinsic antioxidant enzymes', 'MPA', (36, 65))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('oxidative stress', 'Phenotype', 'HP:0025464', (97, 113))	('cancer', 'Disease', (180, 186))
57322	28053678	MnSOD-dependent production of H2O2 increased the expression of matrix-degrading metalloproteinases (MMP), which can alter the cancer microenvironment, forming a permissive conditions for metastatic disease.	('MnSOD', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('increased', 'PosReg', (35, 44))	('men', 'Species', '9606', (145, 148))	('alter', 'Reg', (116, 121))	('expression', 'MPA', (49, 59))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('MnSOD', 'Gene', '6648', (0, 5))	('H2O2', 'Chemical', 'MESH:D006861', (30, 34))	('H2O2', 'Var', (30, 34))
57339	28053678	Upon MnSOD knockdown in UM1 cells, the intracellular levels of H2O2 levels were decreased and the expression of Snail factors was inhibited.	('Snail', 'Gene', '6615', (112, 117))	('Snail', 'Gene', (112, 117))	('intracellular levels of H2O2 levels', 'MPA', (39, 74))	('inhibited', 'NegReg', (130, 139))	('MnSOD', 'Gene', '6648', (5, 10))	('UM1', 'CellLine', 'CVCL:W392', (24, 27))	('decreased', 'NegReg', (80, 89))	('MnSOD', 'Gene', (5, 10))	('H2O2', 'Chemical', 'MESH:D006861', (63, 67))	('knockdown', 'Var', (11, 20))	('expression', 'MPA', (98, 108))
57348	28053678	The majority of patients with N2 status showed strong expression, whereas only 1 patient from the N0 group showed such strong reaction intensity.	('expression', 'MPA', (54, 64))	('patient', 'Species', '9606', (81, 88))	('patients', 'Species', '9606', (16, 24))	('N2 status', 'Var', (30, 39))	('patient', 'Species', '9606', (16, 23))
57374	25919696	We have previously associated KRAS mutations with disease progression and reduced survival in colorectal cancer patients.	('associated', 'Reg', (19, 29))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('KRAS', 'Gene', (30, 34))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('patients', 'Species', '9606', (112, 120))	('disease', 'Disease', (50, 57))	('survival', 'MPA', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Disease', (94, 111))	('reduced', 'NegReg', (74, 81))	('mutations', 'Var', (35, 44))
57375	25919696	We used TaqMan low-density array (TLDA) qRT-PCR analysis to identify miRNAs differentially expressed in normal colorectal mucosa, adenomas and cancers and in isogeneic KRAS WT and mutant HCT116 cells, and used a variety of phenotypic assays to assess the influence of miRNA expression on KRAS activity, chemosensitivity, proliferation and invasion.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mutant', 'Var', (180, 186))	('colorectal mucosa', 'Disease', 'MESH:D015179', (111, 128))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('adenomas and cancers', 'Disease', 'MESH:D000236', (130, 150))	('HCT116', 'CellLine', 'CVCL:0291', (187, 193))	('colorectal mucosa', 'Disease', (111, 128))
57376	25919696	MicroRNA-224 was differentially expressed in dysplastic colorectal disease and in isogeneic KRAS WT and mutant HCT116 cells.	('colorectal disease', 'Phenotype', 'HP:0011024', (56, 74))	('mutant', 'Var', (104, 110))	('dysplastic colorectal disease', 'Disease', 'MESH:D015179', (45, 74))	('dysplastic colorectal disease', 'Disease', (45, 74))	('MicroRNA-224', 'Gene', (0, 12))	('HCT116', 'CellLine', 'CVCL:0291', (111, 117))	('MicroRNA-224', 'Gene', '407009', (0, 12))
57378	25919696	5-FU chemosensitivity was significantly increased in miR-224 knockdown cells, and in NIH3T3 cells expressing KRAS and BRAF mutant proteins.	('miR-224', 'Gene', (53, 60))	('5-FU chemosensitivity', 'MPA', (0, 21))	('5-FU', 'Chemical', 'MESH:D005472', (0, 4))	('miR-224', 'Gene', '407009', (53, 60))	('increased', 'PosReg', (40, 49))	('NIH3T3', 'CellLine', 'CVCL:0594', (85, 91))	('mutant', 'Var', (123, 129))
57385	25919696	Progression from colorectal adenoma to cancer is driven by the acquisition of loss of function mutations in tumour suppressor genes such as APC and TP53, and activating mutations in oncogenes including Kirsten RAS (KRAS).	('tumour', 'Disease', (108, 114))	('Kirsten RAS', 'Gene', (202, 213))	('mutations', 'Var', (169, 178))	('Kirsten RAS', 'Gene', '3845', (202, 213))	('activating', 'PosReg', (158, 168))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('APC', 'Disease', 'MESH:D011125', (140, 143))	('colorectal adenoma to cancer', 'Disease', (17, 45))	('APC', 'Disease', (140, 143))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('colorectal adenoma to cancer', 'Disease', 'MESH:D015179', (17, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('APC', 'cellular_component', 'GO:0005680', ('140', '143'))	('mutations', 'Var', (95, 104))	('tumour', 'Disease', 'MESH:D009369', (108, 114))	('loss of function', 'NegReg', (78, 94))
57386	25919696	We have described significantly increased KRAS mutation burden in advanced Dukes' C cancers and shown that mutation burden is negatively associated with survival.	("Dukes' C cancers", 'Disease', (75, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('mutation', 'Var', (47, 55))	("Dukes' C cancers", 'Disease', 'MESH:D019698', (75, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('increased', 'PosReg', (32, 41))	('negatively', 'NegReg', (126, 136))	('KRAS', 'Protein', (42, 46))
57389	25919696	KRAS and BRAF mutation status are clinically relevant response biomarkers in patients treated with cetuximab and related drugs, monoclonal antibodies targeted to the epidermal growth factor receptor, a key node in the RAS/MAPK signalling pathway.	('BRAF', 'Gene', (9, 13))	('patients', 'Species', '9606', (77, 85))	('mutation', 'Var', (14, 22))	('epidermal growth factor receptor', 'Gene', (166, 198))	('cetuximab', 'Chemical', 'MESH:D000068818', (99, 108))	('KRAS', 'Gene', (0, 4))	('epidermal growth factor receptor', 'Gene', '1956', (166, 198))
57390	25919696	MicroRNAs are frequently differentially expressed in cancer, and have been suggested to influence cancer progression, following negative regulation of both tumour suppressor genes and proto-oncogenes.	('MicroRNAs', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (53, 59))	('influence', 'Reg', (88, 97))	('tumour', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Disease', (98, 104))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('tumour', 'Disease', 'MESH:D009369', (156, 162))
57391	25919696	Previous studies have highlighted significant differences in miRNA expression in colorectal cancer relative to matched normal tissue, where specific miRNAs have consistently increased (e.g., miR-21, miR-135b, miR-183, miR-31, miR-201) or decreased (e.g., miR-145, miR-378) expression.	('miR-31', 'Gene', '407035', (218, 224))	('miR-183', 'Gene', (209, 216))	('miRNA expression', 'MPA', (61, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('miR-378', 'Gene', '494327', (264, 271))	('colorectal cancer', 'Disease', (81, 98))	('miR-201', 'Var', (226, 233))	('decreased', 'NegReg', (238, 247))	('differences', 'Reg', (46, 57))	('miR-21', 'Gene', '406991', (191, 197))	('miR-31', 'Gene', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))	('miR-145', 'Gene', '406937', (255, 262))	('miR-135b', 'Gene', '442891', (199, 207))	('miR-183', 'Gene', '406959', (209, 216))	('miR-135b', 'Gene', (199, 207))	('miR-21', 'Gene', (191, 197))	('miR-145', 'Gene', (255, 262))	('increased', 'PosReg', (174, 183))	('expression', 'MPA', (273, 283))	('miR-378', 'Gene', (264, 271))
57401	25919696	Isogeneic cell lines were created from the parental HCT116 cell line (heterozygous for KRAS WT and G13D KRAS mutated alleles) by deleting an allele by targeted homologous recombination to create KRAS mutant(KRAS G13D/-) and WT(KRASWT/-) HCT116 colorectal cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('colorectal cancer', 'Phenotype', 'HP:0003003', (244, 261))	('deleting', 'Var', (129, 137))	('HCT116', 'CellLine', 'CVCL:0291', (52, 58))	('colorectal cancer', 'Disease', (244, 261))	('HCT116', 'CellLine', 'CVCL:0291', (237, 243))	('homologous recombination', 'biological_process', 'GO:0035825', ('160', '184'))	('KRAS G13D/-', 'Var', (207, 218))	('G13D', 'Mutation', 'rs112445441', (99, 103))	('KRAS', 'Var', (195, 199))	('G13D', 'Mutation', 'rs112445441', (212, 216))	('colorectal cancer', 'Disease', 'MESH:D015179', (244, 261))
57405	25919696	2.5 x 105 cells were transiently transfected in six-well plates with 250 ng of plasmids encoding either WT KRAS, WT BRAF, KRAS G12V, KRAS G13D or BRAF V6000E using Lipofectamine (Invitrogen, Paisley, UK), and harvested 48 h after transfection as previously described.	('V6000E', 'SUBSTITUTION', 'None', (151, 157))	('G13D', 'Mutation', 'rs112445441', (138, 142))	('KRAS G12V', 'Var', (122, 131))	('G12V', 'Mutation', 'rs121913529', (127, 131))	('V6000E', 'Var', (151, 157))	('Lipofectamine', 'Chemical', 'MESH:C086724', (164, 177))	('KRAS G13D', 'Var', (133, 142))
57409	25919696	Cellular extracts were obtained from cells 24 h following transfection with miR-224 inhibitors or from untransfected cells.	('inhibitors', 'Var', (84, 94))	('miR-224', 'Gene', (76, 83))	('miR-224', 'Gene', '407009', (76, 83))
57412	25919696	MTT cytotoxicity assays were performed to compare chemosensitivity of HCT116 KRAS WT and mutant cells, HCT116 KRAS WT cells following miR-224 knockdown and NIH3T3 KRAS and BRAF WT and mutant cells following treatment with 5-FU, oxaliplatin and irinotecan.	('5-FU', 'Chemical', 'MESH:D005472', (222, 226))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('miR-224', 'Gene', (134, 141))	('cytotoxicity', 'Disease', (4, 16))	('HCT116', 'CellLine', 'CVCL:0291', (103, 109))	('HCT116', 'CellLine', 'CVCL:0291', (70, 76))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (228, 239))	('miR-224', 'Gene', '407009', (134, 141))	('NIH3T3', 'CellLine', 'CVCL:0594', (156, 162))	('irinotecan', 'Chemical', 'MESH:D000077146', (244, 254))	('mutant', 'Var', (89, 95))
57416	25919696	Cell doubling time was also compared in HCT116 KRAS WT and mutant cells and KRAS WT miR-224 knockdown cells using CellTrace Violet Cell Proliferation Kits (Life Technologies) according to the manufacturer's guidelines.	('HCT116', 'CellLine', 'CVCL:0291', (40, 46))	('miR-224', 'Gene', (84, 91))	('mutant', 'Var', (59, 65))	('miR-224', 'Gene', '407009', (84, 91))	('CellTrace Violet', 'Chemical', '-', (114, 130))	('Cell Proliferation', 'biological_process', 'GO:0008283', ('131', '149'))
57418	25919696	Invasion in HCT116 KRAS WT and mutant cells and KRAS WT miR-224 knockdown cells was compared using InnoCyte invasion assays (Merck Millipore, Watford, UK) according to the manufacturer's protocol.	('miR-224', 'Gene', (56, 63))	('HCT116', 'CellLine', 'CVCL:0291', (12, 18))	('mutant', 'Var', (31, 37))	('miR-224', 'Gene', '407009', (56, 63))
57422	25919696	Of the 377 miRNAs analysed, 153 (40.6%) were not expressed, 199 (52.7%) expressed in at least 2 cancers and 108 (28.6%) expressed in all 12 cancers, including 18 miRNAs (miR-193b, miR-323-3p, miR-324-3p, miR-331-5p, miR-339-3p, miR-362-5p, miR-365, miR-374, miR-449b, miR-487a, miR-491-5p, miR-494, miR-501, miR-532-5p, miR-574-3p, miR-671-3p, miR-744 and miR-99b) not previously described in colorectal cancer (Supplementary Information and Supplementary Table 1A).	('miR-193b', 'Gene', '574455', (170, 178))	('miR-449b', 'Gene', '693123', (258, 266))	('miR-487a', 'Gene', (268, 276))	('miR-574-3p', 'Gene', (320, 330))	('miR-744', 'Gene', '100126313', (344, 351))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('miR-494', 'Gene', '574452', (290, 297))	('cancers', 'Disease', (96, 103))	('miR-99b', 'Gene', (356, 363))	('miR-494', 'Gene', (290, 297))	('miR-501', 'Gene', (299, 306))	('miR-501', 'Gene', '574503', (299, 306))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('miR-491-5p', 'Var', (278, 288))	('colorectal cancer', 'Phenotype', 'HP:0003003', (393, 410))	('miR-331-5p', 'Var', (204, 214))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('miR-532', 'Gene', '693124', (308, 315))	('miR-671-3p', 'Var', (332, 342))	('miR-744', 'Gene', (344, 351))	('miR-532', 'Gene', (308, 315))	('miR-193b', 'Gene', (170, 178))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (404, 410))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('miR-339-3p', 'Var', (216, 226))	('miR-99b', 'Gene', '407056', (356, 363))	('miR-362-5p', 'Var', (228, 238))	('colorectal cancer', 'Disease', 'MESH:D015179', (393, 410))	('miR-574-3p', 'Gene', '693159', (320, 330))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('miR-449b', 'Gene', (258, 266))	('miR-487a', 'Gene', '619555', (268, 276))	('cancers', 'Disease', (140, 147))	('colorectal cancer', 'Disease', (393, 410))	('miR-323-3p', 'Var', (180, 190))
57425	25919696	To investigate the influence of KRAS mutation status on miRNA expression, we used TLDA qRT-PCR analysis to compare miRNA expression in isogeneic HCT116 colorectal cancer cell lines, expressing either WT or mutant KRAS.	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('mutant', 'Var', (206, 212))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('miRNA expression', 'MPA', (115, 131))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('colorectal cancer', 'Disease', (152, 169))	('HCT116', 'CellLine', 'CVCL:0291', (145, 151))	('KRAS', 'Gene', (213, 217))
57426	25919696	We identified 12 differentially expressed miRNAs (Figure 2A), 3 of which (miR-224, miR-29c and miR-139-5p) were also differentially expressed in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (145, 162))	('miR-139-5p', 'Var', (95, 105))	('miR-224', 'Gene', '407009', (74, 81))	('colorectal cancer', 'Phenotype', 'HP:0003003', (145, 162))	('miR-224', 'Gene', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('colorectal cancer', 'Disease', (145, 162))	('miR-29c', 'Gene', (83, 90))	('miR-29c', 'Gene', '407026', (83, 90))
57427	25919696	Unlike miR-29c and miR-139-5p, miR-224 expression was increased in both colorectal adenomas and cancers, and was prioritised for more detailed analysis, following replication of our TLDA data using a small TaqMan miR-224 RNA assay to confirm differential miR-224 expression in HCT116 KRAS WT and mutant cells (3.3-fold; P=0.0002; Figure 2B), and in colorectal cancers relative to normal colorectal mucosa (n=12; P=0.005; Figure 2C).	('cancer', 'Phenotype', 'HP:0002664', (360, 366))	('mutant', 'Var', (296, 302))	('colorectal cancers', 'Disease', (349, 367))	('miR-29c', 'Gene', (7, 14))	('cancers', 'Phenotype', 'HP:0002664', (360, 367))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('expression', 'MPA', (39, 49))	('HCT116', 'CellLine', 'CVCL:0291', (277, 283))	('colorectal cancers', 'Disease', 'MESH:D015179', (349, 367))	('colorectal mucosa', 'Disease', (387, 404))	('colorectal adenomas and cancers', 'Disease', 'MESH:D015179', (72, 103))	('miR-224', 'Gene', (255, 262))	('colorectal cancer', 'Phenotype', 'HP:0003003', (349, 366))	('miR-224', 'Gene', '407009', (255, 262))	('increased', 'PosReg', (54, 63))	('miR-29c', 'Gene', '407026', (7, 14))	('miR-224', 'Gene', '407009', (213, 220))	('miR-224', 'Gene', (213, 220))	('miR-224', 'Gene', '407009', (31, 38))	('miR-224', 'Gene', (31, 38))	('colorectal mucosa', 'Disease', 'MESH:D015179', (387, 404))
57428	25919696	To further investigate whether miR-224 expression was influenced by KRAS or BRAF mutation status, we compared miR-224 expression in an extended cancer panel, selected by previously determined mutation status (n=41; 18 KRAS mutant, 9 BRAFV600E mutant and 14 KRAS and BRAF WT cancers; Supplementary Information and Supplementary Table 2).	('BRAF WT cancers', 'Disease', 'MESH:D009369', (266, 281))	('miR-224', 'Gene', '407009', (110, 117))	('BRAFV600E', 'Mutation', 'rs113488022', (233, 242))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('cancers', 'Phenotype', 'HP:0002664', (274, 281))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (274, 280))	('cancer', 'Disease', (144, 150))	('BRAFV600E mutant', 'Var', (233, 249))	('BRAF WT cancers', 'Disease', (266, 281))	('miR-224', 'Gene', '407009', (31, 38))	('miR-224', 'Gene', (31, 38))	('miR-224', 'Gene', (110, 117))
57429	25919696	MiR-224 expression was significantly decreased (P=0.012) in BRAF mutant cancers (Figure 2D), although not in KRAS mutant cancers, possibly as a consequence of mixed KRAS genotype; ideally, we would have restricted our analysis to KRAS G13D mutant cancers to facilitate direct comparison with our cell line data, but insufficient cancers with this rare genotype were available for analysis.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('insufficient cancers', 'Disease', (316, 336))	('cancers', 'Disease', (247, 254))	('cancers', 'Disease', (72, 79))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('cancers', 'Disease', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('mutant', 'Var', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Disease', 'MESH:D009369', (329, 336))	('expression', 'MPA', (8, 18))	('BRAF', 'Gene', (60, 64))	('insufficient cancers', 'Disease', 'MESH:D000309', (316, 336))	('cancers', 'Disease', 'MESH:D009369', (247, 254))	('G13D', 'Mutation', 'rs112445441', (235, 239))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('decreased', 'NegReg', (37, 46))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancers', 'Phenotype', 'HP:0002664', (329, 336))	('MiR-224', 'Gene', (0, 7))	('cancers', 'Disease', (329, 336))	('MiR-224', 'Gene', '407009', (0, 7))
57435	25919696	As miR-224 expression is significantly higher in KRAS WT cells, we hypothesised that miR-224 knockdown may phenocopy KRAS mutation by increasing KRAS activity.	('knockdown', 'Var', (93, 102))	('KRAS', 'Disease', (145, 149))	('increasing', 'PosReg', (134, 144))	('KRAS mutation', 'Disease', (117, 130))	('expression', 'MPA', (11, 21))	('miR-224', 'Gene', '407009', (85, 92))	('miR-224', 'Gene', (85, 92))	('miR-224', 'Gene', (3, 10))	('miR-224', 'Gene', '407009', (3, 10))
57436	25919696	The effect of miR-224 knockdown on the amount of GTP-bound KRAS was therefore investigated using a RAS ELISA.	('knockdown', 'Var', (22, 31))	('miR-224', 'Gene', (14, 21))	('GTP', 'Chemical', 'MESH:D006160', (49, 52))	('miR-224', 'Gene', '407009', (14, 21))
57437	25919696	KRAS activity was higher (2.5-fold, P=0.002) in KRAS mutant than in WT HCT116 cells (Figure 3A) and, consistent with our hypothesis, miR-224 knockdown in KRAS WT cells significantly increased RAS activity (1.9-fold, P=0.001).	('increased', 'PosReg', (182, 191))	('KRAS', 'CPA', (0, 4))	('KRAS', 'Gene', (48, 52))	('RAS', 'CPA', (192, 195))	('miR-224', 'Gene', '407009', (133, 140))	('miR-224', 'Gene', (133, 140))	('mutant', 'Var', (53, 59))	('higher', 'PosReg', (18, 24))	('HCT116', 'CellLine', 'CVCL:0291', (71, 77))
57438	25919696	To investigate KRAS specificity, NRAS and HRAS expression was additionally compared in HCT116 KRAS WT and miR-224 knockdown cells, but no significant differences identified (Supplementary Figure 3), although KRAS expression was itself significantly increased following miR-224 knockdown (1.7-fold, P=0.007).	('HRAS', 'Gene', '3265', (42, 46))	('miR-224', 'Gene', '407009', (269, 276))	('NRAS', 'Gene', (33, 37))	('expression', 'MPA', (213, 223))	('HRAS', 'Gene', (42, 46))	('KRAS', 'Gene', (208, 212))	('knockdown', 'Var', (277, 286))	('NRAS', 'Gene', '4893', (33, 37))	('increased', 'PosReg', (249, 258))	('miR-224', 'Gene', (106, 113))	('HCT116', 'CellLine', 'CVCL:0291', (87, 93))	('miR-224', 'Gene', '407009', (106, 113))	('miR-224', 'Gene', (269, 276))
57440	25919696	Consistent with increased KRAS activity, ERK phosphorylation was increased in miR-224 knockdown cells (1.6-fold; P=0.006; Figure 3B).	('activity', 'MPA', (31, 39))	('increased', 'PosReg', (65, 74))	('knockdown', 'Var', (86, 95))	('miR-224', 'Gene', (78, 85))	('increased', 'PosReg', (16, 25))	('phosphorylation', 'MPA', (45, 60))	('miR-224', 'Gene', '407009', (78, 85))	('ERK', 'Gene', '5594', (41, 44))	('ERK', 'Gene', (41, 44))	('KRAS', 'CPA', (26, 30))
57441	25919696	Similarly, AKT phosphorylation was significantly higher (tyrosine 308 1.4-fold, P=0.01; serine 473 1.3-fold, P=0.04) in miR-224 knockdown cells, suggesting that miR-224 directly influences the pro-survival RAS/AKT/PI3K pathway.	('AKT', 'Gene', (11, 14))	('AKT', 'Gene', (210, 213))	('influences', 'Reg', (178, 188))	('pro-survival', 'biological_process', 'GO:0043066', ('193', '205'))	('serine', 'Chemical', 'MESH:D012694', (88, 94))	('knockdown', 'Var', (128, 137))	('miR-224', 'Gene', '407009', (120, 127))	('miR-224', 'Gene', (120, 127))	('tyrosine', 'Chemical', 'MESH:D014443', (57, 65))	('AKT', 'Gene', '207', (11, 14))	('miR-224', 'Gene', '407009', (161, 168))	('miR-224', 'Gene', (161, 168))	('AKT', 'Gene', '207', (210, 213))	('higher', 'PosReg', (49, 55))	('phosphorylation', 'biological_process', 'GO:0016310', ('15', '30'))	('PI3K', 'molecular_function', 'GO:0016303', ('214', '218'))
57442	25919696	Our analysis identified several additional signalling molecules (STAT1, STAT3, AMPK, HSP27, PRAS40 and p38 (MAPK11)) the expression of which was also significantly increased following miR-224 knockdown, highlighting novel candidate miR-224 target genes (Supplementary Figure 4).	('STAT1', 'Gene', (65, 70))	('STAT3', 'Gene', (72, 77))	('expression', 'MPA', (121, 131))	('AMPK', 'molecular_function', 'GO:0004691', ('79', '83'))	('MAPK11', 'Gene', '5600', (108, 114))	('p38', 'Gene', '5594', (103, 106))	('AMPK', 'Gene', '5562', (79, 83))	('STAT3', 'Gene', '6774', (72, 77))	('increased', 'PosReg', (164, 173))	('PRAS40', 'Gene', (92, 98))	('MAPK11', 'Gene', (108, 114))	('STAT1', 'Gene', '6772', (65, 70))	('signalling', 'biological_process', 'GO:0023052', ('43', '53'))	('AMPK', 'molecular_function', 'GO:0047322', ('79', '83'))	('HSP27', 'Gene', '3315', (85, 90))	('miR-224', 'Gene', '407009', (232, 239))	('miR-224', 'Gene', (232, 239))	('AMPK', 'Gene', (79, 83))	('knockdown', 'Var', (192, 201))	('PRAS40', 'Gene', '84335', (92, 98))	('miR-224', 'Gene', '407009', (184, 191))	('p38', 'Gene', (103, 106))	('miR-224', 'Gene', (184, 191))	('AMPK', 'molecular_function', 'GO:0050405', ('79', '83'))	('MAPK', 'molecular_function', 'GO:0004707', ('108', '112'))	('HSP27', 'Gene', (85, 90))
57443	25919696	MTT cytotoxicity assays were used to investigate the effect of miR-224 knockdown on sensitivity to 5-FU, oxaliplatin and irinotecan, the drugs used to treat colorectal cancer.	('5-FU', 'Chemical', 'MESH:D005472', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('colorectal cancer', 'Disease', (157, 174))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))	('knockdown', 'Var', (71, 80))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('cytotoxicity', 'Disease', (4, 16))	('colorectal cancer', 'Disease', 'MESH:D015179', (157, 174))	('irinotecan', 'Chemical', 'MESH:D000077146', (121, 131))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (105, 116))	('colorectal cancer', 'Phenotype', 'HP:0003003', (157, 174))	('miR-224', 'Gene', '407009', (63, 70))	('miR-224', 'Gene', (63, 70))
57444	25919696	MicroRNA-224 knockdown increased the sensitivity of HCT116 KRAS WT cells to 5-FU, with a 1.9-fold decrease in IC50 (P=0.04, Figure 3C) but did not influence sensitivity to oxaliplatin or irinotecan (data not shown).	('IC50', 'MPA', (110, 114))	('decrease', 'NegReg', (98, 106))	('HCT116', 'CellLine', 'CVCL:0291', (52, 58))	('5-FU', 'Chemical', 'MESH:D005472', (76, 80))	('MicroRNA-224', 'Gene', (0, 12))	('increased', 'PosReg', (23, 32))	('MicroRNA-224', 'Gene', '407009', (0, 12))	('knockdown', 'Var', (13, 22))	('sensitivity', 'MPA', (37, 48))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (172, 183))	('irinotecan', 'Chemical', 'MESH:D000077146', (187, 197))
57445	25919696	To investigate whether 5-FU chemosensitivity was KRAS dependent, we additionally compared 5-FU sensitivity in novel NIH3T3-derived cell lines, stably transfected with WT KRAS, WT BRAF, various KRAS mutants and BRAFV600E (Figure 3D).	('5-FU', 'Chemical', 'MESH:D005472', (23, 27))	('BRAFV600E', 'Var', (210, 219))	('BRAFV600E', 'Mutation', 'rs113488022', (210, 219))	('KRAS', 'Gene', (193, 197))	('5-FU', 'Chemical', 'MESH:D005472', (90, 94))	('mutants', 'Var', (198, 205))	('NIH3T3', 'CellLine', 'CVCL:0594', (116, 122))
57446	25919696	Consistent with our miR-224 knockdown data, all mutant KRAS cells (G12V and G13D mutants illustrated as examples) and BRAF mutant (V600E) cells were more sensitive to 5-FU (Figure 3D).	('V600E', 'Mutation', 'rs113488022', (131, 136))	('sensitive to 5-FU', 'MPA', (154, 171))	('G13D', 'Var', (76, 80))	('5-FU', 'Chemical', 'MESH:D005472', (167, 171))	('G12V', 'Var', (67, 71))	('V600E', 'Var', (131, 136))	('G13D', 'Mutation', 'rs112445441', (76, 80))	('G12V', 'Mutation', 'rs121913529', (67, 71))	('miR-224', 'Gene', '407009', (20, 27))	('more', 'PosReg', (149, 153))	('miR-224', 'Gene', (20, 27))
57447	25919696	We used five miRNA target prediction databases (mirDB, miRANDA, miRBase, TargetMiner and TargetScan) to predict targets of miRNAs differentially expressed in HCT116 KRAS WT and mutant cells (Figure 2A), prioritising targets common to at least two databases for further analysis.	('mutant', 'Var', (177, 183))	('HCT116', 'Var', (158, 164))	('HCT116', 'CellLine', 'CVCL:0291', (158, 164))
57449	25919696	A similar approach was used to compare HCT116 WT cells before and after miR-224 knockdown (Supplementary Information and Supplementary Table 4).	('miR-224', 'Gene', (72, 79))	('knockdown', 'Var', (80, 89))	('HCT116', 'CellLine', 'CVCL:0291', (39, 45))	('miR-224', 'Gene', '407009', (72, 79))
57451	25919696	Consistent with our bioinformatics predictions, miR-224 knockdown significantly increased cell doubling time (23.5 to 26.1 h; P<0.001 and 19.8 to 27.5 h; P=0.01, respectively).	('miR-224', 'Gene', '407009', (48, 55))	('miR-224', 'Gene', (48, 55))	('increased', 'PosReg', (80, 89))	('cell doubling time', 'CPA', (90, 108))	('knockdown', 'Var', (56, 65))
57454	25919696	CDH1 (1.12-fold; P=0.005, Figure 4A) expression was significantly increased in miR-224 knockdown cells, although such subtle variation in gene expression is unlikely to significantly influence the EMT phenotype.	('miR-224', 'Gene', '407009', (79, 86))	('increased', 'PosReg', (66, 75))	('CDH1', 'Gene', '999', (0, 4))	('expression', 'MPA', (37, 47))	('miR-224', 'Gene', (79, 86))	('CDH1', 'Gene', (0, 4))	('knockdown', 'Var', (87, 96))
57456	25919696	InnoCyte invasion assays were then used to show that miR-224 knockdown significantly reduced invasion in HCT116 KRAS WT cells (1.75-fold; P=0.009, Figure 4C).	('HCT116', 'CellLine', 'CVCL:0291', (105, 111))	('miR-224', 'Gene', (53, 60))	('miR-224', 'Gene', '407009', (53, 60))	('knockdown', 'Var', (61, 70))	('invasion', 'CPA', (93, 101))	('reduced', 'NegReg', (85, 92))
57457	25919696	HCT116 KRAS mutant cells were significantly less invasive (1.2-fold; P=0.04) than HCT116 KRAS WT cells, further confirming our hypothesis that miR-224 knockdown in KRAS WT cells phenocopies KRAS mutation.	('HCT116 KRAS mutant', 'Var', (0, 18))	('less', 'NegReg', (44, 48))	('HCT116', 'CellLine', 'CVCL:0291', (82, 88))	('HCT116', 'CellLine', 'CVCL:0291', (0, 6))	('KRAS mutation', 'Disease', (190, 203))	('miR-224', 'Gene', '407009', (143, 150))	('miR-224', 'Gene', (143, 150))	('invasive', 'CPA', (49, 57))	('knockdown', 'Var', (151, 160))
57458	25919696	In NIH3T3 cells stably expressing WT or mutant KRAS, however, G13D KRAS mutant cells were significantly more invasive than NIH3T3 KRAS WT cells (4.6-fold; P=0.002).	('NIH3T3', 'CellLine', 'CVCL:0594', (3, 9))	('G13D', 'Mutation', 'rs112445441', (62, 66))	('mutant', 'Var', (72, 78))	('invasive', 'CPA', (109, 117))	('KRAS', 'Gene', (67, 71))	('more', 'PosReg', (104, 108))	('G13D', 'Var', (62, 66))	('NIH3T3', 'CellLine', 'CVCL:0594', (123, 129))
57462	25919696	We have previously described the importance of dysregulated KRAS signalling in the development and progression of colorectal cancer, and now aimed to identify miRNAs associated with disease progression and/or regulation of the RAS/MAPK signalling pathway.	('RAS/MAPK', 'Pathway', (227, 235))	('signalling', 'biological_process', 'GO:0023052', ('65', '75'))	('signalling pathway', 'biological_process', 'GO:0007165', ('236', '254'))	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('regulation', 'biological_process', 'GO:0065007', ('209', '219'))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('KRAS', 'Protein', (60, 64))	('MAPK', 'molecular_function', 'GO:0004707', ('231', '235'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('MAPK signalling', 'biological_process', 'GO:0000165', ('231', '246'))	('associated', 'Reg', (166, 176))	('dysregulated', 'Var', (47, 59))	('colorectal cancer', 'Disease', (114, 131))
57463	25919696	We identified several candidate miRNAs, one of which, miR-224, was differentially expressed in colorectal adenomas and cancers, and also in KRAS WT and mutant HCT116-derived colorectal cancer cell lines.	('colorectal adenomas and cancers', 'Disease', 'MESH:D015179', (95, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (174, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('miR-224', 'Gene', (54, 61))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('miR-224', 'Gene', '407009', (54, 61))	('colorectal cancer', 'Disease', (174, 191))	('mutant', 'Var', (152, 158))	('HCT116', 'CellLine', 'CVCL:0291', (159, 165))	('colorectal cancer', 'Disease', 'MESH:D015179', (174, 191))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
57466	25919696	Inhibition of miR-224 would therefore be predicted to increase RAS/MAPK signalling, either through activation of KRAS or promotion of RAF1/MEK binding following RKIP activation.	('binding', 'Interaction', (143, 150))	('promotion', 'PosReg', (121, 130))	('KRAS', 'Protein', (113, 117))	('increase', 'PosReg', (54, 62))	('RKIP', 'Gene', '5037', (161, 165))	('miR-224', 'Gene', (14, 21))	('RAF1', 'Gene', (134, 138))	('activation', 'PosReg', (99, 109))	('RAF1', 'Gene', '5894', (134, 138))	('Inhibition', 'Var', (0, 10))	('RAS/MAPK signalling', 'MPA', (63, 82))	('RKIP', 'Gene', (161, 165))	('MEK', 'Gene', (139, 142))	('MEK', 'Gene', '5609', (139, 142))	('miR-224', 'Gene', '407009', (14, 21))
57467	25919696	Consistent with this hypothesis, we described increased KRAS activity and increased ERK and AKT phosphorylation following miR-224 knockdown in HCT116 colorectal cancer cells, whereas in colorectal cancer patients, RKIP expression has previously been shown to inversely correlate with patient survival and predict metastatic spread.	('ERK', 'Gene', (84, 87))	('patients', 'Species', '9606', (204, 212))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('phosphorylation', 'biological_process', 'GO:0016310', ('96', '111'))	('knockdown', 'Var', (130, 139))	('increased', 'PosReg', (74, 83))	('colorectal cancer', 'Disease', 'MESH:D015179', (150, 167))	('RKIP', 'Gene', (214, 218))	('colorectal cancer', 'Phenotype', 'HP:0003003', (186, 203))	('AKT', 'Gene', (92, 95))	('ERK', 'molecular_function', 'GO:0004707', ('84', '87'))	('patient', 'Species', '9606', (284, 291))	('KRAS', 'Protein', (56, 60))	('colorectal cancer', 'Disease', (150, 167))	('HCT116', 'CellLine', 'CVCL:0291', (143, 149))	('RKIP', 'Gene', '5037', (214, 218))	('miR-224', 'Gene', (122, 129))	('miR-224', 'Gene', '407009', (122, 129))	('activity', 'MPA', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('metastatic spread', 'CPA', (313, 330))	('patient', 'Species', '9606', (204, 211))	('ERK', 'Gene', '5594', (84, 87))	('colorectal cancer', 'Disease', 'MESH:D015179', (186, 203))	('increased', 'PosReg', (46, 55))	('AKT', 'Gene', '207', (92, 95))	('colorectal cancer', 'Phenotype', 'HP:0003003', (150, 167))	('colorectal cancer', 'Disease', (186, 203))
57469	25919696	Several additional miRNAs (miR-146b-3p, miR-486-5p, miR-92a, miR-127-3p and miR-378) have previously been shown to be differentially expressed in KRAS WT and mutant colorectal cancers.	('miR-378', 'Gene', '494327', (76, 83))	('miR-378', 'Gene', (76, 83))	('colorectal cancer', 'Phenotype', 'HP:0003003', (165, 182))	('miR-92a', 'Var', (52, 59))	('miR-486-5p', 'Var', (40, 50))	('colorectal cancers', 'Disease', 'MESH:D015179', (165, 183))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('miR-127-3p', 'Gene', (61, 71))	('colorectal cancers', 'Disease', (165, 183))	('miR-127-3p', 'Gene', '100302165', (61, 71))	('miR-146b-3p', 'Var', (27, 38))	('mutant', 'Var', (158, 164))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))
57472	25919696	Similar to our findings in colorectal cancer, previous studies have described increased miR-224 expression (and increased expression of other genes located on chromosome Xq28) in hepatocellular carcinoma (HCC), as a result of alternative epigenetic regulation of miRNA expression by the histone deacetylases HDAC1 and HDAC3, and the histone acetylase protein EP300.	('HDAC1', 'Gene', (308, 313))	('colorectal cancer', 'Disease', (27, 44))	('HDAC3', 'Gene', '8841', (318, 323))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (179, 203))	('expression', 'MPA', (96, 106))	('HDAC1', 'Gene', '3065', (308, 313))	('EP300', 'Gene', '2033', (359, 364))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (179, 203))	('colorectal cancer', 'Phenotype', 'HP:0003003', (27, 44))	('epigenetic', 'Var', (238, 248))	('miRNA', 'Protein', (263, 268))	('EP300', 'Gene', (359, 364))	('HDAC3', 'Gene', (318, 323))	('hepatocellular carcinoma', 'Disease', (179, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('miR-224', 'Gene', '407009', (88, 95))	('miR-224', 'Gene', (88, 95))	('increased', 'PosReg', (78, 87))	('colorectal cancer', 'Disease', 'MESH:D015179', (27, 44))
57474	25919696	We have previously described amplification of the q arm of the X chromosome in both colorectal adenomas and colorectal cancers; it will therefore be of particular interest in future studies to investigate whether similar epigenetic and inflammation-mediated mechanisms of miR-224 regulation are important in colorectal cancer.	('colorectal cancer', 'Disease', (308, 325))	('miR-224', 'Gene', '407009', (272, 279))	('amplification', 'Var', (29, 42))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('regulation', 'biological_process', 'GO:0065007', ('280', '290'))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('colorectal adenomas and colorectal cancers', 'Disease', 'MESH:D015179', (84, 126))	('inflammation', 'Disease', 'MESH:D007249', (236, 248))	('colorectal cancer', 'Disease', 'MESH:D015179', (308, 325))	('colorectal cancer', 'Phenotype', 'HP:0003003', (308, 325))	('inflammation', 'biological_process', 'GO:0006954', ('236', '248'))	('X chromosome', 'cellular_component', 'GO:0000805', ('63', '75'))	('colorectal cancer', 'Disease', (108, 125))	('inflammation', 'Disease', (236, 248))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('miR-224', 'Gene', (272, 279))
57475	25919696	MicroRNA-224 knockdown in HCT116 KRAS WT cells increased cell doubling time, suggesting that miR-224 influences disease progression by increasing cell proliferation or by inhibiting apoptosis.	('miR-224', 'Gene', '407009', (93, 100))	('miR-224', 'Gene', (93, 100))	('inhibiting', 'NegReg', (171, 181))	('MicroRNA-224', 'Gene', '407009', (0, 12))	('disease progression', 'CPA', (112, 131))	('increased', 'PosReg', (47, 56))	('cell doubling time', 'CPA', (57, 75))	('apoptosis', 'CPA', (182, 191))	('MicroRNA-224', 'Gene', (0, 12))	('increasing', 'PosReg', (135, 145))	('influences', 'Reg', (101, 111))	('knockdown', 'Var', (13, 22))	('cell proliferation', 'CPA', (146, 164))	('HCT116', 'CellLine', 'CVCL:0291', (26, 32))
57477	25919696	Consistent with these findings, we confirmed increased pro-proliferative ERK and STAT3 phosphorylation following miR-224 knockdown, and increased STAT1 phosphorylation that influences tumour suppressor and anti-angiogenesis pathways.	('knockdown', 'Var', (121, 130))	('pro-proliferative', 'CPA', (55, 72))	('increased', 'PosReg', (45, 54))	('ERK', 'Gene', (73, 76))	('STAT1', 'Gene', (146, 151))	('miR-224', 'Gene', (113, 120))	('STAT3', 'Gene', '6774', (81, 86))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('miR-224', 'Gene', '407009', (113, 120))	('STAT1', 'Gene', '6772', (146, 151))	('STAT3', 'Gene', (81, 86))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('increased', 'PosReg', (136, 145))	('influences', 'Reg', (173, 183))	('tumour', 'Disease', (184, 190))	('ERK', 'Gene', '5594', (73, 76))
57480	25919696	Intriguingly, we have shown that miR-224 knockdown increased 5-FU chemosensitivity, and have suggested that this may result from the creation of a KRAS 'mutant-like' phenotype.	('5-FU', 'Chemical', 'MESH:D005472', (61, 65))	('increased', 'PosReg', (51, 60))	('5-FU chemosensitivity', 'MPA', (61, 82))	('miR-224', 'Gene', '407009', (33, 40))	('miR-224', 'Gene', (33, 40))	("KRAS 'mutant-like", 'Disease', (147, 164))	('knockdown', 'Var', (41, 50))
57481	25919696	In support of this hypothesis, we further demonstrated that introduction of mutant KRAS or BRAF to NIH3T3 cells also significantly increased 5-FU chemosensitivity, whereas) reported protection from 5-FU-induced apoptosis after targeted deletion of a mutant KRAS allele in HCT116 cells, and promotion of cell death following 5-FU challenge in cells transfected with inducible mutant KRAS (V12).	('mutant', 'Var', (375, 381))	('HCT116', 'CellLine', 'CVCL:0291', (272, 278))	('5-FU chemosensitivity', 'MPA', (141, 162))	('KRAS', 'Gene', (257, 261))	('increased', 'PosReg', (131, 140))	('NIH3T3', 'CellLine', 'CVCL:0594', (99, 105))	('cell death', 'CPA', (303, 313))	('protection', 'PosReg', (182, 192))	('deletion', 'Var', (236, 244))	('5-FU-induced', 'MPA', (198, 210))	('cell death', 'biological_process', 'GO:0008219', ('303', '313'))	('5-FU', 'Chemical', 'MESH:D005472', (198, 202))	('apoptosis', 'biological_process', 'GO:0097194', ('211', '220'))	('apoptosis', 'biological_process', 'GO:0006915', ('211', '220'))	('mutant', 'Var', (76, 82))	('mutant', 'Var', (250, 256))	('5-FU', 'Chemical', 'MESH:D005472', (141, 145))	('promotion', 'PosReg', (290, 299))	('5-FU', 'Chemical', 'MESH:D005472', (324, 328))
57482	25919696	However, as KRAS mutation status independently influences disease progression, it is challenging to assess the unique influence of mutation status on chemotherapy response in colorectal cancer patients.	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('patients', 'Species', '9606', (193, 201))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('colorectal cancer', 'Disease', (175, 192))	('mutation', 'Var', (17, 25))	('KRAS', 'Gene', (12, 16))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))	('influences', 'Reg', (47, 57))
57484	25919696	Consistent with this hypothesis, miR-224 knockdown resulted in increased E-cadherin and decreased Vimentin expression.	('E-cadherin', 'Gene', (73, 83))	('increased', 'PosReg', (63, 72))	('E-cadherin', 'Gene', '999', (73, 83))	('Vimentin', 'cellular_component', 'GO:0045098', ('98', '106'))	('miR-224', 'Gene', '407009', (33, 40))	('miR-224', 'Gene', (33, 40))	('expression', 'MPA', (107, 117))	('cadherin', 'molecular_function', 'GO:0008014', ('75', '83'))	('Vimentin', 'cellular_component', 'GO:0045099', ('98', '106'))	('Vimentin', 'Gene', (98, 106))	('decreased', 'NegReg', (88, 97))	('knockdown', 'Var', (41, 50))	('Vimentin', 'Gene', '7431', (98, 106))
57490	25919696	Similar phenotypic associations have been proposed for additional miRNAs, including miR-29c and miR-139-5p that, like miR-224, are differentially expressed in colorectal cancer and in KRAS WT and mutant HCT116 cells.	('miR-224', 'Gene', '407009', (118, 125))	('colorectal cancer', 'Disease', 'MESH:D015179', (159, 176))	('miR-224', 'Gene', (118, 125))	('miR-29c', 'Gene', '407026', (84, 91))	('HCT116', 'CellLine', 'CVCL:0291', (203, 209))	('miR-29c', 'Gene', (84, 91))	('colorectal cancer', 'Phenotype', 'HP:0003003', (159, 176))	('miR-139-5p', 'Var', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('colorectal cancer', 'Disease', (159, 176))	('mutant', 'Var', (196, 202))
57491	25919696	MicroRNA-29c, for example, has recently been shown to promote EMT by regulation of beta-catenin signalling in colorectal tumours, whereas decreased miR-29c expression has been associated with relapse in colorectal cancer patients.	('colorectal tumours', 'Disease', (110, 128))	('patients', 'Species', '9606', (221, 229))	('MicroRNA-29c', 'Var', (0, 12))	('miR-29c', 'Gene', '407026', (148, 155))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (203, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))	('promote', 'PosReg', (54, 61))	('miR-29c', 'Gene', (148, 155))	('colorectal tumours', 'Disease', 'MESH:D015179', (110, 128))	('colorectal cancer', 'Disease', 'MESH:D015179', (203, 220))	('beta-catenin', 'Gene', (83, 95))	('decreased', 'NegReg', (138, 147))	('beta-catenin', 'Gene', '1499', (83, 95))	('associated', 'Reg', (176, 186))	('colorectal cancer', 'Disease', (203, 220))	('expression', 'MPA', (156, 166))	('EMT', 'CPA', (62, 65))	('regulation', 'MPA', (69, 79))
57492	25919696	In previous TLDA analysis, miR-139-5p was shown to inhibit colorectal cancer cell growth, and has recently been described as a Notch1-dependent tumour suppressor in colorectal cancer cell lines and xenograft models, emphasising the need to extend our miR-224 analysis to additional candidate miRNAs in future studies.	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (165, 182))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('Notch1', 'Gene', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('Notch1', 'Gene', '4851', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('colorectal cancer', 'Disease', (59, 76))	('colorectal cancer', 'Disease', (165, 182))	('miR-224', 'Gene', '407009', (251, 258))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('tumour', 'Disease', (144, 150))	('miR-224', 'Gene', (251, 258))	('miR-139-5p', 'Var', (27, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (165, 182))	('inhibit', 'NegReg', (51, 58))	('colorectal cancer', 'Disease', 'MESH:D015179', (59, 76))
57497	25117503	High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry The question of whether prostate cancer is part of the Lynch syndrome spectrum of tumors is unresolved.	('prostate cancer', 'Disease', (180, 195))	('mismatch repair', 'Gene', (79, 94))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumors', 'Disease', (238, 244))	('deficiency in prostate', 'Phenotype', 'HP:0008687', (35, 57))	('prostate cancer', 'Disease', 'MESH:D011471', (49, 64))	('colon cancer', 'Phenotype', 'HP:0003003', (127, 139))	('Lynch syndrome', 'Disease', (211, 225))	('prostate cancer', 'Phenotype', 'HP:0012125', (49, 64))	('prostate cancers', 'Phenotype', 'HP:0012125', (49, 65))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('mismatch repair', 'biological_process', 'GO:0006298', ('19', '34'))	('mismatch repair', 'biological_process', 'GO:0006298', ('79', '94'))	('deficiency in prostate cancers', 'Disease', 'MESH:D011471', (35, 65))	('colon cancer', 'Disease', 'MESH:D015179', (127, 139))	('mismatch repair', 'Gene', (19, 34))	('Lynch syndrome', 'Disease', 'MESH:D003123', (211, 225))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('deficiency in prostate cancers', 'Disease', (35, 65))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('prostate cancer', 'Disease', 'MESH:D011471', (180, 195))	('mutation', 'Var', (100, 108))	('prostate cancer', 'Phenotype', 'HP:0012125', (180, 195))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('colon cancer', 'Disease', (127, 139))
57498	25117503	We investigated the mismatch repair (MMR) status and pathologic features of prostate cancers diagnosed in MMR gene mutation carriers.	('mutation', 'Var', (115, 123))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('prostate cancers', 'Disease', 'MESH:D011471', (76, 92))	('MMR', 'Gene', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('prostate cancers', 'Disease', (76, 92))	('prostate cancers', 'Phenotype', 'HP:0012125', (76, 92))
57499	25117503	Prostate cancers (mean age at diagnosis = 62 +- SD = 8 years) from 32 MMR mutation carriers (23 MSH2, 5 MLH1 and 4 MSH6) enrolled in the Australasian, Mayo Clinic and Ontario sites of the Colon Cancer Family Registry were examined for clinico-pathologic features and MMR-deficiency (immunohistochemical loss of MMR protein expression and high levels of microsatellite instability; MSI-H).	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('protein', 'cellular_component', 'GO:0003675', ('315', '322'))	('MSI-H', 'Disease', (381, 386))	('MMR protein', 'Protein', (311, 322))	('Prostate cancers', 'Disease', 'MESH:D011471', (0, 16))	('Prostate cancers', 'Disease', (0, 16))	('MMR-deficiency', 'Disease', (267, 281))	('mutation', 'Var', (74, 82))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('MMR', 'Gene', (70, 73))	('Prostate cancers', 'Phenotype', 'HP:0012125', (0, 16))	('MSI-H', 'Disease', 'MESH:D000848', (381, 386))	('Mayo', 'Species', '162683', (151, 155))	('Prostate cancer', 'Phenotype', 'HP:0012125', (0, 15))	('loss', 'NegReg', (303, 307))	('Colon Cancer', 'Phenotype', 'HP:0003003', (188, 200))	('MMR', 'biological_process', 'GO:0006298', ('267', '270'))	('Colon Cancer', 'Disease', (188, 200))	('MMR', 'biological_process', 'GO:0006298', ('311', '314'))	('MMR-deficiency', 'Disease', 'MESH:C536143', (267, 281))	('levels', 'MPA', (343, 349))	('Colon Cancer', 'Disease', 'MESH:D015179', (188, 200))	('expression', 'MPA', (323, 333))	('Cancer', 'Phenotype', 'HP:0002664', (194, 200))	('MMR', 'biological_process', 'GO:0006298', ('70', '73'))	('microsatellite instability', 'MPA', (353, 379))
57500	25117503	Tumor MMR-deficiency was observed for 22 cases [69 %; 95 % confidence interval (CI) 50-83 %], with the highest prevalence of MMR-deficiency in tumors from MSH2 mutation carriers (19/23, 83 %) compared with MLH1 and MSH6 carriers combined (3/9, 33 %; p = 0.01).	('Tumor MMR-deficiency', 'Disease', (0, 20))	('MMR', 'biological_process', 'GO:0006298', ('6', '9'))	('mutation', 'Var', (160, 168))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('Tumor MMR-deficiency', 'Disease', 'MESH:C536928', (0, 20))	('MMR-deficiency in tumors', 'Disease', 'MESH:C536928', (125, 149))	('MMR', 'biological_process', 'GO:0006298', ('125', '128'))	('MSH2', 'Gene', (155, 159))	('MMR-deficiency in tumors', 'Disease', (125, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
57502	25117503	Under the assumption that tumour MMR-deficiency occurred only because the cancer was caused by the germline mutation, mutation carriers are at 3.2-fold (95 % CI 2.0-6.3) increased risk of prostate cancer, and when assessed by gene, the relative risk was greatest for MSH2 carriers (5.8, 95 % CI 2.6-20.9).	('MSH2', 'Gene', (267, 271))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('tumour MMR-deficiency', 'Disease', (26, 47))	('cancer', 'Disease', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('prostate cancer', 'Disease', (188, 203))	('cancer', 'Disease', (74, 80))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('mutation', 'Var', (118, 126))	('tumour MMR-deficiency', 'Disease', 'MESH:C536143', (26, 47))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('prostate cancer', 'Disease', 'MESH:D011471', (188, 203))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('MMR', 'biological_process', 'GO:0006298', ('33', '36'))	('prostate cancer', 'Phenotype', 'HP:0012125', (188, 203))
57504	25117503	MMR gene mutation carriers have at least a twofold or greater increased risk of developing MMR-deficient prostate cancer where the risk is highest for MSH2 mutation carriers.	('mutation', 'Var', (9, 17))	('MMR', 'biological_process', 'GO:0006298', ('91', '94'))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))	('MMR-deficient prostate cancer', 'Disease', (91, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('MMR-deficient prostate cancer', 'Disease', 'MESH:D011471', (91, 120))	('MMR', 'Gene', (0, 3))	('MMR', 'biological_process', 'GO:0006298', ('0', '3'))	('deficient prostate', 'Phenotype', 'HP:0008687', (95, 113))
57505	25117503	MMR IHC screening of prostate cancers will aid in identifying MMR gene mutation carriers.	('prostate cancers', 'Disease', 'MESH:D011471', (21, 37))	('prostate cancer', 'Phenotype', 'HP:0012125', (21, 36))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('mutation', 'Var', (71, 79))	('prostate cancers', 'Phenotype', 'HP:0012125', (21, 37))	('MMR gene', 'Gene', (62, 70))	('prostate cancers', 'Disease', (21, 37))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
57506	25117503	Lynch syndrome, formerly known as hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant disorder caused by germline mutations in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2.	('MLH1', 'Gene', (188, 192))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (92, 119))	('HNPCC', 'Phenotype', 'HP:0006716', (78, 83))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('PMS2', 'Gene', (210, 214))	('caused by', 'Reg', (120, 129))	('autosomal dominant disorder', 'Disease', (92, 119))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('MMR', 'Gene', (177, 180))	('Lynch syndrome', 'Disease', (0, 14))	('HNPCC', 'Disease', 'None', (78, 83))	('HNPCC', 'Disease', (78, 83))	('non-polyposis colorectal cancer', 'Disease', 'MESH:D015179', (45, 76))	('MSH2', 'Gene', (194, 198))	('non-polyposis colorectal cancer', 'Disease', (45, 76))	('hereditary non-polyposis colorectal cancer', 'Phenotype', 'HP:0006716', (34, 76))	('mutations', 'Var', (139, 148))	('PMS2', 'Gene', '5395', (210, 214))	('MSH6', 'Gene', (200, 204))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))
57507	25117503	Recently, we have shown that MMR gene mutation carriers are at increased risk of developing cancers of the colorectum and endometrium, as well as cancers of the ovary, kidney, pancreas, stomach, urinary bladder and breast.	('cancers', 'Disease', (146, 153))	('pancreas', 'Disease', 'MESH:D010190', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('urinary bladder', 'Disease', (195, 210))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('MMR', 'Gene', (29, 32))	('stomach', 'Disease', (186, 193))	('MMR', 'biological_process', 'GO:0006298', ('29', '32'))	('cancers of the ovary', 'Disease', (146, 166))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cancers of the ovary', 'Disease', 'MESH:D010051', (146, 166))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pancreas', 'Disease', (176, 184))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', (92, 99))	('mutation', 'Var', (38, 46))	('breast', 'Disease', (215, 221))	('cancers of the ovary', 'Phenotype', 'HP:0100615', (146, 166))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
57511	25117503	Recently, sufficient data on Lynch syndrome has been collected to allow rigorous investigation of associations of MMR gene mutations with the more common cancers.	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('Lynch syndrome', 'Disease', (29, 43))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('Lynch syndrome', 'Disease', 'MESH:D003123', (29, 43))	('cancers', 'Disease', (154, 161))	('MMR gene', 'Gene', (114, 122))	('associations', 'Interaction', (98, 110))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('mutations', 'Var', (123, 132))
57514	25117503	Prostate cancer has not traditionally been considered part of the spectrum of tumors associated with Lynch syndrome, but recent small studies have suggested an increased risk of prostate cancer for people with Lynch syndrome, in particular for MSH2 mutation carriers.	('prostate cancer', 'Phenotype', 'HP:0012125', (178, 193))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('prostate cancer', 'Disease', (178, 193))	('mutation', 'Var', (249, 257))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('MSH2', 'Gene', (244, 248))	('people', 'Species', '9606', (198, 204))	('Lynch syndrome', 'Disease', (101, 115))	('Prostate cancer', 'Disease', 'MESH:D011471', (0, 15))	('Prostate cancer', 'Phenotype', 'HP:0012125', (0, 15))	('tumors', 'Disease', (78, 84))	('Lynch syndrome', 'Disease', (210, 224))	('Lynch syndrome', 'Disease', 'MESH:D003123', (101, 115))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('Prostate cancer', 'Disease', (0, 15))	('Lynch syndrome', 'Disease', 'MESH:D003123', (210, 224))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('prostate cancer', 'Disease', 'MESH:D011471', (178, 193))
57515	25117503	In addition, MMR-deficiency assessed by loss of immunohistochemical (IHC) expression or by polymerase chain reaction-based methods has been reported several times in prostate cancers in a small number of MMR gene mutation carriers.	('prostate cancers', 'Disease', (166, 182))	('MMR-deficiency', 'Disease', (13, 27))	('MMR', 'Gene', (204, 207))	('loss', 'NegReg', (40, 44))	('mutation', 'Var', (213, 221))	('prostate cancers', 'Disease', 'MESH:D011471', (166, 182))	('prostate cancer', 'Phenotype', 'HP:0012125', (166, 181))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('MMR-deficiency', 'Disease', 'MESH:C536143', (13, 27))	('prostate cancers', 'Phenotype', 'HP:0012125', (166, 182))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('reported', 'Reg', (140, 148))
57516	25117503	However, to date, no large studies have examined the expression of MMR proteins and pathology features of prostate cancers diagnosed in MMR gene mutation carriers.	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('MMR', 'biological_process', 'GO:0006298', ('67', '70'))	('prostate cancers', 'Phenotype', 'HP:0012125', (106, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('prostate cancers', 'Disease', (106, 122))	('MMR', 'biological_process', 'GO:0006298', ('136', '139'))	('MMR', 'Gene', (136, 139))	('prostate cancers', 'Disease', 'MESH:D011471', (106, 122))	('mutation', 'Var', (145, 153))
57518	25117503	The aim of this study was to investigate the histological features, MSI and MMR IHC expression of prostate cancers in proven MMR gene mutation carriers from the Colon Cancer Family Registry.	('Colon Cancer', 'Disease', (161, 173))	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('Cancer', 'Phenotype', 'HP:0002664', (167, 173))	('MMR', 'Gene', (125, 128))	('MSI', 'Disease', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('prostate cancers', 'Disease', 'MESH:D011471', (98, 114))	('mutation', 'Var', (134, 142))	('prostate cancers', 'Phenotype', 'HP:0012125', (98, 114))	('prostate cancers', 'Disease', (98, 114))	('Colon Cancer', 'Phenotype', 'HP:0003003', (161, 173))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('MSI', 'Disease', 'None', (68, 71))	('Colon Cancer', 'Disease', 'MESH:D015179', (161, 173))
57520	25117503	Inclusion criteria for this study were: (a) proven to be carrying a pathogenic germline mutation in one of the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2, (b) having a diagnosis of prostate carcinoma confirmed by histological examination, and (c) the availability of archival tissue blocks for additional laboratory testing.	('PMS2', 'Gene', (158, 162))	('MSH2', 'Gene', (143, 147))	('mismatch repair', 'biological_process', 'GO:0006298', ('115', '130'))	('MLH1', 'Gene', (137, 141))	('MSH6', 'Gene', (149, 153))	('PMS2', 'Gene', '5395', (158, 162))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (190, 208))	('prostate carcinoma', 'Disease', (190, 208))	('DNA', 'cellular_component', 'GO:0005574', ('111', '114'))	('germline mutation', 'Var', (79, 96))	('prostate carcinoma', 'Disease', 'MESH:D011472', (190, 208))	('pathogenic', 'Reg', (68, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
57533	25117503	Under the assumption that a MMR-deficient prostate cancer was caused by the MMR gene mutation, the relative risk (RR) of MMR-deficient prostate cancer for men with a germline MMR gene mutation can be estimated by back calculation from the attributable fraction as RR = N/(N-n), where N is the total number of prostate cancer-affected mutation carriers and n is the number of these for which their tumor exhibited MMR-deficiency.	('prostate cancer', 'Phenotype', 'HP:0012125', (42, 57))	('MMR-deficient prostate cancer', 'Disease', 'MESH:D011471', (28, 57))	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutation', 'Var', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('deficient prostate', 'Phenotype', 'HP:0008687', (32, 50))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('MMR-deficient prostate cancer', 'Disease', (28, 57))	('MMR-deficient prostate cancer', 'Disease', 'MESH:D011471', (121, 150))	('deficient prostate', 'Phenotype', 'HP:0008687', (125, 143))	('mutation', 'Var', (334, 342))	('MMR-deficiency', 'Disease', 'MESH:C536143', (413, 427))	('mutation', 'Var', (184, 192))	('prostate cancer', 'Disease', 'MESH:D011471', (309, 324))	('MMR-deficient prostate cancer', 'Disease', (121, 150))	('MMR', 'Gene', (76, 79))	('prostate cancer', 'Phenotype', 'HP:0012125', (309, 324))	('tumor', 'Disease', (397, 402))	('prostate cancer', 'Disease', 'MESH:D011471', (135, 150))	('prostate cancer', 'Disease', (309, 324))	('prostate cancer', 'Phenotype', 'HP:0012125', (135, 150))	('caused by', 'Reg', (62, 71))	('men', 'Species', '9606', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (397, 402))	('MMR-deficiency', 'Disease', (413, 427))	('prostate cancer', 'Disease', 'MESH:D011471', (42, 57))
57535	25117503	No PMS2 gene mutation carriers diagnosed with prostate cancer were identified.	('prostate cancer', 'Disease', (46, 61))	('mutation', 'Var', (13, 21))	('PMS2', 'Gene', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('PMS2', 'Gene', '5395', (3, 7))	('prostate cancer', 'Disease', 'MESH:D011471', (46, 61))	('prostate cancer', 'Phenotype', 'HP:0012125', (46, 61))
57536	25117503	Of the 147 population-based families with MMR gene mutations from the Australasian, Ontario and Mayo sites, the distribution of MLH1, MSH2 and MSH6 mutations was 43 % (n = 63), 43 % (n = 63) and 14 % (n = 21) respectively.	('Mayo', 'Species', '162683', (96, 100))	('mutations', 'Var', (148, 157))	('mutations', 'Var', (51, 60))	('MSH2', 'Gene', (134, 138))	('MMR gene', 'Gene', (42, 50))	('MLH1', 'Gene', (128, 132))	('MSH6', 'Gene', (143, 147))
57537	25117503	Given this distribution of mutation carriers, there was an over-representation of male MSH2 mutation carriers (23/75, 31 %) and an under-representation of male MLH1 mutation carriers (5/58, 9 %) with prostate cancer from these 147 families (p = 0.002).	('over-representation', 'PosReg', (59, 78))	('mutation', 'Var', (92, 100))	('under-representation', 'NegReg', (131, 151))	('prostate cancer', 'Disease', 'MESH:D011471', (200, 215))	('prostate cancer', 'Phenotype', 'HP:0012125', (200, 215))	('MSH2', 'Gene', (87, 91))	('prostate cancer', 'Disease', (200, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
57548	25117503	The tumors from MSH2 mutation carriers had the highest proportion of MMR-deficiency (19 in 23 (83 %; 95 % CI 61-95 %)) compared with tumors in MLH1 mutation carriers (2 in 5 (40 %; 95 % CI 5-85 %)) and tumors in MSH6 carriers (1 in 4 (25 %; 95 % CI 1-81 %)).	('MSH2', 'Gene', (16, 20))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('MMR-deficiency', 'Disease', 'MESH:C536143', (69, 83))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('mutation', 'Var', (21, 29))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('MMR', 'biological_process', 'GO:0006298', ('69', '72'))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('MMR-deficiency', 'Disease', (69, 83))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
57549	25117503	Under the assumption that tumor MMR-deficiency occurs only because the cancer was caused by the underlying germline mutation, the RR of prostate cancer for all MMR gene mutation carriers was estimated to be 3.2-fold (95 % CI 2.0-6.3).	('cancer', 'Disease', (145, 151))	('mutation', 'Var', (169, 177))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('MMR', 'biological_process', 'GO:0006298', ('160', '163'))	('tumor MMR-deficiency', 'Disease', 'MESH:C536928', (26, 46))	('cancer', 'Disease', (71, 77))	('MMR', 'Gene', (160, 163))	('tumor MMR-deficiency', 'Disease', (26, 46))	('prostate cancer', 'Disease', (136, 151))	('caused by', 'Reg', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('prostate cancer', 'Disease', 'MESH:D011471', (136, 151))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('MMR', 'biological_process', 'GO:0006298', ('32', '35'))	('prostate cancer', 'Phenotype', 'HP:0012125', (136, 151))
57550	25117503	The prostate tumor from one MSH6 mutation carrier also had loss of MSH2 expression which was consistently shown on repeated testing.	('MSH2', 'Gene', (67, 71))	('MSH6', 'Gene', (28, 32))	('mutation', 'Var', (33, 41))	('prostate tumor', 'Disease', 'MESH:D011471', (4, 18))	('expression', 'MPA', (72, 82))	('prostate tumor', 'Disease', (4, 18))	('loss', 'NegReg', (59, 63))	('prostate tumor', 'Phenotype', 'HP:0100787', (4, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
57556	25117503	All the high grade prostate cancers were diagnosed in MSH2 mutation carriers.	('prostate cancers', 'Phenotype', 'HP:0012125', (19, 35))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('prostate cancers', 'Disease', (19, 35))	('mutation', 'Var', (59, 67))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('diagnosed', 'Reg', (41, 50))	('prostate cancers', 'Disease', 'MESH:D011471', (19, 35))	('prostate cancer', 'Phenotype', 'HP:0012125', (19, 34))	('MSH2', 'Gene', (54, 58))
57563	25117503	We observed that 69 % of 32 prostate cancers diagnosed in MMR gene mutation carriers had MMR-deficiency, consistent with the 88 and 100 % reported by two previous studies of a total of 10 MMR gene mutation carriers.	('prostate cancers', 'Disease', 'MESH:D011471', (28, 44))	('mutation', 'Var', (67, 75))	('MMR', 'biological_process', 'GO:0006298', ('58', '61'))	('MMR', 'biological_process', 'GO:0006298', ('188', '191'))	('MMR-deficiency', 'Disease', (89, 103))	('MMR-deficiency', 'Disease', 'MESH:C536143', (89, 103))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('prostate cancer', 'Phenotype', 'HP:0012125', (28, 43))	('prostate cancers', 'Phenotype', 'HP:0012125', (28, 44))	('MMR', 'biological_process', 'GO:0006298', ('89', '92'))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('prostate cancers', 'Disease', (28, 44))	('MMR', 'Gene', (58, 61))
57566	25117503	Our demonstration of this phenotype in a large proportion of prostate cancers from mutation carriers adds weight to the argument that prostate cancers can develop as a result of MMR gene mutations.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('MMR', 'biological_process', 'GO:0006298', ('178', '181'))	('men', 'Species', '9606', (124, 127))	('prostate cancers', 'Phenotype', 'HP:0012125', (61, 77))	('prostate cancers', 'Phenotype', 'HP:0012125', (134, 150))	('prostate cancers', 'Disease', (61, 77))	('mutation', 'Var', (83, 91))	('prostate cancers', 'Disease', (134, 150))	('mutations', 'Var', (187, 196))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('MMR', 'Gene', (178, 181))	('prostate cancer', 'Phenotype', 'HP:0012125', (61, 76))	('prostate cancer', 'Phenotype', 'HP:0012125', (134, 149))	('prostate cancers', 'Disease', 'MESH:D011471', (61, 77))	('prostate cancers', 'Disease', 'MESH:D011471', (134, 150))
57568	25117503	We observed an equal proportion of families with mutations in MSH2 and MLH1 overall from the Australasian, Ontario and Mayo sites of 43 %.	('MSH2', 'Gene', (62, 66))	('MLH1', 'Gene', (71, 75))	('Mayo', 'Species', '162683', (119, 123))	('mutations', 'Var', (49, 58))
57569	25117503	However, when comparing the prevalence of mutation carriers with prostate cancer with male mutation carriers overall, we identified a significant over-representation of prostate cancer-affected MSH2 mutation carriers (31 %) while prostate cancer-affected MLH1 mutation carriers were under-represented (9 %).	('MSH2', 'Gene', (194, 198))	('prostate cancer', 'Disease', 'MESH:D011471', (230, 245))	('prostate cancer', 'Disease', (169, 184))	('prostate cancer', 'Phenotype', 'HP:0012125', (230, 245))	('prostate cancer', 'Disease', 'MESH:D011471', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('over-representation', 'PosReg', (146, 165))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('mutation', 'Var', (199, 207))	('prostate cancer', 'Disease', 'MESH:D011471', (169, 184))	('prostate cancer', 'Phenotype', 'HP:0012125', (169, 184))	('prostate cancer', 'Disease', (230, 245))	('prostate cancer', 'Disease', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
57570	25117503	MSH2 mutation carriers also demonstrated a higher prevalence of tumor MMR-deficiency when compared with MLH1 and MSH6 mutation carriers.	('MSH2', 'Gene', (0, 4))	('tumor MMR-deficiency', 'Disease', (64, 84))	('tumor MMR-deficiency', 'Disease', 'MESH:C536928', (64, 84))	('MMR', 'biological_process', 'GO:0006298', ('70', '73'))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mutation', 'Var', (5, 13))
57571	25117503	Previous studies have also reported an over-representation of MSH2 mutations in carriers with a prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (96, 111))	('prostate cancer', 'Phenotype', 'HP:0012125', (96, 111))	('mutations', 'Var', (67, 76))	('MSH2', 'Gene', (62, 66))	('over-representation', 'PosReg', (39, 58))	('prostate cancer', 'Disease', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
57572	25117503	Among MMR gene mutation carriers with a diagnosis of prostate cancer, the MSH2 mutation has been reported as the putative cause for 6/9 tumors by Grindedal et al.	('mutation', 'Var', (15, 23))	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('prostate cancer', 'Disease', (53, 68))	('cause', 'Reg', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('prostate cancer', 'Disease', 'MESH:D011471', (53, 68))	('mutation', 'Var', (79, 87))	('prostate cancer', 'Phenotype', 'HP:0012125', (53, 68))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('MMR', 'Gene', (6, 9))	('MSH2', 'Gene', (74, 78))
57573	25117503	However, unlike these studies, we found that prostate cancer with MMR-deficiency was not restricted to MSH2 and MSH6 mutation carriers: we found five cases in MLH1 mutation carriers, two of which had loss of MLH1 protein expression in tumor cells.	('MLH1', 'Gene', (208, 212))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('prostate cancer', 'Disease', 'MESH:D011471', (45, 60))	('prostate cancer', 'Phenotype', 'HP:0012125', (45, 60))	('loss', 'NegReg', (200, 204))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('mutation', 'Var', (164, 172))	('tumor', 'Disease', (235, 240))	('MMR-deficiency', 'Disease', (66, 80))	('MMR-deficiency', 'Disease', 'MESH:C536143', (66, 80))	('prostate cancer', 'Disease', (45, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('MLH1', 'Gene', (159, 163))	('protein', 'Protein', (213, 220))
57574	25117503	Together these data suggest gene specific differences in the risk of prostate cancer with MSH2 mutation carriers more likely to develop prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (69, 84))	('prostate cancer', 'Disease', (136, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('prostate cancer', 'Phenotype', 'HP:0012125', (69, 84))	('develop', 'PosReg', (128, 135))	('prostate cancer', 'Disease', 'MESH:D011471', (136, 151))	('MSH2', 'Gene', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('prostate cancer', 'Phenotype', 'HP:0012125', (136, 151))	('prostate cancer', 'Disease', (69, 84))	('mutation', 'Var', (95, 103))
57575	25117503	We did not find any case of prostate cancer in PMS2 mutation carriers.	('PMS2', 'Gene', '5395', (47, 51))	('prostate cancer', 'Disease', 'MESH:D011471', (28, 43))	('prostate cancer', 'Phenotype', 'HP:0012125', (28, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('mutation', 'Var', (52, 60))	('carriers', 'Reg', (61, 69))	('prostate cancer', 'Disease', (28, 43))	('PMS2', 'Gene', (47, 51))
57576	25117503	Most published studies did not include PMS2 mutation carriers in their Lynch syndrome patient cohorts.	('PMS2', 'Gene', '5395', (39, 43))	('mutation', 'Var', (44, 52))	('patient', 'Species', '9606', (86, 93))	('Lynch syndrome', 'Disease', (71, 85))	('Lynch syndrome', 'Disease', 'MESH:D003123', (71, 85))	('PMS2', 'Gene', (39, 43))
57577	25117503	Only one prostate cancer in an obligate PMS2 mutation carrier has been reported; however, immunohistochemistry has not been performed to demonstrate loss of PMS2 expression in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('prostate cancer', 'Disease', (9, 24))	('tumor', 'Disease', (176, 181))	('PMS2', 'Gene', '5395', (157, 161))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('PMS2', 'Gene', (40, 44))	('mutation', 'Var', (45, 53))	('prostate cancer', 'Disease', 'MESH:D011471', (9, 24))	('prostate cancer', 'Phenotype', 'HP:0012125', (9, 24))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('PMS2', 'Gene', '5395', (40, 44))	('PMS2', 'Gene', (157, 161))
57581	25117503	In the series of prostate cancers in proven or obligate MMR gene mutation carriers reported by Grindedal et al.	('prostate cancer', 'Phenotype', 'HP:0012125', (17, 32))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('prostate cancers', 'Phenotype', 'HP:0012125', (17, 33))	('prostate cancers', 'Disease', (17, 33))	('mutation', 'Var', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('MMR gene', 'Gene', (56, 64))	('MMR', 'biological_process', 'GO:0006298', ('56', '59'))	('prostate cancers', 'Disease', 'MESH:D011471', (17, 33))
57582	25117503	all 5 tumors with a Gleason score of 8 or more were identified in MSH2 mutation carriers.	('mutation', 'Var', (71, 79))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', (6, 12))	('MSH2', 'Gene', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
57583	25117503	Similarly, we found that all 6 MMR-deficient prostate cancers with a Gleason score >= 8 were diagnosed in MSH2 mutation carriers.	('MSH2', 'Gene', (106, 110))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('prostate cancer', 'Phenotype', 'HP:0012125', (45, 60))	('deficient prostate', 'Phenotype', 'HP:0008687', (35, 53))	('MMR-deficient prostate cancers', 'Disease', (31, 61))	('MMR-deficient prostate cancers', 'Disease', 'MESH:D011471', (31, 61))	('prostate cancers', 'Phenotype', 'HP:0012125', (45, 61))	('diagnosed', 'Reg', (93, 102))	('mutation', 'Var', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
57584	25117503	However, having a MSH2 mutation or MMR-deficiency was not associated with a high Gleason score in prostate cancers in our study.	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('mutation', 'Var', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('prostate cancers', 'Phenotype', 'HP:0012125', (98, 114))	('prostate cancers', 'Disease', (98, 114))	('MSH2', 'Gene', (18, 22))	('MMR-deficiency', 'Disease', (35, 49))	('MMR-deficiency', 'Disease', 'MESH:C536143', (35, 49))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('prostate cancers', 'Disease', 'MESH:D011471', (98, 114))
57585	25117503	Previous studies utilizing the Colon Cancer Family Registry have investigated the risk of prostate cancer for MMR gene mutation carriers compared with men from the general population.	('men', 'Species', '9606', (151, 154))	('Colon Cancer', 'Disease', 'MESH:D015179', (31, 43))	('Colon Cancer', 'Phenotype', 'HP:0003003', (31, 43))	('carriers', 'Var', (128, 136))	('MMR', 'Gene', (110, 113))	('prostate cancer', 'Disease', 'MESH:D011471', (90, 105))	('prostate cancer', 'Phenotype', 'HP:0012125', (90, 105))	('Colon Cancer', 'Disease', (31, 43))	('MMR', 'biological_process', 'GO:0006298', ('110', '113'))	('mutation carriers', 'Var', (119, 136))	('prostate cancer', 'Disease', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Cancer', 'Phenotype', 'HP:0002664', (37, 43))
57586	25117503	observed no evidence of an increased risk of prostate cancer as a first cancer diagnosis in mutation carriers: hazard ratio (HR) of 0.79 (95 % CI 0.25-2.5) for men with MLH1 mutations and 1.0 (95 % CI 0.47-2.3) for men with MSH2 mutations.	('MLH1', 'Gene', (169, 173))	('prostate cancer', 'Disease', 'MESH:D011471', (45, 60))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('mutations', 'Var', (229, 238))	('MSH2', 'Gene', (224, 228))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('prostate cancer', 'Phenotype', 'HP:0012125', (45, 60))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', (54, 60))	('men', 'Species', '9606', (215, 218))	('men', 'Species', '9606', (160, 163))	('mutations', 'Var', (174, 183))	('prostate cancer', 'Disease', (45, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (72, 78))
57587	25117503	estimated the increased risk of prostate cancer for mutation carriers by a standardized incidence ratio (SIR) of 2.49 (95 % CI 0.51-7.28).	('prostate cancer', 'Disease', (32, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('prostate cancer', 'Disease', 'MESH:D011471', (32, 47))	('mutation', 'Var', (52, 60))	('prostate cancer', 'Phenotype', 'HP:0012125', (32, 47))
57589	25117503	estimated a two-fold increased risk of prostate cancer for all mutation carriers combined, compared with the general population (SIR, 2.05; 95 % CI 1.23-3.01).	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('prostate cancer', 'Disease', (39, 54))	('mutation', 'Var', (63, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (39, 54))	('prostate cancer', 'Phenotype', 'HP:0012125', (39, 54))
57590	25117503	In that study, most prostate cancers (15/19) were in men with MSH2 mutations, for whom the SIR was 3.62 (95 % CI 2.07-5.36) compared with 0.87 (95 % CI 0.00-2.19) for men with MLH1 mutations.	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('prostate cancers', 'Disease', 'MESH:D011471', (20, 36))	('prostate cancer', 'Phenotype', 'HP:0012125', (20, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('mutations', 'Var', (67, 76))	('MSH2', 'Gene', (62, 66))	('prostate cancers', 'Phenotype', 'HP:0012125', (20, 36))	('prostate cancers', 'Disease', (20, 36))	('men', 'Species', '9606', (53, 56))	('men', 'Species', '9606', (167, 170))
57591	25117503	Three other independent studies found an increased risk of prostate cancer for MMR gene mutation carriers compared with the general population with SIRs of 2.5 (95 % CI 1.2-4.0) and 5.1 (95 % CI 4.1-17.1) and a RR estimated to 10.4 (95 % CI 2.80-26.65) for MSH2 mutation carriers.	('mutation', 'Var', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('prostate cancer', 'Disease', 'MESH:D011471', (59, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('MMR gene', 'Gene', (79, 87))	('MSH2', 'Gene', (257, 261))	('prostate cancer', 'Disease', (59, 74))
57592	25117503	A further recent study of 198 families carrying MMR gene mutations reported a two-fold increased risk of prostate cancer in mutation carriers compared with the general population (HR = 1.99, 95 % CI 1.31-3.03, p = 0.0013).	('prostate cancer', 'Disease', (105, 120))	('MMR gene', 'Gene', (48, 56))	('mutations', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutation', 'Var', (124, 132))	('prostate cancer', 'Disease', 'MESH:D011471', (105, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))
57593	25117503	We observed that 69 % of prostate cancers in carriers of MMR gene mutations had MMR-deficient tumors, and thus demonstrated a potential link between the germline mutation and prostate tumor initiation.	('mutations', 'Var', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('prostate cancers', 'Disease', 'MESH:D011471', (25, 41))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (25, 40))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('MMR', 'biological_process', 'GO:0006298', ('57', '60'))	('prostate tumor initiation', 'Disease', 'MESH:D011471', (175, 200))	('prostate tumor', 'Phenotype', 'HP:0100787', (175, 189))	('prostate cancers', 'Phenotype', 'HP:0012125', (25, 41))	('MMR-deficient tumors', 'Disease', 'MESH:C536928', (80, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('prostate cancers', 'Disease', (25, 41))	('MMR-deficient tumors', 'Disease', (80, 100))	('MMR', 'biological_process', 'GO:0006298', ('80', '83'))	('MMR gene', 'Gene', (57, 65))	('prostate tumor initiation', 'Disease', (175, 200))
57594	25117503	Based on this high prevalence of MMR-deficiency and the assumption that tumors with MMR-deficiency were caused by the underlying germline mutation (and a somatic mutation as the second hit), we estimated the RR of MMR-deficient prostate cancer for all mutation carriers combined and for MSH2 mutation carriers alone to be 3.2 (95 % CI 2.0-6.3) and 5.8 (95 % CI 2.6-20.9), respectively, providing further support for the inclusion of prostate cancer as part of the Lynch syndrome-associated tumor spectrum.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('MSH2', 'Gene', (287, 291))	('prostate cancer', 'Disease', 'MESH:D011471', (433, 448))	('mutation', 'Var', (252, 260))	('prostate cancer', 'Phenotype', 'HP:0012125', (433, 448))	('tumors', 'Disease', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (490, 495))	('prostate cancer', 'Disease', (433, 448))	('MMR', 'biological_process', 'GO:0006298', ('33', '36'))	('MMR-deficiency', 'Disease', (84, 98))	('MMR-deficiency', 'Disease', 'MESH:C536143', (33, 47))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (490, 495))	('MMR', 'biological_process', 'GO:0006298', ('214', '217'))	('Lynch syndrome', 'Disease', (464, 478))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Disease', (72, 77))	('prostate cancer', 'Disease', 'MESH:D011471', (228, 243))	('prostate cancer', 'Phenotype', 'HP:0012125', (228, 243))	('deficient prostate', 'Phenotype', 'HP:0008687', (218, 236))	('MMR-deficient prostate cancer', 'Disease', 'MESH:D011471', (214, 243))	('cancer', 'Phenotype', 'HP:0002664', (442, 448))	('MMR', 'biological_process', 'GO:0006298', ('84', '87'))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('MMR-deficiency', 'Disease', (33, 47))	('MMR-deficiency', 'Disease', 'MESH:C536143', (84, 98))	('Lynch syndrome', 'Disease', 'MESH:D003123', (464, 478))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('MMR-deficient prostate cancer', 'Disease', (214, 243))	('tumor', 'Disease', (490, 495))
57596	25117503	Therefore, future studies using large prospective studies of known mutation carriers with long follow-up will be needed to conclusively resolve the issue of risk of prostate cancer for MMR gene mutation carriers.	('mutation', 'Var', (194, 202))	('prostate cancer', 'Disease', 'MESH:D011471', (165, 180))	('prostate cancer', 'Phenotype', 'HP:0012125', (165, 180))	('prostate cancer', 'Disease', (165, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('MMR', 'Gene', (185, 188))
57606	25117503	We did not confirm the presence or type of this second hit, however, the fact that inactivation of both alleles is needed to cause loss of MMR function is a well-established tumorigenic mechanism in Lynch syndrome.	('tumor', 'Disease', (174, 179))	('function', 'MPA', (143, 151))	('MMR', 'biological_process', 'GO:0006298', ('139', '142'))	('MMR', 'Gene', (139, 142))	('inactivation', 'Var', (83, 95))	('loss', 'NegReg', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('Lynch syndrome', 'Disease', (199, 213))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('Lynch syndrome', 'Disease', 'MESH:D003123', (199, 213))
57607	25117503	Given that all the men in the study were MMR gene mutation carriers, other mechanisms of MMR-deficiency such as tumor DNA promoter methylation is less likely.	('MMR', 'biological_process', 'GO:0006298', ('41', '44'))	('DNA', 'cellular_component', 'GO:0005574', ('118', '121'))	('MMR gene', 'Gene', (41, 49))	('MMR-deficiency', 'Disease', (89, 103))	('MMR-deficiency', 'Disease', 'MESH:C536143', (89, 103))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('methylation', 'biological_process', 'GO:0032259', ('131', '142'))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('MMR', 'biological_process', 'GO:0006298', ('89', '92'))	('men', 'Species', '9606', (19, 22))	('tumor', 'Disease', (112, 117))	('mutation', 'Var', (50, 58))
57609	25117503	In conclusion, to the best of our knowledge this is the largest study of prostate cancers in proven MMR gene mutation carriers for whom pathology and MMR status has been characterized.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('mutation', 'Var', (109, 117))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('prostate cancers', 'Disease', 'MESH:D011471', (73, 89))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('prostate cancers', 'Phenotype', 'HP:0012125', (73, 89))	('prostate cancers', 'Disease', (73, 89))	('MMR', 'Gene', (100, 103))
57612	25117503	These findings suggest that defective mismatch repair is involved in prostate cancer development in men who carry a MMR gene mutation, in particular a MSH2 gene mutation, and together with other recent evidence of an increased risk of prostate cancer for mutation carriers suggests that this malignancy be considered part of the spectrum of tumors in Lynch syndrome.	('malignancy', 'Disease', 'MESH:D009369', (292, 302))	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('MMR gene', 'Gene', (116, 124))	('prostate cancer', 'Disease', (235, 250))	('MSH2', 'Gene', (151, 155))	('tumors', 'Disease', (341, 347))	('involved', 'Reg', (57, 65))	('defective', 'Var', (28, 37))	('mutation', 'Var', (161, 169))	('malignancy', 'Disease', (292, 302))	('tumors', 'Disease', 'MESH:D009369', (341, 347))	('Lynch syndrome', 'Disease', (351, 365))	('prostate cancer', 'Phenotype', 'HP:0012125', (235, 250))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('men', 'Species', '9606', (100, 103))	('Lynch syndrome', 'Disease', 'MESH:D003123', (351, 365))	('prostate cancer', 'Disease', 'MESH:D011471', (69, 84))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('tumors', 'Phenotype', 'HP:0002664', (341, 347))	('prostate cancer', 'Phenotype', 'HP:0012125', (69, 84))	('men', 'Species', '9606', (92, 95))	('prostate cancer', 'Disease', 'MESH:D011471', (235, 250))	('prostate cancer', 'Disease', (69, 84))	('mutation', 'Var', (125, 133))
57613	25117503	Furthermore, screening for MMR-deficiency in men presenting with prostate cancer, especially those with other indications of Lynch syndrome, could identify MMR gene mutation carriers and provide the opportunity to target cancer prevention strategies to carriers and their relatives.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('men', 'Species', '9606', (45, 48))	('Lynch syndrome', 'Disease', (125, 139))	('cancer', 'Disease', (221, 227))	('prostate cancer', 'Disease', 'MESH:D011471', (65, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('mutation', 'Var', (165, 173))	('Lynch syndrome', 'Disease', 'MESH:D003123', (125, 139))	('cancer', 'Disease', (74, 80))	('MMR-deficiency', 'Disease', (27, 41))	('MMR gene', 'Gene', (156, 164))	('MMR-deficiency', 'Disease', 'MESH:C536143', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('prostate cancer', 'Disease', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
57614	32592277	Dysregulation of microRNA expression during the progression of colorectal tumors MicroRNAs (miRNAs) are potential biomarkers of neoplastic lesions, but additional information on dysregulated miRNA expression during progression of the adenoma-adenocarcinoma sequence may be helpful to identify the role of miRNAs in this sequence.	('neoplastic lesions', 'Disease', (128, 146))	('colorectal tumors', 'Disease', 'MESH:D015179', (63, 80))	('neoplastic lesions', 'Disease', 'MESH:D007680', (128, 146))	('colorectal tumors', 'Disease', (63, 80))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (128, 146))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('adenoma-adenocarcinoma', 'Disease', 'MESH:D000236', (234, 256))	('adenoma-adenocarcinoma', 'Disease', (234, 256))	('dysregulated', 'Var', (178, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
57618	32592277	Although no significant differences in the expression of any of the 13 miRNAs were found between adenomas and IMCs consistently in both cohorts, the expression levels of hsa-miRNA-125b-5p, hsa-miRNA-143-3p, and hsa-miRNA-206 were significantly upregulated in iCRC in both cohorts compared with those in IMC.	('adenomas', 'Disease', 'MESH:D000236', (97, 105))	('miRNA-125b-5p', 'Chemical', '-', (174, 187))	('adenomas', 'Disease', (97, 105))	('miRNA-206', 'Gene', (215, 224))	('miRNA-206', 'Gene', '406989', (215, 224))	('hsa-miRNA-143-3p', 'Var', (189, 205))	('hsa-miRNA-125b-5p', 'Var', (170, 187))	('expression levels', 'MPA', (149, 166))	('iCRC', 'Disease', (259, 263))	('upregulated', 'PosReg', (244, 255))
57619	32592277	The current results suggest that certain miRNAs, including hsa-miRNA-125b-5p, hsa-miRNA-143-3p and hsa-miRNA-206, are candidate markers that play critical roles in the progression of IMC to iCRC.	('hsa-miRNA-143-3p', 'Var', (78, 94))	('miRNA-125b-5p', 'Chemical', '-', (63, 76))	('hsa-miRNA-125b-5p', 'Var', (59, 76))	('miRNA-206', 'Gene', (103, 112))	('miRNA-206', 'Gene', '406989', (103, 112))	('IMC', 'Disease', (183, 186))
57621	32592277	3 ,  4 ,  5  miRNAs are 19-23-nucleotide noncoding endogenous single-stranded RNAs that function as post-transcriptional gene regulators by binding to their target messenger RNAs and have been implicated in tumor progression.	('19-23-nucleotide', 'Chemical', '-', (24, 40))	('single-stranded', 'Var', (62, 77))	('binding', 'Interaction', (140, 147))	('implicated', 'Reg', (193, 203))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))
57623	32592277	7 ,  8 ,  9  Dysregulated miRNAs play an important role in the progression of CRC, but less is known about their role in colorectal adenomas.	('miRNAs', 'Protein', (26, 32))	('colorectal adenomas', 'Disease', (121, 140))	('colorectal adenomas', 'Disease', 'MESH:D015179', (121, 140))	('CRC', 'Disease', (78, 81))	('Dysregulated', 'Var', (13, 25))
57649	32592277	Differences in miRNA dysregulation among each lesion type in cohort 1 In cohort 1, there were statistically significant differences in the downregulation of hsa-miRNA-19a-3p, hsa-miRNA-34b-3p, hsa-miRNA-125b-5p, hsa-miRNA-143-3p, miRNA-191-5p, hsa-miRNA-193b-3p, hsa-miRNA-195-5p and hsa-miRNA-206 between conventional adenomas and invasive CRCs and between intramucosal carcinomas and invasive CRCs, compared with specimens isolated from normal glands.	('miRNA-191-5p', 'Var', (230, 242))	('miRNA-19a', 'Gene', (161, 170))	('invasive CRCs', 'Disease', (332, 345))	('carcinomas', 'Disease', (371, 381))	('miRNA-206', 'Gene', (288, 297))	('carcinoma', 'Phenotype', 'HP:0030731', (371, 380))	('intramucosal carcinoma', 'Disease', 'MESH:D009369', (358, 380))	('downregulation', 'NegReg', (139, 153))	('miRNA dysregulation', 'MPA', (15, 34))	('miRNA-195', 'Gene', (267, 276))	('miRNA-206', 'Gene', '406989', (288, 297))	('miRNA-125b-5p', 'Chemical', '-', (197, 210))	('carcinomas', 'Disease', 'MESH:D009369', (371, 381))	('carcinomas', 'Phenotype', 'HP:0030731', (371, 381))	('intramucosal carcinoma', 'Disease', (358, 380))	('miRNA-195', 'Gene', '406971', (267, 276))	('miRNA-19a', 'Gene', '406979', (161, 170))	('adenomas', 'Disease', 'MESH:D000236', (319, 327))	('adenomas', 'Disease', (319, 327))
57650	32592277	The median expression levels of hsa-miRNA-27a-3p, hsa-miRNA-27b-3p and hsa-miRNA-31-5p were significantly higher in invasive CRC than in conventional adenomas, and the median level of hsa-miRNA-21-5p was significantly higher in intramucosal carcinomas and invasive CRC compared with conventional adenomas.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('carcinomas', 'Phenotype', 'HP:0030731', (241, 251))	('intramucosal carcinoma', 'Disease', (228, 250))	('hsa-miRNA-31-5p', 'Var', (71, 86))	('adenomas', 'Disease', 'MESH:D000236', (150, 158))	('hsa-miRNA-27b-3p', 'Var', (50, 66))	('adenomas', 'Disease', (150, 158))	('miRNA-21', 'Gene', '406991', (188, 196))	('miRNA-21', 'Gene', (188, 196))	('invasive CRC', 'Disease', (256, 268))	('carcinomas', 'Disease', (241, 251))	('higher', 'PosReg', (218, 224))	('hsa-miRNA-27a-3p', 'Var', (32, 48))	('adenomas', 'Disease', 'MESH:D000236', (296, 304))	('intramucosal carcinoma', 'Disease', 'MESH:D009369', (228, 250))	('adenomas', 'Disease', (296, 304))	('expression levels', 'MPA', (11, 28))	('higher', 'PosReg', (106, 112))	('invasive CRC', 'Disease', (116, 128))	('carcinomas', 'Disease', 'MESH:D009369', (241, 251))
57664	32592277	Of the 13 miRNAs, 11 met these criteria in cohort 1: hsa-miRNA-19a-3p, hsa-miRNA-27a-3p, hsa-miRNA-31-5p, hsa-miRNA-34b-3p, hsa-miRNA-125b-5p, hsa-miRNA-143-3p, miRNA-191-5p, hsa-miRNA-193b-3p, hsa-miRNA-195-5p, hsa-miRNA-206 and hsa-let-7a-5p.	('miRNA-195', 'Gene', '406971', (198, 207))	('miRNA-19a', 'Gene', '406979', (57, 66))	('hsa-miRNA-143-3p', 'Var', (143, 159))	('hsa-miRNA-125b-5p', 'Var', (124, 141))	('miRNA-206', 'Gene', (216, 225))	('miRNA-191-5p', 'Var', (161, 173))	('miRNA-19a', 'Gene', (57, 66))	('hsa-miRNA-193b-3p', 'Var', (175, 192))	('miRNA-125b-5p', 'Chemical', '-', (128, 141))	('miRNA-195', 'Gene', (198, 207))	('miRNA-206', 'Gene', '406989', (216, 225))
57670	32592277	In a previous global evaluation of the expression of 735 miRNAs, 31 had a fold change of greater than or equal to 2 in adenomas compared with normal mucosa specimens, including hsa-miRNA-135a, hsa-miRNA-135b, and hsa-miRNA-137.	('adenomas', 'Disease', (119, 127))	('adenomas', 'Disease', 'MESH:D000236', (119, 127))	('hsa-miRNA-135a', 'Var', (177, 191))	('expression', 'MPA', (39, 49))
57674	32592277	Colorectal tumorigenesis is thought to be a multistep process in which genetic alterations accumulate, ultimately producing an aggressive phenotype (adenoma-carcinoma sequence).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('Colorectal tumorigenesis', 'Disease', 'MESH:D015179', (0, 24))	('Colorectal tumorigenesis', 'Disease', (0, 24))	('genetic alterations', 'Var', (71, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (149, 166))	('producing', 'Reg', (114, 123))	('adenoma-carcinoma', 'Disease', (149, 166))
57681	32592277	However, hsa-miRNA-125b-5p, hsa-miRNA-143-3p and hsa-miRNA-206 were closely associated with the progression from intramucosal carcinoma to invasive CRC.	('miRNA-125b-5p', 'Chemical', '-', (13, 26))	('miRNA-206', 'Gene', (53, 62))	('intramucosal carcinoma', 'Disease', 'MESH:D009369', (113, 135))	('miRNA-206', 'Gene', '406989', (53, 62))	('hsa-miRNA-143-3p', 'Var', (28, 44))	('invasive CRC', 'Disease', (139, 151))	('associated with', 'Reg', (76, 91))	('intramucosal carcinoma', 'Disease', (113, 135))	('hsa-miRNA-125b-5p', 'Var', (9, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))
57682	32592277	17  proposed that five miRNAs (miRNA-32, miRNA-181b-1, miRNA-193b, miRNA-195 and miRNA-411) may be useful predictors of the risk of submucosal invasion in CRC.	('miRNA-32', 'Gene', '407036', (31, 39))	('miRNA-193b', 'Var', (55, 65))	('miRNA-195', 'Gene', '406971', (67, 76))	('miRNA-181b-1', 'Var', (41, 53))	('miRNA-195', 'Gene', (67, 76))	('miRNA-32', 'Gene', (31, 39))	('miRNA-411', 'Var', (81, 90))	('submucosal invasion', 'CPA', (132, 151))	('CRC', 'Disease', (155, 158))
57683	32592277	Our results suggest that three additional miRNAs (hsa-miRNA-125b-5p, hsa-miRNA-143-3p and hsa-miRNA-206) might also be helpful in predicting the risk of invasion from the mucosa to submucosa.	('miRNA-206', 'Gene', '406989', (94, 103))	('invasion from the', 'CPA', (153, 170))	('miRNA-206', 'Gene', (94, 103))	('hsa-miRNA-143-3p', 'Var', (69, 85))	('miRNA-125b-5p', 'Chemical', '-', (54, 67))	('hsa-miRNA-125b-5p', 'Var', (50, 67))
57684	32592277	A previous study showed that miRNA-125b-5p suppressed cell invasion and migration by targeting breast-cancer metastasis suppressor 1 (BRMS1), which was found to inhibit cancer metastasis in gastric cancer cells.	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('breast-cancer metastasis suppressor 1', 'Gene', (95, 132))	('miRNA-125b-5p', 'Var', (29, 42))	('breast-cancer metastasis suppressor 1', 'Gene', '25855', (95, 132))	('gastric cancer', 'Disease', 'MESH:D013274', (190, 204))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('BRMS1', 'Gene', (134, 139))	('gastric cancer', 'Phenotype', 'HP:0012126', (190, 204))	('cancer', 'Disease', (102, 108))	('miRNA-125b-5p', 'Chemical', '-', (29, 42))	('cell invasion', 'CPA', (54, 67))	('suppressed', 'NegReg', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('inhibit', 'NegReg', (161, 168))	('BRMS1', 'Gene', '25855', (134, 139))	('gastric cancer', 'Disease', (190, 204))
57685	32592277	28  However, another study demonstrated that expression of miRNA-125b-5p is correlated with a poor prognosis in hepatocellular carcinoma patients by targeting thioredoxin-1 (TXNRD1), a key molecule associated with intracellular redox homeostasis that promotes energy and carbohydrate metabolism.	('carbohydrate', 'Chemical', 'MESH:D002241', (271, 283))	('TXNRD1', 'Gene', (174, 180))	('energy', 'MPA', (260, 266))	('promotes', 'PosReg', (251, 259))	('miRNA-125b-5p', 'Chemical', '-', (59, 72))	('miRNA-125b-5p', 'Var', (59, 72))	('patients', 'Species', '9606', (137, 145))	('TXNRD1', 'Gene', '7296', (174, 180))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (112, 136))	('targeting', 'Reg', (149, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('hepatocellular carcinoma', 'Disease', (112, 136))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (112, 136))
57687	32592277	28 ,  29   Regarding miRNA-143-3p, we demonstrated that its expression was correlated with invasive CRCs compared with intramucosal carcinomas.	('expression', 'MPA', (60, 70))	('miRNA-143-3p', 'Var', (21, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('carcinomas', 'Disease', 'MESH:D009369', (132, 142))	('intramucosal carcinoma', 'Disease', 'MESH:D009369', (119, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('correlated', 'Reg', (75, 85))	('intramucosal carcinoma', 'Disease', (119, 141))	('carcinomas', 'Disease', (132, 142))	('invasive CRCs', 'Disease', (91, 104))
57688	32592277	29  Another study indicated that miRNA-143-3p inhibits catenin delta 1 (CTNND1) in CRC, and that forced expression of CTNND1 induced cell proliferation, migration and invasion in CRC, whereas CTNND1 silencing had the opposite effects.	('catenin delta 1', 'Gene', (55, 70))	('miRNA-143-3p', 'Var', (33, 45))	('CTNND1', 'Gene', '1500', (118, 124))	('cell proliferation', 'CPA', (133, 151))	('CTNND1', 'Gene', (118, 124))	('catenin delta 1', 'Gene', '1500', (55, 70))	('migration', 'CPA', (153, 162))	('inhibits', 'NegReg', (46, 54))	('invasion', 'CPA', (167, 175))	('induced', 'PosReg', (125, 132))	('CTNND1', 'Gene', (192, 198))	('CTNND1', 'Gene', '1500', (192, 198))	('CTNND1', 'Gene', (72, 78))	('CTNND1', 'Gene', '1500', (72, 78))
57689	32592277	30  Thus, miRNA-143-3p may act as a tumor suppressor by negatively regulating CTNND1, which is considered an oncogene.	('miRNA-143-3p', 'Var', (10, 22))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('CTNND1', 'Gene', (78, 84))	('CTNND1', 'Gene', '1500', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('negatively regulating', 'NegReg', (56, 77))
57690	32592277	30  A recent study showed QKI-5, a key post-transcriptional regulator that acts as a tumor suppressor gene in CRC, was identified as a direct target of miRNA-143-3p in that study.	('tumor', 'Disease', (85, 90))	('CRC', 'Disease', (110, 113))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('QKI-5', 'Gene', (26, 31))	('miRNA-143-3p', 'Var', (152, 164))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
57692	32592277	The expression of miRNA-206 was significantly reduced in laryngeal cancer tissues compared with paired adjacent non-neoplastic tissues in a previous study, 32  suggesting that loss of miRNA-206 may be correlated with laryngeal carcinogenesis.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('miRNA-206', 'Gene', '406989', (184, 193))	('loss', 'Var', (176, 180))	('correlated', 'Reg', (201, 211))	('expression', 'MPA', (4, 14))	('carcinogenesis', 'Disease', 'MESH:D063646', (227, 241))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('reduced', 'NegReg', (46, 53))	('laryngeal', 'Disease', (57, 66))	('miRNA-206', 'Gene', (18, 27))	('carcinogenesis', 'Disease', (227, 241))	('miRNA-206', 'Gene', (184, 193))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (57, 73))	('miRNA-206', 'Gene', '406989', (18, 27))
57696	32592277	It is possible that upregulation of miRNAs such as miRNA-125b-5p, miRNA-143-3p and miRNA-206 may result in a tumor oncogenic effect via targeting of unknown oncogenes.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('miRNA-206', 'Gene', (83, 92))	('miRNA-125b-5p', 'Chemical', '-', (51, 64))	('miRNA-143-3p', 'Var', (66, 78))	('miRNA-125b-5p', 'Var', (51, 64))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('upregulation', 'PosReg', (20, 32))	('tumor', 'Disease', (109, 114))	('miRNA-206', 'Gene', '406989', (83, 92))
57698	32592277	However, the expression of specific miRNAs, including hsa-miRNA-125b-5p, hsa-miRNA-143-3p and hsa-miRNA-206, may be associated with intratumoral heterogeneity, which promotes tumor invasiveness, metastatic ability, and drug sensitivity inherent to cancer cells.	('miRNA-125b-5p', 'Chemical', '-', (58, 71))	('miRNA-206', 'Gene', (98, 107))	('tumor invasiveness', 'Disease', (175, 193))	('hsa-miRNA-125b-5p', 'Var', (54, 71))	('cancer', 'Disease', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('drug sensitivity', 'CPA', (219, 235))	('miRNA-206', 'Gene', '406989', (98, 107))	('metastatic ability', 'CPA', (195, 213))	('associated', 'Reg', (116, 126))	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', (137, 142))	('hsa-miRNA-143-3p', 'Var', (73, 89))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('tumor invasiveness', 'Disease', 'MESH:D009361', (175, 193))	('drug sensitivity', 'Phenotype', 'HP:0020174', (219, 235))	('promotes', 'PosReg', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
57720	30385823	Tumour budding counts were higher in CMS4 compared to epithelial CMS2/3 cancers (p < 0.01, all), and associated with KRAS/BRAF mutations (p < 0.01, AMC-AJCCII-90, CAIRO, CAIRO2).	('KRAS', 'Gene', (117, 121))	('CMS4', 'Var', (37, 41))	('BRAF', 'Gene', '673', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('KRAS', 'Gene', '3845', (117, 121))	('BRAF', 'Gene', (122, 126))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('higher', 'PosReg', (27, 33))	('associated', 'Reg', (101, 111))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('cancers', 'Disease', (72, 79))	('mutations', 'Var', (127, 136))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('budding', 'biological_process', 'GO:0007114', ('7', '14'))	('Tumour budding counts', 'CPA', (0, 21))
57722	30385823	KRAS/BRAF mutations are strongly correlated with tumour budding suggesting their involvement in the regulation of this process.	('KRAS', 'Gene', '3845', (0, 4))	('BRAF', 'Gene', '673', (5, 9))	('correlated', 'Reg', (33, 43))	('BRAF', 'Gene', (5, 9))	('budding', 'biological_process', 'GO:0007114', ('56', '63'))	('involvement', 'Reg', (81, 92))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('regulation', 'biological_process', 'GO:0065007', ('100', '110'))	('mutations', 'Var', (10, 19))	('KRAS', 'Gene', (0, 4))	('tumour', 'Disease', (49, 55))
57748	30385823	KRAS and BRAF mutation status was determined in the AMC-AJCCII-90 series and CAIRO2 cohort by PCR of the V600E site in BRAF and codons 12 and 13 of KRAS; and validated by Sanger sequencing of exon 2 of KRAS and exon 15 in BRAF as previously reported.	('KRAS', 'Gene', '3845', (0, 4))	('KRAS', 'Gene', (148, 152))	('V600E', 'Mutation', 'p.V600E', (105, 110))	('BRAF', 'Gene', (9, 13))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', '673', (222, 226))	('KRAS', 'Gene', '3845', (148, 152))	('BRAF', 'Gene', (119, 123))	('BRAF', 'Gene', (222, 226))	('V600E', 'Var', (105, 110))	('KRAS', 'Gene', (202, 206))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (202, 206))	('BRAF', 'Gene', '673', (9, 13))
57751	30385823	BRAF and KRAS mutation testing was performed in the CAIRO, CAIRO2 cohorts only after the completion of these trials for scientific purposes, for example following the discovery that patients with mutations in the KRAS/BRAF axis are refractory to anti-EGFR therapy, and for comparison to other putative (genetic) biomarkers of therapy response.	('KRAS', 'Gene', '3845', (213, 217))	('EGFR', 'Gene', (251, 255))	('BRAF', 'Gene', (218, 222))	('BRAF', 'Gene', '673', (218, 222))	('KRAS', 'Gene', (9, 13))	('BRAF', 'Gene', '673', (0, 4))	('KRAS', 'Gene', '3845', (9, 13))	('patients', 'Species', '9606', (182, 190))	('BRAF', 'Gene', (0, 4))	('KRAS', 'Gene', (213, 217))	('EGFR', 'Gene', '1956', (251, 255))	('mutations', 'Var', (196, 205))
57762	30385823	Differences in the number of tumour buds by CMS groups or KRAS/BRAF mutation were analysed using the Wilcoxon's Rank Sum Test.	('KRAS', 'Gene', (58, 62))	('tumour', 'Disease', (29, 35))	('KRAS', 'Gene', '3845', (58, 62))	('mutation', 'Var', (68, 76))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('BRAF', 'Gene', '673', (63, 67))	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('BRAF', 'Gene', (63, 67))
57780	30385823	In fact, patients with high-grade budding exhibited a 2.3 times greater relative risk of recurrence as compared to patients with low-grade budding, indicating that tumour budding is an independent prognostic factor in this cohort.	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (115, 123))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('high-grade budding', 'Var', (23, 41))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('budding', 'biological_process', 'GO:0007114', ('139', '146'))	('tumour', 'Disease', (164, 170))	('budding', 'biological_process', 'GO:0007114', ('34', '41'))	('budding', 'biological_process', 'GO:0007114', ('171', '178'))
57781	30385823	OS time was significantly worse in patients with high-grade budding within the primary tumour in univariate analysis (HR: 1.34 (1.09-1.65); p = 0.0049; Fig.	('tumour', 'Disease', (87, 93))	('OS time', 'MPA', (0, 7))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (87, 93))	('patients', 'Species', '9606', (35, 43))	('worse', 'NegReg', (26, 31))	('high-grade budding', 'Var', (49, 67))
57782	30385823	In a multivariate analysis that included age, sex, and treatment arm, tumour budding maintained its effect on prognosis, namely, patients with high-grade budding had a worse outcome compared to patients with low-grade budding tumours (HR: 1.36 (1.11-1.68), p = 0.03 (Fig.	('patients', 'Species', '9606', (194, 202))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('patients', 'Species', '9606', (129, 137))	('tumour', 'Disease', 'MESH:D009369', (226, 232))	('tumours', 'Phenotype', 'HP:0002664', (226, 233))	('budding', 'biological_process', 'GO:0007114', ('218', '225'))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('budding', 'biological_process', 'GO:0007114', ('154', '161'))	('tumours', 'Disease', 'MESH:D009369', (226, 233))	('tumour', 'Disease', (226, 232))	('tumours', 'Disease', (226, 233))	('high-grade budding', 'Var', (143, 161))	('tumour', 'Disease', (70, 76))	('budding', 'biological_process', 'GO:0007114', ('77', '84'))
57796	30385823	Given that budding was not shown to be predictive for cetuximab therapy, we also sought to determine whether this could be due to an association between budding and mutational status in the KRAS/BRAF axis.	('association', 'Interaction', (133, 144))	('budding', 'biological_process', 'GO:0007114', ('153', '160'))	('KRAS', 'Gene', (190, 194))	('KRAS', 'Gene', '3845', (190, 194))	('budding', 'biological_process', 'GO:0007114', ('11', '18'))	('BRAF', 'Gene', (195, 199))	('BRAF', 'Gene', '673', (195, 199))	('mutational status', 'Var', (165, 182))
57797	30385823	Interestingly, a significant correlation was found between a higher number of tumour buds and KRAS mutation in all three cohorts (AMC-AJCCII-90 p = 0.002; CAIRO2 p = 0.003; CAIRO p = 0.04, Wilcoxon Rank Sum Test).	('KRAS', 'Gene', (94, 98))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('higher', 'PosReg', (61, 67))	('tumour', 'Disease', (78, 84))	('mutation', 'Var', (99, 107))	('KRAS', 'Gene', '3845', (94, 98))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
57798	30385823	Additionally, higher ITB was observed in BRAF mutant metastatic samples (CAIRO p = 0.0002; CAIRO2 p = 0.01, Wilcoxon Rank Sum Test) (Fig.	('ITB', 'MPA', (21, 24))	('BRAF', 'Gene', '673', (41, 45))	('mutant', 'Var', (46, 52))	('BRAF', 'Gene', (41, 45))	('higher', 'PosReg', (14, 20))
57803	30385823	Evidence suggests that regardless of scoring method, the presence of tumour budding is associated with advanced disease stage and worse clinical outcome.	('tumour', 'Disease', (69, 75))	('advanced disease', 'Disease', (103, 119))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('presence', 'Var', (57, 65))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('advanced disease', 'Disease', 'MESH:D020178', (103, 119))
57807	30385823	A recent retrospective study by Oh and colleagues pooled results from more than 4000 Japanese patients from all stages and validated the effect of high-grade budding on worse OS and DFS.	('patients', 'Species', '9606', (94, 102))	('DFS', 'Disease', (182, 185))	('worse OS', 'Disease', (169, 177))	('budding', 'biological_process', 'GO:0007114', ('158', '165'))	('high-grade budding', 'Var', (147, 165))
57815	30385823	Indeed, we found in all four cohorts a significantly greater number of tumour buds in the CMS4 compared to CMS2/3.	('CMS4', 'Var', (90, 94))	('tumour', 'Disease', (71, 77))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('greater', 'PosReg', (53, 60))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
57824	30385823	Finally, we observed that the extent of tumour budding was significantly greater in cancers with KRAS and BRAF mutations.	('mutations', 'Var', (111, 120))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('KRAS', 'Gene', (97, 101))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('greater', 'PosReg', (73, 80))	('tumour', 'Disease', (40, 46))	('KRAS', 'Gene', '3845', (97, 101))	('cancers', 'Disease', (84, 91))	('BRAF', 'Gene', '673', (106, 110))	('BRAF', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))
57825	30385823	The relationship between KRAS mutation and tumour budding has previously been reported.	('tumour', 'Disease', 'MESH:D009369', (43, 49))	('mutation', 'Var', (30, 38))	('tumour', 'Disease', (43, 49))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('KRAS', 'Gene', (25, 29))	('KRAS', 'Gene', '3845', (25, 29))
57826	30385823	Jang and colleagues found that 21/34 colorectal cancers with high-grade tumour budding also had mutations in KRAS.	('colorectal cancers', 'Disease', (37, 55))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('KRAS', 'Gene', (109, 113))	('KRAS', 'Gene', '3845', (109, 113))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('colorectal cancer', 'Phenotype', 'HP:0003003', (37, 54))	('colorectal cancers', 'Disease', 'MESH:D015179', (37, 55))	('tumour', 'Disease', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('mutations', 'Var', (96, 105))
57829	30385823	We showed not only that tumour budding led to worse clinical outcome in cetuximab-treated patients but that there was an added benefit to KRAS mutation status in terms of identifying possible non-responders.	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('KRAS', 'Gene', (138, 142))	('KRAS', 'Gene', '3845', (138, 142))	('budding', 'biological_process', 'GO:0007114', ('31', '38'))	('tumour', 'Disease', 'MESH:D009369', (24, 30))	('tumour', 'Disease', (24, 30))	('mutation status', 'Var', (143, 158))	('patients', 'Species', '9606', (90, 98))
57832	30385823	In vitro treatment of KRAS mutated cell lines with KY011, a compound that destabilises beta-catenin and RAS proteins, prevented spindle cell morphology as well as E-cadherin loss and vimentin over-expression.	('destabilises', 'NegReg', (74, 86))	('spindle cell morphology', 'CPA', (128, 151))	('KY011', 'Var', (51, 56))	('KRAS', 'Gene', (22, 26))	('vimentin', 'cellular_component', 'GO:0045098', ('183', '191'))	('E-cadherin', 'Gene', (163, 173))	('beta-catenin', 'Gene', (87, 99))	('vimentin', 'Gene', '7431', (183, 191))	('E-cadherin', 'Gene', '999', (163, 173))	('vimentin', 'Gene', (183, 191))	('beta-catenin', 'Gene', '1499', (87, 99))	('prevented', 'NegReg', (118, 127))	('over-expression', 'PosReg', (192, 207))	('cadherin', 'molecular_function', 'GO:0008014', ('165', '173'))	('vimentin', 'cellular_component', 'GO:0045099', ('183', '191'))	('RAS proteins', 'Protein', (104, 116))	('spindle', 'cellular_component', 'GO:0005819', ('128', '135'))	('KRAS', 'Gene', '3845', (22, 26))	('loss', 'NegReg', (174, 178))
57833	30385823	Taken together, these results all point toward KRAS mutation as an element regulating the tumour budding phenotype, which deserves exploration in a further study.	('regulating', 'Reg', (75, 85))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('KRAS', 'Gene', (47, 51))	('mutation', 'Var', (52, 60))	('KRAS', 'Gene', '3845', (47, 51))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('tumour', 'Disease', (90, 96))
57840	30385823	In addition, KRAS/BRAF mutation is strongly correlated with tumour budding suggesting that this molecular change may play a role in regulating the budding phenotype.	('budding', 'biological_process', 'GO:0007114', ('67', '74'))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('mutation', 'Var', (23, 31))	('tumour', 'Disease', (60, 66))	('correlated', 'Reg', (44, 54))	('budding', 'biological_process', 'GO:0007114', ('147', '154'))	('BRAF', 'Gene', '673', (18, 22))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('KRAS', 'Gene', (13, 17))	('BRAF', 'Gene', (18, 22))	('KRAS', 'Gene', '3845', (13, 17))
57841	30385823	: carried out experiments, A.T.: performed statistical analysis, I.Z., A.T.: wrote the manuscript, S.T.H., P.J.K.K., M.S.R., M.K., C.J.A.P., A.L.	('S.T.H', 'Disease', 'MESH:D018455', (99, 104))	('C.J.A.P.', 'Var', (131, 139))	('M.K.', 'Var', (125, 129))	('S.T.H', 'Disease', (99, 104))	('M.S.R.', 'Var', (117, 123))
57843	29104272	Evolving Therapeutic Strategies to Exploit Chromosome Instability in Cancer Cancer is a devastating disease that claims over 8 million lives each year.	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Cancer', 'Disease', (76, 82))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Cancer', 'Disease', (69, 75))	('Chromosome Instability', 'Phenotype', 'HP:0040012', (43, 65))	('Chromosome Instability', 'Var', (43, 65))	('Cancer', 'Disease', 'MESH:D009369', (76, 82))	('Cancer', 'Disease', 'MESH:D009369', (69, 75))
57857	29104272	Numerical CIN underlies aneuploidy, and leads to gene copy number alterations for contiguous gene sets, while structural CIN can induce specific gene amplifications, deletions, or translocations.	('CIN', 'Phenotype', 'HP:0040012', (10, 13))	('gene copy number', 'MPA', (49, 65))	('induce', 'Reg', (129, 135))	('CIN', 'Phenotype', 'HP:0040012', (121, 124))	('translocations', 'Var', (180, 194))	('CIN', 'Disease', 'MESH:D007674', (121, 124))	('CIN', 'Disease', (10, 13))	('CIN', 'Disease', (121, 124))	('CIN', 'Disease', 'MESH:D007674', (10, 13))	('CIN underlies aneuploidy', 'Disease', 'MESH:D000782', (10, 34))	('leads to', 'Reg', (40, 48))	('CIN underlies aneuploidy', 'Disease', (10, 34))	('deletions', 'Var', (166, 175))	('alterations', 'Reg', (66, 77))
57862	29104272	Conceptually, a precision medicine strategy that selectively exploits the aberrant genes (CIN genes) or pathways causing CIN would be effective in a myriad of cancers (at both primary and metastatic sites), and would reduce and/or eliminate many of the off-target side effects associated with many current chemotherapeutics.	('effective', 'PosReg', (134, 143))	('aberrant genes', 'Var', (74, 88))	('CIN', 'Phenotype', 'HP:0040012', (90, 93))	('CIN', 'Phenotype', 'HP:0040012', (121, 124))	('eliminate', 'NegReg', (231, 240))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('myriad of cancers', 'Disease', 'MESH:D009369', (149, 166))	('CIN', 'Disease', (90, 93))	('CIN', 'Disease', (121, 124))	('CIN', 'Disease', 'MESH:D007674', (90, 93))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('myriad of cancers', 'Disease', (149, 166))	('CIN', 'Disease', 'MESH:D007674', (121, 124))
57868	29104272	Genome instability is an abnormal state characterized by a high prevalence of genomic alterations, and can include mutations in nucleic acid sequence, aberrant chromatin modifications, chromosomal rearrangements, or aneuploidy.	('aneuploidy', 'Disease', (216, 226))	('aberrant', 'Var', (151, 159))	('mutations', 'Var', (115, 124))	('chromatin', 'cellular_component', 'GO:0000785', ('160', '169'))	('aneuploidy', 'Disease', 'MESH:D000782', (216, 226))	('nucleic acid', 'cellular_component', 'GO:0005561', ('128', '140'))	('chromosomal', 'Disease', (185, 196))	('Genome instability', 'Disease', (0, 18))	('nucleic acid', 'Protein', (128, 140))
57874	29104272	More specifically, high CIN70 scores are associated with poor prognosis in multiple cancer types, including breast and lung cancers, and were increased in metastases.	('CIN', 'Phenotype', 'HP:0040012', (24, 27))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('high', 'Var', (19, 23))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', (84, 90))	('metastases', 'Disease', 'MESH:D009362', (155, 165))	('lung cancers', 'Phenotype', 'HP:0100526', (119, 131))	('breast and lung cancers', 'Disease', 'MESH:D001943', (108, 131))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('CIN', 'Disease', (24, 27))	('increased', 'Reg', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('CIN', 'Disease', 'MESH:D007674', (24, 27))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('metastases', 'Disease', (155, 165))
57883	29104272	Further, cell-to-cell heterogeneity in DNA content can be assessed through the Stemline Scatter Index (SSI, Table 1), and high SSI scores are indicative of CIN-positive tumors.	('high', 'Var', (122, 126))	('CIN', 'Phenotype', 'HP:0040012', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('CIN-positive tumors', 'Disease', 'MESH:D009369', (156, 175))	('CIN-positive tumors', 'Disease', (156, 175))	('SSI scores', 'MPA', (127, 137))
57916	29104272	AZD1152 is an Aurora Kinase B inhibitor that promotes endoreduplication (replication of DNA in the absence of cell division), the formation of large multinucleated cells, and apoptosis.	('endoreduplication', 'CPA', (54, 71))	('Aurora Kinase B', 'Gene', '9212', (14, 29))	('formation', 'biological_process', 'GO:0009058', ('130', '139'))	('apoptosis', 'CPA', (175, 184))	('AZD1152', 'Var', (0, 7))	('Aurora Kinase B', 'Gene', (14, 29))	('DNA', 'cellular_component', 'GO:0005574', ('88', '91'))	('AZD1152', 'Chemical', 'MESH:C520647', (0, 7))	('promotes', 'PosReg', (45, 53))	('cell division', 'biological_process', 'GO:0051301', ('110', '123'))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))
57917	29104272	AZD1152 inhibits growth of human colon, lung, and hematologic tumor xenografts in immunodeficient mice, and is now undergoing clinical trials in both solid and hematological cancers.	('growth', 'CPA', (17, 23))	('hematologic tumor', 'Disease', 'MESH:D006402', (50, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('lung', 'CPA', (40, 44))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('AZD1152', 'Var', (0, 7))	('inhibits', 'NegReg', (8, 16))	('human', 'Species', '9606', (27, 32))	('hematologic tumor', 'Phenotype', 'HP:0004377', (50, 67))	('AZD1152', 'Chemical', 'MESH:C520647', (0, 7))	('hematological cancers', 'Disease', 'MESH:D009369', (160, 181))	('hematological cancers', 'Disease', (160, 181))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('mice', 'Species', '10090', (98, 102))	('hematologic tumor', 'Disease', (50, 67))
57932	29104272	BRCA1/2-defective cancer cells exhibit enhanced sensitivity to PARP inhibitors, as they are unable to efficiently repair the resultant DNA double-strand breaks, which leads to cell death.	('PARP', 'Gene', '142', (63, 67))	('leads to', 'Reg', (167, 175))	('BRCA1/2', 'Gene', '672;675', (0, 7))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('cell death', 'biological_process', 'GO:0008219', ('176', '186'))	('DNA', 'Var', (135, 138))	('PARP', 'Gene', (63, 67))	('sensitivity', 'MPA', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('unable', 'NegReg', (92, 98))	('BRCA1/2', 'Gene', (0, 7))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('enhanced', 'PosReg', (39, 47))
57938	29104272	Therefore, cells harboring alterations that promote metastasis, cell survival and drug resistance (e.g., inhibit drug uptake, drive drug efflux, inactivate/metabolize the drug, or alter cell signaling to mitigate the effects of the drug) are more likely to be present within a CIN-positive tumor, and likely account for the correlation between CIN and highly aggressive, multidrug-resistant cancers.	('CIN', 'Disease', (277, 280))	('cancers', 'Phenotype', 'HP:0002664', (391, 398))	('cell signaling', 'MPA', (186, 200))	('cancers', 'Disease', (391, 398))	('CIN-positive tumor', 'Disease', 'MESH:D009369', (277, 295))	('drug uptake', 'MPA', (113, 124))	('alterations', 'Var', (27, 38))	('efflux', 'biological_process', 'GO:0140352', ('137', '143'))	('cancer', 'Phenotype', 'HP:0002664', (391, 397))	('uptake', 'biological_process', 'GO:0098657', ('118', '124'))	('inactivate/metabolize', 'Var', (145, 166))	('CIN', 'Disease', (344, 347))	('cell survival', 'CPA', (64, 77))	('CIN', 'Phenotype', 'HP:0040012', (277, 280))	('drug resistance', 'Phenotype', 'HP:0020174', (82, 97))	('drive', 'Reg', (126, 131))	('metastasis', 'CPA', (52, 62))	('uptake', 'biological_process', 'GO:0098739', ('118', '124'))	('CIN', 'Disease', 'MESH:D007674', (277, 280))	('CIN-positive tumor', 'Disease', (277, 295))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('cancers', 'Disease', 'MESH:D009369', (391, 398))	('alter', 'Reg', (180, 185))	('promote', 'PosReg', (44, 51))	('CIN', 'Phenotype', 'HP:0040012', (344, 347))	('inhibit', 'NegReg', (105, 112))	('drug efflux', 'MPA', (132, 143))	('signaling', 'biological_process', 'GO:0023052', ('191', '200'))	('drug resistance', 'biological_process', 'GO:0009315', ('82', '97'))	('CIN', 'Disease', 'MESH:D007674', (344, 347))	('efflux', 'biological_process', 'GO:0140115', ('137', '143'))	('drug resistance', 'biological_process', 'GO:0042493', ('82', '97'))
57943	29104272	While CIN represents a common target that may be exploited for the treatment of highly heterogeneous tumors and distinct metastatic lesions, extensive ITH may also complicate the process of selecting an appropriate treatment.	('complicate', 'NegReg', (164, 174))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('CIN', 'Disease', (6, 9))	('extensive ITH', 'Var', (141, 154))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('CIN', 'Disease', 'MESH:D007674', (6, 9))	('CIN', 'Phenotype', 'HP:0040012', (6, 9))	('tumors', 'Disease', (101, 107))
57945	29104272	For example, a CIN-inducing drug may increase the level of CIN beyond a critical threshold, and induce death for a subset of tumor cells already exhibiting a "high" level of CIN, whereas the viability of cells initially exhibiting a lower level of CIN may not be compromised.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('drug', 'Var', (28, 32))	('CIN', 'Phenotype', 'HP:0040012', (59, 62))	('CIN', 'Disease', (174, 177))	('CIN', 'Disease', 'MESH:D007674', (15, 18))	('CIN', 'Phenotype', 'HP:0040012', (248, 251))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('induce', 'Reg', (96, 102))	('CIN', 'Disease', 'MESH:D007674', (174, 177))	('CIN', 'Disease', (248, 251))	('CIN', 'Disease', (59, 62))	('tumor', 'Disease', (125, 130))	('CIN', 'Phenotype', 'HP:0040012', (15, 18))	('increase', 'PosReg', (37, 45))	('CIN', 'Disease', 'MESH:D007674', (59, 62))	('CIN', 'Phenotype', 'HP:0040012', (174, 177))	('CIN', 'Disease', 'MESH:D007674', (248, 251))	('CIN', 'Disease', (15, 18))
57957	29104272	In this regard, a recent study showed that silencing or inhibition (Monastrol) of KIF11 (Kinesin Family Member 11), a microtubule motor protein required for spindle pole dynamics during mitosis, initially induced monopolar formation and a prometaphase-like arrest; however, these anti-proliferative effects were only transient in both cancerous and immortalized cell lines.	('inhibition', 'NegReg', (56, 66))	('arrest', 'Disease', 'MESH:D006323', (257, 263))	('formation', 'biological_process', 'GO:0009058', ('223', '232'))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('cancerous', 'Disease', 'MESH:D009369', (335, 344))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('induced', 'Reg', (205, 212))	('arrest', 'Disease', (257, 263))	('mitosis', 'Disease', (186, 193))	('Kinesin', 'molecular_function', 'GO:0003777', ('89', '96'))	('silencing', 'Var', (43, 52))	('monopolar formation', 'MPA', (213, 232))	('cancerous', 'Disease', (335, 344))	('Monastrol', 'Chemical', 'MESH:C400223', (68, 77))	('Kinesin Family Member 11', 'Gene', '3832', (89, 113))	('Kinesin Family Member 11', 'Gene', (89, 113))	('microtubule', 'cellular_component', 'GO:0005874', ('118', '129'))	('spindle pole', 'cellular_component', 'GO:0000922', ('157', '169'))	('KIF11', 'Gene', '3832', (82, 87))	('mitosis', 'biological_process', 'GO:0000278', ('186', '193'))	('mitosis', 'Disease', 'None', (186, 193))	('KIF11', 'Gene', (82, 87))
57964	29104272	In particular, deep sequencing of multiple tumor regions/sites can identify common, actionable genetic alterations (see below), while ultra-deep sequencing can identify low frequency (1% or less) variants with important clinical implications, particularly for drug resistance.	('alterations', 'Var', (103, 114))	('drug resistance', 'MPA', (260, 275))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('drug resistance', 'Phenotype', 'HP:0020174', (260, 275))	('variants', 'Var', (196, 204))
57965	29104272	For example, ultra-deep sequencing of a breast cancer sample identified sub-clones with mutations conferring Lapatinib (HER2 (Human Epidermal Growth Factor Receptor 2) inhibitor) resistance, indicating that an alternative treatment (Trastuzumab) may be more appropriate to reduce the risk of drug resistance and disease recurrence.	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('drug resistance', 'Phenotype', 'HP:0020174', (292, 307))	('breast cancer', 'Disease', (40, 53))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (233, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('mutations', 'Var', (88, 97))	('HER2', 'Gene', (120, 124))	('resistance', 'MPA', (179, 189))	('HER2', 'Gene', '2064', (120, 124))	('Lapatinib', 'Chemical', 'MESH:D000077341', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Human Epidermal Growth Factor Receptor 2', 'Gene', '2064', (126, 166))	('Human Epidermal Growth Factor Receptor 2', 'Gene', (126, 166))
57973	29104272	The identification and targeting of common actionable alterations does not preclude the emergence of drug-resistant populations, particularly in tumors with CIN.	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('CIN', 'Disease', (157, 160))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('CIN', 'Disease', 'MESH:D007674', (157, 160))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('alterations', 'Var', (54, 65))	('CIN', 'Phenotype', 'HP:0040012', (157, 160))
57974	29104272	In contrast, loss-of-function alterations stemming from homozygous deletions of CIN genes are unable to be reversed, and are ideal targets to exploit using a synthetic lethal paradigm (detailed below).	('CIN', 'Disease', 'MESH:D007674', (80, 83))	('loss-of-function', 'NegReg', (13, 29))	('deletions', 'Var', (67, 76))	('CIN', 'Phenotype', 'HP:0040012', (80, 83))	('CIN', 'Disease', (80, 83))
57975	29104272	For example, a multi-region sequencing analysis identified inactivation of Polybromo 1 (PBRM1), a component of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complex, as a truncal event in several renal cell carcinoma cases.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (216, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('PBRM1', 'Gene', (88, 93))	('PBRM1', 'Gene', '55193', (88, 93))	('inactivation', 'Var', (59, 71))	('renal cell carcinoma', 'Disease', (216, 236))	('Polybromo 1', 'Gene', '55193', (75, 86))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (216, 236))	('Sucrose', 'Chemical', 'MESH:D013395', (131, 138))	('Polybromo 1', 'Gene', (75, 86))
57976	29104272	Inactivation of PBRM1 and additional members of the SWI/SNF complexes are associated with CIN, and a pre-clinical study showed that truncal PBRM1 alterations may be exploited through CIN-inducing therapies.	('CIN', 'Disease', 'MESH:D007674', (183, 186))	('CIN', 'Phenotype', 'HP:0040012', (90, 93))	('PBRM1', 'Gene', '55193', (16, 21))	('PBRM1', 'Gene', (140, 145))	('CIN', 'Phenotype', 'HP:0040012', (183, 186))	('alterations', 'Var', (146, 157))	('pre', 'molecular_function', 'GO:0003904', ('101', '104'))	('PBRM1', 'Gene', '55193', (140, 145))	('CIN', 'Disease', (90, 93))	('CIN', 'Disease', (183, 186))	('CIN', 'Disease', 'MESH:D007674', (90, 93))	('Inactivation', 'Var', (0, 12))	('PBRM1', 'Gene', (16, 21))	('associated', 'Reg', (74, 84))
57977	29104272	In this context, convergent evolution occurs when alterations in distinct genes adversely impact the same CIN pathway (e.g., microtubule dynamics, SAC function or centrosome biology), but within different sub-clonal populations.	('SAC function', 'MPA', (147, 159))	('CIN', 'Disease', (106, 109))	('alterations', 'Var', (50, 61))	('CIN', 'Disease', 'MESH:D007674', (106, 109))	('microtubule dynamics', 'MPA', (125, 145))	('impact', 'Reg', (90, 96))	('CIN', 'Phenotype', 'HP:0040012', (106, 109))
57978	29104272	For example, in renal carcinomas where PBRM1 inactivation was not deemed a truncal event, many tumor cells still harbored defects in additional SWI/SNF member genes.	('PBRM1', 'Gene', '55193', (39, 44))	('inactivation', 'Var', (45, 57))	('SWI/SNF member genes', 'Gene', (144, 164))	('renal carcinomas', 'Disease', (16, 32))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('renal carcinomas', 'Phenotype', 'HP:0005584', (16, 32))	('defects', 'NegReg', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('renal carcinomas', 'Disease', 'MESH:C538614', (16, 32))	('tumor', 'Disease', (95, 100))	('PBRM1', 'Gene', (39, 44))
57979	29104272	Therefore, it is predicted that disruption of SWI/SNF function, through defects in a diverse array of genes, will induce CIN through a convergent mechanism, and render each sub-population sensitive to any therapy that exploits SWI/SNF defects.	('disruption', 'Var', (32, 42))	('CIN', 'Phenotype', 'HP:0040012', (121, 124))	('render', 'Reg', (161, 167))	('CIN', 'Disease', (121, 124))	('SWI/SNF', 'Gene', (46, 53))	('induce', 'Reg', (114, 120))	('SNF defects', 'Disease', 'MESH:D005128', (231, 242))	('SNF defects', 'Disease', (231, 242))	('defects', 'NegReg', (72, 79))	('CIN', 'Disease', 'MESH:D007674', (121, 124))
57983	29104272	Synthetic lethality is defined as a rare and lethal combination of two independently viable gene mutations or deletions, and is an emerging strategy that can be employed to selectively exploit the underlying truncal (and branch) alterations that cause CIN.	('mutations', 'Var', (97, 106))	('CIN', 'Disease', 'MESH:D007674', (252, 255))	('CIN', 'Phenotype', 'HP:0040012', (252, 255))	('CIN', 'Disease', (252, 255))	('deletions', 'Var', (110, 119))
57984	29104272	In a cancer context, defects in a CIN gene may be exploited by downregulating or inhibiting a synthetic lethal (SL) interactor (i.e., drug target) to induce tumor-specific killing.	('tumor', 'Disease', (157, 162))	('induce', 'PosReg', (150, 156))	('inhibiting', 'NegReg', (81, 91))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('CIN', 'Disease', (34, 37))	('cancer', 'Disease', (5, 11))	('downregulating', 'NegReg', (63, 77))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('CIN', 'Disease', 'MESH:D007674', (34, 37))	('defects', 'Var', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('CIN', 'Phenotype', 'HP:0040012', (34, 37))
57986	29104272	As such, synthetic lethality is ideally suited to exploit the truncal loss-of-function alterations leading to CIN, and is best exemplified by the synthetic lethal targeting of BRCA1/2-deficient ovarian cancers with the PARP inhibitor, Olaparib (detailed above).	('PARP', 'Gene', '142', (219, 223))	('Olaparib', 'Chemical', 'MESH:C531550', (235, 243))	('BRCA1/2-deficient ovarian cancers', 'Disease', (176, 209))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('ovarian cancers', 'Phenotype', 'HP:0100615', (194, 209))	('CIN', 'Phenotype', 'HP:0040012', (110, 113))	('alterations', 'Var', (87, 98))	('PARP', 'Gene', (219, 223))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('CIN', 'Disease', (110, 113))	('loss-of-function', 'NegReg', (70, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (194, 208))	('BRCA1/2-deficient ovarian cancers', 'Disease', 'OMIM:612555', (176, 209))	('CIN', 'Disease', 'MESH:D007674', (110, 113))
57987	29104272	Finally, SL strategies are also expected to reduce adverse side-effects and the occurrence of secondary cancers, as they are inherently restricted to targeting cancer cells with defects in CIN genes.	('CIN', 'Phenotype', 'HP:0040012', (189, 192))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (160, 166))	('CIN', 'Disease', (189, 192))	('defects', 'Var', (178, 185))	('CIN', 'Disease', 'MESH:D007674', (189, 192))	('secondary cancers', 'Disease', 'MESH:D009369', (94, 111))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('secondary cancers', 'Disease', (94, 111))
57990	29104272	For example, PARP inhibitors that target BRCA1/2 defects underlying HRR-deficiencies are also effective at killing cancer cells harboring defects in additional HRR genes, like RAD51, ATM, ATR, CHEK1, and RAD54B.	('defects', 'Var', (138, 145))	('PARP', 'Gene', (13, 17))	('RAD51', 'Gene', (176, 181))	('RAD51', 'Gene', '5888', (176, 181))	('HRR-deficiencies', 'Disease', 'MESH:D007153', (68, 84))	('ATM', 'Gene', (183, 186))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('BRCA1/2', 'Gene', (41, 48))	('CHEK1', 'Gene', (193, 198))	('ATR', 'Gene', (188, 191))	('RAD54B', 'Gene', '25788', (204, 210))	('BRCA1/2', 'Gene', '672;675', (41, 48))	('HRR genes', 'Gene', (160, 169))	('cancer', 'Disease', (115, 121))	('ATM', 'Gene', '472', (183, 186))	('ATR', 'Gene', '545', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('RAD54B', 'Gene', (204, 210))	('PARP', 'Gene', '142', (13, 17))	('CHEK1', 'Gene', '1111', (193, 198))	('HRR-deficiencies', 'Disease', (68, 84))
58003	29104272	Solid tumors typically harbored between 30 and 70 clonal nonsynonymous mutations, with most representing passenger mutations, while 5-10% were driver mutations that provided a selective growth advantage and contributed to oncogenesis.	('oncogenesis', 'CPA', (222, 233))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('nonsynonymous mutations', 'Var', (57, 80))	('oncogenesis', 'biological_process', 'GO:0007048', ('222', '233'))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
58004	29104272	This study also determined that the driver mutations were typically present in 30-100% of primary tumor cells, as well as in the metastatic lesions, and thus identified promising therapeutic targets.	('primary tumor', 'Disease', (90, 103))	('primary tumor', 'Disease', 'MESH:D009369', (90, 103))	('mutations', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))
58017	29104272	In fact, preclinical work evaluating Paclitaxel and inhibitors of the SAC component MPS1 (Monopolar Spindle 1) has revealed a synergistic interaction suggesting that the disruption of one CIN pathway may potentiate the disruption of a second CIN pathway.	('MPS1', 'Gene', '7272', (84, 88))	('CIN', 'Disease', 'MESH:D007674', (242, 245))	('MPS1', 'Gene', (84, 88))	('disruption', 'MPA', (219, 229))	('CIN', 'Disease', (188, 191))	('Paclitaxel', 'Chemical', 'MESH:D017239', (37, 47))	('disruption', 'Var', (170, 180))	('Monopolar Spindle 1', 'Gene', '7272', (90, 109))	('SAC', 'cellular_component', 'GO:0035003', ('70', '73'))	('CIN', 'Disease', 'MESH:D007674', (188, 191))	('Spindle', 'cellular_component', 'GO:0005819', ('100', '107'))	('CIN', 'Phenotype', 'HP:0040012', (242, 245))	('CIN', 'Phenotype', 'HP:0040012', (188, 191))	('potentiate', 'PosReg', (204, 214))	('CIN', 'Disease', (242, 245))	('Monopolar Spindle 1', 'Gene', (90, 109))	('SAC', 'biological_process', 'GO:0071173', ('70', '73'))
58019	29104272	Furthermore, it has been suggested that drug combinations that target distinct cellular processes are less likely to exhibit additive toxicities in healthy cells associated with combinations targeting a single pathway.	('toxicities', 'Disease', (134, 144))	('combinations', 'Var', (45, 57))	('toxicities', 'Disease', 'MESH:D064420', (134, 144))
58021	29104272	For example, while genetic adaptation to CIN is a possible mechanism contributing to Paclitaxel resistance, these cells are expected to remain sensitive to Carboplatin, a conventional chemotherapy and DNA alkylating/cross-linking agent that prevents DNA replication and induces cell death.	('Paclitaxel', 'Chemical', 'MESH:D017239', (85, 95))	('genetic adaptation', 'Var', (19, 37))	('contributing', 'Reg', (69, 81))	('CIN', 'Disease', (41, 44))	('Carboplatin', 'Chemical', 'MESH:D016190', (156, 167))	('cell', 'CPA', (278, 282))	('DNA', 'Protein', (250, 253))	('CIN', 'Disease', 'MESH:D007674', (41, 44))	('CIN', 'Phenotype', 'HP:0040012', (41, 44))	('prevents', 'NegReg', (241, 249))	('induces', 'Reg', (270, 277))
58032	29104272	More specifically, they showed that targeted knock-down of metabolic genes in CIN-positive cells induced increases in oxidative damage, DNA double-strand breaks and apoptosis, resulting in selective killing of cancer cells with CIN.	('CIN', 'Disease', (78, 81))	('increases', 'PosReg', (105, 114))	('CIN', 'Disease', 'MESH:D007674', (228, 231))	('oxidative damage', 'MPA', (118, 134))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('apoptosis', 'CPA', (165, 174))	('knock-down', 'Var', (45, 55))	('CIN', 'Phenotype', 'HP:0040012', (228, 231))	('CIN', 'Disease', 'MESH:D007674', (78, 81))	('DNA double-strand breaks', 'MPA', (136, 160))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('CIN', 'Phenotype', 'HP:0040012', (78, 81))	('metabolic genes', 'Gene', (59, 74))	('CIN', 'Disease', (228, 231))	('cancer', 'Disease', (210, 216))
58033	29104272	Additional studies have shown that increases in reactive oxygen species following SOD1 (Superoxide Dismutase 1) silencing and inhibition induces SL killing in colorectal cancer cells harboring defects in established CIN genes, like RAD54B, BLM, and CHEK2.	('CIN', 'Phenotype', 'HP:0040012', (216, 219))	('SL killing', 'CPA', (145, 155))	('RAD54B', 'Gene', '25788', (232, 238))	('defects', 'Var', (193, 200))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('CIN', 'Disease', 'MESH:D007674', (216, 219))	('inhibition', 'NegReg', (126, 136))	('CHEK2', 'Gene', (249, 254))	('Superoxide Dismutase 1', 'Gene', '6647', (88, 110))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (48, 71))	('BLM', 'Gene', (240, 243))	('colorectal cancer', 'Disease', 'MESH:D015179', (159, 176))	('SOD1', 'molecular_function', 'GO:0004784', ('82', '86'))	('increases', 'PosReg', (35, 44))	('CHEK2', 'Gene', '11200', (249, 254))	('RAD54B', 'Gene', (232, 238))	('colorectal cancer', 'Disease', (159, 176))	('RAD', 'biological_process', 'GO:1990116', ('232', '235'))	('Superoxide Dismutase 1', 'Gene', (88, 110))	('CIN', 'Disease', (216, 219))	('SOD1', 'Gene', (82, 86))	('SOD1', 'Gene', '6647', (82, 86))	('induces', 'Reg', (137, 144))	('reactive oxygen species', 'MPA', (48, 71))	('colorectal cancer', 'Phenotype', 'HP:0003003', (159, 176))	('silencing', 'Var', (112, 121))
58144	27785421	Lynch syndrome and exposure to aristolochic acid in upper-tract urothelial carcinoma: its clinical impact?	('upper-tract urothelial carcinoma', 'Disease', (52, 84))	('aristolochic acid', 'Chemical', 'MESH:C000228', (31, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('Lynch syndrome', 'Disease', (0, 14))	('upper-tract urothelial carcinoma', 'Disease', 'MESH:D012141', (52, 84))	('aristolochic', 'Var', (31, 43))	('Lynch syndrome', 'Disease', 'MESH:D003123', (0, 14))
58146	27785421	A systematic review of the scientific literature was performed using the Medline database (National Library of Medicine, PubMed) using the following keywords: epidemiology, risk factor, AA, Balkan nephropathy (BNe), LS, hereditary cancer, hereditary non-polyposis colorectal cancer (HNPCC), mismatch repair genes, urothelial carcinomas, upper urinary tract, renal pelvis, ureter, Amsterdam criteria, genetic counselling, mismatch repair genes, genetic instability, microsatellite, and Bethesda guidelines.	('hereditary cancer', 'Disease', (220, 237))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (314, 335))	('Balkan nephropathy', 'Disease', 'MESH:D007674', (190, 208))	('Balkan nephropathy', 'Disease', (190, 208))	('hereditary non-polyposis colorectal cancer', 'Disease', 'MESH:D015179', (239, 281))	('hereditary cancer', 'Disease', 'MESH:D009369', (220, 237))	('HNPCC', 'Gene', (283, 288))	('mismatch repair genes', 'Gene', (421, 442))	('genetic', 'Var', (444, 451))	('HNPCC', 'Gene', '4436', (283, 288))	('HNPCC', 'Phenotype', 'HP:0006716', (283, 288))	('carcinoma', 'Phenotype', 'HP:0030731', (325, 334))	('carcinomas', 'Phenotype', 'HP:0030731', (325, 335))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('mismatch', 'Gene', (291, 299))	('colorectal cancer', 'Phenotype', 'HP:0003003', (264, 281))	('hereditary non-polyposis colorectal cancer', 'Disease', (239, 281))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('renal pelvis', 'Phenotype', 'HP:0000125', (358, 370))	('nephropathy', 'Phenotype', 'HP:0000112', (197, 208))	('urothelial carcinomas', 'Disease', (314, 335))	('hereditary non-polyposis colorectal cancer', 'Phenotype', 'HP:0006716', (239, 281))
58148	27785421	Mutation of the MSH2 gene is the most commonly described cause of UTUC in LS.	('MSH2', 'Gene', (16, 20))	('MSH2', 'Gene', '4436', (16, 20))	('cause', 'Reg', (57, 62))	('UTUC', 'Disease', (66, 70))	('Mutation', 'Var', (0, 8))
58158	27785421	Ingestion of aristolochic acid (AA) is now recognized to be a carcinogenic agent that causes severe renal disease and UTUCs in exposed populations worldwide.	('aristolochic acid', 'Chemical', 'MESH:C000228', (13, 30))	('aristolochic acid', 'Var', (13, 30))	('UTUCs', 'Phenotype', 'HP:0010786', (118, 123))	('causes', 'Reg', (86, 92))	('UTUCs', 'Disease', (118, 123))	('renal disease', 'Disease', (100, 113))	('carcinogenic', 'Disease', 'MESH:D063646', (62, 74))	('renal disease', 'Disease', 'MESH:D007674', (100, 113))	('carcinogenic', 'Disease', (62, 74))	('renal disease', 'Phenotype', 'HP:0000112', (100, 113))
58170	27785421	LS is associated with a germline mutation of one of the six genes in the DNA-mismatch repair system (MMR): i.e., hMSH2, hMSH3, hMSH6, hMLH1, hPMS1, hPMS2.	('hMSH', 'molecular_function', 'GO:0018775', ('120', '124'))	('hMLH1', 'Gene', (134, 139))	('hMLH1', 'Gene', '4292', (134, 139))	('hMSH2', 'Gene', '4436', (113, 118))	('hPMS2', 'Gene', '5395', (148, 153))	('germline mutation', 'Var', (24, 41))	('hMSH2', 'Gene', (113, 118))	('mismatch repair', 'biological_process', 'GO:0006298', ('77', '92'))	('hPMS2', 'Gene', (148, 153))	('hMSH', 'molecular_function', 'GO:0018775', ('127', '131'))	('MMR', 'biological_process', 'GO:0006298', ('101', '104'))	('hPMS1', 'Gene', (141, 146))	('associated', 'Reg', (6, 16))	('hMSH', 'molecular_function', 'GO:0018775', ('113', '117'))	('hMSH6', 'Gene', (127, 132))	('hMSH3', 'Gene', '4437', (120, 125))	('hPMS1', 'Gene', '5378', (141, 146))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('hMSH3', 'Gene', (120, 125))	('hMSH6', 'Gene', '2956', (127, 132))
58171	27785421	This type of mutation is causes an unstable tumor phenotype that can be detected by assessing microsatellite instability (MSI).	('mutation', 'Var', (13, 21))	('microsatellite instability', 'MPA', (94, 120))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('MSI', 'Disease', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('MSI', 'Disease', 'None', (122, 125))
58184	27785421	An hMSH2 gene mutation is the most common (60%) in patients with LS and UTUC.	('hMSH', 'molecular_function', 'GO:0018775', ('3', '7'))	('common', 'Reg', (35, 41))	('UTUC', 'Disease', (72, 76))	('hMSH2', 'Gene', '4436', (3, 8))	('mutation', 'Var', (14, 22))	('hMSH2', 'Gene', (3, 8))	('patients', 'Species', '9606', (51, 59))
58186	27785421	Mutations of other genes (hMSH3, hPMS1, and hPSM2) are less common.	('hMSH3', 'Gene', '4437', (26, 31))	('hPMS1', 'Gene', (33, 38))	('hPSM2', 'Gene', (44, 49))	('hPMS1', 'Gene', '5378', (33, 38))	('Mutations', 'Var', (0, 9))	('hMSH3', 'Gene', (26, 31))
58198	27785421	Published data report that those with familial LS and patients carrying a MSH2 mutation are particularly at risk of carcinogenesis of the upper urinary tract and so should be monitored closely.	('MSH2', 'Gene', '4436', (74, 78))	('carcinogenesis', 'Disease', 'MESH:D063646', (116, 130))	('patients', 'Species', '9606', (54, 62))	('carcinogenesis', 'Disease', (116, 130))	('mutation', 'Var', (79, 87))	('risk', 'Reg', (108, 112))	('familial LS', 'Disease', (38, 49))	('MSH2', 'Gene', (74, 78))
58286	27074785	In vivo studies suggested a role for antibodies against integrin beta1 chains in prevention of colorectal, gastric and pancreatic tumour cell adhesion to (traumatised) peritoneum.	('antibodies', 'Var', (37, 47))	('colorectal', 'Disease', 'MESH:D015179', (95, 105))	('gastric', 'Disease', (107, 114))	('colorectal', 'Disease', (95, 105))	('pancreatic tumour', 'Disease', 'MESH:D010190', (119, 136))	('cell adhesion', 'biological_process', 'GO:0007155', ('137', '150'))	('pancreatic tumour', 'Disease', (119, 136))	('integrin beta1', 'Gene', (56, 70))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('integrin beta1', 'Gene', '3688', (56, 70))	('pancreatic tumour', 'Phenotype', 'HP:0002894', (119, 136))
58298	27074785	In particular, CD44 isoforms originating from alternative splicing are thought to be important in tumour metastasis.	('CD44', 'Gene', '960', (15, 19))	('alternative splicing', 'Var', (46, 66))	('CD44', 'Gene', (15, 19))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumour metastasis', 'Disease', 'MESH:D009362', (98, 115))	('important', 'Reg', (85, 94))	('tumour metastasis', 'Disease', (98, 115))
58306	27074785	In vivo blocking of CD44 s prevented PM in ovarian, gastric and pancreatic cancer.	('ovarian', 'Disease', (43, 50))	('PM', 'Chemical', '-', (37, 39))	('CD44', 'Gene', '960', (20, 24))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (64, 81))	('blocking', 'Var', (8, 16))	('prevented', 'NegReg', (27, 36))	('CD44', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('gastric and pancreatic cancer', 'Disease', 'MESH:D010190', (52, 81))
58311	27074785	Although:theoretically:blocking the CD44 ligand hyaluronan might prevent peritoneal dissemination, its therapeutic value is controversial: both tumour promoting and tumour repressing effects were reported after blocking CD44 intraperitoneally with hyaluronan.	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('hyaluronan', 'Chemical', 'MESH:D006820', (48, 58))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('CD44', 'Gene', (36, 40))	('CD44', 'Gene', '960', (220, 224))	('hyaluronan', 'Chemical', 'MESH:D006820', (248, 258))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('tumour', 'Disease', (144, 150))	('CD44', 'Gene', (220, 224))	('tumour', 'Disease', (165, 171))	('blocking', 'Var', (211, 219))	('CD44', 'Gene', '960', (36, 40))
58365	27074785	In vitro and in vivo blocking of CXCR4 with its antagonist ADM3100 was thereby shown to inhibit PM formation.	('blocking', 'Var', (21, 29))	('PM formation', 'MPA', (96, 108))	('CXCR4', 'Gene', (33, 38))	('inhibit', 'NegReg', (88, 95))	('PM', 'Chemical', '-', (96, 98))	('CXCR4', 'Gene', '7852', (33, 38))
58412	27047747	Genetic mutations, epigenetic alterations, inflammation, and environmental factors such as diet are thought to be linked to CRC initiation and progression 2, 3.	('CRC', 'Disease', (124, 127))	('epigenetic alterations', 'Var', (19, 41))	('linked', 'Reg', (114, 120))	('CRC', 'Phenotype', 'HP:0003003', (124, 127))	('inflammation', 'Disease', 'MESH:D007249', (43, 55))	('inflammation', 'Disease', (43, 55))	('Genetic mutations', 'Var', (0, 17))	('inflammation', 'biological_process', 'GO:0006954', ('43', '55'))	('men', 'Species', '9606', (68, 71))
58426	27047747	Alteration in fatty acid metabolism is a hallmark of cancer, and several lines of evidence showed that limiting fatty acid availability controls cancer cell proliferation 22, 23.	('cancer', 'Disease', (145, 151))	('hallmark of cancer', 'Disease', (41, 59))	('fatty acid', 'Chemical', 'MESH:D005227', (14, 24))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('Alteration', 'Var', (0, 10))	('hallmark of cancer', 'Disease', 'MESH:D009369', (41, 59))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('fatty acid', 'Chemical', 'MESH:D005227', (112, 122))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('fatty acid metabolism', 'MPA', (14, 35))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
58472	27047747	Cell cycle analysis revealed that knockdown of FABP5 expression resulted in a marked increase in G1/G0 phase population (Fig.	('FABP5', 'Gene', (47, 52))	('G1/G0 phase population', 'CPA', (97, 119))	('G0 phase', 'biological_process', 'GO:0044838', ('100', '108'))	('knockdown', 'Var', (34, 43))	('increase', 'PosReg', (85, 93))	('Cell cycle', 'biological_process', 'GO:0007049', ('0', '10'))	('FABP5', 'Gene', '2171', (47, 52))
58475	27047747	We also found that the transcription factor c-MYC, a negative regulator of p21WAF1/Cip1 30, was downregulated by FABP5 knockdown (Fig.	('FABP5', 'Gene', (113, 118))	('FABP5', 'Gene', '2171', (113, 118))	('c-MYC', 'Gene', '4609', (44, 49))	('Cip1', 'Gene', '1026', (83, 87))	('downregulated', 'NegReg', (96, 109))	('knockdown', 'Var', (119, 128))	('p21', 'Gene', (75, 78))	('c-MYC', 'Gene', (44, 49))	('Cip1', 'Gene', (83, 87))	('p21', 'Gene', '644914', (75, 78))
58476	27047747	To assess whether knockdown of FABP5 expression induces apoptotic cell death, a cell apoptosis assay based on the evaluation of caspase-3 activity by flow cytometry was performed.	('knockdown', 'Var', (18, 27))	('caspase-3', 'Gene', (128, 137))	('FABP5', 'Gene', (31, 36))	('FABP5', 'Gene', '2171', (31, 36))	('apoptotic', 'CPA', (56, 65))	('induces', 'Reg', (48, 55))	('caspase-3', 'Gene', '836', (128, 137))
58477	27047747	2G, knockdown of FABP5 expression significantly activated caspase-3, up to 2.2 times compared to control.	('caspase-3', 'Gene', '836', (58, 67))	('FABP5', 'Gene', (17, 22))	('FABP5', 'Gene', '2171', (17, 22))	('knockdown', 'Var', (4, 13))	('activated', 'PosReg', (48, 57))	('caspase-3', 'Gene', (58, 67))
58478	27047747	Cell growth suppression upon knockdown of FABP5 can be attributed to p21-mediated G1 arrest and apoptosis.	('G1 arrest', 'CPA', (82, 91))	('knockdown', 'Var', (29, 38))	('FABP5', 'Gene', (42, 47))	('FABP5', 'Gene', '2171', (42, 47))	('p21', 'Gene', (69, 72))	('Cell growth', 'biological_process', 'GO:0016049', ('0', '11'))	('p21', 'Gene', '644914', (69, 72))	('suppression', 'NegReg', (12, 23))	('apoptosis', 'CPA', (96, 105))	('apoptosis', 'biological_process', 'GO:0097194', ('96', '105'))	('Cell growth', 'CPA', (0, 11))	('apoptosis', 'biological_process', 'GO:0006915', ('96', '105'))
58481	27047747	3A,B, knockdown of FABP5 significantly decreased the number of cells invading through the Matrigel-coated membrane.	('coated membrane', 'cellular_component', 'GO:0048475', ('99', '114'))	('knockdown', 'Var', (6, 15))	('FABP5', 'Gene', (19, 24))	('decreased', 'NegReg', (39, 48))	('FABP5', 'Gene', '2171', (19, 24))
58490	27047747	3C, knockdown of FABP5 expression significantly suppressed MAGL and hormone-sensitive lipase (HSL) expression levels.	('hormone-sensitive lipase', 'Gene', (68, 92))	('MAGL', 'Gene', (59, 63))	('HSL', 'Gene', '3991', (94, 97))	('FABP5', 'Gene', (17, 22))	('FABP5', 'Gene', '2171', (17, 22))	('hormone-sensitive lipase', 'Gene', '3991', (68, 92))	('HSL', 'Gene', (94, 97))	('suppressed', 'NegReg', (48, 58))	('HSL', 'molecular_function', 'GO:0033878', ('94', '97'))	('knockdown', 'Var', (4, 13))	('MAGL', 'Gene', '11343', (59, 63))
58497	27047747	In HCT116 cells, activation of PPAR beta/delta with GW0742 resulted in an increase in the mRNA level of adipocyte differentiation-related protein (ADRP), a well-characterized PPAR (beta/delta and gamma) target gene 36, regardless of the FABP5 expression level (Fig.	('PPAR', 'Gene', (31, 35))	('FABP5', 'Gene', (237, 242))	('FABP5', 'Gene', '2171', (237, 242))	('PPAR', 'Gene', '5465', (175, 179))	('HCT116', 'CellLine', 'CVCL:0291', (3, 9))	('mRNA level', 'MPA', (90, 100))	('PPAR beta', 'Gene', (31, 40))	('PPAR beta', 'Gene', '5467', (31, 40))	('increase', 'PosReg', (74, 82))	('adipocyte differentiation-related protein', 'Gene', '123', (104, 145))	('PPAR', 'Gene', '5465', (31, 35))	('activation', 'PosReg', (17, 27))	('ADRP', 'Gene', (147, 151))	('PPAR', 'Gene', (175, 179))	('ADRP', 'Gene', '123', (147, 151))	('adipocyte differentiation-related protein', 'Gene', (104, 145))	('GW0742', 'Var', (52, 58))	('GW0742', 'Chemical', 'MESH:C479979', (52, 58))
58498	27047747	Furthermore, overexpression of FABP5 and treatment with GW0742 in Caco-2 cells did not influence ADRP expression level (Fig.	('GW0742', 'Var', (56, 62))	('ADRP', 'Gene', (97, 101))	('Caco-2', 'CellLine', 'CVCL:0025', (66, 72))	('ADRP', 'Gene', '123', (97, 101))	('GW0742', 'Chemical', 'MESH:C479979', (56, 62))	('FABP5', 'Gene', '2171', (31, 36))	('FABP5', 'Gene', (31, 36))	('men', 'Species', '9606', (46, 49))
58500	27047747	GW0742 also failed to increase the expression of 3-phosphoinositide-dependent protein kinase-1 (PDPK1), which is a PPAR beta/delta target gene 37 and phosphorylates AKT/PKB (protein kinase B), leading to activation of survival signaling (Fig.	('signaling', 'biological_process', 'GO:0023052', ('227', '236'))	('PKB', 'Gene', '207', (169, 172))	('3-phosphoinositide-dependent protein kinase-1', 'Gene', '5170', (49, 94))	('survival', 'MPA', (218, 226))	('PKB', 'Gene', (169, 172))	('GW0742', 'Var', (0, 6))	('PDPK1', 'Gene', '5170', (96, 101))	('AKT', 'Gene', (165, 168))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('PPAR beta', 'Gene', (115, 124))	('GW0742', 'Chemical', 'MESH:C479979', (0, 6))	('PPAR beta', 'Gene', '5467', (115, 124))	('AKT', 'Gene', '207', (165, 168))	('protein kinase B', 'Gene', '2185', (174, 190))	('activation', 'PosReg', (204, 214))	('PDPK1', 'Gene', (96, 101))	('3-phosphoinositide-dependent protein kinase-1', 'Gene', (49, 94))	('protein kinase B', 'Gene', (174, 190))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))
58501	27047747	This result is consistent with recent studies showing no changes in the expression of PDPK1 and phosphorylation of AKT in response to GW0742 in human HaCaT keratinocytes and CRC cells 38, 39, 40.	('CRC', 'Phenotype', 'HP:0003003', (174, 177))	('AKT', 'Gene', '207', (115, 118))	('PDPK1', 'Gene', '5170', (86, 91))	('PDPK1', 'Gene', (86, 91))	('human', 'Species', '9606', (144, 149))	('phosphorylation', 'MPA', (96, 111))	('HaCaT keratinocytes', 'CellLine', 'CVCL:0038', (150, 169))	('phosphorylation', 'biological_process', 'GO:0016310', ('96', '111'))	('AKT', 'Gene', (115, 118))	('GW0742', 'Var', (134, 140))	('GW0742', 'Chemical', 'MESH:C479979', (134, 140))
58502	27047747	In addition, the levels of phosphorylated AKT were unchanged by knockdown of FABP5 (Fig.	('levels of phosphorylated', 'MPA', (17, 41))	('AKT', 'Gene', (42, 45))	('FABP5', 'Gene', '2171', (77, 82))	('knockdown', 'Var', (64, 73))	('AKT', 'Gene', '207', (42, 45))	('FABP5', 'Gene', (77, 82))
58511	27047747	Moreover, knockdown of FABP5 expression resulted in the downregulation of fatty acid metabolizing genes, such as acetyl-CoA carboxylase alpha (ACCalpha) and isocitrate dehydrogenase 1 (IDH1) (Fig.	('IDH1', 'Gene', '3417', (185, 189))	('IDH1', 'Gene', (185, 189))	('ACCalpha', 'Gene', (143, 151))	('ACCalpha', 'Gene', '31', (143, 151))	('isocitrate dehydrogenase 1', 'Gene', '3417', (157, 183))	('FABP5', 'Gene', '2171', (23, 28))	('FABP5', 'Gene', (23, 28))	('isocitrate dehydrogenase 1', 'Gene', (157, 183))	('acetyl-CoA carboxylase', 'MPA', (113, 135))	('downregulation', 'NegReg', (56, 70))	('fatty acid', 'Chemical', 'MESH:D005227', (74, 84))	('fatty acid metabolizing genes', 'Gene', (74, 103))	('knockdown', 'Var', (10, 19))
58513	27047747	In HCT116 cells, treatment with GW0742 or GW1929 (PPAR gamma agonist) had no significant effect on the expression levels of ACCalpha, FASN, and HSL (Fig.	('FASN', 'Gene', (134, 138))	('FASN', 'Gene', '2194', (134, 138))	('HCT116', 'CellLine', 'CVCL:0291', (3, 9))	('expression levels', 'MPA', (103, 120))	('ACCalpha', 'Gene', '31', (124, 132))	('HSL', 'Gene', (144, 147))	('GW0742', 'Var', (32, 38))	('GW0742', 'Chemical', 'MESH:C479979', (32, 38))	('GW1929', 'Var', (42, 48))	('ACCalpha', 'Gene', (124, 132))	('men', 'Species', '9606', (22, 25))	('PPAR gamma', 'Gene', '5468', (50, 60))	('HSL', 'molecular_function', 'GO:0033878', ('144', '147'))	('HSL', 'Gene', '3991', (144, 147))	('PPAR gamma', 'Gene', (50, 60))	('GW1929', 'Chemical', 'MESH:C120099', (42, 48))
58581	26705206	Table 2 shows that the patients with PPOI were more likely to suffer from postoperative complications than the patients without PPOI (P < 0.001).	('postoperative complications', 'CPA', (74, 101))	('patients', 'Species', '9606', (23, 31))	('PPOI', 'Chemical', '-', (128, 132))	('PPOI', 'Chemical', '-', (37, 41))	('suffer', 'Reg', (62, 68))	('PPOI', 'Var', (37, 41))	('patients', 'Species', '9606', (111, 119))
58582	26705206	Moreover, patients with PPOI had a longer postoperative hospitalization stay (P < 0.001), as well as a significant more hospital costs than the patients without PPOI (P < 0.001).	('more', 'PosReg', (115, 119))	('PPOI', 'Chemical', '-', (24, 28))	('PPOI', 'Var', (24, 28))	('patients', 'Species', '9606', (144, 152))	('longer', 'PosReg', (35, 41))	('patients', 'Species', '9606', (10, 18))	('hospital', 'MPA', (120, 128))	('PPOI', 'Chemical', '-', (161, 165))
58601	26705206	The present study confirmed the results of previous studies that PPOI lead to a higher incidence of postoperative complications, a longer length of postoperative hospital stay and more hospital costs (Table 2).	('PPOI', 'Var', (65, 69))	('postoperative complications', 'CPA', (100, 127))	('PPOI', 'Chemical', '-', (65, 69))
58660	26183471	The phosphorylation of FGFR4 enhanced the production of metalloproteinase (MMP)-7 and mitogen-activated protein kinase kinase (Mek)/extracellular signal-regulated kinase (Erk), which was accompanied by excessive vessel generation and cell proliferation.	('excessive', 'PosReg', (202, 211))	('cell proliferation', 'CPA', (234, 252))	('Mek', 'Gene', (127, 130))	('vessel generation', 'CPA', (212, 229))	('metalloproteinase (MMP)-7', 'Gene', '4316', (56, 81))	('production of', 'MPA', (42, 55))	('Mek', 'Gene', '5609', (127, 130))	('mitogen-activated protein kinase kinase', 'Gene', (86, 125))	('mitogen-activated protein kinase kinase', 'Gene', '5609', (86, 125))	('FGFR4', 'Gene', (23, 28))	('metalloproteinase (MMP)-7', 'Gene', (56, 81))	('enhanced', 'PosReg', (29, 37))	('phosphorylation', 'Var', (4, 19))
58701	26183471	Colon tissues were homogenised and sonicated in RIPA lysis buffer (Beyotime Biotechnology, Suzhou, China) supplemented with protease and phosphatase inhibitors (Roche, Rotkreuz, Switzerland) to detect phospho-tyrosine, phospho-Erk, total Erk, phospho-Mek, total Mek, MMP7, and FGFR4.	('MMP7', 'Gene', (267, 271))	('MMP7', 'molecular_function', 'GO:0004235', ('267', '271'))	('Erk', 'molecular_function', 'GO:0004707', ('238', '241'))	('Mek', 'Gene', (251, 254))	('MMP7', 'Gene', '4316', (267, 271))	('lysis', 'biological_process', 'GO:0019835', ('53', '58'))	('phospho-tyrosine', 'Var', (201, 217))	('Mek', 'Gene', (262, 265))	('phospho-Erk', 'Var', (219, 230))	('Mek', 'Gene', '5609', (251, 254))	('Erk', 'molecular_function', 'GO:0004707', ('227', '230'))	('FGFR4', 'Gene', (277, 282))	('Mek', 'Gene', '5609', (262, 265))	('FGFR', 'molecular_function', 'GO:0005007', ('277', '281'))	('phosphatase', 'molecular_function', 'GO:0016791', ('137', '148'))
58713	26183471	We observed that the phosphorylation of FGFR4 and Mek/Erk was enhanced by treatment with AOM and DSS compared with day 0, but the total levels of FGFR4 and Mek/Erk were unaffected (Fig.2e).	('FGFR', 'molecular_function', 'GO:0005007', ('146', '150'))	('Mek', 'Gene', '5609', (50, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('40', '44'))	('Mek', 'Gene', (50, 53))	('Erk', 'molecular_function', 'GO:0004707', ('54', '57'))	('AOM', 'Var', (89, 92))	('enhanced', 'PosReg', (62, 70))	('phosphorylation', 'MPA', (21, 36))	('DSS', 'Chemical', '-', (97, 100))	('phosphorylation', 'biological_process', 'GO:0016310', ('21', '36'))	('FGFR4', 'Gene', (40, 45))	('AOM', 'Chemical', 'MESH:D001397', (89, 92))	('Erk', 'molecular_function', 'GO:0004707', ('160', '163'))	('Mek', 'Gene', '5609', (156, 159))	('Mek', 'Gene', (156, 159))
58731	26183471	PD173074 inhibits the FGF-induced phosphorylation of FGFR4, subsequently reducing the levels of phosphorylated FGFR4, Mek and Erk, but it does not change the levels of total FGFR4, Mek, or Erk (Fig.6a).	('Mek', 'Gene', '5609', (118, 121))	('FGFR', 'molecular_function', 'GO:0005007', ('174', '178'))	('FGFR', 'molecular_function', 'GO:0005007', ('53', '57'))	('phosphorylation', 'biological_process', 'GO:0016310', ('34', '49'))	('PD173074', 'Var', (0, 8))	('PD173074', 'Chemical', 'MESH:C115711', (0, 8))	('reducing', 'NegReg', (73, 81))	('Mek', 'Gene', '5609', (181, 184))	('levels of phosphorylated FGFR4', 'MPA', (86, 116))	('Mek', 'Gene', (181, 184))	('FGFR4', 'Gene', (53, 58))	('inhibits', 'NegReg', (9, 17))	('Erk', 'molecular_function', 'GO:0004707', ('126', '129'))	('FGFR', 'molecular_function', 'GO:0005007', ('111', '115'))	('Erk', 'MPA', (126, 129))	('Erk', 'molecular_function', 'GO:0004707', ('189', '192'))	('Mek', 'Gene', (118, 121))	('FGF-induced phosphorylation', 'MPA', (22, 49))
58733	26183471	Moreover, PD173074 or FGFR4-siRNA treatment reduced the protein expression and activation of MMP-7 in cell lysates and supernatants (Fig.6a,b).	('PD173074', 'Var', (10, 18))	('protein expression', 'MPA', (56, 74))	('MMP-7', 'molecular_function', 'GO:0004235', ('93', '98'))	('PD173074', 'Chemical', 'MESH:C115711', (10, 18))	('MMP-7', 'Gene', (93, 98))	('reduced', 'NegReg', (44, 51))	('activation', 'PosReg', (79, 89))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('FGFR', 'molecular_function', 'GO:0005007', ('22', '26'))
58735	26183471	In addition, the proliferation of colon cancer cells and HUVECs was enhanced in CAF-conditioned media, and this enhanced proliferation could be significantly reduced by anti-FGF-1 or anti-FGF-3 treatments (Fig.8).	('proliferation', 'CPA', (17, 30))	('colon cancer', 'Disease', (34, 46))	('enhanced', 'PosReg', (68, 76))	('anti-FGF-1', 'Var', (169, 179))	('colon cancer', 'Phenotype', 'HP:0003003', (34, 46))	('colon cancer', 'Disease', 'MESH:D015179', (34, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('reduced', 'NegReg', (158, 165))
58753	26183471	Consistent with the in vivo observations, FGFR4 and Mek/Erk phosphorylation were upregulated by CAFs but not by NFs or PFs.	('FGFR4', 'Gene', (42, 47))	('phosphorylation', 'MPA', (60, 75))	('upregulated', 'PosReg', (81, 92))	('CAFs', 'Var', (96, 100))	('Mek', 'Gene', (52, 55))	('Mek', 'Gene', '5609', (52, 55))
58754	26183471	Furthermore, FGF-1 and FGF-3 upregulated Mek/Erk expression in colorectal cancer cells via FGFR4 phosphorylation, whereas the FGFR4 inhibitor or the silencing of FGFR4 expression inhibited the expression of Mek and Erk in the colon cancer cells.	('FGFR4', 'Gene', (162, 167))	('inhibited', 'NegReg', (179, 188))	('colon cancer', 'Disease', 'MESH:D015179', (226, 238))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('phosphorylation', 'MPA', (97, 112))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('expression', 'MPA', (193, 203))	('FGF-3', 'Gene', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('upregulated', 'PosReg', (29, 40))	('silencing', 'Var', (149, 158))	('expression', 'MPA', (49, 59))	('Mek', 'Gene', '5609', (41, 44))	('colorectal cancer', 'Disease', (63, 80))	('Mek', 'Gene', (41, 44))	('colon cancer', 'Disease', (226, 238))	('Mek', 'Gene', '5609', (207, 210))	('Mek', 'Gene', (207, 210))	('FGF-1', 'Gene', (13, 18))	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('colon cancer', 'Phenotype', 'HP:0003003', (226, 238))
58775	25452770	Patients with HER-2 gene amplification may constitute as potential candidates for targeted therapy with trastuzumab.	('Patients', 'Species', '9606', (0, 8))	('HER-2', 'Protein', (14, 19))	('trastuzumab', 'Chemical', 'MESH:D000068878', (104, 115))	('gene amplification', 'Var', (20, 38))
58818	25452770	The FISH-fixed glass slides with 4-mum-thick sections were heated overnight at 65 C, deparaffinized in two 10-min changes of xylene, rehydrated with two 3-min changes of 100% ethanol, one 3 min change of 85% ethanol and one 3 min change of 70% ethanol, and immersed for 15 min in pure water at 90 C. The slides were incubated (in a water bath) for 35 min in sodium sulfite acid at 50 C and washed in 2X sodium saline citrate (SSC; pH 7.2) at room temperature.	('rat', 'Species', '10116', (138, 141))	('ethanol', 'Chemical', 'MESH:D000431', (244, 251))	('rat', 'Species', '10116', (420, 423))	('pure', 'molecular_function', 'GO:0034023', ('280', '284'))	('paraffin', 'Chemical', 'MESH:D010232', (87, 95))	('citrate', 'Chemical', 'MESH:D019343', (417, 424))	('ethanol', 'Chemical', 'MESH:D000431', (208, 215))	('rat', 'Species', '10116', (452, 455))	('changes', 'Var', (114, 121))	('changes', 'Var', (159, 166))	('ethanol', 'Chemical', 'MESH:D000431', (175, 182))
58827	25452770	Cases were defined as chromosome 17 polysomy when the green signal was >2.25 in each nucleus when counting >=30 tumor nuclei.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('chromosome', 'Var', (22, 32))	('polysomy', 'Var', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))
58833	25452770	Among the 21 tumors with HER-2 gene amplification, only one case (5%) exhibited chromosome 17 polysomy, while two cases (2.5%) were observed in the 81 cases without HER-2 gene amplification.	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('gene amplification', 'Var', (31, 49))	('chromosome', 'cellular_component', 'GO:0005694', ('80', '90'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('HER-2', 'Gene', (25, 30))
58848	25452770	Furthermore, no statistically significant difference was observed between HER-2 amplification and HER-2 non-amplification (P=0.736) in the three- and five-year survival rates.	('rat', 'Species', '10116', (169, 172))	('amplification', 'Var', (80, 93))	('HER-2', 'Protein', (74, 79))
58861	25452770	A number of studies have demonstrated that chromosome 17 polysomy may be the main reason for HER-2 overexpression but not HER-2 gene amplification.	('rat', 'Species', '10116', (32, 35))	('chromosome', 'Var', (43, 53))	('overexpression', 'PosReg', (99, 113))	('polysomy', 'Var', (57, 65))	('HER-2', 'Protein', (93, 98))
58863	25452770	At present, FISH is regarded as the most effective method for the detection of HER-2 amplification, as it is has high rates of sensitivity and specificity.	('amplification', 'Var', (85, 98))	('HER-2', 'Protein', (79, 84))	('rat', 'Species', '10116', (118, 121))
58870	25452770	Herreros-Villanueva et al hypothesized that HER-2 gene amplification may be one of the causes of insensitivity to anti-EGFR therapies, including cetuximab.	('EGFR', 'molecular_function', 'GO:0005006', ('119', '123'))	('cetuximab', 'Chemical', 'MESH:D000068818', (145, 154))	('HER-2', 'Gene', (44, 49))	('gene amplification', 'Var', (50, 68))	('causes', 'Reg', (87, 93))	('insensitivity', 'MPA', (97, 110))
58881	25452770	Patients with HER-2 gene amplification may be potential candidates for targeted therapy with Herceptin.	('Patients', 'Species', '9606', (0, 8))	('HER-2', 'Protein', (14, 19))	('Herceptin', 'Chemical', 'MESH:D000068878', (93, 102))	('gene amplification', 'Var', (20, 38))
58882	23649806	Gain-of-function mutations of PPM1D/Wip1 impair the p53-dependent G1 checkpoint Mutations in PPM1D/Wip1 phosphatase impair the DNA damage-induced checkpoint and may predispose cells to tumorigenesis.	('Wip1', 'Gene', '8493', (36, 40))	('predispose', 'Reg', (165, 175))	('DNA damage-induced checkpoint', 'MPA', (127, 156))	('p53', 'Gene', (52, 55))	('Gain-of-function', 'PosReg', (0, 16))	('impair', 'NegReg', (116, 122))	('mutations', 'Var', (17, 26))	('tumor', 'Disease', (185, 190))	('Wip1', 'Gene', (36, 40))	('PPM1D', 'Gene', '8493', (93, 98))	('Wip1', 'Gene', '8493', (99, 103))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('PPM1D', 'Gene', '8493', (30, 35))	('Mutations', 'Var', (80, 89))	('Wip1', 'Gene', (99, 103))	('PPM1D', 'Gene', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('impair', 'NegReg', (41, 47))	('PPM1D', 'Gene', (30, 35))	('p53', 'Gene', '7157', (52, 55))
58886	23649806	In this paper, we have identified novel gain-of-function mutations in exon 6 of PPM1D that result in expression of C-terminally truncated Wip1.	('gain-of-function', 'PosReg', (40, 56))	('PPM1D', 'Gene', '8493', (80, 85))	('mutations', 'Var', (57, 66))	('C-terminally truncated', 'MPA', (115, 137))	('expression', 'MPA', (101, 111))	('Wip1', 'Gene', (138, 142))	('PPM1D', 'Gene', (80, 85))
58887	23649806	Remarkably, mutations in PPM1D are present not only in the tumors but also in other tissues of breast and colorectal cancer patients, indicating that they arise early in development or affect the germline.	('PPM1D', 'Gene', '8493', (25, 30))	('affect', 'Reg', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('mutations', 'Var', (12, 21))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('breast and colorectal cancer', 'Disease', 'MESH:D015179', (95, 123))	('PPM1D', 'Gene', (25, 30))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))	('patients', 'Species', '9606', (124, 132))
58888	23649806	We show that mutations in PPM1D affect the DDR pathway and propose that they could predispose to cancer.	('cancer', 'Disease', (97, 103))	('PPM1D', 'Gene', (26, 31))	('DDR pathway', 'Pathway', (43, 54))	('predispose', 'Reg', (83, 93))	('affect', 'Reg', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('PPM1D', 'Gene', '8493', (26, 31))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
58894	23649806	In addition, Wip1-dependent inactivation of p53 is thought to play a major role in control of checkpoint recovery.	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('inactivation', 'Var', (28, 40))
58896	23649806	According to this model, cells that accumulate mutations circumventing the checkpoint barrier have a selective advantage and can thus promote further development of cancer.	('promote', 'PosReg', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('mutations', 'Var', (47, 56))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('advantage', 'PosReg', (111, 120))
58897	23649806	The most common example of such DDR defect is an inactivating somatic mutation in the TP53 gene that disables proper response to genotoxic stress, leads to genomic instability, and is found in about half of human tumors.	('proper response to genotoxic stress', 'MPA', (110, 145))	('tumors', 'Disease', (213, 219))	('genomic instability', 'MPA', (156, 175))	('leads to', 'Reg', (147, 155))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('TP53', 'Gene', '7157', (86, 90))	('disables', 'NegReg', (101, 109))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('defect', 'Var', (36, 42))	('TP53', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('human', 'Species', '9606', (207, 212))	('inactivating', 'Var', (49, 61))
58898	23649806	On the other hand, tumors that retain wild-type p53 are likely to accumulate other genetic defects that would allow them to overcome the DDR barrier, providing a growth advantage in the presence of replicative stress.	('p53', 'Gene', (48, 51))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('p53', 'Gene', '7157', (48, 51))	('advantage', 'PosReg', (169, 178))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('wild-type', 'Var', (38, 47))	('genetic defects', 'Disease', 'MESH:D030342', (83, 98))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('genetic defects', 'Disease', (83, 98))	('growth', 'MPA', (162, 168))
58899	23649806	Importantly, amplification of the 17q23 locus carrying the PPM1D gene has been reported in various p53 wild-type tumors, pointing toward a role of Wip1 in cancer development, and Wip1 overexpression is associated with poor prognosis .	('reported', 'Reg', (79, 87))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('PPM1D', 'Gene', (59, 64))	('amplification', 'Var', (13, 26))	('p53', 'Gene', '7157', (99, 102))	('p53', 'Gene', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('overexpression', 'PosReg', (184, 198))	('PPM1D', 'Gene', '8493', (59, 64))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
58900	23649806	The oncogenic behavior of Wip1 is further supported by mouse genetics showing that loss of Wip1 protects from cancer development.	('cancer', 'Disease', (110, 116))	('loss', 'Var', (83, 87))	('Wip1', 'Gene', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mouse', 'Species', '10090', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
58901	23649806	Here, we have identified novel truncating mutations of Wip1 that show a gain-of-function effect and impair p53-dependent responses to genotoxic stress.	('gain-of-function', 'PosReg', (72, 88))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('truncating mutations', 'Var', (31, 51))	('impair', 'NegReg', (100, 106))	('Wip1', 'Gene', (55, 59))
58902	23649806	Strikingly, mutations in the PPM1D gene were found also in breast and colorectal cancer patients, suggesting that such truncating mutations of Wip1 may predispose to a wider range of cancer types.	('PPM1D', 'Gene', (29, 34))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('mutations', 'Var', (12, 21))	('PPM1D', 'Gene', '8493', (29, 34))	('Wip1', 'Gene', (143, 147))	('truncating mutations', 'Var', (119, 139))	('predispose', 'Reg', (152, 162))	('cancer', 'Disease', (81, 87))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('breast and colorectal cancer', 'Disease', 'MESH:D015179', (59, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('found', 'Reg', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
58906	23649806	Consistent with this, sequencing of genomic DNA revealed heterozygous mutations (c.1349delT and c.1372C>T) within exon 6 of the PPM1D gene that caused truncation of the Wip1 protein (p.L450X in HCT116 and p.R458X in U2OS cells; Fig.	('U2OS', 'CellLine', 'CVCL:0042', (216, 220))	('p.R458X', 'Mutation', 'rs773389405', (205, 212))	('c.1372C>T', 'Mutation', 'rs773389405', (96, 105))	('c.1349delT', 'Var', (81, 91))	('c.1372C>T', 'Var', (96, 105))	('PPM1D', 'Gene', '8493', (128, 133))	('p.L450X', 'Mutation', 'rs1163049039', (183, 190))	('truncation', 'MPA', (151, 161))	('c.1349delT', 'Mutation', 'c.1349delT', (81, 91))	('p.L450X', 'Var', (183, 190))	('HCT116', 'CellLine', 'CVCL:0291', (194, 200))	('p.R458X', 'Var', (205, 212))	('PPM1D', 'Gene', (128, 133))
58908	23649806	Both, Wip1-L450X and Wip1-R458X localized properly in the nucleus and were bound to the chromatin, suggesting that overall subcellular distribution of Wip1 is not affected by the exon 6 truncations (Fig.	('Wip1-L450X', 'Var', (6, 16))	('Wip1-R458X', 'Var', (21, 31))	('R458X', 'Mutation', 'rs773389405', (26, 31))	('nucleus', 'cellular_component', 'GO:0005634', ('58', '65'))	('chromatin', 'cellular_component', 'GO:0000785', ('88', '97'))	('L450X', 'Mutation', 'rs1163049039', (11, 16))
58910	23649806	Similarly, overexpression of Wip1-L450X and Wip1-R458X (but not phosphatase-dead Wip1-D314A) also caused a dramatic reduction in IRIF formation, suggesting that the mutants retain normal phosphatase activity that opposes IRIF assembly (Fig.	('activity', 'MPA', (199, 207))	('opposes', 'NegReg', (213, 220))	('Wip1-R458X', 'Var', (44, 54))	('IRIF formation', 'MPA', (129, 143))	('D314A', 'Mutation', 'p.D314A', (86, 91))	('IRIF', 'MPA', (221, 225))	('reduction', 'NegReg', (116, 125))	('Wip1-L450X', 'Var', (29, 39))	('L450X', 'Mutation', 'rs1163049039', (34, 39))	('phosphatase', 'Enzyme', (187, 198))	('R458X', 'Mutation', 'rs773389405', (49, 54))
58911	23649806	In addition, expression of FL-Wip1, Wip1-L450X, and Wip1-R458X significantly decreased levels of radiation-induced phosphorylation of histone H2AX (gamma-H2AX) and pSer15-p53 (both established markers of DDR and substrates of Wip1), suggesting that all tested Wip1 proteins are capable of silencing the DDR (Fig.	('gamma-H2AX', 'Gene', (148, 158))	('gamma-H2AX', 'Gene', '3014', (148, 158))	('H2AX', 'Gene', (154, 158))	('levels', 'MPA', (87, 93))	('phosphorylation', 'biological_process', 'GO:0016310', ('115', '130'))	('H2AX', 'Gene', '3014', (154, 158))	('Wip1-R458X', 'Var', (52, 62))	('silencing', 'NegReg', (289, 298))	('H2AX', 'Gene', (142, 146))	('R458X', 'Mutation', 'rs773389405', (57, 62))	('FL-Wip1', 'Gene', '8493', (27, 34))	('Wip1-L450X', 'Var', (36, 46))	('decreased', 'NegReg', (77, 86))	('p53', 'Gene', '7157', (171, 174))	('H2AX', 'Gene', '3014', (142, 146))	('L450X', 'Mutation', 'rs1163049039', (41, 46))	('FL-Wip1', 'Gene', (27, 34))	('p53', 'Gene', (171, 174))	('DDR', 'Disease', (303, 306))
58912	23649806	Indeed, immunopurified FL-Wip1, Wip1-L450X, and Wip1-R458X showed comparable phosphatase activity in vitro, and therefore, it is unlikely that mutation of PPM1D leads to production of a hyperactive Wip1 (Fig.	('hyperactive Wip1', 'Disease', (186, 202))	('PPM1D', 'Gene', '8493', (155, 160))	('R458X', 'Mutation', 'rs773389405', (53, 58))	('FL-Wip1', 'Gene', (23, 30))	('L450X', 'Mutation', 'rs1163049039', (37, 42))	('FL-Wip1', 'Gene', '8493', (23, 30))	('mutation', 'Var', (143, 151))	('hyperactive Wip1', 'Disease', 'MESH:D006948', (186, 202))	('PPM1D', 'Gene', (155, 160))
58913	23649806	Consistent with this notion, we found that both U2OS and HCT116 cells expressed ~10-20-fold more of the truncated Wip1 compared with the FL-Wip1 (Fig.	('Wip1', 'Gene', (114, 118))	('more', 'PosReg', (92, 96))	('U2OS', 'CellLine', 'CVCL:0042', (48, 52))	('truncated', 'Var', (104, 113))	('FL-Wip1', 'Gene', (137, 144))	('FL-Wip1', 'Gene', '8493', (137, 144))	('HCT116', 'CellLine', 'CVCL:0291', (57, 63))
58917	23649806	From this, we conclude that nonsense mutations in exon 6 of the PPM1D gene lead to increased protein levels of enzymatically active truncated Wip1 and thus result in increased total Wip1 activity in cells.	('increased', 'PosReg', (83, 92))	('increased', 'PosReg', (166, 175))	('PPM1D', 'Gene', (64, 69))	('nonsense mutations in', 'Var', (28, 49))	('Wip1 activity', 'MPA', (182, 195))	('protein levels of enzymatically active truncated', 'MPA', (93, 141))	('PPM1D', 'Gene', '8493', (64, 69))	('Wip1', 'Gene', (142, 146))
58919	23649806	This is reminiscent of the behavior of cells lacking p53 or expressing mutant p53 and suggests that the p53 pathway is somehow compromised in U2OS and HCT116 cells.	('p53', 'Gene', (104, 107))	('compromised', 'NegReg', (127, 138))	('p53', 'Gene', '7157', (104, 107))	('U2OS', 'CellLine', 'CVCL:0042', (142, 146))	('HCT116', 'CellLine', 'CVCL:0291', (151, 157))	('mutant', 'Var', (71, 77))	('p53', 'Gene', (53, 56))	('p53', 'Gene', (78, 81))	('p53', 'Gene', '7157', (53, 56))	('p53', 'Gene', '7157', (78, 81))
58921	23649806	Moreover, this arrest was fully dependent on p53 because codepletion of Wip1 and p53 or depletion of Wip1 in p53-negative cell lines SW480, DLD1, and HT29 did not restore any G1 checkpoint function (Fig.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('SW480', 'CellLine', 'CVCL:0546', (133, 138))	('p53', 'Gene', (109, 112))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('p53', 'Gene', '7157', (109, 112))	('G1 checkpoint function', 'MPA', (175, 197))	('codepletion', 'Var', (57, 68))
58922	23649806	In addition, depletion of the truncated Wip1 (but not of the FL-Wip1) by isoform-specific RNAi was sufficient to rescue the G1 arrest in irradiated U2OS cells, thus further supporting the conclusion that expression of the truncated variant of Wip1 abrogates the G1 checkpoint (Fig.	('variant', 'Var', (232, 239))	('G1 checkpoint', 'CPA', (262, 275))	('FL-Wip1', 'Gene', (61, 68))	('U2OS', 'CellLine', 'CVCL:0042', (148, 152))	('FL-Wip1', 'Gene', '8493', (61, 68))	('depletion', 'MPA', (13, 22))	('abrogates', 'NegReg', (248, 257))	('G1 arrest', 'MPA', (124, 133))
58925	23649806	4 C), consistent with previous observations that degradation of Cdc25A and Cyclin D1 can delay S-phase entry in a p53-independent manner.	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('delay', 'NegReg', (89, 94))	('Cyclin D1', 'Gene', '595', (75, 84))	('degradation', 'Var', (49, 60))	('Cdc25A', 'Gene', (64, 70))	('Cdc25A', 'Gene', '993', (64, 70))	('Cyclin D1', 'Gene', (75, 84))	('degradation', 'biological_process', 'GO:0009056', ('49', '60'))	('S-phase entry', 'MPA', (95, 108))	('Cyclin', 'molecular_function', 'GO:0016538', ('75', '81'))	('S-phase', 'biological_process', 'GO:0051320', ('95', '102'))
58928	23649806	We conclude that cells with mutations that enhance Wip1 protein stability are unable to engage p53 function, fail to arrest in G1 after DNA damage, and progress to S phase.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('S phase', 'CPA', (164, 171))	('protein', 'cellular_component', 'GO:0003675', ('56', '63'))	('enhance', 'PosReg', (43, 50))	('protein', 'Protein', (56, 63))	('Wip1', 'Gene', (51, 55))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('progress', 'PosReg', (152, 160))	('S phase', 'biological_process', 'GO:0051320', ('164', '171'))	('unable', 'NegReg', (78, 84))	('mutations', 'Var', (28, 37))	('stability', 'MPA', (64, 73))
58929	23649806	Increased expression of truncated Wip1 impairs the cellular responses to genotoxic stress also via a reduction in H2AX phosphorylation, which is an established substrate of Wip1.	('reduction', 'NegReg', (101, 110))	('cellular responses to genotoxic stress', 'MPA', (51, 89))	('truncated', 'Var', (24, 33))	('impairs', 'NegReg', (39, 46))	('H2AX', 'Gene', '3014', (114, 118))	('H2AX', 'Gene', (114, 118))	('Wip1', 'Gene', (34, 38))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))
58930	23649806	All these mechanisms may contribute to the elimination of the intrinsic DDR-mediated barrier against tumor development in cells carrying gain-of-function mutations of Wip1.	('gain-of-function', 'PosReg', (137, 153))	('Wip1', 'Gene', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('mutations', 'Var', (154, 163))	('elimination', 'NegReg', (43, 54))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
58931	23649806	We therefore performed mutational analysis of the PPM1D gene in a panel of unselected colorectal cancer patients (n = 304) and a panel of high-risk patients with BRCA1/2-negative breast and ovarian cancer (n = 728) and identified four deleterious mutations in exon 6 (c.1372C>T and c.1602insT in patients with colorectal cancer and c.1601del15 and c.1451T>G in patients with breast cancer) compared with no such mutations present in noncancer control samples (n = 450; Fig.	('BRCA1', 'Gene', '672', (162, 167))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('BRCA1', 'Gene', (162, 167))	('c.1451T>G', 'Mutation', 'rs766524048', (348, 357))	('c.1602insT', 'Var', (282, 292))	('patients', 'Species', '9606', (148, 156))	('colorectal cancer', 'Disease', 'MESH:D015179', (310, 327))	('PPM1D', 'Gene', (50, 55))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', (198, 204))	('cancer', 'Disease', (382, 388))	('cancer', 'Disease', 'MESH:D009369', (321, 327))	('c.1372C>T', 'Var', (268, 277))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('c.1601del15', 'Var', (332, 343))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('colorectal cancer', 'Disease', (310, 327))	('cancer', 'Disease', (436, 442))	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('patients', 'Species', '9606', (361, 369))	('cancer', 'Phenotype', 'HP:0002664', (436, 442))	('c.1601del15', 'Mutation', 'c.1601del15', (332, 343))	('colorectal cancer', 'Disease', (86, 103))	('c.1451T>G', 'Var', (348, 357))	('breast cancer', 'Phenotype', 'HP:0003002', (375, 388))	('patients', 'Species', '9606', (296, 304))	('patients', 'Species', '9606', (104, 112))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (179, 204))	('c.1602insT', 'Mutation', 'c.1602insT', (282, 292))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (382, 388))	('c.1372C>T', 'Mutation', 'rs773389405', (268, 277))	('cancer', 'Disease', (321, 327))	('colorectal cancer', 'Phenotype', 'HP:0003003', (310, 327))	('ovarian cancer', 'Phenotype', 'HP:0100615', (190, 204))	('PPM1D', 'Gene', '8493', (50, 55))	('breast cancer', 'Disease', (375, 388))	('breast cancer', 'Disease', 'MESH:D001943', (375, 388))	('cancer', 'Disease', 'MESH:D009369', (436, 442))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))
58932	23649806	All identified Wip1-truncating mutations (p.R458X, p.L484X, p.K535X, and p.F534X) and showed a striking similarity to mutations identified in the tumor cell lines.	('p.L484X', 'Mutation', 'rs766524048', (51, 58))	('Wip1-truncating', 'Gene', (15, 30))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('p.F534X', 'Mutation', 'p.F534X', (73, 80))	('tumor', 'Disease', (146, 151))	('p.R458X', 'Var', (42, 49))	('p.F534X', 'Var', (73, 80))	('p.K535X', 'Mutation', 'p.K535X', (60, 67))	('p.K535X', 'Var', (60, 67))	('p.R458X', 'Mutation', 'rs773389405', (42, 49))	('p.L484X', 'Var', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
58933	23649806	Functional analysis of all Wip1 mutants present in cancer patients confirmed that these truncations retain the enzymatic activity as well as the ability to bind to chromatin (Fig.	('enzymatic activity', 'MPA', (111, 129))	('bind', 'Interaction', (156, 160))	('mutants', 'Var', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Wip1', 'Gene', (27, 31))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('chromatin', 'Protein', (164, 173))
58934	23649806	In addition, we analyzed protein levels of Wip1 in leukocytes in one of the mutant carriers and found that the truncated Wip1 is expressed at a much higher level than the FL-Wip1, thus phenocopying the situation in tumor cell lines (Fig.	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('truncated', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('FL-Wip1', 'Gene', (171, 178))	('FL-Wip1', 'Gene', '8493', (171, 178))	('tumor', 'Disease', (215, 220))	('Wip1', 'Gene', (121, 125))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))
58935	23649806	Finally, we analyzed a noncancer mammary tissue and tumor tissue from one mutation carrier and identified a heterozygous mutation in the tumor tissue (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (137, 142))	('cancer', 'Disease', (26, 32))	('tumor', 'Disease', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('mutation', 'Var', (121, 129))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
58938	23649806	The targeting to a discrete hot-spot region in the exon 6 of the PPM1D oncogene:their gain-of-function character proven by in vitro experiments:the variable onset of cancer in affected individuals, and the versatile spectrum of cancer types appearing in mutation carriers and cancer cell lines all indicate that mutations in PPM1D may represent an unusual and novel genetic risk factor of general cancer predisposition not associated with a single specific cancer type.	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('PPM1D', 'Gene', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (457, 463))	('PPM1D', 'Gene', '8493', (325, 330))	('cancer', 'Disease', (397, 403))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', (228, 234))	('cancer', 'Disease', (276, 282))	('PPM1D', 'Gene', (325, 330))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Disease', (457, 463))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('PPM1D', 'Gene', '8493', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (457, 463))	('mutations', 'Var', (312, 321))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
58939	23649806	Although the majority of hereditary cancers is caused by mutations in tumor suppressor genes, germline mutations in oncogenes are not unprecedented.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('hereditary cancers', 'Disease', 'MESH:D009369', (25, 43))	('tumor', 'Disease', (70, 75))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('mutations', 'Var', (57, 66))	('hereditary cancers', 'Disease', (25, 43))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('caused', 'Reg', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
58940	23649806	For example, germline mutations of oncogenic tyrosine kinases RET, MET, and KIT are linked with medullary thyroid carcinoma, hereditary papillary renal carcinoma, and hereditary gastrointestinal stromal tumor syndrome, respectively.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('hereditary papillary renal carcinoma', 'Disease', 'MESH:D007681', (125, 161))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (178, 208))	('RET', 'Gene', '5979', (62, 65))	('hereditary gastrointestinal stromal tumor syndrome', 'Disease', 'MESH:D046152', (167, 217))	('KIT', 'Gene', (76, 79))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (106, 123))	('hereditary papillary renal carcinoma', 'Disease', (125, 161))	('germline mutations', 'Var', (13, 31))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (96, 123))	('thyroid carcinoma', 'Disease', (106, 123))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('renal carcinoma', 'Phenotype', 'HP:0005584', (146, 161))	('RET', 'Gene', (62, 65))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (136, 161))	('linked', 'Reg', (84, 90))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (106, 123))	('MET', 'Gene', (67, 70))	('hereditary gastrointestinal stromal tumor syndrome', 'Disease', (167, 217))
58941	23649806	Whereas tumor development is substantially boosted by inactivation of the second allele of the tumor suppressor genes, monoallelic gain-of-function mutations are usually sufficient to activate oncogenes.	('boosted', 'PosReg', (43, 50))	('mutations', 'Var', (148, 157))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('95', '111'))	('oncogenes', 'Gene', (193, 202))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('activate', 'PosReg', (184, 192))	('gain-of-function', 'PosReg', (131, 147))	('inactivation', 'Var', (54, 66))	('tumor', 'Disease', (95, 100))	('tumor suppressor', 'biological_process', 'GO:0051726', ('95', '111'))
58942	23649806	In agreement with this, identified mutations of PPM1D in the tumor cell lines were heterozygous, and both wild-type and truncated PPM1D alleles were expressed.	('PPM1D', 'Gene', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('PPM1D', 'Gene', '8493', (130, 135))	('PPM1D', 'Gene', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('PPM1D', 'Gene', '8493', (48, 53))	('tumor', 'Disease', (61, 66))	('mutations', 'Var', (35, 44))
58943	23649806	We propose that the high expression level of truncated Wip1 impairs the p53-dependent genome surveillance system in mutation carriers, making their genomic DNA hypersensitive to various genotoxic insults.	('impairs', 'NegReg', (60, 67))	('truncated', 'Var', (45, 54))	('mutation', 'Var', (116, 124))	('DNA', 'cellular_component', 'GO:0005574', ('156', '159'))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('hypersensitive', 'Disease', 'MESH:D004342', (160, 174))	('hypersensitive', 'Disease', (160, 174))	('Wip1', 'Gene', (55, 59))
58944	23649806	By this mechanism, mutations in other tumor-promoting genes may accumulate throughout the entire life span of the PPM1D mutation carriers and promote cancer development.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('PPM1D', 'Gene', '8493', (114, 119))	('mutation', 'Var', (120, 128))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('mutations', 'Var', (19, 28))	('cancer', 'Disease', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('promote', 'PosReg', (142, 149))	('accumulate', 'PosReg', (64, 74))	('PPM1D', 'Gene', (114, 119))
58945	23649806	The clinical significance of truncating PPM1D mutations in predisposition to breast and ovarian cancer was recently documented by an extensive case control study.	('mutations', 'Var', (46, 55))	('PPM1D', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (77, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (88, 102))	('PPM1D', 'Gene', '8493', (40, 45))
58946	23649806	Further studies are needed to address the possibility that mutations in PPM1D may represent a hereditary cancer predisposition and that truncated Wip1 might be a suitable candidate for pharmacological intervention in cancer patients carrying PPM1D mutations.	('PPM1D', 'Gene', '8493', (72, 77))	('PPM1D', 'Gene', (242, 247))	('hereditary cancer', 'Disease', 'MESH:D009369', (94, 111))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('PPM1D', 'Gene', '8493', (242, 247))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('hereditary cancer', 'Disease', (94, 111))	('mutations', 'Var', (59, 68))	('patients', 'Species', '9606', (224, 232))	('Wip1', 'Gene', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('PPM1D', 'Gene', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
58948	23649806	DNA fragments coding for FLAG-tagged human FL or truncated (R458X, L450X, and F534X) Wip1 were generated by PCR and subcloned into BamHI-XbaI sites of the pcDNA4/TO plasmid.	('F534X', 'Var', (78, 83))	('L450X', 'Var', (67, 72))	('L450X', 'Mutation', 'rs1163049039', (67, 72))	('Wip1', 'Gene', (85, 89))	('R458X', 'Mutation', 'rs773389405', (60, 65))	('R458X', 'Var', (60, 65))	('human', 'Species', '9606', (37, 42))	('F534X', 'Mutation', 'p.F534X', (78, 83))
58953	23649806	Alternatively, isoform-specific siRNAs targeting the FL-Wip1 (5'-AUAGCUCGAGAGAAUGUCC-3') or the 458X-Wip1 (5'-AUAGCUUGAGAGAAUGUCC-3') were used.	('FL-Wip1', 'Gene', (53, 60))	('FL-Wip1', 'Gene', '8493', (53, 60))	('458X-Wip1', 'Var', (96, 105))
58962	23649806	Normalized cell extracts from cells expressing FL or truncated FLAG-Wip1 were incubated with M2 agarose (Sigma-Aldrich).	('agarose', 'Chemical', 'MESH:D012685', (96, 103))	('truncated', 'Var', (53, 62))	('FLAG-Wip1', 'Gene', (63, 72))
58971	23649806	After incubation in 2M hydrochloric acid and 0.1% Triton X-100, cells were stained with anti-BrdU (replication marker) and anti-mpm2 (mitotic marker) followed by incubation with Alexa Fluor-coupled secondary antibodies.	('anti-BrdU', 'Var', (88, 97))	('Alexa Fluor', 'Chemical', '-', (178, 189))	('anti-mpm2', 'Var', (123, 132))	('hydrochloric acid', 'Chemical', 'MESH:D006851', (23, 40))	('BrdU', 'Chemical', 'MESH:D001973', (93, 97))	('Triton X-100', 'Chemical', 'MESH:D017830', (50, 62))
58985	23649806	All identified PPM1D alterations were reconfirmed by sequencing from an independent PCR amplification.	('PPM1D', 'Gene', (15, 20))	('PPM1D', 'Gene', '8493', (15, 20))	('alterations', 'Var', (21, 32))
58990	23649806	Table S1 contains data from mutational analysis of the PPM1D gene and anamnestic data of PPM1D mutation carriers.	('PPM1D', 'Gene', '8493', (55, 60))	('PPM1D', 'Gene', (89, 94))	('PPM1D', 'Gene', (55, 60))	('PPM1D', 'Gene', '8493', (89, 94))	('mutation', 'Var', (95, 103))
59099	32967412	For overall survival, the expression profiles of MUC1 and MUC5AC were analyzed simultaneously, and 4 phenotypes were established, comprising MUC 1+ MUC5AC +, MUC1 - MUC5AC -, MUC1 + MUC5AC -, and MUC1 - MUC5AC +, in addition to each gene separately.	('MUC1 - MUC5AC -', 'Var', (158, 173))	('MUC 1', 'Gene', '4582', (141, 146))	('MUC1 + MUC5AC -', 'Var', (175, 190))	('MUC 1', 'Gene', (141, 146))
59105	32967412	Patients who expressed MUC5AC showed an increase in overall survival when compared to those who did not.	('overall survival', 'MPA', (52, 68))	('increase', 'PosReg', (40, 48))	('MUC5AC', 'Var', (23, 29))	('Patients', 'Species', '9606', (0, 8))
59110	32967412	This supports the idea that the presence of MUC5AC  can be a prognostic factor for nonaggressive colorectal carcinomas and a promising target in the treatment of colon cancer [23].	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('colon cancer', 'Disease', (162, 174))	('nonaggressive colorectal carcinomas', 'Disease', 'MESH:D015179', (83, 118))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('presence', 'Var', (32, 40))	('MUC5AC', 'Protein', (44, 50))	('nonaggressive colorectal carcinomas', 'Disease', (83, 118))	('colon cancer', 'Phenotype', 'HP:0003003', (162, 174))
59112	33531075	A feasibility study of combined epigenetic and vaccine therapy in advanced colorectal cancer with pharmacodynamic endpoint Epigenetic therapies may modulate the tumor microenvironment.	('modulate', 'Reg', (148, 156))	('colorectal cancer', 'Disease', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('epigenetic', 'Var', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))	('tumor', 'Disease', (161, 166))
59121	33531075	Epigenetic alterations govern the differential expression of genetic information and have a prominent role in cancer initiation and progression.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Disease', (110, 116))	('govern', 'Reg', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('differential expression of genetic information', 'MPA', (34, 80))	('role', 'Reg', (102, 106))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
59125	33531075	These data suggest a potential role for epigenetic therapy in sensitizing the tumor to immunotherapy.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('epigenetic therapy', 'Var', (40, 58))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('sensitizing', 'Reg', (62, 73))
59128	33531075	We hypothesized that the addition of guadecitabine to a GM-CSF secreting colon vaccine (GVAX) would enhance the anti-tumor immune response and thus trafficking of effector T cells into the tumor.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (189, 194))	('tumor', 'Disease', (117, 122))	('GVAX', 'Chemical', '-', (88, 92))	('enhance', 'PosReg', (100, 107))	('guadecitabine', 'Var', (37, 50))	('immune response', 'biological_process', 'GO:0006955', ('123', '138'))	('GM-CSF', 'Gene', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('GM-CSF', 'Gene', '1437', (56, 62))	('trafficking', 'CPA', (148, 159))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('guadecitabine', 'Chemical', 'MESH:C580831', (37, 50))
59134	33531075	We further hypothesized that an increase in TILs, specifically CD45RO+ cells, on sequential tumor biopsies could be used as a surrogate for clinical outcomes and would therefore enable the more efficient evaluation of the regimen.	('CD45RO+', 'Var', (63, 70))	('increase', 'PosReg', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('enable', 'Reg', (178, 184))	('tumor', 'Disease', (92, 97))
59135	33531075	CD45RO+ memory T cell density was demonstrated across several studies to have prognostic significance both in early and advanced cancers including colorectal cancer and were felt to broadly represent the T cell compartment.	('CD45RO+', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('colorectal cancer', 'Phenotype', 'HP:0003003', (147, 164))	('colorectal cancer', 'Disease', (147, 164))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('colorectal cancer', 'Disease', 'MESH:D015179', (147, 164))	('memory', 'biological_process', 'GO:0007613', ('8', '14'))	('memory T', 'Disease', 'MESH:D008569', (8, 16))	('memory T', 'Disease', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
59160	33531075	A significant immune response was defined as an increase in CD45RO+ cells from baseline of at least two-fold and 1.8 times the standard deviation of baseline samples calculated across patients.	('patients', 'Species', '9606', (184, 192))	('CD45RO+', 'Var', (60, 67))	('increase', 'PosReg', (48, 56))
59167	33531075	A total of 17 patients underwent baseline tumor biopsies, and of those, 11 had matched pre- and post-treatment biopsies assessable for change in TIL density by CD45RO IHC.	('pre', 'molecular_function', 'GO:0003904', ('87', '90'))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('TIL density', 'MPA', (145, 156))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('patients', 'Species', '9606', (14, 22))	('CD45RO', 'Var', (160, 166))
59190	33531075	We report the results of a trial of the combination of the DNMTi guadecitabine and GVAX colon cancer vaccine in patients with advanced colorectal cancer, the first trial, to our knowledge, designed to identify the optimal sequencing of an immunomodulatory combination using a primary biological endpoint.	('GVAX colon cancer', 'Disease', (83, 100))	('colon cancer', 'Phenotype', 'HP:0003003', (88, 100))	('colorectal cancer', 'Disease', 'MESH:D015179', (135, 152))	('guadecitabine', 'Chemical', 'MESH:C580831', (65, 78))	('DNMTi', 'Var', (59, 64))	('GVAX colon cancer', 'Disease', 'MESH:D015179', (83, 100))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (135, 152))	('DNMTi', 'Chemical', '-', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('colorectal cancer', 'Disease', (135, 152))
59197	33531075	Specifically, HDACi therapy combinations have demonstrated pro-immune effects on monocyte-macrophage populations both in patients and in animal models, and effects on macrophage polarization are a postulated mechanism for the immunomodulatory effects of these agents.	('pro-immune', 'CPA', (59, 69))	('effects', 'Reg', (156, 163))	('combinations', 'Var', (28, 40))	('monocyte-macrophage populations', 'CPA', (81, 112))	('macrophage polarization', 'CPA', (167, 190))	('patients', 'Species', '9606', (121, 129))
59198	33531075	DNMT1 positively regulates the M1 phenotype and some studies have demonstrated downregulation of M1 markers and increased expression of M2 markers with inhibition of DNMT1; however studies of effects in tumor associated macrophages are lacking38.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('expression', 'MPA', (122, 132))	('DNMT1', 'Gene', '1786', (166, 171))	('M1 markers', 'MPA', (97, 107))	('downregulation', 'NegReg', (79, 93))	('DNMT1', 'Gene', (0, 5))	('increased', 'PosReg', (112, 121))	('M1 phenotype', 'MPA', (31, 43))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('DNMT1', 'Gene', '1786', (0, 5))	('inhibition', 'Var', (152, 162))	('DNMT1', 'Gene', (166, 171))
59209	33531075	The potential for epigenetic therapy to sensitize tumors to the activity of immunotherapy remains an area of interest, and other immunotherapy combinations continue to be explored.	('epigenetic therapy', 'Var', (18, 36))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
59230	31139085	In comparison to ICG, the most commonly used cyanine dyes have been rendered less hydrophobic by the inclusion of several charged groups such as sulfonic acids (e.g., sulfo-Cy5, sulfo-Cy7) in their structure resulting in less non-specific protein interactions in vivo (Mujumdar et al.,).	('ICG', 'Chemical', 'MESH:D007208', (17, 20))	('less', 'NegReg', (221, 225))	('sulfo-Cy5', 'Var', (167, 176))	('cyanine', 'Chemical', 'MESH:C009469', (45, 52))	('hydrophobic', 'MPA', (82, 93))	('sulfonic acids', 'Chemical', 'MESH:D013451', (145, 159))	('ICG', 'cellular_component', 'GO:0035061', ('17', '20'))	('sulfo-Cy7', 'Var', (178, 187))	('sulfo-Cy5', 'Chemical', '-', (167, 176))	('non-specific protein interactions', 'MPA', (226, 259))	('protein', 'cellular_component', 'GO:0003675', ('239', '246'))	('sulfo-Cy7', 'Chemical', '-', (178, 187))
59233	31139085	IRDye800CW is primarily cleared via the kidneys when intravenously injected, with some liver uptake, though much less than for ICG (Marshall et al.,).	('uptake', 'biological_process', 'GO:0098657', ('93', '99'))	('uptake', 'biological_process', 'GO:0098739', ('93', '99'))	('IRDye800CW', 'Var', (0, 10))	('liver uptake', 'MPA', (87, 99))	('ICG', 'cellular_component', 'GO:0035061', ('127', '130'))	('ICG', 'Chemical', 'MESH:D007208', (127, 130))
59237	31139085	Even ICG is sometimes used as a conjugatable fluorophore in always-on targeted tracers (Juhl et al.,), though it is most often incorporated in activatable targeted tracers, as aggregation of the dye to the structure of the targeting moiety will cause quenching, until the tracer is metabolized (Kobayashi et al.,).	('ICG', 'Chemical', 'MESH:D007208', (5, 8))	('cause', 'Reg', (245, 250))	('aggregation', 'Var', (176, 187))	('quenching', 'MPA', (251, 260))
59242	31139085	Several preclinical hybrid single photon emission tomography (SPECT)/fluorescent tracers combining IRDye800CW and 111In have been prepared in this manner, including the antibodies BIWA against CD44v6 (Odenthal et al.,) (Figure 3A), MN-14 and Labetuzumab against carcinoembryonic antigen (CEA) (Rijpkema et al.,; Hekman et al.,), and D2B against prostate specific membrane antigen (PSMA) (Lutje et al.,).	('Rijpkema', 'Disease', (294, 302))	('carcinoembryonic antigen', 'Gene', (262, 286))	('PSMA', 'molecular_function', 'GO:0043275', ('381', '385'))	('CD44v6', 'Var', (193, 199))	('CEA', 'Gene', (288, 291))	('PSMA', 'Gene', (381, 385))	('CEA', 'Gene', '1048', (288, 291))	('Rijpkema', 'Disease', 'None', (294, 302))	('carcinoembryonic antigen', 'Gene', '1048', (262, 286))	('prostate specific membrane antigen', 'molecular_function', 'GO:0043275', ('345', '379'))	('BIWA', 'Var', (180, 184))	('PSMA', 'Gene', '2346', (381, 385))	('membrane', 'cellular_component', 'GO:0016020', ('363', '371'))
59255	31139085	This is in accordance with findings for other heptamethine fluorophores, where a high number of negative charges on the fluorophore -as is the case for IRDye800CW- are seen to cause partial hepatobiliary clearance (Sato et al.,) (Figure 2A).	('negative charges', 'Var', (96, 112))	('hepatobiliary clearance', 'Disease', (190, 213))	('heptamethine', 'Chemical', '-', (46, 58))	('cause', 'Reg', (176, 181))	('hepatobiliary clearance', 'Disease', 'MESH:D004066', (190, 213))
59258	31139085	Variations in the overall charge, total number of charges and hydrophilicity of a Cy5 dye have led to a hybrid cRGD-tracer with improved properties regarding non-specific background signals, renal elimination, and tumor uptake (Bunschoten et al.,).	('renal elimination', 'MPA', (191, 208))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('improved', 'PosReg', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('Variations', 'Var', (0, 10))	('Cy5', 'Chemical', 'MESH:C085321', (82, 85))	('properties', 'MPA', (137, 147))	('non-specific background signals', 'MPA', (158, 189))	('tumor', 'Disease', (214, 219))
59286	31139085	The same diabody, site-specifically conjugated to IRDye800CW and directly labeled with 124I, was recently used as bimodal tracer for the visualization of PSCA-positive pancreatic patient-derived orthotopic xenografts with PET and NIR fluorescence imaging.	('patient', 'Species', '9606', (179, 186))	('pancreatic', 'Disease', 'MESH:D010195', (168, 178))	('IRDye800CW', 'Var', (50, 60))	('pancreatic', 'Disease', (168, 178))	('PSCA-positive', 'Gene', (154, 167))
59289	31139085	In preclinical studies, it has been shown that site-specifically IRDye800CW conjugated anti-HER2 and anti-CAIX nanobodies could achieve high contrast and specific imaging of tumor lesions within the first hours (1-4 h) after injection in murine breast and ovarian cancer models (Kijanka et al.,; Debie et al.,).	('murine', 'Species', '10090', (238, 244))	('tumor lesions', 'Disease', (174, 187))	('IRDye800CW', 'Var', (65, 75))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (245, 270))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('tumor lesions', 'Disease', 'MESH:D051437', (174, 187))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('anti-HER2', 'Protein', (87, 96))	('ovarian cancer', 'Phenotype', 'HP:0100615', (256, 270))
59292	31139085	The affibody tracer ABY-029, directed toward EGFR and conjugated site-specifically with IRDye800CW via a C-terminal cysteine, is currently undergoing clinical translation for FIGS in glioma, head and neck cancer and soft tissue sarcoma.	('soft tissue sarcoma', 'Disease', (216, 235))	('neck cancer', 'Disease', (200, 211))	('glioma', 'Disease', (183, 189))	('head and neck cancer', 'Phenotype', 'HP:0012288', (191, 211))	('IRDye800CW', 'Var', (88, 98))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (216, 235))	('sarcoma', 'Phenotype', 'HP:0100242', (228, 235))	('cysteine', 'Chemical', 'MESH:D003545', (116, 124))	('glioma', 'Disease', 'MESH:D005910', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (216, 235))	('neck cancer', 'Disease', 'MESH:D006258', (200, 211))
59305	31139085	cRGD peptides have been conjugated with a variety of different fluorophores, including Cy5.5, ICG, IRDye800CW and ZW800-1.	('ICG', 'Chemical', 'MESH:D007208', (94, 97))	('ICG', 'cellular_component', 'GO:0035061', ('94', '97'))	('IRDye800CW', 'Var', (99, 109))	('ZW800-1', 'Var', (114, 121))	('Cy5', 'Chemical', 'MESH:C085321', (87, 90))
59323	31139085	Upon cleavage by cathepsins, the Cy5 fluorophore regains its fluorescence.	('fluorescence', 'MPA', (61, 73))	('regains', 'PosReg', (49, 56))	('Cy5', 'Var', (33, 36))	('Cy5', 'Chemical', 'MESH:C085321', (33, 36))
59424	26260344	Although most HERVs have lost the capacity of horizontal transmission due to gene defects, some have retained this ability despite their apparent apathogenicity.	('HERVs', 'Disease', (14, 19))	('gene defects', 'Var', (77, 89))	('lost', 'NegReg', (25, 29))	('HERVs', 'Species', '206037', (14, 19))	('horizontal transmission', 'MPA', (46, 69))
59430	26260344	It was recently demonstrated that iRNA targeting HERV-K can suppress tumor growth in melanoma models, suggesting that the overexpression of particular HERVs may play a crucial role in tumor physiology.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('HERVs', 'Species', '206037', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('HERV-K', 'Species', '45617', (49, 55))	('suppress', 'NegReg', (60, 68))	('tumor', 'Disease', (184, 189))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('HERV-K', 'Protein', (49, 55))	('melanoma', 'Disease', (85, 93))	('iRNA', 'Var', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
59465	26260344	: 18S Hs99999901_s1, HERV WE1 Hs01926764_u1, HERV-FRD1 Hs01942443_s1, HERV3-1 Hs 04184598_s1 and HERV-V1 Hs00708335_s1), using the Taqman PCR core reagents according to the manufacturer's recommendations.	('HE', 'Chemical', 'MESH:D006371', (70, 72))	('Hs01942443_s1', 'Var', (55, 68))	('HE', 'Chemical', 'MESH:D006371', (45, 47))	('HERV-FRD', 'Gene', '405754', (45, 53))	('HE', 'Chemical', 'MESH:D006371', (97, 99))	('Hs01926764_u1', 'Var', (30, 43))	('Hs99999901_s1', 'Var', (6, 19))	('Hs 04184598_s1', 'Var', (78, 92))	('HERV-V1', 'Gene', (97, 104))	('HERV-V1', 'Gene', '147664', (97, 104))	('HE', 'Chemical', 'MESH:D006371', (21, 23))	('HERV-FRD', 'Gene', (45, 53))
59518	26260344	As expected, the protein expression of HERV-WE1 and FRD1 is markedly enhanced in HCT8RETO cells (panel 3) compared to HCT8WT cells (panel 1).	('FRD1', 'Gene', (52, 56))	('HERV-W', 'Species', '87786', (39, 45))	('HERV-WE1', 'Protein', (39, 47))	('protein expression', 'MPA', (17, 35))	('HCT8RETO', 'Var', (81, 89))	('enhanced', 'PosReg', (69, 77))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))
59549	26047008	Three ADIPOR1 Polymorphisms and Cancer Risk: A Meta-Analysis of Case-Control Studies Studies have come to conflicting conclusions about whether polymorphisms in the adiponectin receptor 1 gene (ADIPOR1) are associated with cancer risk.	('Cancer', 'Disease', (32, 38))	('ADIPOR1', 'Gene', (194, 201))	('Cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('ADIPOR1', 'Gene', (6, 13))	('polymorphisms', 'Var', (144, 157))	('ADIPOR1', 'Gene', '51094', (194, 201))	('adiponectin receptor 1', 'Gene', (165, 187))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('associated', 'Reg', (207, 217))	('ADIPOR1', 'Gene', '51094', (6, 13))	('adiponectin receptor 1', 'Gene', '51094', (165, 187))	('cancer', 'Disease', (223, 229))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))
59550	26047008	PubMed, EMBASE, Cochrane Library, the Chinese Biological Medical Database and the Chinese National Knowledge Infrastructure Database were systematically searched to identify all case-control studies published through February 2015 examining any ADIPOR1 polymorphisms and risk of any type of cancer.	('polymorphisms', 'Var', (253, 266))	('ADIPOR1', 'Gene', '51094', (245, 252))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('ADIPOR1', 'Gene', (245, 252))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))
59551	26047008	Analysis of the entire study population revealed a significant association between rs1342387(G/A) and overall cancer risk using a homozygous model (OR 0.82, 95%CI 0.72 to 0.94), heterozygous model (OR 0.84, 95%CI 0.76 to 0.93), dominant model (OR 0.85, 95%CI 0.75 to 0.97) and allele contrast model (OR 0.88, 95%CI 0.80 to 0.97).	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('rs1342387', 'Mutation', 'rs1342387', (83, 92))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('rs1342387', 'Var', (83, 92))
59553	26047008	No significant associations were found between rs12733285(C/T) or rs7539542(C/G) and cancer risk, either in analyses of the entire study population or in analyses of subgroups.	('rs7539542', 'Mutation', 'rs7539542', (66, 75))	('rs7539542', 'Var', (66, 75))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('rs12733285', 'Mutation', 'rs12733285', (47, 57))	('cancer', 'Disease', (85, 91))	('rs12733285', 'Var', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
59561	26047008	Exactly how the function or dysfunction of these receptors can lead to cancer remains poorly understood.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('dysfunction', 'Var', (28, 39))	('lead to', 'Reg', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
59563	26047008	Several of these polymorphisms have been associated with cancer risk, but studies have reported contrasting results depending on the cancer type or population involved.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('associated', 'Reg', (41, 51))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('polymorphisms', 'Var', (17, 30))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
59564	26047008	Some work has concluded that certain ADIPOR1 variants, including rs1342387(G/A), protect against colorectal cancer, whereas a third study found that rs1342387(G/A) increases the risk of this cancer.	('cancer', 'Disease', (191, 197))	('ADIPOR1', 'Gene', (37, 44))	('rs1342387(G/A', 'Var', (149, 162))	('increases', 'PosReg', (164, 173))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('colorectal cancer', 'Disease', 'MESH:D015179', (97, 114))	('rs1342387', 'Mutation', 'rs1342387', (65, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('ADIPOR1', 'Gene', '51094', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('rs1342387', 'Mutation', 'rs1342387', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('colorectal cancer', 'Disease', (97, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
59566	26047008	One study showed no relationship between ADIPOR1 variants and breast cancer risk, whereas another study concluded that the SNP rs7539542 was associated with decreased breast cancer risk.	('rs7539542', 'Var', (127, 136))	('rs7539542', 'Mutation', 'rs7539542', (127, 136))	('breast cancer', 'Disease', (167, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ADIPOR1', 'Gene', (41, 48))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('ADIPOR1', 'Gene', '51094', (41, 48))	('decreased', 'NegReg', (157, 166))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
59568	26047008	We focused on the SNPs that have been studied most extensively: -1472C T in intron 1 in linkage disequilibrium block 1 [rs12733285(C/T)], +5843G A in intron 4 in block 1 [rs1342387(G/A)] and +10225 C G in exon 8 in block 2 [rs7539542(C/G)].	('rs7539542', 'Mutation', 'rs7539542', (224, 233))	('rs1342387', 'Mutation', 'rs1342387', (171, 180))	('+10225 C G', 'Var', (191, 201))	('rs12733285', 'Mutation', 'rs12733285', (120, 130))	('+5843G A', 'Var', (138, 146))	('[rs7539542', 'Var', (223, 233))
59569	26047008	A comprehensive search was carried out using PubMed, EMBASE, Cochrane Library, the Chinese Biological Medical database and the Chinese National Knowledge Infrastructure database to identify case-control studies that were published through Feb.28, 2015 and that examined the association of ADIPOR1 polymorphisms with cancer risk.	('ADIPOR1', 'Gene', '51094', (289, 296))	('polymorphisms', 'Var', (297, 310))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('ADIPOR1', 'Gene', (289, 296))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('association', 'Interaction', (274, 285))	('cancer', 'Disease', (316, 322))
59572	26047008	To be included in our meta-analysis, studies had to (1) apply a case-control design, (2) analyze the relationship between ADIPOR1 polymorphisms and cancer risk, and (3) report genotype data for cases and controls in sufficient detail for extracting and pooling with data from other studies.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('polymorphisms', 'Var', (130, 143))	('ADIPOR1', 'Gene', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('ADIPOR1', 'Gene', '51094', (122, 129))	('analyze', 'Reg', (89, 96))
59575	26047008	Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated using RevMan 5.1.0 (The Cochrane Collaboration, Oxford, UK) to assess the strength of associations of ADIPOR1 SNPs rs12733285(C/T), rs1342387(G/A) and rs7539542(C/G) with cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('ADIPOR1', 'Gene', '51094', (186, 193))	('rs1342387', 'Mutation', 'rs1342387', (216, 225))	('associations', 'Interaction', (170, 182))	('rs7539542', 'Var', (235, 244))	('rs7539542', 'Mutation', 'rs7539542', (235, 244))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('rs12733285', 'Mutation', 'rs12733285', (199, 209))	('ADIPOR1', 'Gene', (186, 193))
59578	26047008	Of the 13 studies, 10 analyzed the ADIPOR1 SNP rs12733285(C/T); 12 analyzed rs1342387(G/A); and 8 analyzed rs7539542(C/G) (Table 1).	('rs1342387', 'Var', (76, 85))	('rs7539542', 'Mutation', 'rs7539542', (107, 116))	('rs7539542', 'Var', (107, 116))	('ADIPOR1', 'Gene', (35, 42))	('rs12733285', 'Mutation', 'rs12733285', (47, 57))	('rs12733285', 'Var', (47, 57))	('rs1342387', 'Mutation', 'rs1342387', (76, 85))	('ADIPOR1', 'Gene', '51094', (35, 42))
59579	26047008	In pooled analysis using data from all 10 studies, no significant association was observed between the ADIPOR1 rs12733285C/T polymorphism and risk of any cancer, based on any of the five genetic models.	('rs12733285', 'Mutation', 'rs12733285', (111, 121))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('ADIPOR1', 'Gene', (103, 110))	('rs12733285C/T', 'Var', (111, 124))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('ADIPOR1', 'Gene', '51094', (103, 110))
59581	26047008	In pooled analysis from all 12 studies, a significant association was observed betweenrs1342387(G/A) and cancer risk, according to four genetic models: homozygous (AA vs. GG, OR 0.82, 95%CI 0.72 to 0.94, Pheterogeneity = 0.15), heterozygous (AG vs. GG, OR 0.84, 95%CI 0.76 to 0.93, Pheterogeneity = 0.10), dominant (AA+AG vs. GG, OR 0.85, 95%CI 0.75 to 0.97, Pheterogeneity = 0.02) and allele contrast (A carriers vs. G carriers, OR 0.88, 95%CI 0.80 to 0.97, Pheterogeneity = 0.02) (Table 4, Figs 3-4).	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('betweenrs1342387', 'Var', (79, 95))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('rs1342387', 'Mutation', 'rs1342387', (86, 95))
59583	26047008	The polymorphism was associated with decreased cancer risk in Asians according to all five genetic models: AA vs. GG, OR 0.68, 95%CI 0.56 to 0.83, Pheterogeneity = 0.57; AG vs.GG, OR 0.74, 95%CI 0.64 to 0.84, Pheterogeneity = 0.34; AA+AG vs. GG, OR 0.72, 95%CI 0.63 to 0.82, Pheterogeneity = 0.28; AA vs. AG+GG, OR 0.80, 95%CI 0.67 to 0.96, Pheterogeneity = 0.77; A carriers vs. G carriers, OR 0.79, 95%CI 0.72 to 0.87, Pheterogeneity = 0.29.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('decreased', 'NegReg', (37, 46))	('polymorphism', 'Var', (4, 16))
59585	26047008	The SNP was significantly associated with decreased risk of colorectal cancer, according to all five genetic models: AA vs. GG, OR 0.70, 95%CI 0.59 to 0.83, Pheterogeneity = 0.60; AG vs. GG, OR 0.79, 95%CI 0.66 to 0.94, Pheterogeneity = 0.07; AA+AG vs. GG, OR 0.75, 95%CI 0.67 to 0.84, Pheterogeneity = 0.10; AA vs. AG+GG, OR 0.78, 95%CI 0.67 to 0.91, Pheterogeneity = 0.91; A carriers vs. G carriers, OR 0.81, 95%CI 0.75 to 0.88, Pheterogeneity = 0.19.	('SNP', 'Var', (4, 7))	('decreased', 'NegReg', (42, 51))	('colorectal cancer', 'Disease', 'MESH:D015179', (60, 77))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('colorectal cancer', 'Disease', (60, 77))
59588	26047008	The SNP was significantly associated with decreased risk of colorectal cancer in Asians, according to all five genetic models: AA vs. GG, OR 0.64, 95%CI 0.52 to 0.79, Pheterogeneity = 0.82; AG vs. GG, OR 0.71, 95%CI 0.62 to 0.82, Pheterogeneity = 0.23; AA+AG vs. GG, OR 0.70, 95%CI 0.61 to 0.80, Pheterogeneity = 0.28; AA vs. AG+GG, OR 0.76, 95%CI 0.63 to 0.93, Pheterogeneity = 0.90; A carriers vs. G carriers, OR 0.77, 95%CI 0.70 to 0.85, Pheterogeneity = 0.44, but no significant association was observed for other cancers.	('SNP', 'Var', (4, 7))	('decreased', 'NegReg', (42, 51))	('cancers', 'Phenotype', 'HP:0002664', (518, 525))	('colorectal cancer', 'Disease', 'MESH:D015179', (60, 77))	('cancers', 'Disease', (518, 525))	('cancers', 'Disease', 'MESH:D009369', (518, 525))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (518, 524))	('colorectal cancer', 'Disease', (60, 77))
59594	26047008	Despite numerous studies of the possible association of ADIPOR1 SNPs rs12733285(C/T), rs1342387(G/A) and rs7539542(C/G) with cancer risk, whether these polymorphisms are indeed associated with cancer risk remains unclear.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('ADIPOR1', 'Gene', '51094', (56, 63))	('rs12733285', 'Var', (69, 79))	('cancer', 'Disease', (193, 199))	('rs1342387', 'Mutation', 'rs1342387', (86, 95))	('association', 'Interaction', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('associated', 'Reg', (177, 187))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('ADIPOR1', 'Gene', (56, 63))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('rs7539542', 'Mutation', 'rs7539542', (105, 114))	('rs12733285', 'Mutation', 'rs12733285', (69, 79))
59595	26047008	Combining the statistical power of 13 case-control studies in this meta-analysis, we show that the A allele of ADIPOR1 rs1342387 is associated with significantly lower risk of colorectal cancer than is the G allele in Asians, suggesting that the A allele may protect against such cancer in this ethnic group.	('ADIPOR1', 'Gene', '51094', (111, 118))	('colorectal cancer', 'Disease', 'MESH:D015179', (176, 193))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('cancer', 'Disease', (280, 286))	('rs1342387', 'Mutation', 'rs1342387', (119, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (176, 193))	('lower', 'NegReg', (162, 167))	('colorectal cancer', 'Disease', (176, 193))	('ADIPOR1', 'Gene', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('rs1342387', 'Var', (119, 128))
59597	26047008	The SNPs rs12733285(C/T) and rs7539542(C/G) did not show significant associations with any type of cancer in meta-analyses involving all data or data from subgroups.	('rs12733285', 'Mutation', 'rs12733285', (9, 19))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('rs7539542', 'Mutation', 'rs7539542', (29, 38))	('cancer', 'Disease', (99, 105))	('rs7539542', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
59601	26047008	That these studies failed to detect an association reflects the diverse effects of ADIPOR1 variants in Caucasians, consistent with the present study.	('ADIPOR1', 'Gene', '51094', (83, 90))	('variants', 'Var', (91, 99))	('ADIPOR1', 'Gene', (83, 90))
59604	26047008	Our findings that the A allele of rs1342387 protects against colorectal cancer in Asians and that rs12733285(C/T) shows no significant associations with colorectal cancer risk were also reported in a meta-analysis by Ou et al..	('colorectal cancer', 'Disease', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('colorectal cancer', 'Disease', 'MESH:D015179', (153, 170))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('rs1342387', 'Mutation', 'rs1342387', (34, 43))	('rs12733285', 'Mutation', 'rs12733285', (98, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (61, 78))	('colorectal cancer', 'Disease', 'MESH:D015179', (61, 78))	('colorectal cancer', 'Phenotype', 'HP:0003003', (153, 170))	('rs1342387', 'Var', (34, 43))	('colorectal cancer', 'Disease', (153, 170))
59610	26047008	did not use as large a sample size as we did, nor did they examine relationships betweenrs12733285(C/T) or rs7539542(C/G) and risk of cancer.	('rs12733285', 'Mutation', 'rs12733285', (88, 98))	('rs7539542', 'Mutation', 'rs7539542', (107, 116))	('rs7539542', 'Var', (107, 116))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
59618	25551625	A total of 94 neoplasms, including 34 polypoid adenoma, 16 lateral spreading tumors-granular (LST-G), 20 non-granular LST (LST-NG), and 24 depressed tumors, were subjected for mutational analysis of KRAS (exon 2), BRAF (exon 11 and 15), PIK3CA (exon 9 and 20), AKT (exon 4), EGFR (exon 18-24) and HER2 (exon18-24).	('AKT', 'Gene', (261, 264))	('neoplasm', 'Phenotype', 'HP:0002664', (14, 22))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('depressed tumors', 'Disease', 'MESH:D000275', (139, 155))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('EGFR', 'Gene', '1956', (275, 279))	('BRAF', 'Gene', '673', (214, 218))	('neoplasms', 'Disease', 'MESH:D009369', (14, 23))	('BRAF', 'Gene', (214, 218))	('HER2', 'Gene', (297, 301))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors-granular', 'Disease', (77, 92))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('polypoid adenoma', 'Disease', (38, 54))	('PIK3CA', 'Gene', '5290', (237, 243))	('depressed tumors', 'Disease', (139, 155))	('AKT', 'Gene', '207', (261, 264))	('polypoid adenoma', 'Disease', 'MESH:D000236', (38, 54))	('KRAS', 'Gene', '3845', (199, 203))	('EGFR', 'molecular_function', 'GO:0005006', ('275', '279'))	('neoplasms', 'Disease', (14, 23))	('tumors-granular', 'Disease', 'MESH:D016586', (77, 92))	('KRAS', 'Gene', (199, 203))	('exon', 'Var', (281, 285))	('EGFR', 'Gene', (275, 279))	('PIK3CA', 'Gene', (237, 243))	('HER2', 'Gene', '2064', (297, 301))	('neoplasms', 'Phenotype', 'HP:0002664', (14, 23))
59619	25551625	KRAS mutation was noted more frequently in LST (13/36, 36.1%) than polypoid neoplasms (5/34, 14.7%, p = 0.041).	('neoplasms', 'Phenotype', 'HP:0002664', (76, 85))	('polypoid neoplasms', 'Disease', (67, 85))	('polypoid neoplasms', 'Disease', 'MESH:D009369', (67, 85))	('LST', 'Disease', (43, 46))	('neoplasm', 'Phenotype', 'HP:0002664', (76, 84))	('KRAS', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('KRAS', 'Gene', '3845', (0, 4))
59621	25551625	BRAF mutation (V600E) was found in 2 of 36 (5.6%)LSTs and 1 of 34 (2.9%) polypoid lesions.	('V600E', 'Mutation', 'rs113488022', (15, 20))	('polypoid lesions', 'Disease', (73, 89))	('polypoid lesions', 'Disease', 'MESH:D051437', (73, 89))	('found', 'Reg', (26, 31))	('BRAF', 'Gene', '673', (0, 4))	('V600E', 'Var', (15, 20))	('LSTs', 'Disease', (49, 53))	('BRAF', 'Gene', (0, 4))
59622	25551625	The two LST lesions with BRAF mutation were pathologically proven to be serrated adenoma.	('adenoma', 'Disease', (81, 88))	('mutation', 'Var', (30, 38))	('serrated adenoma', 'Phenotype', 'HP:0032222', (72, 88))	('BRAF', 'Gene', '673', (25, 29))	('BRAF', 'Gene', (25, 29))	('adenoma', 'Disease', 'MESH:D000236', (81, 88))
59623	25551625	PIK3CA mutation (exon 9 E545K) was identified only in LST (5/36, 13.9%).	('E545K', 'Mutation', 'rs104886003', (24, 29))	('PIK3CA', 'Gene', '5290', (0, 6))	('E545K', 'Var', (24, 29))	('PIK3CA', 'Gene', (0, 6))
59624	25551625	Mutations in KRAS, BRAF or PIK3CA occurred in a mutually exclusive manner.	('BRAF', 'Gene', '673', (19, 23))	('BRAF', 'Gene', (19, 23))	('PIK3CA', 'Gene', (27, 33))	('Mutations', 'Var', (0, 9))	('PIK3CA', 'Gene', '5290', (27, 33))	('KRAS', 'Gene', (13, 17))	('occurred', 'Reg', (34, 42))	('KRAS', 'Gene', '3845', (13, 17))
59629	25551625	Among nonpolypoid variants, depressed subtypes have the most aggressive behavior and represent the main lesions of de novo pathway.	('aggressive behavior', 'CPA', (61, 80))	('aggressive behavior', 'biological_process', 'GO:0002118', ('61', '80'))	('aggressive behavior', 'Phenotype', 'HP:0000718', (61, 80))	('depressed', 'Disease', (28, 37))	('variants', 'Var', (18, 26))	('depressed', 'Disease', 'MESH:D000275', (28, 37))
59637	25551625	This is reflected in the current practice that anti-epidermal growth factor receptor antibody therapy is no longer offered to CRC patients with mutant KRAS.	('antibody', 'molecular_function', 'GO:0003823', ('85', '93'))	('KRAS', 'Gene', '3845', (151, 155))	('CRC', 'Phenotype', 'HP:0003003', (126, 129))	('antibody', 'cellular_component', 'GO:0042571', ('85', '93'))	('antibody', 'cellular_component', 'GO:0019814', ('85', '93'))	('epidermal growth factor receptor', 'Gene', (52, 84))	('patients', 'Species', '9606', (130, 138))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('52', '75'))	('epidermal growth factor receptor', 'Gene', '1956', (52, 84))	('antibody', 'cellular_component', 'GO:0019815', ('85', '93'))	('mutant', 'Var', (144, 150))	('KRAS', 'Gene', (151, 155))
59639	25551625	Collectively, elucidation of genetic mechanisms by which these alterations affect colorectal carcinogenesis might have a profound impact on more effective strategies for screening, diagnosis and treatment of CRCs.	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (82, 107))	('alterations', 'Var', (63, 74))	('impact', 'Reg', (130, 136))	('colorectal carcinogenesis', 'Disease', (82, 107))	('affect', 'Reg', (75, 81))	('CRC', 'Phenotype', 'HP:0003003', (208, 211))	('CRCs', 'Disease', (208, 212))
59641	25551625	Alterations of signaling in this pathway had been reported to affect cell proliferation, survival and apoptosis of a variety of malignancies.	('affect', 'Reg', (62, 68))	('apoptosis', 'CPA', (102, 111))	('survival', 'CPA', (89, 97))	('Alterations', 'Var', (0, 11))	('apoptosis', 'biological_process', 'GO:0006915', ('102', '111'))	('apoptosis', 'biological_process', 'GO:0097194', ('102', '111'))	('malignancies', 'Disease', 'MESH:D009369', (128, 140))	('cell proliferation', 'CPA', (69, 87))	('malignancies', 'Disease', (128, 140))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))	('signaling', 'biological_process', 'GO:0023052', ('15', '24'))
59643	25551625	In this study, we aimed to assess the frequency and distribution of EGFR pathway alterations in three subtypes of colorectal neoplasms.	('colorectal neoplasms', 'Disease', 'MESH:D015179', (114, 134))	('neoplasm', 'Phenotype', 'HP:0002664', (125, 133))	('EGFR', 'Gene', '1956', (68, 72))	('alterations', 'Var', (81, 92))	('EGFR', 'molecular_function', 'GO:0005006', ('68', '72'))	('colorectal neoplasms', 'Disease', (114, 134))	('EGFR', 'Gene', (68, 72))	('neoplasms', 'Phenotype', 'HP:0002664', (125, 134))
59644	25551625	Some subcategories of 0-IIa lesions, the so called laterally spreading tumor (LST), extend laterally and circumferentially rather than vertically along the colonic wall and the frequency of invasive carcinoma is known to be less than that of polypoid lesions with similar size.	('invasive carcinoma', 'Disease', 'MESH:D009361', (190, 208))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('0-IIa', 'Var', (22, 27))	('invasive carcinoma', 'Disease', (190, 208))	('polypoid lesions', 'Disease', 'MESH:D051437', (242, 258))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('polypoid lesions', 'Disease', (242, 258))	('tumor', 'Disease', (71, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
59647	25551625	Among different phenotypes of LST, granular type and flat type were reported to have different frequency of KRAS mutation and other genetic or epigenetic changes.	('KRAS', 'Gene', (108, 112))	('mutation', 'Var', (113, 121))	('KRAS', 'Gene', '3845', (108, 112))
59649	25551625	In this study, we aim to elucidate the frequency of KRAS mutation and BRAF mutation in polypoid, flat and depressed colorectal neoplasms and compare these morphological counterparts each other.	('flat', 'Disease', (97, 101))	('depressed colorectal neoplasms', 'Disease', (106, 136))	('neoplasm', 'Phenotype', 'HP:0002664', (127, 135))	('KRAS', 'Gene', (52, 56))	('KRAS', 'Gene', '3845', (52, 56))	('mutation', 'Var', (75, 83))	('depressed colorectal neoplasms', 'Disease', 'MESH:D000275', (106, 136))	('neoplasms', 'Phenotype', 'HP:0002664', (127, 136))	('polypoid', 'Disease', (87, 95))	('BRAF', 'Gene', '673', (70, 74))	('BRAF', 'Gene', (70, 74))
59671	25551625	BRAF mutation (V600E) was found in 2 of 36 (5.6%) LSTs and 1 of 34 (2.9%) polypoid lesions (Table 3).	('LSTs', 'Disease', (50, 54))	('V600E', 'Mutation', 'rs113488022', (15, 20))	('BRAF', 'Gene', '673', (0, 4))	('V600E', 'Var', (15, 20))	('polypoid lesions', 'Disease', 'MESH:D051437', (74, 90))	('BRAF', 'Gene', (0, 4))	('polypoid lesions', 'Disease', (74, 90))
59672	25551625	The two LST lesions with BRAF mutation were macroscopically classified as granular type and pathologically proven to be serrated adenoma (Figure 2).	('adenoma', 'Disease', (129, 136))	('mutation', 'Var', (30, 38))	('BRAF', 'Gene', '673', (25, 29))	('serrated adenoma', 'Phenotype', 'HP:0032222', (120, 136))	('BRAF', 'Gene', (25, 29))	('adenoma', 'Disease', 'MESH:D000236', (129, 136))
59673	25551625	In contrast, the polypoid tumor with BRAF mutation was confirmed as traditional serrated adenoma.	('adenoma', 'Disease', 'MESH:D000236', (89, 96))	('BRAF', 'Gene', '673', (37, 41))	('adenoma', 'Disease', (89, 96))	('polypoid tumor', 'Disease', (17, 31))	('serrated adenoma', 'Phenotype', 'HP:0032222', (80, 96))	('BRAF', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('polypoid tumor', 'Disease', 'MESH:D009369', (17, 31))
59675	25551625	The current study represents the first comprehensive and concurrent analysis of activation mutations in EGFR network.	('EGFR', 'Gene', (104, 108))	('mutations', 'Var', (91, 100))	('EGFR', 'molecular_function', 'GO:0005006', ('104', '108'))	('EGFR', 'Gene', '1956', (104, 108))	('activation', 'PosReg', (80, 90))
59676	25551625	We found flat lesions, especially granular type LST, displayed a higher frequency of KRAS and PIK3CA mutations as compared to those of polypoid tumors.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('polypoid tumors', 'Disease', 'MESH:D009369', (135, 150))	('polypoid tumors', 'Disease', (135, 150))	('mutations', 'Var', (101, 110))	('PIK3CA', 'Gene', (94, 100))	('KRAS', 'Gene', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('KRAS', 'Gene', '3845', (85, 89))	('PIK3CA', 'Gene', '5290', (94, 100))
59680	25551625	Mutations in KRAS can be identified in 30-40% of colorectal cancers and mutated KRAS is constitutively active independent of EGFR signaling.	('mutated', 'Var', (72, 79))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('KRAS', 'Gene', (80, 84))	('EGFR', 'Gene', '1956', (125, 129))	('KRAS', 'Gene', (13, 17))	('colorectal cancers', 'Disease', 'MESH:D015179', (49, 67))	('EGFR', 'Gene', (125, 129))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', '3845', (80, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('125', '129'))	('colorectal cancers', 'Disease', (49, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('KRAS', 'Gene', '3845', (13, 17))	('signaling', 'biological_process', 'GO:0023052', ('130', '139'))
59681	25551625	The presence of a KRAS mutation may predict lack of response to EGFR inhibitors in metastatic CRC.	('metastatic CRC', 'Disease', (83, 97))	('KRAS', 'Gene', (18, 22))	('mutation', 'Var', (23, 31))	('KRAS', 'Gene', '3845', (18, 22))	('CRC', 'Phenotype', 'HP:0003003', (94, 97))	('EGFR', 'molecular_function', 'GO:0005006', ('64', '68'))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))
59689	25551625	BRAF is a downstream molecule of KRAS and mutation of BRAF V600E was detected in 5-10% of CRC.	('CRC', 'Disease', (90, 93))	('detected', 'Reg', (69, 77))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('CRC', 'Phenotype', 'HP:0003003', (90, 93))	('KRAS', 'Gene', (33, 37))	('BRAF', 'Gene', '673', (0, 4))	('KRAS', 'Gene', '3845', (33, 37))	('V600E', 'Mutation', 'rs113488022', (59, 64))	('BRAF', 'Gene', (0, 4))	('V600E', 'Var', (59, 64))
59690	25551625	Tumors with BRAF mutation are microsatellite instable, predominantly located in proximal colon, arising from serrated adenoma and have poor prognosis and unsatisfactory response to EGFR inhibitor.	('EGFR', 'molecular_function', 'GO:0005006', ('181', '185'))	('EGFR', 'Gene', (181, 185))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('mutation', 'Var', (17, 25))	('EGFR', 'Gene', '1956', (181, 185))	('adenoma', 'Disease', 'MESH:D000236', (118, 125))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('serrated adenoma', 'Phenotype', 'HP:0032222', (109, 125))	('adenoma', 'Disease', (118, 125))
59691	25551625	In this study, we found two cases in LST and one case in polypoid tumors displayed BRAF mutations.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('polypoid tumors', 'Disease', 'MESH:D009369', (57, 72))	('polypoid tumors', 'Disease', (57, 72))	('mutations', 'Var', (88, 97))	('LST', 'Disease', (37, 40))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('BRAF', 'Gene', '673', (83, 87))	('BRAF', 'Gene', (83, 87))
59697	25551625	Mutations of PIK3CA occurred in 15-20% of CRC and were associated with poor prognosis among curative resected CRCs.	('PIK3CA', 'Gene', (13, 19))	('CRC', 'Phenotype', 'HP:0003003', (42, 45))	('associated', 'Reg', (55, 65))	('CRC', 'Phenotype', 'HP:0003003', (110, 113))	('PIK3CA', 'Gene', '5290', (13, 19))	('Mutations', 'Var', (0, 9))	('occurred', 'Reg', (20, 28))	('CRC', 'Disease', (42, 45))
59698	25551625	The role of PIK3 mutations in determining EGFR inhibitor remains controversial.	('PIK3', 'Gene', '5294', (12, 16))	('EGFR', 'Gene', '1956', (42, 46))	('EGFR', 'Gene', (42, 46))	('EGFR', 'molecular_function', 'GO:0005006', ('42', '46'))	('PIK3', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
59700	25551625	have demonstrated one of 17 (5.6%) colorectal polyps had PIK3CA mutation.	('colorectal polyps', 'Phenotype', 'HP:0200063', (35, 52))	('PIK3CA', 'Gene', '5290', (57, 63))	('mutation', 'Var', (64, 72))	('colorectal polyps', 'Disease', 'MESH:D003111', (35, 52))	('colorectal polyps', 'Disease', (35, 52))	('PIK3CA', 'Gene', (57, 63))
59701	25551625	In our study, we found PIK3CA mutations occurred predominantly in LST.	('PIK3CA', 'Gene', (23, 29))	('PIK3CA', 'Gene', '5290', (23, 29))	('occurred', 'Reg', (40, 48))	('mutations', 'Var', (30, 39))	('LST', 'Disease', (66, 69))
59707	25551625	have reported that mutation in KRAS and BRAF occurred in 16% and 11% of depressed colorectal neoplasms respectively.	('BRAF', 'Gene', '673', (40, 44))	('KRAS', 'Gene', (31, 35))	('mutation', 'Var', (19, 27))	('BRAF', 'Gene', (40, 44))	('KRAS', 'Gene', '3845', (31, 35))	('neoplasm', 'Phenotype', 'HP:0002664', (93, 101))	('depressed colorectal neoplasms', 'Disease', (72, 102))	('neoplasms', 'Phenotype', 'HP:0002664', (93, 102))	('occurred', 'Reg', (45, 53))	('depressed colorectal neoplasms', 'Disease', 'MESH:D000275', (72, 102))
59713	25551625	Only 3 and 2 depressed colorectal neoplasms had mutations in KRAS and BRAF respectively.	('KRAS', 'Gene', '3845', (61, 65))	('neoplasm', 'Phenotype', 'HP:0002664', (34, 42))	('depressed colorectal neoplasms', 'Disease', (13, 43))	('neoplasms', 'Phenotype', 'HP:0002664', (34, 43))	('KRAS', 'Gene', (61, 65))	('depressed colorectal neoplasms', 'Disease', 'MESH:D000275', (13, 43))	('BRAF', 'Gene', '673', (70, 74))	('mutations', 'Var', (48, 57))	('BRAF', 'Gene', (70, 74))
59721	25551625	LST-G with BRAF mutation is more likely to be a sessile serrated adenoma.	('mutation', 'Var', (16, 24))	('serrated adenoma', 'Phenotype', 'HP:0032222', (56, 72))	('adenoma', 'Disease', 'MESH:D000236', (65, 72))	('adenoma', 'Disease', (65, 72))	('BRAF', 'Gene', '673', (11, 15))	('BRAF', 'Gene', (11, 15))
59734	24927342	Malignant transformation is genetically a complex process, featuring frequent genetic and epigenetic alterations activating oncogenes and inactivating tumour suppressor genes (TSG).	('genetic', 'Var', (78, 85))	('activating', 'PosReg', (113, 123))	('oncogenes', 'Protein', (124, 133))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('Malignant transformation', 'CPA', (0, 24))	('tumour', 'Disease', (151, 157))	('inactivating', 'NegReg', (138, 150))	('epigenetic alterations', 'Var', (90, 112))
59735	24927342	Among these, chromosomal deletion, mutation or hypermethylation which can lead to loss (Class I) or inactivation (Class II) of TSG causing immortality of cancer cells, has provided clues to the identification of genes critical for initiation, promotion and development of tumours, such as the inhibitor of growth (ING) family.	('tumours', 'Disease', (272, 279))	('inactivation', 'NegReg', (100, 112))	('men', 'Species', '9606', (264, 267))	('tumour', 'Phenotype', 'HP:0002664', (272, 278))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('tumours', 'Phenotype', 'HP:0002664', (272, 279))	('loss', 'NegReg', (82, 86))	('TSG', 'Gene', (127, 130))	('mutation', 'Var', (35, 43))	('chromosomal deletion', 'Var', (13, 33))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('hypermethylation', 'Var', (47, 63))	('tumours', 'Disease', 'MESH:D009369', (272, 279))
59736	24927342	ING proteins consist of five members with various isoforms and contain a highly conserved plant homeodomain (PHD), a Cys4-His-Cys3 form of zinc finger interacting directly with histone H3, and a nuclear localization sequence (NLS).	('Cys4-His', 'Chemical', '-', (117, 125))	('histone', 'Protein', (177, 184))	('PHD', 'molecular_function', 'GO:0050175', ('109', '112'))	('localization', 'biological_process', 'GO:0051179', ('203', '215'))	('Cys4-His-Cys3', 'Var', (117, 130))	('interacting', 'Interaction', (151, 162))	('Cys3', 'Chemical', '-', (126, 130))
59746	24927342	Gunduz et al reported that loss of heterozygosity resulted in reduced ING3 expression in human head and neck squamous cell carcinomas.	('neck', 'cellular_component', 'GO:0044326', ('104', '108'))	('loss', 'Var', (27, 31))	('neck squamous cell carcinomas', 'Disease', (104, 133))	('human', 'Species', '9606', (89, 94))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (109, 133))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (95, 133))	('ING3', 'Gene', '54556', (70, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('heterozygosity', 'Var', (35, 49))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (104, 133))	('ING3', 'Gene', (70, 74))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('expression', 'MPA', (75, 85))	('reduced', 'NegReg', (62, 69))
59800	24927342	Chromosomal deletion and/or decrease of ING4 expression has also been reported in glioma and breast cancer.	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('ING4', 'Gene', (40, 44))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('Chromosomal deletion', 'Var', (0, 20))	('ING4', 'Gene', '51147', (40, 44))	('expression', 'MPA', (45, 55))	('decrease', 'NegReg', (28, 36))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('glioma', 'Disease', (82, 88))
59801	24927342	Taken together, these findings suggest that abnormal expression or alteration of ING genes contributes to the pathogenesis of malignant cancers.	('alteration', 'Var', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('malignant cancers', 'Disease', (126, 143))	('ING genes', 'Gene', (81, 90))	('abnormal', 'Var', (44, 52))	('pathogenesis', 'biological_process', 'GO:0009405', ('110', '122'))	('expression', 'MPA', (53, 63))	('malignant cancers', 'Disease', 'MESH:D009369', (126, 143))	('contributes', 'Reg', (91, 102))
59828	23158542	Copy number and mRNA expression of EFNA1 increased from rectal adenoma to carcinoma.	('mRNA expression', 'MPA', (16, 31))	('increased', 'PosReg', (41, 50))	('adenoma to carcinoma', 'Disease', 'MESH:D000236', (63, 83))	('EFNA1', 'Gene', '1942', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('adenoma to carcinoma', 'Disease', (63, 83))	('EFNA1', 'Gene', (35, 40))	('Copy number', 'Var', (0, 11))	('rectal adenoma', 'Phenotype', 'HP:0100896', (56, 70))
59835	23158542	Genomic aberrations are found frequently in cancers and are believed to contribute to initiation and progression of cancer by deletion-induced down-expression of tumor suppressor genes or amplification and activation of oncogenes.	('amplification', 'CPA', (188, 201))	('down-expression', 'NegReg', (143, 158))	('deletion-induced', 'Var', (126, 142))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancer', 'Disease', (116, 122))	('tumor', 'Disease', (162, 167))	('cancers', 'Disease', (44, 51))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('oncogenes', 'Gene', (220, 229))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('contribute', 'Reg', (72, 82))	('activation', 'PosReg', (206, 216))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
59836	23158542	In colorectal cancer the most frequent chromosomal aberrations were gains at 7p, 7q, 8q, 13q, and 20q and losses of 1p, 4p, 4q, 5q, 8p, 14q, 15q, 17p and 18q.	('gains', 'Var', (68, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancer', 'Disease', (3, 20))	('rectal cancer', 'Phenotype', 'HP:0100743', (7, 20))	('losses', 'NegReg', (106, 112))	('frequent chromosomal aberrations', 'Phenotype', 'HP:0040012', (30, 62))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
59839	23158542	Little information is available concerning the genomic aberrations of rectal carcinoma, especially DNA copy number changes in the progression from adenoma to tumor.	('adenoma to tumor', 'Disease', (147, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('rectal carcinoma', 'Disease', 'MESH:D012004', (70, 86))	('rectal carcinoma', 'Disease', (70, 86))	('adenoma to tumor', 'Disease', 'MESH:D000236', (147, 163))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (70, 86))	('copy number', 'Var', (103, 114))	('changes', 'Reg', (115, 122))
59862	23158542	Array CGH results showed that the most frequent copy number alterations in rectal adenoma were gains of 7p21.3-p15.3 and 20p12.3-p11.21 and losses of 5q13.2, 7q11.23, 11q13.1-q14.1, 17q25.1 and 19p13.3-p13.11 (Figure 1A, Tables 2 and 3).	('5q13.2', 'Var', (150, 156))	('p13', 'Gene', (202, 205))	('adenoma', 'Disease', (82, 89))	('p13', 'Gene', '440926', (196, 199))	('gains', 'PosReg', (95, 100))	('adenoma', 'Disease', 'MESH:D000236', (82, 89))	('p13', 'Gene', '440926', (202, 205))	('p11', 'Gene', '6281', (129, 132))	('p15', 'Gene', (111, 114))	('p11', 'Gene', (129, 132))	('CGH', 'Gene', '3342', (6, 9))	('p15', 'Gene', '1030', (111, 114))	('p13', 'Gene', (196, 199))	('7q11.23', 'Var', (158, 165))	('rectal adenoma', 'Phenotype', 'HP:0100896', (75, 89))	('losses', 'NegReg', (140, 146))	('p21', 'Gene', (105, 108))	('p21', 'Gene', '644914', (105, 108))	('CGH', 'Gene', (6, 9))
59863	23158542	And the most common genetic aberrations in rectal carcinoma were gains of 7p21.3-p15.3, 7p15.3-p14.1, 7p14.1-p13, 7p13-p11.2, 13q13.1-q14.11, 13q21.1-q32.1, 13q32.1-q34, 20p11.21, 20q11.23-q12 and 20q13.2-q13.33 and losses of 17p13.1-p11.2, 18p11.32-p11.21 and 18q11.1-q11.2 (Figure 1B, Tables 2 and 3).	('p15', 'Gene', (89, 92))	('p13', 'Gene', '440926', (109, 112))	('rectal carcinoma', 'Disease', (43, 59))	('p11', 'Gene', (172, 175))	('p11', 'Gene', '6281', (250, 253))	('p11', 'Gene', '6281', (243, 246))	('p13', 'Gene', (115, 118))	('p11', 'Gene', '6281', (234, 237))	('rectal carcinoma', 'Disease', 'MESH:D012004', (43, 59))	('p11', 'Gene', (250, 253))	('p15', 'Gene', '1030', (81, 84))	('p11', 'Gene', (243, 246))	('p15', 'Gene', '1030', (89, 92))	('p11', 'Gene', (234, 237))	('13q21.1-q32.1', 'Var', (142, 155))	('losses', 'NegReg', (216, 222))	('p13', 'Gene', '440926', (115, 118))	('p11', 'Gene', '6281', (119, 122))	('p13', 'Gene', (228, 231))	('p14', 'Gene', (95, 98))	('p21', 'Gene', (75, 78))	('gains', 'PosReg', (65, 70))	('p21', 'Gene', '644914', (75, 78))	('p13', 'Gene', (109, 112))	('p14', 'Gene', '11102', (95, 98))	('p11', 'Gene', (119, 122))	('18q11.1-q11.2', 'Gene', (261, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (43, 59))	('p14', 'Gene', (103, 106))	('p11', 'Gene', '6281', (172, 175))	('p14', 'Gene', '11102', (103, 106))	('p13', 'Gene', '440926', (228, 231))	('p15', 'Gene', (81, 84))
59880	23158542	They are gains of 1q and 6p21.33 and losses of 10p14-p11.21, 14q12-q21.1, 14q22.1-q24.3, 14q31.3-q32.1, 14q32.2-q32.32, 15q15.1-q21.1, 15q22.31 and 15q25.1-q25.2.	('gains', 'PosReg', (9, 14))	('losses', 'NegReg', (37, 43))	('14q31.3-q32.1', 'Var', (89, 102))	('p14', 'Gene', (49, 52))	('p11', 'Gene', '6281', (53, 56))	('15q15.1-q21.1', 'Var', (120, 133))	('p14', 'Gene', '11102', (49, 52))	('p21', 'Gene', (26, 29))	('p21', 'Gene', '644914', (26, 29))	('p11', 'Gene', (53, 56))
59881	23158542	These aberrations occurred at the later stages of rectal carcinogenesis, and may contribute the progression from adenoma to carcinoma.	('aberrations', 'Var', (6, 17))	('rectal carcinogenesis', 'Disease', (50, 71))	('contribute', 'Reg', (81, 91))	('adenoma to carcinoma', 'Disease', (113, 133))	('rectal carcinogenesis', 'Disease', 'MESH:D063646', (50, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('adenoma to carcinoma', 'Disease', 'MESH:D000236', (113, 133))	('occurred', 'Reg', (18, 26))
59894	23158542	Loss of 18q is a common event in colorectal cancer, and 18q deletion and loss of SMAD4 expression are associated with liver metastasis.	('loss', 'NegReg', (73, 77))	('associated', 'Reg', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('rectal cancer', 'Phenotype', 'HP:0100743', (37, 50))	('colorectal cancer', 'Disease', 'MESH:D015179', (33, 50))	('SMAD4', 'Gene', (81, 86))	('liver metastasis', 'Disease', 'MESH:D009362', (118, 134))	('liver metastasis', 'Disease', (118, 134))	('expression', 'MPA', (87, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (33, 50))	('18q deletion', 'Var', (56, 68))	('Loss', 'Var', (0, 4))	('colorectal cancer', 'Disease', (33, 50))
59935	33435255	reported that among patients with stage I lung adenocarcinoma, those with high IL-6 and IL-17A levels had a lower 5-year survival rate (46%) than those with low levels of both markers (93%), with a similar trend having been observed for the prognostic signatures of IL-6 and IL-17A in an independent data set.	('5-year survival rate', 'CPA', (114, 134))	('IL-6', 'Gene', '3569', (266, 270))	('IL-6', 'molecular_function', 'GO:0005138', ('266', '270'))	('lower', 'NegReg', (108, 113))	('IL-17A', 'Gene', '3605', (275, 281))	('lung adenocarcinoma', 'Disease', (42, 61))	('IL-6', 'Gene', (266, 270))	('patients', 'Species', '9606', (20, 28))	('IL-17A', 'Gene', '3605', (88, 94))	('IL-17', 'molecular_function', 'GO:0030367', ('275', '280'))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (42, 61))	('IL-17A', 'Gene', (275, 281))	('IL-6', 'molecular_function', 'GO:0005138', ('79', '83'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (42, 61))	('IL-6', 'Gene', '3569', (79, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('high', 'Var', (74, 78))	('IL-17', 'molecular_function', 'GO:0030367', ('88', '93'))	('IL-17A', 'Gene', (88, 94))	('IL-6', 'Gene', (79, 83))
59936	33435255	Multivariate analyses in another study revealed that although the NLR was not predictive of overall survival (OS), a high NLR was an independent risk factor for recurrence, in addition to age, stage, tumor differentiation, and lymphatic invasion.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('recurrence', 'Disease', (161, 171))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('high', 'Var', (117, 121))
59943	33435255	Subgroup analyses further revealed that a low ALI had a significant negative prognostic value in NSCLC, with a low ALI being clearly associated with lower PFS and recurrence-free survival (RFS) in patients with NSCLC.	('low', 'Var', (111, 114))	('patients', 'Species', '9606', (197, 205))	('NSCLC', 'Phenotype', 'HP:0030358', (211, 216))	('NSCLC', 'Disease', (97, 102))	('NSCLC', 'Disease', 'MESH:D002289', (211, 216))	('PFS', 'MPA', (155, 158))	('RFS', 'Disease', (189, 192))	('NSCLC', 'Disease', (211, 216))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('RFS', 'Disease', 'MESH:D005198', (189, 192))	('lower', 'NegReg', (149, 154))	('recurrence-free survival', 'CPA', (163, 187))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))
59952	33435255	Moreover, the inhibition of p21 synthesis increases the rate of cell division and accelerates cell cycle progression from G0 arrest to the G1 phase, the G1 phase to the S phase, and the G2 phase to the M phase.	('arrest', 'Disease', 'MESH:D006323', (125, 131))	('increases', 'PosReg', (42, 51))	('cell division', 'CPA', (64, 77))	('accelerates', 'PosReg', (82, 93))	('p21', 'Gene', (28, 31))	('arrest', 'Disease', (125, 131))	('cell cycle progression', 'CPA', (94, 116))	('inhibition', 'Var', (14, 24))
59972	33435255	Polymorphisms of the cytokine gene are reported to have some effect on breast cancer progression, which also suggests that even a partial reduction in inflammatory signaling may be protective when maintained over time.	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('Polymorphisms', 'Var', (0, 13))	('effect', 'Reg', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('signaling', 'biological_process', 'GO:0023052', ('164', '173'))	('cytokine gene', 'Gene', (21, 34))
60000	33435255	Accordingly, patients with advanced gastric cancer have been found to benefit from fluoropyrimidine-based chemotherapy, whereas those with locally advanced gastric cancer were able to achieve an improved OS with the administration of capecitabine and platinum-based regimens.	('fluoropyrimidine', 'Chemical', '-', (83, 99))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('benefit', 'PosReg', (70, 77))	('gastric cancer', 'Disease', (36, 50))	('gastric cancer', 'Disease', (156, 170))	('capecitabine', 'Chemical', 'MESH:D000069287', (234, 246))	('patients', 'Species', '9606', (13, 21))	('fluoropyrimidine-based', 'Var', (83, 105))	('gastric cancer', 'Disease', 'MESH:D013274', (36, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (156, 170))	('men', 'Species', '9606', (270, 273))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (156, 170))	('platinum', 'Chemical', 'MESH:D010984', (251, 259))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
60020	33435255	Among the cancer characteristics, low LMR was in close association with tumor presence and microvascular infiltration at the time of transplantation.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('microvascular infiltration', 'CPA', (91, 117))	('tumor', 'Disease', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('low LMR', 'Var', (34, 41))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Disease', (10, 16))
60049	33435255	After evaluating the role of GPS in patients with cervical cancer after radical resection, Seebacher's group found that a high GPS assessed before the initial treatment was independently associated with a shorter survival time.	('GPS', 'Disease', (29, 32))	('patients', 'Species', '9606', (36, 44))	('high', 'Var', (122, 126))	('GPS', 'Disease', (127, 130))	('survival time', 'CPA', (213, 226))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('shorter', 'NegReg', (205, 212))	('GPS', 'Disease', 'MESH:D055652', (29, 32))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('GPS', 'Disease', 'MESH:D055652', (127, 130))	('men', 'Species', '9606', (164, 167))
60081	33435255	According to earlier studies, most of which were retrospective in nature, allogeneic blood transfusions were associated with the increased risk of postoperative cancer recurrence and death.	('death', 'Disease', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('allogeneic blood transfusions', 'Var', (74, 103))	('postoperative cancer', 'Disease', (147, 167))	('postoperative cancer', 'Disease', 'MESH:D009369', (147, 167))	('death', 'Disease', 'MESH:D003643', (183, 188))
60107	32833970	A general framework for functionally informed set-based analysis: Application to a large-scale colorectal cancer study Genome-wide association studies (GWAS) have successfully identified tens of thousands of genetic variants associated with various phenotypes, but together they explain only a fraction of heritability, suggesting many variants have yet to be discovered.	('colorectal cancer', 'Disease', (95, 112))	('variants', 'Var', (216, 224))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('cov', 'Species', '11118', (363, 366))	('associated', 'Reg', (225, 235))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
60141	32833970	NT5DC2 has been shown to markedly reduce the expression of Fyn, a Src family proto-oncogene and has been implicated in glioblastoma, though not yet linked to CRC susceptibility.	('glioblastoma', 'Disease', (119, 131))	('Fyn', 'Gene', (59, 62))	('implicated', 'Reg', (105, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (119, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (119, 131))	('NT5DC2', 'Var', (0, 6))	('reduce', 'NegReg', (34, 40))	('expression', 'MPA', (45, 55))
60161	32767993	Patients with deficient mismatch repair gene expression (dMMR) or LS are reported to have certain clinicopathological characteristics including a higher risk of metachronous colorectal tumors, younger age at onset, right-side colon predominance, higher proportion of poorly differentiated tumors, mucinous adenocarcinoma, and a specific tumor lymphocyte infiltration pattern.	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (297, 320))	('mismatch repair gene expression', 'Protein', (24, 55))	('gene expression', 'biological_process', 'GO:0010467', ('40', '55'))	('tumor', 'Disease', (337, 342))	('tumors', 'Disease', (185, 191))	('rectal tumor', 'Phenotype', 'HP:0100743', (178, 190))	('deficient', 'Var', (14, 23))	('tumors', 'Disease', 'MESH:D009369', (289, 295))	('tumor', 'Disease', 'MESH:D009369', (337, 342))	('mucinous adenocarcinoma', 'Disease', (297, 320))	('mismatch repair', 'biological_process', 'GO:0006298', ('24', '39'))	('tumor', 'Disease', (185, 190))	('poorly', 'Disease', (267, 273))	('tumor', 'Disease', (289, 294))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('metachronous colorectal tumors', 'Disease', 'MESH:D015179', (161, 191))	('dMMR', 'Chemical', '-', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('metachronous colorectal tumors', 'Disease', (161, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumors', 'Disease', (289, 295))
60163	32767993	In addition, patients with FCCTX do not have an increased risk of extra-colonic cancers.	('FCCTX', 'Var', (27, 32))	('FCCTX', 'Chemical', '-', (27, 32))	('patients', 'Species', '9606', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('extra-colonic cancers', 'Disease', 'MESH:D015179', (66, 87))	('extra-colonic cancers', 'Disease', (66, 87))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
60195	32767993	Patients who underwent segmental colectomy were more likely to have tumors in the rectum compared to those who underwent extended colectomy (34/37, 91.9% vs. 3/37, 8.1%; p = 0.005) (Table 2) compared to tumors located in the right or left colon.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Disease', (68, 74))	('left colon', 'Disease', (234, 244))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('Patients', 'Species', '9606', (0, 8))	('segmental colectomy', 'Var', (23, 42))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('left colon', 'Disease', 'MESH:D003110', (234, 244))
60207	32767993	Moreover, we found significantly more N0 tumors in dMMR (70.8%) compared with pMMR (50.9%) (p = 0.049), as shown in Table 1.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('dMMR', 'Var', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('pMMR', 'Chemical', '-', (78, 82))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('dMMR', 'Chemical', '-', (51, 55))
60211	32767993	In this study, we determined that the risk of metachronous colorectal cancer in pMMR subtype was significantly lower than that of dMMR subtype and comparable to that of sporadic CRC.	('pMMR', 'Chemical', '-', (80, 84))	('CRC', 'Phenotype', 'HP:0003003', (178, 181))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('metachronous colorectal cancer', 'Disease', (46, 76))	('dMMR', 'Chemical', '-', (130, 134))	('metachronous colorectal cancer', 'Disease', 'MESH:D015179', (46, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lower', 'NegReg', (111, 116))	('rectal cancer', 'Phenotype', 'HP:0100743', (63, 76))	('pMMR', 'Var', (80, 84))
60214	32767993	Clinically, these two disease subtypes are both classified as HNPCC; the inherent difficulty lies in distinguishing the two because preoperative genetic testing such as microsatellite instability or dMMR status are not always available in daily clinical practice and may affect surgical decision making.	('affect', 'Reg', (271, 277))	('HNPCC', 'Phenotype', 'HP:0006716', (62, 67))	('HNPCC', 'Gene', (62, 67))	('dMMR', 'Chemical', '-', (199, 203))	('microsatellite instability', 'Disease', (169, 195))	('microsatellite instability', 'Disease', 'MESH:D053842', (169, 195))	('surgical decision making', 'CPA', (278, 302))	('HNPCC', 'Gene', '4436', (62, 67))	('dMMR status', 'Var', (199, 210))
60228	32767993	CRC Colorectal cancer HNPCC Hereditary non-polyposis colorectal cancer pMMR Proficient mismatch repair gene expression dMMR Deficient mismatch repair gene expression DFS Disease-free survival OS Overall survival LS Lynch syndrome FCCTX Familial colorectal cancer type X JC made the concept and design of this study.	('rectal cancer', 'Phenotype', 'HP:0100743', (57, 70))	('pMMR', 'Chemical', '-', (71, 75))	('Deficient', 'Var', (124, 133))	('colorectal cancer', 'Phenotype', 'HP:0003003', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('HNPCC', 'Gene', (22, 27))	('Lynch syndrome', 'Disease', 'MESH:D003123', (215, 229))	('Hereditary non-polyposis colorectal cancer', 'Phenotype', 'HP:0006716', (28, 70))	('rectal cancer', 'Phenotype', 'HP:0100743', (8, 21))	('gene expression', 'biological_process', 'GO:0010467', ('150', '165'))	('HNPCC', 'Gene', '4436', (22, 27))	('non-polyposis colorectal cancer', 'Disease', (39, 70))	('non-polyposis colorectal cancer', 'Disease', 'MESH:D015179', (39, 70))	('HNPCC', 'Phenotype', 'HP:0006716', (22, 27))	('Familial colorectal cancer', 'Disease', 'MESH:D015179', (236, 262))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (4, 21))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('mismatch repair', 'biological_process', 'GO:0006298', ('87', '102'))	('Familial colorectal cancer', 'Disease', (236, 262))	('mismatch repair', 'biological_process', 'GO:0006298', ('134', '149'))	('Colorectal cancer', 'Disease', 'MESH:D015179', (4, 21))	('gene expression', 'biological_process', 'GO:0010467', ('103', '118'))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('FCCTX', 'Chemical', '-', (230, 235))	('CRC', 'Phenotype', 'HP:0003003', (0, 3))	('rectal cancer', 'Phenotype', 'HP:0100743', (249, 262))	('dMMR', 'Chemical', '-', (119, 123))	('Colorectal cancer', 'Disease', (4, 21))	('colorectal cancer', 'Phenotype', 'HP:0003003', (245, 262))	('Lynch syndrome', 'Disease', (215, 229))
60336	31151223	In this study, both intra-patient and inter-patient classifications were performed, as well as different classifications using different spectral regions within the VNIR range (450-600 nm, 605-850 nm, 855-900 nm, and 450-900 nm).	('605-850 nm', 'Var', (189, 199))	('patient', 'Species', '9606', (26, 33))	('patient', 'Species', '9606', (44, 51))	('855-900 nm', 'Var', (201, 211))	('450-600 nm', 'Var', (177, 187))
60338	31151223	The authors developed a CNN classifier to process the ex-vivo tissues from 50 different patients and compared the deep learning method with traditional machine learning approaches, demonstrating that CNNs outperform the traditional classifiers in this case.	('outperform', 'PosReg', (205, 215))	('patients', 'Species', '9606', (88, 96))	('CNNs', 'Var', (200, 204))
60361	31151223	In contrast, over-resection of brain tumor tissue has been shown to cause permanent neurological damages that affect patients' quality of life.	('affect', 'Reg', (110, 116))	('over-resection', 'Var', (13, 27))	('brain tumor', 'Disease', 'MESH:D001932', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('brain tumor', 'Disease', (31, 42))	('neurological damages', 'Disease', 'MESH:D009422', (84, 104))	('neurological damages', 'Disease', (84, 104))	('patients', 'Species', '9606', (117, 125))	('brain tumor', 'Phenotype', 'HP:0030692', (31, 42))
60395	31151223	The human body is not topographically uniform, so imaging a small area with changes in elevation can create inconsistent illumination of the scene or cast shadows.	('human', 'Species', '9606', (4, 9))	('changes', 'Var', (76, 83))	('create', 'Reg', (101, 107))
60402	31151223	This research was supported in part by the U.S. National Institutes of Health (NIH) grants (R21CA176684, R01CA156775, R01CA204254, and R01HL140325).	('R01HL140325', 'CellLine', 'CVCL:2492', (135, 146))	('R01CA156775', 'Var', (105, 116))	('R21CA176684', 'Var', (92, 103))	('R01HL140325', 'Var', (135, 146))	('R01CA204254', 'Var', (118, 129))
60421	29643976	In the ATG5-ATG12 pathway, ATG7 (E1-like enzyme) activates ATG12 that is transferred to ATG10 (E2-like enzyme) to finally conjugate with ATG5.	('activates', 'PosReg', (49, 58))	('ATG12', 'Gene', '9140', (59, 64))	('conjugate', 'Interaction', (122, 131))	('ATG10', 'Gene', (88, 93))	('ATG10', 'Gene', '83734', (88, 93))	('ATG12', 'Gene', (59, 64))	('ATG12', 'Gene', '9140', (12, 17))	('ATG7', 'Var', (27, 31))	('ATG12', 'Gene', (12, 17))
60455	29643976	Dysregulation of the mTOR pathway is often correlated with cancer, neurodegenerative, cardiovascular, and renal diseases, and for this reason makes it an ideal therapeutic target.	('cardiovascular', 'Disease', (86, 100))	('neurodegenerative', 'Disease', (67, 84))	('Dysregulation', 'Var', (0, 13))	('renal diseases', 'Disease', (106, 120))	('correlated', 'Reg', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('rat', 'Species', '10116', (78, 81))	('renal diseases', 'Disease', 'MESH:D007674', (106, 120))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', (59, 65))	('mTOR', 'Gene', (21, 25))	('mTOR', 'Gene', '2475', (21, 25))
60461	29643976	Considering the fact that autophagy is implicated in many different cellular processes, and also keeping in mind the complexity of the molecular mechanisms of tumor initiation and development, it is not surprising that the disturbance of autophagy was found to be one of the possible causes of tumor formation and progression.	('tumor initiation', 'Disease', 'MESH:D009369', (159, 175))	('tumor', 'Disease', (294, 299))	('disturbance', 'Var', (223, 234))	('implicated', 'Reg', (39, 49))	('causes', 'Reg', (284, 290))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor initiation', 'Disease', (159, 175))	('autophagy', 'CPA', (238, 247))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
60466	29643976	The basis for any malignant cell transformation is the activation of a protooncogene or the inactivation of tumor suppressor genes.	('inactivation', 'Var', (92, 104))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor suppressor', 'biological_process', 'GO:0051726', ('108', '124'))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('108', '124'))	('tumor', 'Disease', (108, 113))	('protooncogene', 'Protein', (71, 84))	('activation', 'PosReg', (55, 65))
60473	29643976	Heterozygous deletion of several other core autophagy genes is reported to promote a tumor-suppressor role of autophagy in cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Disease', (85, 90))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('85', '101'))	('promote', 'PosReg', (75, 82))	('autophagy', 'biological_process', 'GO:0016236', ('44', '53'))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('autophagy', 'biological_process', 'GO:0006914', ('110', '119'))	('autophagy', 'biological_process', 'GO:0016236', ('110', '119'))	('Heterozygous deletion', 'Var', (0, 21))	('cancer', 'Disease', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('autophagy', 'biological_process', 'GO:0006914', ('44', '53'))	('core', 'cellular_component', 'GO:0019013', ('39', '43'))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('85', '101'))
60486	29643976	analyzed and reported that with the removal of FIP200 in human breast cancer mouse models, tumor initiation and progression was suppressed.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('FIP200', 'Gene', (47, 53))	('breast cancer', 'Disease', (63, 76))	('tumor initiation', 'Disease', 'MESH:D009369', (91, 107))	('mouse', 'Species', '10090', (77, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('removal', 'Var', (36, 43))	('suppressed', 'NegReg', (128, 138))	('tumor initiation', 'Disease', (91, 107))	('human', 'Species', '9606', (57, 62))
60492	29643976	Thus, the modulation of the autophagy process is a promising, but complex, therapeutic strategy for the enhancement of anticancer treatments.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('modulation', 'Var', (10, 20))	('autophagy process', 'CPA', (28, 45))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('rat', 'Species', '10116', (89, 92))	('cancer', 'Disease', (123, 129))	('autophagy', 'biological_process', 'GO:0016236', ('28', '37'))	('autophagy', 'biological_process', 'GO:0006914', ('28', '37'))
60495	29643976	Here, we outline a brief overview of current knowledge on modifications of the core autophagy machinery in pancreatic, breast, hepatocellular, colorectal, and lung cancers that represent a promising strategy for the future of drug development.	('breast', 'Disease', (119, 125))	('rat', 'Species', '10116', (201, 204))	('modifications', 'Var', (58, 71))	('hepatocellular', 'Disease', (127, 141))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung cancers', 'Disease', (159, 171))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('lung cancers', 'Disease', 'MESH:D008175', (159, 171))	('pancreatic', 'Disease', 'MESH:D010195', (107, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('colorectal', 'Disease', (143, 153))	('lung cancers', 'Phenotype', 'HP:0100526', (159, 171))	('pancreatic', 'Disease', (107, 117))
60510	29643976	Autophagy inhibition with CQ or genetic manipulations by siRNA showed a positive tumor regression response in PDAC models.	('inhibition', 'NegReg', (10, 20))	('PDAC', 'Chemical', '-', (110, 114))	('siRNA', 'Gene', (57, 62))	('genetic manipulations', 'Var', (32, 53))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('PDAC', 'Disease', (110, 114))	('CQ', 'Chemical', 'MESH:D002738', (26, 28))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Autophagy', 'CPA', (0, 9))	('tumor', 'Disease', (81, 86))
60511	29643976	Activating KRAS mutations were found in over 90% of PDAC that further confirms the critical role of KRAS in PDAC carcinogenesis that came from mouse models.	('KRAS', 'Gene', (11, 15))	('Activating', 'PosReg', (0, 10))	('carcinogenesis', 'Disease', 'MESH:D063646', (113, 127))	('mouse', 'Species', '10090', (143, 148))	('PDAC', 'Chemical', '-', (108, 112))	('mutations', 'Var', (16, 25))	('PDAC', 'Chemical', '-', (52, 56))	('carcinogenesis', 'Disease', (113, 127))	('PDAC', 'Disease', (52, 56))
60512	29643976	Additional p53 tumor suppressor gene mutations and the loss of heterozygosity have been found in ~75% of PDAC cases that contribute to tumor progression.	('PDAC', 'Disease', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('loss', 'Var', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (135, 140))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', (15, 20))	('PDAC', 'Chemical', '-', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
60515	29643976	Autophagy inactivation in these mice promoted the formation of premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, but defected autophagy simultaneously prevented their malignant transformation to PDAC.	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (87, 112))	('Autophagy', 'biological_process', 'GO:0006914', ('0', '9'))	('autophagy', 'CPA', (143, 152))	('formation', 'biological_process', 'GO:0009058', ('50', '59'))	('neoplasia', 'Phenotype', 'HP:0002664', (103, 112))	('promoted', 'PosReg', (37, 45))	('autophagy', 'biological_process', 'GO:0006914', ('143', '152'))	('defected', 'Var', (134, 142))	('premalignant pancreatic intraepithelial neoplasia', 'Disease', 'MESH:D018290', (63, 112))	('Autophagy', 'biological_process', 'GO:0016236', ('0', '9'))	('inactivation', 'Var', (10, 22))	('malignant transformation', 'CPA', (184, 208))	('prevented', 'NegReg', (168, 177))	('mice', 'Species', '10090', (32, 36))	('premalignant pancreatic intraepithelial neoplasia', 'Disease', (63, 112))	('Autophagy', 'CPA', (0, 9))	('PDAC', 'Chemical', '-', (212, 216))	('autophagy', 'biological_process', 'GO:0016236', ('143', '152'))
60516	29643976	using KRAS-driven PDAC models with hemizygous Atg5/Atg7 deletion and with and without the p53 mutation.	('deletion', 'Var', (56, 64))	('KRAS-', 'Gene', (6, 11))	('KRAS-', 'Gene', '3845', (6, 11))	('Atg5/Atg7', 'Gene', (46, 55))	('PDAC', 'Chemical', '-', (18, 22))
60518	29643976	In contrast, in the model without p53 and with partial Atg5/Atg7 deletion, which reduces autophagy, tumor formation was shown to be accelerated probably due to the absence of both copies of p53.	('rat', 'Species', '10116', (138, 141))	('accelerated', 'PosReg', (132, 143))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('autophagy', 'biological_process', 'GO:0016236', ('89', '98'))	('Atg5/Atg7', 'Gene', (55, 64))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('autophagy', 'biological_process', 'GO:0006914', ('89', '98'))	('formation', 'biological_process', 'GO:0009058', ('106', '115'))	('autophagy', 'CPA', (89, 98))	('deletion', 'Var', (65, 73))	('reduces', 'NegReg', (81, 88))
60521	29643976	The first one, "Study of Pre-surgery Gemcitabine + Hydroxychloroquine (GcHc) in Stage IIb or III Adenocarcinoma of the Pancreas," examined the effect of p53 mutation status on disease-free period and their overall survivability (NCT01128296, Table 1).	('Gemcitabine', 'Chemical', 'MESH:C056507', (37, 48))	('III Adenocarcinoma of the Pancreas', 'Disease', 'MESH:D010190', (93, 127))	('III Adenocarcinoma of the Pancreas', 'Disease', (93, 127))	('GcHc', 'Chemical', '-', (71, 75))	('mutation', 'Var', (157, 165))	('IIb', 'Gene', '50771', (86, 89))	('p53', 'Gene', (153, 156))	('Hydroxychloroquine', 'Chemical', 'MESH:D006886', (51, 69))	('Adenocarcinoma of the Pancreas', 'Phenotype', 'HP:0002894', (97, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('IIb', 'Gene', (86, 89))
60522	29643976	The results confirm the data from previous preclinical studies where p53 mutations and autophagy inactivation contributed to poor prognosis of PDAC patients, shortening the disease-free time.	('autophagy', 'CPA', (87, 96))	('shortening', 'NegReg', (158, 168))	('patients', 'Species', '9606', (148, 156))	('p53', 'Gene', (69, 72))	('disease-free time', 'CPA', (173, 190))	('PDAC', 'Disease', (143, 147))	('inactivation', 'NegReg', (97, 109))	('mutations', 'Var', (73, 82))	('PDAC', 'Chemical', '-', (143, 147))
60525	29643976	Although it is expected that most patients with the p53 gene mutation or heterozygous deletion will also have activating KRAS mutations (known presence in more than 90% PDAC patients), the clinical trial is not examining the relationship between the expression status of p53 and KRAS.	('KRAS', 'Gene', (121, 125))	('p53', 'Gene', (52, 55))	('patients', 'Species', '9606', (174, 182))	('activating', 'PosReg', (110, 120))	('patients', 'Species', '9606', (34, 42))	('PDAC', 'Chemical', '-', (169, 173))	('mutations', 'Var', (126, 135))
60528	29643976	However, five clinical trials where the combination of autophagy inhibition with DNA synthesis (gemcitabine and capecitabine) or cell division (abraxane) inhibitors are used are still in progress and the results are highly anticipated (NCT01128296, NCT01506973, NCT01494155, NCT01978184, and NCT03344172; Table 1).	('NCT01494155', 'Var', (262, 273))	('NCT01128296', 'Var', (236, 247))	('NCT01506973', 'Var', (249, 260))	('NCT03344172', 'Var', (292, 303))	('cell division', 'biological_process', 'GO:0051301', ('129', '142'))	('autophagy', 'CPA', (55, 64))	('gemcitabine', 'Chemical', 'MESH:C056507', (96, 107))	('autophagy', 'biological_process', 'GO:0016236', ('55', '64'))	('DNA', 'cellular_component', 'GO:0005574', ('81', '84'))	('DNA synthesis', 'biological_process', 'GO:0071897', ('81', '94'))	('capecitabine', 'Chemical', 'MESH:D000069287', (112, 124))	('autophagy', 'biological_process', 'GO:0006914', ('55', '64'))	('NCT01978184', 'Var', (275, 286))
60530	29643976	The first evidence of how genetic inactivation of autophagy can contribute to the malignant transformation in breast cancer was made by Liang and colleagues in 1999.	('genetic inactivation', 'Var', (26, 46))	('autophagy', 'biological_process', 'GO:0016236', ('50', '59'))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('autophagy', 'biological_process', 'GO:0006914', ('50', '59'))	('contribute', 'Reg', (64, 74))	('autophagy', 'CPA', (50, 59))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('malignant transformation', 'CPA', (82, 106))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
60536	29643976	revealed that FIP200 as a potential target for cancer therapy since FIP200 ablation in mice, and consequently autophagy inhibition, suppressed mammary tumor initiation and progression.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor initiation', 'Disease', (151, 167))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('mice', 'Species', '10090', (87, 91))	('cancer', 'Disease', (47, 53))	('progression', 'CPA', (172, 183))	('ablation', 'Var', (75, 83))	('FIP200', 'Gene', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor initiation', 'Disease', 'MESH:D009369', (151, 167))	('suppressed', 'NegReg', (132, 142))
60538	29643976	The disruption of essential genes within the autophagy pathway, including FIP200, impairs autophagosome biogenesis at the earliest stages and leads to the accumulation of substrates such as p62.	('rat', 'Species', '10116', (176, 179))	('autophagosome', 'cellular_component', 'GO:0005776', ('90', '103'))	('autophagy', 'biological_process', 'GO:0006914', ('45', '54'))	('impairs', 'NegReg', (82, 89))	('accumulation', 'PosReg', (155, 167))	('leads to', 'Reg', (142, 150))	('FIP200', 'Gene', (74, 80))	('autophagosome biogenesis at the earliest stages', 'CPA', (90, 137))	('disruption', 'Var', (4, 14))	('substrates', 'MPA', (171, 181))	('autophagy', 'biological_process', 'GO:0016236', ('45', '54'))
60540	29643976	Several studies showed that p62 has a role in protumorigenesis, and Mathew et al.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('p62', 'Var', (28, 31))	('tumor', 'Disease', (49, 54))
60541	29643976	found that p62 accumulation, upon autophagy inhibition in apoptosis-deficient cells, increased tumorigenesis through increased oxidative stress and deregulation of NF-kappaB signaling.	('NF-kappaB', 'Gene', '4790', (164, 173))	('increased', 'PosReg', (117, 126))	('oxidative stress', 'Phenotype', 'HP:0025464', (127, 143))	('p62', 'Var', (11, 14))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (117, 143))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('NF-kappaB', 'Gene', (164, 173))	('increased', 'PosReg', (85, 94))	('deregulation', 'NegReg', (148, 160))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('oxidative stress', 'MPA', (127, 143))	('accumulation', 'PosReg', (15, 27))	('tumor', 'Disease', (95, 100))
60542	29643976	have demonstrated that p62 knockdown or p62 deficiency in already established FIP200-null tumors dramatically reduced tumor growth.	('deficiency', 'Var', (44, 54))	('reduced', 'NegReg', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('rat', 'Species', '10116', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumor', 'Disease', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('p62', 'Gene', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
60543	29643976	Therefore, this later model demonstrated that p62 impairment and suppression of autophagy by FIP200 deletion could synergize to inhibit tumor growth, suggesting new insights for the future design of anticancer drugs.	('FIP200', 'Gene', (93, 99))	('inhibit', 'NegReg', (128, 135))	('suppression', 'NegReg', (65, 76))	('autophagy', 'biological_process', 'GO:0006914', ('80', '89'))	('autophagy', 'CPA', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('impairment', 'NegReg', (50, 60))	('autophagy', 'biological_process', 'GO:0016236', ('80', '89'))	('deletion', 'Var', (100, 108))	('rat', 'Species', '10116', (35, 38))	('tumor', 'Disease', (136, 141))	('p62', 'Protein', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
60544	29643976	A study from 2010 revealed a significant association between Beclin1 deletion and human epidermal growth factor receptor 2 (ErbB2) amplification, thus providing evidence for decreased Beclin1 expression in a particular breast cancer subtype.	('Beclin1', 'Gene', (61, 68))	('decreased', 'NegReg', (174, 183))	('expression', 'MPA', (192, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('particular breast cancer', 'Disease', (208, 232))	('ErbB2', 'Gene', (124, 129))	('epidermal growth factor receptor 2', 'Gene', (88, 122))	('deletion', 'Var', (69, 77))	('epidermal growth factor receptor 2', 'Gene', '2064', (88, 122))	('particular breast cancer', 'Disease', 'MESH:D001943', (208, 232))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('88', '111'))	('human', 'Species', '9606', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
60546	29643976	was the first link between Beclin1 heterozygosity and ErbB2-driven mammary tumorigenesis.	('Beclin1', 'Gene', (27, 34))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('ErbB2-driven', 'Gene', (54, 66))	('heterozygosity', 'Var', (35, 49))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
60571	29643976	Biallelic Beclin1 deletion reduces autophagy activity and such mice were more likely to develop cancer, including HCC.	('reduces', 'NegReg', (27, 34))	('autophagy activity', 'CPA', (35, 53))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Beclin1', 'Gene', (10, 17))	('cancer', 'Disease', (96, 102))	('mice', 'Species', '10090', (63, 67))	('autophagy', 'biological_process', 'GO:0016236', ('35', '44'))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('autophagy', 'biological_process', 'GO:0006914', ('35', '44'))	('develop', 'PosReg', (88, 95))	('HCC', 'Disease', (114, 117))	('deletion', 'Var', (18, 26))
60572	29643976	In addition, the heterogenic deletion of the Beclin1 reduced autophagy, increasing cell proliferation and initiating spontaneous formations of malignant lesions.	('deletion', 'Var', (29, 37))	('initiating', 'Reg', (106, 116))	('Beclin1', 'Gene', (45, 52))	('rat', 'Species', '10116', (95, 98))	('cell proliferation', 'CPA', (83, 101))	('reduced', 'NegReg', (53, 60))	('increasing', 'PosReg', (72, 82))	('autophagy', 'CPA', (61, 70))	('spontaneous formations of malignant lesions', 'CPA', (117, 160))
60587	29643976	Thus, the Atg5 ablation resulted with impaired autophagy in the liver and the development of benign hepatic tumors with no hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('benign hepatic tumors', 'Disease', (93, 114))	('autophagy', 'biological_process', 'GO:0006914', ('47', '56'))	('ablation', 'Var', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Atg5', 'Gene', (10, 14))	('impaired autophagy in the liver', 'Disease', 'MESH:D008107', (38, 69))	('autophagy', 'biological_process', 'GO:0016236', ('47', '56'))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (123, 147))	('benign hepatic tumors', 'Disease', 'MESH:D056486', (93, 114))	('impaired autophagy in the liver', 'Disease', (38, 69))	('hepatocellular carcinoma', 'Disease', (123, 147))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (123, 147))
60588	29643976	This inability to develop hepatocellular carcinoma was correlated with the induction of tumor suppressors, such as p53, p16, p21, and p27, which negatively regulated the progression of tumorigenesis when autophagy was impaired.	('tumor', 'Disease', (185, 190))	('p53', 'Var', (115, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('p27', 'Gene', '3429', (134, 137))	('p27', 'Gene', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('p16', 'Gene', (120, 123))	('negatively', 'NegReg', (145, 155))	('p21', 'Gene', (125, 128))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (26, 50))	('p21', 'Gene', '644914', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('hepatocellular carcinoma', 'Disease', (26, 50))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (26, 50))	('p16', 'Gene', '1029', (120, 123))	('tumor', 'Disease', (88, 93))
60616	29643976	Interestingly, another study analyzing Beclin1 expression in CRC patients has shown that those patients with a high Beclin1 expression had a better chance of being disease-free and had a better overall survival rate as compared to those with lower Beclin1 expression, indicating that high Beclin1 expression could serve as a favorable prognostic marker in CRC.	('CRC', 'Phenotype', 'HP:0003003', (356, 359))	('Beclin1', 'Gene', (116, 123))	('patients', 'Species', '9606', (95, 103))	('rat', 'Species', '10116', (211, 214))	('disease-free', 'Disease', (164, 176))	('patients', 'Species', '9606', (65, 73))	('CRC', 'Disease', (356, 359))	('CRC', 'Phenotype', 'HP:0003003', (61, 64))	('high', 'Var', (111, 115))
60621	29643976	Alterations in other core autophagy machinery components have also been associated with CRC and its progression and may potentially be good prognostic indicators.	('autophagy', 'biological_process', 'GO:0006914', ('26', '35'))	('Alterations', 'Var', (0, 11))	('associated', 'Reg', (72, 82))	('CRC', 'Disease', (88, 91))	('core', 'cellular_component', 'GO:0019013', ('21', '25'))	('autophagy', 'biological_process', 'GO:0016236', ('26', '35'))	('rat', 'Species', '10116', (4, 7))	('CRC', 'Phenotype', 'HP:0003003', (88, 91))
60622	29643976	Mutations and reduced expression of Atg5 were found in many gastrointestinal carcinomas including CRC, suggesting the tumor suppressor role of autophagy in CRC.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor suppressor', 'biological_process', 'GO:0051726', ('118', '134'))	('CRC', 'Phenotype', 'HP:0003003', (156, 159))	('Atg5', 'Gene', (36, 40))	('autophagy', 'biological_process', 'GO:0006914', ('143', '152'))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Mutations', 'Var', (0, 9))	('CRC', 'Disease', (98, 101))	('CRC', 'Phenotype', 'HP:0003003', (98, 101))	('gastrointestinal carcinomas', 'Disease', 'MESH:D004067', (60, 87))	('gastrointestinal carcinomas', 'Disease', (60, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('expression', 'MPA', (22, 32))	('gastrointestinal carcinomas', 'Phenotype', 'HP:0002672', (60, 87))	('reduced', 'NegReg', (14, 21))	('tumor', 'Disease', (118, 123))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('118', '134'))	('autophagy', 'biological_process', 'GO:0016236', ('143', '152'))
60630	29643976	Currently, the genetically engineered mouse models whereby the NSCLC initiation and progression are driven by the oncogenic KRAS or BRAF mutations are used to study the molecular aspects of the disease.	('BRAF', 'Gene', (132, 136))	('mouse', 'Species', '10090', (38, 43))	('KRAS', 'Gene', (124, 128))	('mutations', 'Var', (137, 146))	('NSCLC initiation', 'Disease', (63, 79))	('NSCLC initiation', 'Disease', 'MESH:D007319', (63, 79))
60631	29643976	Previous studies on different cancer cell lines bearing activating mutations in Ras have shown that the autophagy level is higher than in the healthy cells suggesting that these tumors are autophagy-dependent and that autophagy could serve as a potential therapeutic target in NSCLC treatment.	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', (30, 36))	('autophagy level', 'CPA', (104, 119))	('higher', 'PosReg', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('mutations', 'Var', (67, 76))	('Ras', 'Gene', (80, 83))	('NSCLC', 'Disease', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('NSCLC', 'Disease', 'MESH:D002289', (277, 282))
60632	29643976	When the Atg7 was deleted in the mice lungs bearing NSCLC, a suppression of the tumor cell proliferation was noticed.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('NSCLC', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Atg7', 'Gene', (9, 13))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('deleted', 'Var', (18, 25))	('tumor', 'Disease', (80, 85))	('cell proliferation', 'biological_process', 'GO:0008283', ('86', '104'))	('rat', 'Species', '10116', (98, 101))	('suppression', 'NegReg', (61, 72))	('mice', 'Species', '10090', (33, 37))
60637	29643976	BRAF mutants with Atg7 deletion tend to live longer as opposed to mice with KRAS mutation that die from pneumonia instead of cancer suggesting that autophagy deficiency might promote inflammation.	('Atg7', 'Gene', (18, 22))	('inflammation', 'biological_process', 'GO:0006954', ('183', '195'))	('pneumonia', 'Disease', (104, 113))	('inflammation', 'Disease', (183, 195))	('deletion', 'Var', (23, 31))	('pneumonia', 'Disease', 'MESH:D011014', (104, 113))	('autophagy', 'biological_process', 'GO:0006914', ('148', '157'))	('autophagy deficiency', 'Disease', (148, 168))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mice', 'Species', '10090', (66, 70))	('autophagy', 'biological_process', 'GO:0016236', ('148', '157'))	('promote', 'PosReg', (175, 182))	('autophagy deficiency', 'Disease', 'MESH:C564093', (148, 168))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('pneumonia', 'Phenotype', 'HP:0002090', (104, 113))	('inflammation', 'Disease', 'MESH:D007249', (183, 195))
60645	29643976	Indeed, two studies have shown that when an autophagy inhibitor CQ is used in combination with EGFR-TKI, NSCLC cells are more prone to respond to treatment either by overcoming the resistance in the wild-type EGFR NSCLC or by overcoming the antagonistic effect of EGFR-TKIs and therapeutic agents in wild-type and mutant EGFR NSCLC.	('EGFR', 'molecular_function', 'GO:0005006', ('209', '213'))	('autophagy', 'biological_process', 'GO:0016236', ('44', '53'))	('NSCLC', 'Disease', 'MESH:D002289', (214, 219))	('NSCLC', 'Disease', (214, 219))	('autophagy', 'biological_process', 'GO:0006914', ('44', '53'))	('antagonistic effect', 'MPA', (241, 260))	('EGFR', 'molecular_function', 'GO:0005006', ('264', '268'))	('overcoming', 'NegReg', (226, 236))	('EGFR', 'molecular_function', 'GO:0005006', ('95', '99'))	('CQ', 'Chemical', 'MESH:D002738', (64, 66))	('NSCLC', 'Disease', 'MESH:D002289', (326, 331))	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('prone', 'PosReg', (126, 131))	('mutant', 'Var', (314, 320))	('overcoming', 'PosReg', (166, 176))	('resistance', 'MPA', (181, 191))	('NSCLC', 'Disease', (326, 331))	('NSCLC', 'Disease', (105, 110))	('EGFR', 'molecular_function', 'GO:0005006', ('321', '325'))
60649	29643976	It was found that EB1089 induces a novel cytostatic form of autophagy suppressing NSCLC proliferation.	('EB1089', 'Chemical', 'MESH:C078903', (18, 24))	('rat', 'Species', '10116', (95, 98))	('EB1089', 'Var', (18, 24))	('suppressing', 'NegReg', (70, 81))	('NSCLC', 'Disease', (82, 87))	('autophagy', 'CPA', (60, 69))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
60650	29643976	have shown that simultaneous targeting of CD47 and autophagy in NSCLC xenograft models enhance antitumor activity through the activation of caspase-3, recruitment of macrophages, and overproduction of ROS.	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('enhance', 'PosReg', (87, 94))	('NSCLC', 'Disease', (64, 69))	('tumor', 'Disease', (99, 104))	('CD47', 'Gene', '961', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('caspase-3', 'Gene', '836', (140, 149))	('ROS', 'Chemical', '-', (201, 204))	('recruitment', 'CPA', (151, 162))	('overproduction', 'PosReg', (183, 197))	('activation', 'PosReg', (126, 136))	('autophagy', 'biological_process', 'GO:0016236', ('51', '60'))	('ROS', 'Protein', (201, 204))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('caspase-3', 'Gene', (140, 149))	('targeting', 'Var', (29, 38))	('autophagy', 'CPA', (51, 60))	('CD47', 'Gene', (42, 46))	('autophagy', 'biological_process', 'GO:0006914', ('51', '60'))
60675	29643976	Unfortunately, we still lack the knowledge and tools to specifically activate or inactivate autophagy without disturbing other cellular processes and to specifically modulate autophagy within the tumor cells concurrently avoiding autophagy disruption in healthy cells.	('inactivate', 'Var', (81, 91))	('autophagy', 'biological_process', 'GO:0006914', ('230', '239'))	('modulate', 'Reg', (166, 174))	('tumor', 'Disease', (196, 201))	('autophagy', 'biological_process', 'GO:0016236', ('175', '184'))	('activate', 'PosReg', (69, 77))	('autophagy', 'biological_process', 'GO:0016236', ('92', '101'))	('autophagy', 'biological_process', 'GO:0006914', ('175', '184'))	('autophagy', 'CPA', (92, 101))	('autophagy', 'biological_process', 'GO:0006914', ('92', '101'))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('autophagy', 'biological_process', 'GO:0016236', ('230', '239'))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('autophagy', 'CPA', (175, 184))
60682	29371920	Hypermethylation of BEND5 contributes to cell proliferation and is a prognostic marker of colorectal cancer Aberrant hypermethylation of CpG islands in tumor suppressor genes (TSGs) contributes to colorectal tumorigenesis.	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('BEND5', 'Gene', (20, 25))	('colorectal tumor', 'Disease', (197, 213))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('152', '168'))	('Aberrant hypermethylation', 'Var', (108, 133))	('colorectal cancer', 'Disease', (90, 107))	('tumor suppressor', 'biological_process', 'GO:0051726', ('152', '168'))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('cell proliferation', 'biological_process', 'GO:0008283', ('41', '59'))	('BEND5', 'Gene', '67621', (20, 25))	('contributes to', 'Reg', (182, 196))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('colorectal tumor', 'Disease', 'MESH:D015179', (197, 213))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
60684	29371920	Using HumanMethylation450 BeadChip arrays, CpG regions in BEND5 were the most highly methylated among all genomic regions in 26 colorectal tumors compared to paired non-neoplastic tissues from a Taiwan cohort.	('colorectal tumors', 'Disease', 'MESH:D015179', (128, 145))	('methylated', 'Var', (85, 95))	('colorectal tumors', 'Disease', (128, 145))	('highly', 'PosReg', (78, 84))	('BEND5', 'Gene', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('CpG regions', 'Var', (43, 54))
60685	29371920	Quantitative methylation-specific real-time PCR revealed that 86.7% (117/135) of CRC patients exhibited hypermethylated BEND5.	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('CRC', 'Disease', (81, 84))	('BEND5', 'Protein', (120, 125))	('patients', 'Species', '9606', (85, 93))	('CRC', 'Phenotype', 'HP:0003003', (81, 84))	('hypermethylated', 'Var', (104, 119))
60686	29371920	BEND5 hypermethylation was associated with poor overall survival (OS) in Taiwan patients with early-stage CRC (P = 0.037).	('hypermethylation', 'Var', (6, 22))	('patients', 'Species', '9606', (80, 88))	('overall survival', 'MPA', (48, 64))	('CRC', 'Phenotype', 'HP:0003003', (106, 109))	('poor', 'NegReg', (43, 47))	('BEND5', 'Gene', (0, 5))
60687	29371920	In a CRC tissue set from South Korea, OS was higher in patients with high BEND5 protein expression than in those with low BEND5 protein expression (P = 0.037) by using immunohistochemistry assays.	('high BEND5', 'Var', (69, 79))	('patients', 'Species', '9606', (55, 63))	('higher', 'PosReg', (45, 51))	('expression', 'MPA', (88, 98))	('CRC', 'Phenotype', 'HP:0003003', (5, 8))
60688	29371920	Consistently, BEND5 hypermethylation was associated with poor OS in patients with early-stage CRC in The Cancer Genome Atlas (TCGA) data set (P = 0.003).	('poor OS', 'Disease', (57, 64))	('hypermethylation', 'Var', (20, 36))	('Cancer Genome Atlas', 'Disease', (105, 124))	('Cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (105, 124))	('BEND5', 'Gene', (14, 19))	('CRC', 'Phenotype', 'HP:0003003', (94, 97))	('patients', 'Species', '9606', (68, 76))
60689	29371920	Multivariate Cox proportional hazards regression analysis further supported that hypermethylation of BEND5 genes was significantly associated with OS in Taiwan and TCGA CRC patients (P = 0.023 and 0.033, respectively).	('Cox', 'Gene', (13, 16))	('patients', 'Species', '9606', (173, 181))	('BEND5 genes', 'Gene', (101, 112))	('associated', 'Reg', (131, 141))	('CRC', 'Phenotype', 'HP:0003003', (169, 172))	('hypermethylation', 'Var', (81, 97))	('Cox', 'Gene', '1351', (13, 16))
60690	29371920	Finally, the cell model assay with transient transfection of BEND5 or si-BEND5 knockdown indicated that BEND5 inhibited cancer cell proliferation.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('BEND5', 'Var', (104, 109))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('si-BEND5', 'Gene', (70, 78))	('inhibited', 'NegReg', (110, 119))
60691	29371920	In conclusion, epigenetic alteration in the candidate TSG BEND5 contributes to colorectal cancer development and is a prognostic marker of CRC.	('contributes', 'Reg', (64, 75))	('TSG BEND5', 'Gene', (54, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('epigenetic alteration', 'Var', (15, 36))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('CRC', 'Disease', (139, 142))	('colorectal cancer', 'Disease', (79, 96))	('CRC', 'Phenotype', 'HP:0003003', (139, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))
60694	29371920	CRC results from the accumulation of multiple genetic and epigenetic alterations in tumor suppressor genes (TSGs) and oncogenes, which transform normal colonic epithelium into adenocarcinomas.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('CRC', 'Phenotype', 'HP:0003003', (0, 3))	('adenocarcinomas', 'Disease', (176, 191))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('adenocarcinomas', 'Disease', 'MESH:D000230', (176, 191))	('tumor', 'Disease', (84, 89))	('CRC', 'Disease', (0, 3))	('epigenetic alterations', 'Var', (58, 80))	('transform', 'Reg', (135, 144))
60695	29371920	Hypermethylation of CpG islands associated with TSGs can cause transcriptional silencing, contributing to tumorigenesis.	('TSGs', 'Disease', (48, 52))	('Hypermethylation', 'Var', (0, 16))	('contributing', 'Reg', (90, 102))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('transcriptional silencing', 'MPA', (63, 88))	('tumor', 'Disease', (106, 111))
60712	29371920	Multivariate Cox proportional-hazards survival analysis were further adjusted by sex, age, tumor type, location, differentiation, stage showed that hypermethylation of BEND5 genes was significantly and independently associated with overall survival in 105 CRC patients (Table 2, P = 0.023).	('BEND5 genes', 'Gene', (168, 179))	('Cox', 'Gene', (13, 16))	('associated with', 'Reg', (216, 231))	('hypermethylation', 'Var', (148, 164))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('patients', 'Species', '9606', (260, 268))	('overall survival', 'MPA', (232, 248))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('CRC', 'Phenotype', 'HP:0003003', (256, 259))	('tumor', 'Disease', (91, 96))	('Cox', 'Gene', '1351', (13, 16))
60717	29371920	Again, the exon 1 region of BEND5 was hypermethylated in 38 colorectal tumor tissues, but not in the matched normal colorectal tissues (Figure 1B).	('BEND5', 'Gene', (28, 33))	('colorectal tumor', 'Disease', (60, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('hypermethylated', 'Var', (38, 53))	('colorectal tumor', 'Disease', 'MESH:D015179', (60, 76))
60718	29371920	Notably, hypermethylaion (beta > 0.5) was detected in 109 and 216 of the 314 CRC tumors for probe 3 and probe 7 of the promoter and exon 1 sequences, respectively.	('hypermethylaion', 'Var', (9, 24))	('CRC tumors', 'Disease', (77, 87))	('CRC tumors', 'Disease', 'MESH:D015179', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CRC', 'Phenotype', 'HP:0003003', (77, 80))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('detected', 'Reg', (42, 50))
60721	29371920	Compared with those exhibiting low methylation, prognosis was significantly poorer in patients exhibiting hypermethylation of the BEND5 promoter who had stage I or II CRC (Figure 3D, P = 0.003).	('BEND5', 'Gene', (130, 135))	('CRC', 'Phenotype', 'HP:0003003', (167, 170))	('poorer', 'NegReg', (76, 82))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))	('hypermethylation', 'Var', (106, 122))	('patients', 'Species', '9606', (86, 94))
60722	29371920	Multivariate Cox proportional hazards regression analysis further showed that hypermethylation of BEND5 genes was significantly associated with 5-year overall survival (Supplementary Table 3, P = 0.033).	('Cox', 'Gene', (13, 16))	('associated', 'Reg', (128, 138))	('hypermethylation', 'Var', (78, 94))	('BEND5', 'Gene', (98, 103))	('Cox', 'Gene', '1351', (13, 16))
60726	29371920	According to the cell proliferation SRB assay, BEND5 also repressed DLD-1 cancer cell growth by 32.9% (Figure 5D), whereas si-BEND5 knockdown increased CRC cell proliferation (Supplementary Figure 4).	('repressed', 'NegReg', (58, 67))	('DLD-1 cancer', 'Disease', (68, 80))	('increased', 'PosReg', (142, 151))	('knockdown', 'Var', (132, 141))	('si-BEND5', 'Gene', (123, 131))	('CRC cell proliferation', 'CPA', (152, 174))	('SRB', 'Gene', '10575', (36, 39))	('CRC', 'Phenotype', 'HP:0003003', (152, 155))	('BEND5', 'Var', (47, 52))	('SRB', 'Gene', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('DLD-1 cancer', 'Disease', 'MESH:C573012', (68, 80))
60728	29371920	BEND5 knockdown increased COLO 320DM colon cancer cell growth by 39.75% (Figure 5E).	('COLO', 'Disease', (26, 30))	('colon cancer', 'Phenotype', 'HP:0003003', (37, 49))	('DM colon cancer', 'Disease', 'MESH:D015179', (34, 49))	('BEND5', 'Gene', (0, 5))	('COLO', 'Species', '307630', (26, 30))	('increased', 'PosReg', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('knockdown', 'Var', (6, 15))	('cell growth', 'biological_process', 'GO:0016049', ('50', '61'))	('DM colon cancer', 'Disease', (34, 49))
60729	29371920	BEND5 overexpression in DLD-1 colon cancer cells and BEND5 knockdown in COLO 320 DM colon cancer cells indicated that BEND5 could significantly change their expression levels (Figure 5E), suggesting that BEND5 may directly or indirectly regulate CCNB1, PCNA and BCL2.	('DM colon cancer', 'Disease', 'MESH:D015179', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('BEND5', 'Var', (204, 209))	('BEND5', 'Var', (118, 123))	('regulate', 'Reg', (237, 245))	('DLD-1 colon cancer', 'Disease', 'MESH:C573012', (24, 42))	('DM colon cancer', 'Disease', (81, 96))	('expression levels', 'MPA', (157, 174))	('COLO', 'Species', '307630', (72, 76))	('PCNA', 'molecular_function', 'GO:0003892', ('253', '257'))	('PCNA', 'Gene', (253, 257))	('BCL2', 'molecular_function', 'GO:0015283', ('262', '266'))	('colon cancer', 'Phenotype', 'HP:0003003', (84, 96))	('change', 'Reg', (144, 150))	('CCNB1', 'Gene', (246, 251))	('colon cancer', 'Phenotype', 'HP:0003003', (30, 42))	('DLD-1 colon cancer', 'Disease', (24, 42))	('BCL2', 'Gene', (262, 266))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
60730	29371920	Aberrant promoter hypermethylation of CpG islands associated with TSGs can cause transcriptional silencing, contributing to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('Aberrant', 'Var', (0, 8))	('TSGs', 'Disease', (66, 70))	('tumor', 'Disease', (124, 129))	('promoter', 'MPA', (9, 17))	('contributing to', 'Reg', (108, 123))	('transcriptional silencing', 'MPA', (81, 106))	('CpG', 'Protein', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
60732	29371920	Furthermore, QMSP confirmed BEND5 hypermethylation in the CRC tumor tissues compared with the normal tissues.	('CRC', 'Phenotype', 'HP:0003003', (58, 61))	('hypermethylation', 'Var', (34, 50))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('BEND5', 'Gene', (28, 33))	('CRC tumor', 'Disease', (58, 67))	('CRC tumor', 'Disease', 'MESH:D015179', (58, 67))
60733	29371920	In the Asian cohorts, earlier-stage CRC patients without metastasis having hypermethylation of the promoter region of BEND5 in their tumors had a poor prognosis.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', (133, 139))	('patients', 'Species', '9606', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('CRC', 'Phenotype', 'HP:0003003', (36, 39))	('BEND5', 'Gene', (118, 123))	('hypermethylation', 'Var', (75, 91))
60734	29371920	Moreover, patients with low BEND5 protein expression also had a poor prognosis.	('low', 'Var', (24, 27))	('expression', 'MPA', (42, 52))	('BEND5 protein', 'Protein', (28, 41))	('patients', 'Species', '9606', (10, 18))
60739	29371920	Functional data are presented in this study to demonstrate, for the first time, that BEND5 can reduce cancer cell survival (Figure 5).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('reduce', 'NegReg', (95, 101))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('BEND5', 'Var', (85, 90))
60741	29371920	Further research is warranted to determine whether alterations of BEND5 in CRC cells contribute to tumorigenesis by deregulating the expression of BCL2.	('tumor', 'Disease', (99, 104))	('expression', 'MPA', (133, 143))	('alterations', 'Var', (51, 62))	('deregulating', 'Reg', (116, 128))	('BCL2', 'Gene', (147, 151))	('BEND5', 'Gene', (66, 71))	('contribute', 'Reg', (85, 95))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('CRC', 'Phenotype', 'HP:0003003', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
60742	29371920	Notably, in the G1 phase, BEND5 reduced the proportion of DLD-1 cancer cells by 32.9% but increased cell cycle arrest by only 5% (Figure 5D and Supplementary Figure 6).	('cell cycle arrest', 'Phenotype', 'HP:0011018', (100, 117))	('DLD-1 cancer', 'Disease', 'MESH:C573012', (58, 70))	('increased', 'PosReg', (90, 99))	('cell cycle arrest', 'CPA', (100, 117))	('reduced', 'NegReg', (32, 39))	('DLD-1 cancer', 'Disease', (58, 70))	('BEND5', 'Var', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
60755	29371920	Recent studies have reported that several TSGs are often methylated in the multistep oncogenesis process from normal colonic epithelium to adenocarcinoma.	('adenocarcinoma', 'Disease', (139, 153))	('oncogenesis', 'biological_process', 'GO:0007048', ('85', '96'))	('adenocarcinoma', 'Disease', 'MESH:D000230', (139, 153))	('methylated', 'Var', (57, 67))
60757	29371920	In the present study, the BEND5 promoter and exon 1 regions were hypermethylated only in the CRC tumors, but not in the matched colon tissues (Figures 1-3), suggesting that BEND5 hypermethylation may be a biomarker of CRC.	('BEND5 hypermethylation', 'Var', (173, 195))	('CRC tumors', 'Disease', (93, 103))	('CRC tumors', 'Disease', 'MESH:D015179', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CRC', 'Phenotype', 'HP:0003003', (93, 96))	('CRC', 'Disease', (218, 221))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('hypermethylation', 'Var', (179, 195))	('CRC', 'Phenotype', 'HP:0003003', (218, 221))
60758	29371920	Because prognosis is poor in earlier-stage CRC patients without metastasis exhibiting hypermethylation of the promoter region of BEND5 in their tumors (Figures 2 and 3), BEND5 hypermethylation may be a prognostic indicator that enables identifying high-risk patients for frequent monitoring.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('hypermethylation', 'Var', (86, 102))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('BEND5', 'Var', (170, 175))	('hypermethylation', 'Var', (176, 192))	('patients', 'Species', '9606', (47, 55))	('patients', 'Species', '9606', (258, 266))	('CRC', 'Phenotype', 'HP:0003003', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('BEND5', 'Gene', (129, 134))
60759	29371920	Thus, whether detecting BEND5 hypermethylation in the blood or stool samples of CRC patients can be applied as a noninvasive analytical method for early detection that is worthy of further investigation.	('patients', 'Species', '9606', (84, 92))	('CRC', 'Disease', (80, 83))	('BEND5', 'Gene', (24, 29))	('blood or stool', 'Phenotype', 'HP:0025085', (54, 68))	('CRC', 'Phenotype', 'HP:0003003', (80, 83))	('hypermethylation', 'Var', (30, 46))
60812	27558481	Tumor morphology, microsatellite instability (MSI) and stability (MSS), KRAS and BRAF mutations, and mismatch repair (MMR) expression (MSH2, MLH1, MSH6, PMS2) were assessed.	('MSI', 'Disease', (46, 49))	('mutations', 'Var', (86, 95))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('KRAS', 'Gene', (72, 76))	('MSH2', 'Gene', '4436', (135, 139))	('MSH6', 'Gene', '2956', (147, 151))	('KRAS', 'Gene', '3845', (72, 76))	('BRAF', 'Gene', '673', (81, 85))	('stability', 'MPA', (55, 64))	('MSI', 'Disease', 'None', (46, 49))	('BRAF', 'Gene', (81, 85))	('microsatellite', 'MPA', (18, 32))	('PMS2', 'Gene', (153, 157))	('MLH1', 'Gene', '4292', (141, 145))	('MSH2', 'Gene', (135, 139))	('MLH1', 'Gene', (141, 145))	('MSH6', 'Gene', (147, 151))	('PMS2', 'Gene', '5395', (153, 157))
60816	27558481	MSS/BRAFV600E genotype had poor prognosis and was more prevalent in early-age CRC (9% vs. 3%).	('BRAFV600E', 'Mutation', 'rs113488022', (4, 13))	('prevalent', 'Reg', (55, 64))	('early-age CRC', 'Disease', (68, 81))	('MSS/BRAFV600E', 'Var', (0, 13))	('CRC', 'Phenotype', 'HP:0003003', (78, 81))
60827	27558481	In 1991, Dunlop and colleagues studied 50 cases of CRC diagnosed before age 30 and reported that 14 of these patients possessed a mutation in the MLH1 or MSH2 mismatch repair gene.	('mismatch repair', 'biological_process', 'GO:0006298', ('159', '174'))	('patients', 'Species', '9606', (109, 117))	('mutation', 'Var', (130, 138))	('MSH2', 'Gene', (154, 158))	('CRC', 'Phenotype', 'HP:0003003', (51, 54))	('MSH2', 'Gene', '4436', (154, 158))	('MLH1', 'Gene', '4292', (146, 150))	('MLH1', 'Gene', (146, 150))	('CRC', 'Disease', (51, 54))
60833	27558481	MSI, KRAS codon 12/13 mutations, and BRAFV600E mutations were assessed.	('MSI', 'Disease', 'None', (0, 3))	('KRAS', 'Gene', (5, 9))	('MSI', 'Disease', (0, 3))	('KRAS', 'Gene', '3845', (5, 9))	('BRAFV600E', 'Var', (37, 46))	('BRAFV600E', 'Mutation', 'rs113488022', (37, 46))
60858	27558481	From genetic analysis we found no difference in the overall prevalence of BRAFV600E and KRAS codon 12/13 mutations between age groups (Table 1).	('BRAFV600E', 'Mutation', 'rs113488022', (74, 83))	('KRAS', 'Gene', (88, 92))	('BRAFV600E', 'Var', (74, 83))	('KRAS', 'Gene', '3845', (88, 92))
60870	27558481	This finding provides strong evidence that MSI in early onset patients is due to the presence of germ line mutations in corresponding MMR genes.	('presence', 'Reg', (85, 93))	('mutations', 'Var', (107, 116))	('MSI', 'Disease', (43, 46))	('MMR', 'Gene', (134, 137))	('patients', 'Species', '9606', (62, 70))	('MSI', 'Disease', 'None', (43, 46))
60871	27558481	We next explored the role of BRAFV600E mutations (mut) in relation to MSI/MSS status (Table 3).	('MSI', 'Disease', 'None', (70, 73))	('BRAFV600E', 'Var', (29, 38))	('BRAFV600E', 'Mutation', 'rs113488022', (29, 38))	('MSI', 'Disease', (70, 73))
60877	27558481	Furthermore, although the early onset MSI subgroup had worse survival outcome (Figure 1e, p=0.01), the significance disappeared after adjusting for the presence of the MSI/BRAFV600Emut (p=0.12) Adult onset, proximal tumors were enriched in MSI (p<0.0001) and BRAF (p=0.0006) mutations, relative to distal tumors (Table 4).	('proximal tumors', 'Disease', 'MESH:D009369', (207, 222))	('MSI', 'Disease', 'None', (38, 41))	('tumors', 'Disease', (216, 222))	('MSI', 'Disease', (38, 41))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (305, 311))	('MSI', 'Disease', 'None', (168, 171))	('BRAF', 'Gene', (259, 263))	('BRAF', 'Gene', '673', (259, 263))	('BRAFV600E', 'Mutation', 'rs113488022', (172, 181))	('MSI', 'Disease', 'None', (240, 243))	('MSI', 'Disease', (168, 171))	('MSI', 'Disease', (240, 243))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('BRAF', 'Gene', '673', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('BRAF', 'Gene', (172, 176))	('tumors', 'Disease', (305, 311))	('proximal tumors', 'Disease', (207, 222))	('mutations', 'Var', (275, 284))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumors', 'Disease', 'MESH:D009369', (305, 311))
60879	27558481	Early onset, distal tumors were enriched in KRAS mutations in contradistinction to the adult group, where there was no difference.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (49, 58))	('KRAS', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('KRAS', 'Gene', '3845', (44, 48))
60896	27558481	Other studies have also found the MLH1 gene to be deficient in most adult MSI tumors, and this pattern of MMR inactivation is driven by methylation silencing.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('methylation', 'Var', (136, 147))	('MMR', 'biological_process', 'GO:0006298', ('106', '109'))	('MLH1', 'Gene', '4292', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MLH1', 'Gene', (34, 38))	('MSI tumors', 'Disease', 'MESH:D009369', (74, 84))	('methylation', 'biological_process', 'GO:0032259', ('136', '147'))	('deficient', 'NegReg', (50, 59))	('silencing', 'NegReg', (148, 157))	('MSI tumors', 'Disease', (74, 84))
60899	27558481	Another molecular feature distinguishing early onset from adult onset MSI was the prevalence of BRAF mutations (Table 3).	('mutations', 'Var', (101, 110))	('MSI', 'Disease', 'None', (70, 73))	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('MSI', 'Disease', (70, 73))
60912	27558481	This suggested that BRAFV600Emut is important to the tumor biology that impacts the DSS outcome.	('BRAFV600E', 'Mutation', 'rs113488022', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('impacts', 'Reg', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('DSS', 'Chemical', '-', (84, 87))	('DSS', 'Disease', (84, 87))	('BRAFV600Emut', 'Var', (20, 32))
60914	27558481	The importance of activating mutations in BRAFV600E in the tumor biology of MSI CRC has been demonstrated by other investigators showing it's importance in prognosis, tumor invasion and apoptosis.	('tumor', 'Disease', (59, 64))	('BRAFV600E', 'Mutation', 'rs113488022', (42, 51))	('mutations', 'Var', (29, 38))	('BRAFV600E', 'Gene', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('MSI', 'Disease', 'None', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('activating', 'PosReg', (18, 28))	('CRC', 'Phenotype', 'HP:0003003', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('MSI', 'Disease', (76, 79))	('tumor', 'Disease', (167, 172))
60915	27558481	Our study shows both age groups with MSS/BRAFV600Emut genotype presented with advanced stage disease 100% of the time, and that in the early onset group, patients had a dismal 5-year DSS at 16% (Figure 1c).	('stage disease', 'Disease', (87, 100))	('BRAFV600E', 'Mutation', 'rs113488022', (41, 50))	('stage disease', 'Disease', 'MESH:D058625', (87, 100))	('presented with', 'Reg', (63, 77))	('MSS/BRAFV600Emut', 'Var', (37, 53))	('patients', 'Species', '9606', (154, 162))	('DSS', 'Chemical', '-', (183, 186))
60923	27440078	ROR2 is epigenetically inactivated in the early stages of colorectal neoplasia and is associated with proliferation and migration Colorectal cancer (CRC) is closely linked to Wnt signalling, with 94 % of cases exhibiting a Wnt related mutation.	('epigenetically', 'Var', (8, 22))	('neoplasia', 'Phenotype', 'HP:0002664', (69, 78))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (58, 78))	('ROR2', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('ROR2', 'Gene', '4920', (0, 4))	('associated with', 'Reg', (86, 101))	('CRC', 'Phenotype', 'HP:0003003', (149, 152))	('signalling', 'biological_process', 'GO:0023052', ('179', '189'))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (130, 147))	('Colorectal cancer', 'Disease', 'MESH:D015179', (130, 147))	('Colorectal cancer', 'Disease', (130, 147))	('colorectal neoplasia', 'Disease', (58, 78))
60927	27440078	In addition, the functional effects of ROR2 modulation were investigated in HCT116 cells following ROR2 siRNA knockdown and in RKO and SW620 cells following ectopic ROR2 expression.	('knockdown', 'Var', (110, 119))	('HCT116', 'CellLine', 'CVCL:0291', (76, 82))	('SW620', 'CellLine', 'CVCL:0547', (135, 140))	('ROR2', 'Gene', (99, 103))
60928	27440078	Reduced ROR2 expression was found to correlate with ROR2 promoter hypermethylation in colorectal cancer cell lines, carcinomas and adenomas.	('carcinomas', 'Disease', (116, 126))	('adenomas', 'Disease', 'MESH:D000236', (131, 139))	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('adenomas', 'Disease', (131, 139))	('expression', 'MPA', (13, 23))	('Reduced', 'NegReg', (0, 7))	('promoter hypermethylation', 'Var', (57, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('colorectal cancer', 'Disease', (86, 103))	('ROR2', 'Gene', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('ROR2', 'Gene', (8, 12))	('carcinomas', 'Disease', 'MESH:D002277', (116, 126))
60930	27440078	Methylation analysis of 88 adenomas and 47 normal mucosa samples found greater percentage of adenoma samples to be methylated.	('adenoma', 'Disease', 'MESH:D000236', (27, 34))	('methylated', 'Var', (115, 125))	('adenoma', 'Disease', (27, 34))	('adenoma', 'Disease', 'MESH:D000236', (93, 100))	('adenomas', 'Disease', 'MESH:D000236', (27, 35))	('adenomas', 'Disease', (27, 35))	('adenoma', 'Disease', (93, 100))
60932	27440078	ROR2 knockdown in the CRC cell line HCT116 significantly decreased expression of the beta-catenin independent Wnt targets genes JNK and NFATC1, increased cellular proliferation and migration but decreased invasion.	('invasion', 'CPA', (205, 213))	('HCT116', 'CellLine', 'CVCL:0291', (36, 42))	('JNK', 'molecular_function', 'GO:0004705', ('128', '131'))	('beta-catenin', 'Gene', '1499', (85, 97))	('NFATC1', 'Gene', '4772', (136, 142))	('knockdown', 'Var', (5, 14))	('decreased', 'NegReg', (195, 204))	('JNK', 'Gene', (128, 131))	('JNK', 'Gene', '5599', (128, 131))	('cellular proliferation', 'CPA', (154, 176))	('migration', 'CPA', (181, 190))	('CRC', 'Phenotype', 'HP:0003003', (22, 25))	('expression', 'MPA', (67, 77))	('beta-catenin', 'Gene', (85, 97))	('decreased', 'NegReg', (57, 66))	('increased', 'PosReg', (144, 153))	('NFATC1', 'Gene', (136, 142))
60933	27440078	When ROR2 was ectopically expressed in RKO and SW620 cells, there was no significant change to either cellular proliferation or migration.	('SW620', 'CellLine', 'CVCL:0547', (47, 52))	('ectopically expressed', 'Var', (14, 35))	('migration', 'CPA', (128, 137))	('cellular proliferation', 'CPA', (102, 124))	('ROR2', 'Gene', (5, 9))
60934	27440078	ROR2 is frequently epigenetically inactivated by promoter hypermethylation in the early stages of colorectal neoplasia and this may contribute to colorectal cancer progression by increasing cellular proliferation and migration.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('contribute', 'Reg', (132, 142))	('cellular proliferation', 'CPA', (190, 212))	('colorectal cancer', 'Disease', 'MESH:D015179', (146, 163))	('ROR2', 'Gene', (0, 4))	('colorectal cancer', 'Phenotype', 'HP:0003003', (146, 163))	('increasing', 'PosReg', (179, 189))	('colorectal neoplasia', 'Disease', (98, 118))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (98, 118))	('colorectal cancer', 'Disease', (146, 163))	('neoplasia', 'Phenotype', 'HP:0002664', (109, 118))	('promoter hypermethylation', 'Var', (49, 74))	('migration', 'CPA', (217, 226))
60936	27440078	CRCs develop from benign intraepithelial neoplasms known as adenomas, which progress to cancer after an accumulation of mutations.	('benign intraepithelial neoplasms', 'Disease', (18, 50))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('CRCs', 'Disease', (0, 4))	('CRC', 'Phenotype', 'HP:0003003', (0, 3))	('adenomas', 'Disease', 'MESH:D000236', (60, 68))	('intraepithelial neoplasms', 'Phenotype', 'HP:0032187', (25, 50))	('adenomas', 'Disease', (60, 68))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('benign intraepithelial neoplasms', 'Disease', 'MESH:D002278', (18, 50))	('neoplasms', 'Phenotype', 'HP:0002664', (41, 50))
60937	27440078	One of the early precipitating events for colorectal adenoma development is mutation of the APC gene, an important tumour suppressor and regulator of beta-catenin dependent Wnt signals.	('beta-catenin', 'Gene', '1499', (150, 162))	('colorectal adenoma', 'Disease', (42, 60))	('APC', 'Disease', 'MESH:D011125', (92, 95))	('APC', 'Disease', (92, 95))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('colorectal adenoma', 'Disease', 'MESH:D015179', (42, 60))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('mutation', 'Var', (76, 84))	('beta-catenin', 'Gene', (150, 162))	('tumour', 'Disease', (115, 121))
60938	27440078	APC along with AXIN and GSK3beta are responsible for degradation of cytosolic beta-catenin and loss of APC leads to beta-catenin accumulation, Wnt pathway hyperactivation and increased cellular proliferation and migration.	('GSK', 'molecular_function', 'GO:0050321', ('24', '27'))	('hyperactivation', 'PosReg', (155, 170))	('GSK3beta', 'Gene', '2932', (24, 32))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('degradation', 'MPA', (53, 64))	('APC', 'Disease', (0, 3))	('APC', 'Disease', 'MESH:D011125', (103, 106))	('APC', 'Disease', (103, 106))	('migration', 'CPA', (212, 221))	('loss', 'Var', (95, 99))	('degradation', 'biological_process', 'GO:0009056', ('53', '64'))	('APC', 'cellular_component', 'GO:0005680', ('103', '106'))	('beta-catenin', 'Gene', (78, 90))	('beta-catenin', 'Gene', '1499', (78, 90))	('AXIN', 'Gene', '8312', (15, 19))	('GSK3beta', 'Gene', (24, 32))	('cellular proliferation', 'CPA', (185, 207))	('increased', 'PosReg', (175, 184))	('beta-catenin', 'Gene', (116, 128))	('beta-catenin', 'Gene', '1499', (116, 128))	('APC', 'cellular_component', 'GO:0005680', ('0', '3'))	('Wnt pathway', 'Pathway', (143, 154))	('AXIN', 'Gene', (15, 19))
60947	27440078	Methylation analysis using combined bisulphite restriction analysis (COBRA) showed 25 out of the 30 cell lines had methylation in the ROR2 promoter (Additional file 1).	('methylation', 'Var', (115, 126))	('bisulphite', 'Chemical', 'MESH:C042345', (36, 46))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('ROR2 promoter', 'Gene', (134, 147))	('methylation', 'biological_process', 'GO:0032259', ('115', '126'))
60954	27440078	A direct comparison of methylation and expression in the colorectal tumour samples of the cohort revealed that samples with high methylation (beta values > 0.25) had significantly lower ROR2 expression (P < 0.0001) (Fig.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('methylation', 'biological_process', 'GO:0032259', ('23', '34'))	('lower', 'NegReg', (180, 185))	('colorectal tumour', 'Disease', 'MESH:D015179', (57, 74))	('high methylation', 'Var', (124, 140))	('colorectal tumour', 'Disease', (57, 74))	('ROR2', 'Gene', (186, 190))	('expression', 'MPA', (191, 201))	('methylation', 'biological_process', 'GO:0032259', ('129', '140'))
60955	27440078	To determine whether hypermethylation of the ROR2 promoter was an early or late event in colorectal neoplasia, we compared the number of methylated samples in 88 non-invasive adenomas to 47 normal mucosa specimens.	('hypermethylation', 'Var', (21, 37))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (89, 109))	('ROR2', 'Gene', (45, 49))	('neoplasia', 'Phenotype', 'HP:0002664', (100, 109))	('adenomas', 'Disease', 'MESH:D000236', (175, 183))	('colorectal neoplasia', 'Disease', (89, 109))	('adenomas', 'Disease', (175, 183))
60959	27440078	Bisulphite sequencing showed that 4 of those adenomas were hypermethylated across the ROR2 CGI promoter (Fig.	('Bisulphite', 'Chemical', 'MESH:C042345', (0, 10))	('adenomas', 'Disease', (45, 53))	('adenomas', 'Disease', 'MESH:D000236', (45, 53))	('hypermethylated', 'Var', (59, 74))
60961	27440078	Silencing ROR2 in the HCT116 cell line was associated with a 34 % reduction in JNK (P < 0.01) and 29 % reduction in NFATC1 (P < 0.05) and 31 % reduction in CCND1 (P < 0.05).	('reduction', 'NegReg', (103, 112))	('NFATC1', 'Gene', '4772', (116, 122))	('HCT116', 'CellLine', 'CVCL:0291', (22, 28))	('JNK', 'Gene', '5599', (79, 82))	('ROR2', 'Gene', (10, 14))	('CCND1', 'Gene', (156, 161))	('JNK', 'molecular_function', 'GO:0004705', ('79', '82'))	('reduction', 'NegReg', (143, 152))	('CCND1', 'Gene', '595', (156, 161))	('Silencing', 'Var', (0, 9))	('JNK', 'Gene', (79, 82))	('NFATC1', 'Gene', (116, 122))	('reduction', 'NegReg', (66, 75))
60962	27440078	ROR2 knockdown did not result in significant changes to VIM, AXIN2 and CDH1 expression levels (Fig.	('ROR2', 'Gene', (0, 4))	('VIM', 'Gene', (56, 59))	('knockdown', 'Var', (5, 14))	('expression levels', 'MPA', (76, 93))	('CDH1', 'Gene', (71, 75))	('VIM', 'Gene', '7431', (56, 59))	('AXIN2', 'MPA', (61, 66))	('CDH1', 'Gene', '999', (71, 75))
60963	27440078	ROR2 silencing significantly increased the proliferation at HCT116 cells (P < 0.05) (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (60, 66))	('ROR2', 'Gene', (0, 4))	('silencing', 'Var', (5, 14))	('increased', 'PosReg', (29, 38))	('proliferation', 'CPA', (43, 56))
60966	27440078	Following ectopic ROR2 expression in RKO and SW620 cells, there was no significant change to cellular proliferation (Fig.	('ROR2', 'Gene', (18, 22))	('SW620', 'CellLine', 'CVCL:0547', (45, 50))	('ectopic', 'Var', (10, 17))
60972	27440078	Along with the methylation, there was also a corresponding loss of ROR2 expression in the adenoma samples, leading us to hypothesise that the observed downregulation was caused by epigenetic silencing through promoter hypermethylation.	('ROR2', 'Gene', (67, 71))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('expression', 'MPA', (72, 82))	('adenoma', 'Disease', 'MESH:D000236', (90, 97))	('downregulation', 'NegReg', (151, 165))	('epigenetic silencing', 'Var', (180, 200))	('adenoma', 'Disease', (90, 97))	('promoter hypermethylation', 'Var', (209, 234))	('loss', 'NegReg', (59, 63))
60975	27440078	Together, the clinical data along with the analysis and experimentation of cell lines provides strong evidence that epigenetic silencing of ROR2 through promoter hypermethylation occurs early in colorectal carcinogenesis.	('epigenetic silencing', 'Var', (116, 136))	('clinical', 'Species', '191496', (14, 22))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (195, 220))	('ROR2', 'Gene', (140, 144))	('promoter hypermethylation', 'Var', (153, 178))	('colorectal carcinogenesis', 'Disease', (195, 220))
60979	27440078	A likely explanation for this difference in findings may be the differences in the biological models used, as the previous publication which reported increased AXIN2 expression following ROR2 silencing used in vivo mouse models incorporating the tumour microenvironment.	('silencing', 'Var', (192, 201))	('tumour', 'Disease', (246, 252))	('ROR2', 'Gene', (187, 191))	('increased', 'PosReg', (150, 159))	('mouse', 'Species', '10090', (215, 220))	('tumour', 'Phenotype', 'HP:0002664', (246, 252))	('expression', 'MPA', (166, 176))	('AXIN2', 'Gene', (160, 165))	('tumour', 'Disease', 'MESH:D009369', (246, 252))
60980	27440078	It is possible that in our experiments on an immortal cancer cell line, the cellular and genetic context was significantly different and that the loss of ROR2 resulted in the activation of different signalling pathways.	('signalling pathways', 'Pathway', (199, 218))	('ROR2', 'Gene', (154, 158))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('activation', 'PosReg', (175, 185))	('loss', 'Var', (146, 150))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
60983	27440078	Although there was no observed upregulation in the beta-catenin dependent Wnt target genes following ROR2 knockdown as reported in the literature, our in vitro assays on HCT116 cells still revealed an increase in proliferation and migration.	('proliferation', 'CPA', (213, 226))	('increase', 'PosReg', (201, 209))	('beta-catenin', 'Gene', '1499', (51, 63))	('migration', 'CPA', (231, 240))	('knockdown', 'Var', (106, 115))	('ROR2', 'Gene', (101, 105))	('HCT116', 'CellLine', 'CVCL:0291', (170, 176))	('beta-catenin', 'Gene', (51, 63))
60984	27440078	The effect of ROR2 knockdown on cellular invasion was also investigated in HCT116 cells, with the results revealing a decrease in cellular invasion.	('HCT116', 'CellLine', 'CVCL:0291', (75, 81))	('cellular invasion', 'CPA', (130, 147))	('knockdown', 'Var', (19, 28))	('ROR2', 'Gene', (14, 18))	('decrease', 'NegReg', (118, 126))
60986	27440078	Analysis of gene expression also found no changes to the key EMT-related genes CDH1 and VIM following ROR2 knockdown, suggesting that invasion capacity in CRC only occurs later during disease progression.	('knockdown', 'Var', (107, 116))	('EMT', 'Gene', '3702', (61, 64))	('ROR2', 'Gene', (102, 106))	('CDH1', 'Gene', (79, 83))	('CRC', 'Phenotype', 'HP:0003003', (155, 158))	('CDH1', 'Gene', '999', (79, 83))	('VIM', 'Gene', (88, 91))	('EMT', 'biological_process', 'GO:0001837', ('61', '64'))	('gene expression', 'biological_process', 'GO:0010467', ('12', '27'))	('VIM', 'Gene', '7431', (88, 91))	('EMT', 'Gene', (61, 64))
60992	27440078	Although ~94 % of CRC cases possess a mutation in a Wnt pathway gene with APC being the gene most predominantly mutated, not all CRC cases arise from a dysfunctional Wnt signalling pathway.	('APC', 'Disease', 'MESH:D011125', (74, 77))	('APC', 'Disease', (74, 77))	('CRC', 'Phenotype', 'HP:0003003', (18, 21))	('Wnt pathway', 'Pathway', (52, 63))	('mutation', 'Var', (38, 46))	('arise from', 'Reg', (139, 149))	('CRC', 'Disease', (18, 21))	('CRC', 'Phenotype', 'HP:0003003', (129, 132))
60993	27440078	RKO cells do not have a mutant APC gene but they do have methylated MMR genes as well as possessing the CpG island methylator phenotype.	('MMR genes', 'Gene', (68, 77))	('APC', 'Disease', 'MESH:D011125', (31, 34))	('APC', 'Disease', (31, 34))	('APC', 'cellular_component', 'GO:0005680', ('31', '34'))	('MMR', 'biological_process', 'GO:0006298', ('68', '71'))	('methylated', 'Var', (57, 67))
60994	27440078	This suggests that RKO cells originally became carcinogenic through methylation and loss of function in MMR genes rather than through aberrant Wnt signalling.	('loss of function', 'NegReg', (84, 100))	('signalling', 'biological_process', 'GO:0023052', ('147', '157'))	('carcinogenic', 'Disease', 'MESH:D063646', (47, 59))	('methylation', 'Var', (68, 79))	('carcinogenic', 'Disease', (47, 59))	('MMR', 'biological_process', 'GO:0006298', ('104', '107'))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('MMR genes', 'Gene', (104, 113))
60995	27440078	In SW620 cells, the absence of any change in proliferation and migration following ectopic ROR2 expression may have been because the cell line originated from a secondary tumour site.	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('ROR2', 'Gene', (91, 95))	('tumour', 'Disease', 'MESH:D009369', (171, 177))	('tumour', 'Disease', (171, 177))	('SW620', 'CellLine', 'CVCL:0547', (3, 8))	('ectopic', 'Var', (83, 90))	('migration', 'CPA', (63, 72))
60996	27440078	SW620 and SW480 cells originated from the same patient with SW620 cells obtained from a lymph node metastasis while SW480 were from the primary tumour.	('patient', 'Species', '9606', (47, 54))	('SW480', 'CellLine', 'CVCL:0546', (116, 121))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('SW620', 'Var', (60, 65))	('SW480', 'CellLine', 'CVCL:0546', (10, 15))	('SW620', 'CellLine', 'CVCL:0547', (60, 65))	('SW620', 'CellLine', 'CVCL:0547', (0, 5))	('tumour', 'Disease', (144, 150))
60997	27440078	Having already metastasised to a secondary site, SW620 cells would possess a markedly different genetic composition than that of a primary tumour and may be resistant to any functional effects resulting from restoration of expression in an early gene target such as ROR2.	('tumour', 'Disease', (139, 145))	('different', 'Reg', (86, 95))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('SW620', 'CellLine', 'CVCL:0547', (49, 54))	('ROR2', 'Gene', (266, 270))	('SW620', 'Var', (49, 54))	('tumour', 'Disease', 'MESH:D009369', (139, 145))
60998	27440078	This is a potential issue for all cell line models as they are cancer cells that are different to the colorectal adenomas in which we believe ROR2 methylation and expression loss first occurs.	('methylation', 'biological_process', 'GO:0032259', ('147', '158'))	('colorectal adenomas', 'Disease', (102, 121))	('colorectal adenomas', 'Disease', 'MESH:D015179', (102, 121))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('ROR2', 'Gene', (142, 146))	('methylation', 'Var', (147, 158))	('expression', 'MPA', (163, 173))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('loss', 'NegReg', (174, 178))	('cancer', 'Disease', (63, 69))
61003	27440078	Our study has found that ROR2 promoter hypermethylation and subsequent expression loss is an early event in CRC progression that first occurs in non-invasive adenomas.	('expression', 'MPA', (71, 81))	('ROR2', 'Gene', (25, 29))	('CRC', 'Phenotype', 'HP:0003003', (108, 111))	('adenomas', 'Disease', 'MESH:D000236', (158, 166))	('promoter hypermethylation', 'Var', (30, 55))	('CRC', 'Disease', (108, 111))	('adenomas', 'Disease', (158, 166))
61004	27440078	Although it was hypothesised that hyperactivation of the beta-catenin dependent Wnt signals was the cause, decreases in both beta-catenin dependent and independent genes following ROR2 knockdown suggested that the effects of ROR2 modulation are context dependent and that the observed effects on proliferation and migration may be influence by interactions with pathways other than beta-catenin dependent Wnt.	('proliferation', 'CPA', (296, 309))	('beta-catenin', 'Gene', (125, 137))	('beta-catenin', 'Gene', (382, 394))	('migration', 'CPA', (314, 323))	('decreases', 'NegReg', (107, 116))	('interactions', 'Interaction', (344, 356))	('beta-catenin', 'Gene', '1499', (382, 394))	('knockdown', 'Var', (185, 194))	('beta-catenin', 'Gene', '1499', (125, 137))	('hyperactivation', 'PosReg', (34, 49))	('ROR2', 'Gene', (180, 184))	('ROR2', 'Gene', (225, 229))	('beta-catenin', 'Gene', (57, 69))	('beta-catenin', 'Gene', '1499', (57, 69))
61006	27440078	Examination of ROR2 loss in a more adenoma like biological model instead of in cancer cell lines would also aide in determining if the silencing of the receptor promoted CRC progression.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('silencing', 'Var', (135, 144))	('adenoma', 'Disease', 'MESH:D000236', (35, 42))	('CRC', 'Disease', (170, 173))	('promoted', 'PosReg', (161, 169))	('CRC', 'Phenotype', 'HP:0003003', (170, 173))	('adenoma', 'Disease', (35, 42))	('loss', 'NegReg', (20, 24))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('ROR2', 'Gene', (15, 19))
61037	27440078	24 h after ROR2 siRNA transfection, knockdown and control HCT116 cells were lifted using 1x 0.5 % Trypsin EDTA and resuspended in 1 % FBS media to a concentration of 7 x 105 cells/ml.	('transfection', 'Var', (22, 34))	('HCT116', 'CellLine', 'CVCL:0291', (58, 64))	('media', 'Species', '1115375', (138, 143))	('FBS', 'Disease', 'MESH:D005198', (134, 137))	('EDTA', 'Chemical', 'MESH:D004492', (106, 110))	('FBS', 'Disease', (134, 137))
61052	25767680	Taken together, these results demonstrate that kahweol inhibits colorectal tumor cell growth by promoting apoptosis and suppressing HSP70 expression.	('HSP70', 'Gene', '3308', (132, 137))	('promoting', 'PosReg', (96, 105))	('suppressing', 'NegReg', (120, 131))	('apoptosis', 'CPA', (106, 115))	('inhibits', 'NegReg', (55, 63))	('colorectal tumor', 'Disease', (64, 80))	('cell growth', 'biological_process', 'GO:0016049', ('81', '92'))	('apoptosis', 'biological_process', 'GO:0097194', ('106', '115'))	('HSP70', 'Gene', (132, 137))	('expression', 'MPA', (138, 148))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('kahweol', 'Var', (47, 54))	('kahweol', 'Chemical', 'MESH:C053401', (47, 54))	('apoptosis', 'biological_process', 'GO:0006915', ('106', '115'))	('colorectal tumor', 'Disease', 'MESH:D015179', (64, 80))
61061	25767680	Although kahweol has been shown to induce apoptosis in human breast tumor cells, the underlying mechanism in colorectal cancer cells is not known.	('colorectal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast tumor', 'Phenotype', 'HP:0100013', (61, 73))	('human', 'Species', '9606', (55, 60))	('kahweol', 'Var', (9, 16))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('kahweol', 'Chemical', 'MESH:C053401', (9, 16))	('apoptosis', 'CPA', (42, 51))	('breast tumor', 'Disease', 'MESH:D001943', (61, 73))	('apoptosis', 'biological_process', 'GO:0097194', ('42', '51'))	('apoptosis', 'biological_process', 'GO:0006915', ('42', '51'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('breast tumor', 'Disease', (61, 73))
61091	25767680	To understand how kahweol suppresses the cell viability of HT-29 cells, we examined its effects on the expression levels of several key proteins involved in apoptosis.	('kahweol', 'Var', (18, 25))	('cell viability', 'CPA', (41, 55))	('kahweol', 'Chemical', 'MESH:C053401', (18, 25))	('suppresses', 'NegReg', (26, 36))	('HT-29 cells', 'CellLine', 'CVCL:0320', (59, 70))
61092	25767680	Kahweol increased the expression of activated caspase-3, a pro-apoptotic enzyme, and cleaved PARP in a concentration-dependent manner (Fig.	('PARP', 'Gene', '142', (93, 97))	('caspase-3', 'Gene', (46, 55))	('caspase-3', 'Gene', '836', (46, 55))	('increased', 'PosReg', (8, 17))	('cleaved', 'Var', (85, 92))	('PARP', 'Gene', (93, 97))	('expression', 'MPA', (22, 32))	('Kahweol', 'Chemical', 'MESH:C053401', (0, 7))
61110	25767680	In the present study, kahweol showed cytotoxicity in HT-29 colon cancer cells and exhibited increased activation of caspase-3 and concurrent suppression of anti-apoptotic components such as Bcl-2 and phosphorylated Akt in HT-29 cells.	('anti-apoptotic', 'CPA', (156, 170))	('HT-29 colon cancer', 'Disease', (53, 71))	('HT-29 colon cancer', 'Disease', 'MESH:D015179', (53, 71))	('Bcl-2', 'Gene', '596', (190, 195))	('suppression', 'NegReg', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('kahweol', 'Chemical', 'MESH:C053401', (22, 29))	('caspase-3', 'Gene', '836', (116, 125))	('caspase-3', 'Gene', (116, 125))	('HT-29 cells', 'CellLine', 'CVCL:0320', (222, 233))	('cytotoxicity', 'Disease', (37, 49))	('kahweol', 'Var', (22, 29))	('colon cancer', 'Phenotype', 'HP:0003003', (59, 71))	('Bcl-2', 'Gene', (190, 195))	('cytotoxicity', 'Disease', 'MESH:D064420', (37, 49))	('Akt', 'Gene', (215, 218))	('activation', 'PosReg', (102, 112))	('phosphorylated', 'Pathway', (200, 214))	('Akt', 'Gene', '207', (215, 218))
61111	25767680	Our results are consistent with previous reports that kahweol activates pro-apoptotic caspases, such as caspases 3/7 and 9, in human breast tumor cells and inhibits anti-apoptotic proteins, such as Bcl-2 and phosphorylated Akt, in human leukemia cells.	('Akt', 'Gene', (223, 226))	('caspases 3/7 and 9', 'Gene', '836;840;842', (104, 122))	('Bcl-2', 'Gene', '596', (198, 203))	('caspase', 'Gene', '842', (86, 93))	('human', 'Species', '9606', (231, 236))	('Akt', 'Gene', '207', (223, 226))	('activates', 'PosReg', (62, 71))	('anti-apoptotic', 'MPA', (165, 179))	('leukemia', 'Phenotype', 'HP:0001909', (237, 245))	('breast tumor', 'Disease', 'MESH:D001943', (133, 145))	('kahweol', 'Chemical', 'MESH:C053401', (54, 61))	('inhibits', 'NegReg', (156, 164))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('caspase', 'Gene', (104, 111))	('breast tumor', 'Phenotype', 'HP:0100013', (133, 145))	('human', 'Species', '9606', (127, 132))	('pro-apoptotic', 'MPA', (72, 85))	('leukemia', 'Disease', (237, 245))	('leukemia', 'Disease', 'MESH:D007938', (237, 245))	('caspase', 'Gene', (86, 93))	('breast tumor', 'Disease', (133, 145))	('Bcl-2', 'Gene', (198, 203))	('kahweol', 'Var', (54, 61))	('caspase', 'Gene', '842', (104, 111))
61113	25767680	Especially, HSP70 is often constitutively overexpressed in human colorectal cancer cells, and high expression of HSP70 is associated with resistance to chemotherapy.	('human', 'Species', '9606', (59, 64))	('HSP70', 'Gene', '3308', (12, 17))	('colorectal cancer', 'Phenotype', 'HP:0003003', (65, 82))	('associated with', 'Reg', (122, 137))	('HSP70', 'Gene', '3308', (113, 118))	('colorectal cancer', 'Disease', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('HSP70', 'Gene', (12, 17))	('resistance to chemotherapy', 'CPA', (138, 164))	('HSP70', 'Gene', (113, 118))	('high', 'Var', (94, 98))	('colorectal cancer', 'Disease', 'MESH:D015179', (65, 82))
61114	25767680	Furthermore, knockdown of HSP70 exhibited significant reduction in cell growth.	('cell growth', 'CPA', (67, 78))	('reduction', 'NegReg', (54, 63))	('HSP70', 'Gene', '3308', (26, 31))	('HSP70', 'Gene', (26, 31))	('knockdown', 'Var', (13, 22))	('cell growth', 'biological_process', 'GO:0016049', ('67', '78'))
61115	25767680	Both in vivo and in vitro animal studies showed that inhibition of HSP70 has antitumor effect against colon cancer.	('inhibition', 'Var', (53, 63))	('HSP70', 'Gene', '3308', (67, 72))	('colon cancer', 'Phenotype', 'HP:0003003', (102, 114))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colon cancer', 'Disease', 'MESH:D015179', (102, 114))	('colon cancer', 'Disease', (102, 114))	('HSP70', 'Gene', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
61120	25767680	This is consistent with previous reports that inhibition of HSP70 has antitumor effects against colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('inhibition', 'Var', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('HSP70', 'Gene', '3308', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('colon cancer', 'Phenotype', 'HP:0003003', (96, 108))	('colon cancer', 'Disease', 'MESH:D015179', (96, 108))	('tumor', 'Disease', (74, 79))	('HSP70', 'Gene', (60, 65))	('colon cancer', 'Disease', (96, 108))
61129	25767680	In conclusion, we have shown that kahweol significantly inhibits colorectal tumor cell growth by promoting apoptosis.	('kahweol', 'Var', (34, 41))	('colorectal tumor', 'Disease', 'MESH:D015179', (65, 81))	('kahweol', 'Chemical', 'MESH:C053401', (34, 41))	('promoting', 'PosReg', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('inhibits', 'NegReg', (56, 64))	('apoptosis', 'CPA', (107, 116))	('colorectal tumor', 'Disease', (65, 81))
61167	24886477	During follow-up of patients with liver disease, nodules >=1 cm were diagnosed as HCC based on the typical hallmarks (hyper-vascular in the arterial phase with washout in the portal, venous or delayed phases) from imaging studies, which included a combination of contrast-enhanced ultrasonography, 4-phase multi-detector computed tomography (CT), dynamic contrast-enhanced magnetic resonance imaging (MRI), and CT during hepatic arteriography and arterio-portography studies.	('liver disease', 'Disease', 'MESH:D008107', (34, 47))	('nodules', 'Var', (49, 56))	('HCC', 'Disease', (82, 85))	('hyper-vascular', 'Disease', (118, 132))	('patients', 'Species', '9606', (20, 28))	('hyper-vascular', 'Disease', 'MESH:D000783', (118, 132))	('HCC', 'Phenotype', 'HP:0001402', (82, 85))	('liver disease', 'Phenotype', 'HP:0001392', (34, 47))	('liver disease', 'Disease', (34, 47))
61202	24886477	The LCR was not different between HCC (68.2% +- 11.2%) vs. liver metastasis (68.3% +- 11.2%) in 70 patients with the higher BED10 >= 100 Gy (p = 0.96).	('BED10', 'Var', (124, 129))	('liver metastasis', 'Disease', 'MESH:D009362', (59, 75))	('liver metastasis', 'Disease', (59, 75))	('patients', 'Species', '9606', (99, 107))	('HCC', 'Phenotype', 'HP:0001402', (34, 37))
61203	24886477	The LCR was not different between BED10 >= 100 Gy (68.3% +- 11.2%) vs. < 100 Gy (46.5% +- 16.9%) in 51 patients with liver metastasis (68.2% +- 11.2% vs. 79.2% +- 7.7%, p = 0.72) and in 79 patients with HCC (p = 0.43).	('liver metastasis', 'Disease', 'MESH:D009362', (117, 133))	('BED10 >= 100 Gy', 'Var', (34, 49))	('liver metastasis', 'Disease', (117, 133))	('patients', 'Species', '9606', (103, 111))	('patients', 'Species', '9606', (189, 197))	('HCC', 'Phenotype', 'HP:0001402', (203, 206))
61205	24886477	The LCR was not different between BED10 >= 100 Gy (66.2% +- 33.8%) vs. < 100 Gy (62.3% +- 12.6%) in 41 patients with the bigger tumor diameter > 30 mm (p = 0.78).	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('BED10 >= 100 Gy', 'Var', (34, 49))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('patients', 'Species', '9606', (103, 111))
61206	24886477	By multivariate analysis (Cox proportional hazards regression analysis), the maximum tumor diameter > 30 mm vs. <= 30 mm (other covariates were BED10 >= 100 Gy vs. <100 Gy of p = 0.70, age >70 y.o.	('tumor', 'Disease', (85, 90))	('BED10', 'Var', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
61272	33377061	Timing: 16 h and 30 min incubation Place 0.2 mL of 0.01% w/v poly-L-lysine on AFM-compatible glass bottom dishes.	('AFM', 'Gene', '173', (78, 81))	('AFM', 'Gene', (78, 81))	('poly-L-lysine', 'Var', (61, 74))	('poly-L-lysine', 'Chemical', '-', (61, 74))
61276	33377061	Pluronic will prevent the cantilever from attaching to the sample upon contact.	('Pluronic', 'Var', (0, 8))	('attaching', 'Interaction', (42, 51))	('Pluronic', 'Chemical', 'MESH:D020442', (0, 8))
61345	32388639	However, there is also a small body of evidence to suggest the dysregulated expression of some of these transporters may be linked to cancer metastasis.	('dysregulated', 'Var', (63, 75))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('linked', 'Reg', (124, 130))	('expression', 'MPA', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
61365	32388639	In the prostate, SLCO1A2 may play a role in the growth of prostate cancer cells through DHEA-S uptake suggesting that inhibition of this SLCO1A2 could help to attenuate tumour cell growth.	('prostate cancer', 'Disease', 'MESH:D011471', (58, 73))	('uptake', 'biological_process', 'GO:0098739', ('95', '101'))	('tumour', 'Disease', (169, 175))	('prostate cancer', 'Phenotype', 'HP:0012125', (58, 73))	('cell growth', 'biological_process', 'GO:0016049', ('176', '187'))	('DHEA-S uptake', 'MPA', (88, 101))	('prostate cancer', 'Disease', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('SLCO1A2', 'Gene', '6579', (17, 24))	('SLCO1A2', 'Gene', '6579', (137, 144))	('attenuate', 'NegReg', (159, 168))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('SLCO1A2', 'Gene', (17, 24))	('inhibition', 'Var', (118, 128))	('uptake', 'biological_process', 'GO:0098657', ('95', '101'))	('SLCO1A2', 'Gene', (137, 144))
61381	32388639	While it has been presumed that the SLCO1B3 gene detected in cancers was identical to that seen in the healthy liver, a cancer-specific variant, OATP1B3 V1, is now known to arise due to alternative splicing.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('alternative splicing', 'Var', (186, 206))	('SLCO1B3', 'Gene', (36, 43))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('SLCO1B3', 'Gene', '28234', (36, 43))	('cancers', 'Disease', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('OATP1B3', 'Gene', '28234', (145, 152))	('OATP1B3', 'Gene', (145, 152))
61393	32388639	The authors suggested that SLCO1B3 overexpression may be associated with a hormone-dependent growth mechanism and that expression of this transporter could be a potent prognostic factor in BC.	('overexpression', 'PosReg', (35, 49))	('SLCO1B3', 'Gene', '28234', (27, 34))	('expression', 'Var', (119, 129))	('BC', 'Phenotype', 'HP:0003002', (189, 191))	('SLCO1B3', 'Gene', (27, 34))	('associated', 'Reg', (57, 67))
61448	32388639	In the kidney, SLCO4C1 is localised to the basolateral membrane of proximal tubule cells where it facilitates excretion of exogenous drugs and endogenous compounds including methotrexate, thyroid hormones and E-3-S.	('facilitates', 'PosReg', (98, 109))	('excretion', 'biological_process', 'GO:0007588', ('110', '119'))	('methotrexate', 'MPA', (174, 186))	('thyroid hormones', 'MPA', (188, 204))	('SLCO4C1', 'Var', (15, 22))	('E-3-S', 'Chemical', 'MESH:C017296', (209, 214))	('methotrexate', 'Chemical', 'MESH:D008727', (174, 186))	('membrane', 'cellular_component', 'GO:0016020', ('55', '63'))	('excretion of exogenous drugs', 'MPA', (110, 138))
61462	32388639	In the cell lines, SLCO5A1 expression was 3-fold higher in MCF-7 cells than MCF-10A control cells.	('MCF-7', 'CellLine', 'CVCL:0031', (59, 64))	('SLCO5A1', 'Gene', (19, 26))	('expression', 'MPA', (27, 37))	('SLCO5A1', 'Gene', '81796', (19, 26))	('MCF-10A', 'CellLine', 'CVCL:0598', (76, 83))	('higher', 'PosReg', (49, 55))	('MCF-7', 'Var', (59, 64))
61482	32388639	In most of the cell lines, the levels of all three transporters were negligible; however, in MDA-MB-231, MDA-MB-468 and BT-549, their levels were relatively high.	('MDA-MB-468', 'CellLine', 'CVCL:0419', (105, 115))	('BT-549', 'CellLine', 'CVCL:1092', (120, 126))	('MDA-MB-468', 'Var', (105, 115))	('MDA-MB-231', 'Var', (93, 103))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (93, 103))	('levels', 'MPA', (134, 140))
61488	32388639	Expression of OCTN1 has however been linked to heightened sensitivity to mitoxantrone and doxorubicin.	('mitoxantrone', 'Chemical', 'MESH:D008942', (73, 85))	('Expression', 'Var', (0, 10))	('OCTN1', 'Gene', (14, 19))	('doxorubicin', 'Chemical', 'MESH:D004317', (90, 101))	('OCTN1', 'Gene', '6583', (14, 19))	('heightened', 'PosReg', (47, 57))	('sensitivity to mitoxantrone', 'MPA', (58, 85))
61506	32388639	High OAT2 expression is thought to be a predictor of good treatment response to 5-fluorouracil in colon cancer.	('High', 'Var', (0, 4))	('colon cancer', 'Phenotype', 'HP:0003003', (98, 110))	('OAT2', 'Gene', (5, 9))	('colon cancer', 'Disease', 'MESH:D015179', (98, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('OAT', 'molecular_function', 'GO:0004587', ('5', '8'))	('expression', 'MPA', (10, 20))	('OAT2', 'Gene', '10864', (5, 9))	('colon cancer', 'Disease', (98, 110))	('response to 5-fluorouracil', 'biological_process', 'GO:0036275', ('68', '94'))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (80, 94))
61510	32388639	In humans, disease mutation in the URAT1 gene leads to hereditary renal hypouricemia; however, association of URAT1 with cancer remains un-investigated.	('URAT1', 'Gene', (110, 115))	('mutation', 'Var', (19, 27))	('URAT1', 'Gene', (35, 40))	('URAT1', 'Gene', '116085', (110, 115))	('URAT1', 'Gene', '116085', (35, 40))	('hereditary renal hypouricemia', 'Disease', (55, 84))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('humans', 'Species', '9606', (3, 9))	('hypouricemia', 'Phenotype', 'HP:0003537', (72, 84))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('leads to', 'Reg', (46, 54))	('cancer', 'Disease', (121, 127))	('hereditary renal hypouricemia', 'Disease', 'MESH:C537757', (55, 84))
61532	32388639	Polymorphisms were also investigated for SLCO1B1 (CYP2D6*10, A388G, T521C) in 296 hormone receptor-positive invasive breast tumours following adjuvant tamoxifen (TAM) therapy and revealed that there was a significant difference in overall survival between T521C and A388G but no difference in overall survival between CYP2D6*10 and A388G.	('difference', 'Reg', (217, 227))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('T521C', 'Mutation', 'rs4149056', (68, 73))	('A388G', 'Var', (266, 271))	('A388G', 'Mutation', 'rs2306283', (61, 66))	('SLCO1B1', 'Gene', (41, 48))	('T521C', 'Var', (256, 261))	('invasive breast tumours', 'Disease', (108, 131))	('SLCO1B1', 'Gene', '10599', (41, 48))	('overall', 'MPA', (231, 238))	('CYP2D6', 'Gene', '1565', (318, 324))	('tamoxifen', 'Chemical', 'MESH:D013629', (151, 160))	('T521C', 'Mutation', 'rs4149056', (256, 261))	('CYP2D6', 'Gene', '1565', (50, 56))	('CYP2D6', 'Gene', (50, 56))	('CYP2D6', 'Gene', (318, 324))	('A388G', 'Mutation', 'rs2306283', (266, 271))	('TAM', 'Chemical', 'MESH:D013629', (162, 165))	('invasive breast tumours', 'Disease', 'MESH:D001943', (108, 131))	('breast tumour', 'Phenotype', 'HP:0100013', (117, 130))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('A388G', 'Mutation', 'rs2306283', (332, 337))
61535	32388639	Analysis revealed that combined high OATP1A2/high OCT6 may be a potential predictor of pathological good/complete response to anthracycline/taxane-based chemotherapy in breast cancer, especially in triple-negative tumours.	('high', 'Var', (32, 36))	('tumours', 'Phenotype', 'HP:0002664', (214, 221))	('OCT6', 'Gene', (50, 54))	('tumours', 'Disease', 'MESH:D009369', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('tumours', 'Disease', (214, 221))	('OCT6', 'Gene', '85413', (50, 54))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('taxane', 'Chemical', 'MESH:C080625', (140, 146))	('OATP1A2', 'Gene', '6579', (37, 44))	('anthracycline', 'Chemical', 'MESH:D018943', (126, 139))	('OATP1A2', 'Gene', (37, 44))	('breast cancer', 'Disease', (169, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
61551	32731534	TRIM24, TRIM28, TRIM33 and TRIM66 make up the transcriptional intermediary factor 1 (TIF1) family of chromatin-binding proteins, a subfamily of the large tripartite motif (TRIM) family of E3 ligases.	('TRIM28', 'Var', (8, 14))	('TRIM66', 'Gene', (27, 33))	('TRIM24', 'Var', (0, 6))	('chromatin', 'cellular_component', 'GO:0000785', ('101', '110'))	('chromatin-binding', 'molecular_function', 'GO:0003682', ('101', '118'))	('TIF1', 'Gene', '8805', (85, 89))	('TIF1', 'Gene', (85, 89))	('TRIM66', 'Gene', '9866', (27, 33))	('transcriptional intermediary factor 1', 'Gene', (46, 83))	('transcriptional intermediary factor 1', 'Gene', '8805', (46, 83))	('TRIM33', 'Var', (16, 22))
61555	32731534	Alternatively, if the damage is deemed irreparable, the DDR will promote apoptosis.	('apoptosis', 'CPA', (73, 82))	('DDR', 'Var', (56, 59))	('promote', 'PosReg', (65, 72))	('DDR', 'Chemical', '-', (56, 59))
61556	32731534	TRIM24 (TIF1alpha), TRIM28 (TIF1beta/KAP1), TRIM33 (TIF1gamma) and TRIM66 (TIF1delta) comprise the transcriptional intermediary family 1 (TIF1) family of chromatin-binding proteins, a subfamily of the large, highly conserved tripartite-motif (TRIM) family of E3 ligases.	('TIF1', 'Gene', (138, 142))	('TIF1', 'Gene', (52, 56))	('TIF1', 'Gene', (75, 79))	('TIF1beta', 'Gene', '8805', (28, 36))	('KAP1', 'Gene', '10155', (37, 41))	('TIF1', 'Gene', '8805', (28, 32))	('TIF1', 'Gene', '8805', (138, 142))	('TIF1', 'Gene', '8805', (52, 56))	('TIF1alpha', 'Gene', (8, 17))	('TIF1beta', 'Gene', (28, 36))	('TRIM33', 'Var', (44, 50))	('TIF1delta', 'Gene', '9866', (75, 84))	('TRIM24', 'Var', (0, 6))	('TIF1', 'Gene', '8805', (75, 79))	('TRIM66', 'Gene', (67, 73))	('TIF1delta', 'Gene', (75, 84))	('TIF1alpha', 'Gene', '8805', (8, 17))	('TIF1', 'Gene', (8, 12))	('KAP1', 'Gene', (37, 41))	('TRIM28', 'Var', (20, 26))	('TIF1gamma', 'Gene', '51592', (52, 61))	('TIF1gamma', 'Gene', (52, 61))	('TRIM66', 'Gene', '9866', (67, 73))	('TIF1', 'Gene', '8805', (8, 12))	('TIF1', 'Gene', (28, 32))
61557	32731534	All four TIF1 proteins have been shown to be aberrantly expressed or mutated in multiple cancer types; however, their role in cancer is still not fully understood.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('TIF1', 'Gene', '8805', (9, 13))	('mutated', 'Var', (69, 76))	('TIF1', 'Gene', (9, 13))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
61562	32731534	TRIM24, TRIM28 and TRIM33 are classified as the C-VI subfamily based on the presence of a plant-homeodomain (PHD) and bromodomain at the C-terminus.	('TRIM28', 'Var', (8, 14))	('PHD', 'Disease', 'MESH:D011547', (109, 112))	('PHD', 'Disease', (109, 112))	('PHD', 'molecular_function', 'GO:0050175', ('109', '112'))	('TRIM24', 'Var', (0, 6))	('bromodomain', 'Protein', (118, 129))	('TRIM33', 'Var', (19, 25))
61563	32731534	Together with TRIM66, which lacks a RING domain but similarly contains two B-boxes, a CC domain and a PHD-bromodomain, TRIM24, TRIM28 and TRIM33 can be alternatively classified as the TIF1 family of proteins.	('TRIM66', 'Gene', '9866', (14, 20))	('TIF1', 'Gene', '8805', (184, 188))	('TIF1', 'Gene', (184, 188))	('PHD', 'Disease', 'MESH:D011547', (102, 105))	('TRIM24', 'Var', (119, 125))	('PHD', 'Disease', (102, 105))	('TRIM28', 'Var', (127, 133))	('TRIM66', 'Gene', (14, 20))	('TRIM33', 'Var', (138, 144))
61566	32731534	Additionally, TRIM24, TRIM28 and TRIM66 have HP1 (heterochromatin protein 1) binding domains (HPBD) which allow the interaction of HP1 family proteins through a PxVxL motif.	('HP1', 'Gene', '23468', (131, 134))	('HP1', 'Gene', (131, 134))	('TRIM66', 'Gene', '9866', (33, 39))	('heterochromatin protein 1', 'Gene', '23468', (50, 75))	('TRIM28', 'Var', (22, 28))	('heterochromatin protein 1', 'Gene', (50, 75))	('TRIM24', 'Var', (14, 20))	('HP1', 'Gene', '23468', (45, 48))	('binding', 'Interaction', (77, 84))	('TRIM66', 'Gene', (33, 39))	('HP1', 'Gene', (45, 48))	('interaction', 'Interaction', (116, 127))
61568	32731534	Members of the TIF1 family are often dysregulated in human cancers, most commonly through altered gene expression, but also through deletions, translocations or loss-of-function mutations.	('TIF1', 'Gene', '8805', (15, 19))	('gene expression', 'biological_process', 'GO:0010467', ('98', '113'))	('dysregulated', 'Reg', (37, 49))	('altered', 'Reg', (90, 97))	('cancers', 'Disease', (59, 66))	('loss-of-function', 'NegReg', (161, 177))	('deletions', 'Var', (132, 141))	('TIF1', 'Gene', (15, 19))	('gene expression', 'MPA', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('human', 'Species', '9606', (53, 58))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('translocations', 'Var', (143, 157))	('mutations', 'Var', (178, 187))
61572	32731534	Overexpression of TRIM24 is predominantly associated with cancer progression, inferring an oncogenic function.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('associated', 'Reg', (42, 52))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', (58, 64))	('TRIM24', 'Gene', (18, 24))
61573	32731534	High expression of TRIM24 has been associated with a higher tumour grade in prostate cancer and was proposed to be an independent biomarker for prognosis.	('higher', 'PosReg', (53, 59))	('High', 'Var', (0, 4))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('tumour', 'Disease', (60, 66))	('TRIM24', 'Gene', (19, 25))	('prostate cancer', 'Disease', (76, 91))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
61574	32731534	Similarly, overexpression was observed in head and neck squamous cell carcinoma, glioblastoma, nasopharyngeal carcinoma and human cervical cancer, with high expression being associated with a more aggressive phenotype and tumour progression.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('neck', 'cellular_component', 'GO:0044326', ('51', '55'))	('associated', 'Reg', (174, 184))	('overexpression', 'PosReg', (11, 25))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (42, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('glioblastoma', 'Disease', 'MESH:D005909', (81, 93))	('carcinoma', 'Disease', (70, 79))	('carcinoma', 'Disease', (110, 119))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (95, 119))	('tumour', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Disease', (139, 145))	('tumour', 'Disease', 'MESH:D009369', (222, 228))	('glioblastoma', 'Disease', (81, 93))	('neck squamous cell carcinoma', 'Disease', (51, 79))	('tumour', 'Disease', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (51, 79))	('human', 'Species', '9606', (124, 129))	('glioblastoma', 'Phenotype', 'HP:0012174', (81, 93))	('carcinoma', 'Disease', 'MESH:D009369', (70, 79))	('high', 'Var', (152, 156))	('carcinoma', 'Disease', 'MESH:D009369', (110, 119))
61576	32731534	Contrastingly, TRIM24 was reported to act as a tumour suppressor in murine hepatocellular carcinoma (HCC) by dysregulating retinoic acid receptor (RAR) signalling, and it was later shown that TRIM24, TRIM28 and TRIM33 can form regulatory complexes to suppress murine HCC.	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('TRIM24', 'Var', (15, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('HCC', 'Phenotype', 'HP:0001402', (101, 104))	('TRIM24', 'Var', (192, 198))	('tumour', 'Disease', (47, 53))	('murine', 'Species', '10090', (260, 266))	('murine', 'Species', '10090', (68, 74))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (75, 99))	('HCC', 'Phenotype', 'HP:0001402', (267, 270))	('hepatocellular carcinoma', 'Disease', (75, 99))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (75, 99))	('suppress', 'NegReg', (251, 259))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('TRIM33', 'Var', (211, 217))
61581	32731534	Conversely, loss-of-function TRIM28 mutations can predispose children to Wilms' tumour, the most common type of renal cancer in paediatrics, suggesting a tumour suppressor role in this context.	('tumour', 'Disease', (80, 86))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	("Wilms' tumour", 'Disease', 'MESH:D009396', (73, 86))	('renal cancer', 'Phenotype', 'HP:0009726', (112, 124))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('TRIM28', 'Gene', (29, 35))	('mutations', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', (154, 160))	("Wilms' tumour", 'Disease', (73, 86))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('type of renal cancer', 'Disease', (104, 124))	('loss-of-function', 'NegReg', (12, 28))	('children', 'Species', '9606', (61, 69))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	("Wilms' tumour", 'Phenotype', 'HP:0002667', (73, 86))	('type of renal cancer', 'Disease', 'MESH:D007680', (104, 124))
61584	32731534	reported that in the early stages of lung cancer, TRIM28 expression was associated with better overall survival and reduced proliferation in vitro.	('lung cancer', 'Disease', (37, 48))	('better', 'PosReg', (88, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('overall survival', 'CPA', (95, 111))	('TRIM28 expression', 'Var', (50, 67))	('proliferation in vitro', 'CPA', (124, 146))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('reduced', 'NegReg', (116, 123))
61586	32731534	As mentioned above, TRIM33 acts in conjunction with TRIM24 and TRIM28 to inhibit murine HCC.	('TRIM33', 'Var', (20, 26))	('murine', 'MPA', (81, 87))	('murine', 'Species', '10090', (81, 87))	('HCC', 'Phenotype', 'HP:0001402', (88, 91))	('inhibit', 'NegReg', (73, 80))
61587	32731534	reported that low TRIM33 expression is associated with increased genomic instability and subsequent cancer progression across multiple cancer types, including breast, pancreatic adenocarcinomas and clear cell renal cell carcinoma.	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (167, 193))	('increased', 'PosReg', (55, 64))	('genomic instability', 'MPA', (65, 84))	('associated', 'Reg', (39, 49))	('TRIM33', 'Protein', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', (135, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('expression', 'MPA', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (209, 229))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (198, 229))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('breast', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('pancreatic adenocarcinomas and clear cell renal cell carcinoma', 'Disease', 'MESH:D008649', (167, 229))	('low', 'Var', (14, 17))
61589	32731534	However, in another study, patients with high TRIM33 showed poorer progression-free survival, indicating that there may be a diverse role for TRIM33 in breast cancer.	('poorer', 'NegReg', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('high TRIM33', 'Var', (41, 52))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('patients', 'Species', '9606', (27, 35))	('breast cancer', 'Disease', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('progression-free survival', 'CPA', (67, 92))
61599	32731534	Furthermore, in vitro studies have further shown that knockdown of TRIM66 reduces the proliferation of NSCLC, colorectal, HCC and prostate cancers, indicating an oncogenic role.	('colorectal', 'Disease', (110, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (130, 145))	('knockdown', 'Var', (54, 63))	('TRIM66', 'Gene', '9866', (67, 73))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('NSCLC', 'Disease', (103, 108))	('reduces', 'NegReg', (74, 81))	('prostate cancers', 'Phenotype', 'HP:0012125', (130, 146))	('proliferation', 'CPA', (86, 99))	('prostate cancers', 'Disease', (130, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('HCC', 'Disease', (122, 125))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('HCC', 'Phenotype', 'HP:0001402', (122, 125))	('TRIM66', 'Gene', (67, 73))	('prostate cancers', 'Disease', 'MESH:D011471', (130, 146))
61602	32731534	However, double-strand breaks (DSBs), although less common, are much more toxic, as they can enable genomic rearrangement and are more complex to repair.	('genomic rearrangement', 'CPA', (100, 121))	('double-strand breaks', 'Var', (9, 29))	('DSBs', 'Chemical', '-', (31, 35))	('enable', 'PosReg', (93, 99))
61610	32731534	ATM has hundreds of other substrates, including histone variant H2AX at serine 139 (gammaH2AX), Chk2, topoisomerase II binding protein 1 (TopB1), breast cancer 1 early onset (BRCA1), TRIM24 and TRIM28.	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('topoisomerase II', 'molecular_function', 'GO:0003918', ('102', '118'))	('ATM', 'Gene', (0, 3))	('Chk2', 'Gene', (96, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('H2AX', 'Gene', (64, 68))	('H2AX', 'Gene', (89, 93))	('BRCA1', 'Gene', '672', (175, 180))	('variant', 'Var', (56, 63))	('BRCA1', 'Gene', (175, 180))	('gammaH2AX', 'Chemical', '-', (84, 93))	('H2AX', 'Gene', '3014', (64, 68))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('serine', 'Chemical', 'MESH:D012694', (72, 78))	('breast cancer', 'Disease', (146, 159))	('H2AX', 'Gene', '3014', (89, 93))	('binding', 'molecular_function', 'GO:0005488', ('119', '126'))	('protein', 'cellular_component', 'GO:0003675', ('127', '134'))	('Chk2', 'Gene', '11200', (96, 100))	('ATM', 'Gene', '472', (0, 3))
61613	32731534	ATR phosphorylates and activates Chk1, which in turn phosphorylates Cdc25a and promotes G2/M and intra-S checkpoints.	('Chk1', 'Gene', (33, 37))	('Chk1', 'Gene', '1111', (33, 37))	('ATR', 'Gene', '545', (0, 3))	('ATR', 'Gene', (0, 3))	('activates', 'PosReg', (23, 32))	('promotes', 'PosReg', (79, 87))	('Cdc25a', 'Gene', '993', (68, 74))	('intra-S checkpoints', 'CPA', (97, 116))	('phosphorylates', 'Var', (53, 67))	('G2/M', 'CPA', (88, 92))	('Cdc25a', 'Gene', (68, 74))
61616	32731534	performed a screen of 32 human bromodomain-containing proteins in which TRIM24, TRIM28 and TRIM33 were all shown to localise to sites of damage in the osteosarcoma cell line U2OS after laser microirradiation.	('TRIM28', 'Var', (80, 86))	('osteosarcoma', 'Disease', (151, 163))	('U2OS', 'CellLine', 'CVCL:0042', (174, 178))	('osteosarcoma', 'Phenotype', 'HP:0002669', (151, 163))	('osteosarcoma', 'Disease', 'MESH:D012516', (151, 163))	('human', 'Species', '9606', (25, 30))	('TRIM24', 'Var', (72, 78))	('TRIM33', 'Var', (91, 97))
61617	32731534	Further studies revealed that depletion of each of the four TIF1 proteins reduced the efficiency of HR repair with little impact on NHEJ, increased basal levels of gammaH2AX and increased the frequency of micronuclei, suggesting that they play a key role in orchestrating the DDR.	('increased', 'PosReg', (138, 147))	('efficiency', 'MPA', (86, 96))	('TIF1', 'Gene', '8805', (60, 64))	('proteins', 'Protein', (65, 73))	('depletion', 'Var', (30, 39))	('TIF1', 'Gene', (60, 64))	('gammaH2AX', 'Protein', (164, 173))	('HR repair', 'CPA', (100, 109))	('DDR', 'Chemical', '-', (276, 279))	('gammaH2AX', 'Chemical', '-', (164, 173))	('micronuclei', 'CPA', (205, 216))	('reduced', 'NegReg', (74, 81))	('increased', 'PosReg', (178, 187))
61618	32731534	In this study, TRIM28 deacetylation enhanced TRIM28 interaction with 53BP1, thus promoting NHEJ.	('deacetylation', 'Var', (22, 35))	('interaction', 'Interaction', (52, 63))	('TRIM28', 'Protein', (45, 51))	('53BP1', 'Gene', (69, 74))	('TRIM28', 'Gene', (15, 21))	('53BP1', 'Gene', '7158', (69, 74))	('enhanced', 'PosReg', (36, 44))	('promoting', 'PosReg', (81, 90))	('NHEJ', 'Disease', (91, 95))
61620	32731534	Although TRIM24, TRIM28 and TRIM33 can bind to form a complex to suppress HCC, there is currently no evidence that the three proteins work together during the DDR.	('HCC', 'Disease', (74, 77))	('DDR', 'Chemical', '-', (159, 162))	('TRIM33', 'Var', (28, 34))	('HCC', 'Phenotype', 'HP:0001402', (74, 77))	('TRIM24', 'Var', (9, 15))	('suppress', 'NegReg', (65, 73))
61626	32731534	Furthermore, shRNA knockdown of TRIM33 in HeLa cells lead to increased basal gammaH2AX, phosphorylated Chk2 and heightened sensitivity to bleomycin, a chemotherapeutic agent that induces single and double strand DNA breaks.	('gammaH2AX', 'Protein', (77, 86))	('knockdown', 'Var', (19, 28))	('bleomycin', 'Chemical', 'MESH:D001761', (138, 147))	('gammaH2AX', 'Chemical', '-', (77, 86))	('sensitivity to bleomycin', 'MPA', (123, 147))	('increased', 'PosReg', (61, 70))	('phosphorylated', 'MPA', (88, 102))	('Chk2', 'Gene', '11200', (103, 107))	('heightened', 'PosReg', (112, 122))	('HeLa', 'CellLine', 'CVCL:0030', (42, 46))	('Chk2', 'Gene', (103, 107))	('TRIM33', 'Gene', (32, 38))
61627	32731534	Similarly, we have shown that multiple myeloma cell lines with low TRIM33 expression have higher endogenous DNA damage as assessed by gammaH2AX levels.	('expression', 'MPA', (74, 84))	('multiple myeloma', 'Phenotype', 'HP:0006775', (30, 46))	('DNA', 'cellular_component', 'GO:0005574', ('108', '111'))	('endogenous DNA damage', 'MPA', (97, 118))	('TRIM33', 'Gene', (67, 73))	('myeloma', 'Disease', (39, 46))	('gammaH2AX levels', 'MPA', (134, 150))	('gammaH2AX', 'Chemical', '-', (134, 143))	('myeloma', 'Disease', 'MESH:D009101', (39, 46))	('low', 'Var', (63, 66))	('higher', 'PosReg', (90, 96))
61629	32731534	Contrastingly, in colorectal cancer cells knockdown of TRIM33 did not affect gammaH2AX levels, highlighting the cell-type specificity of TIF1 protein function.	('colorectal cancer', 'Disease', 'MESH:D015179', (18, 35))	('protein', 'cellular_component', 'GO:0003675', ('142', '149'))	('gammaH2AX levels', 'MPA', (77, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (18, 35))	('TIF1', 'Gene', '8805', (137, 141))	('gammaH2AX', 'Chemical', '-', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('colorectal cancer', 'Disease', (18, 35))	('TRIM33', 'Gene', (55, 61))	('TIF1', 'Gene', (137, 141))	('knockdown', 'Var', (42, 51))
61630	32731534	Although TRIM66 was not reported to localise to sites of DNA damage following laser microirradation, siRNA knockdown of TRIM66 reduced the efficiency of HR repair in U2OS cells, although to a lesser extent than that of TRIM24, TRIM28 and TRIM33.	('knockdown', 'Var', (107, 116))	('TRIM66', 'Gene', '9866', (9, 15))	('TRIM66', 'Gene', (120, 126))	('TRIM66', 'Gene', '9866', (120, 126))	('HR repair', 'CPA', (153, 162))	('U2OS', 'CellLine', 'CVCL:0042', (166, 170))	('TRIM66', 'Gene', (9, 15))	('reduced', 'NegReg', (127, 134))	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))
61631	32731534	In embryonic stem cells (ESCs) both shRNA knockdown and CRISPR/Cas9-mediated knockout of TRIM66 resulted in elevated basal DNA damage and genome instability as determined by gammaH2AX and Rad51 foci, comet assays and chromosome metaphase spreads.	('TRIM66', 'Gene', (89, 95))	('knockout', 'Var', (77, 85))	('Rad51', 'Gene', '5888', (188, 193))	('gammaH2AX', 'Chemical', '-', (174, 183))	('TRIM66', 'Gene', '9866', (89, 95))	('elevated', 'PosReg', (108, 116))	('Rad51', 'Gene', (188, 193))	('genome instability', 'CPA', (138, 156))	('basal DNA damage', 'CPA', (117, 133))
61633	32731534	Phosphorylation of TRIM28 at sites of DNA damage is an early event in the DDR and is mainly associated with the repair of DSBs in heterochromatin (Figure 2).	('DDR', 'Disease', (74, 77))	('DSBs', 'Var', (122, 126))	('heterochromatin', 'cellular_component', 'GO:0000792', ('130', '145'))	('Phosphorylation', 'MPA', (0, 15))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('DSBs', 'Chemical', '-', (122, 126))	('DDR', 'Chemical', '-', (74, 77))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('associated', 'Reg', (92, 102))	('TRIM28', 'Protein', (19, 25))
61634	32731534	described phosphorylation of TRIM28 at Ser824 in U2OS cells within 5 min of 9 Gy irradiation, which was diminished within 4 h. This study proposed that ATM, ATR and DNA-PKcs could mediate Ser824 phosphorylation.	('ATM', 'Gene', (152, 155))	('Ser824', 'Chemical', '-', (39, 45))	('phosphorylation', 'biological_process', 'GO:0016310', ('10', '25'))	('ATR', 'Gene', '545', (157, 160))	('ATR', 'Gene', (157, 160))	('Ser824', 'Chemical', '-', (188, 194))	('U2OS', 'CellLine', 'CVCL:0042', (49, 53))	('phosphorylation', 'biological_process', 'GO:0016310', ('195', '210'))	('ATM', 'Gene', '472', (152, 155))	('phosphorylation', 'MPA', (195, 210))	('DNA-PKcs', 'Gene', '5591', (165, 173))	('DNA', 'cellular_component', 'GO:0005574', ('165', '168'))	('Ser', 'cellular_component', 'GO:0005790', ('188', '191'))	('Ser', 'cellular_component', 'GO:0005790', ('39', '42'))	('Ser824', 'Var', (188, 194))	('DNA-PKcs', 'Gene', (165, 173))
61635	32731534	However, multiple groups have identified TRIM28-Ser824 to mainly be a substrate of ATM.	('Ser824', 'Chemical', '-', (48, 54))	('ATM', 'Gene', '472', (83, 86))	('TRIM28-Ser824', 'Var', (41, 54))	('ATM', 'Gene', (83, 86))
61636	32731534	TRIM28-Ser824 phosphorylation co-localised with the DDR proteins 53BP1, gammaH2AX, BRCA1 and TopBP1, and 53BP1 is required for formation of phosphorylated TRIM28 foci.	('53BP1', 'Gene', (105, 110))	('53BP1', 'Gene', '7158', (105, 110))	('TopBP1', 'Gene', '11073', (93, 99))	('BRCA1', 'Gene', '672', (83, 88))	('53BP1', 'Gene', (65, 70))	('53BP1', 'Gene', '7158', (65, 70))	('BRCA1', 'Gene', (83, 88))	('DDR', 'Chemical', '-', (52, 55))	('Ser824', 'Chemical', '-', (7, 13))	('TopBP1', 'Gene', (93, 99))	('gammaH2AX', 'Chemical', '-', (72, 81))	('TRIM28-Ser824', 'Var', (0, 13))
61640	32731534	In addition, TRIM28 is also phosphorylated at Ser473 in response to DNA damage, which is required for efficient DNA repair.	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('Ser473', 'Var', (46, 52))	('Ser473', 'Chemical', '-', (46, 52))	('response to DNA damage', 'MPA', (56, 78))	('Ser', 'cellular_component', 'GO:0005790', ('46', '49'))	('DNA', 'cellular_component', 'GO:0005574', ('112', '115'))	('DNA repair', 'biological_process', 'GO:0006281', ('112', '122'))
61641	32731534	first identified TRIM28-Ser473 as a DNA damage-induced substrate of Chk1 and Hu et al.	('Ser473', 'Chemical', '-', (24, 30))	('Chk1', 'Gene', '1111', (68, 72))	('Chk1', 'Gene', (68, 72))	('TRIM28-Ser473', 'Var', (17, 30))
61642	32731534	reported that Chk1 is indeed responsible for the phosphorylation of TRIM28-Ser473 in response to UV radiation.	('Ser', 'cellular_component', 'GO:0005790', ('75', '78'))	('responsible', 'Reg', (29, 40))	('response to UV', 'biological_process', 'GO:0009411', ('85', '99'))	('Chk1', 'Gene', (14, 18))	('Ser473', 'Chemical', '-', (75, 81))	('TRIM28-Ser473', 'Var', (68, 81))	('phosphorylation', 'biological_process', 'GO:0016310', ('49', '64'))	('phosphorylation', 'MPA', (49, 64))	('Chk1', 'Gene', '1111', (14, 18))	('response to UV radiation', 'MPA', (85, 109))
61644	32731534	Furthermore, protein kinase C-delta (PKCdelta) can also phosphorylate TRIM28 at Ser473.	('Ser473', 'Chemical', '-', (80, 86))	('Ser', 'cellular_component', 'GO:0005790', ('80', '83'))	('protein kinase C-delta', 'Enzyme', (13, 35))	('PKCdelta', 'Gene', (37, 45))	('protein', 'cellular_component', 'GO:0003675', ('13', '20'))	('PKCdelta', 'Gene', '5580', (37, 45))	('PKCdelta', 'molecular_function', 'GO:0004697', ('37', '45'))	('Ser473', 'Var', (80, 86))
61645	32731534	Although phosphorylation of both TRIM28-Ser824 and Ser473 are observed during the DDR, their functions are independent of each other.	('phosphorylation', 'biological_process', 'GO:0016310', ('9', '24'))	('Ser824', 'Chemical', '-', (40, 46))	('Ser473', 'Chemical', '-', (51, 57))	('Ser473', 'Var', (51, 57))	('Ser', 'cellular_component', 'GO:0005790', ('40', '43'))	('DDR', 'Disease', (82, 85))	('TRIM28-Ser824', 'Var', (33, 46))	('Ser', 'cellular_component', 'GO:0005790', ('51', '54'))	('DDR', 'Chemical', '-', (82, 85))	('phosphorylation', 'MPA', (9, 24))
61659	32731534	DSBs promote methylation of H3K9, and H3K9me3 is concentrated within heterochromatin, which is associated with gene repression.	('methylation', 'MPA', (13, 24))	('promote', 'PosReg', (5, 12))	('DSBs', 'Var', (0, 4))	('H3K9', 'Protein', (28, 32))	('DSBs', 'Chemical', '-', (0, 4))
61662	32731534	Furthermore, TRIM28 is known to mediate gene silencing through its interaction with the methyltransferase SETDB1, which specifically tri-methylates H3K9.	('tri-methylates', 'Var', (133, 147))	('SETDB1', 'Gene', (106, 112))	('gene', 'MPA', (40, 44))	('gene silencing', 'biological_process', 'GO:0016458', ('40', '54'))	('TRIM28', 'Var', (13, 19))	('interaction', 'Interaction', (67, 78))	('SETDB1', 'Gene', '9869', (106, 112))	('H3K9', 'Protein', (148, 152))
61664	32731534	Furthermore, ablation of the phosphorylation site Ser824 on TRIM28 leads to loss of chromatin relaxation and the inability to repair DSBs.	('Ser824', 'Chemical', '-', (50, 56))	('loss', 'NegReg', (76, 80))	('ablation', 'Var', (13, 21))	('DSBs', 'Chemical', '-', (133, 137))	('inability', 'NegReg', (113, 122))	('Ser824', 'Var', (50, 56))	('TRIM28', 'Gene', (60, 66))	('chromatin relaxation', 'MPA', (84, 104))
61668	32731534	Upon irradiation, TRIM28-Ser824 is phosphorylated and interrupts CHD3-SUMO1 interaction, resulting in the dispersion of CHD3 from TRIM28, promoting chromatin relaxation and heterochromatic DNA repair.	('chromatin', 'cellular_component', 'GO:0000785', ('148', '157'))	('interrupts', 'NegReg', (54, 64))	('TRIM28-Ser824', 'Var', (18, 31))	('promoting', 'PosReg', (138, 147))	('interaction', 'Interaction', (76, 87))	('SUMO1', 'Gene', '7341', (70, 75))	('Ser824', 'Chemical', '-', (25, 31))	('DNA', 'cellular_component', 'GO:0005574', ('189', '192'))	('CHD3', 'Gene', (120, 124))	('heterochromatic DNA repair', 'CPA', (173, 199))	('dispersion', 'MPA', (106, 116))	('Ser', 'cellular_component', 'GO:0005790', ('25', '28'))	('SUMO1', 'Gene', (70, 75))	('chromatin', 'CPA', (148, 157))	('CHD3', 'Gene', '1107', (120, 124))	('CHD3', 'Gene', (65, 69))	('DNA repair', 'biological_process', 'GO:0006281', ('189', '199'))	('CHD3', 'Gene', '1107', (65, 69))
61669	32731534	TRIM28 can also from a complex with the histone deacetylase HDAC1 to inhibit viral HIV-1 integration.	('HDAC1', 'Gene', (60, 65))	('TRIM28', 'Var', (0, 6))	('HDAC1', 'Gene', '3065', (60, 65))	('inhibit', 'NegReg', (69, 76))	('HIV-1', 'Species', '11676', (83, 88))
61670	32731534	In U2OS cells and human fibroblasts, depletion of TRIM28 resulted in global hyperacetylation of H4.	('depletion', 'Var', (37, 46))	('U2OS', 'CellLine', 'CVCL:0042', (3, 7))	('human', 'Species', '9606', (18, 23))	('hyperacetylation', 'MPA', (76, 92))	('TRIM28', 'Gene', (50, 56))
61674	32731534	The bromodomain of TRIM66 recognises H3K56ac at damaged sites, recruits the deacetylase Sirt6 to chromatin and thus activates the DDR (Figure 3).	('Sirt6', 'Gene', (88, 93))	('DDR', 'MPA', (130, 133))	('chromatin', 'cellular_component', 'GO:0000785', ('97', '106'))	('DDR', 'Chemical', '-', (130, 133))	('H3K56ac', 'Var', (37, 44))	('TRIM66', 'Gene', '9866', (19, 25))	('Sirt6', 'Gene', '51548', (88, 93))	('activates', 'PosReg', (116, 125))	('recruits', 'PosReg', (63, 71))	('TRIM66', 'Gene', (19, 25))
61676	32731534	Together, this proposes the model that TRIM66 is a dual reader of H3K56ac and unmodified H3R2K4, upon damage, to recruit Sirt6 and ultimately maintain genome stability through histone deacetylation.	('TRIM66', 'Gene', '9866', (39, 45))	('genome stability', 'MPA', (151, 167))	('H3K56ac', 'Var', (66, 73))	('maintain', 'PosReg', (142, 150))	('Sirt6', 'Gene', '51548', (121, 126))	('histone deacetylation', 'MPA', (176, 197))	('recruit', 'PosReg', (113, 120))	('Sirt6', 'Gene', (121, 126))	('TRIM66', 'Gene', (39, 45))
61678	32731534	Currently, it is unclear if TRIM24 and TRIM33 can read histone marks or recruit chromatin remodellers specifically in response to DNA lesions like their family members TRIM28 and TRIM66.	('TRIM28', 'Var', (168, 174))	('TRIM66', 'Gene', '9866', (179, 185))	('TRIM66', 'Gene', (179, 185))
61680	32731534	TRIM24 also interacts with HDAC1 to suppress HCC and interacts with other histone marks such as H3K9ac, H3K14ac, H3K27ac and H4ac in breast cancer.	('HCC', 'Phenotype', 'HP:0001402', (45, 48))	('HCC', 'MPA', (45, 48))	('HDAC1', 'Gene', '3065', (27, 32))	('H4ac', 'Var', (125, 129))	('breast cancer', 'Disease', (133, 146))	('H3K14ac', 'Var', (104, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('suppress', 'NegReg', (36, 44))	('TRIM24', 'Var', (0, 6))	('interacts', 'Reg', (53, 62))	('HDAC1', 'Gene', (27, 32))	('H3K9ac', 'Var', (96, 102))	('H3K27ac', 'Var', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
61682	32731534	This was discovered in the context of ESCs, where it was shown that TRIM33 can displace HP1 to bind H3K9me3 in order to allow mesodermal differentiation.	('allow', 'Reg', (120, 125))	('mesodermal differentiation', 'CPA', (126, 152))	('HP1', 'Gene', '23468', (88, 91))	('TRIM33', 'Var', (68, 74))	('HP1', 'Gene', (88, 91))	('H3K9me3', 'Protein', (100, 107))	('bind', 'Interaction', (95, 99))
61687	32731534	However, the regulation of histone modifications by TIF1 members TRIM33 and TRIM24 during the DDR remains unknown.	('TIF1', 'Gene', (52, 56))	('DDR', 'Chemical', '-', (94, 97))	('regulation', 'biological_process', 'GO:0065007', ('13', '23'))	('TRIM33', 'Var', (65, 71))	('TRIM24', 'Var', (76, 82))	('TIF1', 'Gene', '8805', (52, 56))
61689	32731534	Such defects result in cell cycle arrest until the defect is repaired, or if irreparable result in cell death.	('arrest', 'Disease', (34, 40))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (23, 40))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('23', '40'))	('defects', 'Var', (5, 12))	('death', 'Disease', 'MESH:D003643', (104, 109))	('death', 'Disease', (104, 109))	('arrest', 'Disease', 'MESH:D006323', (34, 40))	('result in', 'Reg', (13, 22))	('cell death', 'biological_process', 'GO:0008219', ('99', '109'))
61690	32731534	In response to DNA damage, Chk2 and p53 can arrest cells in G1 phase (G1/S checkpoint), or Chk1 can do so in S or G2 phase (Intra-S checkpoint and G2/M checkpoints, respectively).	('G1 phase', 'CPA', (60, 68))	('Chk1', 'Gene', (91, 95))	('p53', 'Var', (36, 39))	('cells', 'CPA', (51, 56))	('Chk1', 'Gene', '1111', (91, 95))	('Chk2', 'Gene', '11200', (27, 31))	('arrest', 'Disease', 'MESH:D006323', (44, 50))	('Chk2', 'Gene', (27, 31))	('arrest', 'Disease', (44, 50))
61691	32731534	A common effect observed when TIF1 proteins are silenced is a reduction of cells in the S or G2/M phase and an increase in G1 as knockdown of TRIM24, TRIM28 or TRIM66 results in cell cycle arrest.	('cell cycle arrest', 'biological_process', 'GO:0007050', ('178', '195'))	('increase', 'PosReg', (111, 119))	('arrest', 'Disease', 'MESH:D006323', (189, 195))	('TRIM66', 'Gene', '9866', (160, 166))	('cells in the S or G2/M phase', 'CPA', (75, 103))	('knockdown', 'Var', (129, 138))	('arrest', 'Disease', (189, 195))	('TRIM28', 'Var', (150, 156))	('TIF1', 'Gene', '8805', (30, 34))	('reduction', 'NegReg', (62, 71))	('TIF1', 'Gene', (30, 34))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (178, 195))	('TRIM24', 'Var', (142, 148))	('TRIM66', 'Gene', (160, 166))	('M phase', 'biological_process', 'GO:0000279', ('96', '103'))
61692	32731534	However, knockdown of TRIM33 can increase the growth rate of cancer cells in line with its tumour suppressor function.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('knockdown', 'Var', (9, 18))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('tumour', 'Disease', (91, 97))	('increase', 'PosReg', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('TRIM33', 'Gene', (22, 28))
61693	32731534	Specifically, it is involved in the transition from G1 phase to S-phase with shRNA knockdown of TRIM28 leading to a G1 phase arrest in glioma independent of DNA damage.	('arrest', 'Disease', 'MESH:D006323', (125, 131))	('TRIM28', 'Gene', (96, 102))	('glioma', 'Disease', (135, 141))	('arrest', 'Disease', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('knockdown', 'Var', (83, 92))
61694	32731534	Phosphorylation of TRIM28-Ser473 increases as undamaged cells transition from G1 phase to early S-phase, as does the gene expression of cyclin A2.	('cyclin', 'molecular_function', 'GO:0016538', ('136', '142'))	('TRIM28-Ser473', 'Var', (19, 32))	('gene expression', 'biological_process', 'GO:0010467', ('117', '132'))	('Phosphorylation', 'MPA', (0, 15))	('Ser473', 'Chemical', '-', (26, 32))	('increases', 'PosReg', (33, 42))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('S-phase', 'biological_process', 'GO:0051320', ('96', '103'))	('cyclin A2', 'Gene', (136, 145))	('G1 phase', 'biological_process', 'GO:0051318', ('78', '86'))	('cyclin A2', 'Gene', '890', (136, 145))	('Ser', 'cellular_component', 'GO:0005790', ('26', '29'))
61695	32731534	TRIM28 binds the promoter of cyclin A2 when TRIM28-Ser473 remains non-phosphorylated, thus repressing cyclin A2 expression.	('Ser473', 'Chemical', '-', (51, 57))	('cyclin A2', 'Gene', (29, 38))	('cyclin', 'molecular_function', 'GO:0016538', ('29', '35'))	('repressing', 'PosReg', (91, 101))	('TRIM28-Ser473', 'Var', (44, 57))	('cyclin A2', 'Gene', '890', (29, 38))	('cyclin', 'molecular_function', 'GO:0016538', ('102', '108'))	('cyclin A2', 'Gene', (102, 111))	('Ser', 'cellular_component', 'GO:0005790', ('51', '54'))	('cyclin A2', 'Gene', '890', (102, 111))	('expression', 'MPA', (112, 122))
61696	32731534	Additionally, phosphorylation of TRIM28-Ser473 disrupts TRIM28-HP1 interaction due to the close proximity of Ser473 to the HP1-binding domain of TRIM28.	('disrupts', 'NegReg', (47, 55))	('TRIM28-Ser473', 'Var', (33, 46))	('Ser', 'cellular_component', 'GO:0005790', ('40', '43'))	('Ser473', 'Var', (109, 115))	('Ser473', 'Chemical', '-', (109, 115))	('phosphorylation', 'MPA', (14, 29))	('HP1', 'Gene', '23468', (123, 126))	('Ser473', 'Chemical', '-', (40, 46))	('HP1', 'Gene', (123, 126))	('phosphorylation', 'biological_process', 'GO:0016310', ('14', '29'))	('interaction', 'Interaction', (67, 78))	('binding', 'molecular_function', 'GO:0005488', ('127', '134'))	('HP1', 'Gene', '23468', (63, 66))	('Ser', 'cellular_component', 'GO:0005790', ('109', '112'))	('HP1', 'Gene', (63, 66))
61703	32731534	TRIM28 does not directly bind p53, but rather interacts with MDM2 through its CC domain and is thus targeted to p53 in vivo.	('interacts', 'Interaction', (46, 55))	('MDM2', 'Gene', '4193', (61, 65))	('TRIM28', 'Var', (0, 6))	('MDM2', 'Gene', (61, 65))
61704	32731534	In both breast and colon cancer cell lines TRIM28 knockdown enhanced p21 levels, a target gene of p53, following actinomycin D treatment or irradiation resulting in a reduction of cells entering S-phase.	('cells entering S-phase', 'CPA', (180, 202))	('actinomycin D', 'Chemical', 'MESH:D003609', (113, 126))	('colon cancer', 'Phenotype', 'HP:0003003', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('S-phase', 'biological_process', 'GO:0051320', ('195', '202'))	('p21', 'Gene', (69, 72))	('knockdown', 'Var', (50, 59))	('reduction', 'NegReg', (167, 176))	('TRIM28 knockdown', 'Var', (43, 59))	('p21', 'Gene', '644914', (69, 72))	('breast and colon cancer', 'Disease', 'MESH:D001943', (8, 31))	('enhanced', 'PosReg', (60, 68))
61708	32731534	TRIM24 depletion also induced p53-dependent apoptosis in breast cancer cells.	('breast cancer', 'Disease', (57, 70))	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('p53-dependent', 'Protein', (30, 43))	('induced', 'Reg', (22, 29))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('depletion', 'Var', (7, 16))	('TRIM24', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))
61716	32731534	However, long-term TRIM33 inactivation resulted in attenuation of the SAC, which led to the accumulation of chromosomal abnormalities, including micronuclei, lagging chromosomes and multinucleated cells (Figure 5).	('lagging chromosomes', 'CPA', (158, 177))	('inactivation', 'Var', (26, 38))	('accumulation of chromosomal abnormalities', 'Phenotype', 'HP:0040012', (92, 133))	('multinucleated cells', 'CPA', (182, 202))	('SAC', 'cellular_component', 'GO:0035003', ('70', '73'))	('micronuclei', 'CPA', (145, 156))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (108, 133))	('chromosomal abnormalities', 'Disease', (108, 133))	('attenuation', 'NegReg', (51, 62))	('SAC', 'biological_process', 'GO:0071173', ('70', '73'))	('TRIM33', 'Gene', (19, 25))	('accumulation', 'PosReg', (92, 104))
61723	32731534	reported that loss of TRIM33 or TRIM24 can lead to resistance to potent BET inhibitors (BETi) JQ1 and GS-626510 in colorectal cancer, suggesting both TRIM24 and TRIM33 can be directly targeted by BETi.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('BET', 'Gene', '92737', (72, 75))	('colorectal cancer', 'Disease', 'MESH:D015179', (115, 132))	('BET', 'Gene', (196, 199))	('BET', 'Gene', (72, 75))	('loss', 'NegReg', (14, 18))	('BET', 'Gene', '92737', (88, 91))	('TRIM24', 'Gene', (32, 38))	('GS-626510', 'Chemical', '-', (102, 111))	('GS-626510', 'Var', (102, 111))	('BET', 'Gene', (88, 91))	('colorectal cancer', 'Phenotype', 'HP:0003003', (115, 132))	('BET', 'Gene', '92737', (196, 199))	('BETi', 'Chemical', '-', (88, 92))	('colorectal cancer', 'Disease', (115, 132))	('BETi', 'Chemical', '-', (196, 200))	('resistance', 'MPA', (51, 61))	('TRIM33', 'Gene', (22, 28))
61725	32731534	Given that knockdown of all TIF1 proteins has sensitised cells to DNA damaging agents, BETi could be used to sensitise cancer cells to such agents.	('sensitise cancer', 'Disease', 'MESH:D009369', (109, 125))	('sensitised', 'Reg', (46, 56))	('sensitise cancer', 'Disease', (109, 125))	('BETi', 'Chemical', '-', (87, 91))	('TIF1', 'Gene', (28, 32))	('TIF1', 'Gene', '8805', (28, 32))	('proteins', 'Protein', (33, 41))	('knockdown', 'Var', (11, 20))	('cells to DNA damaging agents', 'MPA', (57, 85))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
61727	32731534	PARP inhibitors (PARPi) have proven successful in ovarian and breast cancers with mutated BRCA1 or BRCA2 genes.	('breast cancers', 'Phenotype', 'HP:0003002', (62, 76))	('PARP', 'Gene', (0, 4))	('PARP', 'Gene', (17, 21))	('BRCA1', 'Gene', '672', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('BRCA1', 'Gene', (90, 95))	('mutated', 'Var', (82, 89))	('BRCA2', 'Gene', (99, 104))	('PARP', 'Gene', '142', (17, 21))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('PARP', 'Gene', '142', (0, 4))	('BRCA2', 'Gene', '675', (99, 104))	('ovarian and breast cancers', 'Disease', 'MESH:D001943', (50, 76))
61730	32731534	Additionally, where reduced expression is observed in cancers, for example TRIM33, this could potentially be utilised as a biomarker for predicting prognosis or cancer stage, or to stratify patients who may respond to DNA damaging agents or BETi.	('TRIM33', 'Var', (75, 81))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancers', 'Disease', (54, 61))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('expression', 'MPA', (28, 38))	('patients', 'Species', '9606', (190, 198))	('BETi', 'Chemical', '-', (241, 245))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
61737	32731534	TRIM24, TRIM28 and TRIM66 are most commonly overexpressed in cancer, raising the possibility of targeting them for anti-cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('TRIM66', 'Gene', '9866', (19, 25))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', (120, 126))	('TRIM24', 'Var', (0, 6))	('TRIM28', 'Gene', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('TRIM66', 'Gene', (19, 25))
61739	32731534	Furthermore, knockdown of all four TIF1 proteins individually sensitises cancer cells to DNA damaging agents, raising the possibility of their inhibition in combination with such agents.	('TIF1', 'Gene', (35, 39))	('sensitises cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('proteins', 'Protein', (40, 48))	('sensitises cancer', 'Disease', 'MESH:D009369', (62, 79))	('knockdown', 'Var', (13, 22))	('TIF1', 'Gene', '8805', (35, 39))
61747	32466394	Using the fluorescent cisplatin analog BODIPY-cisplatin, two-dimensional gel electrophoresis, and mass spectrometry, we identified the protein binding partners in A2780 and cisplatin-resistant A2780cis ovarian carcinoma, as well as in HCT-8 and oxaliplatin-resistant HCT-8ox colorectal cell lines.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('binding', 'Interaction', (143, 150))	('A2780cis', 'Var', (193, 201))	('protein binding', 'molecular_function', 'GO:0005515', ('135', '150'))	('HCT-8', 'CellLine', 'CVCL:2478', (267, 272))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('BODIPY-cisplatin', 'Chemical', '-', (39, 55))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (245, 256))	('HCT-8', 'CellLine', 'CVCL:2478', (235, 240))	('cisplatin', 'Chemical', 'MESH:D002945', (173, 182))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('A2780', 'Var', (163, 168))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (202, 219))	('cisplatin', 'Chemical', 'MESH:D002945', (22, 31))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (202, 219))	('ovarian carcinoma', 'Disease', (202, 219))
61749	32466394	The effect of pharmacological inhibition and siRNA-mediated knockdown on cytotoxicity was studied to assess the relevance of these binding partners.	('cytotoxicity', 'Disease', 'MESH:D064420', (73, 85))	('cytotoxicity', 'Disease', (73, 85))	('knockdown', 'Var', (60, 69))
61750	32466394	The silencing of glutathione-S-transferase pi significantly sensitized intrinsically resistant HCT-8 and HCT-8ox cells to cisplatin, suggesting a possible involvement of the protein in the resistance of colorectal cancer cells to the drug.	('sensitized', 'Reg', (60, 70))	('glutathione', 'Chemical', 'MESH:D005978', (17, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('colorectal cancer', 'Phenotype', 'HP:0003003', (203, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('intrinsically', 'MPA', (71, 84))	('colorectal cancer', 'Disease', (203, 220))	('HCT-8', 'CellLine', 'CVCL:2478', (105, 110))	('silencing', 'Var', (4, 13))	('colorectal cancer', 'Disease', 'MESH:D015179', (203, 220))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('involvement', 'Reg', (155, 166))	('HCT-8', 'CellLine', 'CVCL:2478', (95, 100))	('glutathione-S-transferase pi', 'Enzyme', (17, 45))
61751	32466394	The inhibition of vimentin with FiVe1 resulted in a significant sensitization of A2780 and A2780cis cells to cisplatin, revealing new possibilities for improving the chemosensitivity of ovarian cancer cells.	('chemosensitivity of ovarian cancer', 'Disease', 'MESH:D010051', (166, 200))	('vimentin', 'Gene', (18, 26))	('chemosensitivity of ovarian cancer', 'Disease', (166, 200))	('A2780cis', 'Var', (91, 99))	('sensitization', 'MPA', (64, 77))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('ovarian cancer', 'Phenotype', 'HP:0100615', (186, 200))	('A2780', 'Var', (81, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))	('inhibition', 'NegReg', (4, 14))	('vimentin', 'Gene', '7431', (18, 26))
61760	32466394	In this respect, a comparison of drug action in colorectal and ovarian cancer is of particular interest, since cisplatin is used in ovarian cancer treatment with good primary response rates, whereas colorectal cancer is intrinsically resistant to this drug.	('colorectal cancer', 'Disease', 'MESH:D015179', (199, 216))	('ovarian cancer', 'Disease', (132, 146))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('colorectal cancer', 'Phenotype', 'HP:0003003', (199, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('colorectal cancer', 'Disease', (199, 216))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('colorectal and ovarian cancer', 'Disease', 'MESH:D015179', (48, 77))	('ovarian cancer', 'Phenotype', 'HP:0100615', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('ovarian cancer', 'Disease', 'MESH:D010051', (63, 77))	('cisplatin', 'Var', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('ovarian cancer', 'Disease', 'MESH:D010051', (132, 146))	('ovarian cancer', 'Disease', (63, 77))
61806	32466394	Propionamide, PtBDP (BC17F2H26N5O2Pt mass shifts of 576.178992 and 557.160602 with and without water, respectively) were set as dynamic modifications on cysteines.	('Propionamide', 'Chemical', 'MESH:C034666', (0, 12))	('cysteines', 'Chemical', 'MESH:D003545', (153, 162))	('PtBDP', 'Chemical', '-', (14, 19))	('water', 'Chemical', 'MESH:D014867', (95, 100))	('BC17F2H26N5O2Pt', 'Chemical', '-', (21, 36))	('576.178992', 'Var', (52, 62))	('557.160602', 'Var', (67, 77))
61827	32466394	The ratio of cisplatin to FiVe1 in A2780 was 1.247 and in A2780cis, it was 6.225.	('A2780cis', 'Var', (58, 66))	('A2780', 'Var', (35, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))
61836	32466394	The cytotoxicity of BODIPY-cisplatin was much lower in colorectal cancer cells, both in the oxaliplatin-sensitive HCT-8 and oxaliplatin-resistant HCT-8ox cell lines, which are intrinsically resistant to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('HCT-8', 'CellLine', 'CVCL:2478', (146, 151))	('colorectal cancer', 'Disease', 'MESH:D015179', (55, 72))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (124, 135))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (55, 72))	('cytotoxicity', 'Disease', (4, 16))	('HCT-8', 'CellLine', 'CVCL:2478', (114, 119))	('lower', 'NegReg', (46, 51))	('BODIPY-cisplatin', 'Chemical', '-', (20, 36))	('colorectal cancer', 'Disease', (55, 72))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (92, 103))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))	('BODIPY-cisplatin', 'Var', (20, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (203, 212))
61844	32466394	While there were many fluorescent spots in both A2780 and A2780cis cells, BODIPY-cisplatin signals did not overlay to the same extent with the protein staining of HCT-8 and HCT-8ox cells.	('A2780cis', 'Var', (58, 66))	('A2780', 'Var', (48, 53))	('BODIPY-cisplatin', 'Chemical', '-', (74, 90))	('HCT-8', 'CellLine', 'CVCL:2478', (163, 168))	('HCT-8', 'CellLine', 'CVCL:2478', (173, 178))
61845	32466394	Some of the cytosolic proteins identified (Table S1) in A2780 and A2780cis cells were the same as previously reported and studied in detail, such as protein disulfide isomerase 1 (PDIA1).	('protein disulfide isomerase 1', 'Gene', (149, 178))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('PDIA1', 'Gene', '5034', (180, 185))	('protein disulfide isomerase', 'molecular_function', 'GO:0003756', ('149', '176'))	('A2780', 'Var', (56, 61))	('protein disulfide isomerase 1', 'Gene', '5034', (149, 178))	('PDIA1', 'Gene', (180, 185))	('A2780cis', 'Var', (66, 74))
61850	32466394	After determining the non-toxic FiVe1 concentration (EC50 was 0.93 microM in A2780 and 0.80 microM in A2780cis), cells were subjected to cisplatin in combination with 0.2 microM FiVe1 over 72 h. Both A2780 and A2780cis cells were significantly sensitized towards cisplatin (in A2780 EC50, the value changed from 1.17 to 0.78 microM, and in A2780cis, from 4.88 to 2.81 microM, Figure 3a).	('sensitized', 'Reg', (244, 254))	('cisplatin', 'Chemical', 'MESH:D002945', (263, 272))	('A2780', 'Var', (200, 205))	('cisplatin', 'Chemical', 'MESH:D002945', (137, 146))	('A2780cis', 'Var', (340, 348))	('A2780cis', 'Var', (210, 218))	('A2780', 'Var', (277, 282))
61854	32466394	A typical knockdown experiment started with siRNA-mediated transfection for 24 h, followed by exposure to a platinum drug for 48 h. The expression of vimentin as detected by Western Blot 48 h after transfection was decreased only by 33% and 51% in A2780 and A2780cis, respectively, when compared to cells transfected with negative control siRNA (Figure 3d).	('expression', 'MPA', (136, 146))	('platinum', 'Chemical', 'MESH:D010984', (108, 116))	('A2780', 'Var', (248, 253))	('A2780cis', 'Var', (258, 266))	('vimentin', 'Gene', '7431', (150, 158))	('decreased', 'NegReg', (215, 224))	('vimentin', 'Gene', (150, 158))
61855	32466394	Accordingly, no changes in cisplatin cytotoxicity after vimentin knockdown could be detected (Figure 3e).	('vimentin', 'Gene', '7431', (56, 64))	('cytotoxicity', 'Disease', (37, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('cytotoxicity', 'Disease', 'MESH:D064420', (37, 49))	('vimentin', 'Gene', (56, 64))	('vimentin', 'cellular_component', 'GO:0045099', ('56', '64'))	('knockdown', 'Var', (65, 74))	('vimentin', 'cellular_component', 'GO:0045098', ('56', '64'))
61861	32466394	In terms of oxaliplatin, inhibitor A did not affect the cell sensitivity to the drug, whereas the combination with inhibitor B resulted in a reduction in sensitivity in HCT-8 cells (EC50 increased from 2.17 to 5.43 microM, p = 0.0061), but not in the oxaliplatin-resistant HCT-8ox cell line (Figure S3a).	('inhibitor B', 'Var', (115, 126))	('combination', 'Var', (98, 109))	('sensitivity', 'MPA', (154, 165))	('S3a', 'Gene', (299, 302))	('S3a', 'Gene', '6189', (299, 302))	('HCT-8', 'CellLine', 'CVCL:2478', (169, 174))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (12, 23))	('HCT-8', 'CellLine', 'CVCL:2478', (273, 278))	('reduction', 'NegReg', (141, 150))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (251, 262))
61862	32466394	After the knockdown, the amount of Grb2 decreased by 48% in HCT-8 and by 13% in HCT-8ox cells (Figure 4b).	('knockdown', 'Var', (10, 19))	('Grb2', 'Gene', '2885', (35, 39))	('amount', 'MPA', (25, 31))	('Grb2', 'Gene', (35, 39))	('HCT-8', 'CellLine', 'CVCL:2478', (80, 85))	('HCT-8', 'CellLine', 'CVCL:2478', (60, 65))	('decreased', 'NegReg', (40, 49))
61865	32466394	We found that the GSTP1 inhibitor Ezatiostat-HCl (Figure 1,) could be applied at a concentration of up to 10 microM, without harming the cells (EC50 values were 33.69 and 31.97 microM in A2780 and A2780cis, respectively, and 67.79 and 61.60 microM in HCT-8 and HCT-8ox cells, respectively).	('HCT-8', 'CellLine', 'CVCL:2478', (251, 256))	('A2780cis', 'Var', (197, 205))	('HCT-8', 'CellLine', 'CVCL:2478', (261, 266))	('GSTP1', 'Gene', (18, 23))	('A2780', 'Var', (187, 192))	('Ezatiostat-HCl', 'Chemical', '-', (34, 48))	('GSTP1', 'Gene', '2950', (18, 23))
61868	32466394	While GSTP1 knockdown worked nearly perfectly in HCT-8 and HCT-8ox cells (decreased by 91% and 95%, respectively), the expression of GSTP1 could only be reduced by 42% in A2780 cells and by 8% in A2780cis cells (Figure 6a,b).	('expression', 'MPA', (119, 129))	('GSTP1', 'Gene', (6, 11))	('HCT-8', 'CellLine', 'CVCL:2478', (49, 54))	('reduced', 'NegReg', (153, 160))	('GSTP1', 'Gene', '2950', (133, 138))	('GSTP1', 'Gene', '2950', (6, 11))	('A2780', 'Var', (171, 176))	('GSTP1', 'Gene', (133, 138))	('HCT-8', 'CellLine', 'CVCL:2478', (59, 64))
61870	32466394	On the contrary, Figure 6d shows an obvious and significant sensitization of both colorectal cancer cell lines to cisplatin after GSTP1 knockdown (EC50: HCT-8, 7.10 microM; HCT-8ox: 12.79 microM) compared to either the negative control (EC50: HCT-8, 19.10 microM; HCT-8ox, 34.28 microM) or cells without knockdown (EC50: HCT-8, 21.04 microM; HCT-8ox, 38.19 microM).	('colorectal cancer', 'Disease', (82, 99))	('GSTP1', 'Gene', (130, 135))	('HCT-8', 'CellLine', 'CVCL:2478', (264, 269))	('cisplatin', 'MPA', (114, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('knockdown', 'Var', (136, 145))	('HCT-8', 'CellLine', 'CVCL:2478', (153, 158))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('sensitization', 'MPA', (60, 73))	('GSTP1', 'Gene', '2950', (130, 135))	('HCT-8', 'CellLine', 'CVCL:2478', (173, 178))	('HCT-8', 'CellLine', 'CVCL:2478', (342, 347))	('HCT-8', 'CellLine', 'CVCL:2478', (321, 326))	('HCT-8', 'CellLine', 'CVCL:2478', (243, 248))
61874	32466394	These results were further validated by an apoptosis assay, which revealed a significant increase in late apoptosis and necrosis induced by oxaliplatin after GSTP1 knockdown in both the HCT-8 (+38.9% with respect to the negative control, p < 0.0001, and +53.2% compared to the unmodified control, p < 0.0001) and HCT-8ox cell line (+25.8% with respect to the negative control, p = 0.0021, and +40.0% compared to the unmodified control, p < 0.0001, Figures S5 and S2b).	('necrosis', 'Disease', (120, 128))	('HCT-8', 'CellLine', 'CVCL:2478', (313, 318))	('GSTP1', 'Gene', (158, 163))	('necrosis', 'Disease', 'MESH:D009336', (120, 128))	('HCT-8', 'CellLine', 'CVCL:2478', (186, 191))	('knockdown', 'Var', (164, 173))	('GSTP1', 'Gene', '2950', (158, 163))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (140, 151))	('increase', 'PosReg', (89, 97))
61875	32466394	With cisplatin, the results were quite similar: HCT-8 cells showed a significant increase in late apoptosis and necrosis after the knockdown of GSTP1 compared to either the negative knockdown control (+34.5%, p = 0.0088) or cells without knockdown (+52.1%, p < 0.0001, Figure 6e and Figure S2c).	('knockdown', 'Var', (131, 140))	('HCT-8', 'CellLine', 'CVCL:2478', (48, 53))	('necrosis', 'Disease', 'MESH:D009336', (112, 120))	('GSTP1', 'Gene', (144, 149))	('late apoptosis', 'CPA', (93, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (5, 14))	('increase', 'PosReg', (81, 89))	('GSTP1', 'Gene', '2950', (144, 149))	('necrosis', 'Disease', (112, 120))
61876	32466394	In HCT-8ox cells, we could detect significantly elevated levels of cisplatin-induced late apoptosis and necrosis after GSTP1 knockdown when compared to the unmodified control (+36.8%, p = 0.0038), but not in comparison to negative knockdown controls, even though a strong tendency could be observed (+26.3%, p = 0.1014, Figure 6e and Figure S2c).	('GSTP1', 'Gene', (119, 124))	('knockdown', 'Var', (125, 134))	('HCT-8', 'CellLine', 'CVCL:2478', (3, 8))	('necrosis', 'Disease', (104, 112))	('necrosis', 'Disease', 'MESH:D009336', (104, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('GSTP1', 'Gene', '2950', (119, 124))	('elevated', 'PosReg', (48, 56))	('late apoptosis', 'CPA', (85, 99))
61886	32466394	Reduced cisplatin accumulation in A2780cis cells compared to the parent sensitive cell line is well-documented.	('cisplatin', 'Chemical', 'MESH:D002945', (8, 17))	('Reduced', 'NegReg', (0, 7))	('A2780cis', 'Var', (34, 42))	('cisplatin accumulation', 'MPA', (8, 30))
61892	32466394	Nevertheless, some other binding partners, particularly those only identified in colorectal cancer HCT-8 cells (such as ATP synthase subunit beta, mitochondrial, and phosphoglucomutase-2) or only found in resistant A2780cis cells (such as proliferating cell nuclear antigen, polyubiquitin-B, and COP9 signalosome complex subunit 4), are worth investigating further in light of their relevance for intrinsic and acquired cisplatin resistance, respectively.	('polyubiquitin-B', 'Gene', '7314', (275, 290))	('proliferating cell nuclear antigen', 'molecular_function', 'GO:0003892', ('239', '273'))	('polyubiquitin', 'biological_process', 'GO:0000209', ('275', '288'))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('proliferating cell nuclear antigen', 'Gene', (239, 273))	('HCT-8', 'CellLine', 'CVCL:2478', (99, 104))	('ATP synthase', 'molecular_function', 'GO:0016468', ('120', '132'))	('binding', 'molecular_function', 'GO:0005488', ('25', '32'))	('colorectal cancer', 'Disease', (81, 98))	('phosphoglucomutase-2', 'Gene', '55276', (166, 186))	('A2780cis', 'Var', (215, 223))	('cisplatin', 'Chemical', 'MESH:D002945', (420, 429))	('COP9 signalosome complex subunit 4', 'Gene', '51138', (296, 330))	('phosphoglucomutase-2', 'Gene', (166, 186))	('COP9 signalosome', 'cellular_component', 'GO:0008180', ('296', '312'))	('ATP synthase', 'molecular_function', 'GO:0016467', ('120', '132'))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))	('COP9 signalosome complex subunit 4', 'Gene', (296, 330))	('proliferating cell nuclear antigen', 'Gene', '5111', (239, 273))	('polyubiquitin', 'molecular_function', 'GO:0005552', ('275', '288'))	('polyubiquitin-B', 'Gene', (275, 290))
61903	32466394	The effect was more pronounced in the resistant cell line, although no differences in vimentin expression between A2780 and A2780cis cells were detected (Figure S6).	('vimentin', 'Gene', '7431', (86, 94))	('A2780', 'Var', (114, 119))	('vimentin', 'Gene', (86, 94))	('A2780cis', 'Var', (124, 132))
61905	32466394	Therefore, it appears that FiVe1 sensitizes cells to cisplatin through interference with vimentin's function.	('vimentin', 'Gene', (89, 97))	('vimentin', 'cellular_component', 'GO:0045098', ('89', '97'))	('interference', 'NegReg', (71, 83))	('sensitizes', 'Reg', (33, 43))	('function', 'MPA', (100, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('FiVe1', 'Var', (27, 32))	('vimentin', 'cellular_component', 'GO:0045099', ('89', '97'))	('vimentin', 'Gene', '7431', (89, 97))
61916	32466394	Grb2 knockdown was not sufficient to induce changes in susceptibility to the platinum drugs, especially in the resistant cell line.	('susceptibility to the', 'MPA', (55, 76))	('Grb2', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('Grb2', 'Gene', '2885', (0, 4))	('platinum', 'Chemical', 'MESH:D010984', (77, 85))
61917	32466394	However, even with a more successful knockdown, we could expect similar results as those of pharmacological inhibition due to the survival signaling activated by the loss of Grb2.	('Grb2', 'Gene', (174, 178))	('loss', 'Var', (166, 170))	('signaling', 'biological_process', 'GO:0023052', ('139', '148'))	('Grb2', 'Gene', '2885', (174, 178))	('survival signaling', 'MPA', (130, 148))
61925	32466394	Interestingly, we noted a significant sensitization of both intrinsically cisplatin-resistant colorectal cancer cell lines to this drug after GSTP1-siRNA transfection.	('GSTP1', 'Gene', '2950', (142, 147))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('transfection', 'Var', (154, 166))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('GSTP1', 'Gene', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Disease', (94, 111))	('sensitization', 'MPA', (38, 51))
61929	32466394	found that the ROS/JNK pathway was mainly involved in the sensitization of mesothelioma cells to cisplatin upon GSTP1 knockdown, whereas the pathway seemed to be irrelevant for the effect of GSTP1 silencing on cell sensitivity to oxaliplatin.	('sensitization', 'MPA', (58, 71))	('GSTP1', 'Gene', (112, 117))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (230, 241))	('knockdown', 'Var', (118, 127))	('mesothelioma', 'Disease', 'MESH:D008654', (75, 87))	('JNK', 'Gene', (19, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('GSTP1', 'Gene', '2950', (191, 196))	('involved', 'Reg', (42, 50))	('GSTP1', 'Gene', '2950', (112, 117))	('ROS', 'Chemical', '-', (15, 18))	('JNK', 'Gene', '5599', (19, 22))	('GSTP1', 'Gene', (191, 196))	('mesothelioma', 'Disease', (75, 87))
61931	32466394	Using BODIPY-cisplatin followed by two-dimensional gel electrophoresis and mass spectrometry, we were able to identify different protein binding patterns in A2780, HCT-8, and their cisplatin- and oxaliplatin-resistant sublines, respectively.	('binding', 'Interaction', (137, 144))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (196, 207))	('HCT-8', 'CellLine', 'CVCL:2478', (164, 169))	('BODIPY-cisplatin', 'Chemical', '-', (6, 22))	('HCT-8', 'Gene', (164, 169))	('cisplatin', 'Chemical', 'MESH:D002945', (181, 190))	('A2780', 'Var', (157, 162))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))	('protein', 'Protein', (129, 136))
61933	32466394	Interestingly, GSTP1 knockdown sensitized intrinsically resistant colorectal cancer cells to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('sensitized', 'Reg', (31, 41))	('GSTP1', 'Gene', '2950', (15, 20))	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal cancer', 'Disease', (66, 83))	('knockdown', 'Var', (21, 30))	('GSTP1', 'Gene', (15, 20))	('intrinsically resistant', 'CPA', (42, 65))	('colorectal cancer', 'Disease', 'MESH:D015179', (66, 83))
61938	32466394	The following figures and tables are available online at : Figure S1: Overlay of fluorescence image and protein staining (Coomassie) in representative gels after two-dimensional electrophoresis (pH 3-10) of each 20 microg cytosolic fraction of (a) A2780, (b) A2780cis, (c) HCT-8, and (d) HCT-8ox cells treated with BODIPY-cisplatin, Figure S2: Flow cytometry analyses of Annexin V-FITC/propidium iodide double staining (a) in A2780 and A2780cis cells after the co-incubation of cisplatin with FiVe1 (lower right quadrant) in comparison to treatment with the inhibitor (upper right quadrant) or cisplatin (lower left quadrant) alone and untreated cells (upper left quadrant); in HCT-8 and HCT-8ox cells after (b) oxaliplatin or (c) cisplatin treatment following GSTP1 knockdown (lower right quadrant), negative control siRNA treatment (lower left quadrant), or without knockdown (upper right quadrant) or untreated cells (upper left quadrant), Figure S3: Oxaliplatin cytotoxicity (a) in HCT-8 and HCT-8ox cells alone or upon co-incubation with either 1 microM inhibitor A or 50 microM inhibitor B (mean +- SEM, n = 5-6) and (b) in HCT-8 and HCT-8ox cells alone or upon co-incubation with 2 microM Ezatiostat-HCl, either without or with 24 or 48 h pre-incubation with the inhibitor before platinum drug treatment (mean +- SEM, n = 3-7), Figure S4: Oxaliplatin cytotoxicity in HCT-8 and HCT-8ox cells after (a) Grb2 knockdown and (b) GSTP1 knockdown, prior treatment with negative control siRNA, or no pre-treatment (mean +- SEM, n = 4-7), Figure S5: Percentage of early apoptotic, late apoptotic, and necrotic, as well as alive, cells in HCT-8 and HCT-8ox cells after oxaliplatin treatment following GSTP1 knockdown, negative knockdown control, without knockdown, Figure S6: Representative Western Blots of basal vimentin expression in A2780, A2780cis, HCT-8, and HCT-8ox cells.	('Ezatiostat-HCl', 'Chemical', '-', (1196, 1210))	('HCT-8', 'CellLine', 'CVCL:2478', (1646, 1651))	('cisplatin', 'Chemical', 'MESH:D002945', (478, 487))	('HCT-8', 'CellLine', 'CVCL:2478', (1140, 1145))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (1666, 1677))	('HCT-8', 'CellLine', 'CVCL:2478', (996, 1001))	('HCT-8', 'CellLine', 'CVCL:2478', (678, 683))	('GSTP1', 'Gene', '2950', (1431, 1436))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('BODIPY-cisplatin', 'Chemical', '-', (315, 331))	('HCT-8', 'CellLine', 'CVCL:2478', (273, 278))	('cisplatin', 'Chemical', 'MESH:D002945', (731, 740))	('platinum', 'Chemical', 'MESH:D010984', (1287, 1295))	('vimentin', 'Gene', '7431', (1811, 1819))	('HCT-8', 'CellLine', 'CVCL:2478', (986, 991))	('GSTP1', 'Gene', (1431, 1436))	('vimentin', 'Gene', (1811, 1819))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (712, 723))	('cytotoxicity', 'Disease', (1358, 1370))	('propidium iodide', 'Chemical', 'MESH:D011419', (386, 402))	('HCT-8', 'CellLine', 'CVCL:2478', (1130, 1135))	('HCT-8', 'CellLine', 'CVCL:2478', (1636, 1641))	('HCT-8', 'CellLine', 'CVCL:2478', (1851, 1856))	('Grb2', 'Gene', (1408, 1412))	('HCT-8', 'CellLine', 'CVCL:2478', (1384, 1389))	('vimentin', 'cellular_component', 'GO:0045098', ('1811', '1819'))	('cytotoxicity', 'Disease', 'MESH:D064420', (1358, 1370))	('HCT-8', 'CellLine', 'CVCL:2478', (288, 293))	('cisplatin', 'Chemical', 'MESH:D002945', (594, 603))	('pre', 'molecular_function', 'GO:0003904', ('1499', '1502'))	('HCT-8', 'CellLine', 'CVCL:2478', (1374, 1379))	('GSTP1', 'Gene', '2950', (1698, 1703))	('cisplatin', 'Chemical', 'MESH:D002945', (322, 331))	('pre', 'molecular_function', 'GO:0003904', ('1246', '1249'))	('GSTP1', 'Gene', (1698, 1703))	('GSTP1', 'Gene', '2950', (761, 766))	('Annexin V', 'Gene', '308', (371, 380))	('cytotoxicity', 'Disease', (966, 978))	('knockdown', 'Var', (1413, 1422))	('GSTP1', 'Gene', (761, 766))	('Annexin V', 'Gene', (371, 380))	('HCT-8', 'CellLine', 'CVCL:2478', (1862, 1867))	('knockdown', 'Var', (1437, 1446))	('vimentin', 'cellular_component', 'GO:0045099', ('1811', '1819'))	('cytotoxicity', 'Disease', 'MESH:D064420', (966, 978))	('HCT-8', 'CellLine', 'CVCL:2478', (688, 693))	('necrotic', 'Disease', (1599, 1607))	('Grb2', 'Gene', '2885', (1408, 1412))	('necrotic', 'Disease', 'MESH:D009336', (1599, 1607))
61959	28693240	To determine the expression levels of MAGE and hTERT genes in various cancer cells, 14 cancer cell lines were selected as follows: Five gastric (NCI-N87, SNU1, SNU216, SNU484 and SNU688), four colorectal (CRC1306, SNU1197, SNU1411 and SNU175), one cervical (CaSki), one liver (SK-Hep1), one lung (A549), one breast (MDA-MB-361) and one renal (Caki-1) cancer cell line.	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('CRC1306', 'Var', (205, 212))	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('SNU1197', 'Var', (214, 221))	('colorectal', 'Disease', (193, 203))	('SNU175', 'Var', (235, 241))	('hTERT', 'Gene', '7015', (47, 52))	('NCI-N87', 'CellLine', 'CVCL:1603', (145, 152))	('MDA-MB-361', 'CellLine', 'CVCL:0620', (316, 326))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (351, 357))	('colorectal', 'Disease', 'MESH:D015179', (193, 203))	('hTERT', 'Gene', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('CRC1306', 'CellLine', 'CVCL:2266', (205, 212))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('SK-Hep1', 'CellLine', 'CVCL:0525', (277, 284))	('one breast', 'Phenotype', 'HP:0012813', (304, 314))	('SNU216', 'Var', (160, 166))	('SNU1411', 'Var', (223, 230))	('CaSki', 'CellLine', 'CVCL:1100', (258, 263))	('SNU484', 'Var', (168, 174))	('cancer', 'Disease', (351, 357))	('renal (Caki-1) cancer', 'Disease', 'MESH:D007680', (336, 357))	('A549', 'CellLine', 'CVCL:0023', (297, 301))
61999	28693240	A previous study captured tumor cells using epithelial antigens and were able to detect tumor cells using tumor progenitor genes; however, the result was negative rather than positive for the enrichment of tumor cells because CD45 depletion of leukocytes induced significantly greater recovery of spiked hepatocellular carcinoma cells.	('CD45', 'Gene', '5788', (226, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('tumor', 'Disease', (106, 111))	('greater', 'PosReg', (277, 284))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (304, 328))	('tumor', 'Disease', (26, 31))	('recovery', 'MPA', (285, 293))	('tumor', 'Disease', (88, 93))	('depletion', 'Var', (231, 240))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (304, 328))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (206, 211))	('depletion of leukocytes', 'Phenotype', 'HP:0001882', (231, 254))	('hepatocellular carcinoma', 'Disease', (304, 328))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('CD45', 'Gene', (226, 230))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
62031	28100684	In stage III colorectal cancer, poorly differentiated cluster G1/G2 predicts a significant benefit from 5-fluorouracil-based adjuvant chemotherapy, whereas poorly differentiated cluster G3 predicts a poor response to it.	('poorly differentiated', 'Var', (32, 53))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('5-fluorouracil-based', 'MPA', (104, 124))	('colorectal cancer', 'Disease', 'MESH:D015179', (13, 30))	('colorectal cancer', 'Disease', (13, 30))	('cluster G1/G2', 'Gene', (54, 67))	('benefit', 'PosReg', (91, 98))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (104, 118))	('colorectal cancer', 'Phenotype', 'HP:0003003', (13, 30))
62044	28100684	The prognosis of CRC patients with PDC G3 is worse than those with PDC G1 or G2.	('patients', 'Species', '9606', (21, 29))	('CRC', 'Disease', (17, 20))	('CRC', 'Phenotype', 'HP:0003003', (17, 20))	('PDC G3', 'Var', (35, 41))
62045	28100684	We hypothesized that tumors with PDC G3 are more tolerant of adjuvant chemotherapy compared with those with PDC G1 or G2.	('PDC G3', 'Var', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
62072	28100684	To elucidate factors influencing CRR and RFS, 11 clinicopathological variables were tested in all 131 patients: age (<65 vs. >=65 years), sex, American Society of Anesthesiologists physical status (ASA-PS; 1-2 vs. 3-4), tumor location (colon vs. rectum), tumor size (<50 vs. >=50 mm), T category (T1-T3 vs. T4), histopathological grading (G1, G2 vs. G3), lymphatic invasion (absence vs. presence), venous invasion (absence vs. presence), N category (N1 vs. N2), PDC (G1, G2 vs. G3) and adjuvant chemotherapy (absence vs. presence).	('ASA-PS', 'Chemical', '-', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('PDC', 'CPA', (462, 465))	('tumor', 'Disease', (220, 225))	('lymphatic invasion', 'CPA', (355, 373))	('patients', 'Species', '9606', (102, 110))	('histopathological grading', 'CPA', (312, 337))	('venous invasion', 'CPA', (398, 413))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('G1', 'Var', (467, 469))
62091	28100684	Conversely, we speculate that CRC with PDC G3 may be resistant to 5-FU-based adjuvant chemotherapy.	('PDC', 'Var', (39, 42))	('CRC', 'Phenotype', 'HP:0003003', (30, 33))	('CRC', 'Disease', (30, 33))	('5-FU', 'Chemical', 'MESH:D005472', (66, 70))
62096	28100684	Among those with PDC G1/G2, on the other hand, significant differences in 5-year CRR and RFS were observed between the 5-FU-based chemotherapy and the surgery-alone groups (P = 0.035 and P = 0.002, respectively).	('5-FU', 'Chemical', 'MESH:D005472', (119, 123))	('CRR', 'CPA', (81, 84))	('PDC G1/G2', 'Var', (17, 26))	('RFS', 'CPA', (89, 92))	('differences', 'Reg', (59, 70))
62109	28100684	The presence of PDC G1/G2 predicts a significant benefit from 5-FU-based adjuvant chemotherapy, whereas the presence of PDC G3 predicts a poor response to this regimen.	('5-FU', 'Chemical', 'MESH:D005472', (62, 66))	('presence', 'Var', (4, 12))	('benefit', 'PosReg', (49, 56))	('PDC G1/G2', 'Gene', (16, 25))
62142	27768590	Moreover, subgroup analysis showed a significant relationship between CA147 and disease-free survival in both gastric carcinoma (HR 1.63, 95% CI 1.13-2.36) and colorectal carcinoma (HR 3.18, 95% CI 2.02-5.02).	('CA147', 'Var', (70, 75))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (110, 127))	('colorectal carcinoma', 'Disease', (160, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (160, 180))	('gastric carcinoma', 'Disease', 'MESH:D013274', (110, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('disease-free survival', 'CPA', (80, 101))	('CA147', 'Chemical', '-', (70, 75))	('gastric carcinoma', 'Disease', (110, 127))
62150	27768590	Subgroup analysis showed that the high expression of CD147 can predict poor prognosis in both gastric cancer and colorectal cancer.	('gastric cancer', 'Disease', (94, 108))	('colorectal cancer', 'Disease', (113, 130))	('CD147', 'Gene', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('high', 'Var', (34, 38))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('CD147', 'Gene', '682', (53, 58))	('gastric cancer', 'Disease', 'MESH:D013274', (94, 108))
62164	27768590	We conducted subgroup analysis according to malignant disease, and the pooled analysis of gastric cancer and colorectal cancer indicated that the high expression of CD147was associated with poor survival.	('colorectal cancer', 'Disease', (109, 126))	('poor', 'NegReg', (190, 194))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('associated', 'Reg', (174, 184))	('malignant disease', 'Disease', 'MESH:D009369', (44, 61))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('CD147', 'Gene', '682', (165, 170))	('malignant disease', 'Disease', (44, 61))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('CD147', 'Gene', (165, 170))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('high', 'Var', (146, 150))	('gastric cancer', 'Disease', (90, 104))
62184	25825874	Presence of LLMs associated with peritoneal carcinomatosis was significantly associated with poorer prognosis, with survival at 5 years of 13.95% (95 %CI 2.9-33.6) vs. 43.87% (22.2-63.7) when no metastases were present (P= 0.018).	('metastases', 'Disease', 'MESH:D009362', (195, 205))	('LLMs', 'Disease', (12, 16))	('peritoneal carcinomatosis', 'Disease', (33, 58))	('metastases', 'Disease', (195, 205))	('peritoneal carcinomatosis', 'Disease', 'MESH:D010534', (33, 58))	('Presence', 'Var', (0, 8))
62366	25502518	In HT29 cells, CIG induced a dose-dependent decrease of cell number after 6 and 24 hours (Fig.	('decrease', 'NegReg', (44, 52))	('CIG', 'Chemical', 'MESH:C039671', (15, 18))	('CIG', 'Var', (15, 18))	('HT29 cells', 'CellLine', 'CVCL:0320', (3, 13))	('cell number', 'CPA', (56, 67))
62375	25502518	At concentrations of 10 microM CIG, the percentage of cells with reduced Deltapsim increased in SW480 cells, albeit to a lesser extent than HT29 cells.	('Deltapsim', 'MPA', (73, 82))	('reduced', 'NegReg', (65, 72))	('CIG', 'Chemical', 'MESH:C039671', (31, 34))	('CIG', 'Var', (31, 34))	('SW480', 'CellLine', 'CVCL:0546', (96, 101))	('HT29 cells', 'CellLine', 'CVCL:0320', (140, 150))
62381	25502518	Overall, 5 cytoplasmic proteins were synthesized at least three-fold higher in HT29 cells than in SW480 cells (p<0.05, Table 1 and Fig.	('SW480', 'CellLine', 'CVCL:0546', (98, 103))	('HT29 cells', 'CellLine', 'CVCL:0320', (79, 89))	('higher', 'PosReg', (69, 75))	('HT29', 'Var', (79, 83))
62382	25502518	In comparison, 12 cytoplasmic proteins were synthetized at least three-fold higher in SW480 cells than in HT29 cells (p<0.05, Table 1 and Fig.	('higher', 'PosReg', (76, 82))	('SW480', 'CellLine', 'CVCL:0546', (86, 91))	('SW480', 'Var', (86, 91))	('HT29 cells', 'CellLine', 'CVCL:0320', (106, 116))
62402	25502518	Another protein synthesized by SW480 but not HT29 cells is Galectin-1.	('HT29 cells', 'CellLine', 'CVCL:0320', (45, 55))	('SW480', 'Var', (31, 36))	('Galectin-1', 'Gene', (59, 69))	('SW480', 'CellLine', 'CVCL:0546', (31, 36))	('Galectin-1', 'Gene', '3956', (59, 69))
62410	25502518	Cells treated with CIG at 5 microM responded with an upregulation of protein synthesis as compared to cells incubated with DMSO.	('protein synthesis', 'MPA', (69, 86))	('DMSO', 'Chemical', 'MESH:D004121', (123, 127))	('upregulation', 'PosReg', (53, 65))	('CIG', 'Var', (19, 22))	('CIG', 'Chemical', 'MESH:C039671', (19, 22))
62441	31287944	Next are a number of EGF-like domain repeats, thrombomodulin contains six, CD93 five, CD248 three and CLEC14A one.	('CD248', 'Var', (86, 91))	('CD93', 'Var', (75, 79))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('EGF', 'molecular_function', 'GO:0005154', ('21', '24'))
62452	31287944	Interestingly, thrombomodulin-deficient mouse embryos die at embryonic day 8.5 due to defects in nonendothelial tissue within the placenta, but reintroduction of thrombomodulin into the placenta allows normal development of embryos until day 12.5 16.	('mouse', 'Species', '10090', (40, 45))	('thrombomodulin-deficient', 'Disease', (15, 39))	('thrombomodulin-deficient', 'Disease', 'MESH:C536900', (15, 39))	('reintroduction', 'Var', (144, 158))
62455	31287944	Based on these considerations, such embryonic lethality is most likely due to disruptions in the thrombomodulin-mediated coagulation cascade elicited by the EGF domain tandem repeats (see below).	('coagulation', 'Disease', (121, 132))	('rat', 'Species', '10116', (22, 25))	('EGF domain tandem repeats', 'Var', (157, 182))	('coagulation', 'Disease', 'MESH:D025861', (121, 132))	('embryonic lethality', 'Disease', 'MESH:D020964', (36, 55))	('embryonic lethality', 'Disease', (36, 55))
62477	31287944	In genetically engineered mice expressing a mutant form of thrombomodulin with severely compromised thrombin binding, primary tumour growth was unaffected whereas lung metastasis was significantly enhanced 42.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('lung metastasis', 'CPA', (163, 178))	('primary tumour', 'Disease', (118, 132))	('binding', 'molecular_function', 'GO:0005488', ('109', '116'))	('primary tumour', 'Disease', 'MESH:D009369', (118, 132))	('thrombin', 'Protein', (100, 108))	('enhanced', 'PosReg', (197, 205))	('binding', 'Interaction', (109, 116))	('mutant', 'Var', (44, 50))	('mice', 'Species', '10090', (26, 30))
62490	31287944	The inactivation of HMGB1 has potential implications on immunogenic cell death events following anticancer intervention invoked by chemotherapeutic agents or radiotherapy, whereby HMGB1 released by dying cells serves as damage-associated molecular patterns activating antigen-presenting cells and facilitating presentation of tumour antigens 56.	('HMGB1', 'Gene', '15289', (180, 185))	('inactivation', 'Var', (4, 16))	('tumour', 'Phenotype', 'HP:0002664', (326, 332))	('HMGB1', 'Gene', (20, 25))	('tumour', 'Disease', 'MESH:D009369', (326, 332))	('HMGB1', 'Gene', '15289', (20, 25))	('activating', 'PosReg', (257, 267))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumour', 'Disease', (326, 332))	('HMGB1', 'Gene', (180, 185))	('presentation', 'MPA', (310, 322))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cell death', 'biological_process', 'GO:0008219', ('68', '78'))
62515	31287944	Consistent with this, knockdown of thrombomodulin can compromise the integrity of E-cadherin-mediated cell-cell contacts, potentially implicating thrombomodulin downregulation in the induction of EMT in cancer 43.	('E-cadherin-mediated', 'Protein', (82, 101))	('compromise', 'NegReg', (54, 64))	('integrity', 'MPA', (69, 78))	('cadherin', 'molecular_function', 'GO:0008014', ('84', '92'))	('downregulation', 'NegReg', (161, 175))	('knockdown', 'Var', (22, 31))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('EMT', 'biological_process', 'GO:0001837', ('196', '199'))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
62525	31287944	Mice deficient in CD248 are viable and display no obvious defects, suggesting compensatory mechanisms may be employed during development 91.	('CD248', 'Gene', (18, 23))	('Mice', 'Species', '10090', (0, 4))	('deficient', 'Var', (5, 14))
62528	31287944	Further studies revealed that expression of CD248 exhibited negligible effects on primary tumour growth but increased metastasis formation in mouse models of breast cancer 92.	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('CD248', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Disease', (158, 171))	('increased', 'PosReg', (108, 117))	('expression', 'Var', (30, 40))	('mouse', 'Species', '10090', (142, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('formation', 'biological_process', 'GO:0009058', ('129', '138'))	('primary tumour', 'Disease', (82, 96))	('primary tumour', 'Disease', 'MESH:D009369', (82, 96))	('metastasis formation', 'CPA', (118, 138))
62530	31287944	Elevated-CD248 expression also correlated with greater metastasis and poorer survival in human breast cancer patients.	('human', 'Species', '9606', (89, 94))	('greater', 'PosReg', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('metastasis', 'CPA', (55, 65))	('breast cancer', 'Disease', (95, 108))	('patients', 'Species', '9606', (109, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('poorer', 'NegReg', (70, 76))	('Elevated-CD248', 'Var', (0, 14))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
62536	31287944	Also, siRNA-mediated knockdown of CD248 resulted in reduced migration and proliferation of fibroblasts, reinforcing a putative role in adhesion 99.	('rat', 'Species', '10116', (63, 66))	('reduced', 'NegReg', (52, 59))	('rat', 'Species', '10116', (81, 84))	('CD248', 'Gene', (34, 39))	('knockdown', 'Var', (21, 30))	('N', 'Chemical', 'MESH:D009584', (9, 10))
62537	31287944	Interestingly, a characteristic feature identified in CHO cells overexpressing CD248 is the upregulation of MMP9, thereby implicating CD248 in ECM degradation, a key step in sprouting angiogenesis as well as tumour metastasis and invasion 98.	('MMP9', 'Gene', (108, 112))	('CD248', 'Var', (134, 139))	('tumour metastasis', 'Disease', 'MESH:D009362', (208, 225))	('implicating', 'Reg', (122, 133))	('CHO', 'molecular_function', 'GO:0043848', ('54', '57'))	('CD248', 'Gene', (79, 84))	('overexpressing', 'Var', (64, 78))	('upregulation', 'PosReg', (92, 104))	('invasion', 'CPA', (230, 238))	('ECM degradation', 'MPA', (143, 158))	('tumour metastasis', 'Disease', (208, 225))	('MMP9', 'Gene', '100770707', (108, 112))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('sprouting angiogenesis', 'biological_process', 'GO:0002040', ('174', '196'))	('MMP9', 'molecular_function', 'GO:0004229', ('108', '112'))	('CHO', 'CellLine', 'CVCL:0213', (54, 57))	('degradation', 'biological_process', 'GO:0009056', ('147', '158'))
62541	31287944	This interaction invokes repulsion of human fibroblasts and HeLa cells expressing CD248 and Mac-2BP, respectively.	('repulsion', 'CPA', (25, 34))	('CD248', 'Gene', (82, 87))	('human', 'Species', '9606', (38, 43))	('HeLa', 'CellLine', 'CVCL:0030', (60, 64))	('invokes', 'Reg', (17, 24))	('interaction', 'Interaction', (5, 16))	('Mac-2BP', 'Var', (92, 99))
62551	31287944	Moreover, these observations underline the possible therapeutic potential of the CD248-ECD for inducing vessel regression and vascular normalisation, which might conceivably increase the delivery of chemotherapeutic agents into tumour tissue 108.	('CD248-ECD', 'Var', (81, 90))	('tumour', 'Disease', (228, 234))	('vessel regression', 'CPA', (104, 121))	('inducing', 'PosReg', (95, 103))	('increase', 'PosReg', (174, 182))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))	('tumour', 'Disease', 'MESH:D009369', (228, 234))	('vascular normalisation', 'CPA', (126, 148))	('delivery', 'MPA', (187, 195))
62553	31287944	For example, following CD248 knockdown in pericytes, PDGF-mediated proliferation is reduced in vitro.	('CD248', 'Gene', (23, 28))	('knockdown', 'Var', (29, 38))	('rat', 'Species', '10116', (74, 77))	('reduced', 'NegReg', (84, 91))	('PDGF-mediated', 'Gene', (53, 66))
62555	31287944	Such defects could be recapitulated in mice treated with PDGFRbeta inhibitors reinforcing a role for CD248 in PDGF signalling.	('inhibitors', 'Var', (67, 77))	('mice', 'Species', '10090', (39, 43))	('PDGFRbeta', 'Gene', (57, 66))	('signalling', 'biological_process', 'GO:0023052', ('115', '125'))	('PDGF', 'molecular_function', 'GO:0005161', ('110', '114'))	('PDGFRbeta', 'Gene', '18596', (57, 66))
62560	31287944	These highly invasive side populations are also CD248+ in osteosarcoma 118.	('osteosarcoma', 'Disease', (58, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('osteosarcoma', 'Phenotype', 'HP:0002669', (58, 70))	('osteosarcoma', 'Disease', 'MESH:D012516', (58, 70))	('CD248+', 'Var', (48, 54))
62573	31287944	The DNA construct consisted of murine CD248 fused to a fragment of tetanus toxoid, which circumvents tolerance to the self-protein allowing triggering of an adaptive immune response.	('tetanus toxoid', 'Disease', (67, 81))	('protein', 'cellular_component', 'GO:0003675', ('123', '130'))	('N', 'Chemical', 'MESH:D009584', (5, 6))	('tetanus toxoid', 'Disease', 'MESH:D013746', (67, 81))	('CD248', 'Gene', (38, 43))	('fused', 'Var', (44, 49))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('murine', 'Species', '10090', (31, 37))	('adaptive immune response', 'biological_process', 'GO:0002250', ('157', '181'))
62578	31287944	CD248 expression in mice is required for postnatal development of the thymus as well as regeneration of the thymus after S. enterica infection, in CD248 deficient animals this postinfection regeneration is impaired 130.	('deficient', 'Var', (153, 162))	('rat', 'Species', '10116', (94, 97))	('regeneration', 'biological_process', 'GO:0031099', ('190', '202'))	('rat', 'Species', '10116', (196, 199))	('mice', 'Species', '10090', (20, 24))	('CD248', 'Gene', (147, 152))	('regeneration', 'biological_process', 'GO:0031099', ('88', '100'))	('infection', 'Disease', (180, 189))	('infection', 'Disease', 'MESH:D007239', (180, 189))	('S. enterica', 'Species', '28901', (121, 132))	('infection', 'Disease', (133, 142))	('infection', 'Disease', 'MESH:D007239', (133, 142))
62580	31287944	CD248 was shown to promote atherosclerosis as ApoE and CD248 double KO mice displayed less atherosclerosis when fed a Western style diet.	('mice', 'Species', '10090', (71, 75))	('promote', 'PosReg', (19, 26))	('atherosclerosis', 'Disease', 'MESH:D050197', (91, 106))	('atherosclerosis', 'Phenotype', 'HP:0002621', (91, 106))	('CD248', 'Var', (0, 5))	('atherosclerosis', 'Disease', (91, 106))	('atherosclerosis', 'Disease', 'MESH:D050197', (27, 42))	('atherosclerosis', 'Phenotype', 'HP:0002621', (27, 42))	('ApoE', 'Gene', (46, 50))	('ApoE', 'Gene', '11816', (46, 50))	('CD248', 'Gene', (55, 60))	('atherosclerosis', 'Disease', (27, 42))
62582	31287944	Reduced macrophage recruitment in CD248 KO mice was also shown in other models of inflammation not involving atherosclerosis.	('mice', 'Species', '10090', (43, 47))	('macrophage', 'CPA', (8, 18))	('atherosclerosis', 'Disease', 'MESH:D050197', (109, 124))	('atherosclerosis', 'Phenotype', 'HP:0002621', (109, 124))	('atherosclerosis', 'Disease', (109, 124))	('Reduced', 'NegReg', (0, 7))	('inflammation', 'Disease', 'MESH:D007249', (82, 94))	('inflammation', 'Disease', (82, 94))	('CD248 KO', 'Var', (34, 42))
62591	31287944	CD248-deficient mice undergoing renal damage were protected against fibrosis, this was not as a result of reduced inflammation but possibly due to CD248 KO fibroblasts producing less collagen and CD248 KO pericytes displaying impaired differentiation into myofibroblasts (a major cell type involved in fibrosis).	('renal damage', 'Disease', 'MESH:D007674', (32, 44))	('fibrosis', 'Disease', 'MESH:D005355', (68, 76))	('fibrosis', 'Disease', (68, 76))	('renal damage', 'Disease', (32, 44))	('inflammation', 'Disease', (114, 126))	('collagen', 'MPA', (183, 191))	('mice', 'Species', '10090', (16, 20))	('fibrosis', 'Disease', (302, 310))	('less', 'NegReg', (178, 182))	('CD248 KO', 'Var', (196, 204))	('fibrosis', 'Disease', 'MESH:D005355', (302, 310))	('CD248 KO', 'Var', (147, 155))	('inflammation', 'Disease', 'MESH:D007249', (114, 126))
62618	31287944	Silencing of CD93 by RNA interference in HUVEC-impaired proliferation, migration, adhesion and sprout formation 162.	('RNA interference', 'biological_process', 'GO:0016246', ('21', '37'))	('CD93', 'Gene', (13, 17))	('RNA', 'cellular_component', 'GO:0005562', ('21', '24'))	('rat', 'Species', '10116', (63, 66))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('sprout formation 162', 'CPA', (95, 115))	('formation', 'biological_process', 'GO:0009058', ('102', '111'))	('rat', 'Species', '10116', (74, 77))	('proliferation', 'CPA', (56, 69))	('migration', 'CPA', (71, 80))	('RNA interference', 'MPA', (21, 37))	('adhesion', 'CPA', (82, 90))	('Silencing', 'Var', (0, 9))
62629	31287944	Strikingly, reintroduction of wild-type CD93 but not CD93 lacking the moesin binding motif, restored adhesion junctions and highlighted the importance of CD93-moesin interactions in maintaining the integrity of endothelial cell adhesion in vitro.	('binding', 'molecular_function', 'GO:0005488', ('77', '84'))	('adhesion junctions', 'MPA', (101, 119))	('restored', 'PosReg', (92, 100))	('cell adhesion', 'biological_process', 'GO:0007155', ('223', '236'))	('moesin', 'Gene', '17698', (70, 76))	('interactions', 'Interaction', (166, 178))	('moesin', 'Gene', '17698', (159, 165))	('CD93', 'Var', (40, 44))	('moesin', 'Gene', (159, 165))	('moesin', 'Gene', (70, 76))
62634	31287944	CD93 binding to Cbl was proved experimentally by co-immunoprecipitation in HUVEC, and this interaction was abolished upon knockdown of the ECM adhesion molecule beta-dystroglycan 165.	('CD93', 'Gene', (0, 4))	('dystroglycan', 'Gene', (166, 178))	('Cbl', 'Gene', '12402', (16, 19))	('knockdown', 'Var', (122, 131))	('Cbl', 'Gene', (16, 19))	('dystroglycan', 'Gene', '1605', (166, 178))	('binding', 'Interaction', (5, 12))
62636	31287944	The authors suggested that upon laminin binding to beta-dystroglycan src kinase phosphorylates specific tyrosine residues in the cytoplasmic tail of CD93, which in turn facilitates binding to Cbl.	('binding', 'Interaction', (181, 188))	('dystroglycan', 'Gene', (56, 68))	('tyrosine residues', 'Var', (104, 121))	('facilitates', 'PosReg', (169, 180))	('dystroglycan', 'Gene', '1605', (56, 68))	('tyrosine', 'Chemical', 'None', (104, 112))	('Cbl', 'Gene', (192, 195))	('src', 'Gene', (69, 72))	('src', 'Gene', '20779', (69, 72))	('Cbl', 'Gene', '12402', (192, 195))	('binding', 'Interaction', (40, 47))
62638	31287944	Mice deficient in CD93 when subjected to experimental peritonitis displayed increased leucocyte infiltration, and this effect was not restricted to a particular cell type 170.	('peritonitis', 'Disease', (54, 65))	('increased', 'PosReg', (76, 85))	('CD93', 'Gene', (18, 22))	('leucocyte infiltration', 'CPA', (86, 108))	('rat', 'Species', '10116', (102, 105))	('Mice', 'Species', '10090', (0, 4))	('peritonitis', 'Phenotype', 'HP:0002586', (54, 65))	('peritonitis', 'Disease', 'MESH:D010534', (54, 65))	('deficient', 'Var', (5, 14))
62640	31287944	Moreover, cerebral ischaemia in CD93 knockout mice resulted in enhanced neuro-inflammation compared to wild-type animals.	('neuro-inflammation', 'Disease', (72, 90))	('cerebral ischaemia', 'Phenotype', 'HP:0002637', (10, 28))	('cerebral ischaemia', 'Disease', (10, 28))	('enhanced', 'PosReg', (63, 71))	('knockout', 'Var', (37, 45))	('neuro-inflammation', 'Disease', 'MESH:D007249', (72, 90))	('CD93', 'Gene', (32, 36))	('mice', 'Species', '10090', (46, 50))	('cerebral ischaemia', 'Disease', 'MESH:D002545', (10, 28))
62642	31287944	Based on the CD93 expression profile within the tumour vasculature and its potential anti-inflammatory roles, it is plausible to contemplate that CD93 may serve as an immunosuppressive molecule in the tumour microenvironment, limiting immune cell infiltration and facilitating tumour immune evasion mechanisms.	('CD93', 'Gene', (13, 17))	('tumour', 'Disease', (201, 207))	('tumour vasculature', 'Disease', (48, 66))	('tumour', 'Disease', 'MESH:D009369', (277, 283))	('immune cell infiltration', 'CPA', (235, 259))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Disease', (277, 283))	('CD93', 'Var', (146, 150))	('rat', 'Species', '10116', (253, 256))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('immune evasion', 'biological_process', 'GO:0042783', ('284', '298'))	('tumour', 'Disease', (48, 54))	('limiting', 'NegReg', (226, 234))	('tumour', 'Phenotype', 'HP:0002664', (277, 283))	('tumour vasculature', 'Disease', 'MESH:C565633', (48, 66))	('tumour', 'Disease', 'MESH:D009369', (201, 207))	('immune evasion', 'biological_process', 'GO:0051842', ('284', '298'))
62649	31287944	A role for soluble CD93 in the process of efferocytosis has been proposed, whereby cleaved CD93 binds to apoptotic cells via the CTLD in a Ca2+ independent manner 181.	('Ca2+', 'Chemical', 'MESH:D002118', (139, 143))	('CD93', 'Gene', (91, 95))	('cleaved', 'Var', (83, 90))	('binds', 'Interaction', (96, 101))
62652	31287944	Upon knockdown of MMRN2, together with inhibition of new protein synthesis by cycloheximide treatment, cell surface CD93 levels were shown to be diminished whereas soluble CD93 levels increased 167.	('soluble CD93 levels', 'MPA', (164, 183))	('knockdown', 'Var', (5, 14))	('increased', 'PosReg', (184, 193))	('cycloheximide', 'Chemical', 'MESH:D003513', (78, 91))	('cell surface CD93 levels', 'MPA', (103, 127))	('diminished', 'NegReg', (145, 155))	('MMRN2', 'Gene', (18, 23))
62665	31287944	During zebrafish development, clec14a is expressed at 24 h postfertilisation and morpholino knockdown of gene expression can have detrimental effects on vasculature formation 189.	('gene expression', 'biological_process', 'GO:0010467', ('105', '120'))	('formation', 'biological_process', 'GO:0009058', ('165', '174'))	('zebrafish', 'Species', '7955', (7, 16))	('knockdown', 'Var', (92, 101))	('clec14a', 'Gene', (30, 37))	('vasculature formation 189', 'CPA', (153, 178))	('clec14a', 'Gene', '327325', (30, 37))
62688	31287944	In addition, involvement of CLEC14A in sprouting angiogenesis was demonstrated by siRNA knockdown of CLEC14A in HUVEC which led to marked reduction in sprout formation based on spheroid assays, CLEC14A deficient cells were also less likely to be found as tip cells in these sprouts 203.	('sprouting angiogenesis', 'biological_process', 'GO:0002040', ('39', '61'))	('N', 'Chemical', 'MESH:D009584', (85, 86))	('rat', 'Species', '10116', (73, 76))	('knockdown', 'Var', (88, 97))	('sprout formation', 'CPA', (151, 167))	('CLEC14A', 'Gene', (101, 108))	('sprouting angiogenesis', 'CPA', (39, 61))	('formation', 'biological_process', 'GO:0009058', ('158', '167'))	('reduction', 'NegReg', (138, 147))
62691	31287944	Finally, these antibodies could reduce HUVEC cell migration and tube formation based on in vitro assays.	('tube formation', 'CPA', (64, 78))	('reduce', 'NegReg', (32, 38))	('rat', 'Species', '10116', (53, 56))	('HUVEC cell migration', 'CPA', (39, 59))	('antibodies', 'Var', (15, 25))
62702	31287944	This suggests that CLEC14A may have signalling roles, although the authors did not probe whether HSP70-1A-mediated ERK phosphorylation was blocked with knockdown of CLEC14A.	('knockdown', 'Var', (152, 161))	('signalling', 'biological_process', 'GO:0023052', ('36', '46'))	('ERK', 'Gene', (115, 118))	('CLEC14A', 'Gene', (165, 172))	('HSP70-1', 'Gene', '15511', (97, 104))	('ERK', 'Gene', '26413', (115, 118))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))	('HSP70-1', 'Gene', (97, 104))	('ERK', 'molecular_function', 'GO:0004707', ('115', '118'))
62703	31287944	There are currently no other known interactors for the CLEC14A cytoplasmic domain, although global phosphoproteomic analysis of HUVEC has revealed the presence of five serine residues that can be phosphorylated, namely S437, S445, S483 S487 and S488 209, 210.	('S483 S487', 'Chemical', 'MESH:C083382', (231, 240))	('S445', 'Var', (225, 229))	('S488 209', 'Var', (245, 253))	('S488', 'Chemical', 'MESH:C422193', (245, 249))	('S437', 'Var', (219, 223))	('serine', 'Chemical', 'MESH:C047902', (168, 174))	('S483 S487', 'Var', (231, 240))
62717	31287944	Upon point mutation of these long-loop cysteines, the CLEC14A CTLD folds correctly as it is recognised by conformation-specific monoclonal antibodies, but completely diminishes its binding capability with MMRN2 101.	('MMRN2', 'Protein', (205, 210))	('binding', 'Interaction', (181, 188))	('cysteines', 'Chemical', 'MESH:D003545', (39, 48))	('diminishes', 'NegReg', (166, 176))	('point mutation', 'Var', (5, 19))
62719	31287944	Thrombomodulin and CD93 are both anchored to the actin cytoskeleton by associating with ERM adapter proteins; thrombomodulin to ezrin and CD93 to moesin.	('moesin', 'Gene', (146, 152))	('associating', 'Reg', (71, 82))	('CD93', 'Var', (138, 142))	('actin cytoskeleton', 'cellular_component', 'GO:0015629', ('49', '67'))	('moesin', 'Gene', '17698', (146, 152))
62724	31287944	Strikingly, the RKE motif in CLEC14A could potentially abolish binding to ERM proteins due to repulsion effects attributable to the negatively charged glutamic acid side chain.	('glutamic acid', 'Chemical', 'MESH:C030030', (151, 164))	('abolish', 'NegReg', (55, 62))	('binding', 'Interaction', (63, 70))	('RKE motif', 'Var', (16, 25))	('repulsion effects', 'MPA', (94, 111))	('CLEC14A', 'Gene', (29, 36))	('binding', 'molecular_function', 'GO:0005488', ('63', '70'))	('ERM proteins', 'Protein', (74, 86))
62729	31287944	Interestingly, pericyte coverage of endothelium is reduced in the brain, retina and melanoma tumour vasculature of CLEC14A knockout mice 204.	('pericyte coverage of endothelium', 'CPA', (15, 47))	('reduced', 'NegReg', (51, 58))	('melanoma tumour', 'Disease', 'MESH:D008545', (84, 99))	('knockout', 'Var', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma tumour', 'Disease', (84, 99))	('mice', 'Species', '10090', (132, 136))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('CLEC14A', 'Gene', (115, 122))	('tumour vasculature', 'Disease', (93, 111))	('tumour vasculature', 'Disease', 'MESH:C565633', (93, 111))
62730	31287944	However, no defects were reported in pericyte coverage of vessels in models of gliomas between CD93 knockout and wild-type mice 156.	('gliomas', 'Disease', (79, 86))	('gliomas', 'Disease', 'MESH:D005910', (79, 86))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('knockout', 'Var', (100, 108))	('CD93', 'Gene', (95, 99))	('mice', 'Species', '10090', (123, 127))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
62741	31287944	Although high expression of thrombomodulin has been reported by multiple groups in diverse cancer indications, whether thrombomodulin can actually elicit an immunosuppressive function in the context of cancer remains to be elucidated and the finding that low thrombomodulin leads to improved prognosis seems to contradict this theory.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('prognosis', 'MPA', (292, 301))	('low thrombomodulin', 'Phenotype', 'HP:0040229', (255, 273))	('cancer', 'Disease', (91, 97))	('thrombomodulin', 'Gene', (259, 273))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('low', 'Var', (255, 258))	('cancer', 'Disease', (202, 208))	('improved', 'PosReg', (283, 291))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
62768	31287944	Knockdown of CD93 has also been shown to reduce VE-cadherin levels in HUVEC 156, although phenotypic outcomes following double knockdown of both CLEC14A and CD93 have not yet been reported in mammalian cell types.	('CD93', 'Gene', (13, 17))	('Knockdown', 'Var', (0, 9))	('VE-cadherin levels', 'MPA', (48, 66))	('reduce', 'NegReg', (41, 47))	('cadherin', 'molecular_function', 'GO:0008014', ('51', '59'))	('mammalian', 'Species', '9606', (192, 201))
62876	29216709	The high-risk group was defined as having at least one of the following: perforation/obstruction, lymph node harvest less than 12, lymphovascular/perineural invasion, positive resection margin, poor differentiation, or pathologic T4 stage.	('T4 stage', 'CPA', (230, 238))	('positive', 'Var', (167, 175))	('obstruction', 'Disease', 'MESH:D000402', (85, 96))	('poor differentiation', 'CPA', (194, 214))	('lymphovascular/perineural', 'Disease', (131, 156))	('obstruction', 'Disease', (85, 96))	('less', 'NegReg', (117, 121))
62924	29216709	The multivariate analysis revealed that without AC (HR of AC, 0.76; 95% CI, 0.38 to 0.59; p < 0.001), male, age greater than 70, BMI 18 or less and greater than 25, and ASA grade over II worsened the survival outcome (Table 4, Fig.	('worsened', 'NegReg', (187, 195))	('ASA', 'Chemical', '-', (169, 172))	('survival', 'MPA', (200, 208))	('greater than 70', 'Var', (112, 127))
62984	28969096	Aberrant expression of Rab25 was linked to cancer development.	('Aberrant expression', 'Var', (0, 19))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('Rab25', 'Gene', (23, 28))	('linked', 'Reg', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
63011	28969096	The inactive Rab proteins located in the cytosol and are recognized by guanine nucleotide exchange factor (GEF), which catalyzes the exchange of GDP for GTP at the guanine nucleotide binding motif to form the active Rab proteins.	('guanine nucleotide', 'Chemical', 'MESH:D006150', (71, 89))	('Rab', 'Gene', '3267', (13, 16))	('exchange', 'Var', (133, 141))	('GTP', 'MPA', (153, 156))	('GEF', 'Gene', (107, 110))	('Rab', 'Gene', '3267', (216, 219))	('GDP', 'MPA', (145, 148))	('GDP', 'Chemical', 'MESH:D006153', (145, 148))	('Rab', 'Gene', (13, 16))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (164, 182))	('GEF', 'Gene', '9181', (107, 110))	('Rab', 'Gene', (216, 219))	('GTP', 'Chemical', 'MESH:D006160', (153, 156))
63022	28969096	Modified Rab25, which does not interact with beta1 integrin, did not promote cell invasion.	('beta1 integrin', 'Gene', '3688', (45, 59))	('Rab25', 'Gene', (9, 14))	('beta1 integrin', 'Gene', (45, 59))	('Modified', 'Var', (0, 8))	('cell invasion', 'CPA', (77, 90))
63031	28969096	Rab25 knockdown reduced phospho-Akt level, leading to the reduction of cell migration/invasion in bladder cancer cell, hepatocellular carcinoma cells and glioblastoma multiforme cells.	('Akt', 'Gene', '207', (32, 35))	('rat', 'Species', '10116', (79, 82))	('hepatocellular carcinoma', 'Disease', (119, 143))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cell migration/invasion in', 'CPA', (71, 97))	('reduced', 'NegReg', (16, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('reduction', 'NegReg', (58, 67))	('Rab25', 'Gene', (0, 5))	('glioblastoma multiforme', 'Disease', (154, 177))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (119, 143))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (154, 177))	('glioblastoma', 'Phenotype', 'HP:0012174', (154, 166))	('Akt', 'Gene', (32, 35))	('bladder cancer', 'Disease', (98, 112))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('knockdown', 'Var', (6, 15))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (119, 143))
63032	28969096	Rab25 knockdown or Akt inhibitor was found to reduce cisplatin resistance in ovarian cancer cells.	('cisplatin resistance', 'MPA', (53, 73))	('ovarian cancer', 'Phenotype', 'HP:0100615', (77, 91))	('reduce', 'NegReg', (46, 52))	('Akt', 'Gene', '207', (19, 22))	('ovarian cancer', 'Disease', 'MESH:D010051', (77, 91))	('ovarian cancer', 'Disease', (77, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('Akt', 'Gene', (19, 22))	('knockdown', 'Var', (6, 15))	('Rab25', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
63038	28969096	Knockdown of Rab25 was found to reduce anti-apoptotic protein, Bcl-2, in tobacco carcinogen-induced lung cancer.	('anti-apoptotic protein', 'MPA', (39, 61))	('reduce', 'NegReg', (32, 38))	('Knockdown', 'Var', (0, 9))	('Bcl-2', 'MPA', (63, 68))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('63', '68'))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Disease', (100, 111))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tobacco', 'Species', '4097', (73, 80))	('Rab25', 'Gene', (13, 18))
63052	28969096	Epigenetic regulation also led to down-regulation of Rab25 in oral and oropharyngeal squamous cell carcinoma (OOSCC) and esophageal squamous cell carcinoma (ESCC), in which Rab25 acts as a tumor suppressor.	('tumor suppressor', 'biological_process', 'GO:0051726', ('189', '205'))	('esophageal squamous cell carcinoma', 'Disease', (121, 155))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('oral', 'Disease', (62, 66))	('Epigenetic regulation', 'Var', (0, 21))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('regulation', 'biological_process', 'GO:0065007', ('39', '49'))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (121, 155))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (71, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('down-regulation', 'NegReg', (34, 49))	('OOSCC', 'Phenotype', 'HP:0012182', (110, 115))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('tumor', 'Disease', (189, 194))	('regulation', 'biological_process', 'GO:0065007', ('11', '21'))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (132, 155))	('Rab25', 'Gene', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('189', '205'))	('squamous cell carcinoma', 'Disease', (85, 108))
63053	28969096	In ESCC, demethylation treatment and bisulfite genomic sequencing analyses revealed that down-regulation of Rab25 expression in both ESCC cell lines and clinical samples was associated with promoter hypermethylation.	('bisulfite', 'Chemical', 'MESH:C042345', (37, 46))	('regulation', 'biological_process', 'GO:0065007', ('94', '104'))	('promoter hypermethylation', 'Var', (190, 215))	('Rab25', 'Gene', (108, 113))	('clinical samples', 'Species', '191496', (153, 169))	('down-regulation', 'NegReg', (89, 104))	('demethylation', 'biological_process', 'GO:0070988', ('9', '22'))	('expression', 'MPA', (114, 124))
63063	28969096	Suppression of both in vitro cell growth and in vivo xenograft development were observed after knockdown of Rab25 in glioblastoma multiforme cells (U87MG) and breast cancer cells (MCF7).	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (117, 140))	('MCF7', 'CellLine', 'CVCL:0031', (180, 184))	('Rab25', 'Gene', (108, 113))	('glioblastoma multiforme', 'Disease', (117, 140))	('knockdown', 'Var', (95, 104))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('Suppression', 'NegReg', (0, 11))	('breast cancer', 'Disease', (159, 172))	('cell growth', 'biological_process', 'GO:0016049', ('29', '40'))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('U87MG', 'CellLine', 'CVCL:0022', (148, 153))	('glioblastoma', 'Phenotype', 'HP:0012174', (117, 129))
63064	28969096	Knockdown of Rab25 was reported to inhibit tumor growth in tobacco carcinogen-induced lung cancer model.	('Knockdown', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('tobacco', 'Species', '4097', (59, 66))	('lung cancer', 'Disease', (86, 97))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('tumor', 'Disease', (43, 48))	('inhibit', 'NegReg', (35, 42))	('Rab25', 'Gene', (13, 18))
63066	28969096	Rab25 ectopic overexpression was found to increase development of xenograft derived from breast cancer cells (MCF7) and ovarian cancer cells (A2780, HEY).	('ectopic overexpression', 'Var', (6, 28))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('ovarian cancer', 'Disease', 'MESH:D010051', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('ovarian cancer', 'Disease', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Rab25', 'Gene', (0, 5))	('development of xenograft derived', 'CPA', (51, 83))	('MCF7', 'CellLine', 'CVCL:0031', (110, 114))	('increase', 'PosReg', (42, 50))	('ovarian cancer', 'Phenotype', 'HP:0100615', (120, 134))
63068	28969096	Knockdown of Rab25 was reported to increase apoptosis in ovarian cancer cells and tobacco carcinogen-induced lung cancer model.	('lung cancer', 'Disease', (109, 120))	('increase', 'PosReg', (35, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('ovarian cancer', 'Disease', 'MESH:D010051', (57, 71))	('Knockdown', 'Var', (0, 9))	('tobacco', 'Species', '4097', (82, 89))	('apoptosis', 'CPA', (44, 53))	('ovarian cancer', 'Disease', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('ovarian cancer', 'Phenotype', 'HP:0100615', (57, 71))	('Rab25', 'Gene', (13, 18))
63073	28969096	Suppression of cell invasion after Rab25 knockdown was observed in gastric cancer cells.	('gastric cancer', 'Disease', (67, 81))	('Rab25', 'Gene', (35, 40))	('gastric cancer', 'Disease', 'MESH:D013274', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cell invasion', 'CPA', (15, 28))	('Suppression', 'NegReg', (0, 11))	('gastric cancer', 'Phenotype', 'HP:0012126', (67, 81))	('knockdown', 'Var', (41, 50))
63074	28969096	's study, which showed that Rab25 depletion negatively regulated the invasion ability of hepatocellular carcinoma cells.	('hepatocellular carcinoma', 'Disease', (89, 113))	('Rab25', 'Gene', (28, 33))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (89, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('invasion ability of', 'CPA', (69, 88))	('depletion', 'Var', (34, 43))	('negatively', 'NegReg', (44, 54))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (89, 113))
63075	28969096	In the study of bladder cancer, Rab25 knockdown not only suppress in vitro cell migration but also reduce in vivo tumor metastasis.	('rat', 'Species', '10116', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('bladder cancer', 'Disease', 'MESH:D001749', (16, 30))	('bladder cancer', 'Disease', (16, 30))	('reduce', 'NegReg', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('in vitro cell migration', 'CPA', (66, 89))	('tumor metastasis', 'Disease', (114, 130))	('suppress', 'NegReg', (57, 65))	('Rab25', 'Gene', (32, 37))	('tumor metastasis', 'Disease', 'MESH:D009362', (114, 130))	('bladder cancer', 'Phenotype', 'HP:0009725', (16, 30))	('knockdown', 'Var', (38, 47))
63085	28969096	Loss of Rab25 in human colon cancers was associated with poorer patient prognosis.	('colon cancer', 'Phenotype', 'HP:0003003', (23, 35))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('patient', 'Species', '9606', (64, 71))	('human', 'Species', '9606', (17, 22))	('colon cancers', 'Disease', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Rab25', 'Gene', (8, 13))	('colon cancers', 'Phenotype', 'HP:0003003', (23, 36))	('colon cancers', 'Disease', 'MESH:D015179', (23, 36))	('Loss', 'Var', (0, 4))
63086	28969096	Rab25 deficiency promotes intestinal/colon adenoma formation in ApcMin/+ mice.	('promotes', 'PosReg', (17, 25))	('colon adenoma', 'Disease', (37, 50))	('mice', 'Species', '10090', (73, 77))	('deficiency', 'Var', (6, 16))	('colon adenoma', 'Disease', 'MESH:D000236', (37, 50))	('Rab25', 'Gene', (0, 5))
63090	28969096	In the study of head and neck squamous cell carcinoma, Rab25 ectopic overexpression reduced in vitro cell invasion and in vivo tumor metastasis to cervical lymph node.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('neck squamous cell carcinoma', 'Disease', (25, 53))	('tumor metastasis', 'Disease', 'MESH:D009362', (127, 143))	('Rab25', 'Gene', (55, 60))	('tumor metastasis', 'Disease', (127, 143))	('ectopic', 'Var', (61, 68))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (25, 53))	('reduced', 'NegReg', (84, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (30, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))
63094	28969096	Pancreatic cancer patients with high Rab25 and high CLIC3 levels were associated with significantly shorter survival time.	('high', 'Var', (32, 36))	('Pancreatic cancer', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Rab25', 'MPA', (37, 42))	('survival time', 'CPA', (108, 121))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('shorter', 'NegReg', (100, 107))	('patients', 'Species', '9606', (18, 26))	('CLIC3', 'Gene', '9022', (52, 57))	('CLIC3', 'Gene', (52, 57))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))
63097	28969096	When Rab25 acts as an oncogene, Rab25 enhances alpha5beta1 integrin recycling to the plasma membrane, leading to increase in cancer progression of ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('ovarian cancer', 'Disease', 'MESH:D010051', (147, 161))	('beta1 integrin', 'Gene', '3688', (53, 67))	('Rab25', 'Var', (32, 37))	('increase', 'PosReg', (113, 121))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('ovarian cancer', 'Disease', (147, 161))	('enhances', 'PosReg', (38, 46))	('cancer', 'Disease', (155, 161))	('beta1 integrin', 'Gene', (53, 67))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
63104	28969096	The role or Rab25 in promoting cancer metastasis is confirmed by in vitro experiments in which knockdown of Rab25 decreased cell migration and invasion of 786-O and A-498 RCC cells.	('rat', 'Species', '10116', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('invasion', 'CPA', (143, 151))	('Rab25', 'Gene', (108, 113))	('cell migration', 'CPA', (124, 138))	('knockdown', 'Var', (95, 104))	('decreased', 'NegReg', (114, 123))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))
63106	28969096	The cisplatin-based chemotherapy response rate of NSCLC patients with Rab25-positive expression was 30%, as opposed to 52% for patients with Rab25-negative expression.	('patients', 'Species', '9606', (56, 64))	('cisplatin-based', 'CPA', (4, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (50, 55))	('Rab25-positive expression', 'Var', (70, 95))	('patients', 'Species', '9606', (127, 135))	('NSCLC', 'Disease', (50, 55))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))	('rat', 'Species', '10116', (42, 45))
63107	28969096	Elevated expression of Rab25 may be due to amplification of RAB25 gene located in chromosome 1q22.	('RAB25', 'Gene', '57111', (60, 65))	('amplification', 'Var', (43, 56))	('Rab25', 'Gene', (23, 28))	('Elevated', 'PosReg', (0, 8))	('RAB25', 'Gene', (60, 65))	('expression', 'MPA', (9, 19))
63108	28969096	Amplification of RAB25 was reported to associate with markedly decreased disease-free survival or overall survival in ovarian cancer in Cheng et al.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Amplification', 'Var', (0, 13))	('ovarian cancer', 'Disease', (118, 132))	('decreased', 'NegReg', (63, 72))	('RAB25', 'Gene', '57111', (17, 22))	('disease-free survival', 'CPA', (73, 94))	('ovarian cancer', 'Phenotype', 'HP:0100615', (118, 132))	('overall survival', 'CPA', (98, 114))	('RAB25', 'Gene', (17, 22))	('ovarian cancer', 'Disease', 'MESH:D010051', (118, 132))
63110	28969096	Ovarian cancer patients with elevated RAB25 amplification either did not enter a disease free state following surgery and chemotherapy or showed very short disease-free survival, implicating RAB25 as potential driver gene correlated with poor prognosis and aggressive behavior of ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('patients', 'Species', '9606', (15, 23))	('elevated', 'PosReg', (29, 37))	('Ovarian cancer', 'Disease', 'MESH:D010051', (0, 14))	('RAB25', 'Gene', '57111', (38, 43))	('aggressive behavior', 'Phenotype', 'HP:0000718', (257, 276))	('RAB25', 'Gene', (191, 196))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (0, 14))	('ovarian cancer', 'Phenotype', 'HP:0100615', (280, 294))	('amplification', 'Var', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('aggressive behavior', 'biological_process', 'GO:0002118', ('257', '276'))	('aggressive behavior of ovarian cancer', 'Disease', 'MESH:D001523', (257, 294))	('RAB25', 'Gene', (38, 43))	('aggressive behavior of ovarian cancer', 'Disease', (257, 294))	('RAB25', 'Gene', '57111', (191, 196))	('Ovarian cancer', 'Disease', (0, 14))
63115	28969096	Biological and clinicopathological findings revealed that alteration of Rab25 level has high impact on cancer progression and patient survival.	('patient survival', 'CPA', (126, 142))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Rab25', 'Gene', (72, 77))	('patient', 'Species', '9606', (126, 133))	('alteration', 'Var', (58, 68))	('rat', 'Species', '10116', (62, 65))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('impact', 'Reg', (93, 99))
63117	28969096	Rab25 overexpression and gene copy number amplification was reported in various types of cancer.	('gene copy number amplification', 'Var', (25, 55))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('overexpression', 'PosReg', (6, 20))	('Rab25', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
63122	28969096	Moreover, it is important to identify the mechanisms that lead to copy number amplification of RAB25 in order to find out the potential methods for cancer prevention.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('RAB25', 'Gene', '57111', (95, 100))	('copy number amplification', 'Var', (66, 91))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('RAB25', 'Gene', (95, 100))
63132	28542357	For instance, incorrect mitochondrial biogenesis is correlated with increased risk of developing colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (97, 114))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('mitochondrial biogenesis', 'MPA', (24, 48))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('incorrect', 'Var', (14, 23))	('colorectal cancer', 'Disease', (97, 114))
63141	28542357	Consequently, any disruption to the expression of these genes can promote the genesis and progression of colon cancer.	('colon cancer', 'Disease', 'MESH:D015179', (105, 117))	('colon cancer', 'Disease', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('promote', 'PosReg', (66, 73))	('genesis', 'CPA', (78, 85))	('progression', 'CPA', (90, 101))	('disruption', 'Var', (18, 28))	('colon cancer', 'Phenotype', 'HP:0003003', (105, 117))
63147	28542357	ROS are extremely harmful for cellular micromolecules because they induce tumorigenesis through non-specific reactions with nucleic acids, proteins, and lipids.	('ROS', 'Var', (0, 3))	('tumorigenesis', 'CPA', (74, 87))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('lipids', 'Chemical', 'MESH:D008055', (153, 159))	('proteins', 'Protein', (139, 147))	('non-specific reactions', 'MPA', (96, 118))	('induce', 'PosReg', (67, 73))
63170	28542357	As shown in Fig 4, correct expression of NRF2 prevent CRC in humans, while altered expression of this gene promotes tumour genesis and progression (Figs 5 and 6).	('prevent', 'NegReg', (46, 53))	('NRF2', 'Gene', (41, 45))	('tumour genesis', 'Disease', (116, 130))	('humans', 'Species', '9606', (61, 67))	('CRC', 'Disease', (54, 57))	('altered', 'Var', (75, 82))	('promotes', 'PosReg', (107, 115))	('correct expression', 'Var', (19, 37))	('NRF2', 'Gene', '4780', (41, 45))	('tumour genesis', 'Disease', 'MESH:D009369', (116, 130))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
63171	28542357	The articles selected show that research on the role of NRF2 in CRC can be classified into three broad groups: i) those that analyse standard expression and observe a cytoprotective effect on CRC, and those that analyse variations in expression, either ii) overexpression or iii) inhibition, both leading to increased CRC risk.	('NRF2', 'Gene', '4780', (56, 60))	('variations', 'Var', (220, 230))	('expression', 'MPA', (234, 244))	('NRF2', 'Gene', (56, 60))	('CRC', 'Disease', (318, 321))	('inhibition', 'NegReg', (280, 290))	('overexpression', 'PosReg', (257, 271))
63180	28542357	For example, Jung and Kwak, 2013 silenced Keap1 and found that induction of NRF2 promoted the expression of AKR members, which are involved in the detoxification process, leading to reduced risk of CRC.	('Keap1', 'Gene', '9817', (42, 47))	('Keap1', 'Gene', (42, 47))	('NRF2', 'Gene', '4780', (76, 80))	('NRF2', 'Gene', (76, 80))	('induction', 'Var', (63, 72))	('promoted', 'PosReg', (81, 89))	('expression', 'MPA', (94, 104))	('detoxification', 'biological_process', 'GO:0098754', ('147', '161'))	('AKR members', 'Gene', (108, 119))	('reduced', 'NegReg', (182, 189))
63182	28542357	In all of these cases, standard NRF2 expression levels function as a protective factor against CRC by providing cytoprotection and by activating antioxidant target genes.	('NRF2', 'Gene', '4780', (32, 36))	('standard', 'Var', (23, 31))	('CRC', 'Disease', (95, 98))	('NRF2', 'Gene', (32, 36))	('cytoprotection', 'CPA', (112, 126))	('expression', 'MPA', (37, 47))	('activating', 'PosReg', (134, 144))
63183	28542357	These results are corroborated by the review by Pandurangan and Esa, (2014) and Pandurangan et al (2014a, 2014b), who also support the idea that expression of NRF2 decreases the risk of CRC.	('expression', 'Var', (145, 155))	('decreases', 'NegReg', (164, 173))	('NRF2', 'Gene', '4780', (159, 163))	('CRC', 'Disease', (186, 189))	('NRF2', 'Gene', (159, 163))
63185	28542357	This overexpression can occur for a number of reasons, including constitutive mutations in the Keap1 repressor gene or in the NRF2 gene itself.	('Keap1', 'Gene', '9817', (95, 100))	('Keap1', 'Gene', (95, 100))	('mutations', 'Var', (78, 87))	('NRF2', 'Gene', '4780', (126, 130))	('NRF2', 'Gene', (126, 130))
63188	28542357	Other authors have observed similar results when NRF2 is overexpressed as a consequence of silencing, or as a result of epigenetic changes in this gene.	('NRF2', 'Gene', (49, 53))	('epigenetic changes', 'Var', (120, 138))	('overexpressed', 'PosReg', (57, 70))	('silencing', 'Var', (91, 100))	('NRF2', 'Gene', '4780', (49, 53))
63191	28542357	Therefore, as mentioned above, overexpression of the NRF2 gene is closely linked to increased risk of CRC.	('overexpression', 'Var', (31, 45))	('NRF2', 'Gene', '4780', (53, 57))	('CRC', 'Disease', (102, 105))	('NRF2', 'Gene', (53, 57))	('linked', 'Reg', (74, 80))
63193	28542357	Notably, NRF2 overexpression has also been linked to increased resistance to the chemotherapeutic agent 5-FU via the activity of demethylases and methyltransferases.	('activity', 'MPA', (117, 125))	('resistance to the chemotherapeutic agent 5-FU', 'MPA', (63, 108))	('NRF2', 'Gene', '4780', (9, 13))	('overexpression', 'Var', (14, 28))	('5-FU', 'Chemical', 'MESH:D005472', (104, 108))	('NRF2', 'Gene', (9, 13))	('increased', 'PosReg', (53, 62))	('methyltransferases', 'Enzyme', (146, 164))	('demethylases', 'Enzyme', (129, 141))
63196	28542357	(2016) found that silencing Nrf2 resulted in decreased expression of the COX2 gene, leading to an increase in the number of aberrant crypts, resulting in the formation of adenoma, adenocarcinoma and ultimately CRC.	('adenoma', 'Disease', 'MESH:D000236', (171, 178))	('silencing', 'Var', (18, 27))	('decreased', 'NegReg', (45, 54))	('expression', 'MPA', (55, 65))	('adenoma', 'Disease', (171, 178))	('increase', 'PosReg', (98, 106))	('COX2', 'Gene', (73, 77))	('adenocarcinoma', 'Disease', (180, 194))	('Nrf2', 'Gene', (28, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('CRC', 'Disease', (210, 213))	('adenocarcinoma', 'Disease', 'MESH:D000230', (180, 194))	('COX2', 'Gene', '4513', (73, 77))
63197	28542357	Other studies have compared the effects of silencing the Nrf2 gene in mice and exposing them to treatments that induce ulcerative colitis (DSS) or colon carcinogenesis (AOM).	('colitis', 'Phenotype', 'HP:0002583', (130, 137))	('Nrf2', 'Gene', (57, 61))	('colon carcinogenesis', 'Disease', (147, 167))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (147, 167))	('silencing', 'Var', (43, 52))	('mice', 'Species', '10090', (70, 74))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (119, 137))	('ulcerative colitis', 'Disease', (119, 137))	('induce', 'Reg', (112, 118))	('ulcerative colitis', 'Disease', 'MESH:D003093', (119, 137))
63200	28542357	(2009) observed that NRF2 expression is beneficial during early stages, but can contribute to tumorigenesis in the colon at later stages.	('NRF2', 'Gene', (21, 25))	('expression', 'Var', (26, 36))	('NRF2', 'Gene', '4780', (21, 25))	('tumorigenesis in the colon', 'CPA', (94, 120))	('contribute', 'Reg', (80, 90))
63202	28542357	(2016) suggested that some SNP alleles in the NRF2 gene could increase CRC risk based on previous studies of these polymorphisms and the risk of ulcerative colitis.	('ulcerative colitis', 'Phenotype', 'HP:0100279', (145, 163))	('SNP alleles', 'Var', (27, 38))	('colitis', 'Phenotype', 'HP:0002583', (156, 163))	('CRC', 'Disease', (71, 74))	('NRF2', 'Gene', '4780', (46, 50))	('ulcerative colitis', 'Disease', 'MESH:D003093', (145, 163))	('NRF2', 'Gene', (46, 50))	('increase', 'PosReg', (62, 70))	('ulcerative colitis', 'Disease', (145, 163))
63203	28542357	Most of the articles focus on colon stem cells, which need more energy and therefore require greater expression of NRF2 to obtain the necessary ATP for proliferation, migration and differentiation, such that altered expression of NRF2 increases genetic instability leading to increased CRC risk.	('NRF2', 'Gene', (230, 234))	('NRF2', 'Gene', '4780', (115, 119))	('increased', 'PosReg', (276, 285))	('ATP', 'Chemical', 'MESH:D000255', (144, 147))	('NRF2', 'Gene', (115, 119))	('increases', 'PosReg', (235, 244))	('NRF2', 'Gene', '4780', (230, 234))	('altered', 'Var', (208, 215))	('CRC risk', 'Disease', (286, 294))	('genetic instability', 'MPA', (245, 264))
63204	28542357	In vivo, these cells migrate to the apical part of the crypt and become mature epithelial cells, and altered expression of NRF2 during migration and differentiation, will lead to an accumulation of mutations that promote tumorigenesis due to absence of cytoprotection.	('tumorigenesis', 'CPA', (221, 234))	('lead to', 'Reg', (171, 178))	('altered', 'Var', (101, 108))	('promote', 'PosReg', (213, 220))	('mutations', 'Var', (198, 207))	('NRF2', 'Gene', '4780', (123, 127))	('NRF2', 'Gene', (123, 127))
63209	28422056	Adiponectin and Intelectin-1: Important Adipokine Players in Obesity-Related Colorectal Carcinogenesis Overweight is believed to be associated with colorectal cancer risk.	('colorectal cancer', 'Disease', 'MESH:D015179', (148, 165))	('Adiponectin', 'Gene', '9370', (0, 11))	('Obesity', 'Phenotype', 'HP:0001513', (61, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (148, 165))	('Intelectin-1', 'Gene', '55600', (16, 28))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('Colorectal Carcinogenesis', 'Disease', 'MESH:D063646', (77, 102))	('Colorectal Carcinogenesis', 'Disease', (77, 102))	('Overweight', 'Var', (103, 113))	('colorectal cancer', 'Disease', (148, 165))	('Overweight', 'Phenotype', 'HP:0025502', (103, 113))	('Adiponectin', 'Gene', (0, 11))	('associated', 'Reg', (132, 142))	('Intelectin-1', 'Gene', (16, 28))
63210	28422056	Aberrant hormonal systems consisting of modulated adipokines and their receptors are thought to play a role in colorectal carcinogenesis and cancer progression in obese conditions.	('colorectal carcinogenesis', 'Disease', (111, 136))	('role', 'Reg', (103, 107))	('Aberrant', 'Var', (0, 8))	('obese conditions', 'Disease', 'MESH:D009765', (163, 179))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (111, 136))	('play', 'Reg', (96, 100))	('obese conditions', 'Disease', (163, 179))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
63215	28422056	Moreover, our recent study indicated that loss of TMEM207, which is critical for the proper processing of intelectin-1 in the colon mucosa, leads to insufficient intelectin-1 production, thus participating in colorectal carcinogenesis.	('intelectin-1', 'Gene', '55600', (106, 118))	('colon mucosa', 'Disease', 'MESH:D015179', (126, 138))	('loss', 'Var', (42, 46))	('TMEM207', 'Gene', (50, 57))	('intelectin-1', 'Gene', (106, 118))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (209, 234))	('intelectin-1', 'Gene', '55600', (162, 174))	('insufficient', 'NegReg', (149, 161))	('colorectal carcinogenesis', 'Disease', (209, 234))	('colon mucosa', 'Disease', (126, 138))	('intelectin-1', 'Gene', (162, 174))	('participating in', 'Reg', (192, 208))
63224	28422056	Recent studies revealed that the loss or overexpression of several adipokines and the aberrant expression of their receptors may lead to colorectal carcinogenesis (Table 1).	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (137, 162))	('lead to', 'Reg', (129, 136))	('loss', 'NegReg', (33, 37))	('colorectal carcinogenesis', 'Disease', (137, 162))	('aberrant', 'Var', (86, 94))	('overexpression', 'PosReg', (41, 55))
63236	28422056	showed that hypermethylation of the promoter region of the T-cadherin gene is frequently found in colorectal cancers and adenomas.	('colorectal cancers', 'Disease', (98, 116))	('adenomas', 'Disease', (121, 129))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('hypermethylation', 'Var', (12, 28))	('T-cadherin', 'Gene', (59, 69))	('found', 'Reg', (89, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('T-cadherin', 'Gene', '1012', (59, 69))	('adenomas', 'Disease', 'MESH:D000236', (121, 129))	('colorectal cancers', 'Disease', 'MESH:D015179', (98, 116))
63238	28422056	recently reported the methylation status of the T-cadherin promoter in non-neoplastic mucosa as a marker of ulcerative colitis-associated colorectal cancer.	('ulcerative colitis', 'Disease', (108, 126))	('colitis', 'Phenotype', 'HP:0002583', (119, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('T-cadherin', 'Gene', (48, 58))	('colorectal cancer', 'Disease', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('ulcerative colitis', 'Disease', 'MESH:D003093', (108, 126))	('methylation status', 'Var', (22, 40))	('T-cadherin', 'Gene', '1012', (48, 58))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (108, 126))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))
63251	28422056	Moreover, they demonstrated that hyperleptinemia in ApcMin/+ mice, which harbor a point mutation at the Apc gene and are a well-established model for human familial adenomatous polyposis, did not enhance the development of intestinal adenomas.	('Apc', 'Gene', (104, 107))	('hyperleptinemia', 'Disease', (33, 48))	('Apc', 'Gene', (52, 55))	('mice', 'Species', '10090', (61, 65))	('Apc', 'Gene', '11789', (104, 107))	('human', 'Species', '9606', (150, 155))	('Apc', 'Gene', '11789', (52, 55))	('intestinal adenomas', 'Disease', (223, 242))	('Apc', 'cellular_component', 'GO:0005680', ('104', '107'))	('hyperleptinemia', 'Disease', 'None', (33, 48))	('familial adenomatous polyposis', 'Disease', (156, 186))	('men', 'Species', '9606', (215, 218))	('development of intestinal adenomas', 'Phenotype', 'HP:0200008', (208, 242))	('intestinal adenomas', 'Disease', 'MESH:D000236', (223, 242))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (156, 186))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (165, 186))	('point mutation', 'Var', (82, 96))
63292	28422056	These findings imply that antagonists of the apelin/APJ system can prevent the progression of colorectal cancer by impairing tumor cell growth and/or inhibiting tumor neovascularization.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('impairing tumor', 'Disease', 'MESH:D015417', (115, 130))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Disease', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('prevent', 'NegReg', (67, 74))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('apelin', 'Gene', '8862', (45, 51))	('APJ', 'Gene', '187', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('APJ', 'Gene', (52, 55))	('colorectal cancer', 'Disease', (94, 111))	('inhibiting', 'NegReg', (150, 160))	('impairing tumor', 'Disease', (115, 130))	('apelin', 'Gene', (45, 51))	('antagonists', 'Var', (26, 37))	('tumor', 'Disease', (125, 130))
63321	28422056	We summarized studies of aberrant adipokines/receptors in colorectal carcinogenesis in Table 1.	('aberrant', 'Var', (25, 33))	('colorectal carcinogenesis', 'Disease', (58, 83))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (58, 83))
63323	28422056	Low-level adiponectin is thought to be associated with a higher risk of colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (72, 89))	('adiponectin', 'Gene', (10, 21))	('Low-level adiponectin', 'Phenotype', 'HP:0030685', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('associated', 'Reg', (39, 49))	('colorectal cancer', 'Disease', (72, 89))	('adiponectin', 'Gene', '9370', (10, 21))	('Low-level', 'Var', (0, 9))
63324	28422056	recently showed that low-level adiponectin is associated with KRAS-mutated colorectal cancer, but not with KRAS wild-type colorectal cancer.	('low-level', 'Var', (21, 30))	('adiponectin', 'Gene', (31, 42))	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('KRAS', 'Gene', (62, 66))	('KRAS', 'Gene', (107, 111))	('colorectal cancer', 'Disease', (75, 92))	('low-level adiponectin', 'Phenotype', 'HP:0030685', (21, 42))	('KRAS', 'Gene', '3845', (62, 66))	('colorectal cancer', 'Disease', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('KRAS', 'Gene', '3845', (107, 111))	('colorectal cancer', 'Disease', 'MESH:D015179', (122, 139))	('associated', 'Reg', (46, 56))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('adiponectin', 'Gene', '9370', (31, 42))
63341	28344541	We selected for the differential proteomic analyses some tissue samples from early CRC stages (namely pT1N0M0 and pT2N0M0) and compared these to normal and inflamed tissues taken from diverticular diseases.	('pT1', 'Gene', (102, 105))	('diverticular diseases', 'Disease', 'MESH:D000076385', (184, 205))	('diverticular diseases', 'Disease', (184, 205))	('CRC', 'Phenotype', 'HP:0003003', (83, 86))	('pT2N0M0', 'Var', (114, 121))	('pT1', 'Gene', '58492', (102, 105))
63342	28344541	We characterised IHC tissue distributions of some selected proteins in all possible precancerous and cancerous stages, from adenomas with low grade dysplasia to pT4NM of CRC.	('pT4NM', 'Var', (161, 166))	('adenomas', 'Disease', (124, 132))	('dysplasia', 'Disease', (148, 157))	('cancerous', 'Disease', (101, 110))	('cancerous', 'Disease', 'MESH:D009369', (87, 96))	('dysplasia', 'Disease', 'MESH:D004476', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancerous', 'Disease', 'MESH:D009369', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('adenomas', 'Disease', 'MESH:D000236', (124, 132))	('CRC', 'Phenotype', 'HP:0003003', (170, 173))	('cancerous', 'Disease', (87, 96))
63365	28344541	The Anova test was applied to compare the four categories of samples (DH vs. DI vs. pT1N0M0 vs. pT2N0M0) as well as the two cancer stages (pT1N0M0 vs. pT2N0M0).	('cancer', 'Disease', (124, 130))	('pT1', 'Gene', '58492', (139, 142))	('pT1', 'Gene', '58492', (84, 87))	('DH', 'Var', (70, 72))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('DH', 'Chemical', '-', (70, 72))	('pT1', 'Gene', (84, 87))	('DI', 'Chemical', '-', (77, 79))	('pT1', 'Gene', (139, 142))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
63374	28344541	The independent datasets of adequate clinical scopes included were GSE13471, GSE13428 and GSE62932, including the tissues analysis of 96 patients.	('GSE13428', 'Var', (77, 85))	('GSE13471', 'Var', (67, 75))	('GSE62932', 'Var', (90, 98))	('patients', 'Species', '9606', (137, 145))
63377	28344541	Only the proteins found significant in "DH versus DI versus pT1N0M0 versus pT2N0M0" and "pT1N0M0 versus pT2N0M0" and showing a minimum Fc of 2 were considered for GO analyses.	('pT1', 'Gene', '58492', (60, 63))	('pT1', 'Gene', '58492', (89, 92))	('pT2N0M0', 'Var', (75, 82))	('pT1', 'Gene', (60, 63))	('pT1', 'Gene', (89, 92))	('DI', 'Chemical', '-', (50, 52))	('DH', 'Chemical', '-', (40, 42))
63379	28344541	We obtained 5258 proteins identified through 80% of the samples analysed and 3547 proteins quantified in the four groups (DH, DI, pT1N0M0 and pT2N0M0).	('pT1', 'Gene', (130, 133))	('DH', 'Chemical', '-', (122, 124))	('pT2N0M0', 'Var', (142, 149))	('pT1', 'Gene', '58492', (130, 133))	('DI', 'Chemical', '-', (126, 128))
63380	28344541	We performed several comparisons: DH versus DI versus pT1N0M0 versus pT2N0M0 and pT1N0M0 versus pT2N0M0.	('DI', 'Chemical', '-', (44, 46))	('DH', 'Chemical', '-', (34, 36))	('pT2N0M0', 'Var', (69, 76))	('pT1', 'Gene', '58492', (81, 84))	('pT1', 'Gene', '58492', (54, 57))	('pT1', 'Gene', (81, 84))	('pT1', 'Gene', (54, 57))
63381	28344541	The proteins significant in pT1N0M0 versus pT2N0M0 are likely associated to CRC progression.	('proteins', 'Protein', (4, 12))	('associated', 'Reg', (62, 72))	('pT1', 'Gene', (28, 31))	('CRC', 'Phenotype', 'HP:0003003', (76, 79))	('CRC progression', 'Disease', (76, 91))	('pT2N0M0', 'Var', (43, 50))	('pT1', 'Gene', '58492', (28, 31))
63384	28344541	To partially validate our proteomic results, we selected three proteins (in red in Additional file 2: Table S2) that were found differentially distributed in one or both comparisons: (pT1N0M0 vs. pT2N0M0) and (DH vs. DI vs. pT1N0M0 vs. pT2N0M0).	('DI', 'Chemical', '-', (217, 219))	('pT1', 'Gene', '58492', (184, 187))	('DH', 'Var', (210, 212))	('pT1', 'Gene', (224, 227))	('DH', 'Chemical', '-', (210, 212))	('pT1', 'Gene', (184, 187))	('pT1', 'Gene', '58492', (224, 227))
63396	28344541	Sec24C was found significantly more abundant in epithelial cells of pT1 and pT2N0M0 compared to DH (p value <0.01 and p value <0.001, respectively).	('Sec24C', 'Gene', (0, 6))	('DH', 'Chemical', '-', (96, 98))	('pT1', 'Gene', '58492', (68, 71))	('pT2N0M0', 'Var', (76, 83))	('Sec24C', 'Gene', '9632', (0, 6))	('more', 'PosReg', (31, 35))	('pT1', 'Gene', (68, 71))
63411	28344541	Hence we focused on the comparison of tissue proteomes of two early CRC stages (pT1N0M0 and pT2N0M0) with those of normal and inflamed control tissues (DI and DH).	('CRC', 'Phenotype', 'HP:0003003', (68, 71))	('pT1', 'Gene', '58492', (80, 83))	('DH', 'Chemical', '-', (159, 161))	('DI', 'Chemical', '-', (152, 154))	('pT1', 'Gene', (80, 83))	('pT2N0M0', 'Var', (92, 99))
63416	28344541	We could characretise their IHC profiles in a second and larger independent set of samples/patients, including normal tissues, adenoma, pTis and the four progressive CRC stages (from pT1NM to pT4NM).	('pT4NM', 'Var', (192, 197))	('patients', 'Species', '9606', (91, 99))	('adenoma', 'Disease', 'MESH:D000236', (127, 134))	('adenoma', 'Disease', (127, 134))	('pT1', 'Gene', (183, 186))	('CRC', 'Phenotype', 'HP:0003003', (166, 169))	('pT1', 'Gene', '58492', (183, 186))
63453	27903980	Using the bioinformatics model, miR-198, miR-765, miR-671-5p, miR-630, miR-371-5p, miR-575, miR-202, miR-483-5p and miR-513a-5p were screened as putative biomarkers for treatment response.	('miR-671', 'Gene', '768213', (50, 57))	('miR-371', 'Gene', '442916', (71, 78))	('miR-483', 'Gene', '619552', (101, 108))	('miR-671', 'Gene', (50, 57))	('miR-198', 'Gene', (32, 39))	('miR-765', 'Gene', (41, 48))	('miR-483', 'Gene', (101, 108))	('men', 'Species', '9606', (174, 177))	('miR-575', 'Gene', '693160', (83, 90))	('miR-630', 'Gene', (62, 69))	('miR-575', 'Gene', (83, 90))	('miR-371', 'Gene', (71, 78))	('miR-198', 'Gene', '406975', (32, 39))	('miR-513a-5p', 'Var', (116, 127))	('miR-202', 'Gene', (92, 99))	('miR-765', 'Gene', '768220', (41, 48))	('miR-202', 'Gene', '574448', (92, 99))	('miR-630', 'Gene', '693215', (62, 69))
63456	27903980	These results demonstrated the predictive power of our model and suggested that miR-198, miR-765, miR-630, miR-371-5p, miR-575, miR-202 and miR-513a-5p could be used for predicting the response of CRC to preoperative chemoradiotherapy.	('miR-198', 'Gene', '406975', (80, 87))	('miR-765', 'Gene', (89, 96))	('miR-575', 'Gene', (119, 126))	('miR-575', 'Gene', '693160', (119, 126))	('CRC', 'Disease', (197, 200))	('miR-630', 'Gene', (98, 105))	('miR-202', 'Gene', (128, 135))	('miR-371', 'Gene', (107, 114))	('miR-202', 'Gene', '574448', (128, 135))	('miR-765', 'Gene', '768220', (89, 96))	('CRC', 'Phenotype', 'HP:0003003', (197, 200))	('miR-513a-5p', 'Var', (140, 151))	('miR-630', 'Gene', '693215', (98, 105))	('miR-198', 'Gene', (80, 87))	('miR-371', 'Gene', '442916', (107, 114))
63476	27903980	Based on the POMA model, nine miRNAs with significantly high NOD values (p-value < 0.05, Wilcoxon signed-rank test), that is, miR-198, miR-765, miR-671-5p, miR-630, miR-371-5p, miR-575, miR-202, miR-483-5p and miR-513a-5p, were identified as candidate biomarkers for predicting CRC response to preoperative chemoradiotherapy.	('miR-630', 'Gene', '693215', (156, 163))	('miR-371', 'Gene', '442916', (165, 172))	('miR-483', 'Gene', '619552', (195, 202))	('miR-513a-5p', 'Var', (210, 221))	('miR-371', 'Gene', (165, 172))	('miR-198', 'Gene', '406975', (126, 133))	('miR-671', 'Gene', (144, 151))	('miR-765', 'Gene', (135, 142))	('miR-765', 'Gene', '768220', (135, 142))	('miR-202', 'Gene', (186, 193))	('miR-575', 'Gene', (177, 184))	('miR-575', 'Gene', '693160', (177, 184))	('CRC', 'Disease', (278, 281))	('miR-630', 'Gene', (156, 163))	('CRC', 'Phenotype', 'HP:0003003', (278, 281))	('miR-198', 'Gene', (126, 133))	('miR-671', 'Gene', '768213', (144, 151))	('miR-202', 'Gene', '574448', (186, 193))	('miR-483', 'Gene', (195, 202))
63482	27903980	For example, miR-575 contributes to non-small cell lung cancer cell growth and invasion, whereas miR-513 combines with 12 other miRNAs as a 13-miRNA signature that participates in regulating tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('miR-575', 'Gene', (13, 20))	('miR-575', 'Gene', '693160', (13, 20))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (36, 62))	('non-small cell lung cancer', 'Disease', (36, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (40, 62))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('participates', 'Reg', (164, 176))	('invasion', 'CPA', (79, 87))	('miR-513', 'Var', (97, 104))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (36, 62))
63491	27903980	Mediated by miRNA targets, p53 signaling alterations could modify the intrinsic radiosensitivity of normal and tumor cells through the checkpoint control system.	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('p53', 'Gene', '7157', (27, 30))	('intrinsic radiosensitivity', 'CPA', (70, 96))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('checkpoint control system', 'CPA', (135, 160))	('tumor', 'Disease', (111, 116))	('p53', 'Gene', (27, 30))	('modify', 'Reg', (59, 65))	('alterations', 'Var', (41, 52))
63502	27903980	It is implicated that deregulated MAPK signaling has a high correlation with colorectal carcinogenesis.	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (77, 102))	('colorectal carcinogenesis', 'Disease', (77, 102))	('MAPK', 'Protein', (34, 38))	('deregulated', 'Var', (22, 33))
63509	27903980	miR-198, miR-765, miR-630, miR-371-5p, miR-575 and miR-513a-5p were overexpressed in HT-29 cells, whereas expression of miR-202 was reduced in the radio-insensitive CRC cell line.	('miR-202', 'Gene', (120, 127))	('miR-575', 'Gene', (39, 46))	('miR-513a-5p', 'Var', (51, 62))	('miR-202', 'Gene', '574448', (120, 127))	('CRC', 'Phenotype', 'HP:0003003', (165, 168))	('miR-630', 'Gene', '693215', (18, 25))	('miR-198', 'Gene', (0, 7))	('miR-371', 'Gene', (27, 34))	('miR-765', 'Gene', '768220', (9, 16))	('HT-29', 'CellLine', 'CVCL:0320', (85, 90))	('miR-198', 'Gene', '406975', (0, 7))	('miR-371', 'Gene', '442916', (27, 34))	('miR-630', 'Gene', (18, 25))	('miR-765', 'Gene', (9, 16))	('miR-575', 'Gene', '693160', (39, 46))
63513	27903980	Western blotting revealed that CXCR7 (p-value = 0.046) and PSMA6 (p-value = 0.0168) were altered significantly in HCT116 cells, which was in accordance with our basic hypothesis (Figure 8).	('PSMA6', 'Gene', (59, 64))	('HCT116', 'Var', (114, 120))	('PSMA6', 'Gene', '5687', (59, 64))	('CXCR7', 'Gene', '57007', (31, 36))	('HCT116', 'CellLine', 'CVCL:0291', (114, 120))	('CXCR7', 'Gene', (31, 36))	('altered', 'Reg', (89, 96))
63516	27903980	The p- values calculated by Student's t test were 0.2739 and 0.3211 for CXCR7 and PSMA6, respectively.	('PSMA', 'molecular_function', 'GO:0043275', ('82', '86'))	('CXCR7', 'Gene', '57007', (72, 77))	('0.3211', 'Var', (61, 67))	('CXCR7', 'Gene', (72, 77))	('PSMA6', 'Gene', (82, 87))	('CXCR7', 'molecular_function', 'GO:0038147', ('72', '77'))	('PSMA6', 'Gene', '5687', (82, 87))
63523	27903980	miR-125a-3p, miR-188-5p, miR-622, miR-765, miR-483-5p, miR-671-5p and miR-630 are associated with CRC chemoradiotherapy.	('miR-765', 'Gene', '768220', (34, 41))	('miR-125a-3p', 'Var', (0, 11))	('CRC chemoradiotherapy', 'Disease', (98, 119))	('miR-188', 'Gene', (13, 20))	('associated', 'Reg', (82, 92))	('miR-630', 'Gene', '693215', (70, 77))	('miR-188', 'Gene', '406964', (13, 20))	('miR-622', 'Gene', (25, 32))	('miR-483', 'Gene', '619552', (43, 50))	('miR-765', 'Gene', (34, 41))	('miR-630', 'Gene', (70, 77))	('miR-671', 'Gene', '768213', (55, 62))	('miR-483', 'Gene', (43, 50))	('miR-622', 'Gene', '693207', (25, 32))	('miR-671', 'Gene', (55, 62))	('CRC', 'Phenotype', 'HP:0003003', (98, 101))
63524	27903980	After POMA filtration, miR-198, miR-765, miR-671-5p, miR-630, miR-371-5p, miR-575, miR-202, miR-483-5p and miR-513a-5p were identified as candidate biomarkers.	('miR-575', 'Gene', '693160', (74, 81))	('miR-198', 'Gene', '406975', (23, 30))	('miR-198', 'Gene', (23, 30))	('miR-575', 'Gene', (74, 81))	('miR-765', 'Gene', '768220', (32, 39))	('miR-371', 'Gene', (62, 69))	('miR-483', 'Gene', '619552', (92, 99))	('miR-513a-5p', 'Var', (107, 118))	('miR-202', 'Gene', (83, 90))	('miR-202', 'Gene', '574448', (83, 90))	('miR-630', 'Gene', '693215', (53, 60))	('miR-671', 'Gene', '768213', (41, 48))	('miR-671', 'Gene', (41, 48))	('miR-371', 'Gene', '442916', (62, 69))	('miR-765', 'Gene', (32, 39))	('miR-483', 'Gene', (92, 99))	('miR-630', 'Gene', (53, 60))
63539	27903980	miR-198, miR-765, miR-630, miR-371-5p, miR-575, miR-202 and miR-513a-5p were validated by low-throughput experiments, which could be prioritized for further clinical practice.	('miR-575', 'Gene', (39, 46))	('miR-630', 'Gene', '693215', (18, 25))	('miR-198', 'Gene', (0, 7))	('men', 'Species', '9606', (111, 114))	('miR-371', 'Gene', (27, 34))	('miR-202', 'Gene', '574448', (48, 55))	('miR-198', 'Gene', '406975', (0, 7))	('miR-765', 'Gene', '768220', (9, 16))	('miR-202', 'Gene', (48, 55))	('miR-371', 'Gene', '442916', (27, 34))	('miR-513a-5p', 'Var', (60, 71))	('miR-630', 'Gene', (18, 25))	('miR-765', 'Gene', (9, 16))	('miR-575', 'Gene', '693160', (39, 46))
63557	28271094	Clinical outcomes of gastric polyps and neoplasms in patients with familial adenomatous polyposis Background and study aims Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome caused by a germline mutation in the adenomatous polyposis coli (APC) gene, characterized by the presence of more than 100 adenomatous polyps in the colorectum.	('germline mutation', 'Var', (207, 224))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (67, 97))	('adenoma', 'Disease', (76, 83))	('adenoma', 'Disease', (232, 239))	('adenomatous polyps', 'Disease', 'MESH:D018256', (318, 336))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (76, 97))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (167, 194))	('polyps', 'Disease', (29, 35))	('polyposis', 'Disease', (145, 154))	('adenoma', 'Disease', 'MESH:D000236', (232, 239))	('adenoma', 'Disease', 'MESH:D000236', (76, 83))	('neoplasm', 'Disease', 'MESH:D009369', (40, 48))	('neoplasms', 'Disease', 'MESH:D009369', (40, 49))	('APC', 'Phenotype', 'HP:0005227', (260, 263))	('polyposis', 'Disease', (88, 97))	('APC', 'Disease', 'MESH:D011125', (260, 263))	('polyposis', 'Disease', 'MESH:D011125', (145, 154))	('patients', 'Species', '9606', (53, 61))	('adenoma', 'Disease', (318, 325))	('polyposis', 'Disease', 'MESH:D011125', (88, 97))	('APC', 'Disease', (260, 263))	('polyps', 'Disease', (330, 336))	('autosomal dominant syndrome', 'Disease', (167, 194))	('neoplasm', 'Disease', (40, 48))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (232, 253))	('Familial adenomatous polyposis', 'Disease', (124, 154))	('adenoma', 'Disease', 'MESH:D000236', (318, 325))	('neoplasms', 'Disease', (40, 49))	('patient', 'Species', '9606', (53, 60))	('polyps', 'Disease', 'MESH:D011127', (29, 35))	('adenoma', 'Disease', (133, 140))	('polyposis', 'Disease', (244, 253))	('FAP', 'Disease', (156, 159))	('Familial adenomatous polyposis', 'Disease', 'MESH:D011125', (124, 154))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (133, 154))	('FAP', 'Disease', 'MESH:C567782', (156, 159))	('adenomatous polyps', 'Disease', (318, 336))	('polyposis', 'Disease', 'MESH:D011125', (244, 253))	('polyps', 'Disease', 'MESH:D011127', (330, 336))	('neoplasm', 'Phenotype', 'HP:0002664', (40, 48))	('adenoma', 'Disease', 'MESH:D000236', (133, 140))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (318, 336))	('gastric polyps', 'Phenotype', 'HP:0004394', (21, 35))	('gastric polyps', 'Disease', 'MESH:D011127', (21, 35))	('neoplasms', 'Phenotype', 'HP:0002664', (40, 49))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (232, 258))	('caused by', 'Reg', (195, 204))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (232, 258))	('gastric polyps', 'Disease', (21, 35))	('familial adenomatous polyposis', 'Disease', (67, 97))	('adenomatous polyposis coli', 'Disease', (232, 258))
63612	27635108	CRC results from the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic epithelium to colon adenocarcinoma.	('colon adenocarcinoma', 'Disease', (148, 168))	('carcinoma', 'Disease', 'MESH:D002277', (159, 168))	('CRC', 'Phenotype', 'HP:0003003', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('lead to', 'Reg', (89, 96))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (148, 168))	('epigenetic alterations', 'Var', (61, 83))	('carcinoma', 'Disease', (159, 168))	('CRC', 'Disease', (0, 3))
63613	27635108	Both hereditary and environmental factors are involved in the development of CRC, and the majority of cases result from chromosomal instability involving the APC, K-ras, or p53 genes.	('chromosomal instability', 'Phenotype', 'HP:0040012', (120, 143))	('p53', 'Gene', (173, 176))	('K-ras', 'Gene', (163, 168))	('CRC', 'Disease', (77, 80))	('K-ras', 'Gene', '3845', (163, 168))	('APC', 'Disease', (158, 161))	('APC', 'Disease', 'MESH:D011125', (158, 161))	('p53', 'Gene', '7157', (173, 176))	('result from', 'Reg', (108, 119))	('chromosomal instability', 'Var', (120, 143))	('CRC', 'Phenotype', 'HP:0003003', (77, 80))
63678	26692321	Introducing additional mutations into VH-VL and CH1-CL interfaces.	('mutations', 'Var', (23, 32))	('VH-VL', 'Gene', (38, 43))	('CH1-CL', 'Disease', 'None', (48, 54))	('CH1-CL', 'Disease', (48, 54))
63686	26692321	After the introduction of point mutations into the IgG1 CH3 domain, IgG1 antibodies can undergo half-molecule exchange under controlled conditions to become bsAbs.	('IgG1', 'Gene', (51, 55))	('point mutations', 'Var', (26, 41))	('bsAbs', 'Chemical', 'MESH:D018033', (157, 162))	('half-molecule exchange', 'MPA', (96, 118))	('IgG1', 'Gene', (68, 72))
63707	26692321	Fusion with human serum albumin (HSA) or an albumin-binding moiety Fusion of scFvs to HSA or an albumin-binding moiety can prolong their serum half-lives.	('scFv', 'Gene', '652070', (77, 81))	('HSA', 'Gene', (86, 89))	('HSA', 'Gene', '213', (33, 36))	('serum half-lives', 'MPA', (137, 153))	('Fusion', 'Var', (67, 73))	('serum albumin (HSA) or', 'Gene', '213', (18, 40))	('serum albumin (HSA) or', 'Gene', (18, 40))	('human', 'Species', '9606', (12, 17))	('HSA', 'Gene', '213', (86, 89))	('HSA', 'Gene', (33, 36))	('prolong', 'PosReg', (123, 130))	('scFv', 'Gene', (77, 81))
63731	26692321	This protection relies on the presence of the chimeric Fc domain of catumaxomab, which evokes an immunogenic reaction.	('catumaxomab', 'Chemical', 'MESH:C522419', (68, 79))	('chimeric Fc domain', 'Var', (46, 64))	('catumaxomab', 'Gene', (68, 79))	('evokes', 'Reg', (87, 93))
63753	26692321	Besides blinatumomab, some other BiTEs such as solitomab (anti-CD3 x EpCAM, completed phase I for solid tumors), MEDI-565 (anti-CD3 x CEA, completed phase I for gastrointestinal adenocarcinoma), and BAY2010112 (anti-CD3 x PSMA, phase I for prostate cancer) are also under investigation.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('blinatumomab', 'Disease', 'None', (8, 20))	('BAY2010112', 'Var', (199, 209))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('prostate cancer', 'Disease', 'MESH:D011471', (240, 255))	('CD3', 'Gene', (216, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('prostate cancer', 'Phenotype', 'HP:0012125', (240, 255))	('CD3', 'Gene', (128, 131))	('PSMA', 'molecular_function', 'GO:0043275', ('222', '226'))	('CEA', 'Gene', '1048', (134, 137))	('prostate cancer', 'Disease', (240, 255))	('blinatumomab', 'Disease', (8, 20))	('EpCAM', 'Gene', (69, 74))	('solid tumors', 'Disease', (98, 110))	('EpCAM', 'Gene', '4072', (69, 74))	('CD3', 'Gene', (63, 66))	('CD3', 'Gene', '12501', (216, 219))	('PSMA', 'Gene', '2346', (222, 226))	('CD3', 'Gene', '12501', (128, 131))	('gastrointestinal adenocarcinoma', 'Disease', 'MESH:D004067', (161, 192))	('PSMA', 'Gene', (222, 226))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('gastrointestinal adenocarcinoma', 'Disease', (161, 192))	('solid tumors', 'Disease', 'MESH:D009369', (98, 110))	('CD3', 'Gene', '12501', (63, 66))	('CEA', 'Gene', (134, 137))
63761	26692321	MGD006 is designed to treat acute myeloid leukemia (AML) by redirecting T cells to kill leukemic cells.	('leukemic', 'Disease', (88, 96))	('AML', 'Phenotype', 'HP:0004808', (52, 55))	('AML', 'Disease', 'MESH:D015470', (52, 55))	('AML', 'Disease', (52, 55))	('MGD006', 'Var', (0, 6))	('leukemia', 'Phenotype', 'HP:0001909', (42, 50))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (28, 50))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (34, 50))	('leukemic', 'Disease', 'MESH:D007938', (88, 96))	('acute myeloid leukemia', 'Disease', (28, 50))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (28, 50))
63776	26692321	Dose-limiting toxicity such as hemolytic anemia may be seen in patients receiving AFM13.	('hemolytic anemia', 'Disease', (31, 47))	('anemia', 'Phenotype', 'HP:0001903', (41, 47))	('toxicity', 'Disease', 'MESH:D064420', (14, 22))	('toxicity', 'Disease', (14, 22))	('AFM13', 'Var', (82, 87))	('patients', 'Species', '9606', (63, 71))	('hemolytic anemia', 'Disease', 'MESH:D000743', (31, 47))	('hemolytic anemia', 'Phenotype', 'HP:0001878', (31, 47))
63802	26692321	Deregulated EGFR- and HER3-dependent signaling is involved in the pathogenesis of human cancers such as head and neck and colorectal cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('Deregulated', 'Var', (0, 11))	('colorectal cancers', 'Disease', (122, 140))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('colorectal cancers', 'Disease', 'MESH:D015179', (122, 140))	('human', 'Species', '9606', (82, 87))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (88, 95))	('cancers', 'Disease', (133, 140))	('EGFR', 'Gene', '1956', (12, 16))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('HER3', 'Gene', (22, 26))	('EGFR', 'Gene', (12, 16))	('involved', 'Reg', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('HER3', 'Gene', '2065', (22, 26))
63806	26692321	It should be noted that patients receiving duligotuzumab are at high risk of adverse effects such as febrile neutropenia, hypokalemia, nausea, and dehydration.	('duligotuzumab', 'Var', (43, 56))	('neutropenia', 'Phenotype', 'HP:0001875', (109, 120))	('dehydration', 'Phenotype', 'HP:0001944', (147, 158))	('dehydration', 'Disease', 'MESH:D003681', (147, 158))	('hypokalemia', 'Disease', 'MESH:D007008', (122, 133))	('nausea', 'Disease', (135, 141))	('hypokalemia', 'Disease', (122, 133))	('febrile neutropenia', 'Disease', (101, 120))	('febrile neutropenia', 'Disease', 'MESH:D009503', (101, 120))	('patients', 'Species', '9606', (24, 32))	('nausea', 'Disease', 'MESH:D009325', (135, 141))	('nausea', 'Phenotype', 'HP:0002018', (135, 141))	('dehydration', 'Disease', (147, 158))	('hypokalemia', 'Phenotype', 'HP:0002900', (122, 133))
63812	26692321	RG7221 is a human IgG1-like CrossMab targeting two key angiogenic factors, VEGFA and angiopoietin-2 (Ang-2).	('angiopoietin-2', 'Gene', (85, 99))	('VEGFA', 'Gene', '7422', (75, 80))	('Ang-2', 'Gene', '285', (101, 106))	('Ang-2', 'Gene', (101, 106))	('VEGFA', 'Gene', (75, 80))	('human', 'Species', '9606', (12, 17))	('RG7221', 'Var', (0, 6))	('angiopoietin-2', 'Gene', '285', (85, 99))
63813	26692321	In preclinical models, RG7221 strongly inhibited angiogenesis and tumor growth, with superior effect as comparing to single-pathway inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('inhibited', 'NegReg', (39, 48))	('tumor', 'Disease', (66, 71))	('RG7221', 'Var', (23, 29))	('angiogenesis', 'biological_process', 'GO:0001525', ('49', '61'))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('angiogenesis', 'CPA', (49, 61))
63816	26692321	RG7716 is a similar CrossMab, which was also designed to block VEGFA and Ang2, and is in phase II study in patients with wet type age-related macular degeneration (wet AMD).	('Ang2', 'Gene', (73, 77))	('VEGFA', 'Gene', (63, 68))	('rat', 'Species', '10116', (156, 159))	('Ang2', 'Gene', '285', (73, 77))	('AMD', 'Disease', 'MESH:D006009', (168, 171))	('VEGFA', 'Gene', '7422', (63, 68))	('macular degeneration', 'Phenotype', 'HP:0000608', (142, 162))	('AMD', 'Disease', (168, 171))	('RG7716', 'Var', (0, 6))	('patients', 'Species', '9606', (107, 115))
63818	26692321	For example, the inhibition of TNF-alpha exerts profound therapeutic effects on psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, juvenile arthritis, and many other diseases.	('TNF-alpha', 'Gene', '7124', (31, 40))	('arthritis', 'Phenotype', 'HP:0001369', (158, 167))	('arthritis', 'Phenotype', 'HP:0001369', (101, 110))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (129, 147))	('TNF-alpha', 'Gene', (31, 40))	("Crohn's disease", 'Phenotype', 'HP:0100280', (112, 127))	("Crohn's disease", 'Disease', 'MESH:D003424', (112, 127))	("Crohn's disease", 'Disease', (112, 127))	('psoriasis', 'Phenotype', 'HP:0003765', (80, 89))	('psoriatic arthritis', 'Phenotype', 'HP:0003765', (91, 110))	('juvenile arthritis', 'Phenotype', 'HP:0005681', (149, 167))	('inhibition', 'Var', (17, 27))	('colitis', 'Phenotype', 'HP:0002583', (140, 147))	('ulcerative colitis', 'Disease', (129, 147))	('psoriasis', 'Disease', 'MESH:D011565', (80, 89))	('psoriasis', 'Disease', (80, 89))	('psoriatic arthritis', 'Disease', (91, 110))	('juvenile arthritis', 'Disease', 'MESH:D001171', (149, 167))	('ulcerative colitis', 'Disease', 'MESH:D003093', (129, 147))	('psoriatic arthritis', 'Disease', 'MESH:D015535', (91, 110))	('juvenile arthritis', 'Disease', (149, 167))
63822	26692321	Similar nanobodies developed by Ablynx include ALX-0061 against IL-6R/HSA for RA and ALX-0761 against IL-17A/F for inflammatory disease.	('ALX', 'Chemical', '-', (47, 50))	('IL-6R', 'Gene', (64, 69))	('inflammatory disease', 'Disease', 'MESH:D007249', (115, 135))	('HSA', 'Gene', '213', (70, 73))	('IL-17', 'molecular_function', 'GO:0030367', ('102', '107'))	('IL-17A', 'Gene', '3605', (102, 108))	('ALX-0761', 'Var', (85, 93))	('ALX-0761', 'Chemical', '-', (85, 93))	('ALX-0061', 'Var', (47, 55))	('RA', 'Phenotype', 'HP:0001370', (78, 80))	('HSA', 'Gene', (70, 73))	('RA', 'Disease', 'MESH:D001172', (78, 80))	('Ablynx', 'Chemical', '-', (32, 38))	('IL-6R', 'Gene', '3570', (64, 69))	('IL-6R', 'molecular_function', 'GO:0004915', ('64', '69'))	('ALX', 'Chemical', '-', (85, 88))	('IL-17A', 'Gene', (102, 108))	('inflammatory disease', 'Disease', (115, 135))
63823	26692321	SAR156597 is a tetravalent bispecific tandem IgG that simultaneously binds to IL-13 and IL-4.	('IL-4', 'molecular_function', 'GO:0005136', ('88', '92'))	('IL-4', 'Gene', (88, 92))	('IL-13', 'molecular_function', 'GO:0005144', ('78', '83'))	('binds', 'Interaction', (69, 74))	('IL-4', 'Gene', '3565', (88, 92))	('IL-13', 'Gene', (78, 83))	('IL-13', 'Gene', '3596', (78, 83))	('SAR156597', 'Var', (0, 9))
63824	26692321	Structurally, SAR156597 is an IgG molecule (anti-IL4 antibody) with its N terminus fused to the variable domain of an anti-IL13 antibody.	('IL13', 'Gene', '3596', (123, 127))	('IL4', 'Gene', '3565', (49, 52))	('SAR156597', 'Var', (14, 23))	('IL4', 'Gene', (49, 52))	('IL13', 'Gene', (123, 127))
63834	26692321	Other applications of TF2 include targeting against 177Lu HSG/111InHSG and CEA for radioimmunotherapy in patients with colorectal neoplasms and targeting against 68GaHSG and CEA for immuno-positron emission tomography.	('patients', 'Species', '9606', (105, 113))	('colorectal neoplasms', 'Disease', (119, 139))	('CEA', 'Gene', '1048', (75, 78))	('neoplasms', 'Phenotype', 'HP:0002664', (130, 139))	('HSG', 'Chemical', '-', (58, 61))	('177Lu HSG/111InHSG', 'Var', (52, 70))	('TF2', 'Gene', (22, 25))	('CEA', 'Gene', (75, 78))	('CEA', 'Gene', (174, 177))	('CEA', 'Gene', '1048', (174, 177))	('HSG', 'Chemical', '-', (67, 70))	('colorectal neoplasms', 'Disease', 'MESH:D015179', (119, 139))	('HSG', 'Chemical', '-', (166, 169))
63838	26692321	BACE1 is an aspartyl protease that contributes to the pathogenesis of Alzheimer's disease, and targeting BACE1 has been a long-sought-after strategy for treating Alzheimer's disease.	("Alzheimer's disease", 'Disease', 'MESH:D000544', (70, 89))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (70, 89))	("Alzheimer's disease", 'Disease', (70, 89))	('targeting', 'Var', (95, 104))	('BACE1', 'Gene', '23621', (105, 110))	('BACE1', 'Gene', (105, 110))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (162, 181))	('contributes', 'Reg', (35, 46))	('BACE1', 'Gene', (0, 5))	('pathogenesis', 'biological_process', 'GO:0009405', ('54', '66'))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (162, 181))	("Alzheimer's disease", 'Disease', (162, 181))	('BACE1', 'Gene', '23621', (0, 5))	('rat', 'Species', '10116', (142, 145))
63848	26692321	P. aeruginosa remains a significant contributor to hospital-acquired pneumonia and mortality in patients with cystic fibrosis.	('pneumonia', 'Disease', (69, 78))	('pneumonia', 'Disease', 'MESH:D011014', (69, 78))	('P. aeruginosa', 'Var', (0, 13))	('cystic fibrosis', 'Disease', 'MESH:D003550', (110, 125))	('cystic fibrosis', 'Disease', (110, 125))	('patients', 'Species', '9606', (96, 104))	('pneumonia', 'Phenotype', 'HP:0002090', (69, 78))	('P. aeruginosa', 'Species', '287', (0, 13))
63851	26692321	The superior protective activity of BiS4alphaPa was proven in an animal study, and BiS4alphaPa is now a clinical candidate for the treatment of P. aeruginosa.	('BiS4alphaPa', 'Chemical', '-', (83, 94))	('BiS4alphaPa', 'Chemical', '-', (36, 47))	('BiS', 'molecular_function', 'GO:0033815', ('83', '86'))	('protective activity', 'CPA', (13, 32))	('BiS', 'molecular_function', 'GO:0033815', ('36', '39'))	('P. aeruginosa', 'Species', '287', (144, 157))	('BiS4alphaPa', 'Var', (83, 94))
63860	26692321	For example, toxicity of the bispecific 4G7 x H22 leads to the termination of its clinical study (https://clinicaltrials.gov/ct2/show/NCT00014560).	('toxicity', 'Disease', 'MESH:D064420', (13, 21))	('toxicity', 'Disease', (13, 21))	('ct2', 'Gene', '30848', (125, 128))	('ct2', 'Gene', (125, 128))	('4G7 x H22', 'Var', (40, 49))
63888	24855393	No testing for hallmarks of Lynch syndrome was performed (microsatellite instability/mismatch repair defect).	('hallmarks of Lynch syndrome', 'Disease', (15, 42))	('microsatellite instability/mismatch', 'Var', (58, 93))	('instability/mismatch', 'Var', (73, 93))	('hallmarks of Lynch syndrome', 'Disease', 'MESH:D003123', (15, 42))
63893	24855393	Endoscopic evaluation with colonoscopy revealed pathology in the entire length of the large intestine (pancolitis), with the bowel mucosa appearing red, edematous, and friable, with a microgranular texture.	('bowel mucosa', 'Disease', (125, 137))	('edematous', 'Disease', 'MESH:D004487', (153, 162))	('colitis', 'Phenotype', 'HP:0002583', (106, 113))	('pathology', 'Var', (48, 57))	('pancolitis', 'Disease', (103, 113))	('edematous', 'Disease', (153, 162))	('bowel mucosa', 'Disease', 'MESH:D015212', (125, 137))	('pancolitis', 'Disease', 'None', (103, 113))
63929	24855393	These abnormalities refer to aneuploidy, p53 mutations, and clonal chromosomal defects.	('mutations', 'Var', (45, 54))	('p53', 'Gene', (41, 44))	('aneuploidy', 'Disease', (29, 39))	('clonal chromosomal defects', 'Phenotype', 'HP:0040012', (60, 86))	('aneuploidy', 'Disease', 'MESH:D000782', (29, 39))	('p53', 'Gene', '7157', (41, 44))
63935	23874993	In vitro and in vivo experiments showed that omega-3 polyunsaturated fatty acids (n-3 PUFAs) can attenuate the proliferation of cancer cells, including colon cancer, and increase the efficacy of various anticancer drugs.	('n', 'Chemical', 'MESH:D009584', (156, 157))	('n', 'Chemical', 'MESH:D009584', (82, 83))	('n', 'Chemical', 'MESH:D009584', (130, 131))	('n', 'Chemical', 'MESH:D009584', (123, 124))	('n-3 PUFAs', 'Chemical', 'MESH:D015525', (82, 91))	('n', 'Chemical', 'MESH:D009584', (10, 11))	('omega-3 polyunsaturated fatty acids', 'Chemical', 'MESH:D015525', (45, 80))	('n', 'Chemical', 'MESH:D009584', (209, 210))	('n', 'Chemical', 'MESH:D009584', (58, 59))	('rat', 'Species', '10116', (63, 66))	('colon cancer', 'Phenotype', 'HP:0003003', (152, 164))	('cancer', 'Disease', (128, 134))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('rat', 'Species', '10116', (118, 121))	('cancer', 'Disease', (207, 213))	('n', 'Chemical', 'MESH:D009584', (167, 168))	('cancer', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('efficacy', 'MPA', (183, 191))	('colon cancer', 'Disease', 'MESH:D015179', (152, 164))	('n', 'Chemical', 'MESH:D009584', (160, 161))	('increase', 'PosReg', (170, 178))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('attenuate', 'NegReg', (97, 106))	('n', 'Chemical', 'MESH:D009584', (14, 15))	('n', 'Chemical', 'MESH:D009584', (143, 144))	('n', 'Chemical', 'MESH:D009584', (101, 102))	('n', 'Chemical', 'MESH:D009584', (149, 150))	('omega-3', 'Var', (45, 52))	('n', 'Chemical', 'MESH:D009584', (204, 205))	('n', 'Chemical', 'MESH:D009584', (29, 30))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('colon cancer', 'Disease', (152, 164))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('n', 'Chemical', 'MESH:D009584', (171, 172))
63937	23874993	CSLCs have also been linked to the acquisition of chemotherapy resistance and to tumor relapse.	('linked', 'Reg', (21, 27))	('n', 'Chemical', 'MESH:D009584', (19, 20))	('n', 'Chemical', 'MESH:D009584', (23, 24))	('n', 'Chemical', 'MESH:D009584', (75, 76))	('n', 'Chemical', 'MESH:D009584', (70, 71))	('CSLCs', 'Var', (0, 5))	('chemotherapy', 'MPA', (50, 62))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('tumor', 'Disease', (81, 86))
63957	23874993	This incidence is reduced in subjects that consume higher amounts of fruits, vegetables, fibers, and, more importantly, n-3 polyunsaturated fatty acids (PUFAs) of marine origin.	('n', 'Chemical', 'MESH:D009584', (98, 99))	('PUFAs', 'Chemical', 'MESH:D005231', (153, 158))	('n', 'Chemical', 'MESH:D009584', (175, 176))	('n', 'Chemical', 'MESH:D009584', (167, 168))	('n', 'Chemical', 'MESH:D009584', (120, 121))	('n', 'Chemical', 'MESH:D009584', (129, 130))	('reduced', 'NegReg', (18, 25))	('n', 'Chemical', 'MESH:D009584', (6, 7))	('n', 'Chemical', 'MESH:D009584', (62, 63))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('n-3 polyunsaturated fatty acids', 'Chemical', 'MESH:D015525', (120, 151))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('n-3', 'Var', (120, 123))	('n', 'Chemical', 'MESH:D009584', (114, 115))
63959	23874993	Much data have been published about the capability of n-3 PUFAs to decrease proliferation, to exert a pro-apoptotic effect, and to inhibit angiogenesis in several in vitro models of colon cancer.	('n', 'Chemical', 'MESH:D009584', (132, 133))	('angiogenesis', 'CPA', (139, 151))	('pro-apoptotic effect', 'MPA', (102, 122))	('n-3', 'Var', (54, 57))	('n', 'Chemical', 'MESH:D009584', (18, 19))	('n', 'Chemical', 'MESH:D009584', (153, 154))	('n', 'Chemical', 'MESH:D009584', (88, 89))	('colon cancer', 'Phenotype', 'HP:0003003', (182, 194))	('n', 'Chemical', 'MESH:D009584', (190, 191))	('n-3 PUFAs', 'Chemical', 'MESH:D015525', (54, 63))	('decrease', 'NegReg', (67, 75))	('proliferation', 'CPA', (76, 89))	('colon cancer', 'Disease', 'MESH:D015179', (182, 194))	('n', 'Chemical', 'MESH:D009584', (125, 126))	('rat', 'Species', '10116', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('inhibit', 'NegReg', (131, 138))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('n', 'Chemical', 'MESH:D009584', (140, 141))	('n', 'Chemical', 'MESH:D009584', (164, 165))	('n', 'Chemical', 'MESH:D009584', (146, 147))	('colon cancer', 'Disease', (182, 194))	('n', 'Chemical', 'MESH:D009584', (186, 187))	('angiogenesis', 'biological_process', 'GO:0001525', ('139', '151'))
63960	23874993	Omega-3 PUFAs have also been shown to increase the sensitivity to chemotherapy of several human derived cancer cell cultures in vitro such as breast, brain and lung, lymphocytic, and colonic.	('PUFAs', 'Chemical', 'MESH:D005231', (8, 13))	('n', 'Chemical', 'MESH:D009584', (106, 107))	('n', 'Chemical', 'MESH:D009584', (154, 155))	('breast', 'Disease', (142, 148))	('human', 'Species', '9606', (90, 95))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('cancer', 'Disease', (104, 110))	('increase', 'PosReg', (38, 46))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('brain', 'Disease', (150, 155))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('n', 'Chemical', 'MESH:D009584', (157, 158))	('lymphocytic', 'Disease', (166, 177))	('n', 'Chemical', 'MESH:D009584', (180, 181))	('n', 'Chemical', 'MESH:D009584', (94, 95))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('n', 'Chemical', 'MESH:D009584', (53, 54))	('Omega-3', 'Var', (0, 7))	('sensitivity to chemotherapy', 'MPA', (51, 78))	('colonic', 'Disease', (183, 190))	('n', 'Chemical', 'MESH:D009584', (162, 163))	('n', 'Chemical', 'MESH:D009584', (187, 188))
63967	23874993	Additionally, treatment of human breast cancer cells with n-3 PUFAs resulted in their growth inhibition, which was proportional to mammary gland differentiation, and a pro-differentiating effect was also observed in DHA treated human melanoma cells in vitro .	('n', 'Chemical', 'MESH:D009584', (250, 251))	('human', 'Species', '9606', (27, 32))	('n', 'Chemical', 'MESH:D009584', (185, 186))	('n', 'Chemical', 'MESH:D009584', (42, 43))	('n', 'Chemical', 'MESH:D009584', (58, 59))	('n-3 PUFAs', 'Chemical', 'MESH:D015525', (58, 67))	('melanoma', 'Disease', 'MESH:D008545', (234, 242))	('growth inhibition', 'CPA', (86, 103))	('n', 'Chemical', 'MESH:D009584', (232, 233))	('n-3', 'Var', (58, 61))	('n', 'Chemical', 'MESH:D009584', (142, 143))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('n', 'Chemical', 'MESH:D009584', (159, 160))	('n', 'Chemical', 'MESH:D009584', (238, 239))	('n', 'Chemical', 'MESH:D009584', (152, 153))	('n', 'Chemical', 'MESH:D009584', (214, 215))	('n', 'Chemical', 'MESH:D009584', (78, 79))	('n', 'Chemical', 'MESH:D009584', (102, 103))	('n', 'Chemical', 'MESH:D009584', (124, 125))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('n', 'Chemical', 'MESH:D009584', (31, 32))	('melanoma', 'Disease', (234, 242))	('human', 'Species', '9606', (228, 233))	('n', 'Chemical', 'MESH:D009584', (94, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('DHA', 'Chemical', 'MESH:D004281', (216, 219))	('n', 'Chemical', 'MESH:D009584', (179, 180))	('n', 'Chemical', 'MESH:D009584', (21, 22))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('n', 'Chemical', 'MESH:D009584', (163, 164))	('breast cancer', 'Disease', (33, 46))
64007	23874993	After blocking in 5% fat-free-milk in TBS-T, membranes were incubated with the following antibodies: Anti-CD133/1 (AC133 Miltenyi Biotech, Bergisch Gladbach, Germany), Anti-Cytokeratin 20 (EPR1622Y Abcam, Cambridge, MA).	('n', 'Chemical', 'MESH:D009584', (16, 17))	('n', 'Chemical', 'MESH:D009584', (36, 37))	('n', 'Chemical', 'MESH:D009584', (90, 91))	('n', 'Chemical', 'MESH:D009584', (183, 184))	('n', 'Chemical', 'MESH:D009584', (12, 13))	('n', 'Chemical', 'MESH:D009584', (169, 170))	('n', 'Chemical', 'MESH:D009584', (102, 103))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('EPR1622Y', 'Var', (189, 197))	('n', 'Chemical', 'MESH:D009584', (126, 127))	('TBS-T', 'Chemical', '-', (38, 43))	('Anti-CD133/1', 'Var', (101, 113))	('n', 'Chemical', 'MESH:D009584', (86, 87))	('rat', 'Species', '10116', (179, 182))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('n', 'Chemical', 'MESH:D009584', (163, 164))
64079	23874993	Collectively these data suggest that EPA potentiates the efficacy of 5-Fluorouracil, which is one of the first line standard-of-care antineoplastic agents, against colon cancer.	('potentiates', 'PosReg', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('colon cancer', 'Disease', 'MESH:D015179', (164, 176))	('EPA', 'Var', (37, 40))	('n', 'Chemical', 'MESH:D009584', (137, 138))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('n', 'Chemical', 'MESH:D009584', (168, 169))	('colon cancer', 'Disease', (164, 176))	('EPA', 'Chemical', 'MESH:D015118', (37, 40))	('n', 'Chemical', 'MESH:D009584', (160, 161))	('efficacy', 'MPA', (57, 65))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('n', 'Chemical', 'MESH:D009584', (134, 135))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('n', 'Chemical', 'MESH:D009584', (151, 152))	('5-Fluorouracil', 'Chemical', 'MESH:D005472', (69, 83))	('n', 'Chemical', 'MESH:D009584', (172, 173))	('colon cancer', 'Phenotype', 'HP:0003003', (164, 176))	('n', 'Chemical', 'MESH:D009584', (45, 46))
64084	23874993	COLO 320 DM is a Duke's C derived colorectal adenocarcinoma cell line that was used in this work to study stage III, non-metastatic cancer.	('cancer', 'Disease', (132, 138))	('n', 'Chemical', 'MESH:D009584', (67, 68))	('colorectal adenocarcinoma', 'Disease', (34, 59))	('n', 'Chemical', 'MESH:D009584', (85, 86))	('n', 'Chemical', 'MESH:D009584', (134, 135))	('n', 'Chemical', 'MESH:D009584', (55, 56))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (34, 59))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('n', 'Chemical', 'MESH:D009584', (48, 49))	('COLO 320 DM', 'Var', (0, 11))	('COLO', 'Species', '307630', (0, 4))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
64114	23874993	These observations could indicate that EPA may induce a more differentiated status of the bulk of tumor cells, and that on the other side it may trigger the reduction of the stemness status of the CSLCs, as evidenced by a reduction of the CD133 marker expression.	('EPA', 'Var', (39, 42))	('differentiated status', 'CPA', (61, 82))	('n', 'Chemical', 'MESH:D009584', (68, 69))	('n', 'Chemical', 'MESH:D009584', (178, 179))	('n', 'Chemical', 'MESH:D009584', (121, 122))	('tumor', 'Disease', (98, 103))	('EPA', 'Chemical', 'MESH:D015118', (39, 42))	('n', 'Chemical', 'MESH:D009584', (112, 113))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('n', 'Chemical', 'MESH:D009584', (230, 231))	('n', 'Chemical', 'MESH:D009584', (48, 49))	('more', 'PosReg', (56, 60))	('n', 'Chemical', 'MESH:D009584', (16, 17))	('n', 'Chemical', 'MESH:D009584', (165, 166))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('n', 'Chemical', 'MESH:D009584', (261, 262))	('expression', 'MPA', (252, 262))	('reduction', 'NegReg', (222, 231))	('reduction', 'NegReg', (157, 166))	('CD133 marker', 'Protein', (239, 251))	('n', 'Chemical', 'MESH:D009584', (212, 213))	('stemness status of the', 'CPA', (174, 196))
64124	23874993	We showed that the efficacy of oxaliplatin or 5-Fluorouracil mono-therapies on the COLO 320 DM total population was considerably increased by 25 uM EPA (p<0.01 IC25 and IC50 for oxaliplatin and p<0.01 IC25, p<0.001 IC50 for 5-Fluorouracil), but not SA.	('oxaliplatin', 'Chemical', 'MESH:D000077150', (31, 42))	('n', 'Chemical', 'MESH:D009584', (130, 131))	('efficacy', 'MPA', (19, 27))	('5-Fluorouracil', 'Chemical', 'MESH:D005472', (224, 238))	('increased', 'PosReg', (129, 138))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('EPA', 'Chemical', 'MESH:D015118', (148, 151))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('n', 'Chemical', 'MESH:D009584', (166, 167))	('n', 'Chemical', 'MESH:D009584', (245, 246))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (178, 189))	('n', 'Chemical', 'MESH:D009584', (191, 192))	('5-Fluorouracil', 'Chemical', 'MESH:D005472', (46, 60))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('COLO', 'Species', '307630', (83, 87))	('n', 'Chemical', 'MESH:D009584', (118, 119))	('SA', 'Chemical', 'MESH:C031183', (249, 251))	('n', 'Chemical', 'MESH:D009584', (77, 78))	('n', 'Chemical', 'MESH:D009584', (188, 189))	('IC50', 'Var', (169, 173))
64136	23874993	EPA and DHA have been shown to reduce gene expression, protein production, and pump activity of MDR1, another ATP-Binding Cassette protein, which is not involved in oxaliplatin resistance.	('n', 'Chemical', 'MESH:D009584', (5, 6))	('EPA', 'Chemical', 'MESH:D015118', (0, 3))	('n', 'Chemical', 'MESH:D009584', (154, 155))	('gene expression', 'MPA', (38, 53))	('DHA', 'Var', (8, 11))	('reduce', 'NegReg', (31, 37))	('n', 'Chemical', 'MESH:D009584', (184, 185))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (165, 176))	('n', 'Chemical', 'MESH:D009584', (175, 176))	('n', 'Chemical', 'MESH:D009584', (137, 138))	('n', 'Chemical', 'MESH:D009584', (26, 27))	('MDR1', 'Gene', (96, 100))	('n', 'Chemical', 'MESH:D009584', (72, 73))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('pump activity', 'MPA', (79, 92))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('n', 'Chemical', 'MESH:D009584', (119, 120))	('n', 'Chemical', 'MESH:D009584', (149, 150))	('protein production', 'MPA', (55, 73))	('n', 'Chemical', 'MESH:D009584', (116, 117))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('n', 'Chemical', 'MESH:D009584', (20, 21))	('DHA', 'Chemical', 'MESH:D004281', (8, 11))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('MDR1', 'Gene', '5243', (96, 100))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('n', 'Chemical', 'MESH:D009584', (163, 164))
64141	23874993	following treatments with 5-Fluorouracil the cell proliferation rate of CD133 (+) DLD-1 CSLCs increases compared to the CD133 (-) cells, and the sensitivity of CD133 (+) CSLCs to 5-Fluorouracil decreases.	('n', 'Chemical', 'MESH:D009584', (95, 96))	('cell proliferation rate', 'CPA', (45, 68))	('sensitivity', 'MPA', (145, 156))	('increases', 'PosReg', (94, 103))	('n', 'Chemical', 'MESH:D009584', (17, 18))	('n', 'Chemical', 'MESH:D009584', (62, 63))	('CD133 (+', 'Var', (72, 80))	('n', 'Chemical', 'MESH:D009584', (138, 139))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('n', 'Chemical', 'MESH:D009584', (147, 148))	('rat', 'Species', '10116', (57, 60))	('5-Fluorouracil', 'Chemical', 'MESH:D005472', (26, 40))	('rat', 'Species', '10116', (64, 67))	('5-Fluorouracil', 'Chemical', 'MESH:D005472', (179, 193))
64142	23874993	Additionally, the authors found that 5-Flurouracil down-regulated the stem cell marker CD133 expression in colon cancer cell line DLD1 cells.	('DLD1', 'CellLine', 'CVCL:0248', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('colon cancer', 'Disease', 'MESH:D015179', (107, 119))	('CD133', 'Gene', (87, 92))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('n', 'Chemical', 'MESH:D009584', (111, 112))	('5-Flurouracil', 'Chemical', '-', (37, 50))	('colon cancer', 'Disease', (107, 119))	('n', 'Chemical', 'MESH:D009584', (102, 103))	('n', 'Chemical', 'MESH:D009584', (7, 8))	('n', 'Chemical', 'MESH:D009584', (127, 128))	('n', 'Chemical', 'MESH:D009584', (29, 30))	('5-Flurouracil', 'Var', (37, 50))	('n', 'Chemical', 'MESH:D009584', (54, 55))	('down-regulated', 'NegReg', (51, 65))	('expression', 'MPA', (93, 103))	('colon cancer', 'Phenotype', 'HP:0003003', (107, 119))	('n', 'Chemical', 'MESH:D009584', (115, 116))	('stem cell', 'CPA', (70, 79))
64148	23874993	Also, we observed that EPA induced down-regulation of CD133 expression and up-regulation of colonic epithelium differentiation markers Cytokeratin 20 and Mucin 2, indicating that n-3 PUFA increased the differentiation status of both bulk of tumor and CSLCs in colon cancer.	('expression', 'MPA', (60, 70))	('Mucin', 'Gene', '100508689', (154, 159))	('colon cancer', 'Disease', 'MESH:D015179', (260, 272))	('n', 'Chemical', 'MESH:D009584', (209, 210))	('n', 'Chemical', 'MESH:D009584', (248, 249))	('n', 'Chemical', 'MESH:D009584', (264, 265))	('rat', 'Species', '10116', (141, 144))	('increased', 'PosReg', (188, 197))	('n', 'Chemical', 'MESH:D009584', (145, 146))	('EPA', 'Chemical', 'MESH:D015118', (23, 26))	('tumor', 'Disease', (241, 246))	('colon cancer', 'Disease', (260, 272))	('n', 'Chemical', 'MESH:D009584', (216, 217))	('n', 'Chemical', 'MESH:D009584', (72, 73))	('n-3 PUFA', 'Chemical', 'MESH:D015525', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('n-3', 'Var', (179, 182))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('n', 'Chemical', 'MESH:D009584', (96, 97))	('n', 'Chemical', 'MESH:D009584', (49, 50))	('differentiation status', 'CPA', (202, 224))	('n', 'Chemical', 'MESH:D009584', (158, 159))	('n', 'Chemical', 'MESH:D009584', (189, 190))	('n', 'Chemical', 'MESH:D009584', (151, 152))	('n', 'Chemical', 'MESH:D009584', (268, 269))	('CD133', 'Gene', (54, 59))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (125, 126))	('down-regulation', 'NegReg', (35, 50))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('n', 'Chemical', 'MESH:D009584', (118, 119))	('Mucin', 'Gene', (154, 159))	('colon cancer', 'Phenotype', 'HP:0003003', (260, 272))	('n', 'Chemical', 'MESH:D009584', (179, 180))	('n', 'Chemical', 'MESH:D009584', (171, 172))	('n', 'Chemical', 'MESH:D009584', (164, 165))	('n', 'Chemical', 'MESH:D009584', (28, 29))	('n', 'Chemical', 'MESH:D009584', (258, 259))	('up-regulation', 'PosReg', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('n', 'Chemical', 'MESH:D009584', (69, 70))
64156	23530816	Cdk4 pathway alterations have been linked to a number of cancers including CRC.	('Cdk', 'molecular_function', 'GO:0004693', ('0', '3'))	('linked', 'Reg', (35, 41))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('CRC', 'Disease', (75, 78))	('Cdk4 pathway', 'Pathway', (0, 12))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('CRC', 'Phenotype', 'HP:0003003', (75, 78))	('alterations', 'Var', (13, 24))
64164	23530816	Modification of the Cdk4 pathway using a natural plant-derived compound such as silibinin may be a useful chemopreventive strategy for colorectal carcinomas.	('colorectal carcinomas', 'Disease', (135, 156))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (135, 156))	('Modification', 'Var', (0, 12))	('Cdk4 pathway', 'Pathway', (20, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('silibinin', 'Chemical', 'MESH:D000077385', (80, 89))	('Cdk', 'molecular_function', 'GO:0004693', ('20', '23'))
64165	23530816	Disruption of cell cycle regulation through alterations in the Cdk4 pathway appears to play an important role in the development of a variety of cancers including colorectal cancer.	('cancers', 'Disease', (145, 152))	('Disruption', 'NegReg', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('14', '35'))	('colorectal cancer', 'Disease', 'MESH:D015179', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('Cdk4 pathway', 'Pathway', (63, 75))	('alterations', 'Var', (44, 55))	('cell cycle regulation', 'CPA', (14, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('Cdk', 'molecular_function', 'GO:0004693', ('63', '66'))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('colorectal cancer', 'Disease', (163, 180))
64170	23530816	Therefore, Apc mutations, acting in part through the activation of the Cdk4 pathway, play a critical role early in intestinal tumorigenesis.	('intestinal tumor', 'Disease', (115, 131))	('Cdk4 pathway', 'Pathway', (71, 83))	('intestinal tumor', 'Disease', 'MESH:D007414', (115, 131))	('activation', 'PosReg', (53, 63))	('mutations', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('Apc', 'Gene', (11, 14))	('Apc', 'Gene', '11789', (11, 14))
64175	23530816	In this study, we examined the Cdk4 pathway and its blockade in the context of Apc mutation to determine the potential for targeting this pathway in a chemopreventive strategy for colorectal cancer.	('Apc', 'Gene', '11789', (79, 82))	('Cdk', 'molecular_function', 'GO:0004693', ('31', '34'))	('colorectal cancer', 'Disease', 'MESH:D015179', (180, 197))	('Cdk4 pathway', 'Pathway', (31, 43))	('colorectal cancer', 'Phenotype', 'HP:0003003', (180, 197))	('min', 'Gene', (21, 24))	('mutation', 'Var', (83, 91))	('Apc', 'cellular_component', 'GO:0005680', ('79', '82'))	('min', 'Gene', '11789', (21, 24))	('colorectal cancer', 'Disease', (180, 197))	('min', 'Gene', '11789', (100, 103))	('min', 'Gene', (100, 103))	('Apc', 'Gene', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
64222	23530816	HT-29 cells were treated with different concentrations of silibinin, (0.1, 0.5, 1, 10, and 100 muM) or with vehicle (DMSO) for 24 hours.	('0.1', 'Var', (70, 73))	('silibinin', 'Chemical', 'MESH:D000077385', (58, 67))	('HT-29', 'CellLine', 'CVCL:0320', (0, 5))	('muM', 'Gene', '56925', (95, 98))	('DMSO', 'Chemical', 'MESH:D004121', (117, 121))	('muM', 'Gene', (95, 98))
64242	23530816	Figure 1 shows hematoxylin and eosin staining of the intestine and adenomas from mutant Apc-/+ mice.	('eosin', 'Chemical', 'MESH:D004801', (31, 36))	('mice', 'Species', '10090', (95, 99))	('adenomas', 'Disease', 'MESH:D000236', (67, 75))	('adenomas', 'Disease', (67, 75))	('Apc', 'Gene', (88, 91))	('Apc', 'Gene', '11789', (88, 91))	('mutant', 'Var', (81, 87))	('hematoxylin', 'Chemical', 'MESH:D006416', (15, 26))	('Apc', 'cellular_component', 'GO:0005680', ('88', '91'))
64244	23530816	Intestines from Apc-/+ mice were analyzed by immunohistochemistry for the expression and distribution of three central components of the Cdk4 signaling pathway downstream of Apc mutation, Cdk4, cyclin D1, and pRb.	('Apc', 'Gene', (16, 19))	('Apc', 'Gene', '11789', (16, 19))	('mutation', 'Var', (178, 186))	('Rb', 'Phenotype', 'HP:0009919', (210, 212))	('Apc', 'Gene', (174, 177))	('Apc', 'Gene', '11789', (174, 177))	('mice', 'Species', '10090', (23, 27))
64279	23530816	Normal crypt Ki67 staining was substantially reduced (33%) in mice that were on silibinin comparing to the mice that received control diet.	('reduced', 'NegReg', (45, 52))	('mice', 'Species', '10090', (62, 66))	('Ki67', 'Gene', (13, 17))	('mice', 'Species', '10090', (107, 111))	('silibinin', 'Var', (80, 89))	('silibinin', 'Chemical', 'MESH:D000077385', (80, 89))	('crypt', 'Protein', (7, 12))	('Ki67', 'Gene', '17345', (13, 17))
64280	23530816	The mean proliferation index within the normal crypts in the mice that were on silibinin was 61 but was 90 in the mice that received no intervention, (p < 0.01 in t test).	('mice', 'Species', '10090', (61, 65))	('silibinin', 'Var', (79, 88))	('silibinin', 'Chemical', 'MESH:D000077385', (79, 88))	('mice', 'Species', '10090', (114, 118))	('proliferation index', 'CPA', (9, 28))
64282	23530816	In addition, the mean proliferative index within the adenomas was 191 in the mice that were on silibinin but 330 in the mice received control food, (P < 0.01 in t test) (Figure 7).	('mice', 'Species', '10090', (77, 81))	('mice', 'Species', '10090', (120, 124))	('silibinin', 'Chemical', 'MESH:D000077385', (95, 104))	('adenomas', 'Disease', 'MESH:D000236', (53, 61))	('adenomas', 'Disease', (53, 61))	('proliferative index', 'CPA', (22, 41))	('silibinin', 'Var', (95, 104))
64283	23530816	The results demonstrated that the mice that were on silibinin had significantly increased numbers of apoptotic cells (average per field 3.1) in crypts in the normal mucosa compared to the mucosa in mice that were on control diet only (average 1.1 per field) (Figure 8).	('mice', 'Species', '10090', (34, 38))	('increased', 'PosReg', (80, 89))	('silibinin', 'Var', (52, 61))	('silibinin', 'Chemical', 'MESH:D000077385', (52, 61))	('apoptotic cells', 'CPA', (101, 116))	('mice', 'Species', '10090', (198, 202))
64284	23530816	Similarly the number of apoptotic cells was higher within adenomas in the mice that were on silibinin (180) compared to the mice that received no intervention (48) (Figure 8).	('higher', 'PosReg', (44, 50))	('mice', 'Species', '10090', (124, 128))	('apoptotic cells', 'CPA', (24, 39))	('adenomas', 'Disease', 'MESH:D000236', (58, 66))	('mice', 'Species', '10090', (74, 78))	('silibinin', 'Var', (92, 101))	('silibinin', 'Chemical', 'MESH:D000077385', (92, 101))	('adenomas', 'Disease', (58, 66))
64286	23530816	Mutation in the Apc gene leads to nuclear accumulation of beta-catenin and over expression of cyclin D1 and increased Cdk4 activity.	('beta-catenin', 'Gene', (58, 70))	('activity', 'MPA', (123, 131))	('over expression', 'PosReg', (75, 90))	('Cdk', 'molecular_function', 'GO:0004693', ('118', '121'))	('Apc', 'Gene', (16, 19))	('Apc', 'Gene', '11789', (16, 19))	('increased', 'PosReg', (108, 117))	('cyclin D1', 'Protein', (94, 103))	('Mutation', 'Var', (0, 8))	('beta-catenin', 'Gene', '12387', (58, 70))	('Apc', 'cellular_component', 'GO:0005680', ('16', '19'))	('nuclear accumulation', 'MPA', (34, 54))	('Cdk4', 'Protein', (118, 122))	('cyclin', 'molecular_function', 'GO:0016538', ('94', '100'))
64288	23530816	Modulation of these proteins may provide effective chemoprevention against colorectal cancer.	('Modulation', 'Var', (0, 10))	('colorectal cancer', 'Disease', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))
64290	23530816	Apc mutant mice develop large numbers of adenomas in their small intestine and fewer in the large intestine whereas; FAP patients develop low numbers of adenomas in their small intestine and large numbers of adenomas in their large intestine.	('mutant', 'Var', (4, 10))	('adenomas', 'Disease', 'MESH:D000236', (208, 216))	('adenomas', 'Disease', 'MESH:D000236', (153, 161))	('FAP', 'Disease', (117, 120))	('adenomas', 'Disease', (208, 216))	('adenomas', 'Disease', (153, 161))	('mice', 'Species', '10090', (11, 15))	('adenomas', 'Disease', 'MESH:D000236', (41, 49))	('FAP', 'Disease', 'MESH:C567782', (117, 120))	('Apc', 'Gene', (0, 3))	('adenomas', 'Disease', (41, 49))	('Apc', 'cellular_component', 'GO:0005680', ('0', '3'))	('patients', 'Species', '9606', (121, 129))	('Apc', 'Gene', '11789', (0, 3))
64293	23530816	The results of this study revealed that the disruption of Cdk4 activity in Apc-/+ mice led to a significantly reduced number and size of tumors.	('mice', 'Species', '10090', (82, 86))	('tumors', 'Disease', (137, 143))	('activity', 'MPA', (63, 71))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('reduced', 'NegReg', (110, 117))	('disruption', 'Var', (44, 54))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('Apc', 'Gene', (75, 78))	('Cdk4', 'Protein', (58, 62))	('Apc', 'Gene', '11789', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
64304	23530816	These results suggest that silibinin may cause cell cycle arrest at the G0 to G1 stages of the cell cycle due in part to its targeting of the Cdk4 signaling pathway (Cdk4, cyclin D1, pRb) at multiple steps.	('Cdk4 signaling pathway', 'Pathway', (142, 164))	('cyclin', 'molecular_function', 'GO:0016538', ('172', '178'))	('silibinin', 'Var', (27, 36))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (47, 64))	('silibinin', 'Chemical', 'MESH:D000077385', (27, 36))	('signaling pathway', 'biological_process', 'GO:0007165', ('147', '164'))	('cell cycle', 'biological_process', 'GO:0007049', ('95', '105'))	('cause', 'Reg', (41, 46))	('Rb', 'Phenotype', 'HP:0009919', (184, 186))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('47', '64'))	('cell cycle arrest', 'CPA', (47, 64))	('Cdk', 'molecular_function', 'GO:0004693', ('142', '145'))	('Cdk', 'molecular_function', 'GO:0004693', ('166', '169'))
64313	23530816	showed that silibinin significantly inhibited adenoma formation in Apc mutant mice by inhibiting cell proliferation.	('adenoma', 'Disease', (46, 53))	('Apc', 'Gene', (67, 70))	('inhibited', 'NegReg', (36, 45))	('cell proliferation', 'biological_process', 'GO:0008283', ('97', '115'))	('Apc', 'cellular_component', 'GO:0005680', ('67', '70'))	('Apc', 'Gene', '11789', (67, 70))	('inhibiting', 'NegReg', (86, 96))	('mutant', 'Var', (71, 77))	('formation', 'biological_process', 'GO:0009058', ('54', '63'))	('adenoma', 'Disease', 'MESH:D000236', (46, 53))	('cell proliferation', 'CPA', (97, 115))	('silibinin', 'Chemical', 'MESH:D000077385', (12, 21))	('mice', 'Species', '10090', (78, 82))
64314	23530816	However, no studies have explored mechanistically the antiproliferative activity of silibinin on the Cdk4 pathway in Apc mutant mice.	('Apc', 'Gene', '11789', (117, 120))	('mutant', 'Var', (121, 127))	('antiproliferative activity', 'MPA', (54, 80))	('mice', 'Species', '10090', (128, 132))	('Apc', 'cellular_component', 'GO:0005680', ('117', '120'))	('Cdk', 'molecular_function', 'GO:0004693', ('101', '104'))	('Cdk4 pathway', 'Pathway', (101, 113))	('Apc', 'Gene', (117, 120))	('silibinin', 'Chemical', 'MESH:D000077385', (84, 93))
64318	23530816	Increased TUNEL-positive cells were noted within the crypts in the normal, nonpolypoid mucosa in mice that received silibinin as well as in adenomas.	('silibinin', 'Var', (116, 125))	('silibinin', 'Chemical', 'MESH:D000077385', (116, 125))	('adenomas', 'Disease', 'MESH:D000236', (140, 148))	('mice', 'Species', '10090', (97, 101))	('adenomas', 'Disease', (140, 148))
64321	23530816	Alterations in apoptosis also have profound effects on the progression of benign to malignant tumors.	('apoptosis', 'CPA', (15, 24))	('malignant tumors', 'Disease', (84, 100))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('malignant tumors', 'Disease', 'MESH:D018198', (84, 100))	('Alterations', 'Var', (0, 11))	('progression', 'CPA', (59, 70))	('effects', 'Reg', (44, 51))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
64322	23530816	In summary, disruption of the homeostatic balance between proliferation and apoptosis has been broadly implicated in cancer and silibinin tips the balance away from development of colorectal cancer.	('cancer', 'Disease', (191, 197))	('disruption', 'Var', (12, 22))	('colorectal cancer', 'Disease', 'MESH:D015179', (180, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('apoptosis', 'biological_process', 'GO:0097194', ('76', '85'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (180, 197))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('colorectal cancer', 'Disease', (180, 197))	('silibinin', 'Chemical', 'MESH:D000077385', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('implicated', 'Reg', (103, 113))	('apoptosis', 'biological_process', 'GO:0006915', ('76', '85'))	('homeostatic', 'MPA', (30, 41))
64388	23405123	There was a significant association between presence of DM and multivariate adjusted disease-free survival (HR: 1.17, 95% CI: 1.00-1.37).	('disease-free survival', 'CPA', (85, 106))	('DM', 'Disease', 'MESH:D009223', (56, 58))	('presence', 'Var', (44, 52))
64389	23405123	In contrast, there was no significant association between presence of DM and multivariate adjusted overall survival, recurrence-free survival and colorectal cancer-specific survival.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('presence', 'Var', (58, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (146, 163))	('colorectal cancer', 'Phenotype', 'HP:0003003', (146, 163))	('rectal cancer', 'Phenotype', 'HP:0100743', (150, 163))	('colorectal cancer', 'Disease', (146, 163))	('DM', 'Disease', 'MESH:D009223', (70, 72))
64416	23405123	The potential mechanisms for different effects of DM on proximal, distal colon and rectal cancer could include different characteristics of tumor microsatellite instability status as well as chromosomal instability association to proximal and distal colon.	('DM', 'Disease', 'MESH:D009223', (50, 52))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('association', 'Reg', (215, 226))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('chromosomal instability', 'Var', (191, 214))	('rectal cancer', 'Phenotype', 'HP:0100743', (83, 96))	('colon and rectal cancer', 'Disease', 'MESH:D012004', (73, 96))	('chromosomal instability', 'Phenotype', 'HP:0040012', (191, 214))	('tumor', 'Disease', (140, 145))
64417	23405123	Considering more proximal site colon tumors (30-40%) than distal colon or rectal tumors (3-12%) have higher levels of methylated CpG islands in several tumor suppressor genes or inactivated ncRNA, worse prognosis of proximal cancer patients with DM in our study could also be associated with epigenetics which may interact between DM and tumor according to its sites.	('rectal tumors', 'Phenotype', 'HP:0100743', (74, 87))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('cancer', 'Disease', (225, 231))	('tumor', 'Disease', (338, 343))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('152', '168'))	('colon or rectal tumors', 'Disease', 'MESH:D012004', (65, 87))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('DM', 'Disease', 'MESH:D009223', (246, 248))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('colon tumors', 'Disease', 'MESH:D015179', (31, 43))	('methylated', 'MPA', (118, 128))	('colon tumor', 'Phenotype', 'HP:0100273', (31, 42))	('rectal tumor', 'Phenotype', 'HP:0100743', (74, 86))	('tumor suppressor', 'biological_process', 'GO:0051726', ('152', '168'))	('tumor', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('associated', 'Reg', (276, 286))	('colon tumors', 'Phenotype', 'HP:0100273', (31, 43))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('levels', 'MPA', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('higher', 'PosReg', (101, 107))	('colon tumors', 'Disease', (31, 43))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('DM', 'Disease', 'MESH:D009223', (331, 333))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('colon or rectal tumors', 'Disease', (65, 87))	('ncRNA', 'Gene', (190, 195))	('epigenetics', 'Var', (292, 303))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('patients', 'Species', '9606', (232, 240))	('ncRNA', 'Gene', '54719', (190, 195))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
64451	33384962	MDSCs not only suppress anti-tumor immunity but also impede the efficacy of therapeutic agents for cancer treatment.	('MDSCs', 'Var', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('suppress', 'NegReg', (15, 23))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('impede', 'NegReg', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('cancer', 'Disease', (99, 105))	('tumor', 'Disease', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
64471	33384962	Furthermore, while M1 macrophages express CD64, suppressor of cytokine signaling 1 (SOCS1), indoleamine 2,3-dioxygenase (IDO) and chemokine (C-X-C motif) ligand 1 (CXCL1), M2 macrophages express mannose receptor C-type 1 (MRC1), CD23, and chemokine ligand 22 (CCL22).	('MRC1', 'Gene', (222, 226))	('mannose receptor C-type 1', 'Gene', (195, 220))	('MRC1', 'Gene', '4360', (222, 226))	('SOCS1', 'Gene', (84, 89))	('mannose receptor C-type 1', 'Gene', '4360', (195, 220))	('ligand', 'molecular_function', 'GO:0005488', ('154', '160'))	('IDO', 'molecular_function', 'GO:0033754', ('121', '124'))	('suppressor of cytokine signaling 1', 'Gene', '8651', (48, 82))	('signaling', 'biological_process', 'GO:0023052', ('71', '80'))	('IDO', 'Gene', (121, 124))	('ligand', 'molecular_function', 'GO:0005488', ('249', '255'))	('CXCL1', 'Gene', '2919', (164, 169))	('CXCL1', 'Gene', (164, 169))	('CCL', 'molecular_function', 'GO:0044101', ('260', '263'))	('SOCS1', 'Gene', '8651', (84, 89))	('IDO', 'molecular_function', 'GO:0047719', ('121', '124'))	('CCL22', 'Gene', (260, 265))	('CD23', 'Gene', (229, 233))	('IDO', 'Gene', '3620', (121, 124))	('mannose receptor', 'molecular_function', 'GO:0005532', ('195', '211'))	('CCL22', 'Gene', '6367', (260, 265))	('CD64', 'Var', (42, 46))	('indoleamine 2,3-dioxygenase', 'Gene', '3620', (92, 119))	('suppressor of cytokine signaling 1', 'Gene', (48, 82))
64481	33384962	In human peripheral blood, early-stage MDSCs (e-MDSCs), which are comprised of more immature progenitors than conventional MDSCs, are defined by Lin- (including CD3, CD14, CD15, CD19, CD56) HLA-DR-CD33+.	('human', 'Species', '9606', (3, 8))	('CD19', 'Var', (178, 182))	('CD14', 'Var', (166, 170))	('CD15', 'Var', (172, 176))
64510	33384962	Secondly, MDSCs can suppress T cell activation and proliferation by depleting essential amino acids.	('MDSCs', 'Var', (10, 15))	('T cell activation', 'CPA', (29, 46))	('essential amino acids', 'Chemical', 'MESH:D000601', (78, 99))	('depleting', 'NegReg', (68, 77))	('suppress', 'NegReg', (20, 28))	('suppress T cell activation', 'Phenotype', 'HP:0005419', (20, 46))	('T cell activation', 'biological_process', 'GO:0042110', ('29', '46'))
64511	33384962	MDSCs increase arginase-1 activity and induce T cell suppression via the depletion of L-arginine.	('arginase-1', 'Gene', (15, 25))	('depletion of L-arginine', 'MPA', (73, 96))	('MDSCs', 'Var', (0, 5))	('T cell suppression', 'CPA', (46, 64))	('arginase-1', 'Gene', '383', (15, 25))	('increase arginase', 'Phenotype', 'HP:0500153', (6, 23))	('L-arginine', 'Chemical', 'MESH:D001120', (86, 96))	('depletion of L-arginine', 'Phenotype', 'HP:0005961', (73, 96))	('activity', 'MPA', (26, 34))	('increase', 'PosReg', (6, 14))
64512	33384962	The lack of L-arginine suppresses proliferation of activated T cells and decreases the expression of the T cell receptor-zeta (TCR-zeta) chain.	('proliferation', 'CPA', (34, 47))	('decreases', 'NegReg', (73, 82))	('L-arginine', 'Chemical', 'MESH:D001120', (12, 22))	('suppresses', 'NegReg', (23, 33))	('TCR-zeta', 'Gene', (127, 135))	('expression', 'MPA', (87, 97))	('lack', 'Var', (4, 8))	('L-arginine', 'Protein', (12, 22))
64516	33384962	For example, MDSCs can decrease expression level of B-cell lymphoma 2 (Bcl-2) expression and increase FAS (CD95 ligand) expression in T cells.	('decrease', 'NegReg', (23, 31))	('B-cell lymphoma 2', 'Gene', (52, 69))	('MDSCs', 'Var', (13, 18))	('expression', 'MPA', (78, 88))	('expression', 'MPA', (120, 130))	('increase', 'PosReg', (93, 101))	('FAS', 'MPA', (102, 105))	('expression level', 'MPA', (32, 48))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (52, 67))	('Bcl-2', 'Gene', '596', (71, 76))	('lymphoma', 'Phenotype', 'HP:0002665', (59, 67))	('Bcl-2', 'Gene', (71, 76))	('B-cell lymphoma 2', 'Gene', '596', (52, 69))
64523	33384962	Furthermore, the CCR5 ligands CCL3, CCL4, and CCL5 were shown to promote CCR5+ Treg cell recruitment in mouse models of melanoma.	('mouse', 'Species', '10090', (104, 109))	('CCR5+', 'MPA', (73, 78))	('CCL4', 'Gene', (36, 40))	('CCL5', 'Gene', (46, 50))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('promote', 'PosReg', (65, 72))	('CCL5', 'Gene', '20304', (46, 50))	('CCL4', 'Gene', '20303', (36, 40))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('CCL3', 'Var', (30, 34))
64524	33384962	It has been reported that CD14+HLA-DR-/low M-MDSCs could induce CD4+CD25+Foxp3+Treg cells when co-cultured with autologous T cells in hepatocellular carcinoma (HCC) patients.	('hepatocellular carcinoma', 'Disease', (134, 158))	('CD4', 'Gene', '920', (64, 67))	('CD14+HLA-DR-/low', 'Var', (26, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('Foxp3', 'Gene', '50943', (73, 78))	('CD4', 'Gene', (64, 67))	('HCC', 'Phenotype', 'HP:0001402', (160, 163))	('Foxp3', 'Gene', (73, 78))	('patients', 'Species', '9606', (165, 173))	('induce', 'PosReg', (57, 63))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (134, 158))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (134, 158))
64526	33384962	With the exception of Tregs stimulation, MDSCs can also reverse macrophages to an M2-like phenotype with low IL-12 production, thereby promoting tumor growth.	('low', 'NegReg', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('Tregs', 'Chemical', '-', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('IL-12 production', 'MPA', (109, 125))	('IL-12 production', 'biological_process', 'GO:0032615', ('109', '125'))	('MDSCs', 'Var', (41, 46))	('promoting', 'PosReg', (135, 144))	('tumor', 'Disease', (145, 150))	('IL-12', 'molecular_function', 'GO:0005143', ('109', '114'))
64527	33384962	In addition, MDSCs impair NK cell function and cytotoxicity by suppressing the production of IFN-gamma from NK cells and decreasing the expression of natural killer group 2 member D (NKG2D).	('MDSCs', 'Var', (13, 18))	('natural killer group 2 member D', 'Gene', (150, 181))	('expression', 'MPA', (136, 146))	('natural killer group 2 member D', 'Gene', '22914', (150, 181))	('NK cell function', 'CPA', (26, 42))	('cytotoxicity', 'Disease', (47, 59))	('NKG2D', 'Gene', '22914', (183, 188))	('suppressing', 'NegReg', (63, 74))	('decreasing', 'NegReg', (121, 131))	('NKG2D', 'Gene', (183, 188))	('cytotoxicity', 'Disease', 'MESH:D064420', (47, 59))	('impair', 'NegReg', (19, 25))	('production of IFN-gamma', 'MPA', (79, 102))
64530	33384962	It has been reported that the peripheral blood of CRC patients contains a significantly increased percentage and absolute number of CD33+CD11b+HLA-DR-/low MDSCs compared with healthy donors.	('CD33+CD11b+HLA-DR-/low', 'Var', (132, 154))	('patients', 'Species', '9606', (54, 62))	('CRC', 'Disease', (50, 53))	('increased', 'PosReg', (88, 97))	('CRC', 'Phenotype', 'HP:0003003', (50, 53))
64534	33384962	In a recent study, CD33+ MDSCs and Yes-associated protein 1 (YAP1) were identified as predictors for the prognosis of CRC patients.	('CRC', 'Disease', (118, 121))	('YAP1', 'Gene', '10413', (61, 65))	('CD33+ MDSCs', 'Var', (19, 30))	('patients', 'Species', '9606', (122, 130))	('Yes-associated protein 1', 'Gene', '10413', (35, 59))	('CRC', 'Phenotype', 'HP:0003003', (118, 121))	('YAP1', 'Gene', (61, 65))	('Yes-associated protein 1', 'Gene', (35, 59))
64535	33384962	This study demonstrated that CD33+MDSCs numbers and YAP1 expression levels were increased in tumor tissues compared with those of tumor-adjacent tissues from the same CRC patients.	('CRC', 'Phenotype', 'HP:0003003', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('YAP1', 'Gene', (52, 56))	('increased', 'PosReg', (80, 89))	('YAP1', 'Gene', '10413', (52, 56))	('CD33+MDSCs', 'Var', (29, 39))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('patients', 'Species', '9606', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('expression levels', 'MPA', (57, 74))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
64536	33384962	Furthermore, CD33+CD11b+HLA-DR-/low myeloid cells were shown to be expanded in the peripheral blood of CRC patients, with the number of circulating MDSCs positively correlating with poor prognosis and low survival rates.	('poor prognosis', 'CPA', (182, 196))	('CRC', 'Phenotype', 'HP:0003003', (103, 106))	('CD33+CD11b+HLA-DR-/low', 'Var', (13, 35))	('correlating with', 'Reg', (165, 181))	('patients', 'Species', '9606', (107, 115))	('low', 'NegReg', (201, 204))
64538	33384962	Unresectable metastatic CRC patients with high M-MDSCs levels in their peripheral blood were also shown to have a significantly shorter progression-free survival.	('progression-free survival', 'CPA', (136, 161))	('CRC', 'Phenotype', 'HP:0003003', (24, 27))	('shorter', 'NegReg', (128, 135))	('high', 'Var', (42, 46))	('metastatic CRC', 'Disease', (13, 27))	('patients', 'Species', '9606', (28, 36))
64540	33384962	KRAS mutations, for example, are frequently observed in human CRC and correlate positively with tumor aggressiveness and metastasis.	('metastasis', 'CPA', (121, 131))	('CRC', 'Phenotype', 'HP:0003003', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor aggressiveness', 'Disease', (96, 116))	('aggressiveness', 'Phenotype', 'HP:0000718', (102, 116))	('mutations', 'Var', (5, 14))	('human', 'Species', '9606', (56, 61))	('CRC', 'Disease', (62, 65))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (96, 116))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
64546	33384962	Moreover, MUC13 promotes colitis-associated colorectal tumors development through the beta-catenin signaling pathway and increases MDSCs expansion in the TME.	('promotes', 'PosReg', (16, 24))	('colitis', 'Disease', (25, 32))	('MDSCs', 'MPA', (131, 136))	('increases', 'PosReg', (121, 130))	('beta-catenin', 'Gene', (86, 98))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('beta-catenin', 'Gene', '1499', (86, 98))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('colitis', 'Disease', 'MESH:D003092', (25, 32))	('colitis', 'Phenotype', 'HP:0002583', (25, 32))	('colorectal tumors', 'Disease', 'MESH:D015179', (44, 61))	('signaling pathway', 'biological_process', 'GO:0007165', ('99', '116'))	('colorectal tumors', 'Disease', (44, 61))	('MUC13', 'Var', (10, 15))
64547	33384962	In addition, MDSCs can increase the expression levels of ROS and NO, which may result in DNA damage and promote tumor progression in CRC.	('MDSCs', 'Var', (13, 18))	('ROS', 'Chemical', 'MESH:D017382', (57, 60))	('ROS', 'Protein', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('DNA', 'cellular_component', 'GO:0005574', ('89', '92'))	('CRC', 'Disease', (133, 136))	('DNA damage', 'MPA', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('result in', 'Reg', (79, 88))	('promote', 'PosReg', (104, 111))	('increase', 'PosReg', (23, 31))	('tumor', 'Disease', (112, 117))	('CRC', 'Phenotype', 'HP:0003003', (133, 136))	('expression levels', 'MPA', (36, 53))
64550	33384962	In addition, overexpression of CXCR4 has been found to play a crucial role in the invasion of CRC, as well as promoting the epithelial-mesenchymal transition (EMT) and infiltration of MDSCs in colonic tissue, accelerating colitis-associated and Apc mutation-driven colorectal tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('colitis', 'Phenotype', 'HP:0002583', (222, 229))	('promoting', 'PosReg', (110, 119))	('CXCR4', 'Gene', '7852', (31, 36))	('CXCR4', 'Gene', (31, 36))	('invasion', 'CPA', (82, 90))	('accelerating', 'PosReg', (209, 221))	('mutation-driven', 'Var', (249, 264))	('infiltration', 'CPA', (168, 180))	('colitis', 'Disease', (222, 229))	('CXCR4', 'molecular_function', 'GO:0038147', ('31', '36'))	('EMT', 'biological_process', 'GO:0001837', ('159', '162'))	('Apc', 'cellular_component', 'GO:0005680', ('245', '248'))	('tumor', 'Disease', (276, 281))	('colitis', 'Disease', 'MESH:D003092', (222, 229))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('Apc', 'Gene', (245, 248))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('124', '157'))	('epithelial-mesenchymal transition', 'CPA', (124, 157))	('CRC', 'Phenotype', 'HP:0003003', (94, 97))	('Apc', 'Gene', '324', (245, 248))	('overexpression', 'Var', (13, 27))
64556	33384962	It has also been shown that protease-activated receptor 2 (PAR2) deficiency significantly promotes tumor development in the AOM/DSS-induced colitis-associated colon cancer model through accumulation of MDSCs and enhancement of their immunosuppressive activity via STAT3-mediated ROS production.	('protease-activated receptor 2', 'Gene', '2150', (28, 57))	('colitis-associated colon cancer', 'Disease', 'MESH:D015179', (140, 171))	('ROS', 'Chemical', 'MESH:D017382', (279, 282))	('colon cancer', 'Phenotype', 'HP:0003003', (159, 171))	('accumulation', 'PosReg', (186, 198))	('tumor', 'Disease', (99, 104))	('colitis', 'Phenotype', 'HP:0002583', (140, 147))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('enhancement', 'PosReg', (212, 223))	('AOM', 'Chemical', 'MESH:D001397', (124, 127))	('promotes', 'PosReg', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('colitis-associated colon cancer', 'Disease', (140, 171))	('MDSCs', 'MPA', (202, 207))	('PAR2', 'Gene', '2150', (59, 63))	('PAR2', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('protease-activated receptor 2', 'Gene', (28, 57))	('immunosuppressive activity', 'CPA', (233, 259))	('deficiency', 'Var', (65, 75))
64560	33384962	In addition, STAT6 appears to promote expansion of MDSCs and contributes to intestinal tumor progression in ApcMin/+ mice.	('contributes', 'Reg', (61, 72))	('intestinal tumor', 'Disease', 'MESH:D007414', (76, 92))	('STAT6', 'Gene', '20852', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('intestinal tumor', 'Disease', (76, 92))	('mice', 'Species', '10090', (117, 121))	('expansion', 'Var', (38, 47))	('Apc', 'Gene', '324', (108, 111))	('MDSCs', 'Protein', (51, 56))	('STAT6', 'Gene', (13, 18))	('Apc', 'Gene', (108, 111))
64567	33384962	Inhibition of S100A9 was found to suppress the susceptibility of mice to AOM/DSS-induced colitis-associated colon cancer.	('AOM', 'Chemical', 'MESH:D001397', (73, 76))	('colitis', 'Phenotype', 'HP:0002583', (89, 96))	('colitis-associated colon cancer', 'Disease', 'MESH:D015179', (89, 120))	('mice', 'Species', '10090', (65, 69))	('colon cancer', 'Phenotype', 'HP:0003003', (108, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('S100A9', 'Gene', (14, 20))	('susceptibility', 'MPA', (47, 61))	('Inhibition', 'Var', (0, 10))	('suppress', 'NegReg', (34, 42))	('colitis-associated colon cancer', 'Disease', (89, 120))
64577	33384962	Thus, inhibition of CSF-1R signaling can significantly block the number of tumor-infiltrating MDSCs number and enhance anti-tumor T cells responses in tumor bearing mice.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('mice', 'Species', '10090', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', (124, 129))	('block', 'NegReg', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('enhance', 'PosReg', (111, 118))	('inhibition', 'Var', (6, 16))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
64582	33384962	Recently, the TLR7/8 agonist R848, as a new immunologic adjuvant, was found to reverse the functional orientation of MDSCs towards M1 macrophages, suggesting that R848 may be a potential immunologic adjuvant in chemotherapy for oxaliplatin-resistant CRC.	('R848', 'Chemical', 'MESH:C402365', (163, 167))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (228, 239))	('R848', 'Chemical', 'MESH:C402365', (29, 33))	('TLR7/8', 'Gene', '51284;51311', (14, 20))	('R848', 'Var', (163, 167))	('CRC', 'Phenotype', 'HP:0003003', (250, 253))	('TLR7/8', 'Gene', (14, 20))
64583	33384962	It has been reported that treatment with anti-CCR2 antibody can alleviate radiation-induced MDSCs infiltration in CRC tumor tissues by activation of the STING pathway.	('STING pathway', 'Pathway', (153, 166))	('alleviate', 'NegReg', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('CRC', 'Phenotype', 'HP:0003003', (114, 117))	('CRC tumor', 'Disease', 'MESH:D015179', (114, 123))	('CRC tumor', 'Disease', (114, 123))	('anti-CCR2', 'Var', (41, 50))
64587	33384962	Hence, (-)-4-O-(4-O-beta-D-glucopyranosylcaffeoyl) quinic acid (QA), a selective small molecule inhibitor of PI3Kdelta/gamma, has the ability to reshape the tumor immune microenvironment and promote responses to anti-PD-1 treatment in a colon tumor model.	('tumor', 'Disease', (157, 162))	('colon tumor', 'Disease', (237, 248))	('responses', 'MPA', (199, 208))	('colon tumor', 'Disease', 'MESH:D003110', (237, 248))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('reshape', 'Reg', (145, 152))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('O-beta', 'Species', '95145', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('-)-4-O-', 'Var', (8, 15))	('colon tumor', 'Phenotype', 'HP:0100273', (237, 248))	('promote', 'PosReg', (191, 198))	('QA', 'Chemical', 'MESH:D011801', (64, 66))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
64588	33384962	Several clinical studies have also indicated that inhibition of MDSCs is beneficial to CRC patients.	('CRC', 'Disease', (87, 90))	('patients', 'Species', '9606', (91, 99))	('MDSCs', 'Protein', (64, 69))	('inhibition', 'Var', (50, 60))	('CRC', 'Phenotype', 'HP:0003003', (87, 90))
64594	33384962	Interestingly, a significant expansion of CD38+M-MDSCs were observed in PBMCs of CRC patients when compared with healthy donors, and CD38+M-MDSCs frequencies were significantly higher in CRC patients who had previously received any form of cancer treatment (surgery, chemotherapy or radiotherapy, targeted therapy, or a combination of these methods) when compared with treatment-naive patients.	('higher', 'PosReg', (177, 183))	('patients', 'Species', '9606', (191, 199))	('CRC', 'Disease', (187, 190))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('expansion', 'PosReg', (29, 38))	('patients', 'Species', '9606', (85, 93))	('CD38+M-MDSCs', 'MPA', (42, 54))	('CD38+M-MDSCs', 'Var', (133, 145))	('CRC', 'Phenotype', 'HP:0003003', (187, 190))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('patients', 'Species', '9606', (385, 393))	('CRC', 'Phenotype', 'HP:0003003', (81, 84))	('cancer', 'Disease', (240, 246))
64606	33384962	MUC13-deficient mice have fewer MDSCs and are sensitive to anti-PD-L1 therapy, suggesting that MUC13 may be useful for in the treatment of colitis-associated cancer.	('colitis-associated cancer', 'Disease', 'MESH:D009369', (139, 164))	('colitis-associated cancer', 'Disease', (139, 164))	('MDSCs', 'MPA', (32, 37))	('MUC13', 'Var', (95, 100))	('mice', 'Species', '10090', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('colitis', 'Phenotype', 'HP:0002583', (139, 146))
64607	33384962	Additionally, it has been revealed that treatment using an anti-KIT monoclonal antibody in a mouse colon cancer model enhanced the anti-tumor activity of anti-CTLA-4 and anti-PD-1 therapy by selectively reducing the MDSCs population.	('colon cancer', 'Disease', 'MESH:D015179', (99, 111))	('MDSCs population', 'CPA', (216, 232))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('antibody', 'molecular_function', 'GO:0003823', ('79', '87'))	('mouse', 'Species', '10090', (93, 98))	('antibody', 'cellular_component', 'GO:0042571', ('79', '87'))	('enhanced', 'PosReg', (118, 126))	('colon cancer', 'Disease', (99, 111))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('KIT', 'molecular_function', 'GO:0005020', ('64', '67'))	('antibody', 'cellular_component', 'GO:0019815', ('79', '87'))	('KIT', 'Gene', (64, 67))	('KIT', 'Gene', '16590', (64, 67))	('colon cancer', 'Phenotype', 'HP:0003003', (99, 111))	('anti-CTLA-4', 'Var', (154, 165))	('reducing', 'NegReg', (203, 211))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('antibody', 'cellular_component', 'GO:0019814', ('79', '87'))
64612	33384962	showed that CD30L deficiency promote the accumulation of MDSCs, increase the expression of PD-L1 on MDSCs and TAMs, and enhance immunosuppressive function in an AOM/DSS-induced CAC model, suggesting that CD30L/CD30 signaling could be a potential candidate target for immunotherapy in CAC.	('promote', 'PosReg', (29, 36))	('enhance', 'PosReg', (120, 127))	('expression', 'MPA', (77, 87))	('immunosuppressive function', 'CPA', (128, 154))	('CD30L', 'Gene', (204, 209))	('PD-L1', 'Gene', (91, 96))	('CAC', 'Disease', (284, 287))	('CD30L', 'Gene', '944', (204, 209))	('signaling', 'biological_process', 'GO:0023052', ('215', '224'))	('CD30L', 'Gene', (12, 17))	('TAMs', 'Chemical', '-', (110, 114))	('increase', 'PosReg', (64, 72))	('MDSCs', 'MPA', (57, 62))	('CD30L', 'Gene', '944', (12, 17))	('deficiency', 'Var', (18, 28))	('AOM', 'Chemical', 'MESH:D001397', (161, 164))
64635	33175885	miR-196b-5p and miR-142-3p are known to induce cellular stemness, and miR-1249-5p, miR-6737-5p, miR-6819-5p, and miR-10b showed indirect oncogenic activity by modulating the function of fibroblasts.	('miR-196b-5p', 'Var', (0, 11))	('miR-6819', 'Gene', '102465491', (96, 104))	('miR-6737', 'Gene', '102465441', (83, 91))	('miR-10b', 'Gene', (113, 120))	('modulating', 'Reg', (159, 169))	('miR-1249-5p', 'Var', (70, 81))	('miR-142-3p', 'Var', (16, 26))	('function of fibroblasts', 'CPA', (174, 197))	('miR-6737', 'Gene', (83, 91))	('cellular stemness', 'CPA', (47, 64))	('oncogenic activity', 'CPA', (137, 155))	('miR-6819', 'Gene', (96, 104))	('miR-10b', 'Gene', '406903', (113, 120))	('induce', 'PosReg', (40, 46))
64636	33175885	In contrast, there are several miRNAs in the miR-96, -149, -486-5p, -6869-5p, -8073, and -193a classes exhibiting tumor suppressor effects.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor suppressor', 'biological_process', 'GO:0051726', ('114', '130'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('114', '130'))	('miR-96', 'Var', (45, 51))
64643	33175885	The passage number of HT-29 cells and SW480 cells at purchase were P130 (#lot 700190500 and P99 (#lot 70013709), respectively.	('#lot 70013709', 'Var', (97, 110))	('P99', 'Gene', (92, 95))	('SW480', 'CellLine', 'CVCL:0546', (38, 43))	('HT-29', 'CellLine', 'CVCL:0320', (22, 27))	('P130', 'Gene', '9221', (67, 71))	('P130', 'Gene', (67, 71))	('P99', 'Gene', '5514', (92, 95))	('#lot 700190500', 'Var', (73, 87))
64684	33175885	It was found that migration of THP-1 cells was decreased in HT29 and SW480 exosome-treated CAFs rather than CAFs-only conditions (Fig 3B).	('migration of THP-1 cells', 'CPA', (18, 42))	('CAF', 'Gene', '8850', (108, 111))	('CAF', 'Gene', (91, 94))	('decreased', 'NegReg', (47, 56))	('CAF', 'Gene', '8850', (91, 94))	('HT29', 'CellLine', 'CVCL:0320', (60, 64))	('SW480', 'CellLine', 'CVCL:0546', (69, 74))	('CAF', 'Gene', (108, 111))	('HT29', 'Var', (60, 64))	('THP-1', 'CellLine', 'CVCL:0006', (31, 36))	('SW480 exosome-treated', 'Var', (69, 90))
64739	33175885	The passage number of HT-29 cells and SW480 cells at purchase were P130 (#lot 700190500 and P99 (#lot 70013709), respectively."	('#lot 70013709', 'Var', (97, 110))	('P99', 'Gene', (92, 95))	('SW480', 'CellLine', 'CVCL:0546', (38, 43))	('HT-29', 'CellLine', 'CVCL:0320', (22, 27))	('P130', 'Gene', '9221', (67, 71))	('P130', 'Gene', (67, 71))	('P99', 'Gene', '5514', (92, 95))	('#lot 700190500', 'Var', (73, 87))
64773	32461789	H. pylori is listed as a class I carcinogen by the World Health Organization International Agency for Cancer Research and is also involved in the tumorigenesis of extragastric target organs, such as lung cancer, and hepatocellular carcinoma.	('lung cancer', 'Disease', 'MESH:D008175', (199, 210))	('hepatocellular carcinoma', 'Disease', (216, 240))	('Cancer', 'Disease', (102, 108))	('H. pylori', 'Species', '210', (0, 9))	('involved in', 'Reg', (130, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('Cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('Cancer', 'Phenotype', 'HP:0002664', (102, 108))	('lung cancer', 'Disease', (199, 210))	('lung cancer', 'Phenotype', 'HP:0100526', (199, 210))	('H. pylori', 'Var', (0, 9))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (216, 240))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (216, 240))
64843	32461789	Low gastric acid may adversely affect the intestinal flora, cause bacterial overgrowth, colonic disorders, and colorectal carcinogenesis.	('affect', 'Reg', (31, 37))	('colorectal carcinogenesis', 'Disease', (111, 136))	('colorectal carcinogenesis', 'Disease', 'MESH:D015179', (111, 136))	('colonic disorders', 'Disease', 'MESH:D003110', (88, 105))	('cause', 'Reg', (60, 65))	('bacterial overgrowth', 'Disease', (66, 86))	('intestinal flora', 'CPA', (42, 58))	('colonic disorders', 'Disease', (88, 105))	('overgrowth', 'Phenotype', 'HP:0001548', (76, 86))	('bacterial overgrowth', 'Disease', 'MESH:D001765', (66, 86))	('Low', 'Var', (0, 3))
64872	32461789	The future direction of research is to evaluate whether the eradication of gastric H. pylori can reduce the occurrence of colorectal polyps and CRC.	('colorectal polyps', 'Disease', (122, 139))	('eradication', 'Var', (60, 71))	('colorectal polyp', 'Phenotype', 'HP:0200063', (122, 138))	('CRC', 'Phenotype', 'HP:0003003', (144, 147))	('gastric H.', 'Protein', (75, 85))	('H. pylori', 'Species', '210', (83, 92))	('colorectal polyps', 'Phenotype', 'HP:0200063', (122, 139))	('CRC', 'Disease', (144, 147))	('colorectal polyps', 'Disease', 'MESH:D003111', (122, 139))	('reduce', 'NegReg', (97, 103))
64890	32098058	Cancer cells floating into the peritoneal cavity invade the metastasizing peritoneal niche through a mainly transforming growth factor (TGF)-beta1-mediated MMT induction, while a large proportion of cancers display mutational inactivation of the TGF-beta pathway.	('TGF-beta', 'Gene', '7039', (246, 254))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('mutational inactivation', 'Var', (215, 238))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('MMT', 'Chemical', '-', (156, 159))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('MMT', 'MPA', (156, 159))	('TGF-beta', 'Gene', (246, 254))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('metastasizing peritoneal niche', 'CPA', (60, 90))	('cancers', 'Disease', (199, 206))
64984	31281474	Toll-like receptor 6 expression, sequence variants, and their association with colorectal cancer risk This is the first study to examine the potential correlation of the rs3796508 and rs5743810 SNPs of the TLR6 gene in patients with colorectal cancer (CRC) in a subset of the Saudi population.	('TLR6', 'Gene', (206, 210))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('rs5743810', 'Mutation', 'rs5743810', (184, 193))	('colorectal cancer', 'Disease', (233, 250))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))	('colorectal cancer', 'Disease', (79, 96))	('patients', 'Species', '9606', (219, 227))	('rectal cancer', 'Phenotype', 'HP:0100743', (237, 250))	('rs5743810 SNPs', 'Var', (184, 198))	('colorectal cancer', 'Phenotype', 'HP:0003003', (233, 250))	('rs3796508', 'Mutation', 'rs3796508', (170, 179))	('rs3796508', 'Var', (170, 179))	('rectal cancer', 'Phenotype', 'HP:0100743', (83, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('TLR6', 'Gene', '10333', (206, 210))	('Toll-like receptor 6', 'Gene', (0, 20))	('Toll-like receptor 6', 'Gene', '10333', (0, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (233, 250))
64991	31281474	Global analysis revealed no significant association between the TLR6 rs3796508 and rs5743810 and CRC in this population.	('rs3796508', 'Mutation', 'rs3796508', (69, 78))	('CRC', 'Disease', (97, 100))	('rs5743810', 'Mutation', 'rs5743810', (83, 92))	('rs3796508', 'Var', (69, 78))	('rs5743810', 'Var', (83, 92))	('TLR6', 'Gene', (64, 68))	('TLR6', 'Gene', '10333', (64, 68))
64993	31281474	Two non-synonymous single nucleotide polymorphisms (SNP; S249P and V327M) were common in a few patients and were predicted as damaging by SIFT and Polyphen and were further analyzed for their protein stability and function using advanced bioinformatics tools.	('V327M', 'Mutation', 'rs3796508', (67, 72))	('patients', 'Species', '9606', (95, 103))	('SIFT', 'Disease', (138, 142))	('SIFT', 'Disease', 'None', (138, 142))	('V327M', 'Var', (67, 72))	('S249P', 'Mutation', 'rs5743810', (57, 62))
64994	31281474	The results suggest that TLR6 rs3796508 has a crucial role as a protective factor against colorectal cancer in the older Saudi male population.	('rs3796508', 'Var', (30, 39))	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('rectal cancer', 'Phenotype', 'HP:0100743', (94, 107))	('TLR6', 'Gene', '10333', (25, 29))	('colorectal cancer', 'Disease', (90, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('rs3796508', 'Mutation', 'rs3796508', (30, 39))	('TLR6', 'Gene', (25, 29))
65003	31281474	An association between the dysregulation of innate immunity and cancer development risk has been reported previously in our own and other studies.	('cancer', 'Disease', (64, 70))	('dysregulation of innate immunity', 'Phenotype', 'HP:0002958', (27, 59))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('dysregulation', 'Var', (27, 40))	('innate immunity', 'biological_process', 'GO:0045087', ('44', '59'))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
65015	31281474	One common genetic variation that could be used as a biomarker to detect the development of CRC risk are single nucleotide polymorphisms (SNPs), which have a recognized association with the susceptibility to inflammatory disease and other infections in different human populations.	('inflammatory disease', 'Disease', (208, 228))	('inflammatory disease', 'Disease', 'MESH:D007249', (208, 228))	('infections', 'Disease', 'MESH:D007239', (239, 249))	('human', 'Species', '9606', (263, 268))	('CRC', 'Disease', (92, 95))	('single nucleotide polymorphisms', 'Var', (105, 136))	('infections', 'Disease', (239, 249))
65016	31281474	Genetic variations caused by SNPs in TLR may lead to alterations in the immune system and variations have been identified in different types of tumors, such as prostate, gastric, bladder, cervical, breast, endometrial and esophageal cancers.	('tumors', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('prostate', 'Disease', (160, 168))	('gastric', 'Disease', (170, 177))	('SNPs', 'Var', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('bladder', 'Disease', (179, 186))	('esophageal cancers', 'Disease', (222, 240))	('endometrial', 'Disease', (206, 217))	('immune system', 'MPA', (72, 85))	('lead to alterations', 'Reg', (45, 64))	('TLR', 'Gene', (37, 40))	('TLR', 'Gene', '7096;7097;281534;7098;7099;10333;407237;51311;54106;81793', (37, 40))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('cervical', 'Disease', (188, 196))	('esophageal cancers', 'Disease', 'MESH:D004938', (222, 240))	('breast', 'Disease', (198, 204))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
65017	31281474	The presence of SNPs has also been correlated with the following malignancies: acute lymphoblastic leukemia, hepatocellular carcinoma (HCC), Hodgkin's lymphoma, and Burkett's lymphoma.	('lymphoblastic leukemia', 'Disease', (85, 107))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (79, 107))	('SNPs', 'Var', (16, 20))	('malignancies', 'Disease', 'MESH:D009369', (65, 77))	('malignancies', 'Disease', (65, 77))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (109, 133))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (141, 159))	('correlated', 'Reg', (35, 45))	("Burkett's lymphoma", 'Disease', 'MESH:D008223', (165, 183))	('lymphoma', 'Phenotype', 'HP:0002665', (175, 183))	('lymphoma', 'Phenotype', 'HP:0002665', (151, 159))	('hepatocellular carcinoma', 'Disease', (109, 133))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (85, 107))	("Hodgkin's lymphoma", 'Disease', (141, 159))	('presence', 'Var', (4, 12))	('leukemia', 'Phenotype', 'HP:0001909', (99, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	("Burkett's lymphoma", 'Disease', (165, 183))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (109, 133))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (85, 107))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (141, 159))
65018	31281474	However, the TLR 2, 3, 4, and 9 polymorphism genes are not associated with increased breast cancer risk.	('TLR', 'Gene', '7096;7097;281534;7098;7099;10333;407237;51311;54106;81793', (13, 16))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('breast cancer', 'Disease', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('polymorphism', 'Var', (32, 44))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('TLR', 'Gene', (13, 16))
65019	31281474	CRC tissues show higher expression of the TLR1, TLR2, TLR4, TLR8, and TLR9 genes, andTLR6 polymorphisms are linked to a risk of pancreatic cancer.	('TLR1', 'Gene', '7096', (42, 46))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (128, 145))	('polymorphisms', 'Var', (90, 103))	('TLR8', 'Gene', '51311', (60, 64))	('TLR6', 'Gene', '10333', (85, 89))	('expression', 'MPA', (24, 34))	('linked to', 'Reg', (108, 117))	('TLR4', 'Gene', '7099', (54, 58))	('TLR6', 'Gene', (85, 89))	('TLR4', 'Gene', (54, 58))	('TLR8', 'Gene', (60, 64))	('pancreatic cancer', 'Disease', 'MESH:D010190', (128, 145))	('TLR2', 'Gene', '7097', (48, 52))	('TLR9', 'Gene', (70, 74))	('TLR2', 'Gene', (48, 52))	('pancreatic cancer', 'Disease', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('TLR9', 'Gene', '54106', (70, 74))	('TLR1', 'Gene', (42, 46))	('higher', 'PosReg', (17, 23))
65020	31281474	We hypothesized that genetic polymorphisms in TLR6 may be correlated with the risk of CRC.	('TLR6', 'Gene', (46, 50))	('TLR6', 'Gene', '10333', (46, 50))	('genetic polymorphisms', 'Var', (21, 42))	('correlated', 'Reg', (58, 68))	('CRC', 'Disease', (86, 89))
65021	31281474	Consequently, the aim of the present study was to determine the potential effect of the SNPs rs3796508 at Valine 327 and rs5743810 at Serine 249 of the TLR6 gene on the CRC risk in the Saudi population when compared with healthy subjects.	('Valine', 'Chemical', 'MESH:D014633', (106, 112))	('CRC', 'Disease', (169, 172))	('rs5743810 at Serine', 'Var', (121, 140))	('rs3796508', 'Mutation', 'rs3796508', (93, 102))	('rs3796508 at', 'Var', (93, 105))	('rs5743810', 'Mutation', 'rs5743810', (121, 130))	('Serine', 'Chemical', 'MESH:D012694', (134, 140))	('TLR6', 'Gene', (152, 156))	('TLR6', 'Gene', '10333', (152, 156))
65031	31281474	The two selected SNPs, rs3796508 and rs5743810, were genotyped and were previously identified within the TLR6 gene (www.ncbi.nlm.nih.gov/snp/).	('rs5743810', 'Var', (37, 46))	('rs3796508', 'Mutation', 'rs3796508', (23, 32))	('TLR6', 'Gene', (105, 109))	('rs5743810', 'Mutation', 'rs5743810', (37, 46))	('rs3796508', 'Var', (23, 32))	('TLR6', 'Gene', '10333', (105, 109))
65042	31281474	The possible impact of the two SNPs (S249P and V327M) on the structure/ function of the TLR6 protein was predicted using SIFT and PolyPhen.	('SIFT', 'Disease', (121, 125))	('V327M', 'Mutation', 'rs3796508', (47, 52))	('V327M', 'Var', (47, 52))	('SIFT', 'Disease', 'None', (121, 125))	('TLR6', 'Gene', (88, 92))	('S249P', 'Mutation', 'rs5743810', (37, 42))	('TLR6', 'Gene', '10333', (88, 92))	('S249P', 'Var', (37, 42))
65043	31281474	SIFT (http://sift.jcvi.org/) is a sequence homology-based tool that can predict variants as neutral or deleterious based on the normalized probability score.	('SIFT', 'Disease', 'None', (0, 4))	('SIFT', 'Disease', (0, 4))	('variants', 'Var', (80, 88))
65055	31281474	The DNA was genotyped by HWE for the presence of the rs3796508 C/T and rs5743810 C/T TLR6 SNPs.	('TLR6', 'Gene', '10333', (85, 89))	('rs5743810 C/T', 'Var', (71, 84))	('rs3796508 C/T', 'Var', (53, 66))	('rs3796508', 'Mutation', 'rs3796508', (53, 62))	('rs5743810', 'Mutation', 'rs5743810', (71, 80))	('TLR6', 'Gene', (85, 89))
65057	31281474	The prevalences of the Val/Val, Val/Met, and Met/Met genotypes in the TLR-6 rs3796508 SNP were 96%, 2%, and 2%, respectively, in the CRC case group and 94%, 6%, and 0%, respectively, in the control group (Table 3).	('rs3796508 SNP', 'Var', (76, 89))	('Met/Met', 'Var', (45, 52))	('TLR-6', 'Gene', '10333', (70, 75))	('rs3796508', 'Mutation', 'rs3796508', (76, 85))	('Val/Val', 'Var', (23, 30))	('Val/Met', 'Var', (32, 39))	('CRC', 'Disease', (133, 136))	('Val', 'Chemical', 'MESH:D014633', (32, 35))	('TLR-6', 'Gene', (70, 75))	('Val', 'Chemical', 'MESH:D014633', (23, 26))	('Val', 'Chemical', 'MESH:D014633', (27, 30))
65058	31281474	The prevalences of the Ser/Ser, Ser/Pro, and Pro /Pro genotypes in the rs5743810 SNP were 2%, 25%, and 73%, respectively, in the CRC case group and 3%, 19%, and 78%, respectively, in the control group.	('Pro', 'Chemical', 'MESH:D011392', (36, 39))	('Ser', 'Chemical', 'MESH:D012694', (27, 30))	('Pro', 'Chemical', 'MESH:D011392', (50, 53))	('CRC', 'Disease', (129, 132))	('Ser', 'cellular_component', 'GO:0005790', ('27', '30'))	('Ser', 'Chemical', 'MESH:D012694', (32, 35))	('Ser', 'Chemical', 'MESH:D012694', (23, 26))	('Pro', 'Chemical', 'MESH:D011392', (45, 48))	('rs5743810', 'Mutation', 'rs5743810', (71, 80))	('Ser', 'cellular_component', 'GO:0005790', ('23', '26'))	('Ser', 'cellular_component', 'GO:0005790', ('32', '35'))	('rs5743810', 'Var', (71, 80))
65064	31281474	In the male group (66 patients and 60 controls), the heterozygous Val/Met was a more significant genotype of SNP rs3796508 in the control group than in the CRC case group (OR= 0.095, 95% CI: 0.005-1.807, and p= 0.03385), suggesting that the Val/Met genotype was a protective factor against CRC.	('rs3796508', 'Var', (113, 122))	('Val', 'Chemical', 'MESH:D014633', (66, 69))	('CRC', 'Disease', (290, 293))	('patients', 'Species', '9606', (22, 30))	('rs3796508', 'Mutation', 'rs3796508', (113, 122))	('SNP', 'Var', (109, 112))	('Val', 'Chemical', 'MESH:D014633', (241, 244))
65066	31281474	The distribution of the genotypes and alleles for TLR6 rs5743810 in males did not show any statistically significant differences either for genotype or allele frequencies between the CRC cases and healthy controls (Table 4A).	('CRC', 'Disease', (183, 186))	('rs5743810', 'Mutation', 'rs5743810', (55, 64))	('TLR6', 'Gene', (50, 54))	('rs5743810', 'Var', (55, 64))	('TLR6', 'Gene', '10333', (50, 54))
65069	31281474	By contrast, no genotype or allele frequencies differences were observed in female CRC cases or female healthy controls for either of the studied TLR6 SNPs (rs3796508 and rs5743810).	('rs5743810', 'Var', (171, 180))	('TLR6', 'Gene', (146, 150))	('TLR6', 'Gene', '10333', (146, 150))	('rs3796508', 'Mutation', 'rs3796508', (157, 166))	('rs5743810', 'Mutation', 'rs5743810', (171, 180))	('rs3796508', 'Var', (157, 166))
65070	31281474	The frequency distributions for the Val/Met and Met/Met rs3796508 mutations were similar in both study groups and no differences were noted between the female study groups in terms of the prevalence of Ser/Pro and Pro/Pro distribution for rs5743810 (Table 4B).	('rs3796508', 'Mutation', 'rs3796508', (56, 65))	('Ser', 'Chemical', 'MESH:D012694', (202, 205))	('Pro', 'Chemical', 'MESH:D011392', (214, 217))	('rs3796508', 'Var', (56, 65))	('Pro', 'Chemical', 'MESH:D011392', (218, 221))	('Val', 'Chemical', 'MESH:D014633', (36, 39))	('rs5743810', 'Mutation', 'rs5743810', (239, 248))	('Pro', 'Chemical', 'MESH:D011392', (206, 209))	('Met/Met rs3796508', 'Var', (48, 65))	('rs5743810', 'Var', (239, 248))
65074	31281474	However, the Val/Met heterozygote genotype of SNP rs3796508 provided significant protection against the risk of CRC in the patients diagnosed with CRC after 57 years of age.	('CRC', 'Disease', (147, 150))	('SNP', 'Gene', (46, 49))	('rs3796508', 'Mutation', 'rs3796508', (50, 59))	('patients', 'Species', '9606', (123, 131))	('CRC', 'Disease', (112, 115))	('Val', 'Chemical', 'MESH:D014633', (13, 16))	('rs3796508', 'Var', (50, 59))
65076	31281474	This age difference suggests that the presence of this genotype is an essential factor for protection against the risk of CRC development in the Saudi population (OR= 0.152; 95% CI: 0.016-1.415, and p= 0.04069; Table 5B); whereas the genotype frequency did not indicate a significant risk for the same SNPs in patients aged less than 57 years (Table 5A).	('CRC development', 'CPA', (122, 137))	('presence', 'Var', (38, 46))	('patients', 'Species', '9606', (310, 318))
65077	31281474	By contrast, the TLR6 rs5743810 genotype and allele variation did not indicate any difference in CRC susceptibility in either sub-population (Tables 5A and 5B).	('rs5743810', 'Var', (22, 31))	('CRC', 'Disease', (97, 100))	('rs5743810', 'Mutation', 'rs5743810', (22, 31))	('TLR6', 'Gene', (17, 21))	('TLR6', 'Gene', '10333', (17, 21))
65078	31281474	The genotype and allele frequencies for TLR6 rs5743810 were similar in both populations regardless of age at diagnosis (Tables 5A and 5B).	('rs5743810', 'Mutation', 'rs5743810', (45, 54))	('TLR6', 'Gene', '10333', (40, 44))	('TLR6', 'Gene', (40, 44))	('rs5743810', 'Var', (45, 54))
65082	31281474	The distribution of the heterozygous Val/Met mutation and double homozygous Met/Met mutation was 3% in the population having cancer in the colon area and 6% in the controls; this distribution was 0% in both sub-populations for the Met/Met genotype (Table 6A).	('Val/Met', 'Gene', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutation', 'Var', (45, 53))	('Val', 'Chemical', 'MESH:D014633', (37, 40))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('Met/Met', 'Gene', (76, 83))	('mutation', 'Var', (84, 92))
65083	31281474	The Val/Met and Met/Met genotype frequencies for TLR6 rs3796508 were, respectively, 0% and 3% in the CRC patients with rectal cancer and 6% and 0% in normal control patients with rectal cancer (Table 6B).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('TLR6', 'Gene', (49, 53))	('Val', 'Chemical', 'MESH:D014633', (4, 7))	('patients', 'Species', '9606', (105, 113))	('rectal cancer', 'Disease', 'MESH:D012004', (119, 132))	('rectal cancer', 'Disease', 'MESH:D012004', (179, 192))	('TLR6', 'Gene', '10333', (49, 53))	('rectal cancer', 'Disease', (179, 192))	('rs3796508', 'Mutation', 'rs3796508', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('rectal cancer', 'Disease', (119, 132))	('rectal cancer', 'Phenotype', 'HP:0100743', (119, 132))	('Met/Met', 'Var', (16, 23))	('rs3796508', 'Var', (54, 63))	('rectal cancer', 'Phenotype', 'HP:0100743', (179, 192))	('patients', 'Species', '9606', (165, 173))
65084	31281474	The frequency for the mutant "Met" allele was similar in both sub-populations having either colon or rectal cancer when compared to healthy controls (p>0.05) (Tables 6A and 6B).	('rectal cancer', 'Phenotype', 'HP:0100743', (101, 114))	('colon', 'Disease', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutant', 'Var', (22, 28))	('rectal cancer', 'Disease', 'MESH:D012004', (101, 114))	('rectal cancer', 'Disease', (101, 114))
65085	31281474	The TLR6 rs5743810 SNP did not show any correlation with CRC susceptibility or cancer location for either the genotype or phenotype variations (Tables 6A and 6B).	('TLR6', 'Gene', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('TLR6', 'Gene', '10333', (4, 8))	('rs5743810', 'Mutation', 'rs5743810', (9, 18))	('CRC', 'Disease', (57, 60))	('rs5743810', 'Var', (9, 18))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
65086	31281474	We also examined whether amino acid changes might affect the protein function and stability by performing a prediction study for both the S249P and V327M mutations using SIFT and PolyPhen.	('V327M', 'Var', (148, 153))	('protein function', 'MPA', (61, 77))	('SIFT', 'Disease', (170, 174))	('S249P', 'Mutation', 'rs5743810', (138, 143))	('affect', 'Reg', (50, 56))	('S249P', 'Var', (138, 143))	('SIFT', 'Disease', 'None', (170, 174))	('V327M', 'Mutation', 'rs3796508', (148, 153))	('stability', 'MPA', (82, 91))
65088	31281474	The current study is the first to report a solvated model for the mutated TLR6 protein and indicated a high association between the predicted structural and functional effects of TLR6.	('TLR6', 'Gene', (179, 183))	('mutated', 'Var', (66, 73))	('TLR6', 'Gene', '10333', (179, 183))	('protein', 'Protein', (79, 86))	('TLR6', 'Gene', (74, 78))	('TLR6', 'Gene', '10333', (74, 78))
65089	31281474	The SIFT and PolyPhen results indicated that both the S249P and V327M mutations were damaging, so they were further examined in silico for 3D structural functions.	('S249P', 'Var', (54, 59))	('SIFT', 'Disease', 'None', (4, 8))	('V327M', 'Mutation', 'rs3796508', (64, 69))	('V327M', 'Var', (64, 69))	('S249P', 'Mutation', 'rs5743810', (54, 59))	('SIFT', 'Disease', (4, 8))
65109	31281474	For this reason, the focus of the present study was to validate both the TLR6 expression and TLR6 genetic polymorphisms (such as rs3796508 and rs5743810) in the Saudi population.	('rs5743810', 'Mutation', 'rs5743810', (143, 152))	('TLR6', 'Gene', (73, 77))	('rs5743810', 'Var', (143, 152))	('TLR6', 'Gene', '10333', (73, 77))	('TLR6', 'Gene', (93, 97))	('rs3796508', 'Mutation', 'rs3796508', (129, 138))	('TLR6', 'Gene', '10333', (93, 97))	('rs3796508', 'Var', (129, 138))
65116	31281474	These modifications include cytosine-phosphate-guanine (CpG) hypermethylation, alterations of non-coding RNAs, acetylation of the lysine in the histones, and microRNAs.	('acetylation', 'MPA', (111, 122))	('alterations', 'Reg', (79, 90))	('non-coding RNAs', 'Protein', (94, 109))	('cytosine-phosphate-guanine', 'Chemical', '-', (28, 54))	('cytosine-phosphate-guanine', 'MPA', (28, 54))	('microRNAs', 'MPA', (158, 167))	('lysine', 'Protein', (130, 136))	('lysine', 'Chemical', 'MESH:D008239', (130, 136))	('hypermethylation', 'Var', (61, 77))	('histones', 'Protein', (144, 152))
65117	31281474	These mutations or single nucleotide changes, particularly in the TLR6 exons, can contribute to colon cancer formation.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('single nucleotide changes', 'Var', (19, 44))	('TLR6', 'Gene', (66, 70))	('contribute', 'Reg', (82, 92))	('colon cancer', 'Disease', 'MESH:D015179', (96, 108))	('TLR6', 'Gene', '10333', (66, 70))	('colon cancer', 'Phenotype', 'HP:0003003', (96, 108))	('formation', 'biological_process', 'GO:0009058', ('109', '118'))	('colon cancer', 'Disease', (96, 108))
65119	31281474	Our global statistical analysis of two TLR6 SNPs showed no clear evidence for an association between either TLR6 rs3796508 or rs5743810 polymorphisms and susceptibility to CRC development in the Saudi Arabian population, indicating that these SNPs are located in an exon region of the TLR6 gene that may have an impact on TLR6 expression and function.	('rs3796508', 'Var', (113, 122))	('function', 'MPA', (342, 350))	('rs5743810', 'Var', (126, 135))	('TLR6', 'Gene', (285, 289))	('susceptibility', 'Reg', (154, 168))	('CRC development', 'CPA', (172, 187))	('TLR6', 'Gene', (108, 112))	('impact', 'Reg', (312, 318))	('TLR6', 'Gene', '10333', (285, 289))	('TLR6', 'Gene', '10333', (108, 112))	('TLR6', 'Gene', (322, 326))	('TLR6', 'Gene', (39, 43))	('rs3796508', 'Mutation', 'rs3796508', (113, 122))	('expression', 'MPA', (327, 337))	('TLR6', 'Gene', '10333', (322, 326))	('rs5743810', 'Mutation', 'rs5743810', (126, 135))	('TLR6', 'Gene', '10333', (39, 43))
65121	31281474	(2007) showed that, upon TLR2 stimulation, the mutant homozygous genotype of the TLR2 rs4696480 SNP was correlated with a higher pro-inflammatory cytokine secretion, as well as TNF- alpha, IL-6 and IL-12 secretion, when compared to the double mutant heterozygote or wild genotype, indicating an increased risk of development of chronic diseases.	('cytokine secretion', 'biological_process', 'GO:0050663', ('146', '164'))	('IL-6', 'molecular_function', 'GO:0005138', ('189', '193'))	('pro-inflammatory cytokine secretion', 'MPA', (129, 164))	('higher', 'PosReg', (122, 128))	('rs4696480 SNP', 'Var', (86, 99))	('TNF- alpha', 'Gene', '7124', (177, 187))	('TLR2', 'Gene', '7097', (25, 29))	('TLR2', 'Gene', '7097', (81, 85))	('rs4696480', 'Mutation', 'rs4696480', (86, 95))	('chronic diseases', 'Disease', 'MESH:D002908', (328, 344))	('chronic diseases', 'Disease', (328, 344))	('TLR2', 'Gene', (81, 85))	('IL-12', 'molecular_function', 'GO:0005143', ('198', '203'))	('IL-6', 'Gene', (189, 193))	('TLR2', 'Gene', (25, 29))	('IL-6', 'Gene', '3569', (189, 193))	('TNF- alpha', 'Gene', (177, 187))	('IL-12 secretion', 'biological_process', 'GO:0072610', ('198', '213'))
65122	31281474	(2011) reported that the AA genotype of the TLR2 promoter variant rs4696480 SNP was associated with a higher FOXP3 expression in regulatory T cells of maternal atopy.	('TLR2', 'Gene', '7097', (44, 48))	('rs4696480 SNP', 'Var', (66, 79))	('FOXP3', 'Gene', '50943', (109, 114))	('TLR2', 'Gene', (44, 48))	('higher', 'PosReg', (102, 108))	('rs4696480', 'Mutation', 'rs4696480', (66, 75))	('expression', 'MPA', (115, 125))	('maternal atopy', 'Phenotype', 'HP:0001047', (151, 165))	('FOXP3', 'Gene', (109, 114))
65123	31281474	Evidence from the latest studies shows that polymorphisms within TLR6 gene are correlated with mild malaria, pancreatic cancer, and long-term smokers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('malaria', 'Disease', (100, 107))	('TLR6', 'Gene', (65, 69))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (109, 126))	('polymorphisms', 'Var', (44, 57))	('TLR6', 'Gene', '10333', (65, 69))	('malaria', 'Disease', 'MESH:D008288', (100, 107))	('pancreatic cancer', 'Disease', 'MESH:D010190', (109, 126))	('pancreatic cancer', 'Disease', (109, 126))	('correlated', 'Reg', (79, 89))
65124	31281474	In addition, TLR6 SNP rs5743810 is linked with endometritis in the American population.	('endometritis', 'Phenotype', 'HP:0025636', (47, 59))	('rs5743810', 'Var', (22, 31))	('TLR6', 'Gene', '10333', (13, 17))	('rs5743810', 'Mutation', 'rs5743810', (22, 31))	('endometritis', 'Disease', (47, 59))	('endometritis', 'Disease', 'MESH:D004716', (47, 59))	('linked with', 'Reg', (35, 46))	('TLR6', 'Gene', (13, 17))
65125	31281474	(2014) also showed that polymorphism of TLR6 rs3796508 increased the Klebsiella pneumoniae infection risk and polymorphism of TLR6 rs5743810 was correlated with an increased risk of asthma increase.	('TLR6', 'Gene', (126, 130))	('rs3796508', 'Mutation', 'rs3796508', (45, 54))	('polymorphism', 'Var', (24, 36))	('TLR6', 'Gene', '10333', (126, 130))	('rs5743810', 'Mutation', 'rs5743810', (131, 140))	('asthma increase', 'Disease', 'MESH:D001249', (182, 197))	('rs3796508', 'Var', (45, 54))	('increased', 'PosReg', (55, 64))	('asthma', 'Phenotype', 'HP:0002099', (182, 188))	('rs5743810', 'Var', (131, 140))	('Klebsiella pneumoniae infection', 'Disease', (69, 100))	('Klebsiella pneumoniae infection', 'Disease', 'MESH:D007710', (69, 100))	('pneumoniae infection', 'Phenotype', 'HP:0002090', (80, 100))	('TLR6', 'Gene', (40, 44))	('asthma increase', 'Disease', (182, 197))	('TLR6', 'Gene', '10333', (40, 44))
65126	31281474	However, our previous work on the same study population showed that SNP rs3796508 was not associated with cigarette smokers, but a correlation was evident between Saudi cigarette smokers compared to non-smokers for the rs5743810 SNP of TLR6.	('rs3796508', 'Mutation', 'rs3796508', (72, 81))	('rs5743810', 'Var', (219, 228))	('correlation', 'Reg', (131, 142))	('rs3796508', 'Var', (72, 81))	('TLR6', 'Gene', (236, 240))	('TLR6', 'Gene', '10333', (236, 240))	('rs5743810', 'Mutation', 'rs5743810', (219, 228))
65127	31281474	By contrast, our study demonstrated a significant association between genetic variations of TLR6 polymorphism and male CRC cases and CRC cases over 57 years of age at the time of diagnosis.	('polymorphism', 'Var', (97, 109))	('CRC', 'Disease', (119, 122))	('CRC', 'Disease', (133, 136))	('TLR6', 'Gene', (92, 96))	('genetic variations', 'Var', (70, 88))	('TLR6', 'Gene', '10333', (92, 96))
65128	31281474	We found that the Val/Met genotype of SNP rs3796508 had a significantly higher frequency in the control group than in the CRC cases.	('SNP', 'Gene', (38, 41))	('rs3796508', 'Mutation', 'rs3796508', (42, 51))	('Val', 'Chemical', 'MESH:D014633', (18, 21))	('rs3796508', 'Var', (42, 51))	('Val/Met', 'Disease', (18, 25))
65131	31281474	The TLR6 Valine 327 and Serine 249 substitutions altered protein stability due to the size differences between wild-type and mutant residues, which caused the new residue to be in an incorrect position to make the required hydrogen bond (Figure 2; B) as the resulting difference in hydrophobicity affects hydrogen bond formation.	('TLR6', 'Gene', (4, 8))	('affects', 'Reg', (297, 304))	('Valine 327', 'Var', (9, 19))	('altered', 'Reg', (49, 56))	('TLR6', 'Gene', '10333', (4, 8))	('substitutions', 'Var', (35, 48))	('hydrogen', 'Chemical', 'MESH:D006859', (305, 313))	('hydrogen bond formation', 'MPA', (305, 328))	('Valine', 'Chemical', 'MESH:D014633', (9, 15))	('Serine', 'Chemical', 'MESH:D012694', (24, 30))	('Serine 249 substitutions', 'Var', (24, 48))	('hydrogen', 'Chemical', 'MESH:D006859', (223, 231))	('protein stability', 'MPA', (57, 74))	('hydrophobicity', 'MPA', (282, 296))
65135	31281474	Our data suggest that TLR6 rs3796508 has a crucial role as a protective factor against CRC in the older male Saudi population.	('CRC', 'Disease', (87, 90))	('rs3796508', 'Mutation', 'rs3796508', (27, 36))	('rs3796508', 'Var', (27, 36))	('TLR6', 'Gene', (22, 26))	('TLR6', 'Gene', '10333', (22, 26))
65175	31231562	Of these, 92 (41%) had RAS/BRAF wild-type disease, whereas 99 (50%) and 8 (4%) harboured RAS-mutated or BRAF-mutated tumours, respectively.	('tumours', 'Disease', (117, 124))	('RAS-mutated', 'Var', (89, 100))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('BRAF', 'Gene', '673', (27, 31))	('BRAF', 'Gene', '673', (104, 108))	('tumours', 'Phenotype', 'HP:0002664', (117, 124))	('BRAF', 'Gene', (27, 31))	('tumours', 'Disease', 'MESH:D009369', (117, 124))	('BRAF', 'Gene', (104, 108))
65192	31231562	In the subgroup of patients who underwent at least one liver-directed procedure, nodal involvement (HR 1.55, 95% CI 1.02 to 2.36; p=0.04) and MSI-high status (HR 3.03, 95% CI 0.43 to 21.15; p=0.049) were associated with shorter ePFS while undergoing subsequent locoregional retreatments was associated with longer ePFS (HR 0.31, 95% CI 0.19 to 0.52; p<0.001).	('patients', 'Species', '9606', (19, 27))	('MSI-high status', 'Var', (142, 157))	('nodal', 'Gene', '4838', (81, 86))	('nodal', 'Gene', (81, 86))
65213	31231562	Due to the low prevalence of this alteration, especially in the case of LLD, these results should be cautiously interpreted, also taking into account the frequent co-occurrence of MSI and BRAF V600E mutation.	('V600E', 'Mutation', 'rs113488022', (193, 198))	('V600E', 'Var', (193, 198))	('BRAF', 'Gene', (188, 192))	('BRAF', 'Gene', '673', (188, 192))
65228	30875950	In clinical practice, it may be difficult to obtain tumour tissue from patients for gene alteration discoveries to tailor treatment.	('patients', 'Species', '9606', (71, 79))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('gene alteration', 'Var', (84, 99))	('tumour', 'Disease', (52, 58))
65232	30875950	From an oncologist's point of view, reduction in the tumour size is the measured criteria, whereas from a biologist's point of view, the measured criterion is the epigenetic modification causing tumorigenic alteration and cell death in healthy tissues.	('cell death', 'CPA', (222, 232))	('tumour', 'Disease', (53, 59))	('tumorigenic alteration', 'CPA', (195, 217))	('reduction', 'NegReg', (36, 45))	('causing', 'Reg', (187, 194))	('cell death', 'biological_process', 'GO:0008219', ('222', '232'))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('epigenetic modification', 'Var', (163, 186))	('tumour', 'Disease', 'MESH:D009369', (53, 59))
65253	30875950	Research indicates radiotherapy makes the tumour cells more aggressive and potentiates the circulation of non-small lung cancer (NSCLC) cells.	('non-small lung cancer', 'Disease', 'MESH:D002289', (106, 127))	('non-small lung cancer', 'Disease', (106, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (129, 134))	('small lung', 'Phenotype', 'HP:0002089', (110, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('radiotherapy', 'Var', (19, 31))	('potentiates', 'PosReg', (75, 86))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('NSCLC', 'Disease', (129, 134))	('circulation', 'MPA', (91, 102))	('tumour', 'Disease', (42, 48))	('more', 'PosReg', (55, 59))	('aggressive', 'CPA', (60, 70))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))
65254	30875950	The successful use of conventional fractionated high-dose radiotherapy (~2Gy per fraction for 30 days) can result in the destruction of clonogenic tumour cells through DNA damage and cell cycle arrest, through to mitotic catastrophe, apoptosis, necrosis, or autophagy, depending on the dose.	('autophagy', 'CPA', (258, 267))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (183, 200))	('DNA damage', 'CPA', (168, 178))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('~2Gy', 'Var', (72, 76))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('mitotic catastrophe', 'CPA', (213, 232))	('apoptosis', 'CPA', (234, 243))	('necrosis', 'Disease', (245, 253))	('cell cycle arrest', 'CPA', (183, 200))	('tumour', 'Disease', (147, 153))	('necrosis', 'Disease', 'MESH:D009336', (245, 253))
65262	30875950	However, evidence has shown that there is a radiation risk from CT scans inducing malignancy, suggesting that it may not be an ideal method for early cancer detection.	('malignancy', 'Disease', (82, 92))	('inducing', 'Reg', (73, 81))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('CT scans', 'Var', (64, 72))	('malignancy', 'Disease', 'MESH:D009369', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
65270	30875950	Targeted approaches include BEAMing Safe-SeqS, TamSeq, and digital PCR, RTq PCR to detect single-nucleotide mutations for limited genome regions, focusing on predefined gene hot spots like BRAF, KRAS and EGFR.	('BRAF', 'Gene', '673', (189, 193))	('BE', 'Phenotype', 'HP:0100580', (28, 30))	('EGFR', 'molecular_function', 'GO:0005006', ('204', '208'))	('single-nucleotide mutations', 'Var', (90, 117))	('EGFR', 'Gene', '1956', (204, 208))	('BRAF', 'Gene', (189, 193))	('EGFR', 'Gene', (204, 208))	('KRAS', 'Gene', (195, 199))	('KRAS', 'Gene', '3845', (195, 199))
65271	30875950	Murtaza et al., using exome-wide analysis, quantified very high ctDNA levels for 1 to 2 years in 6 cancer patients and also reported on several mutations confirming drug resistance acquired post-treatment.	('drug resistance', 'Phenotype', 'HP:0020174', (165, 180))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('ctDNA levels', 'MPA', (64, 76))	('cancer', 'Disease', (99, 105))	('patients', 'Species', '9606', (106, 114))	('mutations', 'Var', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
65290	30875950	Commonly used CSC markers like CD133, CD44 and ALDH were associated with poor patient outcome.	('CD133', 'Var', (31, 36))	('CD44', 'Var', (38, 42))	('ALDH', 'Disease', (47, 51))	('patient', 'Species', '9606', (78, 85))
65292	30875950	The over-expression of CD44+ and CD133+ cells provides resistance in tumours and the capability for disease relapse after chemo/radiotherapy in immunodeficient mice.	('tumours', 'Disease', (69, 76))	('over-expression', 'PosReg', (4, 19))	('immunodeficient', 'Disease', 'MESH:D007153', (144, 159))	('immunodeficient', 'Disease', (144, 159))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('mice', 'Species', '10090', (160, 164))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('CD133+ cells', 'Var', (33, 45))	('disease relapse', 'CPA', (100, 115))	('CD44+', 'Var', (23, 28))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
65306	30875950	Similar findings were reported for use of CD133 and CD44v9 CSC markers for predicting recurrence, prognosis, and treatment efficacy in colorectal cancer patient CTCs.	('CD44v9', 'Var', (52, 58))	('colorectal cancer', 'Disease', 'MESH:D015179', (135, 152))	('colorectal cancer', 'Phenotype', 'HP:0003003', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('patient', 'Species', '9606', (153, 160))	('colorectal cancer', 'Disease', (135, 152))	('CD133', 'Gene', (42, 47))
65323	30875950	Often, patients with drug resistance EGFR mutations are limited to treatment with tyrosine kinase inhibitors to target the epidermal growth factor receptor gene (EGFR).	('epidermal growth factor receptor', 'Gene', (123, 155))	('drug resistance', 'Phenotype', 'HP:0020174', (21, 36))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'Gene', (162, 166))	('epidermal growth factor receptor', 'Gene', '1956', (123, 155))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('patients', 'Species', '9606', (7, 15))
65350	30875950	c-Met is frequently altered in 90% of HNSCC tumours by mutation and overexpression contributing to HGF/cMet signalling.	('cMet', 'Gene', (103, 107))	('c-Met', 'Gene', '4233', (0, 5))	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('altered', 'Reg', (20, 27))	('HGF', 'Gene', '3082', (99, 102))	('cMet', 'Gene', '4233', (103, 107))	('HNSCC tumours', 'Disease', 'MESH:D000077195', (38, 51))	('mutation', 'Var', (55, 63))	('HNSCC tumours', 'Disease', (38, 51))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('c-Met', 'Gene', (0, 5))	('HGF', 'Gene', (99, 102))
65354	30875950	reported on the role of c-Met/FZD 8 in inhibition of patient derived CSC-like cells by selective c-MET inhibitor PF-2341066.	('c-Met', 'Gene', (24, 29))	('c-MET', 'Gene', (97, 102))	('c-Met', 'Gene', '4233', (24, 29))	('inhibition', 'CPA', (39, 49))	('PF-2341066', 'Var', (113, 123))	('FZD 8', 'Gene', '8325', (30, 35))	('PF', 'Chemical', 'MESH:C002997', (113, 115))	('FZD 8', 'Gene', (30, 35))	('c-MET', 'Gene', '4233', (97, 102))	('patient', 'Species', '9606', (53, 60))
65361	30875950	Furthermore, investigating WNTs, c-Met, PI3K, AKT/mTOR, CCSC epithelial markers and stem cell markers in radiotherapy HNSCC CTCs has the potential to generate future radio-sensitisation modalities.	('AKT', 'Gene', '207', (46, 49))	('mTOR', 'Gene', (50, 54))	('mTOR', 'Gene', '2475', (50, 54))	('c-Met', 'Gene', (33, 38))	('AKT', 'Gene', (46, 49))	('c-Met', 'Gene', '4233', (33, 38))	('PI3K', 'Var', (40, 44))	('PI3K', 'molecular_function', 'GO:0016303', ('40', '44'))
65426	30364783	An R1/Rx resection (a common error during ESD learning) is much more detrimental in the UGI tract than in the colon; especially if high risk colon lesions are avoided during learning.	('R1/Rx resection', 'Var', (3, 18))	('colon lesions', 'Disease', 'MESH:D003108', (141, 154))	('colon lesions', 'Disease', (141, 154))	('detrimental', 'NegReg', (69, 80))
65439	30364783	Berr had suggestions for the "colon heavy-untutored/prevalence based" ESD learners based on his retrospective video analysis of his own work including avoiding: (1) wide SM injection around the lesion (which forces a "perpendicular" instead of "tangential approach"); (2) injection deep to muscle layer (lack of submucosal fluid cushion); (3) disruption of vessels leading to hematoma and loss of transparency of submucosa; (4) dissection without direct vision of the tip of the knife; (5) contact coagulation of small vessel directly on colonic proper muscle layer; and (6) mucosal incision using knife in "pullback fashion" across a haustral fold.	('disruption', 'Var', (343, 353))	('leading to', 'Reg', (365, 375))	('hematoma', 'Disease', (376, 384))	('hematoma', 'Disease', 'MESH:D006406', (376, 384))
65460	27007150	Among patients, high KRAS, positive nuclear beta-catenin expression and high ZEB1 were more commonly occurred in high-DDX3 tumors than in low-DDX3 tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (123, 129))	('KRAS', 'Gene', '3845', (21, 25))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('occurred', 'Reg', (101, 109))	('low-DDX3 tumors', 'Disease', (138, 153))	('ZEB1', 'Gene', (77, 81))	('positive nuclear beta-catenin', 'Protein', (27, 56))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('patients', 'Species', '9606', (6, 14))	('KRAS', 'Gene', (21, 25))	('low-DDX3 tumors', 'Disease', 'MESH:D009800', (138, 153))	('high', 'Var', (72, 76))
65461	27007150	High-DDX3, high-KRAS, positive nuclear beta-catenin tumors, and high-ZEB1 exhibited worse overall survival (OS) and relapse free survival (RFS) than their counterparts.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('positive nuclear beta-catenin', 'Protein', (22, 51))	('RFS', 'Chemical', '-', (139, 142))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('overall survival', 'CPA', (90, 106))	('OS', 'Chemical', '-', (108, 110))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('KRAS', 'Gene', (16, 20))	('relapse free survival', 'CPA', (116, 137))	('worse', 'NegReg', (84, 89))	('High-DDX3', 'Var', (0, 9))	('KRAS', 'Gene', '3845', (16, 20))
65463	27007150	We therefore suggest that AKT or beta-catenin may potentially act as a therapeutic target to improve tumor regression and outcomes in colorectal cancer patients who harbored high-DDX3 tumors.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('colorectal cancer', 'Disease', (134, 151))	('high-DDX3', 'Var', (174, 183))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumor', 'Disease', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('improve', 'PosReg', (93, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))	('patients', 'Species', '9606', (152, 160))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
65464	27007150	Mutations of the K-ras (KRAS) oncogene are observed in up to 50% of colorectal cancerat the stage of the adenomatous precursors.	('K-ras', 'Gene', '3845', (17, 22))	('KRAS', 'Gene', '3845', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('observed', 'Reg', (43, 51))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('Mutations', 'Var', (0, 9))	('colorectal cancerat', 'Disease', (68, 87))	('adenomatous', 'Disease', (105, 116))	('adenomatous', 'Disease', 'MESH:D011125', (105, 116))	('colorectal cancerat', 'Disease', 'MESH:D015179', (68, 87))	('K-ras', 'Gene', (17, 22))	('KRAS', 'Gene', (24, 28))
65465	27007150	A two-step model for colon adenoma initiation is caused by adenomatous polyposis coli (APC) mutation as the first step, whereas KRAS activation and beta-catenin nuclear localization promote adenoma progression to adenocarcinoma as a second step.	('mutation', 'Var', (92, 100))	('adenoma', 'Disease', 'MESH:D000236', (59, 66))	('adenocarcinoma', 'Disease', (213, 227))	('adenoma', 'Disease', 'MESH:D000236', (27, 34))	('APC', 'Phenotype', 'HP:0005227', (87, 90))	('colon adenoma initiation', 'Disease', 'MESH:D000236', (21, 45))	('KRAS', 'Gene', '3845', (128, 132))	('APC', 'Gene', (87, 90))	('adenocarcinoma', 'Disease', 'MESH:D000230', (213, 227))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (59, 85))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (59, 85))	('KRAS', 'Gene', (128, 132))	('adenoma', 'Disease', (190, 197))	('adenomatous polyposis coli', 'Disease', (59, 85))	('adenoma', 'Disease', 'MESH:D000236', (190, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('adenoma', 'Disease', (27, 34))	('adenoma', 'Disease', (59, 66))	('colon adenoma initiation', 'Disease', (21, 45))	('APC', 'Gene', '324', (87, 90))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (59, 80))
65466	27007150	This finding supported by a previous study and indicated that KRAS mutation is not necessary for beta-catenin activation in APC-familiar adenomatous polyposis (FAP)-associated adenomas, but synergistically promotes APC loss-induced tumor progression in colorectal cancer.	('KRAS', 'Gene', (62, 66))	('FAP', 'Disease', (160, 163))	('APC', 'Gene', '324', (124, 127))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (137, 158))	('APC', 'Gene', (215, 218))	('FAP', 'Disease', 'MESH:C567782', (160, 163))	('mutation', 'Var', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('colorectal cancer', 'Disease', 'MESH:D015179', (253, 270))	('APC', 'Phenotype', 'HP:0005227', (124, 127))	('tumor', 'Disease', (232, 237))	('APC-familiar adenomatous polyposis', 'Disease', (124, 158))	('loss-induced', 'NegReg', (219, 231))	('colorectal cancer', 'Disease', (253, 270))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('APC', 'Gene', (124, 127))	('adenomas', 'Disease', 'MESH:D000236', (176, 184))	('APC', 'Gene', '324', (215, 218))	('KRAS', 'Gene', '3845', (62, 66))	('adenomas', 'Disease', (176, 184))	('promotes', 'PosReg', (206, 214))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('colorectal cancer', 'Phenotype', 'HP:0003003', (253, 270))	('APC', 'Phenotype', 'HP:0005227', (215, 218))	('APC-familiar adenomatous polyposis', 'Disease', 'MESH:D011125', (124, 158))
65467	27007150	However, the underlying mechanism of the cross-talk between oncogenic KRAS and APC mutation in colorectal tumorigenesis is not fully understood.	('APC', 'Phenotype', 'HP:0005227', (79, 82))	('KRAS', 'Gene', (70, 74))	('APC', 'Gene', (79, 82))	('KRAS', 'Gene', '3845', (70, 74))	('colorectal tumor', 'Disease', (95, 111))	('mutation', 'Var', (83, 91))	('APC', 'Gene', '324', (79, 82))	('colorectal tumor', 'Disease', 'MESH:D015179', (95, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
65477	27007150	Patients with high-DDX3, high-KRAS, and high-beta-catenin tumors exhibited poorer overall survival (OS) and relapse free survival (RFS) than their counterparts.	('relapse free survival', 'CPA', (108, 129))	('high-beta-catenin', 'Var', (40, 57))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('OS', 'Chemical', '-', (100, 102))	('high-DDX3', 'Var', (14, 23))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('Patients', 'Species', '9606', (0, 8))	('KRAS', 'Gene', (30, 34))	('overall survival', 'CPA', (82, 98))	('RFS', 'Chemical', '-', (131, 134))	('poorer', 'NegReg', (75, 81))	('KRAS', 'Gene', '3845', (30, 34))
65479	27007150	Seven colon cancer cell lines harbored KRAS, APC, and p53 mutations, but possessed wild-type beta-catenin gene were enrolled to test the possibility.	('mutations', 'Var', (58, 67))	('APC', 'Phenotype', 'HP:0005227', (45, 48))	('colon cancer', 'Phenotype', 'HP:0003003', (6, 18))	('p53', 'Gene', (54, 57))	('APC', 'Gene', (45, 48))	('APC', 'Gene', '324', (45, 48))	('KRAS', 'Gene', '3845', (39, 43))	('KRAS', 'Gene', (39, 43))	('p53', 'Gene', '7157', (54, 57))	('colon cancer', 'Disease', 'MESH:D015179', (6, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('colon cancer', 'Disease', (6, 18))
65480	27007150	Western blotting analysis showed that DDX3 was highly expressed in CCM2 and CCM3 cells followed by SW620, HCT15, T84, SW480, and DLD1 cells (Figure 1A).	('CCM2', 'Gene', '83605', (67, 71))	('DDX3', 'Gene', (38, 42))	('CCM2', 'Gene', (67, 71))	('SW620', 'Var', (99, 104))	('SW480', 'CellLine', 'CVCL:0546', (118, 123))	('HCT15', 'CellLine', 'CVCL:0292', (106, 111))	('CCM3', 'Gene', (76, 80))	('CCM3', 'Gene', '11235', (76, 80))
65482	27007150	The invasion capability decreased significantly in DDX3-knockdown CCM2 cells, but increased in DDX3-overexpressing T84 cells (Figure 1B).	('decreased', 'NegReg', (24, 33))	('CCM2', 'Gene', '83605', (66, 70))	('increased', 'PosReg', (82, 91))	('DDX3-knockdown', 'Var', (51, 65))	('invasion capability', 'CPA', (4, 23))	('CCM2', 'Gene', (66, 70))
65485	27007150	We therefore examined the possibility that DDX3 could activate the MEK/ERK and the PI3K/AKT signaling pathways to promote invasion capability in KRAS-mutated colon cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('invasion capability', 'CPA', (122, 141))	('KRAS', 'Gene', (145, 149))	('ERK', 'Gene', '5594', (71, 74))	('PI3K/AKT signaling pathways', 'Pathway', (83, 110))	('ERK', 'Gene', (71, 74))	('colon cancer', 'Phenotype', 'HP:0003003', (158, 170))	('colon cancer', 'Disease', 'MESH:D015179', (158, 170))	('KRAS', 'Gene', '3845', (145, 149))	('MEK', 'Gene', (67, 70))	('MEK', 'Gene', '5609', (67, 70))	('DDX3', 'Var', (43, 47))	('activate', 'PosReg', (54, 62))	('colon cancer', 'Disease', (158, 170))	('promote', 'PosReg', (114, 121))
65487	27007150	Unexpectedly, KRAS expression was markedly decreased by DDX3 knockdown in CCM2 and CCM3 cells, but was increased by DDX3 overexpression in T84 and HCT15 cells (Figure 1D).	('CCM2', 'Gene', '83605', (74, 78))	('expression', 'MPA', (19, 29))	('increased', 'PosReg', (103, 112))	('KRAS', 'Gene', '3845', (14, 18))	('CCM2', 'Gene', (74, 78))	('DDX3', 'Gene', (56, 60))	('CCM3', 'Gene', (83, 87))	('knockdown', 'Var', (61, 70))	('CCM3', 'Gene', '11235', (83, 87))	('HCT15', 'CellLine', 'CVCL:0292', (147, 152))	('KRAS', 'Gene', (14, 18))	('decreased', 'NegReg', (43, 52))
65488	27007150	The expression levels of p-ERK and p-AKT expression were elevated and reduced by DDX3 manipulation in these cell types.	('expression levels', 'MPA', (4, 21))	('reduced', 'NegReg', (70, 77))	('p-ERK', 'Gene', '9451', (25, 30))	('p-ERK', 'Gene', (25, 30))	('expression', 'MPA', (41, 51))	('elevated', 'PosReg', (57, 65))	('p-AKT', 'Protein', (35, 40))	('DDX3', 'Gene', (81, 85))	('manipulation', 'Var', (86, 98))
65492	27007150	The increase of invasion capability in DDX3-overexpressing T84 cells can be reversed by ERK or AKT inhibitor (U0126 or LY294002) treatment or shERK or shAKT transfection.	('ERK', 'Gene', (144, 147))	('LY294002', 'Chemical', 'MESH:C085911', (119, 127))	('ERK', 'Gene', '5594', (88, 91))	('U0126', 'Chemical', 'MESH:C113580', (110, 115))	('invasion capability', 'CPA', (16, 35))	('AKT', 'Protein', (95, 98))	('ERK', 'Gene', (88, 91))	('ERK', 'Gene', '5594', (144, 147))	('LY294002', 'Var', (119, 127))	('increase', 'PosReg', (4, 12))	('U0126', 'Var', (110, 115))
65493	27007150	The invasion capability was suppressed by shDDX3, shERK, shAKT transfection or U0126 and LY294002 treatment (Figure 1F).	('ERK', 'Gene', '5594', (52, 55))	('U0126', 'Chemical', 'MESH:C113580', (79, 84))	('ERK', 'Gene', (52, 55))	('LY294002', 'Chemical', 'MESH:C085911', (89, 97))	('suppressed', 'NegReg', (28, 38))	('U0126', 'Var', (79, 84))	('LY294002 treatment', 'Var', (89, 107))	('invasion capability', 'CPA', (4, 23))
65498	27007150	Luciferase reporter assay and real-time PCR analysis indicated that the -1255/+1 KRAS promoter activity and its mRNA expression levels were significantly reduced by DDX3-knockdown in CCM2 and CCM3 cells, but were elevated by DDX3-overexpression in T84 and HCT15 cells (Figure 2B).	('KRAS', 'Gene', '3845', (81, 85))	('mRNA expression levels', 'MPA', (112, 134))	('CCM3', 'Gene', (192, 196))	('CCM3', 'Gene', '11235', (192, 196))	('DDX3-knockdown', 'Var', (165, 179))	('HCT15', 'CellLine', 'CVCL:0292', (256, 261))	('KRAS', 'Gene', (81, 85))	('CCM2', 'Gene', '83605', (183, 187))	('reduced', 'NegReg', (154, 161))	('CCM2', 'Gene', (183, 187))
65499	27007150	To verify whether the SP1 binding site located at the -1255/+1 KRAS promoter could be involved in DDX3-induced KRAS transcription, the three short KRAS promoters (-907/+1, -750/+1 and -328/+1) were constructed by PCR and deletion mutation (Figure 2A).	('KRAS', 'Gene', '3845', (63, 67))	('KRAS', 'Gene', (111, 115))	('KRAS', 'Gene', '3845', (111, 115))	('-907/+1', 'Var', (163, 170))	('deletion mutation', 'Var', (221, 238))	('KRAS', 'Gene', (147, 151))	('KRAS', 'Gene', '3845', (147, 151))	('KRAS', 'Gene', (63, 67))
65500	27007150	Luciferase reporter assay revealed that the -1255/+1 KRAS promoter activity was significantly elevated by DDX3 overexpression, but the -750/+1 and -328/+1 KRAS promoter activity were almost unchanged by DDX3 overexpression in T84 cells (Figure 2C).	('KRAS', 'Gene', (155, 159))	('elevated', 'PosReg', (94, 102))	('KRAS', 'Gene', '3845', (155, 159))	('-1255/+1', 'Var', (44, 52))	('KRAS', 'Gene', (53, 57))	('KRAS', 'Gene', '3845', (53, 57))	('DDX3', 'Var', (106, 110))
65501	27007150	The -1255/+1 KRAS promoter was markedly decreased and increased by DDX3-knockdown and -overexpression in CCM2 and T84 cells, but the -907/+1, -750/+1 and -328/+1 KRAS promoter activity was almost unchanged by DDX3 manipulation in both cell types (Figure 2C).	('KRAS', 'Gene', (162, 166))	('DDX3-knockdown', 'Gene', (67, 81))	('DDX3-knockdown', 'Var', (67, 81))	('CCM2', 'Gene', '83605', (105, 109))	('CCM2', 'Gene', (105, 109))	('KRAS', 'Gene', '3845', (162, 166))	('increased', 'PosReg', (54, 63))	('KRAS', 'Gene', (13, 17))	('decreased', 'NegReg', (40, 49))	('KRAS', 'Gene', '3845', (13, 17))
65502	27007150	In addition, the promoter activity were also unchanged by transfecting the -1255/+1 KRAS promoter, which harbored a mutant SP1 binding site, into DDX3-overexpressing T84 and DDX3-knockdown CCM2 cells (Figure 2D).	('binding', 'Interaction', (127, 134))	('KRAS', 'Gene', (84, 88))	('CCM2', 'Gene', '83605', (189, 193))	('SP1', 'Gene', (123, 126))	('KRAS', 'Gene', '3845', (84, 88))	('promoter activity', 'MPA', (17, 34))	('mutant', 'Var', (116, 122))	('CCM2', 'Gene', (189, 193))
65503	27007150	Western blotting and immunoprecipitation (IP) showed that the interaction of DDX3 with SP1 was significantly increased in DDX3-overexpressing T84 cells, but was decreased in DDX3-knockdown CCM2 cells (Figure 2E).	('interaction', 'Interaction', (62, 73))	('DDX3-overexpressing', 'Var', (122, 141))	('CCM2', 'Gene', '83605', (189, 193))	('DDX3', 'Gene', (77, 81))	('increased', 'PosReg', (109, 118))	('CCM2', 'Gene', (189, 193))	('SP1', 'Gene', (87, 90))
65504	27007150	ChIP and ChIP-reChIP further indicated that the binding activity of SP1 onto the -1255/+1 KRAS promoter was dose-dependently increased in DDX3-overexpressing T84 cells (Figure 2E right panel) and the opposite was observed in DDX3-knockdown CCM2 cells (Figure 2E left panel).	('increased', 'PosReg', (125, 134))	('KRAS', 'Gene', (90, 94))	('CCM2', 'Gene', '83605', (240, 244))	('binding', 'Interaction', (48, 55))	('KRAS', 'Gene', '3845', (90, 94))	('SP1', 'Gene', (68, 71))	('DDX3-overexpressing', 'Var', (138, 157))	('CCM2', 'Gene', (240, 244))
65505	27007150	These results clearly indicated that KRAS transcription can be enhanced by DDX3 overexpression via increased SP1 binding to the KRAS promoter.	('KRAS', 'Gene', (128, 132))	('enhanced', 'PosReg', (63, 71))	('KRAS', 'Gene', '3845', (128, 132))	('overexpression', 'Var', (80, 94))	('KRAS', 'Gene', (37, 41))	('SP1', 'Protein', (109, 112))	('increased', 'PosReg', (99, 108))	('DDX3', 'Gene', (75, 79))	('KRAS', 'Gene', '3845', (37, 41))	('binding', 'Interaction', (113, 120))
65506	27007150	The TOP flash (a reporter plasmid containing wild-type TCF-binding site) and FOP flash (a reporter plasmid containing mutant TCF-binding site) plasmids was used to verify whether the transcriptional activity of beta-catenin was modulated by DDX3 manipulation in colon cancer cells.	('manipulation', 'Var', (246, 258))	('binding', 'molecular_function', 'GO:0005488', ('59', '66'))	('TCF', 'Gene', (55, 58))	('modulated', 'Reg', (228, 237))	('beta-catenin', 'Protein', (211, 223))	('colon cancer', 'Disease', (262, 274))	('TCF', 'Gene', '3172', (55, 58))	('DDX3', 'Gene', (241, 245))	('transcriptional activity', 'MPA', (183, 207))	('TCF', 'Gene', (125, 128))	('TCF', 'Gene', '3172', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('mutant', 'Var', (118, 124))	('colon cancer', 'Phenotype', 'HP:0003003', (262, 274))	('binding', 'molecular_function', 'GO:0005488', ('129', '136'))	('colon cancer', 'Disease', 'MESH:D015179', (262, 274))
65507	27007150	Luciferase reporter assay showed that the TOP flash was decreased in DDX3-knockdown CCM2 cells and was increased in DDX3-overexpressing T84 cells in a dose-dependent manner.	('TOP flash', 'MPA', (42, 51))	('increased', 'PosReg', (103, 112))	('CCM2', 'Gene', (84, 88))	('decreased', 'NegReg', (56, 65))	('DDX3-knockdown', 'Gene', (69, 83))	('DDX3-knockdown', 'Var', (69, 83))	('CCM2', 'Gene', '83605', (84, 88))
65510	27007150	In the presence of MG132, beta-catenin ubiquitin pattern evaluated by immunoprecipitation (IP) and western blotting was more revealed in DDX3-knockdown CCM2 and in T84 VC cells when compared with CCM2 cells transfecting with non-specific shRNA (NC) and DDX3-overexpressing T84 cells (Supplementary Figure S2A).	('CCM2', 'Gene', (152, 156))	('CCM2', 'Gene', '83605', (196, 200))	('DDX3-knockdown', 'Var', (137, 151))	('beta-catenin ubiquitin pattern', 'MPA', (26, 56))	('CCM2', 'Gene', (196, 200))	('MG132', 'Chemical', 'MESH:C072553', (19, 24))	('MG132', 'Var', (19, 24))	('CCM2', 'Gene', '83605', (152, 156))	('T84 VC', 'CellLine', 'CVCL:M545', (164, 170))	('revealed', 'Reg', (125, 133))
65512	27007150	Western blotting revealed that the expression of KRAS and beta-catenin was eliminated by DDX3 or KRAS silencing, but KRAS expression was unchanged by LY294002, shDDX3 plus KRAS or shDDX3, LY294002 plus KRAS treatments in CCM2 cells (Figure 3C).	('KRAS', 'Gene', (117, 121))	('expression', 'MPA', (122, 132))	('KRAS', 'Gene', '3845', (172, 176))	('LY294002', 'Chemical', 'MESH:C085911', (188, 196))	('LY294002', 'Chemical', 'MESH:C085911', (150, 158))	('silencing', 'Var', (102, 111))	('CCM2', 'Gene', '83605', (221, 225))	('KRAS', 'Gene', (202, 206))	('KRAS', 'Gene', (172, 176))	('shDDX3', 'Var', (160, 166))	('KRAS', 'Gene', '3845', (49, 53))	('KRAS', 'Gene', '3845', (97, 101))	('KRAS', 'Gene', (49, 53))	('CCM2', 'Gene', (221, 225))	('KRAS', 'Gene', (97, 101))	('LY294002', 'Var', (188, 196))	('LY294002', 'Var', (150, 158))	('KRAS', 'Gene', '3845', (117, 121))	('KRAS', 'Gene', '3845', (202, 206))
65514	27007150	Conversely, beta-catenin expression was markedly increased by DDX3 overexpression in T84 cells, but its expression was reversed by DDX3 plus shKRAS or DDX3 plus LY294002 treatments (Figure 3C).	('beta-catenin', 'Protein', (12, 24))	('DDX3', 'Gene', (62, 66))	('increased', 'PosReg', (49, 58))	('expression', 'MPA', (25, 35))	('LY294002', 'Chemical', 'MESH:C085911', (161, 169))	('overexpression', 'Var', (67, 81))	('KRAS', 'Gene', (143, 147))	('KRAS', 'Gene', '3845', (143, 147))
65515	27007150	These results suggested that an increase in beta-catenin expression by DDX3 overexpression is through activation of the PI3K/AKT pathway due to increasing KRAS expression.	('PI3K/AKT pathway', 'Pathway', (120, 136))	('expression', 'MPA', (57, 67))	('expression', 'MPA', (160, 170))	('KRAS', 'Gene', (155, 159))	('increase', 'PosReg', (32, 40))	('beta-catenin', 'Protein', (44, 56))	('KRAS', 'Gene', '3845', (155, 159))	('overexpression', 'Var', (76, 90))	('PI3K', 'molecular_function', 'GO:0016303', ('120', '124'))	('activation', 'PosReg', (102, 112))	('increasing', 'PosReg', (144, 154))	('DDX3', 'Gene', (71, 75))
65516	27007150	In addition, an increase in beta-catenin expression by DDX3 overexpression was correlated with beta-catenin nuclear localization in colon cancer cells (Figure 3D).	('DDX3', 'Gene', (55, 59))	('colon cancer', 'Disease', (132, 144))	('expression', 'MPA', (41, 51))	('colon cancer', 'Disease', 'MESH:D015179', (132, 144))	('increase', 'PosReg', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('beta-catenin nuclear localization', 'MPA', (95, 128))	('colon cancer', 'Phenotype', 'HP:0003003', (132, 144))	('beta-catenin', 'Protein', (28, 40))	('overexpression', 'Var', (60, 74))
65521	27007150	However, the expression of Snail, Slug, and TWIST was unchanged by DDX3 manipulation in both cell types (Figure 3F upper panel).	('Slug', 'Gene', '6591', (34, 38))	('expression', 'MPA', (13, 23))	('Slug', 'Gene', (34, 38))	('Snail', 'Gene', '6615', (27, 32))	('Snail', 'Gene', (27, 32))	('TWIST', 'Gene', (44, 49))	('DDX3', 'Gene', (67, 71))	('manipulation', 'Var', (72, 84))
65526	27007150	ZEB1 expression was significantly decreased by an AKT inhibitor (perifosine) or a beta-catenin inhibitor (XAV939) in tumors of mice injected with DDX3-overexpressiong T84 stable clone (Figure 3H lower panel).	('mice', 'Species', '10090', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('expression', 'MPA', (5, 15))	('AKT', 'Pathway', (50, 53))	('decreased', 'NegReg', (34, 43))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('XAV939', 'Chemical', 'MESH:C544261', (106, 112))	('tumors', 'Disease', (117, 123))	('perifosine', 'Var', (65, 75))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('ZEB1', 'Gene', (0, 4))	('perifosine', 'Chemical', 'MESH:C105905', (65, 75))
65527	27007150	The number of lung tumor nodule in mice injected with DDX3-overexpressing T84 stable clone was markedly higher than in mice injected with VC cells.	('lung tumor', 'Disease', 'MESH:D008175', (14, 24))	('mice', 'Species', '10090', (119, 123))	('T84', 'Var', (74, 77))	('lung tumor', 'Phenotype', 'HP:0100526', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mice', 'Species', '10090', (35, 39))	('higher', 'PosReg', (104, 110))	('lung tumor', 'Disease', (14, 24))
65534	27007150	Kaplan-Meier analysis showed that high-DDX3, high-KRAS, positive nuclear beta-catenin, and high-ZEB1 tumors exhibited shorter OS and RFS periods than low-DDX3, low-KRAS, negative nuclear beta-catenin, and low-ZEB1 tumors (Figure 4B).	('KRAS', 'Gene', '3845', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('KRAS', 'Gene', '3845', (50, 54))	('tumors', 'Disease', (214, 220))	('KRAS', 'Gene', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('high-ZEB1', 'Var', (91, 100))	('KRAS', 'Gene', (50, 54))	('positive nuclear beta-catenin', 'Var', (56, 85))	('low-ZEB1 tumors', 'Disease', (205, 220))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('OS', 'Chemical', '-', (126, 128))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('RFS', 'Chemical', '-', (133, 136))	('tumors', 'Disease', (101, 107))	('high-DDX3', 'Var', (34, 43))	('shorter', 'NegReg', (118, 125))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('low-ZEB1 tumors', 'Disease', 'MESH:D009800', (205, 220))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
65535	27007150	Cox-regression analysis further indicated that the hazard ratio of high-DDX3, high-KRAS, positive nuclear beta-catenin, high-ZEB1, and high-DDX3/high-ZEB1 tumors was 3.05, 2.72, 2.90, 3.17, and 2.40 for OS and 2.52, 2.21, 2.47, 2.03, and 1.81 for RFS when the counterpart or others was used as the reference (Table 2).	('KRAS', 'Gene', (83, 87))	('KRAS', 'Gene', '3845', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('high-ZEB1', 'Var', (120, 129))	('RFS', 'Disease', (247, 250))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('RFS', 'Chemical', '-', (247, 250))	('tumors', 'Disease', (155, 161))	('high-DDX3/high-ZEB1', 'Var', (135, 154))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('OS', 'Chemical', '-', (203, 205))	('high-DDX3', 'Var', (67, 76))
65536	27007150	The highest HR value for OS and RFS was observed in high-DDX3/high-ZEB tumors when compared with low-DDX3/low-ZEB1 tumors (11.87 for OS, 5.01 for RFS).	('low-ZEB1 tumors', 'Disease', (106, 121))	('high-DDX3/high-ZEB', 'Var', (52, 70))	('OS', 'Chemical', '-', (25, 27))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('low-ZEB1 tumors', 'Disease', 'MESH:D009800', (106, 121))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('OS', 'Chemical', '-', (133, 135))	('RFS', 'Chemical', '-', (146, 149))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('RFS', 'Chemical', '-', (32, 35))
65549	27007150	APC-mutated T84 cells were used to knockdown APC and then co-transfected with a wild-type APC expression vector.	('knockdown', 'Var', (35, 44))	('APC', 'Phenotype', 'HP:0005227', (0, 3))	('APC', 'Gene', (0, 3))	('APC', 'Phenotype', 'HP:0005227', (45, 48))	('APC', 'Gene', (45, 48))	('APC', 'Gene', (90, 93))	('APC', 'Phenotype', 'HP:0005227', (90, 93))	('APC', 'Gene', '324', (0, 3))	('APC', 'Gene', '324', (45, 48))	('APC', 'Gene', '324', (90, 93))
65552	27007150	However, the TCF promoter activity and both protein expressions in APC-knockdown T84 cells was significantly reduced by APC-wild-type expression vector transfection, but the decrease of the TCF promoter activity and both protein expressions were relatively elevated by DDX3 overexpression compared with its VC cells (Supplementary Figure S3).	('reduced', 'NegReg', (109, 116))	('APC', 'Phenotype', 'HP:0005227', (120, 123))	('APC', 'Gene', (120, 123))	('decrease', 'NegReg', (174, 182))	('overexpression', 'PosReg', (274, 288))	('APC', 'Gene', '324', (120, 123))	('TCF', 'Gene', '3172', (190, 193))	('DDX3', 'Var', (269, 273))	('APC', 'Gene', (67, 70))	('APC', 'Phenotype', 'HP:0005227', (67, 70))	('TCF', 'Gene', (190, 193))	('elevated', 'PosReg', (257, 265))	('TCF', 'Gene', (13, 16))	('TCF', 'Gene', '3172', (13, 16))	('APC', 'Gene', '324', (67, 70))
65553	27007150	We further examined whether DDX3 could also activate the beta-catenin/ZEB1 axis in HCT116 cells which harbored beta-catenin mutation and wild-type APC.	('beta-catenin', 'Protein', (111, 123))	('APC', 'Phenotype', 'HP:0005227', (147, 150))	('APC', 'Gene', (147, 150))	('DDX3', 'Gene', (28, 32))	('APC', 'Gene', '324', (147, 150))	('HCT116', 'CellLine', 'CVCL:0291', (83, 89))	('beta-catenin/ZEB1 axis', 'Pathway', (57, 79))	('mutation', 'Var', (124, 132))	('activate', 'PosReg', (44, 52))
65556	27007150	The AKT/GSK3beta signaling pathway promoted nuclear beta-catenin expression via reducing N-terminal beta-catenin phosphorylation (Ser33, Ser37, Thr41), which is associated with degradation of beta-catenin.	('signaling pathway', 'biological_process', 'GO:0007165', ('17', '34'))	('degradation', 'biological_process', 'GO:0009056', ('177', '188'))	('Ser33', 'Var', (130, 135))	('GSK', 'molecular_function', 'GO:0050321', ('8', '11'))	('Ser37', 'Chemical', '-', (137, 142))	('Ser33', 'Chemical', '-', (130, 135))	('GSK3beta', 'Gene', '2932', (8, 16))	('Ser', 'cellular_component', 'GO:0005790', ('137', '140'))	('phosphorylation', 'biological_process', 'GO:0016310', ('113', '128'))	('Ser', 'cellular_component', 'GO:0005790', ('130', '133'))	('Thr41', 'Chemical', '-', (144, 149))	('Ser37', 'Var', (137, 142))	('promoted', 'PosReg', (35, 43))	('nuclear beta-catenin expression', 'MPA', (44, 75))	('reducing', 'NegReg', (80, 88))	('N-terminal beta-catenin phosphorylation', 'MPA', (89, 128))	('Thr41', 'Var', (144, 149))	('GSK3beta', 'Gene', (8, 16))
65564	27007150	Therefore, we suggest that AKT or beta-catenin may be potentially targeted to suppress tumor invasion and in turn to improve outcomes in patients who harbored high-DDX3 tumors.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('patients', 'Species', '9606', (137, 145))	('high-DDX3', 'Var', (159, 168))	('suppress', 'NegReg', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (169, 174))	('improve', 'PosReg', (117, 124))	('beta-catenin', 'Protein', (34, 46))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('outcomes', 'MPA', (125, 133))	('tumors', 'Disease', (169, 175))	('AKT', 'Protein', (27, 30))
65578	27007150	DDX3 (#1 TRCN0000000001; #2 TRCN0000 000003), ERK1/2 (p42 TRCN0000010050; p44 TRCN0000 006150), AKT (TRCN0000010163), KRAS (TRCN00 00033260), beta-catenin (TRCN0000314991), JUN (TRCN0 000338221), APC (3'UTR: TRCN0000010297) and ZEB1 (TRCN0000017565) shRNAs were purchased from the National shRNA Core Facility, Academia Sinica, Taiwan, ROC.	('p42', 'Gene', (54, 57))	('KRAS', 'Gene', (118, 122))	('APC', 'Gene', '324', (196, 199))	('TRCN0000010163', 'Var', (101, 115))	('APC', 'cellular_component', 'GO:0005680', ('196', '199'))	('ERK1', 'molecular_function', 'GO:0004707', ('46', '50'))	('APC', 'Phenotype', 'HP:0005227', (196, 199))	('Academia Sinica', 'Disease', (311, 326))	('p44', 'Gene', (74, 77))	('TRCN0000314991', 'Var', (156, 170))	('p42', 'Gene', '2038', (54, 57))	('TRCN0000017565', 'Var', (234, 248))	('p44', 'Gene', '2966', (74, 77))	('APC', 'Gene', (196, 199))	('ERK1/2', 'Gene', (46, 52))	('TRCN0000000001', 'Disease', 'None', (9, 23))	('ERK1/2', 'Gene', '5595;5594', (46, 52))	('TRCN0 000338221', 'Var', (178, 193))	('TRCN0000000001', 'Disease', (9, 23))	('KRAS', 'Gene', '3845', (118, 122))	('Academia Sinica', 'Disease', 'None', (311, 326))
65580	27007150	TOP flash (a reporter plasmid containing multiple copies of wild-type TCF-binding sites), FOP flash (a reporter plasmid containing mutant TCF-binding sites) plasmids was purchased from Millipore (Billerica, MA, USA).	('binding', 'molecular_function', 'GO:0005488', ('142', '149'))	('mutant', 'Var', (131, 137))	('TCF', 'Gene', '3172', (70, 73))	('TCF', 'Gene', (138, 141))	('TCF', 'Gene', '3172', (138, 141))	('TCF', 'Gene', (70, 73))	('binding', 'molecular_function', 'GO:0005488', ('74', '81'))
65582	27007150	The SP1-mutated binding site on the KRAS promoter constructs containing multiple-point mutations were constructed by the QuickChange site-directed mutagenesis system (Stratagene, La Jolla, CA, USA).	('binding', 'molecular_function', 'GO:0005488', ('16', '23'))	('mutagenesis', 'biological_process', 'GO:0006280', ('147', '158'))	('KRAS', 'Gene', (36, 40))	('KRAS', 'Gene', '3845', (36, 40))	('mutations', 'Var', (87, 96))
65690	26094822	Intestinal tumorigenesis was examined to determine the effects of either exogenous ghrelin administration or ghrelin deficiency following deletion of the Ghrl gene.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('deficiency', 'Disease', (117, 127))	('tumor', 'Disease', (11, 16))	('Ghrl', 'Gene', (154, 158))	('ghrelin', 'Gene', (83, 90))	('deficiency', 'Disease', 'MESH:D007153', (117, 127))	('deletion', 'Var', (138, 146))	('Ghrl', 'Gene', '58991', (154, 158))	('rat', 'Species', '10116', (99, 102))	('ghrelin', 'Gene', '58991', (83, 90))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('ghrelin', 'Gene', '58991', (109, 116))	('ghrelin', 'Gene', (109, 116))
65720	26094822	Specifically, we used: (i) a UC-associated colorectal carcinogenesis model with combined treatment with AOM and DSS; and (ii) a genetic intestinal tumor susceptibility model based upon mutation of the Apc gene.	('DSS', 'Chemical', '-', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (43, 68))	('Apc', 'Gene', (201, 204))	('AOM', 'Chemical', 'MESH:D001397', (104, 107))	('Apc', 'Gene', '11789', (201, 204))	('colorectal carcinogenesis', 'Disease', (43, 68))	('mutation', 'Var', (185, 193))	('UC', 'Phenotype', 'HP:0100279', (29, 31))	('intestinal tumor', 'Disease', (136, 152))	('intestinal tumor', 'Disease', 'MESH:D007414', (136, 152))
65743	26094822	The Apc mutant mice were killed by a lethal dose of sodium pentobarbital at 15 weeks of age and autopsied to evaluate the number and sizes of tumors formed.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('sodium pentobarbital', 'Chemical', 'MESH:D010424', (52, 72))	('mutant', 'Var', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('mice', 'Species', '10090', (15, 19))	('Apc', 'Gene', (4, 7))	('Apc', 'Gene', '11789', (4, 7))
65765	26094822	Given that exogenous ghrelin administration suppressed AOM/DSS-induced colitis-associated carcinogenesis, we asked whether genetic deletion of endogenous ghrelin enhanced carcinogenesis in this model.	('suppressed', 'NegReg', (44, 54))	('genetic deletion', 'Var', (123, 139))	('AOM', 'Chemical', 'MESH:D001397', (55, 58))	('ghrelin', 'Gene', (154, 161))	('ghrelin', 'Gene', (21, 28))	('carcinogenesis', 'Disease', 'MESH:D063646', (171, 185))	('ghrelin', 'Gene', '58991', (154, 161))	('ghrelin', 'Gene', '58991', (21, 28))	('carcinogenesis', 'Disease', (171, 185))	('colitis', 'Phenotype', 'HP:0002583', (71, 78))	('rat', 'Species', '10116', (37, 40))	('colitis', 'Disease', 'MESH:D003092', (71, 78))	('DSS', 'Chemical', '-', (59, 62))	('colitis', 'Disease', (71, 78))	('carcinogenesis', 'Disease', 'MESH:D063646', (90, 104))	('carcinogenesis', 'Disease', (90, 104))
65766	26094822	We found that the incidence of colon tumor formation was not altered by the deletion of the Ghrl gene (Fig.4a), suggesting that the physiological level of ghrelin may not be functioning as a carcinogenesis suppressor.	('deletion', 'Var', (76, 84))	('colon tumor', 'Phenotype', 'HP:0100273', (31, 42))	('Ghrl', 'Gene', (92, 96))	('carcinogenesis', 'Disease', (191, 205))	('Ghrl', 'Gene', '58991', (92, 96))	('colon tumor', 'Disease', (31, 42))	('ghrelin', 'Gene', (155, 162))	('ghrelin', 'Gene', '58991', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('colon tumor', 'Disease', 'MESH:D015179', (31, 42))	('carcinogenesis', 'Disease', 'MESH:D063646', (191, 205))
65779	26094822	Finally, we asked whether knocking out ghrelin would affect tumorigenesis in ApcMin/+ mice.	('Apc', 'Gene', (77, 80))	('affect', 'Reg', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('mice', 'Species', '10090', (86, 90))	('Apc', 'Gene', '11789', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('knocking out', 'Var', (26, 38))	('tumor', 'Disease', (60, 65))	('ghrelin', 'Gene', (39, 46))	('ghrelin', 'Gene', '58991', (39, 46))
65783	26094822	We concluded that neither ghrelin administration nor deletion altered intestinal tumorigenesis in Apc mutant mice.	('mutant', 'Var', (102, 108))	('Apc', 'cellular_component', 'GO:0005680', ('98', '101'))	('intestinal tumor', 'Disease', (70, 86))	('rat', 'Species', '10116', (42, 45))	('deletion', 'Var', (53, 61))	('Apc', 'Gene', (98, 101))	('Apc', 'Gene', '11789', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mice', 'Species', '10090', (109, 113))	('ghrelin', 'Gene', '58991', (26, 33))	('ghrelin', 'Gene', (26, 33))	('intestinal tumor', 'Disease', 'MESH:D007414', (70, 86))
65791	26094822	In the present study, deletion of the Ghrl gene did not affect the number of Ki-67-positive proliferating cells or cleaved caspase 3-positive apoptotic cells in the tumors formed in the AOM/DSS model, though the tumor sizes tended to be larger in the Ghrl-/- mice.	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumors', 'Disease', (165, 171))	('deletion', 'Var', (22, 30))	('Ghrl', 'Gene', (251, 255))	('rat', 'Species', '10116', (99, 102))	('Ghrl', 'Gene', (38, 42))	('Ghrl', 'Gene', '58991', (251, 255))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('Ghrl', 'Gene', '58991', (38, 42))	('AOM', 'Chemical', 'MESH:D001397', (186, 189))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('mice', 'Species', '10090', (259, 263))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('DSS', 'Chemical', '-', (190, 193))	('tumor', 'Disease', (212, 217))	('tumor', 'Disease', (165, 170))
65798	26094822	In this model, DSS causes oxidative/nitrosative DNA damage in the inflamed colon, and it eventually results in colitis-related colorectal adenocarcinoma (colitic cancer).	('DSS', 'Var', (15, 18))	('colorectal adenocarcinoma', 'Disease', (127, 152))	('causes', 'Reg', (19, 25))	('colitic cancer', 'Disease', (154, 168))	('colitis', 'Disease', 'MESH:D003092', (111, 118))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (127, 152))	('DNA', 'cellular_component', 'GO:0005574', ('48', '51'))	('oxidative/nitrosative DNA damage', 'MPA', (26, 58))	('colitis', 'Disease', (111, 118))	('DSS', 'Chemical', '-', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('colitic cancer', 'Disease', 'MESH:D009369', (154, 168))	('colitis', 'Phenotype', 'HP:0002583', (111, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('results in', 'Reg', (100, 110))
65803	26094822	This presumptive mechanism underlying ghrelin's effect in the AOM/DSS model was also supported by the observations made in our Apc mutant mouse model.	('mouse', 'Species', '10090', (138, 143))	('mutant', 'Var', (131, 137))	('DSS', 'Chemical', '-', (66, 69))	('ghrelin', 'Gene', '58991', (38, 45))	('ghrelin', 'Gene', (38, 45))	('Apc', 'Gene', (127, 130))	('AOM/DSS', 'Disease', (62, 69))	('Apc', 'Gene', '11789', (127, 130))	('AOM', 'Chemical', 'MESH:D001397', (62, 65))
65805	26094822	In contrast to the ghrelin administration study, homozygous deletion of the Ghrl gene did not enhance the tumor incidence in the AOM/DSS model.	('ghrelin', 'Gene', '58991', (19, 26))	('rat', 'Species', '10116', (35, 38))	('AOM/DSS', 'Disease', (129, 136))	('Ghrl', 'Gene', '58991', (76, 80))	('homozygous deletion', 'Var', (49, 68))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('AOM', 'Chemical', 'MESH:D001397', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('Ghrl', 'Gene', (76, 80))	('ghrelin', 'Gene', (19, 26))	('DSS', 'Chemical', '-', (133, 136))	('tumor', 'Disease', (106, 111))
65807	26094822	Alternatively, a redundant mechanism may develop that compensates for the anti-inflammatory role of endogenous ghrelin in the case of genetic loss of ghrelin.	('genetic loss', 'Var', (134, 146))	('ghrelin', 'Gene', '58991', (111, 118))	('ghrelin', 'Gene', (111, 118))	('ghrelin', 'Gene', '58991', (150, 157))	('ghrelin', 'Gene', (150, 157))
65822	32708729	Ectopic CENP-A deposition leads to mitotic defects, centromere dysfunction and chromosomal instability (CIN), a hallmark of cancer.	('CIN', 'Phenotype', 'HP:0040012', (104, 107))	('centromere', 'cellular_component', 'GO:0005698', ('52', '62'))	('chromosomal instability', 'Disease', (79, 102))	('Ectopic', 'Var', (0, 7))	('CIN', 'Disease', 'MESH:D007674', (104, 107))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('leads to', 'Reg', (26, 34))	('CENP-A deposition', 'biological_process', 'GO:0034080', ('8', '25'))	('chromosomal instability', 'Phenotype', 'HP:0040012', (79, 102))	('CENP-A', 'Gene', (8, 14))	('mark', 'Gene', '4139', (116, 120))	('CIN', 'Disease', (104, 107))	('centromere dysfunction', 'Disease', (52, 74))	('mark', 'Gene', (116, 120))	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('centromere', 'cellular_component', 'GO:0000775', ('52', '62'))	('mitotic defects', 'Disease', (35, 50))	('mitotic defects', 'Disease', 'MESH:C536987', (35, 50))
65824	32708729	Alterations in CENP-A posttranslational modifications are also linked to chromosome segregation errors and CIN.	('CIN', 'Phenotype', 'HP:0040012', (107, 110))	('chromosome segregation errors', 'CPA', (73, 102))	('linked', 'Reg', (63, 69))	('Alterations', 'Var', (0, 11))	('CIN', 'Disease', (107, 110))	('posttranslational', 'Var', (22, 39))	('CENP-A', 'Gene', (15, 21))	('CIN', 'Disease', 'MESH:D007674', (107, 110))
65825	32708729	Collectively, CENP-A is pivotal to genomic stability through centromere maintenance, perturbation of which can lead to tumorigenesis.	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('perturbation', 'Var', (85, 97))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('lead to', 'Reg', (111, 118))
65826	32708729	Such chromosome segregation errors often lead to micronuclei formation and may result in aneuploidy, the presence of additional or fewer chromosomes.	('micronuclei formation', 'CPA', (49, 70))	('aneuploidy', 'Disease', 'MESH:D000782', (89, 99))	('chromosome segregation', 'CPA', (5, 27))	('lead to', 'Reg', (41, 48))	('result in', 'Reg', (79, 88))	('aneuploidy', 'Disease', (89, 99))	('errors', 'Var', (28, 34))
65828	32708729	Cancers are frequently aneuploid, and the specific loss or gain of tumor suppressors and oncogenes associated with changes in chromosome number may contribute to tumorigenesis, malignancy, frequency of metastasis, and overall patient prognosis.	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('tumor', 'Disease', (162, 167))	('chromosome number', 'Gene', (126, 143))	('chromosome', 'cellular_component', 'GO:0005694', ('126', '136'))	('tumor', 'Disease', (67, 72))	('loss', 'NegReg', (51, 55))	('changes in', 'Var', (115, 125))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('contribute', 'Reg', (148, 158))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('oncogenes', 'Gene', (89, 98))	('aneuploid', 'Disease', 'MESH:D000782', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('aneuploid', 'Disease', (23, 32))	('gain of tumor', 'Disease', (59, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('malignancy', 'Disease', 'MESH:D009369', (177, 187))	('gain of tumor', 'Disease', 'MESH:D015430', (59, 72))	('patient', 'Species', '9606', (226, 233))	('malignancy', 'Disease', (177, 187))
65831	32708729	Centromeric alpha-satellite DNA sequences represent ~2-3% of the human genome, and can vary between individuals in a population through acquisition of rearrangements and/or repeat expansions.	('human', 'Species', '9606', (65, 70))	('repeat expansions', 'Var', (173, 190))	('rearrangements', 'Var', (151, 165))
65838	32708729	CENP-A is a rare histone variant that represents only ~0.1% of the total histone H3 variants in the genome, while marking all active centromeres, including neocentromeres.	('histone H3', 'Gene', '3772191', (73, 83))	('active centromeres', 'CPA', (126, 144))	('mark', 'Gene', (114, 118))	('mark', 'Gene', '4139', (114, 118))	('variants', 'Var', (84, 92))	('histone H3', 'Gene', (73, 83))
65846	32708729	CCAN proteins are located in the inner kinetochore plate and distributed in several functional groups as follows: CENP-C, CENP-H/I/K, CENP-L/M/N, CENP-O/P/Q/R/U, CENP-T/W/S/X (for a detailed review see Hara and Fukagawa).	('CENP-C', 'Gene', '1060', (114, 120))	('CENP-T', 'Gene', (162, 168))	('CENP-L', 'Gene', '91687', (134, 140))	('CENP-L', 'Gene', (134, 140))	('CENP-O', 'Gene', (146, 152))	('CENP-T', 'Gene', '80152', (162, 168))	('CENP-C', 'Gene', (114, 120))	('CENP-H/I/K', 'Var', (122, 132))	('CENP-O', 'Gene', '79172', (146, 152))	('inner kinetochore plate', 'cellular_component', 'GO:0000939', ('33', '56'))
65853	32708729	SENP6 depletion leads to hyper-SUMOylation of CENP-C and CENP-I, and strong reduction of centromere-bound CENP-C, CENP-T, and CENP-A.	('centromere', 'cellular_component', 'GO:0000775', ('89', '99'))	('reduction', 'NegReg', (76, 85))	('CENP-C', 'Gene', '1060', (46, 52))	('SUMOylation', 'biological_process', 'GO:0016925', ('31', '42'))	('hyper-SUMOylation', 'PosReg', (25, 42))	('hyper-SUMOylation', 'MPA', (25, 42))	('CENP-C', 'Gene', '1060', (106, 112))	('CENP-I', 'Gene', (57, 63))	('CENP-I', 'Gene', '2491', (57, 63))	('depletion', 'Var', (6, 15))	('CENP-T', 'Gene', '80152', (114, 120))	('CENP-C', 'Gene', (46, 52))	('SENP6', 'Gene', (0, 5))	('SENP6', 'Gene', '26054', (0, 5))	('centromere', 'cellular_component', 'GO:0005698', ('89', '99'))	('CENP-T', 'Gene', (114, 120))	('CENP-C', 'Gene', (106, 112))
65876	32708729	Furthermore, as mentioned above, tethering HJURP to an ectopic non-centromeric locus is sufficient to induce incorporation of CENP-A into the chromatin at this site and leads to nucleation of a functional de novo kinetochore.	('CENP-A', 'Gene', (126, 132))	('HJURP', 'Gene', '55355', (43, 48))	('tethering', 'Var', (33, 42))	('induce', 'PosReg', (102, 108))	('kinetochore', 'cellular_component', 'GO:0000776', ('213', '224'))	('nucleation', 'CPA', (178, 188))	('chromatin', 'cellular_component', 'GO:0000785', ('142', '151'))	('incorporation', 'MPA', (109, 122))	('leads to', 'Reg', (169, 177))	('HJURP', 'Gene', (43, 48))
65883	32708729	Loss of SENP6 results in loss of old and newly deposited CENP-A, and both Mis18BP1 and Mis18alpha are regulated by SENP6.	('Mis18BP1', 'Gene', (74, 82))	('SENP6', 'Gene', (115, 120))	('Mis18alpha', 'Gene', '54069', (87, 97))	('Mis18alpha', 'Gene', (87, 97))	('SENP6', 'Gene', (8, 13))	('SENP6', 'Gene', '26054', (115, 120))	('SENP6', 'Gene', '26054', (8, 13))	('Mis18BP1', 'Gene', '55320', (74, 82))	('loss', 'NegReg', (25, 29))	('Loss', 'Var', (0, 4))
65906	32708729	As such, specific centromere inactivation of the Y chromosome, using CENP-A/histone H3 chimaera that cannot directly recruit CENP-C, leads to high levels of aberrant mitoses followed by similarly high levels of aneuploidy for the Y chromosome.	('aneuploidy', 'Disease', 'MESH:D000782', (211, 221))	('centromere', 'cellular_component', 'GO:0000775', ('18', '28'))	('CENP-C', 'Gene', (125, 131))	('aberrant mitoses', 'CPA', (157, 173))	('Y chromosome', 'cellular_component', 'GO:0000806', ('230', '242'))	('Y chromosome', 'cellular_component', 'GO:0000806', ('49', '61'))	('aneuploidy', 'Disease', (211, 221))	('centromere', 'cellular_component', 'GO:0005698', ('18', '28'))	('histone H3', 'Gene', (76, 86))	('CENP-C', 'Gene', '1060', (125, 131))	('inactivation', 'Var', (29, 41))	('histone H3', 'Gene', '3772191', (76, 86))
65924	32708729	Most importantly, mislocalization of overexpressed CENP-A to the chromosome arms in HeLa and RPE-1 cells resulted in chromosome congression defects, lagging chromosomes, micronuclei formation and a delay in mitotic exit, directly linking CENP-A overexpression and ectopic CENP-A deposition with CIN.	('mislocalization', 'Var', (18, 33))	('RPE-1', 'CellLine', 'CVCL:4388', (93, 98))	('CIN', 'Disease', (295, 298))	('chromosome congression defects', 'Disease', (117, 147))	('chromosome congression defects', 'Disease', 'MESH:D002869', (117, 147))	('micronuclei formation', 'CPA', (170, 191))	('HeLa', 'CellLine', 'CVCL:0030', (84, 88))	('CIN', 'Phenotype', 'HP:0040012', (295, 298))	('CENP-A', 'Gene', (51, 57))	('CIN', 'Disease', 'MESH:D007674', (295, 298))	('lagging chromosomes', 'CPA', (149, 168))	('delay', 'NegReg', (198, 203))	('mitotic exit', 'CPA', (207, 219))
65937	32708729	Occlusion of CTCF binding has been shown in many cancer types, is associated with aberrant gene expression and is thought to contribute to tumorigenicity.	('binding', 'molecular_function', 'GO:0005488', ('18', '25'))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('Occlusion', 'Var', (0, 9))	('aberrant gene expression', 'MPA', (82, 106))	('CTCF', 'Gene', '10664', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('associated', 'Reg', (66, 76))	('shown', 'Reg', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('binding', 'Interaction', (18, 25))	('gene expression', 'biological_process', 'GO:0010467', ('91', '106'))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('contribute', 'Reg', (125, 135))	('CTCF', 'Gene', (13, 17))	('cancer', 'Disease', (49, 55))
65938	32708729	Surprisingly, no significant gene expression changes were identified in HeLa cells showing ectopic CENP-A mislocalization and occlusion of CTCF binding sites.	('CTCF', 'Gene', '10664', (139, 143))	('HeLa', 'CellLine', 'CVCL:0030', (72, 76))	('binding', 'molecular_function', 'GO:0005488', ('144', '151'))	('binding', 'Interaction', (144, 151))	('CTCF', 'Gene', (139, 143))	('gene expression', 'biological_process', 'GO:0010467', ('29', '44'))	('mislocalization', 'Var', (106, 121))	('CENP-A', 'Gene', (99, 105))	('occlusion', 'NegReg', (126, 135))
65947	32708729	Several sites of posttranslational modification have been identified for CENP-A, including alpha-amino trimethylation, Ser7 phosphorylation, Ser16/18 phosphorylation, Ser68 phosphorylation, Lys124 ubiquitination, Lys124 acetylation, and Lys124 monomethylation, some of which are emerging as important regulators of CENP-A deposition and function within the centromere [reviewed at Srivastava and Foltz ].	('Lys124', 'Var', (213, 219))	('Ser68', 'Chemical', '-', (167, 172))	('Ser7', 'Chemical', '-', (119, 123))	('Lys124', 'Var', (237, 243))	('Lys124', 'Chemical', '-', (213, 219))	('Lys124', 'Chemical', '-', (237, 243))	('Lys124', 'Var', (190, 196))	('Lys124', 'Chemical', '-', (190, 196))	('Ser16', 'Chemical', '-', (141, 146))
65948	32708729	Several perturbations in CENP-A posttranslational modifications have been linked to chromosome segregation defects and cancer (Figure 5A).	('perturbations', 'Var', (8, 21))	('posttranslational modifications', 'Var', (32, 63))	('CENP-A', 'Gene', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('chromosome segregation defects', 'CPA', (84, 114))	('cancer', 'Disease', (119, 125))	('linked', 'Reg', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
65949	32708729	Inhibition of CENP-A alpha-amino trimethylation causes a reduction in CENP-T and CENP-I at the centromere, leading to lagging chromosomes.	('reduction', 'NegReg', (57, 66))	('CENP-A', 'Gene', (14, 20))	('CENP-T', 'Gene', '80152', (70, 76))	('lagging chromosomes', 'CPA', (118, 137))	('CENP-I', 'Gene', (81, 87))	('Inhibition', 'Var', (0, 10))	('CENP-I', 'Gene', '2491', (81, 87))	('CENP-T', 'Gene', (70, 76))	('alpha-amino trimethylation', 'Protein', (21, 47))
65950	32708729	Furthermore, CENP-A is known to be phosphorylated at two highly conserved residues, Ser16 and Ser18 (located within the amino terminal tail of CENP-A), prior to its deposition and in the CENP-A nucleosome.	('Ser16', 'Chemical', '-', (84, 89))	('Ser18', 'Var', (94, 99))	('Ser18', 'Chemical', '-', (94, 99))	('Ser16', 'Var', (84, 89))
65952	32708729	In contrast, hyper-phosphorylation at Ser18 also lead to chromosome missegregation and severe CIN phenotype and is linked to the loss of FBW7, an E3 ubiquitin ligase and one of the most frequently lost tumor suppressors in human cancers.	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('FBW7', 'Gene', (137, 141))	('E3 ubiquitin ligase', 'Gene', '79594', (146, 165))	('ubiquitin', 'molecular_function', 'GO:0031386', ('149', '158'))	('phosphorylation', 'biological_process', 'GO:0016310', ('19', '34'))	('tumor', 'Disease', (202, 207))	('FBW7', 'Gene', '55294', (137, 141))	('human', 'Species', '9606', (223, 228))	('CIN', 'Phenotype', 'HP:0040012', (94, 97))	('Ser', 'cellular_component', 'GO:0005790', ('38', '41'))	('hyper-phosphorylation', 'Var', (13, 34))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('CIN', 'Disease', 'MESH:D007674', (94, 97))	('Ser18', 'Var', (38, 43))	('E3 ubiquitin ligase', 'Gene', (146, 165))	('Ser18', 'Chemical', '-', (38, 43))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('chromosome missegregation', 'CPA', (57, 82))	('cancers', 'Disease', (229, 236))	('loss', 'Var', (129, 133))	('lead to', 'Reg', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('linked', 'Reg', (115, 121))	('chromosome', 'cellular_component', 'GO:0005694', ('57', '67'))	('CIN', 'Disease', (94, 97))
65959	32708729	Specifically, siRNA-mediated depletion of CENP-A promote proteasome-dependent degradation of HJURP and HJURP stabilizes CENP-A.	('depletion', 'Var', (29, 38))	('proteasome-dependent degradation', 'MPA', (57, 89))	('HJURP', 'Gene', '55355', (93, 98))	('HJURP', 'Gene', (103, 108))	('CENP-A', 'Gene', (42, 48))	('HJURP', 'Gene', '55355', (103, 108))	('HJURP', 'Gene', (93, 98))	('stabilizes CENP-A', 'MPA', (109, 126))	('promote', 'PosReg', (49, 56))
65971	32708729	In cells with p53, depletion of HJURP causes slow depletion of CENP-A at centromeres that can be sensed by p53 resulting in cell cycle arrest and maintenance of genome integrity.	('depletion', 'Var', (19, 28))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('p53', 'Gene', (107, 110))	('depletion of CENP-A', 'MPA', (50, 69))	('arrest', 'Disease', 'MESH:D006323', (135, 141))	('p53', 'Gene', '7157', (107, 110))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('124', '141'))	('arrest', 'Disease', (135, 141))	('HJURP', 'Gene', '55355', (32, 37))	('HJURP', 'Gene', (32, 37))	('genome integrity', 'MPA', (161, 177))	('maintenance of genome integrity', 'biological_process', 'GO:0051276', ('146', '177'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (124, 141))
65973	32708729	However, the loss of p53 prevents sensing of CENP-A loss, leading to severe centromere dysfunction, aneuploidy and apoptosis.	('aneuploidy', 'Disease', (100, 110))	('p53', 'Gene', '7157', (21, 24))	('aneuploidy', 'Disease', 'MESH:D000782', (100, 110))	('centromere dysfunction', 'Disease', (76, 98))	('apoptosis', 'CPA', (115, 124))	('loss', 'Var', (13, 17))	('p53', 'Gene', (21, 24))
65974	32708729	Together, these data highlight that overexpression of CENP-A and HJURP is essential for maintaining centromere identity and promoting survival in cancer cells, particularly as loss of p53 and cell cycle checkpoints allow rapid cell cycle progression without sensing of genome integrity.	('cancer', 'Disease', (146, 152))	('allow', 'Reg', (215, 220))	('HJURP', 'Gene', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('HJURP', 'Gene', '55355', (65, 70))	('promoting', 'PosReg', (124, 133))	('loss', 'Var', (176, 180))	('centromere', 'MPA', (100, 110))	('p53', 'Gene', (184, 187))	('p53', 'Gene', '7157', (184, 187))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
65978	32708729	Subsequently, sites of ectopic CENP-A may acquire partial neocentromeric function, weakening endogenous centromeres and contributing to increased occurrence of CIN.	('endogenous centromeres', 'MPA', (93, 115))	('CIN', 'Disease', 'MESH:D007674', (160, 163))	('CENP-A', 'Gene', (31, 37))	('ectopic', 'Var', (23, 30))	('CIN', 'Phenotype', 'HP:0040012', (160, 163))	('increased', 'PosReg', (136, 145))	('weakening', 'NegReg', (83, 92))	('CIN', 'Disease', (160, 163))
65980	32708729	Ectopic CENP-A can also occlude binding of CTCF, a regulator of gene expression.	('CTCF', 'Gene', '10664', (43, 47))	('gene expression', 'biological_process', 'GO:0010467', ('64', '79'))	('occlude', 'NegReg', (24, 31))	('binding', 'molecular_function', 'GO:0005488', ('32', '39'))	('Ectopic', 'Var', (0, 7))	('binding', 'Interaction', (32, 39))	('CTCF', 'Gene', (43, 47))
65984	32708729	Although currently unexplored, CENP-A is a potential target for modulating CIN as a therapeutic strategy in cancers.	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('CIN', 'Disease', 'MESH:D007674', (75, 78))	('CIN', 'Phenotype', 'HP:0040012', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('modulating', 'Var', (64, 74))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('CIN', 'Disease', (75, 78))	('cancers', 'Disease', (108, 115))
66003	32340275	The immune system is educated in such a way that it does not respond to normal cells, while several mutations in cancer cells result in the expression of tumor-specific antigens that can be identified as non-self and activate the immune system, finally resulting in the elimination of cancer cells.	('mutations', 'Var', (100, 109))	('tumor', 'Disease', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('expression', 'MPA', (140, 150))	('activate', 'PosReg', (217, 225))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', (113, 119))	('result in', 'Reg', (126, 135))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('resulting in', 'Reg', (253, 265))	('cancer', 'Disease', (285, 291))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('elimination', 'CPA', (270, 281))
66007	32340275	Dysregulation of the balance between the effector and regulatory cell compartments is one of the key strategies for tumors to escape immune eradication.	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumors', 'Disease', (116, 122))	('ecto', 'Gene', '94093', (44, 48))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('ecto', 'Gene', (44, 48))
66025	32340275	Normally mutation rates are low in such cancers and exhibit poor de novo antigens.	('mutation', 'Var', (9, 17))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('cancers', 'Disease', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
66052	32340275	This interaction is necessary for CRT translocation because the deletion of ERp57 stops CRT exposure.	('stops', 'NegReg', (82, 87))	('deletion', 'Var', (64, 72))	('CRT exposure', 'MPA', (88, 100))	('ERp57', 'Gene', '14827', (76, 81))	('ERp57', 'Gene', (76, 81))
66110	32340275	The apoptotic cell death stimulated by anthracyclines has been described with potent immunogenicity that is related to the emission of early and late danger signals including CRT exposure, ATP secretion, and HMGB1 release.	('death', 'Disease', (19, 24))	('anthracyclines', 'Chemical', 'MESH:D018943', (39, 53))	('release', 'MPA', (214, 221))	('ATP', 'Chemical', 'MESH:D000255', (189, 192))	('secretion', 'biological_process', 'GO:0046903', ('193', '202'))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('4', '24'))	('CRT exposure', 'MPA', (175, 187))	('ATP secretion', 'MPA', (189, 202))	('HMGB1', 'Gene', (208, 213))	('anthracyclines', 'Var', (39, 53))	('death', 'Disease', 'MESH:D003643', (19, 24))
66114	32340275	Administration of doxorubicin by intraperitoneal injection in mice showed that noncancerous cells undergo ICD in response to doxorubicin (injected at 10 mg/kg) that was associated with TLR-2/TLR-9-MyD88-dependent signaling, leading to the inflammatory response.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MyD88', 'Gene', '17874', (197, 202))	('TLR-9', 'Gene', '81897', (191, 196))	('TLR-2', 'Gene', '24088', (185, 190))	('mice', 'Species', '10090', (62, 66))	('doxorubicin', 'Var', (125, 136))	('TLR-9', 'Gene', (191, 196))	('inflammatory response', 'CPA', (239, 260))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('MyD88', 'Gene', (197, 202))	('doxorubicin', 'Chemical', 'MESH:D004317', (18, 29))	('doxorubicin', 'Chemical', 'MESH:D004317', (125, 136))	('leading to', 'Reg', (224, 234))	('TLR-2', 'Gene', (185, 190))
66120	32340275	It was shown that suppression of gammadelta T17 cells by the knockout of T cell receptor delta or Vgamma4/6 inhibited the production of IL-17 by T cells surrounding the tumor bed and abrogated the therapeutic efficacy of anthracyclines.	('therapeutic efficacy', 'CPA', (197, 217))	('anthracyclines', 'Chemical', 'MESH:D018943', (221, 235))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('suppression', 'NegReg', (18, 29))	('IL-17', 'Gene', '16171', (136, 141))	('abrogated', 'NegReg', (183, 192))	('knockout', 'Var', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('IL-17', 'Gene', (136, 141))	('inhibited', 'NegReg', (108, 117))	('Vgamma4/6', 'Gene', (98, 107))
66156	32340275	HHP affects human cell viability and has been suggested as a physical technique to manufacture therapeutically efficient cell-based tumor vaccines.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('HHP', 'Var', (0, 3))	('affects', 'Reg', (4, 11))	('human', 'Species', '9606', (12, 17))	('HHP', 'Chemical', '-', (0, 3))	('human cell viability', 'CPA', (12, 32))
66158	32340275	Similarly, to anthracyclines, HHP rapidly upregulates the expression of ICD markers (CRT, HSP70, and HSP90) on the cell surface and activates ATP release into the extracellular environment.	('HSP90', 'Gene', '111042', (101, 106))	('ATP release into the extracellular environment', 'MPA', (142, 188))	('HHP', 'Var', (30, 33))	('cell surface', 'cellular_component', 'GO:0009986', ('115', '127'))	('expression', 'MPA', (58, 68))	('activates', 'PosReg', (132, 141))	('HSP70', 'Gene', (90, 95))	('HSP70', 'Gene', '15511', (90, 95))	('HHP', 'Chemical', '-', (30, 33))	('ATP', 'Chemical', 'MESH:D000255', (142, 145))	('extracellular', 'cellular_component', 'GO:0005576', ('163', '176'))	('HSP90', 'Gene', (101, 106))	('CRT', 'Protein', (85, 88))	('anthracyclines', 'Chemical', 'MESH:D018943', (14, 28))	('upregulates', 'PosReg', (42, 53))
66171	32340275	To date, there is no clinical evidence of UVC treatment in human tumors, since UVC light can cause a high rate of putative pro-oncogenic mutations leading to tumor progression.	('tumor', 'Disease', (158, 163))	('human', 'Species', '9606', (59, 64))	('tumor', 'Disease', (65, 70))	('mutations', 'Var', (137, 146))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('pro-oncogenic', 'CPA', (123, 136))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
66175	32340275	Comparing tumor growth in immunodeficient and immunocompetent Balb/C mice showed that long-term effects of PDT therapy were attributed to the activation of the antitumor immune response as tumor development frequently occurred in deficient but not in normal mice, whereas short-term responses were similar in both normal and immunocompromised mice.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('PDT', 'Gene', (107, 110))	('tumor', 'Disease', (189, 194))	('tumor', 'Disease', (164, 169))	('immunodeficient', 'Disease', (26, 41))	('immunodeficient', 'Disease', 'MESH:D007153', (26, 41))	('activation', 'PosReg', (142, 152))	('tumor', 'Disease', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('deficient', 'Var', (230, 239))	('mice', 'Species', '10090', (258, 262))	('mice', 'Species', '10090', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('immune response', 'biological_process', 'GO:0006955', ('170', '185'))	('mice', 'Species', '10090', (343, 347))
66180	32340275	Hypericin predominantly causes ER-associated oxidative stress and initiates different signaling pathways of UPR, which finally leads to amplified mitochondria-dependent apoptosis.	('initiates', 'Reg', (66, 75))	('apoptosis', 'biological_process', 'GO:0097194', ('169', '178'))	('mitochondria', 'cellular_component', 'GO:0005739', ('146', '158'))	('leads to', 'Reg', (127, 135))	('mitochondria-dependent apoptosis', 'MPA', (146, 178))	('causes', 'Reg', (24, 30))	('ER-associated oxidative stress', 'MPA', (31, 61))	('apoptosis', 'biological_process', 'GO:0006915', ('169', '178'))	('oxidative stress', 'Phenotype', 'HP:0025464', (45, 61))	('signaling', 'biological_process', 'GO:0023052', ('86', '95'))	('amplified', 'PosReg', (136, 145))	('Hypericin', 'Var', (0, 9))	('Hypericin', 'Chemical', 'MESH:C004965', (0, 9))
66183	32340275	ICD induced by Hyp-PDT was much more effective when compared to that induced by chemotherapy or radiotherapy.	('Hyp', 'Chemical', 'MESH:C004965', (15, 18))	('ICD', 'Disease', (0, 3))	('Hyp-PDT', 'Var', (15, 22))
66184	32340275	Specifically, using Hyp-PDT prevents tumorigenesis by impeding tumor-promoting cytokines signaling and downregulating mediators of tumor metastasis-like cancer-derived matrix metalloproteinase-9 (MMP-9).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('cancer', 'Disease', (153, 159))	('matrix metalloproteinase-9', 'Gene', (168, 194))	('tumor', 'Disease', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor metastasis', 'Disease', 'MESH:D009362', (131, 147))	('MMP-9', 'Gene', '17395', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('MMP-9', 'Gene', (196, 201))	('matrix metalloproteinase-9', 'Gene', '17395', (168, 194))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('prevents', 'NegReg', (28, 36))	('tumor metastasis', 'Disease', (131, 147))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('impeding', 'NegReg', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('downregulating', 'NegReg', (103, 117))	('mediators', 'MPA', (118, 127))	('Hyp', 'Chemical', 'MESH:C004965', (20, 23))	('Hyp-PDT', 'Var', (20, 27))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
66185	32340275	It has been reported that Hyp-PDT strongly inhibits transcriptional activities of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and Activator protein 1 (AP-1) in treated cancer cells.	('Hyp', 'Chemical', 'MESH:C004965', (26, 29))	('AP-1', 'Gene', '16476', (178, 182))	('protein', 'cellular_component', 'GO:0003675', ('167', '174'))	('AP-1', 'cellular_component', 'GO:0005907', ('178', '182'))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('transcriptional activities', 'MPA', (52, 78))	('Activator protein 1', 'Gene', (157, 176))	('AP-1', 'Gene', (178, 182))	('Activator protein 1', 'Gene', '16476', (157, 176))	('inhibits', 'NegReg', (43, 51))	('Hyp-PDT', 'Var', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
66186	32340275	Moreover, Hyp-PDT can reduce the cancer cell-secreted tumor-promoting cytokines such as Granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and TNF.	('GM-CSF', 'Gene', '12981', (138, 144))	('Granulocyte-macrophage colony-stimulating factor', 'Gene', (88, 136))	('cancer', 'Disease', (33, 39))	('reduce', 'NegReg', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('TNF', 'Gene', '21926', (157, 160))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (54, 59))	('IL-6', 'Gene', (147, 151))	('Granulocyte-macrophage colony-stimulating factor', 'Gene', '12981', (88, 136))	('Hyp-PDT', 'Var', (10, 17))	('Hyp', 'Chemical', 'MESH:C004965', (10, 13))	('IL-6', 'Gene', '16193', (147, 151))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('GM-CSF', 'Gene', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('TNF', 'Gene', (157, 160))
66192	32340275	It has been demonstrated that Pt-NHC selectively localizes in the ER and enhances ER stress-mediated cell death indicating that Pt-NHC is a type II ICD inducer.	('Pt-NHC', 'Chemical', '-', (30, 36))	('death', 'Disease', 'MESH:D003643', (106, 111))	('death', 'Disease', (106, 111))	('Pt-NHC', 'Chemical', '-', (128, 134))	('cell death', 'biological_process', 'GO:0008219', ('101', '111'))	('Pt-NHC', 'Var', (30, 36))	('enhances', 'PosReg', (73, 81))
66202	32340275	For example, the TAT protein from human immunodeficiency virus 1 (HIV1), M156R from myxoma virus, C8L from swinepox virus, and hepatitis C virus envelope protein E2 are contained in this group.	('HIV1', 'Species', '11676', (66, 70))	('TAT', 'Gene', (17, 20))	('hepatitis', 'Phenotype', 'HP:0012115', (127, 136))	('swinepox virus', 'Species', '10276', (107, 121))	('M156R', 'Mutation', 'p.M156R', (73, 78))	('immunodeficiency', 'Phenotype', 'HP:0002721', (40, 56))	('M156R', 'Var', (73, 78))	('myxoma virus', 'Species', '10273', (84, 96))	('TAT', 'Gene', '6898', (17, 20))	('human immunodeficiency virus 1', 'Species', '11676', (34, 64))	('hepatitis C virus', 'Species', '11103', (127, 144))
66216	32340275	The caspase-dependent mechanism of ICD induction implicates caspase-8 but not the executioner caspase-3 and -7 or ER-resident caspase-12, which is demonstrated by the experiments that gene knockout models for caspase-8 prevented CRT exposure elicited by oxaliplatin, anthracyclines, or UVC light.	('caspase-12', 'Gene', (126, 136))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (254, 265))	('anthracyclines', 'Chemical', 'MESH:D018943', (267, 281))	('CRT exposure', 'MPA', (229, 241))	('caspase-12', 'Gene', '12364', (126, 136))	('gene knockout', 'Var', (184, 197))	('implicates', 'Reg', (49, 59))	('caspase-3 and -7', 'Gene', '12367;12369', (94, 110))	('caspase-8', 'Gene', (209, 218))
66219	32340275	Bap31 is required for the conversion of endoplasmic CRT to the plasma membrane CRT as the knockdown of Bap31 in HeLa cells or mutation of Bap31 to render it uncleavable similarly caused disruption of CRT exposure.	('caused', 'Reg', (179, 185))	('knockdown', 'Var', (90, 99))	('CRT exposure', 'MPA', (200, 212))	('mutation', 'Var', (126, 134))	('HeLa', 'CellLine', 'CVCL:0030', (112, 116))	('Bap31', 'Gene', (138, 143))	('Bap31', 'Gene', (103, 108))
66227	32340275	Additionally, the loss of TP53 is the most common process to circumvent apoptosis.	('TP53', 'Gene', (26, 30))	('loss', 'Var', (18, 22))	('apoptosis', 'biological_process', 'GO:0097194', ('72', '81'))	('apoptosis', 'biological_process', 'GO:0006915', ('72', '81'))	('TP53', 'Gene', '22059', (26, 30))
66229	32340275	Focusing on the intercellular events in the elimination of dying tumor cells, it was found that the absence of HMGB1 expression can attenuate DC-dependent T cell responses toward tumor-associated antigens.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('HMGB1', 'Gene', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('attenuate', 'NegReg', (132, 141))	('expression', 'Protein', (117, 127))	('absence', 'Var', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (179, 184))
66230	32340275	In line with these data, previous reports have shown that the efficacy of chemotherapy or radiotherapy is largely confined in patients with breast cancer who carry certain alleles of TLR4 causing loss of function mutations.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('loss of function', 'NegReg', (196, 212))	('TLR4', 'Gene', (183, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('patients', 'Species', '9606', (126, 134))	('mutations', 'Var', (213, 222))
66232	32340275	Likewise, there are diverse strategies to subvert ICD such as polymorphisms within Interferon Alpha and Beta Receptor Subunit 1 (IFNAR1), the weak expression of interferon regulatory factor IRF7 and low Signal transducer and activator of transcription 1 (STAT1) levels which require more detailed studies.	('STAT1', 'Gene', '20846', (255, 260))	('Interferon Alpha and Beta Receptor Subunit 1', 'Gene', '15975', (83, 127))	('weak', 'NegReg', (142, 146))	('expression', 'MPA', (147, 157))	('STAT1', 'Gene', (255, 260))	('IRF7', 'Gene', (190, 194))	('IRF7', 'Gene', '54123', (190, 194))	('IFNAR1', 'Gene', (129, 135))	('polymorphisms', 'Var', (62, 75))	('low', 'NegReg', (199, 202))	('IFNAR1', 'Gene', '15975', (129, 135))	('transcription', 'biological_process', 'GO:0006351', ('238', '251'))	('Signal transducer and activator of transcription 1', 'Gene', '20846', (203, 253))
66254	32340275	Another study was documented that mice with osteosarcoma tumors were treated with DCs and doxorubicin in combination and showed an increased frequency of CD8+ T cells in metastatic tumors and suppression of metastatic growth as well as increased expression of CRT and the release of HMGB1 from tumor tissues.	('suppression', 'NegReg', (192, 203))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('CRT', 'Protein', (260, 263))	('increased', 'PosReg', (236, 245))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('doxorubicin', 'Chemical', 'MESH:D004317', (90, 101))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('HMGB1', 'Gene', (283, 288))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('osteosarcoma tumors', 'Disease', 'MESH:D012516', (44, 63))	('increased', 'PosReg', (131, 140))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('CD8+ T cells', 'Var', (154, 166))	('expression', 'MPA', (246, 256))	('tumor', 'Disease', (57, 62))	('mice', 'Species', '10090', (34, 38))	('CD8', 'Species', '1151253', (154, 157))	('tumors', 'Disease', (181, 187))	('osteosarcoma tumors', 'Disease', (44, 63))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('osteosarcoma', 'Phenotype', 'HP:0002669', (44, 56))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('release', 'MPA', (272, 279))	('tumor', 'Disease', (294, 299))	('tumor', 'Disease', (181, 186))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('metastatic growth', 'CPA', (207, 224))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumors', 'Disease', (57, 63))
66257	32340275	It was indicated that oxaliplatin but not cisplatin mediates its antitumor effects through an immunogenic mode of tumor cell death in colorectal cancer.	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor cell death', 'Disease', (114, 130))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('colorectal cancer', 'Disease', (134, 151))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', (114, 119))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (22, 33))	('tumor cell death', 'Disease', 'MESH:D003643', (114, 130))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('cell death', 'biological_process', 'GO:0008219', ('120', '130'))	('oxaliplatin', 'Var', (22, 33))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))
66277	32340275	Furthermore, the treatment of urothelial bladder cancer with inhibitors of PD-1/PD-L1 pathways revealed an increment in response rate in the range of 13 and 24%.	('inhibitors', 'Var', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('urothelial bladder cancer', 'Disease', (30, 55))	('bladder cancer', 'Phenotype', 'HP:0009725', (41, 55))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (30, 55))	('PD-1/PD-L1', 'Gene', (75, 85))
66278	32340275	Different clinical experiments have recently demonstrated that the use of anthracyclines as an ICD inducer led to an increase in the blocking of PD-1 and PD-L1 efficacy.	('anthracyclines', 'Var', (74, 88))	('increase', 'PosReg', (117, 125))	('PD-L1', 'Gene', (154, 159))	('anthracyclines', 'Chemical', 'MESH:D018943', (74, 88))	('blocking', 'MPA', (133, 141))	('PD-1', 'Protein', (145, 149))
66281	32340275	Crizotinib, as an inhibitor for tyrosine kinase, and oxaliplatin, as a chemotherapeutic agent, have a natural potential to induce ICD.	('induce', 'Reg', (123, 129))	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('Crizotinib', 'Var', (0, 10))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (53, 64))	('ICD', 'Disease', (130, 133))
66300	32340275	KT-1 could considerably induce ICD in vivo condition and also sensitizes cancer cells to checkpoint blockade through targeting of polymer-enhanced tumors.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('KT-1', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('ICD', 'Disease', (31, 34))	('tumors', 'Disease', (147, 153))	('induce', 'PosReg', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('sensitizes', 'Reg', (62, 72))
66301	32340275	Another study indicated that the encapsulated CRISPR/Cas9 in nanoparticles is able to knock out more specifically the function of cyclin-dependent kinase 5 gene to attenuate PD-L1 expression on cancer cells remarkably.	('cancer', 'Disease', (194, 200))	('cyclin-dependent kinase 5', 'Gene', (130, 155))	('attenuate', 'NegReg', (164, 173))	('expression', 'MPA', (180, 190))	('cyclin-dependent kinase 5', 'Gene', '12568', (130, 155))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('PD-L1', 'Gene', (174, 179))	('knock', 'Var', (86, 91))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
66313	32340275	In line, DNA damage and subsequent tumor cell death has been attributed to four underlying principles (known as the 4 "Rs" of radiobiology): First, reorganization of cancer cells into radiosensitive phases of the cell cycle (G2/M); second, reoxygenation of formerly hypoxic cells within a TME; third, rectification of fatal DNA impairment and; the last, repopulation of living cancer cells, whereby the modifying of each factor changes cancer cell radiosensitivity.	('tumor cell death', 'Disease', (35, 51))	('cancer', 'Phenotype', 'HP:0002664', (377, 383))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('changes', 'Reg', (428, 435))	('cancer', 'Phenotype', 'HP:0002664', (436, 442))	('tumor cell death', 'Disease', 'MESH:D003643', (35, 51))	('cancer cell radiosensitivity', 'Phenotype', 'HP:0010997', (436, 464))	('cancer', 'Disease', (377, 383))	('cancer', 'Disease', 'MESH:D009369', (377, 383))	('cancer', 'Disease', 'MESH:D009369', (436, 442))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('oxygen', 'Chemical', 'MESH:D010100', (242, 248))	('cancer', 'Disease', (436, 442))	('modifying', 'Var', (403, 412))
66345	32340275	suggested that anti-PD-L1, when administrated in combination with radiotherapy, can decrease the numbers of MDSCs and, therefore, their suppressive effects on the tumor immune system.	('decrease', 'NegReg', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('anti-PD-L1', 'Var', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('suppressive effects', 'NegReg', (136, 155))	('tumor', 'Disease', (163, 168))
66354	32340275	Although the impressive immune-modulatory potential of PDT makes it apt to devise effective cancer disease-management plots, high-inflammatory PDT factors can trigger acute inflammation typified by heightened expression of pro-inflammatory cytokines, adhesion molecules' E-selection and Intercellular Adhesion Molecule 1 (ICAM-1), and quickly amass leukocytes in the treated tumor area.	('expression', 'MPA', (209, 219))	('inflammation', 'Disease', 'MESH:D007249', (173, 185))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('Intercellular Adhesion Molecule 1', 'Gene', '15894', (287, 320))	('heightened', 'PosReg', (198, 208))	('high-inflammatory', 'Var', (125, 142))	('tumor', 'Disease', (375, 380))	('inflammation', 'Disease', (173, 185))	('Intercellular Adhesion Molecule 1', 'Gene', (287, 320))	('tumor', 'Disease', 'MESH:D009369', (375, 380))	('cancer', 'Disease', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('ICAM-1', 'Gene', (322, 328))	('factors', 'Var', (147, 154))	('acute', 'Disease', (167, 172))	('trigger', 'Reg', (159, 166))	('ICAM-1', 'Gene', '15894', (322, 328))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('inflammation', 'biological_process', 'GO:0006954', ('173', '185'))	('PDT', 'Gene', (143, 146))
66361	32340275	ICD activated by Hyp-PDT was much more operative when compared to that stimulated by chemotherapy or radiotherapy.	('Hyp-PDT', 'Var', (17, 24))	('operative', 'MPA', (39, 48))	('Hyp', 'Chemical', 'MESH:C004965', (17, 20))
66362	32340275	Principally, using Hyp-PDT prevents tumorigenesis by impeding tumor-promoting cytokines' signaling and downregulating mediators of tumor metastasis like matrix metalloproteinase-9 (MMP9).	('Hyp-PDT', 'Var', (19, 26))	('MMP9', 'Gene', '17395', (181, 185))	('tumor', 'Disease', (131, 136))	('matrix metalloproteinase-9', 'Gene', '17395', (153, 179))	('tumor metastasis', 'Disease', 'MESH:D009362', (131, 147))	('tumor', 'Disease', (36, 41))	('MMP9', 'Gene', (181, 185))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('prevents', 'NegReg', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor metastasis', 'Disease', (131, 147))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('downregulating', 'NegReg', (103, 117))	('mediators', 'MPA', (118, 127))	('tumor', 'Disease', (62, 67))	('impeding', 'NegReg', (53, 61))	('MMP9', 'molecular_function', 'GO:0004229', ('181', '185'))	('matrix metalloproteinase-9', 'Gene', (153, 179))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('Hyp', 'Chemical', 'MESH:C004965', (19, 22))
66363	32340275	It has been reported that Hyp-PDT strongly inhibits transcriptional functions of NF-kB and AP-1 in treated cancer cells.	('Hyp', 'Chemical', 'MESH:C004965', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('AP-1', 'cellular_component', 'GO:0005907', ('91', '95'))	('AP-1', 'Gene', (91, 95))	('NF-kB', 'Protein', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('inhibits', 'NegReg', (43, 51))	('AP-1', 'Gene', '16476', (91, 95))	('cancer', 'Disease', (107, 113))	('Hyp-PDT', 'Var', (26, 33))	('transcriptional functions', 'MPA', (52, 77))
66364	32340275	Moreover, Hyp-PDT can reduce the cancer cell-secreted tumor-promoting cytokines, such as GM-CSF, IL-6, and TNF.	('cancer', 'Disease', (33, 39))	('reduce', 'NegReg', (22, 28))	('TNF', 'Gene', (107, 110))	('GM-CSF', 'Gene', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('Hyp', 'Chemical', 'MESH:C004965', (10, 13))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Hyp-PDT', 'Var', (10, 17))	('GM-CSF', 'Gene', '12981', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('TNF', 'Gene', '21926', (107, 110))	('tumor', 'Disease', (54, 59))	('IL-6', 'Gene', (97, 101))	('IL-6', 'Gene', '16193', (97, 101))
66382	32340275	According to studies, stimulating antitumor immunity, besides the tumor cells' death, can result in durable therapeutic benefits.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('death', 'Disease', 'MESH:D003643', (79, 84))	('death', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('stimulating', 'Var', (22, 33))	('therapeutic benefits', 'CPA', (108, 128))
66388	32111819	The antisense lncRNA LDLRAD4-AS1 is the longest lncRNA of LDLRAD4, and its expression levels, cellular localization, precise function, and mechanism in colorectal cancer (CRC) remain unknown.	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('CRC', 'Disease', 'MESH:D015179', (171, 174))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('CRC', 'Disease', (171, 174))	('colorectal cancer', 'Disease', (152, 169))	('expression', 'Species', '29278', (75, 85))	('antisense', 'Var', (4, 13))	('CRC', 'Phenotype', 'HP:0003003', (171, 174))
66389	32111819	In this study, we observed that lncRNA LDLRAD4-AS1 was located in the nucleus of CRC cells and that lncRNA LDLRAD4-AS1 was upregulated in most CRC specimens and cell lines.	('CRC', 'Disease', 'MESH:D015179', (143, 146))	('upregulated', 'PosReg', (123, 134))	('lncRNA LDLRAD4-AS1', 'Var', (100, 118))	('CRC', 'Disease', (81, 84))	('CRC', 'Disease', (143, 146))	('CRC', 'Phenotype', 'HP:0003003', (81, 84))	('CRC', 'Phenotype', 'HP:0003003', (143, 146))	('CRC', 'Disease', 'MESH:D015179', (81, 84))
66390	32111819	Overexpression of lncRNA LDLRAD4-AS1 was correlated with poor prognosis in CRC patients.	('expression', 'Species', '29278', (4, 14))	('CRC', 'Disease', (75, 78))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (79, 87))	('CRC', 'Phenotype', 'HP:0003003', (75, 78))	('CRC', 'Disease', 'MESH:D015179', (75, 78))
66400	32111819	Recent research has focused on the function of lncRNAs in human cancer pathogenesis; antisense (AS) lncRNAs are reverse complements of their endogenous sense counterparts and comprise a substantial proportion of the entire long noncoding transcriptome.	('human', 'Species', '9606', (58, 63))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('antisense', 'Var', (85, 94))	('pathogenesis', 'biological_process', 'GO:0009405', ('71', '83'))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
66408	32111819	LncRNA LDLRAD4-AS1 silencing inhibits CRC cell migration and invasion, while lncRNA LDLRAD4-AS1 overexpression promotes CRC cell migration and invasion.	('CRC', 'Phenotype', 'HP:0003003', (120, 123))	('CRC', 'Disease', 'MESH:D015179', (120, 123))	('CRC', 'Phenotype', 'HP:0003003', (38, 41))	('expression', 'Species', '29278', (100, 110))	('invasion', 'CPA', (143, 151))	('silencing', 'Var', (19, 28))	('invasion', 'CPA', (61, 69))	('CRC', 'Disease', 'MESH:D015179', (38, 41))	('promotes', 'PosReg', (111, 119))	('inhibits', 'NegReg', (29, 37))	('CRC', 'Disease', (120, 123))	('CRC', 'Disease', (38, 41))
66417	32111819	Then, to determine the relationship between the expression of lncRNA LDLRAD4-AS1 and CRC patient prognosis, Kaplan-Meier analysis was performed to show that lncRNA LDLRAD4-AS1 expression was markedly associated with a shorter time after surgical resection.	('CRC', 'Disease', 'MESH:D015179', (85, 88))	('lncRNA LDLRAD4-AS1', 'Var', (157, 175))	('patient', 'Species', '9606', (89, 96))	('expression', 'Species', '29278', (48, 58))	('expression', 'Species', '29278', (176, 186))	('CRC', 'Disease', (85, 88))	('CRC', 'Phenotype', 'HP:0003003', (85, 88))
66418	32111819	The 5-year cause-specific survival (CSS) and disease-free survival (DFS) rates for patients in the high lncRNA LDLRAD4-AS1 expression group were 56.0% and 38.8%, respectively, compared with 68.0% and 64.3% in CRC patients in the low lncRNA LDLRAD4-AS1 expression group (p = 0.035, Fig.	('CRC', 'Disease', 'MESH:D015179', (209, 212))	('CSS', 'Chemical', '-', (36, 39))	('CRC', 'Disease', (209, 212))	('expression', 'Species', '29278', (252, 262))	('high lncRNA LDLRAD4-AS1', 'Var', (99, 122))	('patients', 'Species', '9606', (213, 221))	('patients', 'Species', '9606', (83, 91))	('CRC', 'Phenotype', 'HP:0003003', (209, 212))	('expression', 'Species', '29278', (123, 133))
66425	32111819	Then, we knocked down lncRNA LDLRAD4-AS1 in both DLD1 and HCT116 cells (Fig.	('knocked', 'Var', (9, 16))	('HCT116', 'CellLine', 'CVCL:0291', (58, 64))	('lncRNA LDLRAD4-AS1', 'Gene', (22, 40))
66431	32111819	The above data demonstrated that LDLRAD4-AS1 could promote the metastasis of CRC cells in vitro and in vivo.	('metastasis of CRC', 'Disease', 'MESH:D015179', (63, 80))	('LDLRAD4-AS1', 'Var', (33, 44))	('promote', 'PosReg', (51, 58))	('metastasis of CRC', 'Disease', (63, 80))	('CRC', 'Phenotype', 'HP:0003003', (77, 80))
66436	32111819	In addition, Kaplan-Meier analysis showed that LDLRAD4 expression was markedly associated with better survival outcomes.	('expression', 'Species', '29278', (55, 65))	('expression', 'Var', (55, 65))	('survival outcomes', 'CPA', (102, 119))	('better', 'PosReg', (95, 101))	('LDLRAD4', 'Gene', (47, 54))
66437	32111819	The 5-year CSS and DFS rates for patients in the high LDLRAD4 expression group were 82.0% and 70.4%, respectively, compared with 46.0% and 38.0% in CRC patients in the low LDLRAD4 expression group (p = 0.031, Fig.	('CSS', 'CPA', (11, 14))	('patients', 'Species', '9606', (33, 41))	('CRC', 'Disease', (148, 151))	('expression', 'Species', '29278', (62, 72))	('expression', 'Species', '29278', (180, 190))	('CRC', 'Phenotype', 'HP:0003003', (148, 151))	('CRC', 'Disease', 'MESH:D015179', (148, 151))	('DFS', 'CPA', (19, 22))	('LDLRAD4', 'Gene', (54, 61))	('high', 'Var', (49, 53))	('CSS', 'Chemical', '-', (11, 14))	('patients', 'Species', '9606', (152, 160))
66441	32111819	Kaplan-Meier analyses showed that high LDLRAD4 protein expression was associated with better survival outcomes.	('protein', 'Protein', (47, 54))	('survival outcomes', 'CPA', (93, 110))	('expression', 'Species', '29278', (55, 65))	('expression', 'MPA', (55, 65))	('better', 'PosReg', (86, 92))	('high', 'Var', (34, 38))	('LDLRAD4', 'Gene', (39, 46))
66442	32111819	The 5-year CSS and DFS rates for patients in the high LDLRAD4 protein expression group were 83.1% and 75.9%, respectively, compared with 65.6% and 59.7% in CRC patients in the low LDLRAD4 protein expression group (p = 0.022, Fig.	('CSS', 'CPA', (11, 14))	('protein', 'Protein', (62, 69))	('patients', 'Species', '9606', (160, 168))	('CRC', 'Disease', (156, 159))	('patients', 'Species', '9606', (33, 41))	('expression', 'Species', '29278', (196, 206))	('expression', 'Species', '29278', (70, 80))	('CRC', 'Phenotype', 'HP:0003003', (156, 159))	('DFS', 'CPA', (19, 22))	('LDLRAD4', 'Gene', (54, 61))	('high', 'Var', (49, 53))	('CRC', 'Disease', 'MESH:D015179', (156, 159))	('CSS', 'Chemical', '-', (11, 14))
66449	32111819	4m-p, the silencing of LDLRAD4 significantly promoted the migration and invasion of DLD1 and HCT116 cells in vitro.	('promoted', 'PosReg', (45, 53))	('HCT116', 'CellLine', 'CVCL:0291', (93, 99))	('silencing', 'Var', (10, 19))	('invasion', 'CPA', (72, 80))	('LDLRAD4', 'Gene', (23, 30))	('migration', 'CPA', (58, 67))
66452	32111819	Given the negative correlation between the expression of lncRNA LDLRAD4-AS1 and LDLRAD4 and the metastasis suppressor role of LDLRAD4, we sought to uncover the mechanism by which lncRNA LDLRAD4-AS1 promotes CRC metastasis by analyzing its role in regulating LDLRAD4.	('CRC', 'Disease', (207, 210))	('LDLRAD4-AS1', 'Var', (186, 197))	('LDLRAD4', 'Gene', (80, 87))	('CRC', 'Phenotype', 'HP:0003003', (207, 210))	('expression', 'Species', '29278', (43, 53))	('CRC', 'Disease', 'MESH:D015179', (207, 210))	('promotes', 'PosReg', (198, 206))
66457	32111819	In addition, knockdown of lncRNA LDLRAD4-AS1 increased the mRNA and protein levels of LDLRAD4 in DLD1 and HCT116 cells (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (106, 112))	('knockdown', 'Var', (13, 22))	('LDLRAD4', 'Gene', (86, 93))	('increased', 'PosReg', (45, 54))
66459	32111819	After blocking RNA transcription by adding actinomycin D, LDLRAD4 mRNA exhibited an obvious decrease in its stability mediated by lncRNA LDLRAD4-AS1 in both RKO and LoVo cells (Fig.	('decrease', 'NegReg', (92, 100))	('LDLRAD4', 'Var', (58, 65))	('stability', 'MPA', (108, 117))	('actinomycin D', 'Chemical', 'MESH:D003609', (43, 56))	('LoVo', 'CellLine', 'CVCL:0399', (165, 169))	('LDLRAD4-AS1', 'Var', (137, 148))	('RNA', 'Protein', (15, 18))
66460	32111819	In accordance, knockdown of lncRNA LDLRAD4-AS1 extended the half-life of LDLRAD4 mRNA in DLD1 and HCT116 cells (Fig.	('knockdown', 'Var', (15, 24))	('HCT116', 'CellLine', 'CVCL:0291', (98, 104))	('LDLRAD4', 'Gene', (73, 80))	('extended', 'PosReg', (47, 55))	('half-life', 'MPA', (60, 69))
66462	32111819	The results showed that forced expression of three truncated mutants (TM-549-5', TM-1098-5', and TM-1098-M) significantly downregulated the levels of LDLRAD4 mRNA in the same manner as full-length lncRNA LDLRAD4-AS1 (Fig.	('downregulated', 'NegReg', (122, 135))	('TM-1098-M', 'Var', (97, 106))	('TM-549', 'CellLine', 'CVCL:0023', (70, 76))	('expression', 'Species', '29278', (31, 41))	('levels', 'MPA', (140, 146))	("TM-549-5'", 'Var', (70, 79))	("TM-1098-5'", 'Var', (81, 91))	('LDLRAD4 mRNA', 'MPA', (150, 162))
66476	32111819	Overexpression of lncRNA FEZF1-AS1 was associated with advanced T stage, lymph node metastasis, distant metastasis and poor overall survival in CRC.	('expression', 'Species', '29278', (4, 14))	('CRC', 'Phenotype', 'HP:0003003', (144, 147))	('CRC', 'Disease', 'MESH:D015179', (144, 147))	('poor', 'NegReg', (119, 123))	('Overexpression', 'Var', (0, 14))	('FEZF1-AS1', 'Gene', '154860', (25, 34))	('lymph node metastasis', 'CPA', (73, 94))	('distant metastasis', 'CPA', (96, 114))	('CRC', 'Disease', (144, 147))	('FEZF1-AS1', 'Gene', (25, 34))
66478	32111819	In our study, overexpression of lncRNA LDLRAD4-AS1 was related to advanced stage, lymph node metastasis, tumor size, vascular invasion, and poor prognosis in CRC.	('CRC', 'Phenotype', 'HP:0003003', (158, 161))	('CRC', 'Disease', 'MESH:D015179', (158, 161))	('advanced stage', 'CPA', (66, 80))	('tumor', 'Disease', (105, 110))	('vascular invasion', 'CPA', (117, 134))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('expression', 'Species', '29278', (18, 28))	('lymph node metastasis', 'CPA', (82, 103))	('CRC', 'Disease', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('lncRNA LDLRAD4-AS1', 'Var', (32, 50))	('overexpression', 'PosReg', (14, 28))
66479	32111819	Furthermore, we found that lncRNA LDLRAD4-AS1 is an independent prognostic factor in CRC patients that could act as a potential biomarker and treatment target in CRC.	('CRC', 'Disease', 'MESH:D015179', (85, 88))	('lncRNA LDLRAD4-AS1', 'Var', (27, 45))	('CRC', 'Disease', (162, 165))	('CRC', 'Disease', (85, 88))	('CRC', 'Phenotype', 'HP:0003003', (162, 165))	('CRC', 'Disease', 'MESH:D015179', (162, 165))	('patients', 'Species', '9606', (89, 97))	('CRC', 'Phenotype', 'HP:0003003', (85, 88))
66482	32111819	Interestingly, lncRNA LDLRAD4-AS1 was significantly correlated with vascular invasion in terms of clinicopathological features, and lncRNA LDLRAD4-AS1 and vascular invasion were both independent risk factors for prognosis in CRC after both univariate and multivariate analyses.	('correlated', 'Reg', (52, 62))	('CRC', 'Disease', (225, 228))	('lncRNA LDLRAD4-AS1', 'Var', (132, 150))	('CRC', 'Phenotype', 'HP:0003003', (225, 228))	('CRC', 'Disease', 'MESH:D015179', (225, 228))	('vascular invasion', 'CPA', (68, 85))
66491	32111819	These findings demonstrate that dysregulated expression of lncRNA LDLRAD4-AS1 could serve as a biomarker or therapeutic target in CRC.	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('CRC', 'Disease', 'MESH:D015179', (130, 133))	('expression', 'Species', '29278', (45, 55))	('dysregulated', 'Var', (32, 44))	('expression', 'MPA', (45, 55))	('CRC', 'Disease', (130, 133))	('LDLRAD4-AS1', 'Gene', (66, 77))
66493	32111819	The effects of lncRNA LDLRAD4-AS1 on cell migration and invasion suggest that lncRNA LDLRAD4-AS1 promotes the tumorigenesis and progression of CRC.	('CRC', 'Disease', 'MESH:D015179', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('cell migration', 'biological_process', 'GO:0016477', ('37', '51'))	('CRC', 'Phenotype', 'HP:0003003', (143, 146))	('CRC', 'Disease', (143, 146))	('promotes', 'PosReg', (97, 105))	('lncRNA LDLRAD4-AS1', 'Var', (78, 96))	('progression', 'CPA', (128, 139))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
66526	32111819	Based on the full-length lncRNA LDLRAD4-AS1 sequence (2196 bp), we established truncated mutants as follows (5'-3'): mutant TM-549-5' (TM indicates truncated mutant) is the 1-549 bp region, mutant TM-1098-5' is the 1-1098 bp region, mutant TM-1098-M is the 549-1647 bp region, mutant TM-1098-3' is the 1098-2196 bp region, and mutant TM-549-3' is the 1647-2196 bp region.	('mutant', 'Var', (233, 239))	('mutant', 'Var', (117, 123))	('TM-549', 'CellLine', 'CVCL:0023', (334, 340))	('TM-549', 'CellLine', 'CVCL:0023', (124, 130))	('mutant', 'Var', (190, 196))	('mutant', 'Var', (277, 283))
66542	31114229	Correspondingly, ectopic expression of MACC1 mutant, which does not contain miR-940 binding site, blocked the antitumor effect of miR-940 on CRC cells.	('miR-940', 'Gene', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('mutant', 'Var', (45, 51))	('miR-940', 'Gene', (130, 137))	('miR-940', 'Gene', '100126328', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('blocked', 'NegReg', (98, 105))	('binding', 'molecular_function', 'GO:0005488', ('84', '91'))	('tumor', 'Disease', (114, 119))	('miR-940', 'Gene', '100126328', (76, 83))	('MACC1', 'Gene', (39, 44))
66554	31114229	Zhang et al (2016) showed that knockdown of MACC1 overcame the resistance of cisplatin in the cisplatin-resistant epithelial ovarian cancer cell line.	('MACC1', 'Gene', (44, 49))	('resistance of cisplatin', 'MPA', (63, 86))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (114, 139))	('epithelial ovarian cancer', 'Disease', (114, 139))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (114, 139))	('ovarian cancer', 'Phenotype', 'HP:0100615', (125, 139))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('overcame', 'PosReg', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('knockdown', 'Var', (31, 40))
66566	31114229	Vectors of MACC1 or vectors of MACC1 with a mutation of miR-940 target sequences in 3'UTR was purchased from Vigene Corporation, Jinan City, Shandong Province, China.	('miR-940', 'Gene', (56, 63))	('mutation', 'Var', (44, 52))	('miR-940', 'Gene', '100126328', (56, 63))
66580	31114229	For the subcutaneous tumor model, cells were transfected with miRNA-940 or miR-940 + mutated MACC1 (MACC1Mut) and injected into nude mice (1x106 cells per animal).	('nude mice', 'Species', '10090', (128, 137))	('miR-940', 'Gene', (75, 82))	('tumor', 'Disease', (21, 26))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (8, 26))	('miRNA-940', 'Var', (62, 71))	('MACC1', 'Gene', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('miR-940', 'Gene', '100126328', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
66597	31114229	In contrast, inhibition of miR-940 by transfection of miR-940's inhibitor or MACC1 with a mutated miR-940 binding site (MACC1Mut) blocked the effect of miR-940 on MACC1's expression.	('expression', 'MPA', (171, 181))	('miR-940', 'Gene', (54, 61))	('miR-940', 'Gene', '100126328', (54, 61))	('mutated', 'Var', (90, 97))	('miR-940', 'Gene', '100126328', (98, 105))	('binding', 'molecular_function', 'GO:0005488', ('106', '113'))	('miR-940', 'Gene', (98, 105))	('miR-940', 'Gene', '100126328', (27, 34))	('miR-940', 'Gene', '100126328', (152, 159))	('miR-940', 'Gene', (27, 34))	('MACC1', 'Gene', (163, 168))	('miR-940', 'Gene', (152, 159))
66613	31114229	As shown in Figure 4, Anlotinib significantly inhibited the SW620 tumor growth in nude mice; transfection of miR-940 significantly enhanced the antitumor effect of Anlotinib.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('miR-940', 'Gene', (109, 116))	('tumor', 'Disease', (66, 71))	('SW620', 'CellLine', 'CVCL:0547', (60, 65))	('tumor', 'Disease', (148, 153))	('Anlotinib', 'Chemical', 'MESH:C000625192', (22, 31))	('nude mice', 'Species', '10090', (82, 91))	('miR-940', 'Gene', '100126328', (109, 116))	('Anlotinib', 'Chemical', 'MESH:C000625192', (164, 173))	('enhanced', 'PosReg', (131, 139))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('inhibited', 'NegReg', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('transfection', 'Var', (93, 105))
66614	31114229	Moreover, ectopic expression of MACC1Mut in tumors could significantly block the effect of miR-940.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('MACC1Mut', 'Gene', (32, 40))	('miR-940', 'Gene', (91, 98))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('effect', 'MPA', (81, 87))	('block', 'NegReg', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('ectopic expression', 'Var', (10, 28))	('miR-940', 'Gene', '100126328', (91, 98))
66616	31114229	Similar to what we found in the subcutaneous tumor model, as shown in Figure 5, Anlotinib treatment had a strong antitumor effect, while miR-940 enhanced the effect of Anlotinib (Figure 5); and ectopic expression of MACC1Mut could significantly block the effect of miR-940.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('ectopic expression', 'Var', (194, 212))	('miR-940', 'Gene', '100126328', (137, 144))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', (45, 50))	('miR-940', 'Gene', '100126328', (265, 272))	('miR-940', 'Gene', (137, 144))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (32, 50))	('MACC1Mut', 'Gene', (216, 224))	('miR-940', 'Gene', (265, 272))	('Anlotinib', 'Chemical', 'MESH:C000625192', (168, 177))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('Anlotinib', 'Chemical', 'MESH:C000625192', (80, 89))
66622	31114229	Therefore, transfection of miR-940 increases the in vivo antitumor effect of Anlotinib.	('increases', 'PosReg', (35, 44))	('Anlotinib', 'Chemical', 'MESH:C000625192', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('miR-940', 'Gene', '100126328', (27, 34))	('Anlotinib', 'Gene', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('transfection', 'Var', (11, 23))	('miR-940', 'Gene', (27, 34))	('tumor', 'Disease', (61, 66))
66626	31114229	In the present work, we showed that Anlotinib inhibited the proliferation and invasive growth of CRC cells.	('Anlotinib', 'Var', (36, 45))	('inhibited', 'NegReg', (46, 55))	('Anlotinib', 'Chemical', 'MESH:C000625192', (36, 45))	('invasive growth of CRC cells', 'CPA', (78, 106))
66634	31114229	Inhibition of the EMT could enhance the sensitivity of human cancer cells to therapeutic strategies, such as sorafenib and radiofrequency ablation.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('EMT', 'Gene', (18, 21))	('cancer', 'Disease', (61, 67))	('human', 'Species', '9606', (55, 60))	('enhance', 'PosReg', (28, 35))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('sorafenib', 'Chemical', 'MESH:D000077157', (109, 118))	('sensitivity', 'MPA', (40, 51))
66729	30936723	The results of the FIRE-3 and the PEAK trials are also important, which indicate that anti-EGFR antibodies may result in early tumor shrinkage and depth of response.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('EGFR', 'Gene', (91, 95))	('depth of response', 'CPA', (147, 164))	('tumor', 'Disease', (127, 132))	('antibodies', 'Var', (96, 106))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('EGFR', 'Gene', '1956', (91, 95))
66738	30936723	In oncologic emergencies requiring an early response to treatment, the rapid and deep tumor shrinkage provided by anti-EGFR antibodies may be a highly effective treatment option.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('deep tumor', 'Disease', 'MESH:D057887', (81, 91))	('deep tumor', 'Disease', (81, 91))	('oncologic emergencies', 'Phenotype', 'HP:0002664', (3, 24))	('EGFR', 'Gene', '1956', (119, 123))	('antibodies', 'Var', (124, 134))	('EGFR', 'Gene', (119, 123))
66754	30360598	Overexpression of HLA-G and increased plasma levels of soluble HLA-G (sHLA-G) have been reported in different human malignancies, and are believed to protect tumor cells from immune surveillance (Amiot et al., 2011).	('increased', 'PosReg', (28, 37))	('HLA-G', 'Gene', (63, 68))	('tumor', 'Disease', (158, 163))	('HLA-G', 'Gene', '3135', (63, 68))	('malignancies', 'Disease', 'MESH:D009369', (116, 128))	('HLA-G', 'Gene', (18, 23))	('HLA-G', 'Gene', '3135', (18, 23))	('malignancies', 'Disease', (116, 128))	('human', 'Species', '9606', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('HLA-G', 'Gene', (71, 76))	('HLA-G', 'Gene', '3135', (71, 76))	('plasma levels', 'MPA', (38, 51))
66793	30360598	The atypical expression of HLA-G in malignant lesions may explained by epigenetic changes in tumor cells (Mouillot et al., 2005), although HLA-G production is primarily controlled by inherited alleles as well as polymorphisms in the 5' upstream regulatory region and the 3' untranslated region of the gene (Dias et al., 2015).	('polymorphisms', 'Var', (212, 225))	('HLA-G', 'Gene', '3135', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('HLA-G', 'Gene', (27, 32))	('HLA-G', 'Gene', '3135', (27, 32))	('tumor', 'Disease', (93, 98))	('HLA-G', 'Gene', (139, 144))	('controlled', 'Reg', (169, 179))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
66814	30360598	Unexpectedly, Genre et al., (2016) observed a strong association between the insertion/insertion genotype and increased susceptibility to H. pylori infection, but it should be noted that H. pylori uses different strategies to evade immune responses (Lina et al., 2014).	('insertion/insertion', 'Var', (77, 96))	('H. pylori infection', 'Phenotype', 'HP:0005202', (138, 157))	('H. pylori', 'Species', '210', (138, 147))	('infection', 'Disease', (148, 157))	('infection', 'Disease', 'MESH:D007239', (148, 157))	('H. pylori', 'Species', '210', (187, 196))
66828	29675892	High expression of XPA protein showed significant relationship with better survival of CRC, especially rectal cancer.	('CRC', 'Disease', (87, 90))	('better', 'PosReg', (68, 74))	('High', 'Var', (0, 4))	('rectal cancer', 'Phenotype', 'HP:0100743', (103, 116))	('rectal cancer', 'Disease', 'MESH:D012004', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('XPA', 'Gene', '7507', (19, 22))	('rectal cancer', 'Disease', (103, 116))	('XPA', 'Gene', (19, 22))
66837	29675892	19 found that high expression of XPA correlated with poor prognosis in 129 nasopharyngeal carcinoma patients treated with platinum-based chemoradiotherapy using immunohistochemistry.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('XPA', 'Gene', (33, 36))	('high', 'Var', (14, 18))	('patients', 'Species', '9606', (100, 108))	('XPA', 'Gene', '7507', (33, 36))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (75, 99))	('nasopharyngeal carcinoma', 'Disease', (75, 99))	('platinum', 'Chemical', 'MESH:D010984', (122, 130))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (75, 99))
66883	29675892	Univariate Cox proportional hazards model revealed that CRC patients with high XPA protein expression had longer overall survival (OS) (HR = 0.62, 95%CI: 0.39-0.97, P = 0.037, Fig.	('XPA', 'Gene', (79, 82))	('XPA', 'Gene', '7507', (79, 82))	('high', 'Var', (74, 78))	('patients', 'Species', '9606', (60, 68))	('longer', 'PosReg', (106, 112))	('overall survival', 'MPA', (113, 129))
66887	29675892	In the subgroup without distant metastasis, high XPA expression showed significant association with better OS (HR = 0.58, 95% CI: 0.35-0.96, P = 0.033, Fig.	('better OS', 'Disease', (100, 109))	('XPA', 'Gene', (49, 52))	('high', 'Var', (44, 48))	('XPA', 'Gene', '7507', (49, 52))
66897	29675892	Univariate Cox proportional hazards model revealed that CRC patients with high XPA protein expression had longer overall survival (OS), but the association was not statistically significant in multivariate analysis.	('XPA', 'Gene', (79, 82))	('XPA', 'Gene', '7507', (79, 82))	('high', 'Var', (74, 78))	('patients', 'Species', '9606', (60, 68))	('longer', 'PosReg', (106, 112))	('overall survival', 'MPA', (113, 129))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))
66928	29748584	The question of what causes a cancer to have its specific collection of mutations instead of another remains unanswered.	('mutations', 'Var', (72, 81))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
66929	29748584	In this study, we investigate the contributions of both mutation and selection in shaping the pattern of cancer-associated 'driver' mutations across cancer types.	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', (105, 111))	('mutations', 'Var', (132, 141))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
66932	29748584	The likelihood of acquisition of specific cancer-causing mutations, hereafter referred to as 'driver mutations', is dependent on the underlying mutational processes, as the probability of a mutation in a particular channel differs between processes.	('mutations', 'Var', (57, 66))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))
66933	29748584	For example, a previous report has highlighted links between APOBEC-induced mutagenesis and specific driver PIK3CA mutations across cancer types.	('APOBEC-induced', 'Gene', (61, 75))	('cancer', 'Disease', (132, 138))	('APOBEC', 'cellular_component', 'GO:0030895', ('61', '67'))	('mutations', 'Var', (115, 124))	('mutagenesis', 'biological_process', 'GO:0006280', ('76', '87'))	('mutagenesis', 'Var', (76, 87))	('links', 'Interaction', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('PIK3CA', 'Gene', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('PIK3CA', 'Gene', '5290', (108, 114))
66935	29748584	The strength of selection experienced by a mutation is also expected to influence the frequency at which the mutation is detected in the patient population.	('mutation', 'Var', (43, 51))	('influence', 'Reg', (72, 81))	('patient', 'Species', '9606', (137, 144))
66936	29748584	Traditionally, it has been convenient to classify mutations found in cancer as drivers or passengers, but it is likely that the effects of driver mutations actually lie on a continuum, including both 'mini-drivers' and major drivers.	('mutations', 'Var', (146, 155))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
66939	29748584	We therefore tested for a difference in the levels of relative mutational process activity between cancers with and without specific driver mutations (Fig.	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Disease', (99, 106))	('tested', 'Reg', (13, 19))	('mutations', 'Var', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
66940	29748584	Where the activity of a mutational process was significantly higher in cancers with a mutation of interest compared with those without, we considered it supporting evidence for a causative relationship between the mutational process activity and the acquisition of the driver mutation.	('activity', 'MPA', (10, 18))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('higher', 'PosReg', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mutation', 'Var', (86, 94))
66944	29748584	In each cancer type, we classed as 'recurrent' non-silent DNA mutations in driver genes as those that occurred at least four times in the cancer type (these recurrent mutations were considered candidate tissue-specific driver mutations).	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', (8, 14))	('mutations', 'Var', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
66948	29748584	We found that the power was influenced by the number of times a mutation occurred, as well as the enrichment of the mutation causal channel in the signature compared with average in the cancer type (Multiple Regression, P < 2E-16 both variables).	('mutation', 'Var', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
66949	29748584	There were 43 significant correlations between signature activity and driver mutations (Mann-Whitney U-test, false discovery rate = 0.05; one-sided test), out of 1019 triplets of specific mutations in individual driver genes, mutational signatures and cancer types tested.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', (252, 258))	('false', 'biological_process', 'GO:0071877', ('109', '114'))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('mutations', 'Var', (188, 197))	('false', 'biological_process', 'GO:0071878', ('109', '114'))
66953	29748584	Remarkably, PIK3CA E542K (TCA > TTA) and E545K (TCA > TTA) were associated with these signatures across five cancer types, accounting for 82% (9/11) of all APOBEC associations (Fig.	('TCA', 'Chemical', 'MESH:D014238', (26, 29))	('PIK3CA', 'Gene', '5290', (12, 18))	('TTA', 'Chemical', 'MESH:C062078', (54, 57))	('TTA', 'Chemical', 'MESH:C062078', (32, 35))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('E542K', 'Var', (19, 24))	('cancer', 'Disease', (109, 115))	('E545K', 'Mutation', 'rs104886003', (41, 46))	('E545K', 'Var', (41, 46))	('TCA', 'Chemical', 'MESH:D014238', (48, 51))	('E542K', 'Mutation', 'rs121913273', (19, 24))	('APOBEC', 'cellular_component', 'GO:0030895', ('156', '162'))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('APOBEC', 'Gene', (156, 162))	('PIK3CA', 'Gene', (12, 18))
66957	29748584	FBXW7 R465C (GCG > GTG), was associated with MMR signatures in both colorectum and stomach cancer (Fig.	('FBXW7', 'Gene', '55294', (0, 5))	('R465C', 'Var', (6, 11))	('colorectum', 'Disease', (68, 78))	('stomach cancer', 'Disease', (83, 97))	('GCG', 'Gene', '2641', (13, 16))	('GTG', 'Gene', (19, 22))	('MMR', 'biological_process', 'GO:0006298', ('45', '48'))	('FBXW7', 'Gene', (0, 5))	('stomach cancer', 'Phenotype', 'HP:0012126', (83, 97))	('GCG', 'Gene', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('associated', 'Reg', (29, 39))	('R465C', 'Mutation', 'rs867384286', (6, 11))	('GTG', 'Gene', '2678', (19, 22))	('stomach cancer', 'Disease', 'MESH:D013274', (83, 97))
66959	29748584	These results suggest an important role for MMR defects shaping the driver mutation spectrum of common cancers, and illustrate the likely sequence of events (early MMR-linked mutational processes relative to driver mutation acquisition) in some cancers with these defects.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('defects', 'Var', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('cancers', 'Disease', (245, 252))	('driver mutation spectrum', 'MPA', (68, 92))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('shaping', 'Reg', (56, 63))	('cancers', 'Disease', (103, 110))
66962	29748584	2/11 positive associations involved stop-gain mutations in the APC gene, one in colorectum and one in uterine carcinoma.	('uterine carcinoma', 'Phenotype', 'HP:0010784', (102, 119))	('mutations', 'Var', (46, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('APC', 'Disease', 'MESH:D011125', (63, 66))	('carcinoma', 'Disease', (110, 119))	('APC', 'cellular_component', 'GO:0005680', ('63', '66'))	('APC', 'Disease', (63, 66))	('carcinoma', 'Disease', 'MESH:D002277', (110, 119))
66967	29748584	We note that there are cases of a common driver mutation in a cancer, which do not match the dominant signature in that cancer type.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('mutation', 'Var', (48, 56))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
66972	29748584	Consequently, the frequency that a particular driver is observed across cancers is a function both of the mutational likelihood of it occurring in the first place, and also the selective advantage that the mutation confers.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutation', 'Var', (206, 214))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
66975	29748584	We explored potential differential selection among the most common driver mutations ( > 1% of non-synonymous mutations) in nine genes: KRAS, BRAF, NRAS, IDH1, IDH2, TP53, PIK3CA, SMAD4 and CTNNB1 (Supplementary Data 3) in individual cancer types.	('IDH2', 'Gene', (159, 163))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('IDH1', 'Gene', (153, 157))	('PIK3CA', 'Gene', (171, 177))	('TP53', 'Gene', (165, 169))	('IDH2', 'Gene', '3418', (159, 163))	('CTNNB1', 'Gene', (189, 195))	('IDH1', 'Gene', '3417', (153, 157))	('SMAD4', 'Gene', (179, 184))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('BRAF', 'Gene', '673', (141, 145))	('NRAS', 'Gene', '4893', (147, 151))	('TP53', 'Gene', '7157', (165, 169))	('BRAF', 'Gene', (141, 145))	('PIK3CA', 'Gene', '5290', (171, 177))	('KRAS', 'Gene', '3845', (135, 139))	('CTNNB1', 'Gene', '1499', (189, 195))	('SMAD4', 'Gene', '4089', (179, 184))	('KRAS', 'Gene', (135, 139))	('mutations', 'Var', (74, 83))	('cancer', 'Disease', (233, 239))	('NRAS', 'Gene', (147, 151))
66976	29748584	We conducted pairwise tests among the mutations from each gene in each cancer type where the common mutations in the gene occurred at least 10 times.	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mutations', 'Var', (38, 47))
66979	29748584	7), as did BRAF V600E compared with other BRAF common mutations, including BRAF K601E, in thyroid, melanoma and colorectal cancer.	('colorectal cancer', 'Disease', (112, 129))	('BRAF', 'Gene', '673', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('K601E', 'Mutation', 'rs121913364', (80, 85))	('BRAF', 'Gene', '673', (75, 79))	('V600E', 'Mutation', 'rs113488022', (16, 21))	('thyroid', 'Disease', (90, 97))	('K601E', 'Var', (80, 85))	('BRAF', 'Gene', (75, 79))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('BRAF', 'Gene', '673', (11, 15))	('BRAF', 'Gene', (42, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('BRAF', 'Gene', (11, 15))
66980	29748584	Also highly significant was apparent preferential selection for PIK3CA H1047R compared with multiple PIK3CA mutations, including PIK3CA E545K and E542K, in breast cancer (Fig.	('PIK3CA', 'Gene', (64, 70))	('H1047R', 'Var', (71, 77))	('PIK3CA', 'Gene', (129, 135))	('PIK3CA', 'Gene', '5290', (101, 107))	('E545K', 'Mutation', 'rs104886003', (136, 141))	('E545K', 'Var', (136, 141))	('E542K', 'Mutation', 'rs121913273', (146, 151))	('PIK3CA', 'Gene', '5290', (64, 70))	('PIK3CA', 'Gene', '5290', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('H1047R', 'Mutation', 'rs121913279', (71, 77))	('breast cancer', 'Disease', (156, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('PIK3CA', 'Gene', (101, 107))	('E542K', 'Var', (146, 151))
66981	29748584	9), and for NRAS Q61K and Q61R above NRAS G12D and G13D in melanoma.	('G12D', 'Mutation', 'rs121913529', (42, 46))	('Q61R', 'Var', (26, 30))	('NRAS', 'Gene', (37, 41))	('NRAS', 'Gene', (12, 16))	('Q61K', 'Mutation', 'rs121913254', (17, 21))	('Q61R', 'Mutation', 'rs11554290', (26, 30))	('NRAS', 'Gene', '4893', (12, 16))	('G13D', 'Var', (51, 55))	('NRAS', 'Gene', '4893', (37, 41))	('melanoma', 'Disease', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('G13D', 'Mutation', 'rs112445441', (51, 55))
66982	29748584	These results suggest that there are strong selective differences among important driver mutations in the same gene in these cancer types.	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (89, 98))
66985	29748584	This is of particular interest given the potential specificity of therapeutic small molecular inhibitors that target IDH1 and IDH2 mutations.	('mutations', 'Var', (131, 140))	('IDH1', 'Gene', '3417', (117, 121))	('IDH2', 'Gene', (126, 130))	('IDH2', 'Gene', '3418', (126, 130))	('IDH1', 'Gene', (117, 121))
66986	29748584	KRAS G12C, which was found to be associated with smoking-associated signature 4 in lung adenocarcinoma (see above), also appears more strongly selected than other KRAS mutations (including G12D, G12R and G13D) in this cancer type (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('KRAS', 'Gene', '3845', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', (218, 224))	('lung adenocarcinoma', 'Disease', (83, 102))	('G13D', 'Var', (204, 208))	('KRAS', 'Gene', (163, 167))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (83, 102))	('G12R', 'Mutation', 'rs121913530', (195, 199))	('KRAS', 'Gene', '3845', (163, 167))	('G13D', 'Mutation', 'rs112445441', (204, 208))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('G12C', 'Mutation', 'rs121913530', (5, 9))	('G12D', 'Var', (189, 193))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (83, 102))	('KRAS', 'Gene', (0, 4))	('G12R', 'Var', (195, 199))	('G12D', 'Mutation', 'rs121913529', (189, 193))
66987	29748584	Thus, it appears that the high frequency of this KRAS mutation compared with others in lung adenocarcinoma is, potentially, owing to both smoking-associated mutational processes and the intrinsic selective advantage of the mutation.	('mutation', 'Var', (54, 62))	('KRAS', 'Gene', '3845', (49, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung adenocarcinoma', 'Disease', (87, 106))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (87, 106))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))	('KRAS', 'Gene', (49, 53))
66988	29748584	Interestingly, the relative selective advantages of particular pathogenic mutations in each gene were broadly consistent across cancer types.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (74, 83))	('cancer', 'Disease', (128, 134))
66989	29748584	Specifically, there were only 7/118 cases of differentially selected mutations where a mutation appeared selected more strongly than another in the same gene in one cancer type, but less strongly in another cancer type.	('mutations', 'Var', (69, 78))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))
66990	29748584	As our method controls for differences in mutational process activity between cancer types, these results provide evidence to support the hypothesis that the mechanisms that underpin the selective advantage caused by a specific driver mutation are broadly uniform across tissue types.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mutation', 'Var', (235, 243))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))
66994	29748584	22):there was significant heterogeneity across cancer types in terms of the number of mutations in each gene with evidence of preferential selection (selection above at least one other mutation in the set) (Fisher test, q = 2.2 x 10-3, 7.2 x 10-7, respectively), supporting a model where gene-specific effects on selection vary across cancer types.	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', (335, 341))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
66995	29748584	Among KRAS, BRAF and NRAS mutations, only particular KRAS mutations showed evidence of preferential selection over mutations in other genes in pancreatic cancer and uterine carcinoma (Fig.	('NRAS', 'Gene', '4893', (21, 25))	('mutations', 'Var', (58, 67))	('KRAS', 'Gene', '3845', (6, 10))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('carcinoma', 'Disease', 'MESH:D002277', (173, 182))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (165, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (143, 160))	('mutations', 'Var', (26, 35))	('NRAS', 'Gene', (21, 25))	('KRAS', 'Gene', '3845', (53, 57))	('KRAS', 'Gene', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('pancreatic cancer', 'Disease', (143, 160))	('carcinoma', 'Disease', (173, 182))	('KRAS', 'Gene', (6, 10))	('pancreatic cancer', 'Disease', 'MESH:D010190', (143, 160))
66996	29748584	4a, b), whereas preferential selection across genes was predominantly in favour of BRAF and NRAS mutations in melanoma and thyroid cancer (Fig.	('mutations', 'Var', (97, 106))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('NRAS', 'Gene', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('melanoma and thyroid cancer', 'Disease', 'MESH:D013964', (110, 137))	('NRAS', 'Gene', '4893', (92, 96))	('BRAF', 'Gene', '673', (83, 87))	('BRAF', 'Gene', (83, 87))	('thyroid cancer', 'Phenotype', 'HP:0002890', (123, 137))
66999	29748584	When APC and CTNNB1 mutations were compared, there was evidence for selection of CTNNB1 mutations over common APC mutations in each of liver cancer, uterine carcinoma, prostate cancer and colorectal cancer (Fig.	('CTNNB1', 'Gene', (13, 19))	('mutations', 'Var', (88, 97))	('APC', 'Disease', 'MESH:D011125', (110, 113))	('CTNNB1', 'Gene', '1499', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('APC', 'Disease', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('prostate cancer', 'Phenotype', 'HP:0012125', (168, 183))	('colorectal cancer', 'Disease', 'MESH:D015179', (188, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (149, 166))	('CTNNB1', 'Gene', (81, 87))	('colorectal cancer', 'Disease', (188, 205))	('APC', 'Disease', 'MESH:D011125', (5, 8))	('APC', 'Disease', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('liver cancer', 'Disease', 'MESH:D006528', (135, 147))	('CTNNB1', 'Gene', '1499', (13, 19))	('carcinoma, prostate cancer', 'Disease', 'MESH:D011471', (157, 183))	('liver cancer', 'Phenotype', 'HP:0002896', (135, 147))	('liver cancer', 'Disease', (135, 147))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))
67000	29748584	Interestingly however, evidence for selection of APC mutations above CTNNB1 mutations was found in colorectal cancer only (Fig.	('CTNNB1', 'Gene', '1499', (69, 75))	('colorectal cancer', 'Disease', (99, 116))	('APC', 'cellular_component', 'GO:0005680', ('49', '52'))	('APC', 'Disease', 'MESH:D011125', (49, 52))	('mutations', 'Var', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('CTNNB1', 'Gene', (69, 75))	('APC', 'Disease', (49, 52))	('colorectal cancer', 'Disease', 'MESH:D015179', (99, 116))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))
67002	29748584	Among IDH1 and IDH2 mutations, we found preferential selection for IDH1 R132H (glioma low grade, AML and glioblastoma), IDH1 R132C (glioma low grade, AML, liver cancer and melanoma), IDH1 R132G and IDH1 R132S (glioma low grade) above common IDH2 mutations, as well as preferential selection for IDH2 R172K above IDH1 R132C in glioma low grade (Supplementary Fig.	('IDH2', 'Gene', (15, 19))	('glioma', 'Disease', (132, 138))	('liver cancer', 'Phenotype', 'HP:0002896', (155, 167))	('glioma', 'Phenotype', 'HP:0009733', (326, 332))	('IDH2', 'Gene', '3418', (15, 19))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('R132C', 'Mutation', 'rs121913499', (317, 322))	('liver cancer', 'Disease', (155, 167))	('IDH1', 'Gene', (120, 124))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('IDH1', 'Gene', '3417', (67, 71))	('R172K', 'Mutation', 'rs121913503', (300, 305))	('AML', 'Disease', 'MESH:D015470', (97, 100))	('IDH1', 'Gene', '3417', (312, 316))	('glioma', 'Disease', (210, 216))	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('IDH1', 'Gene', '3417', (183, 187))	('glioblastoma', 'Disease', 'MESH:D005909', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('AML', 'Disease', 'MESH:D015470', (150, 153))	('AML', 'Disease', (97, 100))	('R132G', 'Mutation', 'rs121913499', (188, 193))	('IDH1', 'Gene', (198, 202))	('glioma', 'Disease', 'MESH:D005910', (210, 216))	('R132H', 'Mutation', 'rs121913500', (72, 77))	('AML', 'Disease', (150, 153))	('R132G', 'Var', (188, 193))	('R132C', 'Mutation', 'rs121913499', (125, 130))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('IDH1', 'Gene', (6, 10))	('glioblastoma', 'Disease', (105, 117))	('IDH1', 'Gene', '3417', (120, 124))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('glioma', 'Phenotype', 'HP:0009733', (210, 216))	('IDH1', 'Gene', '3417', (198, 202))	('glioma', 'Disease', (326, 332))	('IDH2', 'Gene', (241, 245))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanoma', 'Disease', (172, 180))	('IDH1', 'Gene', '3417', (6, 10))	('IDH2', 'Gene', '3418', (241, 245))	('glioma', 'Disease', (79, 85))	('glioma', 'Disease', 'MESH:D005910', (326, 332))	('R132H', 'Var', (72, 77))	('IDH1', 'Gene', (67, 71))	('IDH2', 'Gene', (295, 299))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('liver cancer', 'Disease', 'MESH:D006528', (155, 167))	('IDH1', 'Gene', (312, 316))	('R132S', 'Mutation', 'rs121913499', (203, 208))	('IDH2', 'Gene', '3418', (295, 299))	('IDH1', 'Gene', (183, 187))
67007	29748584	Here, we have demonstrated correlations between mutational processes and key driver mutations across cancer types, and highlighted the possibility that these correlations may actually be the result of the mutational process causing specific driver mutations.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('mutations', 'Var', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('correlations', 'Reg', (27, 39))	('mutational', 'Var', (48, 58))
67008	29748584	Moreover, by normalising for mutational likelihood we have quantified relative selective differences between related key driver mutations across cancer types, which sheds light on the selective landscape constraining cancer evolution.	('cancer', 'Disease', (145, 151))	('mutations', 'Var', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
67010	29748584	examined the relationship between APOBEC-associated mutational processes (signatures 2 and 13) and driver mutations and found that clonal non-synonymous mutations in driver genes occur in an APOBEC context in bladder cancer.	('occur', 'Reg', (179, 184))	('bladder cancer', 'Phenotype', 'HP:0009725', (209, 223))	('non-synonymous mutations', 'Var', (138, 162))	('bladder cancer', 'Disease', 'MESH:D001749', (209, 223))	('bladder cancer', 'Disease', (209, 223))	('APOBEC', 'cellular_component', 'GO:0030895', ('191', '197'))	('APOBEC', 'cellular_component', 'GO:0030895', ('34', '40'))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
67013	29748584	Notably, we report novel associations between APOBEC activity and ERBB2 S310F mutations in bladder cancer.	('associations', 'Interaction', (25, 37))	('S310F mutations', 'Var', (72, 87))	('APOBEC activity', 'Protein', (46, 61))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('bladder cancer', 'Disease', (91, 105))	('ERBB2', 'Gene', '2064', (66, 71))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('ERBB2', 'Gene', (66, 71))	('S310F', 'Mutation', 'rs1057519816', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
67015	29748584	Some associations we describe have been reported previously, notably the association between pack years of smoking and the KRAS G12C mutation in lung adenocarcinoma where the connection between the causal channel of this mutation (C > A in a CCA context) and the general tendency for tobacco carcinogens to cause transversions is well known.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('mutation', 'Var', (133, 141))	('lung adenocarcinoma', 'Disease', (145, 164))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (145, 164))	('G12C', 'Mutation', 'rs121913530', (128, 132))	('association', 'Interaction', (73, 84))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (145, 164))	('KRAS', 'Gene', (123, 127))	('KRAS', 'Gene', '3845', (123, 127))	('tobacco', 'Species', '4097', (284, 291))
67016	29748584	Remarkably, 14/43 associations between mutational signatures and driver mutations involved PIK3CA mutations, and most of these associations involved signatures linked to APOBEC, which tends to occur later in carcinogenesis.	('PIK3CA', 'Gene', (91, 97))	('mutations', 'Var', (72, 81))	('associations', 'Interaction', (18, 30))	('carcinogenesis', 'Disease', (208, 222))	('carcinogenesis', 'Disease', 'MESH:D063646', (208, 222))	('PIK3CA', 'Gene', '5290', (91, 97))	('mutations', 'Var', (98, 107))	('APOBEC', 'Gene', (170, 176))
67019	29748584	We found evidence for widespread differences in selective effects between mutations in the same gene and related genes, and moreover, that these differences appear to vary across cancer types.	('cancer', 'Disease', (179, 185))	('mutations', 'Var', (74, 83))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))
67020	29748584	Both mutational likelihood and selective difference strongly contribute to the occurrence of specific driver mutations in cancers.	('mutational', 'Var', (5, 15))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('mutations', 'Var', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))
67022	29748584	The differences we identified could reflect variation in the potential of the mutations in question to initiate disease, or alternately variation in the growth advantages conferred by these cells in established tumours.	('growth advantages', 'CPA', (153, 170))	('tumours', 'Disease', 'MESH:D009369', (211, 218))	('tumours', 'Disease', (211, 218))	('mutations', 'Var', (78, 87))	('tumours', 'Phenotype', 'HP:0002664', (211, 218))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))
67023	29748584	Interestingly, if there are differences in on-going growth advantages, then our data suggest that the forces of selection acting in tumours are often insufficient (or have insufficient temporal opportunity) to displace sub-optimal mutations, as less highly selected mutations remain detectable.	('insufficient temporal opportunity', 'Disease', (172, 205))	('sub-optimal mutations', 'Var', (219, 240))	('tumours', 'Disease', 'MESH:D009369', (132, 139))	('tumours', 'Disease', (132, 139))	('insufficient temporal opportunity', 'Disease', 'MESH:D000309', (172, 205))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))
67025	29748584	The same is also true for PIK3CA H1047R mutations in stomach cancer, wherein MMR-associated processes increase the likelihood of the driver mutation, which is then subsequently strongly selected.	('PIK3CA', 'Gene', '5290', (26, 32))	('stomach cancer', 'Disease', 'MESH:D013274', (53, 67))	('stomach cancer', 'Phenotype', 'HP:0012126', (53, 67))	('H1047R', 'Mutation', 'rs121913279', (33, 39))	('MMR', 'biological_process', 'GO:0006298', ('77', '80'))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('stomach cancer', 'Disease', (53, 67))	('H1047R mutations', 'Var', (33, 49))	('PIK3CA', 'Gene', (26, 32))
67031	29748584	In colon cancer, for example, BRAF mutations (that are relatively uncommon) are mutationally unlikely, but are strongly selected.	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('mutations', 'Var', (35, 44))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('colon cancer', 'Disease', (3, 15))
67033	29748584	Our data also offer an explanation for the high frequency of driver APC mutations and relative paucity of driver CTNNB1 mutations in the colon: APC mutations can be both more strongly selected and more mutationally likely than CTNNB1 mutations.	('mutations', 'Var', (148, 157))	('CTNNB1', 'Gene', (113, 119))	('APC', 'Disease', 'MESH:D011125', (68, 71))	('APC', 'Disease', (68, 71))	('APC', 'Disease', 'MESH:D011125', (144, 147))	('APC', 'Disease', (144, 147))	('CTNNB1', 'Gene', (227, 233))	('CTNNB1', 'Gene', '1499', (113, 119))	('CTNNB1', 'Gene', '1499', (227, 233))
67034	29748584	Overall, our results begin to quantitatively delineate the distinct contributions of mutation and selection in shaping the spectra of driver mutations in the cancer genome.	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('mutations', 'Var', (141, 150))
67042	29748584	We sought to test the power to detect an association between mutation M and the signature A in cancer type C, where M occurred m times in C. We considered a simple model of cancer initiation, where M is one of a set of mutations R of size  R  = n, one of which is required for cancer initiation.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer initiation', 'Disease', 'MESH:D009369', (173, 190))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('mutation', 'Var', (61, 69))	('cancer initiation', 'Disease', (173, 190))	('cancer', 'Disease', (95, 101))	('cancer initiation', 'Disease', 'MESH:D009369', (277, 294))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer initiation', 'Disease', (277, 294))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))
67043	29748584	Out of 1019 triplets tested where a signature represented a fold increase in the causal channel of a recurrent driver mutation in a cancer type, relatively few significant associations (43) were found.	('increase', 'PosReg', (65, 73))	('cancer', 'Disease', (132, 138))	('causal channel', 'MPA', (81, 95))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutation', 'Var', (118, 126))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
67045	29748584	Then by well-known results the probability of cancer incidence at time t is given by:Extending this framework to take into account cancer causation by multiple sequences of mutations Sj = < M1(j),...,Mn(j) > , with rate lambdaj.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('Sj = < M1(j', 'Var', (183, 194))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Mn(j) >', 'Var', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
67047	29748584	Definition:Mutations M1 and M2 are similar with relative risk r1,2 if they satisfy the following property: a mutation sequence Sj containing M2 causes cancer with rate lambdaj, just if the mutation sequence Sk, that results from substituting M1 for M2 in Sj, causes cancer with rate r1,2lambdaj.	('mutation sequence', 'Var', (109, 126))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('sequence', 'Var', (118, 126))	('substituting', 'Var', (229, 241))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (266, 272))	('causes', 'Reg', (144, 150))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))
67048	29748584	Then the probability that M1 occurs in a cancer sample, given that either M1 or M2 occurs is given by: Given two mutations M1 and M2 in a cancer type C, we identified the samples in which exactly one of the two mutations occurred, and no other mutation in the set of mutations under consideration for differential selection occurred.	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (113, 122))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
67051	29748584	Defining I1 and I2 as the sets of sample numbers where M1 and M2 occurred, respectively, then the likelihood of the data, L, is given by:We used numerical methods to find the maximum likelihood estimate of r1,2 for each pair of mutations in each tumour type, based on this formula.	('I1 and I2', 'Gene', '29965', (9, 18))	('tumour', 'Disease', (246, 252))	('mutations', 'Var', (228, 237))	('tumour', 'Phenotype', 'HP:0002664', (246, 252))	('tumour', 'Disease', 'MESH:D009369', (246, 252))
67053	29748584	In total, five associations between mutational signatures and driver mutations were identified across these eight cancer types.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutational', 'Var', (36, 46))	('cancer', 'Disease', (114, 120))
67055	29748584	For each mutation, the probability of the mutation in each sample of a cancer type was calculated based on sample-specific mutational signature exposures.	('mutation', 'Var', (9, 17))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
67057	29387480	Sequential HER2 blockade as effective therapy in chemorefractory, HER2 gene-amplified, RAS wild-type, metastatic colorectal cancer: learning from a clinical case Constitutive activation of HER2-dependent intracellular signalling by HER2 gene amplification or by HER2 mutations has been demonstrated as a mechanism of primary and secondary cancer resistance to cetuximab or panitumumab in preclinical and clinical models of metastatic colorectal cancer (mCRC).	('colorectal cancer', 'Disease', (113, 130))	('HER2', 'Gene', '2064', (66, 70))	('cancer', 'Disease', 'MESH:D009369', (339, 345))	('colorectal cancer', 'Phenotype', 'HP:0003003', (434, 451))	('HER2', 'Gene', '2064', (232, 236))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('HER2', 'Gene', '2064', (262, 266))	('cancer', 'Disease', (445, 451))	('activation', 'PosReg', (175, 185))	('cancer', 'Phenotype', 'HP:0002664', (445, 451))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('HER2', 'Gene', (11, 15))	('HER2', 'Gene', (66, 70))	('HER2', 'Gene', '2064', (189, 193))	('colorectal cancer', 'Disease', 'MESH:D015179', (434, 451))	('mutations', 'Var', (267, 276))	('panitumumab', 'Chemical', 'MESH:D000077544', (373, 384))	('HER2', 'Gene', (232, 236))	('cancer', 'Disease', (339, 345))	('signalling', 'biological_process', 'GO:0023052', ('218', '228'))	('HER2', 'Gene', (262, 266))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('colorectal cancer', 'Disease', (434, 451))	('cetuximab', 'Chemical', 'MESH:D000068818', (360, 369))	('cancer', 'Disease', (124, 130))	('intracellular', 'cellular_component', 'GO:0005622', ('204', '217'))	('cancer', 'Disease', 'MESH:D009369', (445, 451))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('HER2', 'Gene', (189, 193))	('HER2', 'Gene', '2064', (11, 15))
67058	29387480	Both HER2 Amplification for Colorectal Cancer Enhanced Stratification (HERACLES) cohort A and My Pathway clinical trials provided clinical evidence that anti-HER2 therapies could be active in these patients.	('Cancer', 'Phenotype', 'HP:0002664', (39, 45))	('patients', 'Species', '9606', (198, 206))	('Amplification', 'Var', (10, 23))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (28, 45))	('Colorectal Cancer', 'Disease', (28, 45))	('HER2', 'Protein', (5, 9))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (28, 45))	('Enhanced Stratification', 'PosReg', (46, 69))
67061	29387480	We report the clinical case of a patient with HER2 gene amplified and RAS/BRAF wild-type mCRC who experienced a long lasting and relevant clinical efficacy from sequential anti-HER2 therapies (trastuzumab plus lapatinib, pertuzumab plus trastuzumab, trastuzumab emtansine, trastuzumab plus capecitabine) achieving a cumulative clinical benefit of 29 months, after failure of the first three lines of standard treatments, which included all the potentially active drugs in mCRC, and which accounted for only 14 months of disease control.	('pertuzumab plus trastuzumab', 'Disease', (221, 248))	('patient', 'Species', '9606', (33, 40))	('trastuzumab emtansine', 'Chemical', 'MESH:C550911', (250, 271))	('trastuzumab', 'Chemical', 'MESH:D000068878', (237, 248))	('BRAF', 'Gene', (74, 78))	('lapatinib', 'Chemical', 'MESH:D000077341', (210, 219))	('BRAF', 'Gene', '673', (74, 78))	('trastuzumab', 'Var', (250, 261))	('pertuzumab plus trastuzumab', 'Disease', 'MESH:D007625', (221, 248))	('trastuzumab', 'Chemical', 'MESH:D000068878', (193, 204))	('capecitabine', 'Chemical', 'MESH:D000069287', (290, 302))	('trastuzumab', 'Chemical', 'MESH:D000068878', (250, 261))	('trastuzumab', 'Chemical', 'MESH:D000068878', (273, 284))
67062	29387480	The clinical case highlights the role of HER2 gene amplification as a key genetic driver of cancer development and progression in mCRC and suggests that sequential HER2 blockade could be a potential therapeutic strategy.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('gene amplification', 'Var', (46, 64))	('HER2', 'Protein', (41, 45))
67065	29387480	Here we report a clinical case of a patient with HER2-amplified mCRC tumour highlighting its role as a key genetic driver of cancer development and progression.	('tumour', 'Disease', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('HER2-amplified', 'Var', (49, 63))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('patient', 'Species', '9606', (36, 43))
67066	29387480	Our data, in agreement with large body of preclinical and clinical evidence, support the need to identify HER2 gene amplification in mCRC because it defines a relatively homogeneous subset of patients with mCRC with intrinsic resistance to EGFR-targeted therapy that could have a significant clinical benefit from anti-HER2 treatments.	('EGFR', 'Gene', (240, 244))	('patients', 'Species', '9606', (192, 200))	('amplification', 'Var', (116, 129))	('HER2', 'Gene', (106, 110))	('EGFR', 'Gene', '1956', (240, 244))
67069	29387480	However, the presence of gene alterations in the EGFR-activated downstream intracellular signalling pathways or in other tyrosine kinase receptors could impair the clinical efficacy of anti-EGFR moAbs, leading to primary or intrinsic cancer cell resistance.	('EGFR', 'Gene', '1956', (49, 53))	('intrinsic cancer', 'Disease', 'MESH:D009369', (224, 240))	('intrinsic cancer', 'Disease', (224, 240))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('EGFR', 'Gene', (49, 53))	('EGFR', 'Gene', '1956', (190, 194))	('clinical', 'MPA', (164, 172))	('gene alterations', 'Var', (25, 41))	('presence', 'Var', (13, 21))	('EGFR', 'Gene', (190, 194))	('downstream intracellular signalling pathways', 'Pathway', (64, 108))	('leading to', 'Reg', (202, 212))	('impair', 'NegReg', (153, 159))	('primary', 'CPA', (213, 220))
67073	29387480	In this respect, Bertotti and colleagues identified HER2 amplification as a potential mechanism of primary resistance to cetuximab, in KRAS, NRAS, BRAF and PIK3CA WT tumours.	('HER2', 'Protein', (52, 56))	('NRAS', 'Gene', '4893', (141, 145))	('PIK3CA', 'Gene', '5290', (156, 162))	('cetuximab', 'Chemical', 'MESH:D000068818', (121, 130))	('KRAS', 'Gene', (135, 139))	('WT tumours', 'Disease', (163, 173))	('amplification', 'Var', (57, 70))	('WT tumours', 'Disease', 'MESH:C536751', (163, 173))	('KRAS', 'Gene', '3845', (135, 139))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('tumours', 'Phenotype', 'HP:0002664', (166, 173))	('PIK3CA', 'Gene', (156, 162))	('NRAS', 'Gene', (141, 145))
67076	29387480	HER2 gene amplification was demonstrated as a relevant molecular driver for these tumours, suggesting that anti-HER2 therapy could be effective in a selected subset of patients with mCRC.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('mCRC', 'Disease', (182, 186))	('tumours', 'Disease', 'MESH:D009369', (82, 89))	('tumours', 'Disease', (82, 89))	('patients', 'Species', '9606', (168, 176))	('anti-HER2', 'Var', (107, 116))
67078	29387480	The role of HER2 in cancer resistance to anti-EGFR moAbs in mCRC has been also investigated by Yonesaka and colleagues, which reported increased HER2 signalling, either by HER2 gene amplification or through enhanced production of the HER3-activating ligand heregulin, as a mediator of colon cancer cell resistance to cetuximab.	('HER3', 'Gene', (234, 238))	('colon cancer', 'Disease', (285, 297))	('cetuximab', 'Chemical', 'MESH:D000068818', (317, 326))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('EGFR', 'Gene', '1956', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('production', 'MPA', (216, 226))	('enhanced', 'PosReg', (207, 215))	('HER2 signalling', 'MPA', (145, 160))	('colon cancer', 'Phenotype', 'HP:0003003', (285, 297))	('HER3', 'Gene', '2065', (234, 238))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', (20, 26))	('EGFR', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('colon cancer', 'Disease', 'MESH:D015179', (285, 297))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('HER2', 'Protein', (172, 176))	('increased', 'PosReg', (135, 144))	('gene amplification', 'Var', (177, 195))
67080	29387480	Inhibition of HER2 signalling or disruption of HER2/HER3 heterodimerisation restored cetuximab sensitivity both in vitro and in vivo in these colon cancer models.	('disruption', 'Var', (33, 43))	('HER3', 'Gene', (52, 56))	('colon cancer', 'Disease', (142, 154))	('cetuximab', 'Chemical', 'MESH:D000068818', (85, 94))	('HER3', 'Gene', '2065', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('heterodimerisation', 'Protein', (57, 75))	('restored', 'PosReg', (76, 84))	('Inhibition', 'Var', (0, 10))	('colon cancer', 'Phenotype', 'HP:0003003', (142, 154))	('colon cancer', 'Disease', 'MESH:D015179', (142, 154))	('cetuximab sensitivity', 'MPA', (85, 106))	('HER2', 'Protein', (14, 18))
67082	29387480	In fact, in these cases, HER2 gene amplification in tumour samples or high levels of circulating heregulin in patient plasma were found.	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('patient', 'Species', '9606', (110, 117))	('tumour', 'Disease', (52, 58))	('gene amplification', 'Var', (30, 48))	('HER2', 'Protein', (25, 29))
67083	29387480	The Cancer Genome Atlas project identified HER2 gene amplification as well as HER2 gene mutations in CRC.	('CRC', 'Disease', (101, 104))	('amplification', 'Var', (53, 66))	('mutations', 'Var', (88, 97))	('HER2', 'Gene', (78, 82))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('HER2', 'Protein', (43, 47))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
67084	29387480	Activating HER2 gene mutations could be equally important for determining resistance to anti-EGFR therapy in CRC.	('EGFR', 'Gene', '1956', (93, 97))	('CRC', 'Disease', (109, 112))	('EGFR', 'Gene', (93, 97))	('HER2', 'Gene', (11, 15))	('mutations', 'Var', (21, 30))
67085	29387480	In fact, Kavuri et al have demonstrated that the introduction of activating HER2 gene mutations (S310F, L755S, V777L, V841I and L866M) in colon cells increased HER2-activated signalling pathways, anchorage-independent cell growth, and determined cell resistance to cetuximab or to panitumumab treatment with sustained mitogen-activated protein kinase phosphorylation.	('S310F', 'Mutation', 'rs1057519816', (97, 102))	('V777L', 'Var', (111, 116))	('L755S', 'Var', (104, 109))	('HER2-activated signalling pathways', 'Pathway', (160, 194))	('colon', 'Disease', (138, 143))	('activating', 'PosReg', (65, 75))	('anchorage-independent cell growth', 'CPA', (196, 229))	('mitogen-activated protein kinase phosphorylation', 'MPA', (318, 366))	('HER2', 'Gene', (76, 80))	('L755S', 'Mutation', 'rs121913470', (104, 109))	('panitumumab', 'Chemical', 'MESH:D000077544', (281, 292))	('L866M', 'Var', (128, 133))	('S310F', 'Var', (97, 102))	('cell resistance', 'CPA', (246, 261))	('cetuximab', 'Chemical', 'MESH:D000068818', (265, 274))	('determined', 'Reg', (235, 245))	('L866M', 'Mutation', 'p.L866M', (128, 133))	('V841I', 'Var', (118, 123))	('V841I', 'Mutation', 'p.V841I', (118, 123))	('V777L', 'Mutation', 'rs121913471', (111, 116))	('increased', 'PosReg', (150, 159))	('colon', 'Disease', 'MESH:D015179', (138, 143))
67086	29387480	Treatments of mice-bearing HER2-mutated PDTX with trastuzumab, neratinib (a small molecule anti-HER2 tyrosine kinase inhibitor) or lapatinib, as single agents or in combination, determined tumour regression.	('HER2-mutated', 'Var', (27, 39))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('110', '126'))	('mice', 'Species', '10090', (14, 18))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('lapatinib', 'Chemical', 'MESH:D000077341', (131, 140))	('neratinib', 'Chemical', 'MESH:C487932', (63, 72))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('trastuzumab', 'Chemical', 'MESH:D000068878', (50, 61))	('PDTX', 'Gene', (40, 44))	('tumour', 'Disease', (189, 195))
67091	29387480	First, pathologists adapted fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) protocols, which are currently used for defining HER2 positivity in human breast and gastric cancer, to CRC.	('gastric cancer', 'Disease', (186, 200))	('gastric cancer', 'Disease', 'MESH:D013274', (186, 200))	('positivity', 'Var', (155, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('human', 'Species', '9606', (169, 174))	('breast', 'Disease', (175, 181))
67108	29387480	Here we report the clinical case of a patient with HER2 gene amplified and RAS and BRAF WT mCRC, who experienced a long lasting and relevant clinical efficacy from sequential anti-HER2 therapies.	('patient', 'Species', '9606', (38, 45))	('BRAF', 'Gene', '673', (83, 87))	('gene amplified', 'Var', (56, 70))	('BRAF', 'Gene', (83, 87))	('HER2', 'Protein', (51, 55))
67139	29387480	HER2 gene amplification (with 70% allele frequency) was confirmed, while a novel TP53p.R175H gene mutation (c.524G>A, 70.4% allele frequency) was found.	('p.R175H', 'Var', (85, 92))	('p.R175H', 'SUBSTITUTION', 'None', (85, 92))	('c.524G>A', 'Mutation', 'rs531563820', (108, 116))	('c.524G>A', 'Var', (108, 116))
67148	29387480	Constitutive activation of HER2-dependent intracellular signalling by HER2 gene amplification or by HER2 mutations has been demonstrated as a mechanism of cancer resistance to cetuximab or panitumumab in PDTX models of mCRC.	('amplification', 'Var', (80, 93))	('HER2-dependent', 'Protein', (27, 41))	('cetuximab', 'Chemical', 'MESH:D000068818', (176, 185))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('HER2', 'Protein', (70, 74))	('activation', 'PosReg', (13, 23))	('mutations', 'Var', (105, 114))	('signalling', 'biological_process', 'GO:0023052', ('56', '66'))	('intracellular', 'cellular_component', 'GO:0005622', ('42', '55'))	('HER2', 'Gene', (100, 104))	('panitumumab', 'Chemical', 'MESH:D000077544', (189, 200))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
67160	24196786	KRAS, V600E BRAF mutations and microsatellite instability were investigated.	('V600E', 'Var', (6, 11))	('BRAF', 'Gene', '673', (12, 16))	('BRAF', 'Gene', (12, 16))	('V600E', 'Mutation', 'rs113488022', (6, 11))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
67164	24196786	For all patients, in univariate analysis, stages I-II (P<0.001), WHO PS 0-1 (P=0.01) and dMMR phenotype (P=0.02) were significantly associated with longer OS.	('dMMR', 'Var', (89, 93))	('PS 0-1', 'Gene', (69, 75))	('dMMR', 'Chemical', '-', (89, 93))	('PS 0-1', 'Gene', '5663', (69, 75))	('associated with', 'Reg', (132, 147))	('longer OS', 'Disease', (148, 157))	('patients', 'Species', '9606', (8, 16))
67167	24196786	In multivariate analysis, WHO PS 0-1 (P=0.0001) and mutated KRAS status (P=0.02) independently predicted longer OS.	('mutated', 'Var', (52, 59))	('PS 0-1', 'Gene', '5663', (30, 36))	('longer OS', 'Disease', (105, 114))	('KRAS', 'Gene', (60, 64))	('KRAS', 'Gene', '3845', (60, 64))	('PS 0-1', 'Gene', (30, 36))
67185	24196786	The inactivation of APC protein leads to an accumulation of beta-catenin in the nuclei.	('inactivation', 'Var', (4, 16))	('APC', 'Disease', 'MESH:D011125', (20, 23))	('beta-catenin', 'Gene', (60, 72))	('APC', 'Disease', (20, 23))	('protein', 'cellular_component', 'GO:0003675', ('24', '31'))	('beta-catenin', 'Gene', '1499', (60, 72))	('APC', 'cellular_component', 'GO:0005680', ('20', '23'))	('accumulation', 'PosReg', (44, 56))
67189	24196786	Mutations in the p53 gene occur commonly in a wide range of cancers and result in overexpression of inactive p53 protein in the nuclei.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('overexpression', 'PosReg', (82, 96))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (109, 112))	('p53', 'Gene', '7157', (109, 112))	('protein', 'Protein', (113, 120))	('p53', 'Gene', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('p53', 'Gene', '7157', (17, 20))
67190	24196786	P53 mutations are a late event in colorectal carcinogenesis.	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (34, 59))	('P53', 'Gene', (0, 3))	('colorectal carcinogenesis', 'Disease', (34, 59))	('P53', 'Gene', '7157', (0, 3))	('mutations', 'Var', (4, 13))
67192	24196786	A KRAS mutation has been described in around 40% of CRCs, mainly in codons 12 or 13.	('CRCs', 'Disease', (52, 56))	('CRC', 'Phenotype', 'HP:0003003', (52, 55))	('KRAS', 'Gene', (2, 6))	('mutation', 'Var', (7, 15))	('KRAS', 'Gene', '3845', (2, 6))
67193	24196786	Moreover, KRAS mutations are predictive of the lack of efficacy of anti-EGFR antibody in treatment of metastatic CRC.	('KRAS', 'Gene', '3845', (10, 14))	('antibody', 'cellular_component', 'GO:0019814', ('77', '85'))	('EGFR', 'molecular_function', 'GO:0005006', ('72', '76'))	('EGFR', 'Gene', '1956', (72, 76))	('antibody', 'cellular_component', 'GO:0042571', ('77', '85'))	('mutations', 'Var', (15, 24))	('EGFR', 'Gene', (72, 76))	('metastatic CRC', 'Disease', (102, 116))	('antibody', 'cellular_component', 'GO:0019815', ('77', '85'))	('CRC', 'Phenotype', 'HP:0003003', (113, 116))	('antibody', 'molecular_function', 'GO:0003823', ('77', '85'))	('KRAS', 'Gene', (10, 14))
67195	24196786	Gene amplification and overexpression of HER-2/neu have been reported in around 15% of gastric cancers.	('overexpression', 'PosReg', (23, 37))	('gastric cancers', 'Phenotype', 'HP:0012126', (87, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('HER-2/neu', 'Gene', (41, 50))	('Gene amplification', 'Var', (0, 18))	('gastric cancers', 'Disease', 'MESH:D013274', (87, 102))	('HER-2/neu', 'Gene', '2064', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('gastric cancers', 'Disease', (87, 102))	('reported', 'Reg', (61, 69))
67196	24196786	Treatment with trastuzumab, an anti-HER-2 antibody, results in prolonged survival in gastric cancer if HER-2 is overexpressed or amplified in tumour cells.	('tumour', 'Disease', (142, 148))	('prolonged', 'PosReg', (63, 72))	('amplified', 'Var', (129, 138))	('trastuzumab', 'Chemical', 'MESH:D000068878', (15, 26))	('antibody', 'cellular_component', 'GO:0019814', ('42', '50'))	('gastric cancer', 'Disease', (85, 99))	('overexpressed', 'PosReg', (112, 125))	('antibody', 'molecular_function', 'GO:0003823', ('42', '50'))	('HER-2', 'Gene', '2064', (36, 41))	('antibody', 'cellular_component', 'GO:0042571', ('42', '50'))	('gastric cancer', 'Disease', 'MESH:D013274', (85, 99))	('HER-2', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('survival', 'CPA', (73, 81))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('HER-2', 'Gene', '2064', (103, 108))	('gastric cancer', 'Phenotype', 'HP:0012126', (85, 99))	('antibody', 'cellular_component', 'GO:0019815', ('42', '50'))	('HER-2', 'Gene', (103, 108))
67197	24196786	Inactivation of the DNA mismatch repair (MMR) gene is characterised by tumour microsatellite instability.	('DNA', 'Gene', (20, 23))	('tumour microsatellite instability', 'Disease', 'MESH:D053842', (71, 104))	('tumour microsatellite instability', 'Disease', (71, 104))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('MMR', 'Gene', (41, 44))	('Inactivation', 'Var', (0, 12))
67198	24196786	The germline mutation of one of the MMR genes is responsible for Lynch syndrome and predisposes to SBA.	('Lynch syndrome', 'Disease', (65, 79))	('SBA', 'Disease', (99, 102))	('Lynch syndrome', 'Disease', 'MESH:D003123', (65, 79))	('MMR', 'Gene', (36, 39))	('predisposes', 'Reg', (84, 95))	('germline mutation', 'Var', (4, 21))	('responsible', 'Reg', (49, 60))	('SBA', 'Chemical', '-', (99, 102))
67200	24196786	A BRAF V600 E mutation is frequently associated with MLH1 promoter methylation in sporadic colorectal carcinomas.	('promoter methylation', 'MPA', (58, 78))	('MLH1', 'Gene', (53, 57))	('BRAF', 'Gene', '673', (2, 6))	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('colorectal carcinomas', 'Disease', (91, 112))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (91, 112))	('BRAF', 'Gene', (2, 6))	('V600 E', 'Var', (7, 13))	('associated', 'Reg', (37, 47))	('V600 E', 'Mutation', 'rs113488022', (7, 13))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))
67222	24196786	The seven most frequent mutations on codons 12 and 13 of KRAS were assessed as previously described.	('KRAS', 'Gene', (57, 61))	('mutations', 'Var', (24, 33))	('KRAS', 'Gene', '3845', (57, 61))
67224	24196786	MSI status was assessed using five microsatellites (BAT25, BAT26, NR21, NR24, NR27), and the deficient MMR phenotype was assigned if >=2 microsatellites were unstable.	('BAT25', 'Var', (52, 57))	('BAT26', 'Var', (59, 64))	('NR24', 'Var', (72, 76))	('NR27', 'Var', (78, 82))	('MSI', 'Gene', (0, 3))	('MSI', 'Gene', '5928', (0, 3))
67267	24196786	A BRAF V600E mutation was assessed in 40 patients.	('V600E', 'Var', (7, 12))	('BRAF', 'Gene', '673', (2, 6))	('BRAF', 'Gene', (2, 6))	('patients', 'Species', '9606', (41, 49))	('V600E', 'Mutation', 'rs113488022', (7, 12))
67279	24196786	In univariate analysis, poor WHO PS, poor differentiation grade, synchronous metastasis and wild-type KRAS were associated with poor prognosis (Table 6).	('poor', 'Var', (37, 41))	('synchronous metastasis', 'Disease', 'MESH:D009362', (65, 87))	('synchronous metastasis', 'Disease', (65, 87))	('poor', 'Var', (24, 28))	('KRAS', 'Gene', (102, 106))	('KRAS', 'Gene', '3845', (102, 106))
67287	24196786	Our results support a role of p53 mutation in 40-50% of SBA cases, as in colorectal or gastric carcinogenesis.	('colorectal or gastric carcinogenesis', 'Disease', (73, 109))	('mutation', 'Var', (34, 42))	('SBA', 'Chemical', '-', (56, 59))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('colorectal or gastric carcinogenesis', 'Disease', 'MESH:D013274', (73, 109))
67294	24196786	One study reported a shorter survival in the case of combined loss of E-cadherin and aberrant beta-catenin expression.	('loss', 'NegReg', (62, 66))	('aberrant', 'Var', (85, 93))	('shorter', 'NegReg', (21, 28))	('survival', 'MPA', (29, 37))	('beta-catenin', 'Gene', (94, 106))	('beta-catenin', 'Gene', '1499', (94, 106))	('E-cadherin', 'Gene', (70, 80))	('E-cadherin', 'Gene', '999', (70, 80))
67295	24196786	The accumulation of beta-catenin could occur either in the case of APC gene mutation preventing beta-catenin degradation or by gain-of-function mutations.	('APC', 'Disease', (67, 70))	('beta-catenin', 'Gene', '1499', (96, 108))	('accumulation', 'PosReg', (4, 16))	('beta-catenin', 'Gene', '1499', (20, 32))	('mutation', 'Var', (76, 84))	('gain-of-function', 'PosReg', (127, 143))	('degradation', 'biological_process', 'GO:0009056', ('109', '120'))	('APC', 'cellular_component', 'GO:0005680', ('67', '70'))	('preventing', 'NegReg', (85, 95))	('APC', 'Disease', 'MESH:D011125', (67, 70))	('mutations', 'Var', (144, 153))	('beta-catenin', 'Gene', (20, 32))	('beta-catenin', 'Gene', (96, 108))
67298	24196786	We found a KRAS mutation in 21 out of 49 (43%) tumours, compared with 8 out of 15 (53.3%) and 12 out of 21 (57%) in literature reports, range of mutation rates similar to that in CRC and higher than in gastric cancer.	('KRAS', 'Gene', (11, 15))	('mutation', 'Var', (16, 24))	('CRC', 'Phenotype', 'HP:0003003', (179, 182))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('gastric cancer', 'Phenotype', 'HP:0012126', (202, 216))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('KRAS', 'Gene', '3845', (11, 15))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('tumours', 'Disease', (47, 54))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('gastric cancer', 'Disease', (202, 216))	('CRC', 'Disease', (179, 182))	('found', 'Reg', (3, 8))	('gastric cancer', 'Disease', 'MESH:D013274', (202, 216))
67300	24196786	The latter study found KRAS mutations only in duodenal tumours, in contrast to our results showing no difference in KRAS mutation rate according to the small intestine segment.	('duodenal tumours', 'Disease', (46, 62))	('duodenal tumours', 'Disease', 'MESH:D004379', (46, 62))	('KRAS', 'Gene', (23, 27))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('KRAS', 'Gene', (116, 120))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('found', 'Reg', (17, 22))	('KRAS', 'Gene', '3845', (23, 27))	('mutations', 'Var', (28, 37))	('KRAS', 'Gene', '3845', (116, 120))
67301	24196786	A recent large study on resected stages I-III duodenal adenocarcinomas revealed a KRAS mutation rate of 34.6% and KRAS G>A mutation carriers were at increased risk of distant relapse and had a significantly shorter OS.	('KRAS', 'Gene', (114, 118))	('adenocarcinomas', 'Disease', 'MESH:D000230', (55, 70))	('adenocarcinomas', 'Disease', (55, 70))	('KRAS', 'Gene', '3845', (114, 118))	('duodenal adenocarcinomas', 'Phenotype', 'HP:0006771', (46, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('distant relapse', 'CPA', (167, 182))	('KRAS', 'Gene', (82, 86))	('mutation', 'Var', (87, 95))	('KRAS', 'Gene', '3845', (82, 86))
67308	24196786	In the study of, ERBB2 amplification is a rare event observed in only 1 out of 27 SBA that cluster with colorectal cancer and not gastric cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (104, 121))	('amplification', 'Var', (23, 36))	('gastric cancer', 'Disease', (130, 144))	('ERBB2', 'Gene', '2064', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gastric cancer', 'Disease', 'MESH:D013274', (130, 144))	('ERBB2', 'Gene', (17, 22))	('colorectal cancer', 'Phenotype', 'HP:0003003', (104, 121))	('colorectal cancer', 'Disease', (104, 121))	('gastric cancer', 'Phenotype', 'HP:0012126', (130, 144))	('SBA', 'Chemical', '-', (82, 85))
67314	24196786	In CRC, the relation between dMMR status and age is complex as young age is associated with Lynch syndrome, but on the other hand advanced age is associated with a high frequency of dMMR tumours due to hypermethylation of the MLH1 promoter.	('hypermethylation', 'Var', (202, 218))	('tumours', 'Disease', 'MESH:D009369', (187, 194))	('CRC', 'Phenotype', 'HP:0003003', (3, 6))	('tumours', 'Disease', (187, 194))	('MLH1', 'Gene', (226, 230))	('Lynch syndrome', 'Disease', (92, 106))	('associated', 'Reg', (76, 86))	('dMMR', 'Chemical', '-', (182, 186))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('Lynch syndrome', 'Disease', 'MESH:D003123', (92, 106))	('associated', 'Reg', (146, 156))	('tumours', 'Phenotype', 'HP:0002664', (187, 194))	('dMMR', 'Disease', (182, 186))	('dMMR', 'Chemical', '-', (29, 33))
67316	24196786	So, our results suggest that the majority of SBA dMMR tumours are not related to a methylation mechanism but to a germline mutation.	('germline mutation', 'Var', (114, 131))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('SBA', 'Chemical', '-', (45, 48))	('tumours', 'Disease', (54, 61))	('methylation', 'biological_process', 'GO:0032259', ('83', '94'))	('dMMR', 'Chemical', '-', (49, 53))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))
67317	24196786	In accordance with the result in CRC, dMMR status was associated with an early stage in the present study.	('early stage', 'Disease', (73, 84))	('dMMR', 'Chemical', '-', (38, 42))	('dMMR status', 'Var', (38, 49))	('CRC', 'Phenotype', 'HP:0003003', (33, 36))	('associated', 'Reg', (54, 64))
67325	24196786	Prognostic factors associated with a better overall survival were early tumour stage, R0 resection, WHO PS 0-1 and dMMR tumour in univariate analysis and tumour stage and WHO PS in multivariate analysis.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('PS 0-1', 'Gene', '5663', (104, 110))	('PS 0-1', 'Gene', (104, 110))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumour', 'Disease', (120, 126))	('tumour', 'Disease', (154, 160))	('overall', 'MPA', (44, 51))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('better', 'PosReg', (37, 43))	('tumour', 'Disease', (72, 78))	('R0 resection', 'Var', (86, 98))	('dMMR', 'Chemical', '-', (115, 119))
67329	24196786	Nevertheless, a trend for a protective effect of dMMR and well or moderately differentiated tumours was observed.	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('dMMR', 'Var', (49, 53))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('tumours', 'Disease', (92, 99))	('dMMR', 'Chemical', '-', (49, 53))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))
67335	24196786	P53 alteration and KRAS mutation are in the same range as in CRC.	('KRAS', 'Gene', (19, 23))	('alteration', 'Var', (4, 14))	('KRAS', 'Gene', '3845', (19, 23))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))	('CRC', 'Phenotype', 'HP:0003003', (61, 64))
67340	24196786	Surprisingly, KRAS mutation is associated with a good prognosis in a metastatic setting.	('KRAS', 'Gene', (14, 18))	('mutation', 'Var', (19, 27))	('KRAS', 'Gene', '3845', (14, 18))
67403	33042104	One of the good examples of a TSA is the mutated p53 protein that is present in many cancer cells including colorectal cancer.	('mutated', 'Var', (41, 48))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('TSA', 'molecular_function', 'GO:0033984', ('30', '33'))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (119, 125))	('protein', 'Protein', (53, 60))	('colorectal cancer', 'Disease', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
67411	33042104	A widely studied CTA in CRC is the melanoma-associated antigen (MAGE) group, particularly MAGE-A, MAGE-A-12, and MAGE-A3 variants.	('MAGE', 'Gene', '57730', (64, 68))	('MAGE', 'Gene', '57730', (98, 102))	('MAGE', 'Gene', (98, 102))	('MAGE-A3', 'Gene', '4102', (113, 120))	('CRC', 'Phenotype', 'HP:0003003', (24, 27))	('melanoma-associated antigen', 'Gene', '57730', (35, 62))	('variants', 'Var', (121, 129))	('melanoma-associated antigen', 'Gene', (35, 62))	('MAGE', 'Gene', (90, 94))	('MAGE-A3', 'Gene', (113, 120))	('MAGE', 'Gene', '57730', (90, 94))	('MAGE', 'Gene', (113, 117))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('MAGE', 'Gene', (64, 68))	('MAGE', 'Gene', '57730', (113, 117))
67457	33042104	There was a significantly longer survival rate with minimum side effects among advanced non-small cell lung cancer (NSCLC) with high PDL1 expression compared to patients treated with platinum-based chemotherapy.	('longer', 'PosReg', (26, 32))	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('survival', 'CPA', (33, 41))	('platinum', 'Chemical', 'MESH:D010984', (183, 191))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('PDL1', 'Gene', (133, 137))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('expression', 'Species', '29278', (138, 148))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (92, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('patients', 'Species', '9606', (161, 169))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (88, 114))	('high', 'Var', (128, 132))	('NSCLC', 'Disease', (116, 121))	('expression', 'Var', (138, 148))
67458	33042104	In CRC patients, Pembrolizumab shows significant benefit to the mismatch-repair deficient or microsatellite instability-high CRC patients (dMMR/MSI-H).	('CRC', 'Disease', (125, 128))	('benefit', 'PosReg', (49, 56))	('CRC', 'Phenotype', 'HP:0003003', (3, 6))	('patients', 'Species', '9606', (129, 137))	('CRC', 'Phenotype', 'HP:0003003', (125, 128))	('microsatellite instability-high', 'Var', (93, 124))	('deficient', 'NegReg', (80, 89))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (17, 30))	('mismatch-repair', 'biological_process', 'GO:0006298', ('64', '79'))	('CRC', 'Disease', (3, 6))	('mismatch-repair', 'Protein', (64, 79))	('patients', 'Species', '9606', (7, 15))
67465	33042104	There are 3 methods for the ACT; use of tumor-infiltrating lymphocytes (TILs), insertion of chimeric antigen receptor (CAR), and modification of T cell receptors (TCR).	('modification', 'Var', (129, 141))	('TCR', 'cellular_component', 'GO:0042101', ('163', '166'))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('CAR', 'cellular_component', 'GO:0005826', ('119', '122'))	('chimeric antigen receptor', 'Gene', (92, 117))	('TCR', 'biological_process', 'GO:0006283', ('163', '166'))	('T cell receptors', 'Gene', '6962', (145, 161))	('TIL', 'Gene', '7096', (72, 75))	('insertion', 'Var', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('chimeric antigen receptor', 'Gene', '9970', (92, 117))	('T cell receptors', 'Gene', (145, 161))	('TIL', 'Gene', (72, 75))
67472	33042104	In the CAR approach, T cells are isolated from a patient (autologous) or HLA-matched donor (allogeneic), cultured through ex vivo and genetically modified through the insertion of the chimeric antigen receptor (CAR) onto the T cells as CAR-T cells.	('insertion', 'Var', (167, 176))	('chimeric antigen receptor', 'Gene', (184, 209))	('patient', 'Species', '9606', (49, 56))	('chimeric antigen receptor', 'Gene', '9970', (184, 209))	('CAR', 'Gene', (211, 214))
67477	33042104	In addition, co-stimulatory domains such as CD28 or 4-1BB (CD137) can be added to improve CAR-T cells' proliferation and survival rate in vivo, thus enhancing the anti-tumor activity of CAR-T cells.	('CD137', 'Gene', '3604', (59, 64))	('4-1BB', 'Gene', '3604', (52, 57))	('improve', 'PosReg', (82, 89))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('CAR-T cells', 'CPA', (90, 101))	('CAR', 'cellular_component', 'GO:0005826', ('90', '93'))	('survival rate', 'CPA', (121, 134))	('4-1BB', 'Gene', (52, 57))	('enhancing', 'PosReg', (149, 158))	('CD28', 'Var', (44, 48))	('CAR', 'cellular_component', 'GO:0005826', ('186', '189'))	('CD137', 'Gene', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
67513	33042104	Modification of T cell receptors (TCR) is another approach for ACT and it is known as TCR transduced therapy.	('T cell receptors', 'Gene', (16, 32))	('TCR', 'cellular_component', 'GO:0042101', ('86', '89'))	('TCR', 'biological_process', 'GO:0006283', ('34', '37'))	('Modification', 'Var', (0, 12))	('TCR', 'biological_process', 'GO:0006283', ('86', '89'))	('T cell receptors', 'Gene', '6962', (16, 32))	('TCR', 'Gene', (34, 37))	('TCR', 'cellular_component', 'GO:0042101', ('34', '37'))
67515	33042104	This allows recognition of an intracellular, cell surface antigen or a neo-antigen produced by tumor cells after mutation.	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('mutation', 'Var', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
67523	33042104	For example in the multiple myeloma patients, TCR was engineered through modifications of several key amino acids in order to have a higher affinity for cancer antigens, NY-ESO-1.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('patients', 'Species', '9606', (36, 44))	('modifications', 'Var', (73, 86))	('TCR', 'Gene', (46, 49))	('myeloma', 'Disease', 'MESH:D009101', (28, 35))	('NY-ESO-1', 'Gene', '246100', (170, 178))	('higher', 'PosReg', (133, 139))	('NY-ESO-1', 'Gene', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('multiple myeloma', 'Phenotype', 'HP:0006775', (19, 35))	('affinity', 'Interaction', (140, 148))	('myeloma', 'Disease', (28, 35))
67533	33042104	This was using mRNA-engineered T Cells targeting transforming growth factor beta- receptor type II (TGFbetaII) frameshift antigen which is expressed in microsatellite instability positive (MSI+) colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (195, 207))	('TGFbetaII', 'Gene', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('colon cancer', 'Disease', 'MESH:D015179', (195, 207))	('colon cancer', 'Disease', (195, 207))	('frameshift antigen', 'Var', (111, 129))
67534	33042104	Other ongoing TCR therapies are against KRAS G12V + tumor (NCT03190941) and KRAS G12D + tumor (NCT03745326), both are at clinical trials phase I/II.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('NCT03745326', 'Var', (95, 106))	('NCT03190941', 'Var', (59, 70))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (52, 57))	('KRAS', 'Gene', (76, 80))	('KRAS', 'Gene', (40, 44))	('KRAS', 'Gene', '3845', (76, 80))	('G12D', 'Mutation', 'rs121913529', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('KRAS', 'Gene', '3845', (40, 44))	('G12V', 'Mutation', 'rs121913529', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (88, 93))
67536	33042104	In addition, since TCR therapy is highly dependent on MHC for peptide presentation, it may escape immune surveillance due to the downregulation or mutation of MHC molecules in the tumor environment, resulting in clinical limitations.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('MHC molecules', 'Gene', (159, 172))	('downregulation', 'NegReg', (129, 143))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('mutation', 'Var', (147, 155))	('tumor', 'Disease', (180, 185))	('immune surveillance', 'MPA', (98, 117))	('escape', 'NegReg', (91, 97))
67554	33042104	The immune cells were cultured and incubated with PA2024, a fusion protein made up of prostatic acid phosphatase (PAP) which is linked to granulocyte-macrophage colony-stimulating factor (GM-CSF) as the adjuvant.	('prostatic acid phosphatase', 'Gene', '55', (86, 112))	('prostatic acid phosphatase', 'Gene', (86, 112))	('granulocyte-macrophage colony-stimulating factor', 'Gene', (138, 186))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('GM-CSF', 'Gene', (188, 194))	('PA2024', 'Var', (50, 56))	('PAP', 'Gene', (114, 117))	('GM-CSF', 'Gene', '1437', (188, 194))	('granulocyte-macrophage colony-stimulating factor', 'molecular_function', 'GO:0005129', ('138', '186'))	('phosphatase', 'molecular_function', 'GO:0016791', ('101', '112'))	('granulocyte-macrophage colony-stimulating factor', 'Gene', '1437', (138, 186))	('PAP', 'molecular_function', 'GO:0043751', ('114', '117'))
67684	30795767	The AUCs for 2D LAD and the scoring system were 0.691 (cut-off value, 7.15 mm) and 0.842, respectively, for right-sided primary tumors, while the AUCs were 0.805 (cut-off value, 7.05 mm) and 0.844, respectively, for left-sided primary tumors.	('primary tumors', 'Disease', 'MESH:D009369', (120, 134))	('0.842', 'Var', (83, 88))	('primary tumors', 'Disease', (227, 241))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('primary tumors', 'Disease', 'MESH:D009369', (227, 241))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('primary tumors', 'Disease', (120, 134))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))
67686	30795767	Among the various measures available on MDCT, 2D LAD was the most sensitive measure; moreover, the presence of ENS was associated with LN metastases.	('ENS', 'Gene', (111, 114))	('metastases', 'Disease', (138, 148))	('associated with', 'Reg', (119, 134))	('metastases', 'Disease', 'MESH:D009362', (138, 148))	('presence', 'Var', (99, 107))
67693	30795767	A previous study reported that the cut-off value of 0.8 in size ratio was associated with an increased incidence of LN metastases, while another study reported that a measurement of >= 100 Hounsfield units was correlated with LN metastases.	('metastases', 'Disease', (229, 239))	('metastases', 'Disease', (119, 129))	('size', 'MPA', (59, 63))	('cut-off value', 'Var', (35, 48))	('metastases', 'Disease', 'MESH:D009362', (229, 239))	('metastases', 'Disease', 'MESH:D009362', (119, 129))
67706	30089773	We find that knock down of LGR5 or suppression of Wnt signaling pathway by inhibitor C59 arrests gastric adenocarcinoma cell proliferation and invasion.	('suppression', 'NegReg', (35, 46))	('cell proliferation', 'biological_process', 'GO:0008283', ('120', '138'))	('LGR5', 'Gene', '8549', (27, 31))	('invasion', 'CPA', (143, 151))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('50', '71'))	('LGR5', 'Gene', (27, 31))	('knock down', 'Var', (13, 23))	('Wnt signaling pathway', 'Pathway', (50, 71))	('C59 arrests gastric adenocarcinoma', 'Disease', 'MESH:D013274', (85, 119))	('C59 arrests gastric adenocarcinoma', 'Disease', (85, 119))
67707	30089773	Moreover, treatment of Wnt3a, the activator of Wnt signaling pathway, partially recovers the proliferation defect observed in LGR5 knockdown gastric adenocarcinoma cells.	('Wnt3a', 'Gene', (23, 28))	('knockdown', 'Var', (131, 140))	('LGR5', 'Gene', (126, 130))	('LGR5', 'Gene', '8549', (126, 130))	('proliferation defect', 'CPA', (93, 113))	('Wnt3a', 'Gene', '89780', (23, 28))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (141, 163))	('gastric adenocarcinoma', 'Disease', (141, 163))
67725	30089773	This LGR5-dependent negative regulation specifically restricts colon stem cells to their niche, and loss of LGR5 concomitant with activated Wnt signaling may contribute to the invasive phenotype of colorectal carcinomas.	('regulation', 'biological_process', 'GO:0065007', ('29', '39'))	('loss', 'Var', (100, 104))	('LGR5', 'Gene', '8549', (5, 9))	('colorectal carcinomas', 'Disease', (198, 219))	('negative', 'NegReg', (20, 28))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (198, 219))	('signaling', 'biological_process', 'GO:0023052', ('144', '153'))	('contribute', 'Reg', (158, 168))	('LGR5', 'Gene', (108, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (209, 219))	('LGR5', 'Gene', '8549', (108, 112))	('restricts', 'NegReg', (53, 62))	('LGR5', 'Gene', (5, 9))
67737	30089773	We performed colony formation assays and MTT assays with LGR5-overexpressed and knockdown in gastric adenocarcinoma cells.	('LGR5', 'Gene', (57, 61))	('knockdown', 'Var', (80, 89))	('LGR5', 'Gene', '8549', (57, 61))	('MTT', 'Chemical', 'MESH:C070243', (41, 44))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (93, 115))	('gastric adenocarcinoma', 'Disease', (93, 115))
67746	30089773	Moreover, we also stably overexpressed or knockdown LGR5 in SGC7901 and BGC823 (Supplemental Fig.	('LGR5', 'Gene', '8549', (52, 56))	('knockdown', 'Var', (42, 51))	('LGR5', 'Gene', (52, 56))
67750	30089773	Wound healing assay showed that LGR5 overexpression promoted mobility of gastric adenocarcinoma cells; whereas knockdown of LGR5 resulted in a significant decrease in cellular migration (Fig.	('knockdown', 'Var', (111, 120))	('promoted', 'PosReg', (52, 60))	('LGR5', 'Gene', '8549', (32, 36))	('decrease', 'NegReg', (155, 163))	('LGR5', 'Gene', (124, 128))	('LGR5', 'Gene', '8549', (124, 128))	('cellular migration', 'CPA', (167, 185))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (73, 95))	('LGR5', 'Gene', (32, 36))	('gastric adenocarcinoma', 'Disease', (73, 95))	('mobility', 'CPA', (61, 69))
67756	30089773	In contrast, activation of the Wnt pathway by Wnt3a partially rescued the proliferation defect observed in LGR5 knockdown cells.	('Wnt3a', 'Gene', '89780', (46, 51))	('Wnt pathway', 'Pathway', (31, 42))	('knockdown', 'Var', (112, 121))	('LGR5', 'Gene', '8549', (107, 111))	('Wnt3a', 'Gene', (46, 51))	('LGR5', 'Gene', (107, 111))	('proliferation defect', 'CPA', (74, 94))
67759	30089773	In contrast, Wnt3a treatment partially rescued the migration defect observed in LGR5 knockdown cells (Fig.	('migration defect', 'CPA', (51, 67))	('Wnt3a', 'Gene', (13, 18))	('knockdown', 'Var', (85, 94))	('LGR5', 'Gene', '8549', (80, 84))	('Wnt3a', 'Gene', '89780', (13, 18))	('LGR5', 'Gene', (80, 84))
67772	30089773	Moreover, when these cells were treated with 10 muM C59 for 4 h, C59 significantly inhibited mRNA expression level of Axin2 and TCF1 in LGR5-overexpressing cells compared to control groups (Fig.	('C59', 'Var', (65, 68))	('mRNA expression level', 'MPA', (93, 114))	('LGR5', 'Gene', (136, 140))	('LGR5', 'Gene', '8549', (136, 140))	('Axin2', 'Gene', (118, 123))	('Axin2', 'Gene', '8313', (118, 123))	('inhibited', 'NegReg', (83, 92))	('TCF1', 'Gene', (128, 132))	('TCF1', 'Gene', '6927', (128, 132))
67798	30089773	C59 exerts its effect by inhibiting the enzymatic activity of PORCN acyltransferase that carries out palmitoylation of Wnts.	('C59', 'Var', (0, 3))	('PORCN', 'Gene', (62, 67))	('inhibiting', 'NegReg', (25, 35))	('enzymatic activity', 'MPA', (40, 58))	('PORCN', 'Gene', '64840', (62, 67))	('carries out palmitoylation', 'MPA', (89, 115))
67801	30089773	We observed that inactivation of the Wnt pathway led to a decrease in LGR5-induced proliferation and migration in gastric adenocarcinoma cells.	('inactivation', 'Var', (17, 29))	('Wnt pathway', 'Pathway', (37, 48))	('proliferation', 'CPA', (83, 96))	('migration', 'CPA', (101, 110))	('decrease', 'NegReg', (58, 66))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (114, 136))	('LGR5', 'Gene', (70, 74))	('gastric adenocarcinoma', 'Disease', (114, 136))	('LGR5', 'Gene', '8549', (70, 74))
67802	30089773	Wnt3a-mediated rescue could partially recover this proliferation defect observed after LGR5 knockdown.	('Wnt3a', 'Gene', (0, 5))	('knockdown', 'Var', (92, 101))	('LGR5', 'Gene', (87, 91))	('LGR5', 'Gene', '8549', (87, 91))	('Wnt3a', 'Gene', '89780', (0, 5))
67815	30089773	Interestingly, our study also indicates that alterations in LGR5 expression for a short period of time is sufficient to reprogram tumor cell growth via Wnt signaling pathway that is in agreement with previous studies.	('alterations', 'Var', (45, 56))	('LGR5', 'Gene', '8549', (60, 64))	('LGR5', 'Gene', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('152', '173'))	('cell growth', 'biological_process', 'GO:0016049', ('136', '147'))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
67841	30089773	The effect of LGR5 overexpression and or knockdown on the gastric adenocarcinoma cells was determined by using MTT assay.	('overexpression', 'PosReg', (19, 33))	('gastric adenocarcinoma', 'Disease', (58, 80))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (58, 80))	('LGR5', 'Gene', (14, 18))	('LGR5', 'Gene', '8549', (14, 18))	('MTT', 'Chemical', 'MESH:C070243', (111, 114))	('knockdown', 'Var', (41, 50))
67863	27302926	The results indicated that miR-875-5p was significantly down-regulated in primary tumor tissues and very low levels were found in CRC cell lines.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('-875-5p', 'Chemical', '-', (30, 37))	('down-regulated', 'NegReg', (56, 70))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('miR-875-5p', 'Var', (27, 37))	('tumor', 'Disease', (82, 87))
67864	27302926	Ectopic expression of miR-875-5p in CRC cell lines significantly suppressed cell growth as evidenced by cell viability assay, colony formation assay and BrdU staining, through inhibition of cyclin D1, cyclin D2, CDK4 and up-regulation of p57(Kip2) and p21(Waf1/Cip1).	('cyclin D2', 'Gene', (201, 210))	('regulation', 'biological_process', 'GO:0065007', ('224', '234'))	('suppressed', 'NegReg', (65, 75))	('p57', 'Gene', (238, 241))	('cell viability assay', 'CPA', (104, 124))	('CDK4', 'Gene', '1019', (212, 216))	('Cip1', 'Gene', (261, 265))	('formation', 'biological_process', 'GO:0009058', ('133', '142'))	('cyclin D1', 'Gene', (190, 199))	('colony formation assay', 'CPA', (126, 148))	('Waf1', 'Gene', (256, 260))	('up-regulation', 'PosReg', (221, 234))	('p21', 'Gene', (252, 255))	('Kip2', 'Gene', (242, 246))	('BrdU', 'Chemical', 'MESH:D001973', (153, 157))	('cyclin D1', 'Gene', '595', (190, 199))	('CDK', 'molecular_function', 'GO:0004693', ('212', '215'))	('Kip2', 'Gene', '1028', (242, 246))	('Waf1', 'Gene', '1026', (256, 260))	('cyclin', 'molecular_function', 'GO:0016538', ('201', '207'))	('cyclin', 'molecular_function', 'GO:0016538', ('190', '196'))	('p57', 'Gene', '1028', (238, 241))	('Cip1', 'Gene', '1026', (261, 265))	('cell growth', 'CPA', (76, 87))	('cyclin D2', 'Gene', '894', (201, 210))	('inhibition', 'NegReg', (176, 186))	('miR-875-5p', 'Var', (22, 32))	('p21', 'Gene', '1026', (252, 255))	('cell growth', 'biological_process', 'GO:0016049', ('76', '87'))	('CDK4', 'Gene', (212, 216))	('-875-5p', 'Chemical', '-', (25, 32))
67865	27302926	In addition, miR-875-5p induced apoptosis, as indicated by concomitantly with up-regulation of key apoptosis protein cleaved caspase-3, and down-regulation of anti-apoptosis protein Bcl2.	('apoptosis', 'biological_process', 'GO:0097194', ('32', '41'))	('apoptosis', 'CPA', (32, 41))	('-875-5p', 'Chemical', '-', (16, 23))	('apoptosis', 'biological_process', 'GO:0006915', ('32', '41'))	('Bcl2', 'Gene', (182, 186))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('Bcl2', 'molecular_function', 'GO:0015283', ('182', '186'))	('Bcl2', 'Gene', '596', (182, 186))	('apoptosis', 'biological_process', 'GO:0097194', ('99', '108'))	('apoptosis', 'biological_process', 'GO:0006915', ('99', '108'))	('caspase-3', 'Gene', '836', (125, 134))	('down-regulation', 'NegReg', (140, 155))	('up-regulation', 'PosReg', (78, 91))	('down-regulation of anti-apoptosis', 'biological_process', 'GO:0019987', ('140', '173'))	('caspase-3', 'Gene', (125, 134))	('anti-apoptosis protein', 'MPA', (159, 181))	('regulation', 'biological_process', 'GO:0065007', ('81', '91'))	('miR-875-5p', 'Var', (13, 23))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))
67866	27302926	Moreover, miR-875-5p inhibited cellular migration and invasiveness through inhibition of matrix metalloproteinases (MMP)-7 and MMP-9.	('MMP-9', 'molecular_function', 'GO:0004229', ('127', '132'))	('MMP-9', 'Gene', (127, 132))	('cellular migration', 'CPA', (31, 49))	('inhibition', 'NegReg', (75, 85))	('invasiveness', 'CPA', (54, 66))	('inhibited', 'NegReg', (21, 30))	('MMP)-7', 'molecular_function', 'GO:0004235', ('116', '122'))	('matrix metalloproteinases (MMP)-7', 'Gene', '4316', (89, 122))	('MMP-9', 'Gene', '4318', (127, 132))	('miR-875-5p', 'Var', (10, 20))
67867	27302926	Taken together, our results demonstrated that miR-875-5p played a pivotal role on CRC through inhibiting cell proliferation, migration, invasion, and promoting apoptosis by targeting oncogenic EGFR.	('apoptosis', 'CPA', (160, 169))	('oncogenic EGFR', 'Protein', (183, 197))	('miR-875-5p', 'Var', (46, 56))	('CRC', 'Disease', (82, 85))	('EGFR', 'Protein', (193, 197))	('invasion', 'CPA', (136, 144))	('inhibiting', 'NegReg', (94, 104))	('promoting', 'PosReg', (150, 159))	('-875-5p', 'Chemical', '-', (49, 56))	('cell proliferation', 'CPA', (105, 123))	('targeting', 'Reg', (173, 182))
67872	27302926	Numerous of publications have confirmed that dysregulation of miRNAs play an important role in various types of cancers.	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('miRNAs', 'Protein', (62, 68))	('cancers', 'Disease', (112, 119))	('dysregulation', 'Var', (45, 58))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
67876	27302926	It is also reported that miR-875-5p targets the HPV genomic sites, and negatively influences exogenous and endogenous E6 gene expression.	('influences', 'Reg', (82, 92))	('negatively', 'NegReg', (71, 81))	('miR-875-5p', 'Var', (25, 35))	('gene expression', 'biological_process', 'GO:0010467', ('121', '136'))	('-875-5p', 'Chemical', '-', (28, 35))
67877	27302926	Additionally, high level of miR-875 inhibits cell growth and promotes apoptosis in SiHa cells.	('promotes', 'PosReg', (61, 69))	('apoptosis', 'biological_process', 'GO:0097194', ('70', '79'))	('SiHa', 'CellLine', 'CVCL:0032', (83, 87))	('miR-875', 'Var', (28, 35))	('inhibits', 'NegReg', (36, 44))	('apoptosis', 'biological_process', 'GO:0006915', ('70', '79'))	('cell growth', 'biological_process', 'GO:0016049', ('45', '56'))	('apoptosis', 'CPA', (70, 79))	('cell growth', 'CPA', (45, 56))
67878	27302926	These results suggest tumor-suppressive functions of miR-875-5p in cancer but up to now this suggestion has not been rigorously tested.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('-875-5p', 'Chemical', '-', (56, 63))	('cancer', 'Disease', (67, 73))	('miR-875-5p', 'Var', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', (22, 27))
67885	27302926	Collectively, we discovered that miR-875-5p suppressed cell proliferation, metastasis, and promoted cell apoptosis by directly targeting 3'-UTR of EGFR in CRC.	('suppressed', 'NegReg', (44, 54))	('promoted', 'PosReg', (91, 99))	('EGFR', 'Gene', (147, 151))	('miR-875-5p', 'Var', (33, 43))	('targeting', 'Reg', (127, 136))	('-875-5p', 'Chemical', '-', (36, 43))	('cell proliferation', 'CPA', (55, 73))	('metastasis', 'CPA', (75, 85))	('cell apoptosis', 'CPA', (100, 114))	("3'-UTR", 'MPA', (137, 143))
67887	27302926	Results demonstrated miR-875-5p expression in the tumors was significantly (P < 0.05) reduced (mean = 32% of decrease) in 92 CRC cancers in comparison to their matched controls among 92 samples analyzed (Figure 1A).	('decrease', 'NegReg', (109, 117))	('CRC cancers', 'Disease', (125, 136))	('reduced', 'NegReg', (86, 93))	('-875-5p', 'Chemical', '-', (24, 31))	('CRC cancers', 'Disease', 'MESH:D015179', (125, 136))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('miR-875-5p', 'Var', (21, 31))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
67888	27302926	Next, we examined miR-875-5p expression in CRC cell lines, and results demonstrated a lower expression of miR-875-5p in HCT116, LOVO, RKO, LS174T, HCT8, HR28348, SW480, SW620, DLD-1 and HT29 cell lines, compared with that of in normal colorectal epithelial cells, NCM460 (Figure 1B).	('HCT116', 'CellLine', 'CVCL:0291', (120, 126))	('HT29', 'CellLine', 'CVCL:0320', (186, 190))	('lower', 'NegReg', (86, 91))	('-875-5p', 'Chemical', '-', (109, 116))	('SW480', 'CellLine', 'CVCL:0546', (162, 167))	('LS174T', 'Var', (139, 145))	('miR-875-5p', 'Var', (106, 116))	('HCT8', 'CellLine', 'CVCL:2478', (147, 151))	('-875-5p', 'Chemical', '-', (21, 28))	('SW620', 'CellLine', 'CVCL:0547', (169, 174))	('expression', 'MPA', (92, 102))	('HCT116', 'Gene', (120, 126))
67889	27302926	Among the ten CRC cell lines, miR-875-5p decreased the most in HCT116 and SW480 cell lines, thus, we chose HCT116 and SW480 for model of CRC cell lines.	('decreased', 'NegReg', (41, 50))	('miR-875-5p', 'Var', (30, 40))	('-875-5p', 'Chemical', '-', (33, 40))	('HCT116', 'CellLine', 'CVCL:0291', (107, 113))	('HCT116', 'CellLine', 'CVCL:0291', (63, 69))	('SW480', 'CellLine', 'CVCL:0546', (118, 123))	('SW480', 'CellLine', 'CVCL:0546', (74, 79))
67891	27302926	However, miR-875-5p expression was not associated with other clinical characteristics such as age (P = 0.7452), gender (P = 0.4916) or Tumor site (P = 0.2393) in CRC patients (Table 1).	('-875-5p', 'Chemical', '-', (12, 19))	('CRC', 'Disease', (162, 165))	('miR-875-5p expression', 'Var', (9, 30))	('Tumor', 'Phenotype', 'HP:0002664', (135, 140))	('patients', 'Species', '9606', (166, 174))
67892	27302926	Additionally, Kaplan-Meier survival analysis demonstrated that CRC patients with low miR-875-5p expression levels (<= 32% of decrease, n = 66) of had shorter overall survival, in comparison to patients with high miR-875-5p expression levels (> 32% of decrease, n = 26) (Figure 1C), which demonstrated decreased expression of miR-875-5p was associated with poor prognosis.	('patients', 'Species', '9606', (193, 201))	('low', 'NegReg', (81, 84))	('patients', 'Species', '9606', (67, 75))	('-875-5p', 'Chemical', '-', (215, 222))	('miR-875-5p', 'Var', (85, 95))	('-875-5p', 'Chemical', '-', (88, 95))	('-875-5p', 'Chemical', '-', (328, 335))	('overall', 'MPA', (158, 165))	('shorter', 'NegReg', (150, 157))
67893	27302926	Thus, down-regulated expression of miR-875-5p might play a crucial role on CRC progression and development.	('-875-5p', 'Chemical', '-', (38, 45))	('CRC progression', 'CPA', (75, 90))	('development', 'CPA', (95, 106))	('down-regulated', 'NegReg', (6, 20))	('expression', 'MPA', (21, 31))	('miR-875-5p', 'Var', (35, 45))
67896	27302926	Since EGFR is the key role on regulation of cell cycle, aberrations of these three proteins might contribute to human CRC.	('EGFR', 'molecular_function', 'GO:0005006', ('6', '10'))	('contribute', 'Reg', (98, 108))	('aberrations', 'Var', (56, 67))	('regulation of cell cycle', 'biological_process', 'GO:0051726', ('30', '54'))	('human CRC', 'Disease', (112, 121))	('human', 'Species', '9606', (112, 117))
67898	27302926	We then investigated the potential molecular mechanism of the anti-tumorigenic property of miR-875-5p in CRC cells.	('-875-5p', 'Chemical', '-', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('miR-875-5p', 'Var', (91, 101))	('investigated', 'Reg', (8, 20))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
67899	27302926	EGFR, which harbors one conserved miR-875-5p cognate site, namely, 256-278 of EGFR 3'-UTR) (Figure 3B), is a predicted target of miR-875-5p.	('EGFR', 'Gene', (78, 82))	('-875-5p', 'Chemical', '-', (37, 44))	('256-278', 'Var', (67, 74))	('-875-5p', 'Chemical', '-', (132, 139))
67900	27302926	Next, we used luciferase reporter assays to determine whether EGFR expression are indeed regulated by miR-875-5p, And results demonstrate that miR-875-5p inhibits luciferase activity by around 46% in HCT116 cells and 51% in SW480 cells when the reporter plasmid carried the WT EGFR 3'-UTR (Figure 3C), but no significant inhibition was observed at the reporter plasmid carried a mutant EGFR 3'-UTR.	('luciferase activity', 'molecular_function', 'GO:0050397', ('163', '182'))	('inhibits', 'NegReg', (154, 162))	('luciferase', 'Enzyme', (163, 173))	('EGFR', 'molecular_function', 'GO:0005006', ('386', '390'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('163', '182'))	('-875-5p', 'Chemical', '-', (146, 153))	('EGFR', 'molecular_function', 'GO:0005006', ('277', '281'))	('-875-5p', 'Chemical', '-', (105, 112))	('luciferase activity', 'molecular_function', 'GO:0047077', ('163', '182'))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))	('HCT116', 'CellLine', 'CVCL:0291', (200, 206))	('SW480', 'CellLine', 'CVCL:0546', (224, 229))	('miR-875-5p', 'Var', (143, 153))	('luciferase activity', 'molecular_function', 'GO:0045289', ('163', '182'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('163', '182'))	('activity', 'MPA', (174, 182))
67902	27302926	Our results of western blot demonstrated that miR-875-5p inhibited expression of EGFR protein by approximately 65% and 75%, when compared with blank HCT116 and SW480 cells (Figure 3D), respectively.	('SW480', 'CellLine', 'CVCL:0546', (160, 165))	('protein', 'Protein', (86, 93))	('inhibited', 'NegReg', (57, 66))	('miR-875-5p', 'Var', (46, 56))	('EGFR', 'molecular_function', 'GO:0005006', ('81', '85'))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('expression', 'MPA', (67, 77))	('HCT116', 'CellLine', 'CVCL:0291', (149, 155))	('EGFR', 'Gene', (81, 85))
67903	27302926	Our results reveal that miR-875-5p targets human EGFR by directly binding to the predicted sites in 3'-UTR of EGFR mRNA.	('binding', 'molecular_function', 'GO:0005488', ('66', '73'))	('EGFR', 'molecular_function', 'GO:0005006', ('49', '53'))	('binding', 'Interaction', (66, 73))	('miR-875-5p', 'Var', (24, 34))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('human', 'Species', '9606', (43, 48))
67906	27302926	In addition, inhibition of EGFR expression promoted apoptosis in CRC cell (8.5-fold of increase or 7.7-fold of increase at caspase 3 activity, 6.5-fold of increase or 7.8-fold of increase at caspase 7 activity in HCT116 or SW480 cells) (Figure 4J-4K).	('caspase 7', 'Gene', (191, 200))	('EGFR', 'Gene', (27, 31))	('caspase 3', 'Gene', '836', (123, 132))	('caspase 7', 'Gene', '840', (191, 200))	('promoted', 'PosReg', (43, 51))	('inhibition', 'Var', (13, 23))	('HCT116', 'CellLine', 'CVCL:0291', (213, 219))	('SW480', 'CellLine', 'CVCL:0546', (223, 228))	('apoptosis', 'CPA', (52, 61))	('activity', 'MPA', (133, 141))	('caspase 3', 'Gene', (123, 132))
67908	27302926	However, inhibition of miR-875-5p does not reverse the anticancer efficacy of silence of EGFR expression in CRC cell lines (both HCT116 and SW480 cells).	('HCT116', 'CellLine', 'CVCL:0291', (129, 135))	('EGFR', 'Gene', (89, 93))	('SW480', 'CellLine', 'CVCL:0546', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('silence', 'Var', (78, 85))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
67909	27302926	These results indicate the anticancer efficacy of miR-875-5p is partly attributed to its inhibitory role on EGFR.	('inhibitory', 'NegReg', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('-875-5p', 'Chemical', '-', (53, 60))	('EGFR', 'Gene', (108, 112))	('miR-875-5p', 'Var', (50, 60))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))
67912	27302926	Our results demonstrated that the tumor volume and weight of mice treated with miR-875-5p mimic were significantly reduced (55% of decrease in tumor weight) relative to that of treated with miR mimic NC (Figure 5A and 5B).	('mice', 'Species', '10090', (61, 65))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', (143, 148))	('reduced', 'NegReg', (115, 122))	('-875-5p', 'Chemical', '-', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('decrease', 'NegReg', (131, 139))	('miR-875-5p mimic', 'Var', (79, 95))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
67913	27302926	This result demonstrates miR-875-5p significantly suppresses the tumorigenicity of HCT116 cells in the nude mouse xenograft model.	('tumor', 'Disease', (65, 70))	('suppresses', 'NegReg', (50, 60))	('mouse', 'Species', '10090', (108, 113))	('HCT116', 'CellLine', 'CVCL:0291', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('miR-875-5p', 'Var', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
67915	27302926	Moreover, immunohistochemical staining of resected tumor tissues found that tumors formed from miR-875-5p-transfected HCT116 cells exhibited reduced positivity (78% of decrease) for Ki67 compared with those formed from control cells (Figure 5D).	('miR-875-5p-transfected', 'Var', (95, 117))	('positivity', 'MPA', (149, 159))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('reduced', 'NegReg', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (51, 56))	('-875-5p', 'Chemical', '-', (98, 105))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('HCT116', 'Gene', (118, 124))	('decrease', 'NegReg', (168, 176))	('HCT116', 'CellLine', 'CVCL:0291', (118, 124))	('Ki67', 'Protein', (182, 186))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
67916	27302926	Thus, miR-875-5p reduces the growth of established colorectal carcinoma xenografts.	('reduces', 'NegReg', (17, 24))	('colorectal carcinoma xenografts', 'Disease', (51, 82))	('growth of established', 'CPA', (29, 50))	('-875-5p', 'Chemical', '-', (9, 16))	('colorectal carcinoma xenografts', 'Disease', 'MESH:D015179', (51, 82))	('miR-875-5p', 'Var', (6, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
67918	27302926	Our results of BrdU staining revealed that miR-875-5p inhibited HCT116 and SW480 cell DNA synthesis by approximately 60% (Figure 6A and 6B) and 53% (Figure 6A and 6B), compared with blank HCT116 and SW480 cells, respectively.	('inhibited', 'NegReg', (54, 63))	('HCT116', 'CellLine', 'CVCL:0291', (64, 70))	('SW480', 'CellLine', 'CVCL:0546', (199, 204))	('miR-875-5p', 'Var', (43, 53))	('HCT116', 'CellLine', 'CVCL:0291', (188, 194))	('DNA synthesis', 'biological_process', 'GO:0071897', ('86', '99'))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('BrdU', 'Chemical', 'MESH:D001973', (15, 19))	('SW480', 'CellLine', 'CVCL:0546', (75, 80))	('HCT116', 'Gene', (64, 70))	('SW480', 'Gene', (75, 80))
67919	27302926	However, miR-875-5p inhibitor treatment increased HCT116 and SW480 cell DNA synthesis by approximately 2.4 folds (Figure 6A and 6B) and 1.6 folds (Figure 6A and 6B) compared with blank HCT116 and SW480 cells, separately.	('miR-875-5p', 'Var', (9, 19))	('HCT116', 'CellLine', 'CVCL:0291', (50, 56))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('SW480', 'CellLine', 'CVCL:0546', (196, 201))	('HCT116', 'CellLine', 'CVCL:0291', (185, 191))	('DNA synthesis', 'biological_process', 'GO:0071897', ('72', '85'))	('increased', 'PosReg', (40, 49))	('HCT116', 'Gene', (50, 56))	('SW480', 'CellLine', 'CVCL:0546', (61, 66))
67920	27302926	To verify these results, we also did the CCK8 assay, and results demonstrated that miR-875-5p over-expression significantly attenuated HCT116 and SW480 cells vitality, while loss of miR-875-5p promoted cell proliferation (Figure 6C-6F).	('promoted', 'PosReg', (193, 201))	('cell proliferation', 'CPA', (202, 220))	('miR-875-5p', 'Gene', (83, 93))	('over-expression', 'PosReg', (94, 109))	('attenuated', 'NegReg', (124, 134))	('cell proliferation', 'biological_process', 'GO:0008283', ('202', '220'))	('SW480', 'CellLine', 'CVCL:0546', (146, 151))	('-875-5p', 'Chemical', '-', (185, 192))	('HCT116', 'CellLine', 'CVCL:0291', (135, 141))	('-875-5p', 'Chemical', '-', (86, 93))	('loss', 'Var', (174, 178))
67921	27302926	In addition, we also investigated the role of miR-875-5p on clonogenic survival, and results demonstrated miR-875-5p mimic treatment caused a decrease in the clonogenic survival of HCT116 and SW480 cells compared with blank HCT116and blank SW480 cells (Figure 6G and 6H), while miR-875-5p inhibitor-treated HCT116 cells showed an significant increase in the clonogenic survival, when compared with blank HCT116 and blank SW480 cells (Figure 6G and 6H).	('SW480', 'CellLine', 'CVCL:0546', (421, 426))	('clonogenic survival', 'CPA', (158, 177))	('HCT116', 'CellLine', 'CVCL:0291', (404, 410))	('SW480', 'CellLine', 'CVCL:0546', (192, 197))	('SW480', 'CellLine', 'CVCL:0546', (240, 245))	('HCT116', 'CellLine', 'CVCL:0291', (181, 187))	('-875-5p', 'Chemical', '-', (109, 116))	('decrease', 'NegReg', (142, 150))	('HCT116', 'CellLine', 'CVCL:0291', (224, 230))	('miR-875-5p', 'Var', (106, 116))	('clonogenic survival', 'CPA', (358, 377))	('increase', 'PosReg', (342, 350))	('HCT116', 'CellLine', 'CVCL:0291', (307, 313))	('-875-5p', 'Chemical', '-', (281, 288))	('-875-5p', 'Chemical', '-', (49, 56))	('clonogenic survival', 'CPA', (60, 79))
67922	27302926	Furthermore, the growth-inhibitory role of miR-875-5p in HCT116 and SW480 cell lines was accompanied by a corresponding decrease in the proportion of cells in the S phase and an increase in the proportion of cells in G1 (Figure 6I and 6J).	('SW480', 'CellLine', 'CVCL:0546', (68, 73))	('miR-875-5p', 'Var', (43, 53))	('-875-5p', 'Chemical', '-', (46, 53))	('decrease', 'NegReg', (120, 128))	('growth-inhibitory', 'MPA', (17, 34))	('increase', 'PosReg', (178, 186))	('HCT116', 'CellLine', 'CVCL:0291', (57, 63))
67924	27302926	Our results discovered miR-875-5p significantly inhibited the protein expression of EGFR, while loss of miR-875-5p remarkably increased the level of EGFR in HCT116 and SW480 cells (Figure 6K).	('loss', 'Var', (96, 100))	('protein expression', 'MPA', (62, 80))	('EGFR', 'molecular_function', 'GO:0005006', ('84', '88'))	('miR-875-5p', 'Gene', (104, 114))	('HCT116', 'CellLine', 'CVCL:0291', (157, 163))	('SW480', 'CellLine', 'CVCL:0546', (168, 173))	('miR-875-5p', 'Var', (23, 33))	('EGFR', 'molecular_function', 'GO:0005006', ('149', '153'))	('EGFR', 'Protein', (84, 88))	('inhibited', 'NegReg', (48, 57))	('increased', 'PosReg', (126, 135))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
67926	27302926	In our research, the protein expression of cyclin D2 was repressed by over-expression of miR-875-5p (Figure 6K).	('cyclin D2', 'Gene', '894', (43, 52))	('protein expression', 'MPA', (21, 39))	('over-expression', 'PosReg', (70, 85))	('-875-5p', 'Chemical', '-', (92, 99))	('cyclin D2', 'Gene', (43, 52))	('miR-875-5p', 'Var', (89, 99))	('cyclin', 'molecular_function', 'GO:0016538', ('43', '49'))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))
67928	27302926	In our research, the protein expression of CDK4 was repressed by over-expression of miR-875-5p in HCT116 and SW480 cells (Figure 6K).	('miR-875-5p', 'Var', (84, 94))	('-875-5p', 'Chemical', '-', (87, 94))	('SW480', 'CellLine', 'CVCL:0546', (109, 114))	('protein expression', 'MPA', (21, 39))	('over-expression', 'PosReg', (65, 80))	('CDK4', 'Gene', (43, 47))	('HCT116', 'CellLine', 'CVCL:0291', (98, 104))	('CDK4', 'Gene', '1019', (43, 47))
67929	27302926	Our study revealed over-expression of miR-875-5p is a mechanism for the up-regulation of p57 (a cyclin-dependent kinase inhibitor) level in CRC cell lines (HCT116 and SW480) (Figure 6K).	('p57', 'Gene', (89, 92))	('cyclin-dependent kinase inhibitor', 'Gene', '1033', (96, 129))	('-875-5p', 'Chemical', '-', (41, 48))	('SW480', 'CellLine', 'CVCL:0546', (167, 172))	('HCT116', 'CellLine', 'CVCL:0291', (156, 162))	('up-regulation', 'PosReg', (72, 85))	('cyclin-dependent kinase inhibitor', 'Gene', (96, 129))	('miR-875-5p', 'Var', (38, 48))	('over-expression', 'PosReg', (19, 34))	('p57', 'Gene', '1028', (89, 92))
67931	27302926	Our study revealed that miR-875-5p up-regulated p21 level in CRC cell lines (HCT116 and SW480) (Figure 6K).	('HCT116', 'CellLine', 'CVCL:0291', (77, 83))	('p21', 'Gene', '1026', (48, 51))	('p21', 'Gene', (48, 51))	('miR-875-5p', 'Var', (24, 34))	('-875-5p', 'Chemical', '-', (27, 34))	('SW480', 'CellLine', 'CVCL:0546', (88, 93))	('up-regulated', 'PosReg', (35, 47))
67932	27302926	It is concluded that miR-875-5p markedly inhibited cell growth in CRC cell lines.	('-875-5p', 'Chemical', '-', (24, 31))	('cell growth in CRC cell lines', 'CPA', (51, 80))	('inhibited', 'NegReg', (41, 50))	('miR-875-5p', 'Var', (21, 31))
67937	27302926	As expected, migration of miR-875-5p-expressing clones was inhibited by 65% in HCT116 and 56% in SW480 cells, compared with the blank HCT116 and SW480 cells (Figure 7C and 7D), respectively.	('HCT116', 'Var', (79, 85))	('HCT116', 'CellLine', 'CVCL:0291', (134, 140))	('miR-875-5p-expressing', 'Gene', (26, 47))	('-875-5p', 'Chemical', '-', (29, 36))	('inhibited', 'NegReg', (59, 68))	('HCT116', 'CellLine', 'CVCL:0291', (79, 85))	('SW480', 'CellLine', 'CVCL:0546', (145, 150))	('SW480', 'CellLine', 'CVCL:0546', (97, 102))	('migration', 'CPA', (13, 22))
67938	27302926	However, when treated with miR-875-5p inhibitor, migration in miR-875-5p-expression defect HCT116 and SW480 cells were significantly increased by approximately 2.5 and 2.8 folds relative to blank HCT116 and SW480 cells (Figure 7C and 7D) respectively.	('HCT116', 'CellLine', 'CVCL:0291', (91, 97))	('SW480', 'CellLine', 'CVCL:0546', (207, 212))	('SW480', 'CellLine', 'CVCL:0546', (102, 107))	('miR-875-5p-expression defect', 'Var', (62, 90))	('migration', 'CPA', (49, 58))	('HCT116', 'CellLine', 'CVCL:0291', (196, 202))	('-875-5p', 'Chemical', '-', (30, 37))	('increased', 'PosReg', (133, 142))	('-875-5p', 'Chemical', '-', (65, 72))
67940	27302926	As expected, invasion of miR-875-5p-expressing clones was inhibited by 68% in HCT116 and 77% in SW480 cells, relative to blank HCT116 and SW480 cells (Figure 7C and 7D), respectively.	('HCT116', 'CellLine', 'CVCL:0291', (78, 84))	('invasion', 'CPA', (13, 21))	('SW480', 'CellLine', 'CVCL:0546', (96, 101))	('SW480', 'CellLine', 'CVCL:0546', (138, 143))	('HCT116', 'CellLine', 'CVCL:0291', (127, 133))	('HCT116', 'Var', (78, 84))	('miR-875-5p-expressing', 'Var', (25, 46))	('inhibited', 'NegReg', (58, 67))	('-875-5p', 'Chemical', '-', (28, 35))
67941	27302926	However, when treated with miR-875-5p inhibitor, invasion in miR-875-5p-expression defect HCT116 and SW480 cells were significantly increased by approximately 3.0 and 2.3 folds relative to blank HCT116 and SW480 cells (Figure 7C and 7D), separately.	('HCT116', 'CellLine', 'CVCL:0291', (195, 201))	('miR-875-5p-expression defect', 'Var', (61, 89))	('-875-5p', 'Chemical', '-', (30, 37))	('increased', 'PosReg', (132, 141))	('-875-5p', 'Chemical', '-', (64, 71))	('HCT116', 'CellLine', 'CVCL:0291', (90, 96))	('SW480', 'CellLine', 'CVCL:0546', (206, 211))	('invasion', 'CPA', (49, 57))	('SW480', 'CellLine', 'CVCL:0546', (101, 106))
67942	27302926	We also investigated the role of miR-875-5p on expression of MMP-7 and MMP-9, which all play a key role on tumor metastasis, and results indicated miR-875-5p inhibited the protein expression of MMP-7 and MMP-9 both in HCT116 and SW480 cells (Figure 7E).	('MMP-7', 'Gene', (61, 66))	('protein expression', 'MPA', (172, 190))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('MMP-7', 'Gene', '4316', (194, 199))	('MMP-9', 'Gene', '4318', (204, 209))	('MMP-7', 'Gene', '4316', (61, 66))	('-875-5p', 'Chemical', '-', (36, 43))	('inhibited', 'NegReg', (158, 167))	('-875-5p', 'Chemical', '-', (150, 157))	('MMP-9', 'Gene', (204, 209))	('MMP-9', 'Gene', '4318', (71, 76))	('tumor metastasis', 'Disease', 'MESH:D009362', (107, 123))	('tumor metastasis', 'Disease', (107, 123))	('SW480', 'CellLine', 'CVCL:0546', (229, 234))	('miR-875-5p', 'Var', (147, 157))	('MMP-7', 'Gene', (194, 199))	('MMP-9', 'Gene', (71, 76))	('HCT116', 'CellLine', 'CVCL:0291', (218, 224))
67943	27302926	As expected, loss of miR-875-5p significantly increased the protein expression of MMP-7 and MMP-9 in both HCT116 and SW480 cells (Figure 7E).	('MMP-7', 'molecular_function', 'GO:0004235', ('82', '87'))	('MMP-7', 'Gene', (82, 87))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('increased', 'PosReg', (46, 55))	('HCT116', 'CellLine', 'CVCL:0291', (106, 112))	('MMP-7', 'Gene', '4316', (82, 87))	('MMP-9', 'molecular_function', 'GO:0004229', ('92', '97'))	('MMP-9', 'Gene', '4318', (92, 97))	('SW480', 'CellLine', 'CVCL:0546', (117, 122))	('miR-875-5p', 'Var', (21, 31))	('MMP-9', 'Gene', (92, 97))	('loss', 'Var', (13, 17))	('protein expression', 'MPA', (60, 78))
67945	27302926	Our results of flow cytometric analysis (FCA) revealed that forced expression of miR-875-5p resulted in a ~2.3 folds and ~1.7 folds of increase in apoptotic cell death of HCT116 and SW480 cells (Figure 8A), respectively.	('HCT116', 'CellLine', 'CVCL:0291', (171, 177))	('increase', 'PosReg', (135, 143))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('147', '167'))	('SW480', 'CellLine', 'CVCL:0546', (182, 187))	('miR-875-5p', 'Var', (81, 91))	('apoptotic cell death', 'CPA', (147, 167))
67946	27302926	However, the percentage of apoptotic cells induced by miR-875-5p was decreased to the basal level when the cells were treated with the specific miR-875-5p inhibitor (Figure 8A).	('apoptotic cells', 'CPA', (27, 42))	('miR-875-5p', 'Var', (54, 64))	('decreased', 'NegReg', (69, 78))	('-875-5p', 'Chemical', '-', (57, 64))	('-875-5p', 'Chemical', '-', (147, 154))
67947	27302926	In addition, we also tested the caspase-3 and caspase-7 activity after treatment of HCT116 and SW480 cells with relative RNAs, and results demonstrated that miR-875-5p remarkably increased caspase-3 and caspase-7 activities in HCT116 and SW480 cell lysate, by approximately 3.9 and 4.1 folds increase (caspase-3 activity), 2.8 and 3.3 folds increase (caspase-7 activity), than that of in bank HCT116 and SW480 cells (Figure 8B and 8C), respectively.	('SW480', 'CellLine', 'CVCL:0546', (95, 100))	('increase', 'PosReg', (341, 349))	('-875-5p', 'Chemical', '-', (160, 167))	('caspase-3', 'Gene', '836', (302, 311))	('caspase-7', 'Gene', '840', (203, 212))	('caspase-7', 'Gene', (46, 55))	('increased', 'PosReg', (179, 188))	('caspase-3', 'Gene', '836', (32, 41))	('caspase-3', 'Gene', (302, 311))	('increase', 'PosReg', (292, 300))	('caspase-3', 'Gene', '836', (189, 198))	('caspase-3', 'Gene', (32, 41))	('caspase-7', 'Gene', '840', (351, 360))	('caspase-3', 'Gene', (189, 198))	('caspase-7', 'Gene', (203, 212))	('HCT116', 'CellLine', 'CVCL:0291', (84, 90))	('caspase-7', 'Gene', '840', (46, 55))	('activities', 'MPA', (213, 223))	('HCT116', 'CellLine', 'CVCL:0291', (227, 233))	('caspase-7', 'Gene', (351, 360))	('miR-875-5p', 'Var', (157, 167))	('HCT116', 'CellLine', 'CVCL:0291', (393, 399))	('SW480', 'CellLine', 'CVCL:0546', (404, 409))	('SW480', 'CellLine', 'CVCL:0546', (238, 243))
67949	27302926	Moreover, miR-875-5p also inhibited the expression level of anti-apoptotic protein Bcl2 (Figure 8D), and increased the protein expression of cleaved-caspase-3 (Figure 8D) in HCT116 and SW480 cells.	('protein expression', 'MPA', (119, 137))	('HCT116', 'CellLine', 'CVCL:0291', (174, 180))	('Bcl2', 'Gene', (83, 87))	('caspase-3', 'Gene', (149, 158))	('inhibited', 'NegReg', (26, 35))	('SW480', 'CellLine', 'CVCL:0546', (185, 190))	('expression level', 'MPA', (40, 56))	('caspase-3', 'Gene', '836', (149, 158))	('Bcl2', 'Gene', '596', (83, 87))	('-875-5p', 'Chemical', '-', (13, 20))	('increased', 'PosReg', (105, 114))	('miR-875-5p', 'Var', (10, 20))
67950	27302926	These results demonstrated that miR-875-5p indeed promoted apoptosis in HCT116 and SW480 cells.	('-875-5p', 'Chemical', '-', (35, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('59', '68'))	('apoptosis', 'biological_process', 'GO:0006915', ('59', '68'))	('promoted', 'PosReg', (50, 58))	('miR-875-5p', 'Var', (32, 42))	('SW480', 'CellLine', 'CVCL:0546', (83, 88))	('apoptosis', 'CPA', (59, 68))	('HCT116', 'CellLine', 'CVCL:0291', (72, 78))
67951	27302926	Our present study has revealed the following novel findings: (i) exogenously overexpressed miR-875-5p suppresses tumor regeneration in 6 CRC xenograft models and suppresses cell growth in vitro and in vivo; (ii) miR-875-5p overexpression inhibits CRC cells metastasis; (iii) inhibition of miR-875-5p in CRC cells results in high clonal clonogenic, and tumorigenic properties; (iv) miR-875-5p overexpression promotes CRC cells apoptosis, and inhibition of miR-875-5p inhibits CRC cell apoptosis; (v) miR-875-5p targets EGFR in CRC cells and negatively expressed with EGFR.	('inhibition', 'Var', (441, 451))	('-875-5p', 'Chemical', '-', (502, 509))	('high clonal clonogenic', 'CPA', (324, 346))	('-875-5p', 'Chemical', '-', (215, 222))	('-875-5p', 'Chemical', '-', (292, 299))	('CRC cells metastasis', 'CPA', (247, 267))	('-875-5p', 'Chemical', '-', (94, 101))	('-875-5p', 'Chemical', '-', (458, 465))	('CRC cell apoptosis', 'CPA', (475, 493))	('tumor', 'Disease', (352, 357))	('inhibits', 'NegReg', (466, 474))	('tumor', 'Disease', (113, 118))	('CRC cells apoptosis', 'CPA', (416, 435))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('-875-5p', 'Chemical', '-', (384, 391))	('miR-875-5p', 'Var', (499, 509))	('promotes', 'PosReg', (407, 415))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('inhibition', 'Var', (275, 285))	('EGFR', 'Protein', (518, 522))	('suppresses', 'NegReg', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
67954	27302926	Our results also indicated that miR-875-5p was decreased in CRC tissues and cell lines, indicating disorder of miR-875-5p is an early event of CRC tumorigenesis.	('miR-875-5p', 'Var', (111, 121))	('-875-5p', 'Chemical', '-', (35, 42))	('tumor', 'Disease', (147, 152))	('-875-5p', 'Chemical', '-', (114, 121))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('CRC', 'Disease', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
67955	27302926	We therefore explored the speculative tumor suppressive efficiency of miR-875-5p on human CRC cell lines.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('human', 'Species', '9606', (84, 89))	('miR-875-5p', 'Var', (70, 80))
67956	27302926	Firstly, we examined the mechanism of miR-875-5p on CRC cell growth, and results indicated restoration of miR-875-5p in the HCT116 and SW480 cells significantly suppressed cell growth as evidenced by colony formation assays, BrdU, and cell viability (CCK8).	('HCT116', 'CellLine', 'CVCL:0291', (124, 130))	('-875-5p', 'Chemical', '-', (41, 48))	('colony formation assays', 'CPA', (200, 223))	('BrdU', 'CPA', (225, 229))	('suppressed', 'NegReg', (161, 171))	('-875-5p', 'Chemical', '-', (109, 116))	('miR-875-5p', 'Var', (106, 116))	('SW480', 'CellLine', 'CVCL:0546', (135, 140))	('BrdU', 'Chemical', 'MESH:D001973', (225, 229))	('cell growth', 'CPA', (172, 183))	('cell viability', 'CPA', (235, 249))
67957	27302926	The growth-inhibitory role of miR-875-5p may be attributed to miR-875-5p targets 3'-UTR of EGFR mRNA, and inhibits the expression of EGFR in CRC cells.	('inhibits', 'NegReg', (106, 114))	('expression', 'MPA', (119, 129))	('EGFR', 'Gene', (91, 95))	('growth-inhibitory', 'MPA', (4, 21))	('-875-5p', 'Chemical', '-', (33, 40))	("3'-UTR", 'MPA', (81, 87))	('miR-875-5p', 'Var', (62, 72))	('EGFR', 'Gene', (133, 137))	('-875-5p', 'Chemical', '-', (65, 72))
67958	27302926	In addition, miR-875-5p also inhibited cyclin D1, cyclin D2 and promoted p57 and p21 expression levels in CRC cells, which further contributed to the growth-delay efficacy of miR-875-5p.	('inhibited', 'NegReg', (29, 38))	('cyclin D2', 'Gene', '894', (50, 59))	('promoted', 'PosReg', (64, 72))	('cyclin D2', 'Gene', (50, 59))	('-875-5p', 'Chemical', '-', (16, 23))	('cyclin D1', 'Gene', '595', (39, 48))	('p21', 'Gene', '1026', (81, 84))	('growth-delay', 'Phenotype', 'HP:0001510', (150, 162))	('miR-875-5p', 'Var', (13, 23))	('cyclin D1', 'Gene', (39, 48))	('p57', 'Gene', (73, 76))	('p57', 'Gene', '1028', (73, 76))	('-875-5p', 'Chemical', '-', (178, 185))	('p21', 'Gene', (81, 84))	('growth-delay', 'CPA', (150, 162))
67959	27302926	We discovered that miR-875-5p induced cell apoptosis happens by the regulation of extrinsic apoptosis pathway, which had been viewed as a crucial antitumor mechanism.	('extrinsic apoptosis pathway', 'Pathway', (82, 109))	('miR-875-5p', 'Var', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('cell apoptosis', 'CPA', (38, 52))	('-875-5p', 'Chemical', '-', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
67960	27302926	The expression of critical anti-apoptosis protein Bcl2 was decreased after transfecting with miR-875-5p, and the activity of its downstream factor, active apoptosis executor caspase-3 was up-regulated, leading to initiate a caspase cascade, and finally resulted in cell apoptosis.	('miR-875-5p', 'Var', (93, 103))	('resulted in', 'Reg', (253, 264))	('expression', 'MPA', (4, 14))	('up-regulated', 'PosReg', (188, 200))	('cell apoptosis', 'CPA', (265, 279))	('caspase-3', 'Gene', '836', (174, 183))	('caspase-3', 'Gene', (174, 183))	('Bcl2', 'Gene', (50, 54))	('initiate', 'PosReg', (213, 221))	('Bcl2', 'Gene', '596', (50, 54))	('Bcl2', 'molecular_function', 'GO:0015283', ('50', '54'))	('caspase cascade', 'Pathway', (224, 239))	('anti-apoptosis', 'biological_process', 'GO:0043066', ('27', '41'))	('apoptosis', 'biological_process', 'GO:0097194', ('155', '164'))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('decreased', 'NegReg', (59, 68))	('apoptosis', 'biological_process', 'GO:0006915', ('155', '164'))	('apoptosis', 'biological_process', 'GO:0097194', ('270', '279'))	('apoptosis', 'biological_process', 'GO:0006915', ('270', '279'))	('activity', 'MPA', (113, 121))
67961	27302926	Restoration of miR-875-5p suppressed the cell metastasis in vitro assays.	('cell metastasis in vitro assays', 'CPA', (41, 72))	('miR-875-5p', 'Var', (15, 25))	('suppressed', 'NegReg', (26, 36))	('-875-5p', 'Chemical', '-', (18, 25))
67962	27302926	The reduced disseminating efficiency and cell motility induced by miR-875-5p in CRC cell lines were demonstrated to be related to decreased protein expression of cell migration and invasion molecules matrix metalloproteinases 7 (MMP-7) and matrix metalloproteinases (MMP-9).	('protein expression', 'MPA', (140, 158))	('disseminating efficiency', 'CPA', (12, 36))	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('reduced', 'NegReg', (4, 11))	('cell migration', 'CPA', (162, 176))	('matrix metalloproteinases 7', 'Gene', (200, 227))	('MMP-9', 'Gene', '4318', (267, 272))	('miR-875-5p', 'Var', (66, 76))	('matrix metalloproteinases 7', 'Gene', '4316', (200, 227))	('MMP-9', 'Gene', (267, 272))	('cell migration', 'biological_process', 'GO:0016477', ('162', '176'))	('MMP-7', 'Gene', (229, 234))	('-875-5p', 'Chemical', '-', (69, 76))	('cell motility', 'biological_process', 'GO:0048870', ('41', '54'))	('cell motility', 'CPA', (41, 54))	('MMP-7', 'molecular_function', 'GO:0004235', ('229', '234'))	('MMP-9', 'molecular_function', 'GO:0004229', ('267', '272'))	('MMP-7', 'Gene', '4316', (229, 234))	('invasion', 'CPA', (181, 189))	('decreased', 'NegReg', (130, 139))
67966	27302926	Thus, decreased expression of MMP-7 and MMP-9 by miR-875-5p led to alleviated cell metastasis ability.	('decreased', 'NegReg', (6, 15))	('MMP-7', 'Gene', (30, 35))	('alleviated', 'NegReg', (67, 77))	('MMP-7', 'Gene', '4316', (30, 35))	('MMP-9', 'Gene', '4318', (40, 45))	('cell metastasis ability', 'CPA', (78, 101))	('MMP-9', 'Gene', (40, 45))	('expression', 'MPA', (16, 26))	('miR-875-5p', 'Var', (49, 59))
67968	27302926	In our present study, we discovered miR-875-5p was an underlying prognostic factor for CRC, and found miR-875-5p is remarkably decreased in human CRC tissues in comparison to normal colorectal tissues.	('CRC', 'Disease', (87, 90))	('CRC', 'Disease', (146, 149))	('decreased', 'NegReg', (127, 136))	('human', 'Species', '9606', (140, 145))	('-875-5p', 'Chemical', '-', (105, 112))	('-875-5p', 'Chemical', '-', (39, 46))	('miR-875-5p', 'Var', (102, 112))
67969	27302926	Moreover, we also revealed over-expression of miR-875-5p inhibits cell growth, metastasis, and promotes cell apoptosis in CRC cell lines, through directly targeting EGFR.	('EGFR', 'Gene', (165, 169))	('cell growth', 'biological_process', 'GO:0016049', ('66', '77'))	('over-expression', 'PosReg', (27, 42))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))	('miR-875-5p', 'Var', (46, 56))	('targeting', 'Reg', (155, 164))	('EGFR', 'molecular_function', 'GO:0005006', ('165', '169'))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('cell growth', 'CPA', (66, 77))	('-875-5p', 'Chemical', '-', (49, 56))	('cell apoptosis', 'CPA', (104, 118))	('metastasis', 'CPA', (79, 89))	('inhibits', 'NegReg', (57, 65))	('promotes', 'PosReg', (95, 103))
67970	27302926	The present results elucidate a potential mechanism underlying the tumor-suppressor role of miR-875-5p, and indicate that miR-875-5p could be a useful marker and potential therapeutic target in colorectal cancer.	('miR-875-5p', 'Var', (92, 102))	('-875-5p', 'Chemical', '-', (125, 132))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('colorectal cancer', 'Disease', 'MESH:D015179', (194, 211))	('miR-875-5p', 'Var', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('-875-5p', 'Chemical', '-', (95, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (194, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Disease', (67, 72))	('colorectal cancer', 'Disease', (194, 211))
68022	27143928	Seventeen patients (28.8%) had the KRAS mutation and 46 patients (80.0%) had the PIK3CA mutation when considering both the primary and metastatic sites.	('mutation', 'Var', (40, 48))	('patients', 'Species', '9606', (56, 64))	('PIK3CA', 'Gene', (81, 87))	('KRAS', 'Gene', (35, 39))	('patients', 'Species', '9606', (10, 18))
68023	27143928	KRAS mutation was observed in ten primary tumors and eleven related metastases (16.9% vs 18.6%), while PIK3CA mutation was found in 26 primary tumors and 32 related metastases (44.1% vs 54.2%).	('primary tumors', 'Disease', (34, 48))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('primary tumors', 'Disease', 'MESH:D009369', (34, 48))	('metastases', 'Disease', 'MESH:D009362', (165, 175))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('metastases', 'Disease', (165, 175))	('PIK3CA', 'Gene', (103, 109))	('primary tumors', 'Disease', (135, 149))	('metastases', 'Disease', 'MESH:D009362', (68, 78))	('primary tumors', 'Disease', 'MESH:D009369', (135, 149))	('metastases', 'Disease', (68, 78))	('observed', 'Reg', (18, 26))	('KRAS', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('mutation', 'Var', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
68032	27143928	Emerging data have proposed phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation might account for nonresponders to EGFR targeting in CRC.	('PIK3CA', 'Gene', (100, 106))	('mutation', 'Var', (108, 116))	('CRC', 'Phenotype', 'HP:0003003', (170, 173))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:D019269', (28, 65))	('EGFR', 'molecular_function', 'GO:0005006', ('152', '156'))
68033	27143928	For example, De Roock et al found that patients with PIK3CA mutations had a significantly lower response rate in KRAS wild-type patient.	('patient', 'Species', '9606', (39, 46))	('patients', 'Species', '9606', (39, 47))	('rat', 'Species', '10116', (105, 108))	('response rate', 'MPA', (96, 109))	('lower', 'NegReg', (90, 95))	('patient', 'Species', '9606', (128, 135))	('mutations', 'Var', (60, 69))	('PIK3CA', 'Gene', (53, 59))
68056	27143928	Age in MRCRC patients was different according to the KRAS mutational status.	('patients', 'Species', '9606', (13, 21))	('CRC', 'Phenotype', 'HP:0003003', (9, 12))	('KRAS', 'Gene', (53, 57))	('MRCRC', 'Disease', (7, 12))	('mutational', 'Var', (58, 68))
68060	27143928	Seventeen patients (28.8%) had the KRAS mutation and 46 patients (80.0%) had PIK3CA mutation in any place of the primary or metastatic sites.	('PIK3CA', 'Gene', (77, 83))	('mutation', 'Var', (40, 48))	('patients', 'Species', '9606', (56, 64))	('KRAS', 'Gene', (35, 39))	('patients', 'Species', '9606', (10, 18))
68061	27143928	Of those 17 patients with KRAS mutation, two patients had a KRAS12 codon GGT-AGT mutation, five had a KRAS12 codon GGT-GCT mutation, four had a KRAS12 codon GGT-GAT mutation, three had a KRAS12 codon GGT-GTT mutation, two had a KRAS13 codon GGC-GAC mutation (one combined with KRAS12 mutation), one had a KRAS61 codon CAA-CAT mutation, and one patient had a KRAS117 codon AAA-ATA mutation.	('patients', 'Species', '9606', (12, 20))	('mutation', 'Var', (31, 39))	('mutation', 'Var', (81, 89))	('AGT', 'Gene', (77, 80))	('patient', 'Species', '9606', (45, 52))	('AGT', 'Gene', '183', (77, 80))	('patients', 'Species', '9606', (45, 53))	('patient', 'Species', '9606', (344, 351))	('patient', 'Species', '9606', (12, 19))	('GAT', 'Gene', '10249', (161, 164))	('GAT', 'Gene', (161, 164))
68062	27143928	In addition, of those 46 patients with PIK3CA mutation, 45 patients had a PIK3CA545 codon CAG-GCG mutation and one had a PIK3CA 545 codon CAG-AAG mutation (Table 3).	('CAG-GCG', 'Gene', (90, 97))	('PIK3CA545 codon', 'Var', (74, 89))	('GCG', 'Chemical', '-', (94, 97))	('patients', 'Species', '9606', (25, 33))	('patients', 'Species', '9606', (59, 67))	('CAG', 'Chemical', '-', (90, 93))	('CAG', 'Chemical', '-', (138, 141))	('mutation', 'Var', (46, 54))	('PIK3CA', 'Gene', (39, 45))
68064	27143928	Of the 14 discordant cases, seven patients had the KRAS mutation in the primary tumors, but not in the metastatic sites; seven patients had the KRAS mutation only in the metastatic tumors and not in the primary tumors.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('primary tumors', 'Disease', 'MESH:D009369', (203, 217))	('tumors', 'Disease', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('KRAS', 'Gene', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('primary tumors', 'Disease', (72, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('tumors', 'Disease', (181, 187))	('primary tumors', 'Disease', 'MESH:D009369', (72, 86))	('patients', 'Species', '9606', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('mutation', 'Var', (56, 64))	('tumors', 'Disease', (211, 217))	('primary tumors', 'Disease', (203, 217))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('patients', 'Species', '9606', (127, 135))
68066	27143928	Of the 34 discordant cases, 14 patients had the KRAS mutation in the primary tumors, and not in the metastatic sites; 20 patients had the KRAS mutation in the metastatic tumors without in the primary tumors (Table 4).	('mutation', 'Var', (53, 61))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('primary tumors', 'Disease', 'MESH:D009369', (69, 83))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('primary tumors', 'Disease', (192, 206))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumors', 'Disease', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('primary tumors', 'Disease', 'MESH:D009369', (192, 206))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('patients', 'Species', '9606', (121, 129))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('KRAS', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('primary tumors', 'Disease', (69, 83))	('tumors', 'Disease', (200, 206))	('patients', 'Species', '9606', (31, 39))	('tumors', 'Disease', (170, 176))
68080	27143928	Heterogeneous in genes have been reported to play a role in resistance to anti-EGFR drugs in CRC, including activating mutations in KRAS, NRAS, BRAF, and PIK3CA.	('KRAS', 'Gene', (132, 136))	('PIK3CA', 'Gene', (154, 160))	('NRAS', 'Gene', '4893', (138, 142))	('CRC', 'Phenotype', 'HP:0003003', (93, 96))	('EGFR', 'molecular_function', 'GO:0005006', ('79', '83'))	('BRAF', 'Gene', '673', (144, 148))	('resistance', 'MPA', (60, 70))	('activating', 'PosReg', (108, 118))	('BRAF', 'Gene', (144, 148))	('mutations', 'Var', (119, 128))	('NRAS', 'Gene', (138, 142))
68083	27143928	We evaluated all the genes statuses, such as KRAS, NRAS, BRAF, and PIK3CA in primary CRC and their matched metastasis, and compared the discordance between the two sites.	('BRAF', 'Gene', '673', (57, 61))	('BRAF', 'Gene', (57, 61))	('NRAS', 'Gene', (51, 55))	('CRC', 'Phenotype', 'HP:0003003', (85, 88))	('PIK3CA', 'Gene', (67, 73))	('KRAS', 'Var', (45, 49))	('NRAS', 'Gene', '4893', (51, 55))
68087	27143928	While PIK3CA mutations were detected in 80% of patients with 44.1% of primary tumors and 54.2% of related metastatic sites, respectively, which showed relatively higher mutational rate than that of prior reports.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('detected', 'Reg', (28, 36))	('rat', 'Species', '10116', (180, 183))	('patients', 'Species', '9606', (47, 55))	('primary tumors', 'Disease', (70, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('PIK3CA', 'Gene', (6, 12))	('primary tumors', 'Disease', 'MESH:D009369', (70, 84))	('mutations', 'Var', (13, 22))
68088	27143928	Furthermore, ten patients out of 59 in our study harbored both KRAS and PIK3CA mutations, which may be a certain cluster having the low response to EGFR-targeted treatment and a poor prognosis, which can be deduced from the previous reports.	('PIK3CA', 'Gene', (72, 78))	('harbored', 'Reg', (49, 57))	('patients', 'Species', '9606', (17, 25))	('mutations', 'Var', (79, 88))	('KRAS', 'Gene', (63, 67))
68089	27143928	Our findings demonstrate a high level of concordance of KRAS mutation status and a significant discordance of PIK3CA mutation status in primary tumors and matched metastases, which is in agreement with previous studies.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('metastases', 'Disease', (163, 173))	('primary tumors', 'Disease', 'MESH:D009369', (136, 150))	('KRAS', 'Gene', (56, 60))	('mutation', 'Var', (61, 69))	('metastases', 'Disease', 'MESH:D009362', (163, 173))	('rat', 'Species', '10116', (20, 23))	('PIK3CA', 'Gene', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('primary tumors', 'Disease', (136, 150))
68092	27143928	Nevertheless, PIK3CA gene mutational rate was more frequently observed in metastatic specimens than primary sites (61.5% vs 44.6%; P=0.025) in our unselected CRC patients (table not shown).	('patients', 'Species', '9606', (162, 170))	('CRC', 'Phenotype', 'HP:0003003', (158, 161))	('rat', 'Species', '10116', (37, 40))	('CRC', 'Disease', (158, 161))	('mutational', 'Var', (26, 36))	('PIK3CA gene', 'Gene', (14, 25))	('observed', 'Reg', (62, 70))
68093	27143928	De Roock et al9 reported that PIK3CA mutations may negatively impact the response to EGFR inhibitors of CRC patients, and PIK3CA exon 20 mutations were also significantly associated with shorter survival.7 Also, Domingo et al22 found that patients with PIK3CA mutant could benefit from aspirin therapy after CRC diagnosis and had a reduced rate of CRC recurrence.	('PIK3CA', 'Gene', (253, 259))	('CRC', 'Disease', (348, 351))	('patients', 'Species', '9606', (108, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('85', '89'))	('patients', 'Species', '9606', (239, 247))	('CRC', 'Phenotype', 'HP:0003003', (104, 107))	('CRC', 'Phenotype', 'HP:0003003', (308, 311))	('CRC', 'Phenotype', 'HP:0003003', (348, 351))	('rat', 'Species', '10116', (340, 343))	('mutant', 'Var', (260, 266))	('benefit', 'PosReg', (273, 280))	('aspirin', 'Chemical', 'MESH:D001241', (286, 293))
68100	27143928	This study demonstrated the existence of a significant discordance of PIK3CA and relative concordance of KRAS mutations occurring in primary tumors and their corresponding metastases in patients with CRC.	('rat', 'Species', '10116', (18, 21))	('primary tumors', 'Disease', (133, 147))	('mutations', 'Var', (110, 119))	('metastases', 'Disease', 'MESH:D009362', (172, 182))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('KRAS', 'Gene', (105, 109))	('primary tumors', 'Disease', 'MESH:D009369', (133, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('CRC', 'Phenotype', 'HP:0003003', (200, 203))	('metastases', 'Disease', (172, 182))	('patients', 'Species', '9606', (186, 194))
68102	27143928	In conclusion, our findings indicate a concordance of KRAS mutation and a discordance of PIK3CA mutation between the primary tumors and the matched metastases in CRC and suggest that status of specific molecules in metastatic tumors need to be reevaluated when the patients with metastases are about to use the EGFR-targeted therapy.	('metastases', 'Disease', (148, 158))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('mutation', 'Var', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('metastases', 'Disease', 'MESH:D009362', (279, 289))	('tumors', 'Disease', (125, 131))	('mutation', 'Var', (96, 104))	('CRC', 'Phenotype', 'HP:0003003', (162, 165))	('patients', 'Species', '9606', (265, 273))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('metastases', 'Disease', (279, 289))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('primary tumors', 'Disease', (117, 131))	('PIK3CA', 'Gene', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (226, 232))	('primary tumors', 'Disease', 'MESH:D009369', (117, 131))	('KRAS', 'Gene', (54, 58))	('metastases', 'Disease', 'MESH:D009362', (148, 158))
68213	23115701	Although long-term use of these drugs is considered safe, concern has risen regarding the possible link between PPI-induced hypergastrinemia and gastrointestinal cancers, including colorectal cancer (CRC).	('colorectal cancer', 'Phenotype', 'HP:0003003', (181, 198))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (124, 140))	('PPI-induced', 'Var', (112, 123))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('hypergastrinemia and gastrointestinal cancers', 'Disease', 'MESH:D004067', (124, 169))	('colorectal cancer', 'Disease', (181, 198))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (181, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
68239	23115701	Usually, the cumulative duration of hypergastrinemia due to PPI therapy might be shorter than other chronic conditions such as pernicious anemia or Zollinger-Ellison syndrome.	('Zollinger-Ellison syndrome', 'Phenotype', 'HP:0002044', (148, 174))	('anemia', 'Disease', 'MESH:D000740', (138, 144))	('hypergastrinemia', 'Disease', (36, 52))	('hypergastrinemia', 'Disease', 'None', (36, 52))	('Zollinger-Ellison syndrome', 'Disease', 'MESH:D015043', (148, 174))	('anemia', 'Phenotype', 'HP:0001903', (138, 144))	('Zollinger-Ellison syndrome', 'Disease', (148, 174))	('PPI therapy', 'Var', (60, 71))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (36, 52))	('anemia', 'Disease', (138, 144))
68244	23115701	It is possible that, if some patients under chronic conditions of acid suppression might receive high-dose PPI therapy, this could lead to a more significant degree of additive hypergastrinemia and may have a clinical impact on increase of CRC risk.	('CRC', 'Disease', (240, 243))	('patients', 'Species', '9606', (29, 37))	('increase', 'PosReg', (228, 236))	('additive hypergastrinemia', 'Disease', 'MESH:C538523', (168, 193))	('hypergastrinemia', 'Phenotype', 'HP:0500167', (177, 193))	('additive hypergastrinemia', 'Disease', (168, 193))	('lead to', 'Reg', (131, 138))	('PPI', 'Var', (107, 110))
68250	31209889	To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls.	('Colon Cancer', 'Disease', 'MESH:D015179', (220, 232))	('single nucleotide', 'Var', (128, 145))	('cancer', 'Disease', (82, 88))	('Cancer', 'Phenotype', 'HP:0002664', (226, 232))	('rectum cancer', 'Disease', (372, 385))	('colon cancer', 'Disease', 'MESH:D015179', (352, 364))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (358, 364))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (293, 310))	('Cancer', 'Phenotype', 'HP:0002664', (304, 310))	('colon', 'Disease', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (358, 364))	('rectum cancer', 'Phenotype', 'HP:0100743', (372, 385))	('colon', 'Disease', (352, 357))	('cancer', 'Disease', (379, 385))	('colon', 'Disease', 'MESH:D003110', (65, 70))	('colon cancer', 'Disease', (352, 364))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('colon', 'Disease', 'MESH:D003110', (352, 357))	('Colon Cancer', 'Phenotype', 'HP:0003003', (220, 232))	('cancer', 'Disease', 'MESH:D009369', (358, 364))	('Colon Cancer', 'Disease', (220, 232))	('rectal cancer', 'Phenotype', 'HP:0100743', (75, 88))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (293, 310))	('rectum cancer', 'Disease', 'MESH:D012004', (372, 385))	('Colorectal Cancer', 'Disease', (293, 310))	('cancer', 'Disease', 'MESH:D009369', (379, 385))	('colon cancer', 'Phenotype', 'HP:0003003', (352, 364))
68251	31209889	Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value=3.5x10-6) and rs2189517 (in RAD51B) with rectal cancer risk (p-value=5.7x10-6).	('Rs1800734', 'Var', (0, 9))	('colon cancer', 'Disease', (45, 57))	('Rs1800734', 'Mutation', 'Rs1800734', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('rectal cancer', 'Phenotype', 'HP:0100743', (113, 126))	('MLH1', 'Gene', (14, 18))	('rs2189517', 'Var', (86, 95))	('colon cancer', 'Phenotype', 'HP:0003003', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('colon cancer', 'Disease', 'MESH:D015179', (45, 57))	('associated', 'Reg', (29, 39))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('RAD', 'biological_process', 'GO:1990116', ('100', '103'))	('rs2189517', 'Mutation', 'rs2189517', (86, 95))
68252	31209889	Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively.	('mismatch repair', 'biological_process', 'GO:0006298', ('170', '185'))	('DNA', 'cellular_component', 'GO:0005574', ('166', '169'))	('MMR', 'biological_process', 'GO:0006298', ('187', '190'))	('homologous recombination', 'biological_process', 'GO:0035825', ('196', '220'))	('SNPs', 'Var', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('rectal cancer', 'Phenotype', 'HP:0100743', (56, 69))	('colorectal cancer', 'Disease', (52, 69))	('colon and rectum cancer', 'Disease', 'MESH:D015179', (234, 257))	('associated with', 'Reg', (36, 51))	('rectum cancer', 'Phenotype', 'HP:0100743', (244, 257))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))
68253	31209889	Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer.	('important', 'Reg', (154, 163))	('sporadic colon cancer', 'Disease', 'MESH:D015179', (205, 226))	('colon cancer', 'Phenotype', 'HP:0003003', (214, 226))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('variations', 'Var', (131, 141))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal cancer', 'Disease', (66, 83))	('rectal cancer', 'Phenotype', 'HP:0100743', (70, 83))	('sporadic colon cancer', 'Disease', (205, 226))	('MLH1', 'Gene', (145, 149))	('MMR', 'biological_process', 'GO:0006298', ('11', '14'))	('colorectal cancer', 'Disease', 'MESH:D015179', (66, 83))
68255	31209889	rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.	('rs16906252', 'Var', (0, 10))	('colon', 'Disease', (67, 72))	('mRNA expression levels', 'MPA', (41, 63))	('carcinogenesis', 'Disease', 'MESH:D063646', (161, 175))	('rs16906252', 'Mutation', 'rs16906252', (0, 10))	('carcinogenesis', 'Disease', (161, 175))	('affect', 'Reg', (34, 40))	('colon', 'Disease', 'MESH:D003110', (67, 72))
68261	31209889	The role of surveillance operated by MMR seems pivotal for colonocytes, as deficiencies within this pathway are observed also at somatic level in 7-10% of the sporadic forms conferring the so-called "microsatellite instability" (MSI) phenotype .	('colon', 'Disease', 'MESH:D003110', (59, 64))	('colon', 'Disease', (59, 64))	('deficiencies', 'Var', (75, 87))
68264	31209889	Positive associations were described for single-nucleotide polymorphisms (SNPs) within APEX, ERCC1, MUTYH, OGG1, XPC, XPG, XRCC1, and XRCC3 genes , but some results were either discordant or not replicated  likely as the consequence of a limited statistical power.	('XRCC3', 'Gene', (134, 139))	('single-nucleotide', 'Chemical', '-', (41, 58))	('ERCC1', 'Gene', (93, 98))	('XRCC1', 'Gene', (123, 128))	('XPC', 'Gene', (113, 116))	('APEX', 'Gene', (87, 91))	('APEX', 'cellular_component', 'GO:0097683', ('87', '91'))	('MUTYH', 'Gene', (100, 105))	('XPG', 'Gene', (118, 121))	('OGG1', 'Gene', (107, 111))	('single-nucleotide polymorphisms', 'Var', (41, 72))
68265	31209889	Similarly, GWASs carried out on other types of cancer detected only few DNA repair SNPs (see the GWAS catalog https://www.ebi.ac.uk/gwas/home) such as in breast cancer the rs999737 near RAD51L1, likely affecting the DSB DNA repair .	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('DNA', 'cellular_component', 'GO:0005574', ('220', '223'))	('rs999737', 'Mutation', 'rs999737', (172, 180))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('RAD51L1', 'Gene', (186, 193))	('rs999737', 'Var', (172, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('cancer', 'Disease', (47, 53))	('affecting', 'Reg', (202, 211))	('RAD', 'biological_process', 'GO:1990116', ('186', '189'))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (161, 167))	('DNA repair', 'biological_process', 'GO:0006281', ('220', '230'))	('DNA repair', 'biological_process', 'GO:0006281', ('72', '82'))
68267	31209889	However, a previous study with adequate statistical power showed that the set of DNA repair SNPs, as a whole, could be associated with colorectal cancer risk .	('colorectal cancer', 'Disease', 'MESH:D015179', (135, 152))	('associated with', 'Reg', (119, 134))	('SNPs', 'Var', (92, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('DNA', 'Gene', (81, 84))	('colorectal cancer', 'Disease', (135, 152))	('rectal cancer', 'Phenotype', 'HP:0100743', (139, 152))
68268	31209889	Meta-analyses suggested also positive associations for rs1052133 and rs861539, respectively within hOGG1  and XRCC3  genes.	('positive', 'PosReg', (29, 37))	('rs861539', 'Mutation', 'rs861539', (69, 77))	('rs1052133', 'Mutation', 'rs1052133', (55, 64))	('rs1052133', 'Var', (55, 64))	('hOGG1', 'Gene', (99, 104))	('rs861539', 'Var', (69, 77))	('XRCC3', 'Gene', (110, 115))
68281	31209889	The SNP rs1800734 in MLH1 was significantly associated with the risk of colon cancer after Bonferroni's adjustment (OR=1.13, 95%CI= 1.07-1.18, p=3.5X10-6; Table 2).	('associated', 'Reg', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colon cancer', 'Disease', (72, 84))	('MLH1', 'Gene', (21, 25))	('rs1800734', 'Mutation', 'rs1800734', (8, 17))	('SNP rs1800734', 'Var', (4, 17))	('colon cancer', 'Phenotype', 'HP:0003003', (72, 84))	('colon cancer', 'Disease', 'MESH:D015179', (72, 84))
68282	31209889	rs6784088 (OR=0.94, 95%CI= 0.90-0.98, p= 3.3x10-3) and rs9855475 (OR=0.94, 95%CI= 0.90-0.98, p=3.4X10-3), were associated with the risk of colon cancer when BSGoF was applied (Table 2).	('colon cancer', 'Disease', 'MESH:D015179', (139, 151))	('rs9855475', 'Mutation', 'rs9855475', (55, 64))	('colon cancer', 'Disease', (139, 151))	('rs6784088', 'Mutation', 'rs6784088', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('rs6784088', 'Var', (0, 9))	('rs9855475', 'Var', (55, 64))	('colon cancer', 'Phenotype', 'HP:0003003', (139, 151))
68285	31209889	Concerning rectal cancer, the strongest signal was found for rs2189517 within RAD51B (OR=1.15, 95% CI=1.08-1.22, p-value=5.7x10-6), a gene involved in Homologous recombination repair (HR), statistically significant also following the Bonferroni's correction (Table 3).	('rs2189517', 'Mutation', 'rs2189517', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('RAD51B', 'Gene', (78, 84))	('rectal cancer', 'Phenotype', 'HP:0100743', (11, 24))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('rs2189517', 'Var', (61, 70))
68287	31209889	The list of these SNPs includes rs12587232, rs187645011, rs7350713, rs6573841, rs111611396, rs1989974, rs117544253, rs77726787, rs8016488, rs11628293, rs113020754, rs80085210, rs113300322, and rs74933543.	('rs74933543', 'Var', (193, 203))	('rs7350713', 'Var', (57, 66))	('rs11628293', 'Var', (139, 149))	('rs11628293', 'Mutation', 'rs11628293', (139, 149))	('rs80085210', 'Var', (164, 174))	('rs8016488', 'Var', (128, 137))	('rs6573841', 'Mutation', 'rs6573841', (68, 77))	('rs187645011', 'Var', (44, 55))	('rs111611396', 'Mutation', 'rs111611396', (79, 90))	('rs12587232', 'Var', (32, 42))	('rs77726787', 'Var', (116, 126))	('rs117544253', 'Mutation', 'rs117544253', (103, 114))	('rs6573841', 'Var', (68, 77))	('rs1989974', 'Mutation', 'rs1989974', (92, 101))	('rs187645011', 'Mutation', 'rs187645011', (44, 55))	('rs113020754', 'Mutation', 'rs113020754', (151, 162))	('rs111611396', 'Var', (79, 90))	('rs74933543', 'Mutation', 'rs74933543', (193, 203))	('rs77726787', 'Mutation', 'rs77726787', (116, 126))	('rs7350713', 'Mutation', 'rs7350713', (57, 66))	('rs80085210', 'Mutation', 'rs80085210', (164, 174))	('rs113300322', 'Var', (176, 187))	('rs113300322', 'Mutation', 'rs113300322', (176, 187))	('rs12587232', 'Mutation', 'rs12587232', (32, 42))	('rs1989974', 'Var', (92, 101))	('rs113020754', 'Var', (151, 162))	('rs8016488', 'Mutation', 'rs8016488', (128, 137))	('rs117544253', 'Var', (103, 114))
68289	31209889	Rs2189517 was not in LD with the others (r<0.3) with the exception of rs12587232, having r of 0.77.	('rs12587232', 'Mutation', 'rs12587232', (70, 80))	('rs12587232', 'Var', (70, 80))	('Rs2189517', 'Var', (0, 9))	('Rs2189517', 'Mutation', 'Rs2189517', (0, 9))
68290	31209889	Rs2189517 was associated also with colorectal cancer risk (OR= 1.05, 95%CI= 1.02-1.09, p=1.7x10-3) although statistically significant only following BSGoF correction.	('rectal cancer', 'Phenotype', 'HP:0100743', (39, 52))	('colorectal cancer', 'Disease', 'MESH:D015179', (35, 52))	('Rs2189517', 'Var', (0, 9))	('colorectal cancer', 'Phenotype', 'HP:0003003', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('colorectal cancer', 'Disease', (35, 52))	('Rs2189517', 'Mutation', 'Rs2189517', (0, 9))
68291	31209889	When more exploratory and hypothesis-generating analyses were performed by considering statistically significant SNPs following BSGoF adjustment, several genes had multiple htSNPs associated with the risk of colon carcinoma, such as ATM (rs11212592, rs61915066), FANCA (rs2238526, rs3743860), FANCE (rs6907678, rs10947550), and LIG1 (rs1971775, rs73054038).	('rs3743860', 'Mutation', 'rs3743860', (281, 290))	('rs10947550', 'Var', (311, 321))	('FANCA', 'Disease', (263, 268))	('colon carcinoma', 'Disease', 'MESH:D003110', (208, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('associated', 'Reg', (180, 190))	('rs11212592', 'Var', (238, 248))	('rs10947550', 'Mutation', 'rs10947550', (311, 321))	('rs3743860', 'Var', (281, 290))	('rs61915066', 'Mutation', 'rs61915066', (250, 260))	('rs61915066', 'Var', (250, 260))	('rs73054038', 'Mutation', 'rs73054038', (345, 355))	('rs6907678', 'Mutation', 'rs6907678', (300, 309))	('FANCE', 'Disease', (293, 298))	('rs73054038', 'Var', (345, 355))	('rs1971775', 'Var', (334, 343))	('rs1971775', 'Mutation', 'rs1971775', (334, 343))	('rs2238526', 'Mutation', 'rs2238526', (270, 279))	('rs2238526', 'Var', (270, 279))	('rs11212592', 'Mutation', 'rs11212592', (238, 248))	('colon carcinoma', 'Disease', (208, 223))	('rs6907678', 'Var', (300, 309))
68292	31209889	For rectal carcinoma, multiple hits were found within BLM (rs2518967, rs35787687), PMS1 (rs1233258, rs1233262) and RAD51B (14 hits).	('rs1233258', 'Var', (89, 98))	('rs2518967', 'Var', (59, 68))	('rs1233258', 'Mutation', 'rs1233258', (89, 98))	('rectal carcinoma', 'Disease', 'MESH:D012004', (4, 20))	('rs35787687', 'Mutation', 'rs35787687', (70, 80))	('rectal carcinoma', 'Disease', (4, 20))	('rs2518967', 'Mutation', 'rs2518967', (59, 68))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (4, 20))	('rs35787687', 'Var', (70, 80))	('rs1233262', 'Mutation', 'rs1233262', (100, 109))	('rs1233262', 'Var', (100, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
68293	31209889	Rs1800734 was associated with MLH1 expression in colon transverse but the statistical significance did not reach the genome-wide level (p=9.9x10-4, normalized effect size, NES, of 0.12).	('Rs1800734', 'Var', (0, 9))	('Rs1800734', 'Mutation', 'Rs1800734', (0, 9))	('colon', 'Disease', 'MESH:D003110', (49, 54))	('expression', 'MPA', (35, 45))	('MLH1', 'Gene', (30, 34))	('colon', 'Disease', (49, 54))
68294	31209889	On the other hand, rs2189517 lacked completely any association with the expression of RAD51B in colonic tissues as well as in all other tissues available in GTex portal.	('RAD51B', 'Gene', (86, 92))	('rs2189517', 'Mutation', 'rs2189517', (19, 28))	('RAD', 'biological_process', 'GO:1990116', ('86', '89'))	('colon', 'Disease', 'MESH:D003110', (96, 101))	('colon', 'Disease', (96, 101))	('rs2189517', 'Var', (19, 28))	('lacked', 'NegReg', (29, 35))
68295	31209889	In the present study, we comprehensively analyzed variations in 185 DNA repair genes in over 27,000 individuals  to ascertain their implication for colon and rectal cancer risk.	('DNA repair genes', 'Gene', (68, 84))	('colon', 'Disease', 'MESH:D003110', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('rectal cancer', 'Phenotype', 'HP:0100743', (158, 171))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('colon', 'Disease', (148, 153))	('variations', 'Var', (50, 60))
68296	31209889	rs1800734 in MLH1 and rs2189517 in RAD51B) were associated in a statistically significant way with increased risk for cancer in colon and rectum, respectively.	('RAD', 'biological_process', 'GO:1990116', ('35', '38'))	('cancer', 'Disease', (118, 124))	('rs1800734', 'Mutation', 'rs1800734', (0, 9))	('RAD51B', 'Gene', (35, 41))	('MLH1', 'Gene', (13, 17))	('associated', 'Reg', (48, 58))	('rs2189517', 'Mutation', 'rs2189517', (22, 31))	('colon and rectum', 'Disease', 'MESH:D012004', (128, 144))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('rs1800734', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('rs2189517', 'Var', (22, 31))
68298	31209889	Mutations within MLH1 (MMR) predispose to HNPCC type-2 .	('HNPCC', 'Disease', 'None', (42, 47))	('HNPCC', 'Disease', (42, 47))	('MLH1 (MMR', 'Gene', (17, 26))	('Mutations', 'Var', (0, 9))	('predispose', 'Reg', (28, 38))
68299	31209889	Somatic mutations as well as hyper-methylation of the gene promoter were frequently observed also in sporadic colorectal cancer tissues associated with a MSI phenotype .	('associated', 'Reg', (136, 146))	('colorectal cancer', 'Disease', 'MESH:D015179', (110, 127))	('rectal cancer', 'Phenotype', 'HP:0100743', (114, 127))	('hyper-methylation', 'Var', (29, 46))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('observed', 'Reg', (84, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (110, 127))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))	('colorectal cancer', 'Disease', (110, 127))
68301	31209889	The polymorphism has been associated with promoter methylation and gene silencing  and a meta-analysis by Wang and colleagues  reported that carriers of the A-allele are at increased risk of colorectal cancer, in agreement with the present results.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('colorectal cancer', 'Disease', (191, 208))	('promoter methylation', 'MPA', (42, 62))	('colorectal cancer', 'Disease', 'MESH:D015179', (191, 208))	('gene', 'MPA', (67, 71))	('rectal cancer', 'Phenotype', 'HP:0100743', (195, 208))	('colorectal cancer', 'Phenotype', 'HP:0003003', (191, 208))	('polymorphism', 'Var', (4, 16))
68302	31209889	Our results, carried out on a very large series of patients, suggest that rs1800734 plays a role particularly in colon, perhaps causing a decreased activity of the MMR in this tissue .	('colon', 'Disease', (113, 118))	('decreased', 'NegReg', (138, 147))	('activity', 'MPA', (148, 156))	('rs1800734', 'Var', (74, 83))	('rs1800734', 'Mutation', 'rs1800734', (74, 83))	('MMR', 'Protein', (164, 167))	('colon', 'Disease', 'MESH:D003110', (113, 118))
68303	31209889	This hypothesis is corroborated by the data from GTEx reporting that rs1800734 could act as a cis-eQTL by affecting mRNA expression levels in colon transverse (p=9.9x10-4 with NES of 0.12).	('rs1800734', 'Var', (69, 78))	('mRNA expression levels', 'MPA', (116, 138))	('affecting', 'Reg', (106, 115))	('colon', 'Disease', 'MESH:D003110', (142, 147))	('rs1800734', 'Mutation', 'rs1800734', (69, 78))	('colon', 'Disease', (142, 147))
68306	31209889	Interestingly, previous studies reported that various RAD51B SNPs in LD with those reported in our study were associated with the susceptibility to prostate and breast cancer .	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('susceptibility', 'Reg', (130, 144))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('RAD', 'biological_process', 'GO:1990116', ('54', '57'))	('breast cancer', 'Disease', (161, 174))	('RAD51B', 'Gene', (54, 60))	('associated', 'Reg', (110, 120))	('SNPs', 'Var', (61, 65))	('prostate', 'Disease', (148, 156))
68307	31209889	Finally, rs2189517 has been recently related to the risk of prostate cancer in a GWAS .	('rs2189517', 'Mutation', 'rs2189517', (9, 18))	('prostate cancer', 'Disease', (60, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('related', 'Reg', (37, 44))	('rs2189517', 'Var', (9, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (60, 75))	('prostate cancer', 'Phenotype', 'HP:0012125', (60, 75))
68308	31209889	Furthermore, it should be stressed that other SNPs within the last intron of RAD51B, and not in LD with those presented here, were involved in the susceptibility to breast cancer in males , and females .	('SNPs', 'Var', (46, 50))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('susceptibility', 'Reg', (147, 161))	('RAD51B', 'Gene', (77, 83))	('involved', 'Reg', (131, 139))
68309	31209889	Germline mutations within RAD51B were also found to confer predisposition to familial breast and ovarian cancer , and cutaneous melanoma .	('Germline mutations', 'Var', (0, 18))	('cutaneous melanoma', 'Disease', (118, 136))	('predisposition', 'Reg', (59, 73))	('RAD51B', 'Gene', (26, 32))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (118, 136))	('familial breast and ovarian cancer', 'Disease', 'MESH:D000071298', (77, 111))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (118, 136))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))	('RAD', 'biological_process', 'GO:1990116', ('26', '29'))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))
68311	31209889	In fact, MMR showed more signals such as rs12112229 in PMS2, rs4658549 in EXO1, and rs72812338 in MSH2 associated with increased colon cancer risk.	('rs72812338', 'Mutation', 'rs72812338', (84, 94))	('EXO1', 'Gene', (74, 78))	('colon cancer', 'Phenotype', 'HP:0003003', (129, 141))	('MSH2', 'Gene', (98, 102))	('associated', 'Reg', (103, 113))	('PMS2', 'Gene', (55, 59))	('colon cancer', 'Disease', 'MESH:D015179', (129, 141))	('MSH2', 'Chemical', '-', (98, 102))	('rs12112229', 'Mutation', 'rs12112229', (41, 51))	('rs4658549', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('colon cancer', 'Disease', (129, 141))	('rs12112229', 'Var', (41, 51))	('rs4658549', 'Mutation', 'rs4658549', (61, 70))	('rs72812338', 'Var', (84, 94))
68313	31209889	Additionally, together with the RAD51B SNPs found in the present study, other htSNPs within the same gene resulted associated with risk of rectal cancer being the association of rs2189517 with the lowest P-value while that of rs187645011 with the highest OR.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('rs2189517', 'Var', (178, 187))	('associated', 'Reg', (115, 125))	('rs2189517', 'Mutation', 'rs2189517', (178, 187))	('rs187645011', 'Var', (226, 237))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('rs187645011', 'Mutation', 'rs187645011', (226, 237))	('RAD', 'biological_process', 'GO:1990116', ('32', '35'))	('rectal cancer', 'Phenotype', 'HP:0100743', (139, 152))
68314	31209889	In summary, according to all these observations, RAD51B and HR appear as pivotal in the individual susceptibility to various types of tumors, including rectal carcinoma.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('RAD51B', 'Var', (49, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('rectal carcinoma', 'Disease', 'MESH:D012004', (152, 168))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('rectal carcinoma', 'Disease', (152, 168))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (152, 168))
68315	31209889	All findings hereby presented suggest the importance of genetic variations within MMR genes (in particular those that could physically interact with each other for intact MMR activity) in the predisposition to non-inherited forms of colon cancer.	('colon cancer', 'Disease', (233, 245))	('MMR genes', 'Gene', (82, 91))	('non-inherited forms', 'Disease', (210, 229))	('colon cancer', 'Phenotype', 'HP:0003003', (233, 245))	('colon cancer', 'Disease', 'MESH:D015179', (233, 245))	('genetic variations', 'Var', (56, 74))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
68316	31209889	In contrast, for rectal carcinoma, the strongest associations were observed for a SNP within RAD51B, a gene involved in HR.	('rectal carcinoma', 'Phenotype', 'HP:0100743', (17, 33))	('rectal carcinoma', 'Disease', (17, 33))	('RAD51B', 'Gene', (93, 99))	('RAD', 'biological_process', 'GO:1990116', ('93', '96'))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('SNP', 'Var', (82, 85))	('rectal carcinoma', 'Disease', 'MESH:D012004', (17, 33))
68317	31209889	Thus, our results show that genetic variations within DNA repair genes, in particular MMR and HR, significantly affect the risk of colon and rectal carcinoma independently with a significant impact not only, as known, for the familial forms but also for the sporadic ones.	('DNA repair genes', 'Gene', (54, 70))	('colon and rectal carcinoma', 'Disease', 'MESH:D003110', (131, 157))	('affect', 'Reg', (112, 118))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (141, 157))	('genetic variations', 'Var', (28, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('MMR', 'Gene', (86, 89))
68318	31209889	BSGoF binomial sequential goodness of fit CCFR Colon Cancer Family Registry CI confidence interval eQTL expression quantitative trait loci FDR false discovery rate GECCO Genetics and Epidemiology of Colorectal Cancer GWAS genome-wide association studies HNPCC hereditary nonpolyposis colorectal cancer HR homologous recombination HRC Haplotype Reference Consortium htSNPs haplotype tagging SNPs HWE Hardy-Weinberg Equilibrium LD linkage disequilibrium MAF minor allele frequency MMR mismatch repair pathway MSI microsatellite instability NES normalized effect size OR odds ratio PARP poly(ADP-ribose) polymerase PCs principal components SNPs single-nucleotide polymorphisms The results presented in this study provide new insights on candidate SNPs (rs1800734 in MLH1 gene and rs2189517 in RAD51B) involved in DNA repair that may spur downstream investigation into the biology of risk for colon and rectal cancers with a reflection in improving drug development and clinical guidelines, such as personalized screening decisions.	('rs1800734', 'Var', (750, 759))	('rs2189517', 'Var', (777, 786))	('cancers', 'Phenotype', 'HP:0002664', (906, 913))	('rectal cancer', 'Phenotype', 'HP:0100743', (899, 912))	('rs1800734', 'Mutation', 'rs1800734', (750, 759))	('Cancer', 'Phenotype', 'HP:0002664', (210, 216))	('HRC', 'Disease', 'None', (330, 333))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('hereditary nonpolyposis colorectal cancer', 'Disease', (260, 301))	('goodness of fit', 'Disease', (26, 41))	('cancer', 'Phenotype', 'HP:0002664', (906, 912))	('goodness of fit', 'Disease', 'MESH:D012640', (26, 41))	('HNPCC', 'Disease', 'None', (254, 259))	('HNPCC', 'Disease', (254, 259))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (199, 216))	('hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (260, 301))	('Colorectal Cancer', 'Disease', (199, 216))	('hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (260, 301))	('MLH1', 'Gene', (763, 767))	('rs2189517', 'Mutation', 'rs2189517', (777, 786))	('Colon Cancer', 'Phenotype', 'HP:0003003', (47, 59))	('Colon Cancer', 'Disease', (47, 59))	('colon and rectal cancers', 'Disease', 'MESH:D015179', (889, 913))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('RAD51B', 'Gene', (790, 796))	('rectal cancer', 'Phenotype', 'HP:0100743', (288, 301))	('HRC', 'Disease', (330, 333))	('single-nucleotide', 'Chemical', '-', (642, 659))	('colorectal cancer', 'Phenotype', 'HP:0003003', (284, 301))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (199, 216))	('Colon Cancer', 'Disease', 'MESH:D015179', (47, 59))
68330	31653137	Concomitantly, several studies aiming to find other tests capable of detecting mutations in colorectal carcinogenesis are being developed to improve the chance to trace the cancer (Itzkowitz et al., 2007, AHRQ, 2012, MLDT, 2014).	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('colorectal carcinogenesis', 'Disease', (92, 117))	('colorectal carcinogenesis', 'Disease', 'MESH:D015179', (92, 117))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('mutations', 'Var', (79, 88))
68334	31653137	Currently, the commercially available in the United States called Cologuard  test analyzes KRAS mutations, NDRG4 and BMP3 methylation and ACTB gene (MLDT, 2014).	('methylation', 'biological_process', 'GO:0032259', ('122', '133'))	('BMP3', 'Gene', '651', (117, 121))	('NDRG4', 'Gene', '65009', (107, 112))	('NDRG4', 'Gene', (107, 112))	('BMP3', 'Gene', (117, 121))	('analyzes', 'Reg', (82, 90))	('KRAS', 'Gene', (91, 95))	('ACTB', 'Gene', '60', (138, 142))	('KRAS', 'Gene', '3845', (91, 95))	('mutations', 'Var', (96, 105))	('ACTB', 'Gene', (138, 142))
68350	31653137	The Evidence InvestigatorTM KBP Array detects 20 mutations in KRAS, BRAF and PIK3CA genes in DNA extracted from CRC tissue.	('PIK3CA', 'Gene', (77, 83))	('KRAS', 'Gene', (62, 66))	('mutations', 'Var', (49, 58))	('BRAF', 'Gene', '673', (68, 72))	('KRAS', 'Gene', '3845', (62, 66))	('PIK3CA', 'Gene', '5290', (77, 83))	('BRAF', 'Gene', (68, 72))	('detects', 'Reg', (38, 45))	('CRC', 'Phenotype', 'HP:0003003', (112, 115))
68358	31653137	KRAS gene mutations were the most prevalent, mainly in the CRC group (41.2%) (Table 1).	('KRAS', 'Gene', '3845', (0, 4))	('CRC', 'Phenotype', 'HP:0003003', (59, 62))	('mutations', 'Var', (10, 19))	('CRC', 'Disease', (59, 62))	('KRAS', 'Gene', (0, 4))	('prevalent', 'Reg', (34, 43))
68359	31653137	KRAS mutations were prevalent in CRC and polyp groups (52% and 32%, respectively).	('CRC', 'Disease', (33, 36))	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('polyp', 'Disease', (41, 46))	('prevalent', 'Reg', (20, 29))	('CRC', 'Phenotype', 'HP:0003003', (33, 36))	('KRAS', 'Gene', '3845', (0, 4))
68360	31653137	KRAS genes had 85% mutations confirmed and BRAF and PIK3CA confirmed in 100%.	('BRAF', 'Gene', '673', (43, 47))	('PIK3CA', 'Gene', (52, 58))	('BRAF', 'Gene', (43, 47))	('mutations', 'Var', (19, 28))	('PIK3CA', 'Gene', '5290', (52, 58))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
68361	31653137	Polyp group had 80% mutation confirmed to KRAS gene, but only 25% for BRAF gene.	('KRAS', 'Gene', (42, 46))	('KRAS', 'Gene', '3845', (42, 46))	('mutation', 'Var', (20, 28))	('BRAF', 'Gene', '673', (70, 74))	('BRAF', 'Gene', (70, 74))
68362	31653137	KRAS mutations were prevalent in CRC and BRAF in the polyp group.	('CRC', 'Disease', (33, 36))	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (41, 45))	('BRAF', 'Gene', (41, 45))	('prevalent', 'Reg', (20, 29))	('CRC', 'Phenotype', 'HP:0003003', (33, 36))	('KRAS', 'Gene', '3845', (0, 4))
68375	31653137	Microvesicular hyperplastic polyp subtype may present mutation in BRAF oncogene suggesting this type of injury as a precursor serrated adenoma that can be a CRC precursor (Sweetser et al., 2013).	('mutation', 'Var', (54, 62))	('adenoma', 'Disease', (135, 142))	('injury', 'Disease', 'MESH:D014947', (104, 110))	('injury', 'Disease', (104, 110))	('BRAF', 'Gene', '673', (66, 70))	('adenoma', 'Disease', 'MESH:D000236', (135, 142))	('BRAF', 'Gene', (66, 70))	('CRC', 'Phenotype', 'HP:0003003', (157, 160))
68380	31653137	Among tissue samples, mutations were observed in 53% of patients with CRC, 40% in polyp group and 7% in the control group.	('patients', 'Species', '9606', (56, 64))	('observed', 'Reg', (37, 45))	('CRC', 'Phenotype', 'HP:0003003', (70, 73))	('mutations', 'Var', (22, 31))	('CRC', 'Disease', (70, 73))
68382	31653137	Mutations at codon 12 and 13 promote oncogenic KRAS gene potential and the most frequently described within the literature (Tsiatis et al., 2010).	('promote', 'PosReg', (29, 36))	('Tsiatis', 'Disease', 'None', (124, 131))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (47, 51))	('Tsiatis', 'Disease', (124, 131))	('KRAS', 'Gene', '3845', (47, 51))
68385	31653137	Through KBP Array we observed 60.7% of mutations in cancer patients and 35.7% adenomatous or hyperplastic polyps.	('adenoma', 'Disease', 'MESH:D000236', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('adenoma', 'Disease', (78, 85))	('hyperplastic polyps', 'Disease', (93, 112))	('mutations', 'Var', (39, 48))	('patients', 'Species', '9606', (59, 67))	('hyperplastic polyps', 'Disease', 'MESH:D011127', (93, 112))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
68387	31653137	In polyp group, BRAF gene mutation was most frequent (30.3%) (Table 2).	('frequent', 'Reg', (44, 52))	('BRAF', 'Gene', (16, 20))	('BRAF', 'Gene', '673', (16, 20))	('mutation', 'Var', (26, 34))
68388	31653137	Yamane et al., (2014) related two studies that demonstrated a high KRAS mutation frequency (45.2%) in serrated adenocarcinoma and suggest that a significant proportion of KRAS mutated CRC originates from serrated polyps and referenced high BRAF mutation frequency (V600E) among serrated carcinomas (82%), emphasizing that this mutation is a specific marker in the serrated pathway.	('polyps', 'Disease', (213, 219))	('carcinomas', 'Disease', 'MESH:D009369', (287, 297))	('serrated polyps', 'Phenotype', 'HP:0032222', (204, 219))	('serrated adenocarcinoma', 'Phenotype', 'HP:0032222', (102, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (287, 297))	('KRAS', 'Gene', (171, 175))	('KRAS', 'Gene', '3845', (67, 71))	('adenocarcinoma', 'Disease', 'MESH:D000230', (111, 125))	('KRAS', 'Gene', (67, 71))	('polyps', 'Disease', 'MESH:D011127', (213, 219))	('V600E', 'Mutation', 'rs113488022', (265, 270))	('serrated carcinomas', 'Phenotype', 'HP:0032222', (278, 297))	('CRC', 'Phenotype', 'HP:0003003', (184, 187))	('carcinomas', 'Disease', (287, 297))	('V600E', 'Var', (265, 270))	('CRC', 'Gene', (184, 187))	('adenocarcinoma', 'Disease', (111, 125))	('BRAF', 'Gene', '673', (240, 244))	('BRAF', 'Gene', (240, 244))	('KRAS', 'Gene', '3845', (171, 175))
68390	31653137	Genetic mutation analysis was also carried out with a method developed specifically for stool that identifies 28 mutations in four genes (APC, KRAS, BRAF, and TP53) involved in colorectal carcinogenesis, RanplexCRC Array.	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('APC', 'cellular_component', 'GO:0005680', ('138', '141'))	('colorectal carcinogenesis', 'Disease', (177, 202))	('colorectal carcinogenesis', 'Disease', 'MESH:D015179', (177, 202))	('TP53', 'Gene', '7157', (159, 163))	('TP53', 'Gene', (159, 163))	('mutations', 'Var', (113, 122))	('APC', 'Gene', (138, 141))	('APC', 'Gene', '324', (138, 141))	('CRC', 'Phenotype', 'HP:0003003', (211, 214))	('KRAS', 'Gene', (143, 147))	('KRAS', 'Gene', '3845', (143, 147))
68394	31653137	Assessing RanplexCRC staged method, we observed 36% mutations in TP53, KRAS or APC genes and 18% in BRAF gene.	('mutations', 'Var', (52, 61))	('TP53', 'Gene', '7157', (65, 69))	('CRC', 'Phenotype', 'HP:0003003', (17, 20))	('TP53', 'Gene', (65, 69))	('APC', 'Gene', (79, 82))	('BRAF', 'Gene', '673', (100, 104))	('KRAS', 'Gene', (71, 75))	('APC', 'Gene', '324', (79, 82))	('KRAS', 'Gene', '3845', (71, 75))	('BRAF', 'Gene', (100, 104))
68396	31653137	With a cut-off of 0.4 ng/ul and we observed that from 28 mutations positive on stool DNA by KBP Array test, 25 had human DNA quantified and from this, 7 had less than 0.4 ng/ul and 18 more than 0.4 ng/ul.	('human', 'Species', '9606', (115, 120))	('mutations', 'Var', (57, 66))	('less', 'NegReg', (157, 161))
68397	31653137	Ahlquist et al., (2012) studied stool DNA methylation in 4 genes and mutation in KRAS gene found a sensitivity of 78% and specificity of 90% for CRC.	('KRAS', 'Gene', '3845', (81, 85))	('CRC', 'Phenotype', 'HP:0003003', (145, 148))	('mutation', 'Var', (69, 77))	('DNA methylation', 'biological_process', 'GO:0006306', ('38', '53'))	('KRAS', 'Gene', (81, 85))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('CRC', 'Disease', (145, 148))
68399	31653137	Some stool DNA mutations considered as a false positive can also indicate a mistake of small tumor during colonoscopy.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mutations', 'Var', (15, 24))	('DNA', 'cellular_component', 'GO:0005574', ('11', '14'))	('tumor', 'Disease', (93, 98))	('false', 'biological_process', 'GO:0071878', ('41', '46'))	('stool DNA', 'Gene', (5, 14))	('small', 'Disease', (87, 92))	('false', 'biological_process', 'GO:0071877', ('41', '46'))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
68402	31653137	Microarray methods should be promised as a potential biomarker for colorectal cancer screening, given that KBP Array identified several mutations in precursor genes in stool DNA and it can be completed in under 3 hours via DNA input.	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('DNA', 'cellular_component', 'GO:0005574', ('223', '226'))	('mutations', 'Var', (136, 145))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('DNA', 'cellular_component', 'GO:0005574', ('174', '177'))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colorectal cancer', 'Disease', (67, 84))
68449	30538882	Postoperative adhesions and scar tissue have been reported to cause shunt obstruction and dysfunction.	('obstruction and dysfunction', 'Disease', 'MESH:D000402', (74, 101))	('scar', 'Phenotype', 'HP:0100699', (28, 32))	('adhesions', 'Var', (14, 23))	('cause', 'Reg', (62, 67))
68463	30265974	mTORC1 inhibition enhances cell proliferation, increases DNA damage in IEC.	('DNA', 'cellular_component', 'GO:0005574', ('57', '60'))	('mTORC1', 'cellular_component', 'GO:0031931', ('0', '6'))	('mTORC1', 'Gene', '382056', (0, 6))	('cell proliferation', 'CPA', (27, 45))	('DNA damage', 'MPA', (57, 67))	('inhibition', 'Var', (7, 17))	('increases', 'PosReg', (47, 56))	('mTORC1', 'Gene', (0, 6))	('enhances', 'PosReg', (18, 26))	('cell proliferation', 'biological_process', 'GO:0008283', ('27', '45'))	('IEC', 'Disease', (71, 74))
68464	30265974	In macrophages, mTORC1 inhibition strongly reduces the expression of pro-inflammatory markers.	('inhibition', 'Var', (23, 33))	('mTORC1', 'Gene', (16, 22))	('expression of pro-inflammatory markers', 'MPA', (55, 93))	('mTORC1', 'Gene', '382056', (16, 22))	('reduces', 'NegReg', (43, 50))
68465	30265974	As a consequence, mTORC1 inhibition exacerbated disease activity, increased mucosal damage, enhanced ulceration, augmented cell infiltration, decreased survival and stimulated tumor formation in a model of colorectal cancer CRC associated to colitis.	('colorectal cancer', 'Phenotype', 'HP:0003003', (206, 223))	('ulcer', 'Disease', (101, 106))	('colitis', 'Phenotype', 'HP:0002583', (242, 249))	('augmented', 'PosReg', (113, 122))	('stimulated', 'Reg', (165, 175))	('tumor', 'Disease', (176, 181))	('decreased', 'NegReg', (142, 151))	('inhibition', 'Var', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('colorectal cancer', 'Disease', 'MESH:D015179', (206, 223))	('mTORC1', 'Gene', (18, 24))	('increased', 'PosReg', (66, 75))	('colitis', 'Disease', (242, 249))	('colorectal cancer', 'Disease', (206, 223))	('mTORC1', 'Gene', '382056', (18, 24))	('enhanced', 'PosReg', (92, 100))	('mucosal damage', 'Disease', 'MESH:D009059', (76, 90))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('disease activity', 'CPA', (48, 64))	('ulcer', 'Disease', 'MESH:D014456', (101, 106))	('colitis', 'Disease', 'MESH:D003092', (242, 249))	('exacerbated', 'PosReg', (36, 47))	('cell infiltration', 'CPA', (123, 140))	('mucosal damage', 'Disease', (76, 90))	('survival', 'CPA', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
68467	30265974	Disruption of IEC homeostasis actively contributes to development and establishment of several pathologies, including inflammatory bowel diseases (IBD) and colorectal cancer.	('contributes', 'Reg', (39, 50))	('colorectal cancer', 'Disease', 'MESH:D015179', (156, 173))	('inflammatory bowel diseases', 'Disease', 'MESH:D015212', (118, 145))	('inflammatory bowel diseases', 'Phenotype', 'HP:0002037', (118, 145))	('IBD', 'Phenotype', 'HP:0002037', (147, 150))	('inflammatory bowel diseases', 'Disease', (118, 145))	('colorectal cancer', 'Phenotype', 'HP:0003003', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('colorectal cancer', 'Disease', (156, 173))	('Disruption', 'Var', (0, 10))
68480	30265974	Thus, mTORC1 inactivation augmented disease activity and mortality in a colitis model induced by the administration of DSS.	('inactivation', 'Var', (13, 25))	('colitis', 'Disease', (72, 79))	('mTORC1', 'Gene', '382056', (6, 12))	('mortality', 'CPA', (57, 66))	('mTORC1', 'Gene', (6, 12))	('colitis', 'Phenotype', 'HP:0002583', (72, 79))	('disease activity', 'CPA', (36, 52))	('augmented', 'PosReg', (26, 35))	('colitis', 'Disease', 'MESH:D003092', (72, 79))
68481	30265974	Furthermore, mTORC1 inhibition triggered beta-catenin dependent DNA damage in IECs and therefore stimulates CRC development associated to colitis.	('colitis', 'Disease', 'MESH:D003092', (138, 145))	('stimulates', 'PosReg', (97, 107))	('beta-catenin dependent DNA damage', 'MPA', (41, 74))	('mTORC1', 'Gene', '382056', (13, 19))	('inhibition', 'Var', (20, 30))	('colitis', 'Disease', (138, 145))	('CRC development', 'CPA', (108, 123))	('mTORC1', 'Gene', (13, 19))	('colitis', 'Phenotype', 'HP:0002583', (138, 145))
68482	30265974	Such effects occurred because after mTORC1 inhibition macrophages failed to polarize to M1-phenotype and therefore an anti-inflammatory environment is created in the colon.	('inhibition', 'Var', (43, 53))	('mTORC1', 'Gene', (36, 42))	('mTORC1', 'Gene', '382056', (36, 42))
68483	30265974	Thus our findings strongly suggest that inhibition of mTORC1 during colitis could play important role in the development of colorectal cancer.	('inhibition', 'Var', (40, 50))	('mTORC1', 'cellular_component', 'GO:0031931', ('54', '60'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('colitis', 'Phenotype', 'HP:0002583', (68, 75))	('mTORC1', 'Gene', (54, 60))	('colorectal cancer', 'Disease', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('colitis', 'Disease', 'MESH:D003092', (68, 75))	('mTORC1', 'Gene', '382056', (54, 60))	('colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))	('colitis', 'Disease', (68, 75))
68485	30265974	Six- to eight-week-old (22-25 g of weight) C57BL/6 J or Lgr5-EGFP-IRES-creERT2 (beta-catenin reporter mice; The Jackson Laboratories, Bar Harbor, ME) male mice were kept in standard day/night cycles conditions with free access to food and water.	('mice', 'Species', '10090', (102, 106))	('water', 'Chemical', 'MESH:D014867', (239, 244))	('Lgr5', 'Gene', '14160', (56, 60))	('Lgr5', 'Gene', (56, 60))	('mice', 'Species', '10090', (155, 159))	('C57BL/6', 'Var', (43, 50))
68511	30265974	As shown in Figure 1C, phosphorylation of pS6 significantly increased in colonic IECs of DSS treated mice when compared with control animals.	('phosphorylation', 'MPA', (23, 38))	('pS6', 'Gene', (42, 45))	('DSS', 'Var', (89, 92))	('mice', 'Species', '10090', (101, 105))	('pS6', 'Gene', '338413', (42, 45))	('increased', 'PosReg', (60, 69))
68517	30265974	IFNgamma activates PI3K/Akt signaling in the mucosa of colitic mice and reduces proliferation, therefore we analyzed mTORC1 status in SW480 and RKO cells treated with IFNgamma for 3 h. As shown in Figure 2A increased phosphorylation of STAT1 phosphorylation at Y701 was observed after IFNgamma stimulation demonstrating the functionality of our assay.	('SW480', 'CellLine', 'CVCL:0546', (134, 139))	('Y701', 'Var', (261, 265))	('phosphorylation', 'MPA', (217, 232))	('mTORC1', 'Gene', '382056', (117, 123))	('increased', 'PosReg', (207, 216))	('mice', 'Species', '10090', (63, 67))	('RKO', 'CellLine', 'CVCL:0504', (144, 147))	('STAT1', 'Gene', '20846', (236, 241))	('STAT1', 'Gene', (236, 241))	('Akt', 'Gene', '11651', (24, 27))	('mTORC1', 'Gene', (117, 123))	('Akt', 'Gene', (24, 27))
68521	30265974	Next we analyzed the activation mTORC1 in the mucosa of C57BL/6 J animals that were administered intraperitoneally with IFNgamma.	('mTORC1', 'Gene', '382056', (32, 38))	('mTORC1', 'Gene', (32, 38))	('C57BL/6', 'Var', (56, 63))
68523	30265974	Furthermore, pS6 staining was almost absent the mucosa of control animals but a strong presence of the molecule was induced in IECs of C57BL/6 J stimulated with IFNgamma (Figure 2, C and D, arrows).	('pS6', 'Gene', (13, 16))	('C57BL/6', 'Var', (135, 142))	('pS6', 'Gene', '338413', (13, 16))
68529	30265974	To this purpose, mTORC1 signaling was inhibited with LiCl, AZD8055 or Rapamycin in SW480 cells stimulated with IFNgamma.	('mTORC1', 'Gene', '382056', (17, 23))	('AZD8055', 'Var', (59, 66))	('AZD8055', 'Chemical', 'MESH:C546624', (59, 66))	('inhibited', 'NegReg', (38, 47))	('SW480', 'CellLine', 'CVCL:0546', (83, 88))	('mTORC1', 'Gene', (17, 23))	('Rapamycin', 'Chemical', 'MESH:D020123', (70, 79))	('mTORC1', 'cellular_component', 'GO:0031931', ('17', '23'))	('LiCl', 'Chemical', 'MESH:D018021', (53, 57))	('signaling', 'biological_process', 'GO:0023052', ('24', '33'))
68530	30265974	Rapamycin inhibits mTORC1 directly and AZD8055 targets mTOR, but in contrast LiCl has a more broad specter that results in Akt inhibition in cells stimulated with cytokines.	('LiCl', 'Chemical', 'MESH:D018021', (77, 81))	('inhibits', 'NegReg', (10, 18))	('mTOR', 'Gene', (55, 59))	('Rapamycin', 'Chemical', 'MESH:D020123', (0, 9))	('Akt', 'Gene', '11651', (123, 126))	('mTOR', 'Gene', '56717', (55, 59))	('mTORC1', 'Gene', (19, 25))	('AZD8055', 'Chemical', 'MESH:C546624', (39, 46))	('mTOR', 'Gene', (19, 23))	('mTORC1', 'cellular_component', 'GO:0031931', ('19', '25'))	('Akt', 'Gene', (123, 126))	('inhibition', 'NegReg', (127, 137))	('mTOR', 'Gene', '56717', (19, 23))	('mTORC1', 'Gene', '382056', (19, 25))	('AZD8055', 'Var', (39, 46))
68533	30265974	AZD8055 treatment reduced pGSK3beta, pS6 and pAkt levels and in contrast rapamycin inhibited S6 phosphorylation but failed to prevent Akt activation or GSK3beta inhibition.	('Akt', 'Gene', (46, 49))	('inhibited', 'NegReg', (83, 92))	('S6 phosphorylation', 'MPA', (93, 111))	('GSK3beta', 'Gene', '56637', (152, 160))	('rapamycin', 'Chemical', 'MESH:D020123', (73, 82))	('Akt', 'Gene', (134, 137))	('GSK3beta', 'Gene', (152, 160))	('Akt', 'Gene', '11651', (46, 49))	('reduced', 'NegReg', (18, 25))	('Akt', 'Gene', '11651', (134, 137))	('phosphorylation', 'biological_process', 'GO:0016310', ('96', '111'))	('pGSK3beta', 'Chemical', '-', (26, 35))	('pS6', 'Gene', (37, 40))	('AZD8055', 'Var', (0, 7))	('GSK', 'molecular_function', 'GO:0050321', ('152', '155'))	('pS6', 'Gene', '338413', (37, 40))	('GSK3beta', 'Gene', '56637', (27, 35))	('AZD8055', 'Chemical', 'MESH:C546624', (0, 7))	('GSK3beta', 'Gene', (27, 35))
68540	30265974	Hypophosphorylation of pS6 and pAkt demonstrated the efficiency of our treatments.	('pS6', 'Gene', '338413', (23, 26))	('Akt', 'Gene', '11651', (32, 35))	('Akt', 'Gene', (32, 35))	('pS6', 'Gene', (23, 26))	('Hypophosphorylation', 'Var', (0, 19))
68542	30265974	In addition, intestinal proliferation analysis carried out by EdU incorporation corroborated that inhibition of mTORC1 by LiCl stimulated cell proliferation in IEC in the mucosa of colitic mice (Figure 3, C and D).	('LiCl', 'Chemical', 'MESH:D018021', (122, 126))	('inhibition', 'Var', (98, 108))	('mTORC1', 'Gene', (112, 118))	('mice', 'Species', '10090', (189, 193))	('EdU', 'Chemical', 'MESH:C031086', (62, 65))	('stimulated', 'PosReg', (127, 137))	('cell proliferation', 'CPA', (138, 156))	('mTORC1', 'Gene', '382056', (112, 118))
68546	30265974	Thus all these results strongly suggest that inhibiting mTORC1 signaling by LiCl or Rapamycin during colitis stimulates proliferation and generation of new cells in the colonic mucosa in a process that is independent of the integrity status of the epithelium.	('proliferation', 'CPA', (120, 133))	('generation', 'CPA', (138, 148))	('inhibiting', 'Var', (45, 55))	('stimulates', 'PosReg', (109, 119))	('colitis', 'Disease', 'MESH:D003092', (101, 108))	('Rapamycin', 'Chemical', 'MESH:D020123', (84, 93))	('colitis', 'Disease', (101, 108))	('mTORC1', 'Gene', '382056', (56, 62))	('LiCl', 'Chemical', 'MESH:D018021', (76, 80))	('mTORC1', 'Gene', (56, 62))	('colitis', 'Phenotype', 'HP:0002583', (101, 108))
68551	30265974	The inhibition of mTORC1 by Rapamycin also enhanced colitis-like symptoms in DSS-treated mice, but the animals survived the whole treatment (data not shown).	('enhanced', 'PosReg', (43, 51))	('mTORC1', 'Gene', (18, 24))	('colitis', 'Disease', 'MESH:D003092', (52, 59))	('mTORC1', 'cellular_component', 'GO:0031931', ('18', '24'))	('mice', 'Species', '10090', (89, 93))	('colitis', 'Disease', (52, 59))	('Rapamycin', 'Chemical', 'MESH:D020123', (28, 37))	('inhibition', 'Var', (4, 14))	('mTORC1', 'Gene', '382056', (18, 24))	('colitis', 'Phenotype', 'HP:0002583', (52, 59))
68553	30265974	AZD8055, a more powerful and specific inhibitor for mTOR displayed similar effects to the observed with LiCl, as shown by enhanced weight loss and increased mortality in colitic mice (Supplementary Figure 2A).	('mTOR', 'Gene', (52, 56))	('weight loss', 'Phenotype', 'HP:0001824', (131, 142))	('enhanced', 'PosReg', (122, 130))	('increased', 'PosReg', (147, 156))	('mTOR', 'Gene', '56717', (52, 56))	('AZD8055', 'Var', (0, 7))	('AZD8055', 'Chemical', 'MESH:C546624', (0, 7))	('mice', 'Species', '10090', (178, 182))	('LiCl', 'Chemical', 'MESH:D018021', (104, 108))	('weight loss', 'Disease', 'MESH:D015431', (131, 142))	('mortality', 'CPA', (157, 166))	('weight loss', 'Disease', (131, 142))
68554	30265974	Also, DAI in DSS/LiCl and DSS/AZD8055 treated mice was comparable and significantly higher than the observed in mice receiving DSS alone (Figure 4B).	('LiCl', 'Chemical', 'MESH:D018021', (17, 21))	('DSS/AZD8055', 'Var', (26, 37))	('DAI', 'MPA', (6, 9))	('higher', 'PosReg', (84, 90))	('mice', 'Species', '10090', (46, 50))	('AZD8055', 'Chemical', 'MESH:C546624', (30, 37))	('mice', 'Species', '10090', (112, 116))
68555	30265974	Colon length in DSS, DSS/LiCl or DSS/AZD8055 treated mice displayed no significant variations in size, demonstrating that the presence of the inhibitors does not affect this parameter (Figure 4C).	('DSS/AZD8055', 'Var', (33, 44))	('Colon length', 'CPA', (0, 12))	('LiCl', 'Chemical', 'MESH:D018021', (25, 29))	('mice', 'Species', '10090', (53, 57))	('AZD8055', 'Chemical', 'MESH:C546624', (37, 44))
68561	30265974	Similar to the observed with LiCl, inhibition of mTOR by AZD8055 or mTORC1 by rapamycin enhanced epithelial damage and cell death in the mucosa of colitic mice as reported previously (data not shown).	('mTOR', 'Gene', (49, 53))	('LiCl', 'Chemical', 'MESH:D018021', (29, 33))	('mTORC1', 'Gene', '382056', (68, 74))	('mTOR', 'Gene', '56717', (49, 53))	('cell death', 'CPA', (119, 129))	('AZD8055', 'Chemical', 'MESH:C546624', (57, 64))	('rapamycin', 'Chemical', 'MESH:D020123', (78, 87))	('mTOR', 'Gene', (68, 72))	('epithelial damage', 'CPA', (97, 114))	('mTORC1', 'Gene', (68, 74))	('mice', 'Species', '10090', (155, 159))	('inhibition', 'Var', (35, 45))	('mTOR', 'Gene', '56717', (68, 72))	('enhanced', 'PosReg', (88, 96))	('AZD8055', 'Var', (57, 64))
68581	30265974	Because of these results we analyzed the presence of the so called Active beta-catenin (ABC) in the mucosa of colitic mice after mTORC1 inhibition.	('inhibition', 'Var', (136, 146))	('mTORC1', 'cellular_component', 'GO:0031931', ('129', '135'))	('mTORC1', 'Gene', (129, 135))	('mice', 'Species', '10090', (118, 122))	('mTORC1', 'Gene', '382056', (129, 135))
68589	30265974	Our results prompted us to speculate that inhibition of beta-catenin co-transcriptional activity plays a protective role in the generation of DSB in IEC.	('beta-catenin', 'Protein', (56, 68))	('inhibition', 'Var', (42, 52))	('DSB', 'Chemical', '-', (142, 145))	('IEC', 'Disease', (149, 152))	('DSB', 'Disease', (142, 145))
68592	30265974	Inhibition of mTORC1 activity by LiCl or AZD8055 blocked the protective effect in the formation of DSB that was elicited by IFNgamma.	('mTORC1', 'Gene', (14, 20))	('DSB', 'Chemical', '-', (99, 102))	('AZD8055', 'Var', (41, 48))	('AZD8055', 'Chemical', 'MESH:C546624', (41, 48))	('mTORC1', 'Gene', '382056', (14, 20))	('LiCl', 'Chemical', 'MESH:D018021', (33, 37))	('protective effect', 'CPA', (61, 78))	('blocked', 'NegReg', (49, 56))	('formation of DSB', 'MPA', (86, 102))
68593	30265974	Furthermore, in agreement with our previous results mTORC1 inhibition by LiCl or AZD8055 resulted in increased presence of beta-catenin in our epithelial cells.	('inhibition', 'NegReg', (59, 69))	('mTORC1', 'Gene', '382056', (52, 58))	('increased', 'PosReg', (101, 110))	('AZD8055', 'Chemical', 'MESH:C546624', (81, 88))	('mTORC1', 'cellular_component', 'GO:0031931', ('52', '58'))	('beta-catenin', 'Protein', (123, 135))	('LiCl', 'Chemical', 'MESH:D018021', (73, 77))	('mTORC1', 'Gene', (52, 58))	('presence', 'MPA', (111, 119))	('AZD8055', 'Var', (81, 88))
68599	30265974	The administration of the beta-catenin inhibitor, XAV939, prevented the reduction in iNOS and IL-1beta stimulated by LiCl and also reduced of beta-catenin protein levels (Figure 5L).	('reduction', 'NegReg', (72, 81))	('iNOS', 'Gene', (85, 89))	('IL-1beta', 'Gene', (94, 102))	('prevented', 'NegReg', (58, 67))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('LiCl', 'Chemical', 'MESH:D018021', (117, 121))	('reduced', 'NegReg', (131, 138))	('XAV939', 'Chemical', 'MESH:C544261', (50, 56))	('XAV939', 'Var', (50, 56))	('IL-1beta', 'Gene', '16176', (94, 102))	('iNOS', 'Gene', '18126', (85, 89))	('beta-catenin protein levels', 'MPA', (142, 169))	('IL-1', 'molecular_function', 'GO:0005149', ('94', '98'))
68605	30265974	Furthermore, as shown in Figure 6B tumor formation was only detected in DSS/AOM and DSS/AOM/LiCl treated animals but not in AOM or DSS administered mice.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('formation', 'biological_process', 'GO:0009058', ('41', '50'))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('mice', 'Species', '10090', (148, 152))	('DSS/AOM/LiCl', 'Var', (84, 96))	('LiCl', 'Chemical', 'MESH:D018021', (92, 96))
68606	30265974	As expected from our previous results demonstrating that LiCl enhances proliferation and DNA damage in IECs the number and size of the tumors greatly increased in the mucosa of DSS/AOM/LiCl when compared with DSS/AOM (Figure 6C).	('DSS/AOM/LiCl', 'Var', (177, 189))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('LiCl', 'Chemical', 'MESH:D018021', (185, 189))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('increased', 'PosReg', (150, 159))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('proliferation', 'CPA', (71, 84))	('enhances', 'PosReg', (62, 70))	('LiCl', 'Chemical', 'MESH:D018021', (57, 61))
68608	30265974	Thus taken together our results strongly suggest that inhibition of mTORC1 during colitis strongly contributes to colorectal cancer development and growth.	('inhibition', 'Var', (54, 64))	('contributes', 'Reg', (99, 110))	('mTORC1', 'Gene', '382056', (68, 74))	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('colitis', 'Phenotype', 'HP:0002583', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('growth', 'CPA', (148, 154))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('colitis', 'Disease', 'MESH:D003092', (82, 89))	('mTORC1', 'Gene', (68, 74))	('mTORC1', 'cellular_component', 'GO:0031931', ('68', '74'))	('colorectal cancer', 'Disease', (114, 131))	('colitis', 'Disease', (82, 89))
68614	30265974	Interestingly, pharmacological inhibition of mTORC1 also resulted in a high rate of DNA damage.	('mTORC1', 'Gene', (45, 51))	('DNA damage', 'CPA', (84, 94))	('mTORC1', 'Gene', '382056', (45, 51))	('pharmacological inhibition', 'Var', (15, 41))
68615	30265974	Accordingly, mTORC1 inactivation by MCRS1 or Rheb ablation also resulted in high epithelial cell death due to high levels of DNA damage.	('DNA damage', 'MPA', (125, 135))	('inactivation', 'NegReg', (20, 32))	('mTORC1', 'Gene', '382056', (13, 19))	('MCRS1', 'Gene', (36, 41))	('ablation', 'Var', (50, 58))	('epithelial cell death', 'CPA', (81, 102))	('Rheb', 'Gene', '19744', (45, 49))	('mTORC1', 'Gene', (13, 19))	('Rheb', 'Gene', (45, 49))	('MCRS1', 'Gene', '51812', (36, 41))
68624	30265974	inactivation of GSK3beta) we cannot rule the existence of another mechanism.	('GSK3beta', 'Gene', '56637', (16, 24))	('GSK3beta', 'Gene', (16, 24))	('GSK', 'molecular_function', 'GO:0050321', ('16', '19'))	('inactivation', 'Var', (0, 12))
68626	30265974	Inhibition of cell proliferation during colitis leads to ulcer formation and epithelial barrier breakdown.	('ulcer', 'Disease', 'MESH:D014456', (57, 62))	('colitis', 'Phenotype', 'HP:0002583', (40, 47))	('cell proliferation', 'CPA', (14, 32))	('epithelial barrier breakdown', 'CPA', (77, 105))	('colitis', 'Disease', 'MESH:D003092', (40, 47))	('Inhibition', 'Var', (0, 10))	('colitis', 'Disease', (40, 47))	('ulcer', 'Disease', (57, 62))
68630	30265974	However, we cannot rule out the possibility that transactivation of beta-catenin after mTORC1 inhibition could stimulate the production of soluble factors in IECs, that in turns will stimulate the recruitment of M2 macrophages (IL-6+) at the inflamed epithelium as described previously.	('mTORC1', 'Gene', (87, 93))	('IL-6', 'Gene', (228, 232))	('production of soluble factors', 'MPA', (125, 154))	('IL-6', 'Gene', '16193', (228, 232))	('recruitment', 'MPA', (197, 208))	('transactivation', 'Var', (49, 64))	('mTORC1', 'Gene', '382056', (87, 93))	('stimulate', 'PosReg', (111, 120))	('beta-catenin', 'Protein', (68, 80))	('inhibition', 'Var', (94, 104))	('stimulate', 'PosReg', (183, 192))
68633	30265974	Thus uncontrolled activation of convergent signaling pathways could be stimulated by mTORC1 inhibition and this process will enhances not only epithelial damage but proinflammatory environments that contribute to cancer development.	('mTORC1', 'Gene', '382056', (85, 91))	('inhibition', 'Var', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('enhances', 'PosReg', (125, 133))	('epithelial damage', 'CPA', (143, 160))	('stimulated', 'PosReg', (71, 81))	('mTORC1', 'Gene', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('convergent signaling pathways', 'Pathway', (32, 61))	('cancer', 'Disease', (213, 219))	('activation', 'PosReg', (18, 28))
68647	29740204	When cell monolayers were treated with LPS in the presence of plecanatide or dolcanatide, occludin and ZO-1 were localized at the cell surface of adjoining cells, similar to that observed for vehicle treated cells.	('plecanatide', 'Var', (62, 73))	('LPS', 'Disease', 'MESH:C536528', (39, 42))	('dolcanatide', 'Gene', (77, 88))	('LPS', 'Disease', (39, 42))	('dolcanatide', 'Chemical', 'MESH:C000614048', (77, 88))	('plecanatide', 'Chemical', 'MESH:C584575', (62, 73))	('ZO-1', 'Gene', (103, 107))
68650	29740204	Consistent with these findings, plecanatide and dolcanatide showed potent anti-nociceptive activity in rat visceral hypersensitivity models.	('plecanatide', 'Chemical', 'MESH:C584575', (32, 43))	('rat', 'Species', '10116', (103, 106))	('dolcanatide', 'Chemical', 'MESH:C000614048', (48, 59))	('hypersensitivity', 'biological_process', 'GO:0002524', ('116', '132'))	('hypersensitivity', 'Disease', (116, 132))	('plecanatide', 'Var', (32, 43))	('hypersensitivity', 'Disease', 'MESH:D004342', (116, 132))	('anti-nociceptive activity', 'CPA', (74, 99))
68655	29740204	Additionally, inhibition of sodium-hydrogen exchanger 3 is being explored for treating IBS-C.	('IBS-C', 'Disease', 'MESH:D043183', (87, 92))	('IBS-C', 'Disease', (87, 92))	('sodium-hydrogen exchanger', 'molecular_function', 'GO:0015385', ('28', '53'))	('inhibition', 'Var', (14, 24))	('sodium-hydrogen exchanger 3', 'Gene', (28, 55))	('sodium-hydrogen exchanger 3', 'Gene', '24784', (28, 55))
68657	29740204	Lubiprostone, a bicyclic fatty acid metabolite of prostaglandin E1, specifically stimulates chloride channel type 2 causing an efflux of chloride into the lumen of the GI tract, which promotes fluid secretion, facilitating bowel movement.	('bicyclic fatty acid', 'Chemical', '-', (16, 35))	('prostaglandin E1', 'Chemical', 'MESH:D000527', (50, 66))	('fluid secretion', 'MPA', (193, 208))	('stimulates', 'PosReg', (81, 91))	('chloride channel type 2', 'MPA', (92, 115))	('Lubiprostone', 'Var', (0, 12))	('bowel movement', 'Disease', 'MESH:D009069', (223, 237))	('chloride', 'Chemical', 'MESH:D002712', (92, 100))	('chloride', 'Chemical', 'MESH:D002712', (137, 145))	('bowel movement', 'Disease', (223, 237))	('efflux', 'biological_process', 'GO:0140115', ('127', '133'))	('efflux', 'biological_process', 'GO:0140352', ('127', '133'))	('efflux of chloride into the lumen of the GI', 'MPA', (127, 170))	('secretion', 'biological_process', 'GO:0046903', ('199', '208'))	('Lubiprostone', 'Chemical', 'MESH:D000068238', (0, 12))	('promotes', 'PosReg', (184, 192))
68662	29740204	Alterations in the structure and/or function of the TJ protein complexes are associated with epithelial barrier disruption and increased permeability of the mucosa, allowing entry of inflammatory mediators to promote low-grade inflammation and visceral hypersensitivity.	('inflammation', 'Disease', (227, 239))	('promote', 'PosReg', (209, 216))	('Alterations', 'Var', (0, 11))	('entry', 'MPA', (174, 179))	('epithelial barrier', 'CPA', (93, 111))	('inflammation', 'biological_process', 'GO:0006954', ('227', '239'))	('TJ protein', 'Protein', (52, 62))	('hypersensitivity', 'biological_process', 'GO:0002524', ('253', '269'))	('hypersensitivity', 'Disease', (253, 269))	('hypersensitivity', 'Disease', 'MESH:D004342', (253, 269))	('protein', 'cellular_component', 'GO:0003675', ('55', '62'))	('rat', 'Species', '10116', (4, 7))	('inflammation', 'Disease', 'MESH:D007249', (227, 239))	('associated', 'Reg', (77, 87))
68670	29740204	Plecanatide is structurally identical to uroguanylin, differing only in the substitution of Asp with Glu at the 3-position at the N-terminus for greater binding affinity.	('Glu', 'MPA', (101, 104))	('Asp with Glu at the 3', 'Mutation', 'p.D3E', (92, 113))	('greater', 'PosReg', (145, 152))	('binding', 'molecular_function', 'GO:0005488', ('153', '160'))	('binding', 'Interaction', (153, 160))	('Plecanatide', 'Chemical', 'MESH:C584575', (0, 11))	('substitution', 'Var', (76, 88))
68671	29740204	Dolcanatide is similar to plecanatide in structure except that L-Asn1 and L-Leu16 are replaced by D-Asn1 and D-Leu16 at the N- and C-termini, respectively, which is thought to provide enhanced biostability.	('L-Asn1', 'Var', (63, 69))	('plecanatide', 'Chemical', 'MESH:C584575', (26, 37))	('Dolcanatide', 'Chemical', 'MESH:C000614048', (0, 11))	('D-Asn1', 'Var', (98, 104))	('L-Leu16', 'Var', (74, 81))	('D-Leu16', 'Var', (109, 116))
68720	29740204	Importantly, the LPS-induced increase in the permeability of FITCdextran was completely suppressed in both cell monolayers treated with plecanatide (Figure 1A and C) or dolcanatide (Figure 1B and D).	('plecanatide', 'Chemical', 'MESH:C584575', (136, 147))	('LPS', 'Disease', 'MESH:C536528', (17, 20))	('FITCdextran', 'Chemical', 'MESH:C015219', (61, 72))	('dolcanatide', 'Chemical', 'MESH:C000614048', (169, 180))	('increase', 'PosReg', (29, 37))	('plecanatide', 'Var', (136, 147))	('suppressed', 'NegReg', (88, 98))	('permeability of FITCdextran', 'MPA', (45, 72))	('LPS', 'Disease', (17, 20))
68722	29740204	Consistent with the results presented in Figure 1, LPS treatment resulted in a statistically significant increase in the paracellular permeability of FITC-dextran across rat colon tissues, which was effectively suppressed by treatment with plecanatide or dolcanatide (Figure 2).	('paracellular permeability of FITC-dextran', 'MPA', (121, 162))	('rat', 'Species', '10116', (170, 173))	('increase', 'PosReg', (105, 113))	('LPS', 'Disease', 'MESH:C536528', (51, 54))	('plecanatide', 'Chemical', 'MESH:C584575', (240, 251))	('treatment', 'Var', (55, 64))	('FITC-dextran', 'Chemical', 'MESH:C015219', (150, 162))	('dolcanatide', 'Chemical', 'MESH:C000614048', (255, 266))	('LPS', 'Disease', (51, 54))
68726	29740204	Importantly, when cell monolayers were treated with LPS in the presence of plecanatide or dolcanatide, expression of occludin and ZO-1 were normalized and localized at the cell surface of adjoining cells, similar to that observed for vehicle treated cells (Figures 3 and 4).	('dolcanatide', 'Chemical', 'MESH:C000614048', (90, 101))	('plecanatide', 'Chemical', 'MESH:C584575', (75, 86))	('LPS', 'Disease', (52, 55))	('cell surface', 'cellular_component', 'GO:0009986', ('172', '184'))	('expression', 'MPA', (103, 113))	('occludin', 'Gene', (117, 125))	('ZO-1', 'Gene', (130, 134))	('LPS', 'Disease', 'MESH:C536528', (52, 55))	('plecanatide', 'Var', (75, 86))
68733	29740204	As expected, TNBS treatment resulted in increased abdominal contractions even in the absence of distending pressure.	('abdominal contractions', 'CPA', (50, 72))	('TNBS', 'Gene', (13, 17))	('treatment', 'Var', (18, 27))	('TNBS', 'Chemical', 'MESH:D014302', (13, 17))	('increased', 'PosReg', (40, 49))
68747	29740204	In this context, we recently reported that oral treatment with plecanatide or dolcanatide ameliorated GI inflammation through activation of GC-C signaling in the distal large intestine.	('plecanatide', 'Var', (63, 74))	('GC-C signaling', 'MPA', (140, 154))	('GI inflammation', 'Disease', (102, 117))	('activation', 'PosReg', (126, 136))	('dolcanatide', 'Chemical', 'MESH:C000614048', (78, 89))	('plecanatide', 'Chemical', 'MESH:C584575', (63, 74))	('GI inflammation', 'Disease', 'MESH:D007249', (102, 117))	('rat', 'Species', '10116', (96, 99))	('GI inflammation', 'Phenotype', 'HP:0004386', (102, 117))	('ameliorated', 'NegReg', (90, 101))	('inflammation', 'biological_process', 'GO:0006954', ('105', '117'))	('signaling', 'biological_process', 'GO:0023052', ('145', '154'))
68771	29740204	Electromyographic recordings were used to assess suppression of visceral hypersensitivity by plecanatide or dolcanatide in rat models of inflammatory and non-inflammatory visceral pain.	('suppression', 'NegReg', (49, 60))	('visceral pain', 'Disease', 'MESH:D059265', (171, 184))	('dolcanatide', 'Chemical', 'MESH:C000614048', (108, 119))	('pain', 'Phenotype', 'HP:0012531', (180, 184))	('plecanatide', 'Var', (93, 104))	('rat', 'Species', '10116', (123, 126))	('visceral pain', 'Disease', (171, 184))	('hypersensitivity by', 'Disease', 'MESH:D004342', (73, 92))	('plecanatide', 'Chemical', 'MESH:C584575', (93, 104))	('hypersensitivity by', 'Disease', (73, 92))
68773	29740204	Oral treatment with plecanatide or dolcanatide considerably attenuated visceral hypersensitivity in inflammatory and non-inflammatory models of visceral pain.	('dolcanatide', 'Chemical', 'MESH:C000614048', (35, 46))	('plecanatide', 'Var', (20, 31))	('hypersensitivity in', 'Disease', (80, 99))	('hypersensitivity in', 'Disease', 'MESH:D004342', (80, 99))	('pain', 'Phenotype', 'HP:0012531', (153, 157))	('visceral pain', 'Disease', 'MESH:D059265', (144, 157))	('plecanatide', 'Chemical', 'MESH:C584575', (20, 31))	('visceral pain', 'Disease', (144, 157))	('attenuated', 'NegReg', (60, 70))	('dolcanatide', 'Var', (35, 46))
68777	25836926	EMAST is a Form of Microsatellite Instability That is Initiated by Inflammation and Modulates Colorectal Cancer Progression DNA mismatch repair (MMR) function is critical for correcting errors coincident with polymerase-driven DNA replication, and its proteins are frequent targets for inactivation (germline or somatic), generating a hypermutable tumor that drives cancer progression.	('Cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (366, 372))	('tumor', 'Disease', 'MESH:D009369', (348, 353))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (94, 111))	('cancer', 'Disease', (366, 372))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('inactivation', 'Var', (286, 298))	('Colorectal Cancer', 'Disease', (94, 111))	('tumor', 'Disease', (348, 353))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (94, 111))
68781	25836926	Specifically, EMAST is an acquired somatic defect observed in up to 60% of colorectal cancers and caused by unique dysfunction of the DNA MMR protein MSH3 (and its DNA MMR complex MutSbeta, a heterodimer of MSH2-MSH3), and in particular a loss-of-function phenotype due to a reversible shift from its normal nuclear location into the cytosol in response to oxidative stress and the pro-inflammatory cytokine interleukin-6.	('colorectal cancers', 'Disease', (75, 93))	('dysfunction', 'Var', (115, 126))	('interleukin-6', 'Gene', (408, 421))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('oxidative stress', 'Phenotype', 'HP:0025464', (357, 373))	('interleukin-6', 'Gene', '3569', (408, 421))	('MSH3', 'Gene', (150, 154))	('rectal cancer', 'Phenotype', 'HP:0100743', (79, 92))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('EMAST', 'Disease', (14, 19))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))	('colorectal cancers', 'Disease', 'MESH:D015179', (75, 93))	('loss-of-function', 'NegReg', (239, 255))
68784	25836926	In addition to defective DNA MMR recognized by tetranucleotide (and di- and tri-nucleotide) frameshifts, loss of MSH3 also contributes to homologous recombination-mediated repair of DNA double stranded breaks, indicating the MSH3 dysfunction is a complex defect for cancer cells that generates not only EMAST but also may contribute to chromosomal instability and aneuploidy.	('contribute', 'Reg', (322, 332))	('chromosomal instability', 'Phenotype', 'HP:0040012', (336, 359))	('contributes', 'Reg', (123, 134))	('chromosomal instability', 'CPA', (336, 359))	('homologous recombination-mediated repair', 'MPA', (138, 178))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('aneuploidy', 'Disease', 'MESH:D000782', (364, 374))	('MMR', 'biological_process', 'GO:0006298', ('29', '32'))	('MSH3', 'Gene', (113, 117))	('MSH3 dysfunction', 'Disease', 'MESH:D006331', (225, 241))	('di- and tri-nucleotide', 'Chemical', '-', (68, 90))	('EMAST', 'MPA', (303, 308))	('loss', 'Var', (105, 109))	('DNA', 'cellular_component', 'GO:0005574', ('25', '28'))	('aneuploidy', 'Disease', (364, 374))	('MSH3 dysfunction', 'Disease', (225, 241))	('cancer', 'Disease', (266, 272))	('tetranucleotide', 'Chemical', '-', (47, 62))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('homologous recombination', 'biological_process', 'GO:0035825', ('138', '162'))	('DNA', 'cellular_component', 'GO:0005574', ('182', '185'))
68785	25836926	Areas for future investigation for this most common DNA MMR defect among colorectal cancers include relationships between EMAST and chemotherapy response, patient outcome with aneuploid changes in colorectal cancers, target gene mutation analysis, and mechanisms related to inflammation-induced compartmentalization and inactivation for MSH3.	('colorectal cancers', 'Disease', (197, 215))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('inflammation', 'Disease', 'MESH:D007249', (274, 286))	('rectal cancer', 'Phenotype', 'HP:0100743', (77, 90))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('patient', 'Species', '9606', (155, 162))	('inflammation', 'Disease', (274, 286))	('colorectal cancers', 'Disease', 'MESH:D015179', (73, 91))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('inactivation', 'Var', (320, 332))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancers', 'Disease', (73, 91))	('rectal cancer', 'Phenotype', 'HP:0100743', (201, 214))	('MSH3', 'Gene', (337, 341))	('colorectal cancer', 'Phenotype', 'HP:0003003', (197, 214))	('colorectal cancers', 'Disease', 'MESH:D015179', (197, 215))
68787	25836926	Shortly thereafter, with realization that bacteria and yeast microsatellite frameshift mutations were caused by a defect in DNA mismatch repair (MMR) function, successful efforts identifying the human counterparts to the bacteria and yeast DNA MMR genes were undertaken.	('human', 'Species', '9606', (195, 200))	('MMR', 'biological_process', 'GO:0006298', ('244', '247'))	('function', 'MPA', (150, 158))	('DNA', 'cellular_component', 'GO:0005574', ('124', '127'))	('yeast', 'Species', '4932', (234, 239))	('defect', 'NegReg', (114, 120))	('microsatellite frameshift mutations', 'Var', (61, 96))	('MMR', 'biological_process', 'GO:0006298', ('145', '148'))	('yeast', 'Species', '4932', (55, 60))	('mismatch repair', 'biological_process', 'GO:0006298', ('128', '143'))	('DNA', 'cellular_component', 'GO:0005574', ('240', '243'))
68788	25836926	Those efforts demonstrated that mutations in DNA MMR within the germline was associated with a form of hereditary cancer now termed Lynch syndrome, where affected patients share an extremely high risk for CRC and other cancers of the female reproductive track, gastrointestinal track, and urological track.	('patients', 'Species', '9606', (163, 171))	('hereditary cancer', 'Disease', 'MESH:D009369', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('CRC', 'Disease', (205, 208))	('Lynch syndrome', 'Disease', (132, 146))	('hereditary cancer', 'Disease', (103, 120))	('Lynch syndrome', 'Disease', 'MESH:D003123', (132, 146))	('mutations', 'Var', (32, 41))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancers', 'Disease', (219, 226))	('DNA MMR', 'Gene', (45, 52))	('associated', 'Reg', (77, 87))
68789	25836926	Furthermore, some sporadic colorectal cancers were shown to have defective DNA MMR caused by hypermethylation of the promoter of the DNA MMR gene MLH1, preventing transcription of MLH1.	('colorectal cancers', 'Disease', 'MESH:D015179', (27, 45))	('defective', 'NegReg', (65, 74))	('MLH1', 'Gene', (180, 184))	('MLH1', 'Gene', '4292', (180, 184))	('rectal cancer', 'Phenotype', 'HP:0100743', (31, 44))	('MLH1', 'Gene', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (27, 44))	('hypermethylation', 'Var', (93, 109))	('DNA', 'cellular_component', 'GO:0005574', ('75', '78'))	('colorectal cancers', 'Disease', (27, 45))	('transcription', 'MPA', (163, 176))	('MLH1', 'Gene', '4292', (146, 150))	('transcription', 'biological_process', 'GO:0006351', ('163', '176'))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('DNA', 'cellular_component', 'GO:0005574', ('133', '136'))	('preventing', 'NegReg', (152, 162))	('DNA MMR', 'Gene', (75, 82))	('MMR', 'biological_process', 'GO:0006298', ('137', '140'))	('MMR', 'biological_process', 'GO:0006298', ('79', '82'))
68790	25836926	However, testing for microsatellite alterations among cancers and other conditions was initially haphazard until a standard definition was put in place through an National Cancer Institute-sponsored workshop, allowing comparisons to take place between studies that occurred thereafter.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('Cancer', 'Phenotype', 'HP:0002664', (172, 178))	('Cancer', 'Disease', (172, 178))	('Cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('microsatellite', 'Var', (21, 35))
68795	25836926	Both MLH1 and MSH2 are the most common targets for mutation in the germline of Lynch syndrome patients, which completely abrogates DNA MMR function.	('MLH1', 'Gene', (5, 9))	('Lynch syndrome', 'Disease', 'MESH:D003123', (79, 93))	('MLH1', 'Gene', '4292', (5, 9))	('patients', 'Species', '9606', (94, 102))	('DNA MMR function', 'MPA', (131, 147))	('MSH2', 'Gene', (14, 18))	('mutation in', 'Var', (51, 62))	('Lynch syndrome', 'Disease', (79, 93))	('abrogates', 'NegReg', (121, 130))
68796	25836926	Germline mutation of MSH6, a component of MutSalpha, causes a more moderate Lynch syndrome phenotype presumably due to overlap with MSH3 (MutSbeta function) coupled with a compensatory increase in MSH3 expression.	('causes', 'Reg', (53, 59))	('increase', 'PosReg', (185, 193))	('Lynch syndrome', 'Disease', (76, 90))	('MSH3', 'Gene', (197, 201))	('Lynch syndrome', 'Disease', 'MESH:D003123', (76, 90))	('expression', 'MPA', (202, 212))	('MSH6', 'Gene', (21, 25))	('Germline mutation', 'Var', (0, 17))	('MSH3', 'Gene', (132, 136))	('overlap', 'Var', (119, 126))
68797	25836926	MSH6-mutant carriers present at older ages than patients with MLH1 or MSH2 germline mutations.	('MSH6-mutant', 'Gene', (0, 11))	('MLH1', 'Gene', '4292', (62, 66))	('MLH1', 'Gene', (62, 66))	('patients', 'Species', '9606', (48, 56))	('MSH6-mutant', 'Var', (0, 11))
68798	25836926	Germline mutation of PMS2, a component of MutLalpha, is relatively rare.	('PMS2', 'Gene', (21, 25))	('Germline mutation', 'Var', (0, 17))	('PMS2', 'Gene', '5395', (21, 25))
68799	25836926	There has been no description of a germline MSH3 mutation as a cause of Lynch syndrome.	('Lynch syndrome', 'Disease', (72, 86))	('MSH3', 'Gene', (44, 48))	('Lynch syndrome', 'Disease', 'MESH:D003123', (72, 86))	('cause', 'Reg', (63, 68))	('mutation', 'Var', (49, 57))
68801	25836926	The cause for EMAST was elusive despite its observation, likely because (a) it did not involve MSH2 or MLH1, the two major DNA MMR proteins; (b) tools to study MSH6 and in particular MSH3 lagged behind those developed for MLH1 and MSH2; (c) there was no germline mutation detected for MSH3 as a cause for Lynch syndrome, rendering it less important at least initially for this syndrome; and (d) no connection could be made between somatic MSH3 mutations and EMAST as MSH3 frameshift mutations are observed in microsatellite instability-high (MSH-H) tumors, which already have complete deficiency of DNA MMR.	('tumors', 'Disease', (549, 555))	('MLH1', 'Gene', (222, 226))	('MLH1', 'Gene', '4292', (103, 107))	('MSH', 'Gene', (439, 442))	('MSH', 'Gene', '4488', (542, 545))	('tumors', 'Disease', 'MESH:D009369', (549, 555))	('MLH1', 'Gene', '4292', (222, 226))	('frameshift mutations', 'Var', (472, 492))	('Lynch syndrome', 'Disease', (305, 319))	('MSH', 'Gene', '4488', (183, 186))	('MSH', 'Gene', '4488', (231, 234))	('MSH', 'Gene', '4488', (95, 98))	('MSH', 'Gene', '4488', (160, 163))	('MSH', 'Gene', (542, 545))	('MSH', 'Gene', '4488', (467, 470))	('MSH', 'Gene', '4488', (285, 288))	('MSH', 'Gene', (183, 186))	('MSH', 'Gene', (231, 234))	('MSH', 'Gene', (95, 98))	('MSH', 'Gene', (160, 163))	('Lynch syndrome', 'Disease', 'MESH:D003123', (305, 319))	('tumors', 'Phenotype', 'HP:0002664', (549, 555))	('MSH', 'Gene', (467, 470))	('MSH', 'Gene', (285, 288))	('MLH1', 'Gene', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (549, 554))	('MSH', 'Gene', '4488', (439, 442))
68809	25836926	In that study, five tetranucleotide repeats were used (MYCL1, D9S242, D20S85, D8S321, and D20S82) and among them, the highest correlation between tetranucleotide frameshift mutation and loss of MSH3 expression, particularly its nuclear heterogeneity, was when three tetranucleotide markers were mutated.	('MSH3', 'Gene', (194, 198))	('MYCL1', 'Gene', (55, 60))	('expression', 'MPA', (199, 209))	('D8S321', 'Var', (78, 84))	('loss', 'NegReg', (186, 190))	('D20S85', 'Var', (70, 76))	('tetranucleotide frameshift mutation', 'Var', (146, 181))	('D9S242', 'Var', (62, 68))	('tetranucleotide', 'Chemical', '-', (146, 161))	('tetranucleotide', 'Chemical', '-', (20, 35))	('MYCL1', 'Gene', '4610', (55, 60))	('D20S82', 'Var', (90, 96))	('tetranucleotide', 'Chemical', '-', (266, 281))
68810	25836926	However, only three of 78 tumors showed more than three tetranuclueotide marker mutations, whereas the majority of tumors showed one, two or three markers mutated (Figure 2).	('tetranuclueotide', 'Chemical', '-', (56, 72))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tetranuclueotide marker', 'MPA', (56, 79))	('mutations', 'Var', (80, 89))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))
68812	25836926	On the contrary, nuclear heterogeneity for MSH3, in addition to loss of MSH3 expression, correlated well with increasing number of tetranucleotide repeat mutations, from one tetranucleotide repeat to three repeats.	('expression', 'MPA', (77, 87))	('MSH3', 'Gene', (43, 47))	('tetranucleotide repeat mutations', 'Var', (131, 163))	('tetranucleotide', 'Chemical', '-', (174, 189))	('loss', 'NegReg', (64, 68))	('tetranucleotide', 'Chemical', '-', (131, 146))	('MSH3', 'Gene', (72, 76))
68814	25836926	For instance, among rectal tumors, the frequency of mutation of MYCL1, D9S242, D20S85, D8S321, and D20S82 among EMAST tumors varies from 10%-65%.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('rectal tumors', 'Disease', 'MESH:D012004', (20, 33))	('rectal tumors', 'Disease', (20, 33))	('D20S82', 'Var', (99, 105))	('D20S85', 'Var', (79, 85))	('MYCL1', 'Gene', '4610', (64, 69))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('rectal tumors', 'Phenotype', 'HP:0100743', (20, 33))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mutation', 'Var', (52, 60))	('D9S242', 'Var', (71, 77))	('MYCL1', 'Gene', (64, 69))	('D8S321', 'Var', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
68815	25836926	Additionally, mutant TP53 status has been associated with EMAST in non-melanoma skin, bladder, and non-small cell lung cancers, which may influence the detection of EMAST.	('TP53', 'Gene', (21, 25))	('associated with', 'Reg', (42, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('lung cancers', 'Phenotype', 'HP:0100526', (114, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('non-melanoma skin', 'Disease', (67, 84))	('non-small cell lung cancers', 'Disease', (99, 126))	('EMAST', 'Disease', (58, 63))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (103, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (99, 126))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (99, 125))	('non-melanoma skin', 'Disease', 'MESH:D008545', (67, 84))	('influence', 'Reg', (138, 147))	('mutant', 'Var', (14, 20))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (103, 126))	('bladder', 'Disease', (86, 93))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (99, 126))
68818	25836926	Since that definition, multiple observations indicate that MSI-L is most often seen with frameshift mutation among dinucleotide repeats, a lack of association with MSH6 mutation or loss, a lack of association with MSH2 or MLH1 loss, an association with inflammation, and is observed among EMAST cancers.	('seen', 'Reg', (79, 83))	('MSH2', 'Gene', (214, 218))	('mutation', 'Var', (169, 177))	('MSI-L', 'Disease', (59, 64))	('inflammation', 'Disease', 'MESH:D007249', (253, 265))	('MLH1 loss', 'Disease', (222, 231))	('dinucleotide', 'Chemical', 'MESH:D015226', (115, 127))	('inflammation', 'Disease', (253, 265))	('frameshift mutation', 'Var', (89, 108))	('cancers', 'Disease', 'MESH:D009369', (295, 302))	('lack', 'NegReg', (139, 143))	('MLH1 loss', 'Disease', 'MESH:D015431', (222, 231))	('loss', 'NegReg', (181, 185))	('cancers', 'Disease', (295, 302))	('cancers', 'Phenotype', 'HP:0002664', (295, 302))	('MSH6', 'Gene', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))
68822	25836926	For instance, tetranucleotide microsatellite changes matching those in primary bladder tumors were detected in the urine from 19 of 20 (95%) patients, compared to only nine of 18 (50%) patients showing cancer cells from urine cytology, making tetranucleotide microsatellite instability a reliable biomarker for this tumor.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tetranucleotide', 'Chemical', '-', (243, 258))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('bladder tumors', 'Phenotype', 'HP:0009725', (79, 93))	('changes', 'Var', (45, 52))	('patients', 'Species', '9606', (141, 149))	('tetranucleotide', 'MPA', (14, 29))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('tumor', 'Disease', (87, 92))	('bladder tumors', 'Disease', 'MESH:D001749', (79, 93))	('patients', 'Species', '9606', (185, 193))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (316, 321))	('tetranucleotide', 'Chemical', '-', (14, 29))	('cancer', 'Disease', (202, 208))	('bladder tumors', 'Disease', (79, 93))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
68832	25836926	Indeed, EMAST colorectal tumors show higher density of CD8+ T cells, but not CD4+ T cells, in the surrounding tumor nest stroma compared to EMAST-negative tumors.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('colorectal tumors', 'Disease', (14, 31))	('tumors', 'Disease', (25, 31))	('tumor', 'Disease', (155, 160))	('rectal tumors', 'Phenotype', 'HP:0100743', (18, 31))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('higher', 'PosReg', (37, 43))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('colorectal tumors', 'Disease', 'MESH:D015179', (14, 31))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (25, 30))	('tumors', 'Disease', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('CD8+', 'Var', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Disease', (110, 115))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
68833	25836926	Additionally, the density of CD8+ T cells increased with adenoma-to-carcinoma progression, mirroring the increase in EMAST observance found during this histological advancement.	('increased', 'PosReg', (42, 51))	('T cells increased', 'Phenotype', 'HP:0100828', (34, 51))	('CD8+', 'Var', (29, 33))	('adenoma-to-carcinoma', 'Disease', (57, 77))	('adenoma-to-carcinoma', 'Disease', 'MESH:D000236', (57, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))
68836	25836926	In retrospect, these studies found dinucleotide microsatellite instability within these non-cancer but inflamed tissues, and applying current NCI consensus definitions, most samples would be reclassified as MSI-L.	('non-cancer', 'Disease', 'MESH:D009369', (88, 98))	('dinucleotide', 'Chemical', 'MESH:D015226', (35, 47))	('non-cancer', 'Disease', (88, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('dinucleotide microsatellite', 'Var', (35, 62))
68837	25836926	Given the association of MSI-L (defined by dinucleotide instability among the NCI consensus markers) and its correlation with EMAST (defined by tetranucleotide instability) and changes in MSH3 expression, these studies likely described EMAST among these inflamed tissues (although these studies did not examine MSH3 expression).	('changes', 'Var', (177, 184))	('tetranucleotide', 'Chemical', '-', (144, 159))	('EMAST', 'Disease', (236, 241))	('MSH3', 'Gene', (188, 192))	('association', 'Interaction', (10, 21))	('EMAST', 'Disease', (126, 131))	('described', 'Reg', (226, 235))	('MSI-L', 'Gene', (25, 30))	('expression', 'MPA', (193, 203))	('dinucleotide', 'Chemical', 'MESH:D015226', (43, 55))
68845	25836926	EMAST has proven to be a very common finding among colorectal cancers, a finding more widespread than MSI due to hypermethylation of MLH1 that is seen in ~15% of all colorectal cancers.	('MLH1', 'Gene', '4292', (133, 137))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('MLH1', 'Gene', (133, 137))	('colorectal cancer', 'Phenotype', 'HP:0003003', (51, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (166, 183))	('colorectal cancers', 'Disease', 'MESH:D015179', (166, 184))	('EMAST', 'Disease', (0, 5))	('colorectal cancers', 'Disease', 'MESH:D015179', (51, 69))	('hypermethylation', 'Var', (113, 129))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('colorectal cancers', 'Disease', (51, 69))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('colorectal cancers', 'Disease', (166, 184))	('rectal cancer', 'Phenotype', 'HP:0100743', (55, 68))	('rectal cancer', 'Phenotype', 'HP:0100743', (170, 183))
68852	25836926	MSI-L/EMAST colorectal cancer patients demonstrated the worse recurrence-free survival among the three groups, and distant metastasis was more likely in this group, and was an independent predictor of recurrent metastasis from stage II/III colorectal cancer (Hazard Ratio 1.83, range 1.06-3.15, p = 0.03).	('colorectal cancer', 'Disease', (12, 29))	('distant metastasis', 'CPA', (115, 133))	('colorectal cancer', 'Phenotype', 'HP:0003003', (240, 257))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('rectal cancer', 'Phenotype', 'HP:0100743', (16, 29))	('III colorectal cancer', 'Disease', (236, 257))	('worse', 'NegReg', (56, 61))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('recurrence-free survival', 'CPA', (62, 86))	('MSI-L/EMAST', 'Var', (0, 11))	('patients', 'Species', '9606', (30, 38))	('rectal cancer', 'Phenotype', 'HP:0100743', (244, 257))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('III colorectal cancer', 'Disease', 'MESH:D015179', (236, 257))	('colorectal cancer', 'Disease', 'MESH:D015179', (240, 257))
68860	25836926	Based on bacteria and yeast data for DNA mismatch repair, defects in MSH3 (part of the MutSbeta complex) for human tetranucleotide frameshift mutations might seem obvious, but this was not proven in humans until relatively recently.	('human', 'Species', '9606', (109, 114))	('human', 'Species', '9606', (199, 204))	('yeast', 'Species', '4932', (22, 27))	('frameshift mutations', 'Var', (131, 151))	('humans', 'Species', '9606', (199, 205))	('MSH3', 'Gene', (69, 73))	('defects', 'Var', (58, 65))	('tetranucleotide', 'Chemical', '-', (115, 130))
68862	25836926	experimentally linked the first connection between EMAST and MSH3 in human colon cancer, showing: (a) loss of expression of MSH3 in colorectal cancers with EMAST; and (b) that MSH3-deficient cells (deficient background or through knockdown of MSH3) exhibited dinucleotide or greater microsatellite frameshift mutation.	('colon cancer', 'Phenotype', 'HP:0003003', (75, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (132, 149))	('rectal cancer', 'Phenotype', 'HP:0100743', (136, 149))	('exhibited', 'Reg', (249, 258))	('dinucleotide', 'Chemical', 'MESH:D015226', (259, 271))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('MSH3', 'Gene', (124, 128))	('microsatellite frameshift mutation', 'Var', (283, 317))	('MSH3-deficient', 'Gene', (176, 190))	('MSH3', 'Gene', (243, 247))	('colon cancer', 'Disease', 'MESH:D015179', (75, 87))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('colorectal cancers', 'Disease', (132, 150))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('human', 'Species', '9606', (69, 74))	('colon cancer', 'Disease', (75, 87))	('expression', 'MPA', (110, 120))	('colorectal cancers', 'Disease', 'MESH:D015179', (132, 150))	('loss', 'NegReg', (102, 106))	('dinucleotide', 'Var', (259, 271))
68864	25836926	created human colon cancer cells permanently transfected with plasmids containing the human tetranucleotide microsatellite loci D8S321 [AAAG12] or D20S82 [AAAG16] by which frameshift mutation would trigger enhanced green fluorescent protein expression.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tetranucleotide', 'Chemical', '-', (92, 107))	('colon cancer', 'Disease', (14, 26))	('human', 'Species', '9606', (8, 13))	('frameshift mutation', 'Var', (172, 191))	('trigger', 'Reg', (198, 205))	('enhanced green fluorescent protein expression', 'MPA', (206, 251))	('human', 'Species', '9606', (86, 91))	('protein', 'cellular_component', 'GO:0003675', ('233', '240'))	('colon cancer', 'Phenotype', 'HP:0003003', (14, 26))	('colon cancer', 'Disease', 'MESH:D015179', (14, 26))	('D8S321', 'Var', (128, 134))	('D20S82 [', 'Var', (147, 155))
68865	25836926	By transfecting into colon cancer cells with various DNA mismatch repair backgrounds or by knockdown of MSH3, the authors demonstrate that MSH3 loss is responsible for ongoing tetranucleotide frameshifts, with rates of ~18 x 10-4 to 34 x 10-4 mutations/cell/generation, compared to MSH6-deficient cells at rates of ~0.8 x 10-4 mutations/cell/generation.	('tetranucleotide', 'MPA', (176, 191))	('frameshifts', 'Var', (192, 203))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('colon cancer', 'Phenotype', 'HP:0003003', (21, 33))	('mutations/cell/generation', 'Var', (243, 268))	('colon cancer', 'Disease', 'MESH:D015179', (21, 33))	('tetranucleotide', 'Chemical', '-', (176, 191))	('colon cancer', 'Disease', (21, 33))	('loss', 'NegReg', (144, 148))	('MSH3', 'Gene', (139, 143))
68866	25836926	Although these experiments were designed to detect deletion of one microsatellite repeat unit, an important observation from the sequencing of clones after mutation was that both contraction and expansion frameshifts of the microsatellite occurred with MSH3-deficiency.	('MSH3-deficiency', 'Disease', 'MESH:D007153', (253, 268))	('microsatellite', 'Gene', (224, 238))	('frameshifts', 'Var', (205, 216))	('occurred', 'Reg', (239, 247))	('MSH3-deficiency', 'Disease', (253, 268))
68867	25836926	showed with the use of [AAAG17] and [CA13] reporter plasmids that the presence of MSH3 resulted in increased stability at the tetranucleotide sequence and increased but only partial stability at the dinucleotide sequence.	('presence', 'Var', (70, 78))	('dinucleotide', 'Chemical', 'MESH:D015226', (199, 211))	('MSH3', 'Gene', (82, 86))	('increased', 'PosReg', (155, 164))	('stability at the tetranucleotide sequence', 'MPA', (109, 150))	('tetranucleotide', 'Chemical', '-', (126, 141))	('increased', 'PosReg', (99, 108))
68869	25836926	Both papers data on tetranucleotide frameshifts from MSH3 dysfunction contrast the near uniform observation that mono- or dinucleotide microsatellite sequences in human colorectal cancer only contract in size.	('rectal cancer', 'Phenotype', 'HP:0100743', (173, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('colorectal cancer', 'Disease', 'MESH:D015179', (169, 186))	('tetranucleotide frameshifts', 'Var', (20, 47))	('tetranucleotide', 'Chemical', '-', (20, 35))	('mono- or dinucleotide', 'Chemical', '-', (113, 134))	('MSH3 dysfunction', 'Disease', 'MESH:D006331', (53, 69))	('human', 'Species', '9606', (163, 168))	('colorectal cancer', 'Phenotype', 'HP:0003003', (169, 186))	('MSH3 dysfunction', 'Disease', (53, 69))	('colorectal cancer', 'Disease', (169, 186))
68872	25836926	An association between the presence of mutant TP53 and EMAST has been made in non-melanoma skin, bladder, and non-small cell lung cancer specimens, particularly for non-invasive disease.	('bladder', 'Disease', (97, 104))	('non-small cell lung cancer', 'Disease', (110, 136))	('non-invasive disease', 'Disease', (165, 185))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (114, 136))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (110, 136))	('non-melanoma skin', 'Disease', 'MESH:D008545', (78, 95))	('TP53', 'Gene', (46, 50))	('mutant', 'Var', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('non-melanoma skin', 'Disease', (78, 95))	('presence', 'Var', (27, 35))	('EMAST', 'Disease', (55, 60))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (110, 136))
68873	25836926	This raises the possibility of mutant TP53 influencing the formation of tetranucleotide frameshifts, but this has not been further proven, nor shown for colorectal cancers.	('mutant', 'Var', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('formation', 'MPA', (59, 68))	('TP53', 'Gene', (38, 42))	('rectal cancer', 'Phenotype', 'HP:0100743', (157, 170))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('colorectal cancers', 'Disease', 'MESH:D015179', (153, 171))	('tetranucleotide', 'Chemical', '-', (72, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (153, 170))	('colorectal cancers', 'Disease', (153, 171))	('influencing', 'Reg', (43, 54))
68874	25836926	Aside from secondary mutation of MSH3 in the setting of an MSI-H colorectal cancer caused by frameshift of its [A8] microsatellite, there has been no example in the literature for: (a) germline mutation for MSH3 for which to study its consequences; (b) evidence for somatic inactivation of MSH3 (aside from MSI-H cancers) for which MSH3 function could be lost; or (c) epigenetic inactivation of MSH3 (such as that seen for MLH1).	('MSI-H cancers', 'Disease', (307, 320))	('colorectal cancer', 'Phenotype', 'HP:0003003', (65, 82))	('MSH3', 'Gene', (290, 294))	('MSI-H cancers', 'Disease', 'MESH:D009369', (307, 320))	('MSI-H colorectal cancer', 'Disease', (59, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('MSH3', 'Gene', (395, 399))	('epigenetic inactivation', 'Var', (368, 391))	('MSI-H colorectal cancer', 'Disease', 'MESH:D015179', (59, 82))	('MLH1', 'Gene', '4292', (423, 427))	('MLH1', 'Gene', (423, 427))	('rectal cancer', 'Phenotype', 'HP:0100743', (69, 82))	('inactivation', 'NegReg', (274, 286))	('caused by', 'Reg', (83, 92))	('cancers', 'Phenotype', 'HP:0002664', (313, 320))
68883	25836926	Cell sensitivity to oxidative stress varies based on the status of DNA mismatch repair, with mismatch repair deficient cells being more sensitive to hydrogen peroxide compared to mismatch repair proficient cells.	('mismatch repair', 'biological_process', 'GO:0006298', ('179', '194'))	('mismatch repair', 'biological_process', 'GO:0006298', ('93', '108'))	('mismatch repair', 'biological_process', 'GO:0006298', ('71', '86'))	('sensitive to hydrogen peroxide', 'MPA', (136, 166))	('oxidative stress', 'Phenotype', 'HP:0025464', (20, 36))	('mismatch repair deficient', 'Var', (93, 118))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (149, 166))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))
68884	25836926	Mismatch repair deficient mice demonstrate increased susceptibility to oxidative stress-induced intestinal cancers, suggesting that intact DNA mismatch repair simultaneously protects against mutagenesis and suppresses tumorigenesis induced by oxidative stress.	('oxidative stress', 'Phenotype', 'HP:0025464', (243, 259))	('oxidative stress', 'Phenotype', 'HP:0025464', (71, 87))	('suppresses', 'NegReg', (207, 217))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Mismatch repair', 'biological_process', 'GO:0006298', ('0', '15'))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('mutagenesis', 'biological_process', 'GO:0006280', ('191', '202'))	('intestinal cancers', 'Disease', 'MESH:D007414', (96, 114))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('intact DNA mismatch repair', 'Var', (132, 158))	('mutagenesis', 'MPA', (191, 202))	('DNA', 'cellular_component', 'GO:0005574', ('139', '142'))	('mismatch repair', 'biological_process', 'GO:0006298', ('143', '158'))	('tumor', 'Disease', (218, 223))	('intestinal cancers', 'Disease', (96, 114))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('mice', 'Species', '10090', (26, 30))
68893	25836926	Mutations at genomic tetranucleotide loci were detected within two weeks in cells under IL6 treatment.	('tetranucleotide', 'Chemical', '-', (21, 36))	('Mutations', 'Var', (0, 9))	('IL6', 'Gene', '3569', (88, 91))	('IL6', 'Gene', (88, 91))
68905	25836926	Because PMS2 stability is dependent on association with its heterodimer partner MLH1, loss of MLH1 protein destabilizes PMS2.	('PMS2', 'Gene', '5395', (8, 12))	('destabilizes', 'NegReg', (107, 119))	('MLH1', 'Gene', '4292', (94, 98))	('MLH1', 'Gene', (80, 84))	('loss', 'Var', (86, 90))	('MLH1', 'Gene', '4292', (80, 84))	('PMS2', 'Gene', '5395', (120, 124))	('PMS2', 'Gene', (8, 12))	('protein', 'Protein', (99, 106))	('MLH1', 'Gene', (94, 98))	('PMS2', 'Gene', (120, 124))
68907	25836926	Within murine and human stem cells, HIF-1alpha positively regulated MLH1 and MSH6 expression with short-term hypoxia, but prolonged hypoxia reduced both MLH1 and MSH6 expression through epigenetic regulation of these two gene promoters.	('MLH1', 'Gene', '4292', (153, 157))	('MLH1', 'Gene', (153, 157))	('hypoxia', 'Disease', (132, 139))	('MSH6', 'Gene', (162, 166))	('MLH1', 'Gene', (68, 72))	('expression', 'MPA', (82, 92))	('hypoxia', 'Disease', (109, 116))	('epigenetic regulation', 'Var', (186, 207))	('hypoxia', 'Disease', 'MESH:D000860', (132, 139))	('hypoxia', 'Disease', 'MESH:D000860', (109, 116))	('MLH1', 'Gene', '4292', (68, 72))	('human', 'Species', '9606', (18, 23))	('HIF-1alpha', 'Gene', '3091', (36, 46))	('HIF-1alpha', 'Gene', (36, 46))	('MSH6', 'Gene', (77, 81))	('murine', 'Species', '10090', (7, 13))	('expression', 'MPA', (167, 177))	('reduced', 'NegReg', (140, 147))
68911	25836926	Unlike MSI-H colorectal cancers in which hypermethylation of MLH1 drives multiple target gene mutations, to date there has been little evidence for mutation of specific target genes that might drive or alter the pathogenesis of colorectal cancer with loss of MSH3 function.	('rectal cancer', 'Phenotype', 'HP:0100743', (232, 245))	('function', 'MPA', (264, 272))	('rectal cancer', 'Phenotype', 'HP:0100743', (17, 30))	('alter', 'Reg', (202, 207))	('colorectal cancer', 'Phenotype', 'HP:0003003', (228, 245))	('drive', 'Reg', (193, 198))	('colorectal cancer', 'Phenotype', 'HP:0003003', (13, 30))	('MSH3', 'Gene', (259, 263))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('MLH1', 'Gene', (61, 65))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('MLH1', 'Gene', '4292', (61, 65))	('mutations', 'Var', (94, 103))	('colorectal cancer', 'Disease', 'MESH:D015179', (228, 245))	('colorectal cancer', 'Disease', 'MESH:D015179', (13, 30))	('colorectal cancer', 'Disease', (228, 245))	('MSI-H colorectal cancers', 'Disease', 'MESH:D015179', (7, 31))	('pathogenesis', 'biological_process', 'GO:0009405', ('212', '224'))	('MSI-H colorectal cancers', 'Disease', (7, 31))	('loss', 'NegReg', (251, 255))
68914	25836926	Several genes have trinucleotide coding repeats that might be capable of undergoing frameshift mutation, but again, there is little evidence that this occurs and contributes to colorectal cancer pathogenesis.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('colorectal cancer', 'Disease', (177, 194))	('colorectal cancer', 'Disease', 'MESH:D015179', (177, 194))	('rectal cancer', 'Phenotype', 'HP:0100743', (181, 194))	('trinucleotide coding repeats', 'Var', (19, 47))	('contributes', 'Reg', (162, 173))	('frameshift mutation', 'Var', (84, 103))	('colorectal cancer', 'Phenotype', 'HP:0003003', (177, 194))	('trinucleotide', 'Chemical', '-', (19, 32))
68915	25836926	One group found an association among MSI-H colorectal cancers with frameshift mutations in the transcription factor E2F4 [CAG13] and secondary frameshift mutations of MSH3 [A8] (see below).	('MSI-H colorectal cancers', 'Disease', (37, 61))	('MSI-H colorectal cancers', 'Disease', 'MESH:D015179', (37, 61))	('E2F4', 'Gene', '1874', (116, 120))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('rectal cancer', 'Phenotype', 'HP:0100743', (47, 60))	('frameshift mutations', 'Var', (67, 87))	('E2F4', 'Gene', (116, 120))	('colorectal cancer', 'Phenotype', 'HP:0003003', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('MSH3 [', 'Gene', (167, 173))	('frameshift mutations', 'Var', (143, 163))
68916	25836926	E2F4 frameshift mutations have previously been found among MSI-H colorectal cancers.	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('colorectal cancer', 'Phenotype', 'HP:0003003', (65, 82))	('E2F4', 'Gene', '1874', (0, 4))	('found', 'Reg', (47, 52))	('MSI-H colorectal cancers', 'Disease', 'MESH:D015179', (59, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('frameshift mutations', 'Var', (5, 25))	('MSI-H colorectal cancers', 'Disease', (59, 83))	('rectal cancer', 'Phenotype', 'HP:0100743', (69, 82))	('E2F4', 'Gene', (0, 4))
68918	25836926	Mutation of MSH3 itself can occur as a consequence of MSI-H cancers (sporadic or Lynch) due to its exon 7 coding [A8] microsatellite that can be subject to frameshift.	('MSH3', 'Gene', (12, 16))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('MSI-H cancers', 'Disease', (54, 67))	('Mutation', 'Var', (0, 8))	('MSI-H cancers', 'Disease', 'MESH:D009369', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
68921	25836926	What is not known if the additional loss of MSH3 function enhances any characteristic of an already MSI-H colorectal cancer which already has full loss of DNA mismatch repair (as in the case of MLH1 hypermethylation, or germline mutation of MLH1 or MSH2, or PMS2, but perhaps could enhance characteristics of germline MSH6 mutation carriers).	('MLH1', 'Gene', (194, 198))	('rectal cancer', 'Phenotype', 'HP:0100743', (110, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))	('MSH3', 'Gene', (44, 48))	('hypermethylation', 'Var', (199, 215))	('PMS2', 'Gene', (258, 262))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('loss', 'NegReg', (36, 40))	('germline mutation', 'Var', (220, 237))	('MSI-H colorectal cancer', 'Disease', (100, 123))	('PMS2', 'Gene', '5395', (258, 262))	('MLH1', 'Gene', '4292', (194, 198))	('MLH1', 'Gene', '4292', (241, 245))	('MSI-H colorectal cancer', 'Disease', 'MESH:D015179', (100, 123))	('MLH1', 'Gene', (241, 245))	('enhances', 'PosReg', (58, 66))	('MSH2', 'Gene', (249, 253))
68922	25836926	The addition of an MSH3 mutation on top of hypermethylation of MLH1, for instance, would combine the defects for recognition and repair outlined in Table 1, conceivably influencing the ultimate behavior of the cancer.	('MSH3', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('influencing', 'Reg', (169, 180))	('MLH1', 'Gene', '4292', (63, 67))	('MLH1', 'Gene', (63, 67))	('mutation', 'Var', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))
68923	25836926	One report indicates that MSH-H colorectal cancers with secondary MSH3 mutation demonstrates decreased wall invasiveness and aneuploidy histologically, but this has not been confirmed in any other study.	('MSH', 'Gene', (66, 69))	('colorectal cancers', 'Disease', (32, 50))	('aneuploidy', 'Disease', (125, 135))	('MSH', 'Gene', '4488', (66, 69))	('mutation', 'Var', (71, 79))	('colorectal cancer', 'Phenotype', 'HP:0003003', (32, 49))	('rectal cancer', 'Phenotype', 'HP:0100743', (36, 49))	('invasiveness', 'Disease', 'MESH:D009362', (108, 120))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('decreased', 'NegReg', (93, 102))	('invasiveness', 'Disease', (108, 120))	('MSH', 'Gene', (26, 29))	('aneuploidy', 'Disease', 'MESH:D000782', (125, 135))	('MSH', 'Gene', '4488', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('colorectal cancers', 'Disease', 'MESH:D015179', (32, 50))
68924	25836926	Cell-free extracts containing defective MutSbeta can catalyze expansions and contractions at trinucleotide repeats in the absence of any DNA replication:an important concept for several neurological conditions in which trinucleotide repeat expansions are pathogenic, but without neuronal mitosis.	('neuronal mitosis', 'Disease', 'MESH:D009410', (279, 295))	('expansions', 'Var', (62, 72))	('trinucleotide', 'Chemical', '-', (219, 232))	('trinucleotide', 'Chemical', '-', (93, 106))	('neuronal mitosis', 'Disease', (279, 295))	('trinucleotide repeat expansions', 'Var', (219, 250))	('pathogenic', 'Reg', (255, 265))
68925	25836926	Utilizing congenic mouse models, biased expansion of the [CAG] repeat in the Huntington's gene (which potentially causes disease) in liver and striatum occurred as a consequence of a polymorphism in the MSH3 gene, which altered its protein levels and function.	('function', 'MPA', (251, 259))	('altered', 'Reg', (220, 227))	('protein levels', 'MPA', (232, 246))	("Huntington's", 'Disease', 'MESH:D006816', (77, 89))	('Huntington', 'Disease', (77, 87))	('polymorphism', 'Var', (183, 195))	('protein', 'cellular_component', 'GO:0003675', ('232', '239'))	('MSH3', 'Gene', (203, 207))	('mouse', 'Species', '10090', (19, 24))
68928	25836926	The number of repeat units of the microsatellite may dictate slippage and proneness for repair, with longer lengths more likely to mutate with MutSbeta deficiency.	('MutSbeta deficiency', 'Disease', 'MESH:D007153', (143, 162))	('dictate', 'Reg', (53, 60))	('proneness', 'MPA', (74, 83))	('slippage', 'MPA', (61, 69))	('mutate', 'Var', (131, 137))	('microsatellite', 'Gene', (34, 48))	('MutSbeta deficiency', 'Disease', (143, 162))
68929	25836926	Additionally, the nucleotides surrounding the microsatellites can dictate the likelihood for frameshift mutation and repair, and formational dynamics of trinucleotide repeat loop junctions may dictate the ability of MutSbeta to bind, bend, and dissociate from DNA.	('bend', 'MPA', (234, 238))	('dictate', 'Reg', (193, 200))	('frameshift mutation', 'Var', (93, 112))	('bind', 'Interaction', (228, 232))	('repair', 'CPA', (117, 123))	('trinucleotide', 'Chemical', '-', (153, 166))	('dictate', 'Reg', (66, 73))	('ability', 'MPA', (205, 212))
68930	25836926	demonstrated with MSH3 silencing in HCEC cells that RAD50 and MRE11 were overexpressed, indicative of DSBs.	('MRE11', 'Gene', '4361', (62, 67))	('RAD', 'biological_process', 'GO:1990116', ('52', '55'))	('MRE11', 'Gene', (62, 67))	('RAD50', 'Gene', (52, 57))	('RAD50', 'Gene', '10111', (52, 57))	('overexpressed', 'PosReg', (73, 86))	('silencing', 'Var', (23, 32))	('MSH3', 'Gene', (18, 22))	('HCEC', 'CellLine', 'CVCL:2064', (36, 40))	('DSBs', 'Chemical', 'MESH:C007563', (102, 106))
68932	25836926	showed that murine MSH3-null fibroblasts developed chromatid breaks after radiation compared with MSH3-proficient cells, and that MSH3-deficient mice in a TP53-null background developed late onset tumors with increased loss of heterozygosity (LOH) and copy number variation (both indicative of chromosomal instability), and demonstrated EMAST.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('chromatid', 'cellular_component', 'GO:0005695', ('51', '60'))	('chromatid', 'cellular_component', 'GO:0005694', ('51', '60'))	('chromosomal instability', 'Phenotype', 'HP:0040012', (294, 317))	('copy number variation', 'Var', (252, 273))	('murine', 'Species', '10090', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('chromatid breaks', 'Phenotype', 'HP:0040012', (51, 67))	('MSH3-deficient', 'Gene', (130, 144))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('mice', 'Species', '10090', (145, 149))	('tumors', 'Disease', (197, 203))	('loss', 'NegReg', (219, 223))
68933	25836926	These authors suggest that in contrast to an MSH2 defect in which there is a strong and dominant mismatch repair defect and only a moderate DSB repair defect, an MSH3 defect is moderate for mismatch repair as well as for DSB repair with observation of both defects in tumors.	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('mismatch repair', 'MPA', (97, 112))	('mismatch repair', 'biological_process', 'GO:0006298', ('190', '205'))	('defect', 'Var', (167, 173))	('tumors', 'Disease', (268, 274))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('tumors', 'Disease', 'MESH:D009369', (268, 274))	('defect', 'Var', (113, 119))	('MSH3', 'Gene', (162, 166))	('mismatch repair', 'biological_process', 'GO:0006298', ('97', '112'))
68934	25836926	showed that human cells with MSH3 mutations have a clear defect in homologous recombination repair for DSBs, making the cells dependent on non-homologous end joining (NHEJ) repair for DSBs mediated by DNA PKcs, encoded by PRKDC.	('MSH3', 'Gene', (29, 33))	('NHEJ', 'biological_process', 'GO:0006303', ('167', '171'))	('DNA', 'cellular_component', 'GO:0005574', ('201', '204'))	('DSBs', 'Chemical', 'MESH:C007563', (103, 107))	('PRKDC', 'Gene', '5591', (222, 227))	('homologous recombination repair', 'MPA', (67, 98))	('DSBs', 'Chemical', 'MESH:C007563', (184, 188))	('defect', 'NegReg', (57, 63))	('human', 'Species', '9606', (12, 17))	('PRKDC', 'Gene', (222, 227))	('mutations', 'Var', (34, 43))	('homologous recombination', 'biological_process', 'GO:0035825', ('67', '91'))
68935	25836926	Because MSH3-deficient cells are addicted to DNA PKcs for repair of DSBs, the authors demonstrate that inhibition of DNA PKcs can induce apoptosis in MSH3-mutant cells, a promising therapeutic approach to target these cells.	('induce', 'PosReg', (130, 136))	('apoptosis', 'CPA', (137, 146))	('apoptosis', 'biological_process', 'GO:0097194', ('137', '146'))	('apoptosis', 'biological_process', 'GO:0006915', ('137', '146'))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('inhibition', 'Var', (103, 113))	('DSBs', 'Chemical', 'MESH:C007563', (68, 72))	('MSH3-mutant', 'Gene', (150, 161))	('DNA', 'cellular_component', 'GO:0005574', ('117', '120'))
68936	25836926	Thus, MSH3 participates in both DNA mismatch repair as well as in homologous recombination repair of DSBs, making loss of MSH3 function (or the appearance of EMAST) a complex repair defect in cells.	('function', 'MPA', (127, 135))	('MSH3', 'Gene', (122, 126))	('DSBs', 'Chemical', 'MESH:C007563', (101, 105))	('loss', 'Var', (114, 118))	('participates', 'Reg', (11, 23))
68937	25836926	Loss of MSH3 can occur with mutation in MSI-H colorectal cancers, but it is not clear if the additional loss of MSH3 adds further phenotype to the cancer cells.	('MSI-H colorectal cancers', 'Disease', (40, 64))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('MSH3', 'Gene', (8, 12))	('MSI-H colorectal cancers', 'Disease', 'MESH:D015179', (40, 64))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (46, 63))	('MSH3', 'Gene', (112, 116))	('Loss', 'NegReg', (0, 4))	('mutation', 'Var', (28, 36))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', (147, 153))	('rectal cancer', 'Phenotype', 'HP:0100743', (50, 63))
68938	25836926	Isolated loss of MSH3 function can occur with inflammation, directed by cytokines like IL6 to mis-localize MSH3 from the nucleus to the cytosol, allowing accumulation of mutations in nuclear DNA.	('inflammation', 'Disease', 'MESH:D007249', (46, 58))	('mutations', 'Var', (170, 179))	('inflammation', 'Disease', (46, 58))	('IL6', 'Gene', '3569', (87, 90))	('MSH3', 'Gene', (17, 21))	('loss', 'NegReg', (9, 13))	('IL6', 'Gene', (87, 90))	('MSH3', 'Gene', (107, 111))	('function', 'MPA', (22, 30))
68940	25836926	The loss of MSH3 function may do more than generate EMAST; it may contribute to aneuploidy due to its role in DSB repair.	('MSH3', 'Gene', (12, 16))	('aneuploidy', 'Disease', (80, 90))	('contribute', 'Reg', (66, 76))	('aneuploidy', 'Disease', 'MESH:D000782', (80, 90))	('DSB', 'Disease', (110, 113))	('loss', 'Var', (4, 8))
68943	25836926	Specifically, the topoisomerase I inhibitor irinotecan may be more effective in MSI-H cells, but this may not be due to specific MutS complex binding compared to other factors, such as TP53 mutational status, frameshift mutation of target genes such as MRE11, or increased levels of gamma-H2AX and phospho-Chk2 to stabilize cell cycle dynamics.	('Chk2', 'Gene', (306, 310))	('Chk2', 'Gene', '11200', (306, 310))	('H2AX', 'Gene', (289, 293))	('cell cycle dynamics', 'CPA', (324, 343))	('MSI-H', 'Disease', 'MESH:D000848', (80, 85))	('MutS complex', 'cellular_component', 'GO:1990710', ('129', '141'))	('binding', 'molecular_function', 'GO:0005488', ('142', '149'))	('irinotecan', 'Chemical', 'MESH:D000077146', (44, 54))	('MRE11', 'Gene', '4361', (253, 258))	('effective', 'MPA', (67, 76))	('topoisomerase', 'molecular_function', 'GO:0003917', ('18', '31'))	('MRE11', 'Gene', (253, 258))	('more', 'PosReg', (62, 66))	('topoisomerase', 'molecular_function', 'GO:0003918', ('18', '31'))	('cell cycle', 'biological_process', 'GO:0007049', ('324', '334'))	('MSI-H', 'Disease', (80, 85))	('frameshift mutation', 'Var', (209, 228))	('H2AX', 'Gene', '3014', (289, 293))
68956	24906690	Univariate analysis showed that there was no significant difference in the initial distribution of disease between KRAS mutant and wild type tumors (P > 0.05).	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('KRAS', 'Gene', (115, 119))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('KRAS', 'Gene', '3845', (115, 119))	('type tumors', 'Disease', 'MESH:D009369', (136, 147))	('type tumors', 'Disease', (136, 147))	('mutant', 'Var', (120, 126))
68957	24906690	Exploratory analyses showed that patients with poorly differentiated histology had a statistically significant increase in hepatic metastases in the presence of KRAS mutations vs. KRAS wild type genotype (median 5.0 vs. 0.5, P = 0.02).	('increase', 'PosReg', (111, 119))	('KRAS', 'Gene', (180, 184))	('mutations', 'Var', (166, 175))	('patients', 'Species', '9606', (33, 41))	('hepatic metastases', 'Disease', (123, 141))	('hepatic metastases', 'Disease', 'MESH:D009362', (123, 141))	('KRAS', 'Gene', '3845', (180, 184))	('KRAS', 'Gene', (161, 165))	('KRAS', 'Gene', '3845', (161, 165))
68959	24906690	Patients with both poorly differentiated histology and KRAS mutations had more liver metastases in subgroup analyses.	('KRAS', 'Gene', (55, 59))	('more', 'PosReg', (74, 78))	('liver metastases', 'Disease', (79, 95))	('KRAS', 'Gene', '3845', (55, 59))	('Patients', 'Species', '9606', (0, 8))	('liver metastases', 'Disease', 'MESH:D009362', (79, 95))	('mutations', 'Var', (60, 69))
68967	24906690	These anti-EGFR agents have diminished efficacy in the presence of mutations in the downstream components of the EGFR signaling pathway, including the Ras, Raf, and MAPK pathway.	('efficacy', 'MPA', (39, 47))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('diminished', 'NegReg', (28, 38))	('mutations', 'Var', (67, 76))	('Raf', 'Gene', '22882', (156, 159))	('Ras', 'Pathway', (151, 154))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('MAPK pathway', 'Pathway', (165, 177))	('Raf', 'Gene', (156, 159))
68968	24906690	The KRAS gene, which belongs to the RAS family of oncogenes in this signaling pathway, is mutated in approximately 40% of colorectal cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('KRAS', 'Gene', '3845', (4, 8))	('signaling pathway', 'biological_process', 'GO:0007165', ('68', '85'))	('mutated', 'Var', (90, 97))	('colorectal cancers', 'Disease', (122, 140))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('colorectal cancers', 'Disease', 'MESH:D015179', (122, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('KRAS', 'Gene', (4, 8))
68970	24906690	KRAS mutations and TP53 inactivation are known to promote the emergence of aggressive subclones in the evolution of colorectal cancer, and some studies have suggested an association with advanced tumor staging or increased occurrence of liver metastasis.	('colorectal cancer', 'Phenotype', 'HP:0003003', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('promote', 'PosReg', (50, 57))	('tumor', 'Disease', (196, 201))	('colorectal cancer', 'Disease', (116, 133))	('inactivation', 'Var', (24, 36))	('mutations', 'Var', (5, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (116, 133))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('liver metastasis', 'CPA', (237, 253))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('KRAS', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('KRAS', 'Gene', '3845', (0, 4))
68971	24906690	There have also been conflicting reports of the prognostic significance of KRAS mutation status beyond its effect on anti-EGFR therapies, with some studies suggesting that KRAS mutations conferred worse outcomes while others showed no significant differences.	('KRAS', 'Gene', (172, 176))	('KRAS', 'Gene', '3845', (172, 176))	('EGFR', 'molecular_function', 'GO:0005006', ('122', '126'))	('mutations', 'Var', (177, 186))	('KRAS', 'Gene', (75, 79))	('worse', 'NegReg', (197, 202))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', (122, 126))	('KRAS', 'Gene', '3845', (75, 79))
68972	24906690	No report has been made of the relationship between KRAS mutations and the global radiographic volume and distribution of metastases in stage IV colorectal cancers.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('IV colorectal cancer', 'Disease', (142, 162))	('KRAS', 'Gene', (52, 56))	('KRAS', 'Gene', '3845', (52, 56))	('IV colorectal cancer', 'Disease', 'MESH:D015179', (142, 162))	('colorectal cancer', 'Phenotype', 'HP:0003003', (145, 162))	('colorectal cancers', 'Disease', 'MESH:D015179', (145, 163))	('mutations', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('metastases', 'Disease', (122, 132))	('metastases', 'Disease', 'MESH:D009362', (122, 132))	('colorectal cancers', 'Disease', (145, 163))
68985	24906690	The baseline characteristics of the cohort are summarized in Table 1 by KRAS mutation status.	('mutation', 'Var', (77, 85))	('KRAS', 'Gene', '3845', (72, 76))	('KRAS', 'Gene', (72, 76))
68987	24906690	Among those with KRAS mutations, 25 were in codon 12, 8 were in codon 13, and 2 were without specific codon mutation data.	('KRAS', 'Gene', '3845', (17, 21))	('KRAS', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))
68988	24906690	Between subjects with KRAS mutation and KRAS wild type, there was no significant difference in age, sex, histologic differentiation, and histologic presence of mucin, Subjects with KRAS mutations had proximal colonic tumors more frequently than those with KRAS wild type genotypes (51% vs. 23%, P = 0.024).	('colonic tumors', 'Disease', 'MESH:D015179', (209, 223))	('mucin', 'Gene', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('mutations', 'Var', (186, 195))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('KRAS', 'Gene', (40, 44))	('colonic tumors', 'Disease', (209, 223))	('KRAS', 'Gene', '3845', (22, 26))	('KRAS', 'Gene', (22, 26))	('KRAS', 'Gene', (256, 260))	('mucin', 'Gene', '100508689', (160, 165))	('KRAS', 'Gene', '3845', (40, 44))	('KRAS', 'Gene', '3845', (256, 260))	('KRAS', 'Gene', (181, 185))	('KRAS', 'Gene', '3845', (181, 185))
68989	24906690	Table 2 shows the baseline distribution of disease by KRAS mutation status.	('KRAS', 'Gene', (54, 58))	('mutation', 'Var', (59, 67))	('KRAS', 'Gene', '3845', (54, 58))
68993	24906690	The stratified distribution of metastasis did not vary significantly between the KRAS wild type and mutant groups (P = 0.202).	('mutant', 'Var', (100, 106))	('KRAS', 'Gene', (81, 85))	('KRAS', 'Gene', '3845', (81, 85))
68994	24906690	Univariate analysis showed no statistically significant difference in the counts of lesions larger than 1 cm in the liver, retroperitoneum, lungs, and thoracic and retroperitoneal lymph nodes between the KRAS mutant and wild type groups (P > 0.05 for all comparisons).	('KRAS', 'Gene', (204, 208))	('mutant', 'Var', (209, 215))	('KRAS', 'Gene', '3845', (204, 208))
68996	24906690	Among subjects with poorly differentiated histology, there was a significant difference in the count of liver metastases between the KRAS mutant and wild type groups (median 5.0 vs. 0.5, interquartile range 14 vs. 2, P = 0.02).	('liver metastases', 'Disease', (104, 120))	('mutant', 'Var', (138, 144))	('liver metastases', 'Disease', 'MESH:D009362', (104, 120))	('KRAS', 'Gene', (133, 137))	('KRAS', 'Gene', '3845', (133, 137))
68998	24906690	The main objective of this study was to assess whether KRAS mutation status affects the initial volume and distribution of metastatic disease of subjects with stage IV colorectal cancers.	('KRAS', 'Gene', (55, 59))	('mutation', 'Var', (60, 68))	('IV colorectal cancer', 'Disease', 'MESH:D015179', (165, 185))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('colorectal cancers', 'Disease', 'MESH:D015179', (168, 186))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('KRAS', 'Gene', '3845', (55, 59))	('metastatic disease', 'CPA', (123, 141))	('colorectal cancers', 'Disease', (168, 186))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('IV colorectal cancer', 'Disease', (165, 185))	('affects', 'Reg', (76, 83))
68999	24906690	KRAS mutations confer resistance to treatments that target the EGFR pathway, so KRAS mutation testing is currently the only genotype test that is recommended for patients with stage 4 colorectal cancer in the NCCN guidelines.	('EGFR', 'Gene', '1956', (63, 67))	('patients', 'Species', '9606', (162, 170))	('KRAS', 'Gene', (80, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (184, 201))	('EGFR', 'Gene', (63, 67))	('mutations', 'Var', (5, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (184, 201))	('KRAS', 'Gene', '3845', (80, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('63', '67'))	('colorectal cancer', 'Disease', (184, 201))	('KRAS', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('KRAS', 'Gene', '3845', (0, 4))
69001	24906690	In this cohort, few differences were observed in the baseline distribution and volumes of disease between subjects with KRAS mutant and wild type tumors.	('type tumors', 'Disease', (141, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('type tumors', 'Disease', 'MESH:D009369', (141, 152))	('mutant', 'Var', (125, 131))	('KRAS', 'Gene', (120, 124))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('KRAS', 'Gene', '3845', (120, 124))
69002	24906690	These differences included a bias toward distal primary sites for KRAS wild type tumors (P = 0.024), as has been previously described, and an increased count of liver lesions in KRAS mutant tumors with poorly differentiated histology (P = 0.02), which does not have a known biological basis at this time.	('liver lesions', 'Disease', 'MESH:D017093', (161, 174))	('tumors', 'Disease', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumors', 'Disease', (190, 196))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('KRAS', 'Gene', '3845', (178, 182))	('type tumors', 'Disease', (76, 87))	('KRAS', 'Gene', '3845', (66, 70))	('mutant', 'Var', (183, 189))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('KRAS', 'Gene', (66, 70))	('KRAS', 'Gene', (178, 182))	('liver lesions', 'Disease', (161, 174))	('increased count of liver', 'Phenotype', 'HP:0002240', (142, 166))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('type tumors', 'Disease', 'MESH:D009369', (76, 87))	('increased', 'PosReg', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
69003	24906690	These limited findings require further investigation, but the bulk of the analysis suggests that there is no significant difference in the volume and distribution of metastatic disease by KRAS mutation status at the time of initial presentation of stage IV colorectal cancer.	('IV colorectal cancer', 'Disease', (254, 274))	('IV colorectal cancer', 'Disease', 'MESH:D015179', (254, 274))	('colorectal cancer', 'Phenotype', 'HP:0003003', (257, 274))	('mutation status', 'Var', (193, 208))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('KRAS', 'Gene', (188, 192))	('metastatic disease', 'Disease', (166, 184))	('KRAS', 'Gene', '3845', (188, 192))
69007	24906690	As with all observational studies, it is possible that an unmeasured confounder has masked the effects of KRAS mutations in this cohort.	('KRAS', 'Gene', '3845', (106, 110))	('mutations', 'Var', (111, 120))	('KRAS', 'Gene', (106, 110))
69008	24906690	First, the statistical power of some of the analyses is modest due to the relatively small number of subjects, especially in subgroup analysis of patients with KRAS mutations.	('KRAS', 'Gene', '3845', (160, 164))	('KRAS', 'Gene', (160, 164))	('patients', 'Species', '9606', (146, 154))	('mutations', 'Var', (165, 174))
69011	24906690	Nonetheless, since codon 12/13 mutations in KRAS represent the vast majority of RAS mutations in colorectal cancer, our analysis provides a reasonable representation of RAS activated tumors.	('mutations', 'Var', (31, 40))	('KRAS', 'Gene', '3845', (44, 48))	('colorectal cancer', 'Disease', 'MESH:D015179', (97, 114))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('codon', 'Var', (19, 24))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('mutations', 'Var', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('KRAS', 'Gene', (44, 48))	('RAS', 'Gene', (80, 83))	('colorectal cancer', 'Disease', (97, 114))	('tumors', 'Disease', (183, 189))
69013	24906690	In particular, mutations in BRAF, NRAS, and PIK3CA have been shown to hold additional prognostic significance in patients with colorectal cancer and may be adopted into global treatment guidelines.	('PIK3CA', 'Gene', (44, 50))	('BRAF', 'Gene', '673', (28, 32))	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('patients', 'Species', '9606', (113, 121))	('mutations', 'Var', (15, 24))	('PIK3CA', 'Gene', '5290', (44, 50))	('colorectal cancer', 'Disease', 'MESH:D015179', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('colorectal cancer', 'Disease', (127, 144))	('NRAS', 'Gene', (34, 38))	('BRAF', 'Gene', (28, 32))	('NRAS', 'Gene', '4893', (34, 38))
69015	24906690	In conclusion, our study has shown that KRAS mutation status confers no significant overall difference in the amount and distribution of metastatic disease at the baseline assessment of stage IV colorectal cancer.	('IV colorectal cancer', 'Disease', 'MESH:D015179', (192, 212))	('colorectal cancer', 'Phenotype', 'HP:0003003', (195, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('KRAS', 'Gene', (40, 44))	('mutation', 'Var', (45, 53))	('KRAS', 'Gene', '3845', (40, 44))	('IV colorectal cancer', 'Disease', (192, 212))
69016	24906690	The exploratory finding that patients with both poorly differentiated histology and KRAS mutations had more liver metastases will require confirmation in subsequent studies.	('patients', 'Species', '9606', (29, 37))	('liver metastases', 'Disease', (108, 124))	('KRAS', 'Gene', (84, 88))	('KRAS', 'Gene', '3845', (84, 88))	('mutations', 'Var', (89, 98))	('liver metastases', 'Disease', 'MESH:D009362', (108, 124))
69101	33706757	Compared to PMP associated with a low grade mucinous tumor of the appendix (LAMN), the prognosis of PMP in teratoma-associated lesions appears to be better (except in cases of peritoneal carcinomatosis associated with MC).	('peritoneal carcinomatosis', 'Disease', (176, 201))	('mucinous tumor', 'Disease', 'MESH:D002288', (44, 58))	('teratoma', 'Phenotype', 'HP:0009792', (107, 115))	('PMP', 'Var', (100, 103))	('teratoma', 'Disease', 'MESH:D013724', (107, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('mucinous tumor', 'Phenotype', 'HP:0031495', (44, 58))	('LAMN', 'Chemical', '-', (76, 80))	('peritoneal carcinomatosis', 'Disease', 'MESH:D010534', (176, 201))	('MC', 'Phenotype', 'HP:0031494', (218, 220))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mucinous tumor', 'Disease', (44, 58))	('teratoma', 'Disease', (107, 115))
69133	33706757	SATB2 positivity is reported in 87% of appendiceal and 75% of colorectal tumors, and is almost always diffuse as well.	('colorectal tumors', 'Disease', 'MESH:D015179', (62, 79))	('positivity', 'Var', (6, 16))	('colorectal tumors', 'Disease', (62, 79))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('SATB2', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('appendiceal', 'Disease', (39, 50))	('SATB2', 'Gene', '23314', (0, 5))
69177	33706757	Briefly, the most common aberrations occurring in primary mucinous ovarian carcinoma are mutations of KRAS (  55%), CDKN2A (  55%, including deletions), TP53 (  52%), ARID1A (  10%), BRAF (  8%), and amplification of HER2 (  28%).	('TP53', 'Gene', '7157', (153, 157))	('CDKN2A', 'Gene', '1029', (116, 122))	('mutations', 'Var', (89, 98))	('ARID1A', 'Gene', (167, 173))	('mucinous ovarian carcinoma', 'Phenotype', 'HP:0031494', (58, 84))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (67, 84))	('HER2', 'Gene', (217, 221))	('ARID1A', 'Gene', '8289', (167, 173))	('amplification', 'Var', (200, 213))	('primary mucinous ovarian carcinoma', 'Disease', 'MESH:D010051', (50, 84))	('TP53', 'Gene', (153, 157))	('KRAS', 'Gene', '3845', (102, 106))	('CDKN2A', 'Gene', (116, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('BRAF', 'Gene', '673', (183, 187))	('deletions', 'Var', (141, 150))	('primary mucinous ovarian carcinoma', 'Disease', (50, 84))	('KRAS', 'Gene', (102, 106))	('BRAF', 'Gene', (183, 187))	('HER2', 'Gene', '2064', (217, 221))
69178	33706757	The aberrations occurring in MBT are similar, with mutations of KRAS (  55%), CDKN2A (  44%, including deletions), TP53 (  12%), BRAF (  11%), and amplification of HER2 (  10%).	('mutations', 'Var', (51, 60))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('CDKN2A', 'Gene', (78, 84))	('TP53', 'Gene', '7157', (115, 119))	('KRAS', 'Gene', (64, 68))	('deletions', 'Var', (103, 112))	('CDKN2A', 'Gene', '1029', (78, 84))	('HER2', 'Gene', (164, 168))	('TP53', 'Gene', (115, 119))	('amplification', 'Var', (147, 160))	('HER2', 'Gene', '2064', (164, 168))	('KRAS', 'Gene', '3845', (64, 68))
69194	33706757	Diffuse expression of p16 (> 90% of tumor cells) is very rare in primary mucinous tumors - the largest study focusing on this issue reported diffuse p16 positivity in 5.7% of primary ovarian mucinous carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('carcinomas', 'Phenotype', 'HP:0030731', (200, 210))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (36, 41))	('primary ovarian mucinous carcinomas', 'Disease', 'MESH:D010051', (175, 210))	('mucinous tumor', 'Phenotype', 'HP:0031495', (73, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (191, 209))	('ovarian mucinous carcinomas', 'Phenotype', 'HP:0031494', (183, 210))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('p16', 'Gene', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('positivity', 'Var', (153, 163))	('p16', 'Gene', (22, 25))	('mucinous tumors', 'Disease', (73, 88))	('p16', 'Gene', '1029', (149, 152))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('p16', 'Gene', '1029', (22, 25))	('mucinous tumors', 'Disease', 'MESH:D002288', (73, 88))	('primary ovarian mucinous carcinomas', 'Disease', (175, 210))
69195	33706757	In another study the sensitivity of p16 positivity for ovarian metastases of cervical adenocarcinoma reached 100%, with specificity of 98%.	('ovarian metastases of cervical adenocarcinoma', 'Disease', 'MESH:D009362', (55, 100))	('ovarian metastases of cervical adenocarcinoma', 'Disease', (55, 100))	('p16', 'Gene', '1029', (36, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('p16', 'Gene', (36, 39))	('positivity', 'Var', (40, 50))
69275	30274538	170-173  C; numax (ATR) 666, 746, 854, 987, 1033, 1199, 1267, 1363, 1405, 1502, 1614, 1676, 3082 cm-1; deltaH (CDCl3) 2.92 (3H, s, CH3), 7.03 (1H, s, H-3), 7.34 (2H, d, J = 8.1 Hz, Ar), 7.85 (2H, d, J = 9.3 Hz, Ar), 7.98 (2H, d, J = 1.8 Hz, Ar); deltaC (CDCl3) 30.8, 101.1, 116.6, 121.5, 123.0, 126.7, 127.7, 127.9, 128.0, 128.3, 130.2 (t, J = 25.6 Hz) 132.6, 152.1, 156.4, 194.4; HRMS (ES): 398.9663. found C17H11O3F379Br + requires 398.9745.	('C', 'Chemical', 'MESH:D002244', (251, 252))	('C', 'Chemical', 'MESH:D002244', (254, 255))	('C', 'Chemical', 'MESH:D002244', (111, 112))	('C', 'Chemical', 'MESH:D002244', (131, 132))	('C', 'Chemical', 'MESH:D002244', (9, 10))	('C17H11O3F379Br +', 'Var', (408, 424))	('1H', 'Chemical', '-', (143, 145))	('HRMS', 'Disease', 'None', (381, 385))	('HRMS', 'Disease', (381, 385))	('H-3', 'Gene', (150, 153))	('CDCl3', 'Chemical', '-', (254, 259))	('C', 'Chemical', 'MESH:D002244', (113, 114))	('CDCl3', 'Chemical', '-', (111, 116))	('C', 'Chemical', 'MESH:D002244', (256, 257))	('C', 'Chemical', 'MESH:D002244', (408, 409))	('H-3', 'Gene', '126961', (150, 153))
69286	30274538	199-201  C; numax (ATR) 748, 906, 1029, 1154, 1262, 1316, 1453, 1555, 1603, 3108, 3187 cm-1; deltaH (DMSO-d6); 2.38 (3H, s, CH3), 7.48 (1H, s, H-3), 7.49 (1H, d, J = 8.0 Hz, H-6'), 7.54 (1H, t, J 7.5 Hz, H-4'), 7.59 (1H, d, J = 7.5 Hz, H-2'), 7.86 (1H, t, J = 7.0 Hz, H-5'), 7.88 (1H, d, J = 2.0 Hz, H-4), 7.94 (1H, d, J = 2.0 Hz, H-6), 11.6 (1H, s, OH); deltaC (DMSO-d6) 14.0, 103.3, 112.1 (d, 2JCF=23.6 Hz) 116.1 (d, 2JCF = 21.9 Hz), 119.5, 120.9 (d, 4JCF = 2.8 Hz), 123.9, 127.7, 129.6, 130.8, 131.5 (d, 3JCF = 7.5 Hz), 132.2, 134.4, 150.7 (d, 4JCF = 2.9 Hz), 156.5, 163.1 (d, 1JCF = 249.4 Hz); HRMS (ES): found 348.0028 C16H12NO2F79Br+ requires 348.0035.	('C', 'Chemical', 'MESH:D002244', (624, 625))	('1H', 'Chemical', '-', (281, 283))	('1H', 'Chemical', '-', (312, 314))	('C', 'Chemical', 'MESH:D002244', (455, 456))	('C', 'Chemical', 'MESH:D002244', (124, 125))	('DMSO-d6', 'Chemical', '-', (363, 370))	('C', 'Chemical', 'MESH:D002244', (360, 361))	('H-6', 'Gene', '3166', (174, 177))	('H-5', 'Gene', '5414', (268, 271))	('C', 'Chemical', 'MESH:D002244', (9, 10))	('H-2', 'Gene', (236, 239))	('DMSO-d6', 'Chemical', '-', (101, 108))	('C', 'Chemical', 'MESH:D002244', (582, 583))	('348.0028 C16H12NO2F79Br+', 'Var', (615, 639))	('C16H12NO2', 'CellLine', 'CVCL:2322', (624, 633))	('C', 'Chemical', 'MESH:D002244', (549, 550))	('H-3', 'Gene', (143, 146))	('HRMS', 'Disease', (598, 602))	('H-6', 'Gene', (174, 177))	('C', 'Chemical', 'MESH:D002244', (509, 510))	('J 7.5 Hz', 'CellLine', 'CVCL:Z674', (194, 202))	('H-3', 'Gene', '126961', (143, 146))	('1H', 'Chemical', '-', (155, 157))	('C', 'Chemical', 'MESH:D002244', (397, 398))	('C', 'Chemical', 'MESH:D002244', (421, 422))	('H-6', 'Gene', '3166', (331, 334))	('C16H12NO2F79Br+', 'Var', (624, 639))	('1H', 'Chemical', '-', (187, 189))	('1H', 'Chemical', '-', (217, 219))	('H-6', 'Gene', (331, 334))	('H-5', 'Gene', (268, 271))	('HRMS', 'Disease', 'None', (598, 602))	('H-2', 'Gene', '6019', (236, 239))	('1H', 'Chemical', '-', (249, 251))	('1H', 'Chemical', '-', (136, 138))	('1H', 'Chemical', '-', (343, 345))
69309	30274538	Anal calcd for C14H9NOFBr: C, 54.93; H, 2.96; N, 4.58.	('N', 'Chemical', 'MESH:D009584', (46, 47))	('C', 'Chemical', 'MESH:D002244', (27, 28))	('C', 'Chemical', 'MESH:D002244', (15, 16))	('C14H9NOFBr', 'Chemical', '-', (15, 25))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('C14H9NOFBr', 'Var', (15, 25))	('C, 54.93', 'Var', (27, 35))
69327	30274538	Anal calcd for C28H15N3OFBr: C, 57.07; H, 2.74; N, 7.13.	('C', 'Chemical', 'MESH:D002244', (15, 16))	('C28H15N3OFBr', 'Var', (15, 27))	('C', 'Chemical', 'MESH:D002244', (29, 30))	('C28H15N3OFBr', 'Chemical', '-', (15, 27))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('C, 57.07', 'Var', (29, 37))	('N', 'Chemical', 'MESH:D009584', (21, 22))
69397	30274538	The latter are the result of the initial Beckmann rearrangement via aryl carbon migration followed by an in situ acid-mediated hydrolysis of the intermediate 7-acetamido-2-aryl-5-bromobenzofuran derivatives.	('aryl carbon migration', 'MPA', (68, 89))	('carbon', 'Chemical', 'MESH:D002244', (73, 79))	('7-acetamido-2-aryl-5-bromobenzofuran', 'Chemical', '-', (158, 194))	('rearrangement', 'Var', (50, 63))
69415	30274538	No cytotoxicity was observed against the Caco-2 and C3A cell lines for compound 10c substituted with the 4-fluorophenyl group at the 2-positions of the benzofuran and quinazoline moieties.	('cytotoxicity', 'Disease', 'MESH:D064420', (3, 15))	('10c', 'Gene', '64333', (80, 83))	('C3A', 'Gene', (52, 55))	('10c', 'Gene', (80, 83))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('quinazoline', 'Chemical', 'MESH:D011799', (167, 178))	('C3A', 'Gene', '718', (52, 55))	('cytotoxicity', 'Disease', (3, 15))	('substituted', 'Var', (84, 95))	('Caco-2', 'CellLine', 'CVCL:0025', (41, 47))	('benzofuran', 'Chemical', 'MESH:C105430', (152, 162))
69417	30274538	A combination of 3-chlorophenyl on the benzofuran ring and 4-fluorophenyl group on the quinazoline framework in 10d was found to result in reduced cytotoxicity against the A549 and Caco-2 cell lines, but increased anti-growth effect against the C3A (LC50 = 9.0 microM) and the HeLa (LC50 = 22.1 microM) cell lines when compared to Gefitinib.	('C', 'Chemical', 'MESH:D002244', (251, 252))	('increased', 'PosReg', (204, 213))	('reduced', 'NegReg', (139, 146))	('C3A', 'Gene', (245, 248))	('3-chlorophenyl', 'Var', (17, 31))	('anti-growth effect', 'CPA', (214, 232))	('benzofuran', 'Chemical', 'MESH:C105430', (39, 49))	('quinazoline', 'Chemical', 'MESH:D011799', (87, 98))	('C', 'Chemical', 'MESH:D002244', (245, 246))	('HeLa', 'CellLine', 'CVCL:0030', (277, 281))	('Gefitinib', 'Chemical', 'MESH:D000077156', (331, 340))	('C', 'Chemical', 'MESH:D002244', (181, 182))	('C3A', 'Gene', '718', (245, 248))	('Caco-2', 'CellLine', 'CVCL:0025', (181, 187))	('A549', 'CellLine', 'CVCL:0023', (172, 176))	('cytotoxicity', 'Disease', (147, 159))	('cytotoxicity', 'Disease', 'MESH:D064420', (147, 159))	('C', 'Chemical', 'MESH:D002244', (284, 285))	('4-fluorophenyl group', 'Var', (59, 79))
69421	30274538	Likewise, a combination of 4-chlorophenyl group on the quinazoline ring and a 4-fluorophenyl group on the benzofuran arm resulted in loss of activity for 10h against the A549, Caco-2 and C3A cell lines.	('Caco-2', 'CellLine', 'CVCL:0025', (176, 182))	('C3A', 'Gene', (187, 190))	('activity', 'MPA', (141, 149))	('benzofuran', 'Chemical', 'MESH:C105430', (106, 116))	('loss', 'NegReg', (133, 137))	('A549', 'CellLine', 'CVCL:0023', (170, 174))	('4-chlorophenyl group', 'Var', (27, 47))	('C3A', 'Gene', '718', (187, 190))	('quinazoline', 'Chemical', 'MESH:D011799', (55, 66))
69428	30274538	Apoptosis is an essential mechanism by the body to get rid of unwanted cells and induction of this process in cancer cells would lead to automatic death and decrease cancer proliferation.	('induction', 'Var', (81, 90))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', (166, 172))	('lead to', 'Reg', (129, 136))	('automatic death', 'Disease', (137, 152))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('decrease', 'NegReg', (157, 165))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('automatic death', 'Disease', 'MESH:D003643', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
69442	30274538	Inhibition of EGFR-TK activity is regarded as the most promising approach for innovative therapeutic strategies in cancer treatment.	('cancer', 'Disease', (115, 121))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Inhibition', 'Var', (0, 10))	('activity', 'MPA', (22, 30))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
69445	30274538	A combination of 4-fluorophenyl group at the 2-positons of the quinazoline and benzofuran moieties in 10c, on the other hand, resulted in moderate inhibitory effect with an IC50 value of 52.2 nM.	('10c', 'Gene', '64333', (102, 105))	('10c', 'Gene', (102, 105))	('benzofuran', 'Chemical', 'MESH:C105430', (79, 89))	('inhibitory effect', 'MPA', (147, 164))	('4-fluorophenyl group', 'Var', (17, 37))	('quinazoline', 'Chemical', 'MESH:D011799', (63, 74))	('C', 'Chemical', 'MESH:D002244', (174, 175))
69481	28554991	miR-17, miR-18b, miR-20a, miR-31, and miR-193a_3p, were significantly downregulated in pre-treatment plasma samples of patients with rectal cancer (p < 0.05).	('rectal cancer', 'Disease', (133, 146))	('miR-18b', 'Gene', '574033', (8, 15))	('miR-193a_3p', 'Var', (38, 49))	('miR-20a', 'Gene', (17, 24))	('miR-31', 'Gene', '407035', (26, 32))	('miR-20a', 'Gene', '406982', (17, 24))	('miR-17', 'Gene', '406952', (0, 6))	('patients', 'Species', '9606', (119, 127))	('rectal cancer', 'Phenotype', 'HP:0100743', (133, 146))	('downregulated', 'NegReg', (70, 83))	('miR-18b', 'Gene', (8, 15))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('miR-31', 'Gene', (26, 32))	('rectal cancer', 'Disease', 'MESH:D012004', (133, 146))	('miR-17', 'Gene', (0, 6))
69511	28554991	Five of them were significantly downregulated (p < 0.05): miR-17, miR-18b, miR-20a, miR-31, and miR-193a_3p (Figure 1).	('miR-31', 'Gene', '407035', (84, 90))	('downregulated', 'NegReg', (32, 45))	('miR-20a', 'Gene', '406982', (75, 82))	('miR-18b', 'Gene', (66, 73))	('miR-17', 'Gene', '406952', (58, 64))	('miR-193a_3p', 'Var', (96, 107))	('miR-31', 'Gene', (84, 90))	('miR-20a', 'Gene', (75, 82))	('miR-18b', 'Gene', '574033', (66, 73))	('miR-17', 'Gene', (58, 64))
69514	28554991	The five significantly downregulated miRNAs of the first set (miR-17, miR-18b, miR-20a, miR-31, and miR-193a_3p) were selected for further validation.	('miR-17', 'Gene', (62, 68))	('downregulated', 'NegReg', (23, 36))	('miR-31', 'Gene', '407035', (88, 94))	('miR-17', 'Gene', '406952', (62, 68))	('miR-18b', 'Gene', (70, 77))	('miR-193a_3p', 'Var', (100, 111))	('miR-20a', 'Gene', (79, 86))	('miR-20a', 'Gene', '406982', (79, 86))	('miR-31', 'Gene', (88, 94))	('miR-18b', 'Gene', '574033', (70, 77))
69632	28327112	Mutations in p53 occur early in the adenoma-carcinoma sequence and are often detected in non-dysplastic or indefinite dysplasia in UC, whereas p53 mutations occur in the late phase in sporadic adenoma.	('adenoma', 'Disease', (193, 200))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (36, 53))	('p53', 'Gene', '7157', (143, 146))	('adenoma', 'Disease', (36, 43))	('adenoma-carcinoma', 'Disease', (36, 53))	('p53', 'Gene', (13, 16))	('p53', 'Gene', '7157', (13, 16))	('dysplasia', 'Disease', (118, 127))	('UC', 'Phenotype', 'HP:0100279', (131, 133))	('Mutations', 'Var', (0, 9))	('dysplasia', 'Disease', 'MESH:D004476', (118, 127))	('detected', 'Reg', (77, 85))	('non-dysplastic', 'Disease', (89, 103))	('adenoma', 'Disease', 'MESH:D000236', (193, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('adenoma', 'Disease', 'MESH:D000236', (36, 43))	('p53', 'Gene', (143, 146))	('non-dysplastic', 'Disease', 'MESH:D004416', (89, 103))
69634	28327112	Hypermethylation of hMLH1, p16INK4a, and p14ARF seems to precede dysplasia and contribute to the genetic alterations in UCCC.	('dysplasia', 'Disease', (65, 74))	('hMLH1', 'Gene', (20, 25))	('p14ARF', 'Gene', '1029', (41, 47))	('dysplasia', 'Disease', 'MESH:D004476', (65, 74))	('Hypermethylation', 'Var', (0, 16))	('hMLH1', 'Gene', '4292', (20, 25))	('contribute', 'Reg', (79, 89))	('p16INK4a', 'Gene', '1029', (27, 35))	('p14ARF', 'Gene', (41, 47))	('p16INK4a', 'Gene', (27, 35))	('CC', 'Phenotype', 'HP:0002664', (121, 123))	('genetic', 'MPA', (97, 104))	('UC', 'Phenotype', 'HP:0100279', (120, 122))	('UCCC', 'Disease', (120, 124))
69653	28327112	In a subgroup analysis of UCCC patients, female sex was associated with a significantly better prognosis.	('CC', 'Phenotype', 'HP:0002664', (27, 29))	('patients', 'Species', '9606', (31, 39))	('female sex', 'Var', (41, 51))	('UCCC', 'Disease', (26, 30))	('UC', 'Phenotype', 'HP:0100279', (26, 28))
69673	28144108	Microsatellite Instability has again been confirmed to be an important predictor in patients with stage IV colon cancer receiving immunotherapy.	('patients', 'Species', '9606', (84, 92))	('stage IV colon cancer', 'Disease', (98, 119))	('stage IV colon cancer', 'Disease', 'MESH:D015179', (98, 119))	('Microsatellite Instability', 'Var', (0, 26))	('colon cancer', 'Phenotype', 'HP:0003003', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
69675	28144108	Several retrospective studies in CRC patients receiving anti-EGFR antibody treatment have shown that patients with mutated KRAS did not benefit from anti-EGFR therapy.	('EGFR', 'Gene', (154, 158))	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (37, 45))	('mutated', 'Var', (115, 122))	('KRAS', 'Gene', (123, 127))	('EGFR', 'Gene', '1956', (154, 158))	('KRAS', 'Gene', '3845', (123, 127))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
69677	28144108	The retrospective analyses of KRAS data from CRYSTAL, OPUS and EVEREST have further demonstrated patients with K-RAS mutant CRC do not benefit from anti-EGFR antibody treatment.	('antibody', 'cellular_component', 'GO:0019815', ('158', '166'))	('antibody', 'cellular_component', 'GO:0019814', ('158', '166'))	('antibody', 'cellular_component', 'GO:0042571', ('158', '166'))	('mutant', 'Var', (117, 123))	('K-RAS', 'Gene', '3845', (111, 116))	('antibody', 'molecular_function', 'GO:0003823', ('158', '166'))	('EGFR', 'Gene', '1956', (153, 157))	('K-RAS', 'Gene', (111, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('153', '157'))	('EGFR', 'Gene', (153, 157))	('KRAS', 'Gene', (30, 34))	('KRAS', 'Gene', '3845', (30, 34))	('patients', 'Species', '9606', (97, 105))
69698	28144108	Molecular analyses suggest that these right sided tumors are impacted by high BRAF, hypermethylation and so distinct gene expression patterns.	('BRAF', 'Gene', '673', (78, 82))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('BRAF', 'Gene', (78, 82))	('gene expression', 'biological_process', 'GO:0010467', ('117', '132'))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('hypermethylation', 'Var', (84, 100))	('high', 'Var', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('impacted', 'Reg', (61, 69))
69700	28144108	It seems the side of cancer really is a surrogate marker for the tumor biology with differential BRAF and hypermethylation status.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Disease', (65, 70))	('hypermethylation status', 'Var', (106, 129))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('BRAF', 'Gene', '673', (97, 101))	('BRAF', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
69751	28144108	MEK inhibition increased intra and peri-tumoral T cell accumulation by up regulation of MHC-1 on tumoral cells and therefore combined with PDL1 inhibitor it resulted in synergistic action.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('MEK', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('regulation', 'biological_process', 'GO:0065007', ('74', '84'))	('peri-tumoral T', 'Disease', (35, 49))	('tumor', 'Disease', (97, 102))	('inhibition', 'Var', (4, 14))	('synergistic', 'MPA', (169, 180))	('increased', 'PosReg', (15, 24))	('up regulation', 'PosReg', (71, 84))	('peri-tumoral T', 'Disease', 'MESH:D057873', (35, 49))	('PDL1', 'Gene', '29126', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('MHC-1', 'Gene', (88, 93))	('PDL1', 'Gene', (139, 143))
69758	28144108	With this study as background Dr. Overman from the MD Anderson Cancer Center presented data (Checkmate 142 trial, Abstract 3501) on nivolimumab (PD1 inhibitor) with or without ipilimumab (CTLA4 inhibitor) in patients with microsatellite stable or high.	('microsatellite stable', 'Var', (222, 243))	('PD1', 'Gene', '5133', (145, 148))	('CTLA4', 'Gene', '1493', (188, 193))	('patients', 'Species', '9606', (208, 216))	('PD1', 'Gene', (145, 148))	('MD Anderson Cancer', 'Disease', 'MESH:C535460', (51, 69))	('CTLA4', 'Gene', (188, 193))	('ipilimumab', 'Chemical', 'MESH:D000074324', (176, 186))	('MD Anderson Cancer', 'Disease', (51, 69))	('Cancer', 'Phenotype', 'HP:0002664', (63, 69))	('nivolimumab', 'Chemical', '-', (132, 143))
69829	27824926	reported that the combined evaluation of positive HK2 and negative phosphorylated pyruvate dehydrogenase (p-PDH) was associated with reduced RFS in stage II and III patients with CRC.	('PDH', 'molecular_function', 'GO:0004739', ('108', '111'))	('PDH', 'molecular_function', 'GO:0033718', ('108', '111'))	('positive', 'Var', (41, 49))	('HK2', 'Gene', (50, 53))	('HK2', 'Gene', '3099', (50, 53))	('RFS', 'Disease', (141, 144))	('HK2', 'molecular_function', 'GO:0008256', ('50', '53'))	('patients', 'Species', '9606', (165, 173))	('reduced', 'NegReg', (133, 140))	('PDH', 'molecular_function', 'GO:0004246', ('108', '111'))
69853	27121375	The effects of NR4A2 on chemoresistance are also seen in colorectal cancers, and high expression of NR4A2 predicts a poor outcome for gastric cancer patients receiving 5-FU therapy.	('chemoresistance', 'CPA', (24, 39))	('high expression', 'Var', (81, 96))	('patients', 'Species', '9606', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('colorectal cancers', 'Disease', (57, 75))	('colorectal cancer', 'Phenotype', 'HP:0003003', (57, 74))	('gastric cancer', 'Disease', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('NR4A2', 'Gene', (100, 105))	('5-FU', 'Chemical', 'MESH:D005472', (168, 172))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))	('colorectal cancers', 'Disease', 'MESH:D015179', (57, 75))
69860	27121375	The miR-34 isoforms have been clinically characterized as tumor suppressors in multiple cancer types, often independent of p53 mutation, as in neuroblastoma, where mir-34a is commonly deleted, or in other cancers characterized by epigenetic silencing of miR-34.	('miR-34', 'Gene', (4, 10))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('epigenetic silencing', 'Var', (230, 250))	('neuroblastoma', 'Disease', (143, 156))	('mir-34a', 'Gene', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('miR-34', 'Gene', (254, 260))	('neuroblastoma', 'Phenotype', 'HP:0003006', (143, 156))	('tumor', 'Disease', (58, 63))	('neuroblastoma', 'Disease', 'MESH:D009447', (143, 156))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('deleted', 'Var', (184, 191))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('miR-34', 'Gene', '407040', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancers', 'Disease', (205, 212))	('cancer', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('miR-34', 'Gene', '407040', (254, 260))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))
69867	27121375	Together, they reveal a novel regulatory network linking p53, miR-34, and NR4A2, in which p53 can overcome its inhibition by endogenous NR4A2 through upregulating miR-34.	('miR-34', 'Gene', (163, 169))	('miR-34', 'Gene', '407040', (62, 68))	('upregulating', 'PosReg', (150, 162))	('miR-34', 'Gene', '407040', (163, 169))	('miR-34', 'Gene', (62, 68))	('p53', 'Var', (90, 93))
69875	27121375	By using the prediction algorithms, we identified a predicted miRNA recognition element complementary to the miR-34 seed region in the 3' UTR of NR4A2 and mutated this sequence to disrupt the complementarity in order to determine if there was direct regulation by miR-34 at this specific site (Fig.	('mutated', 'Var', (155, 162))	('miR-34', 'Gene', (264, 270))	('miRNA recognition element', 'MPA', (62, 87))	('miR-34', 'Gene', '407040', (264, 270))	('regulation', 'biological_process', 'GO:0065007', ('250', '260'))	('NR4A2', 'Gene', (145, 150))	('miR-34', 'Gene', (109, 115))	('disrupt', 'NegReg', (180, 187))	('complementarity', 'MPA', (192, 207))	('miR-34', 'Gene', '407040', (109, 115))
69877	27121375	The effect of miR-34a or miR-34c, compared to that of the control, was not significant when the miRNA was cotransfected with the 3' UTR containing the seed-region mutation (34mut).	('miR-34a', 'Gene', '407040', (14, 21))	('miR-34a', 'Gene', (14, 21))	('34mut', 'Var', (173, 178))	('miR-34c', 'Gene', '407042', (25, 32))	('miR-34c', 'Gene', (25, 32))
69878	27121375	Mutation of this predicted seed region was able to rescue the attenuation of the luminescence signal by miR-34a or miR-34c (Fig.	('miR-34c', 'Gene', (115, 122))	('miR-34a', 'Gene', (104, 111))	('Mutation', 'Var', (0, 8))	('luminescence signal', 'MPA', (81, 100))	('attenuation', 'NegReg', (62, 73))	('miR-34a', 'Gene', '407040', (104, 111))	('miR-34c', 'Gene', '407042', (115, 122))
69923	27121375	After 48 h of siRNA-mediated knockdown, the cells were treated with Nutlin-3a for an additional 24 h to determine the effects of NR4A2 knockdown on p53 target gene expression.	('Nutlin-3a', 'Chemical', 'MESH:C482205', (68, 77))	('NR4A2', 'Gene', (129, 134))	('knockdown', 'Var', (135, 144))
69924	27121375	We found that knocking down NR4A2 caused an enhancement of Nutlin-3a-induced expression of CDKN1A/p21, MDM2, and mir-34a (Fig.	('Nutlin-3a-induced expression', 'MPA', (59, 87))	('knocking down', 'Var', (14, 27))	('mir-34a', 'Var', (113, 120))	('NR4A2', 'Gene', (28, 33))	('CDKN1A', 'Gene', '1026', (91, 97))	('CDKN1A', 'Gene', (91, 97))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (59, 68))	('enhancement', 'PosReg', (44, 55))	('MDM2', 'Gene', '4193', (103, 107))	('MDM2', 'Gene', (103, 107))	('p21', 'Gene', '1026', (98, 101))	('p21', 'Gene', (98, 101))
69925	27121375	4d), knocking down NR4A2 led to an increase in TP53/p53 gene expression for both the DMSO- and Nutlin-3a-treated groups (Fig.	('TP53/p53 gene', 'Gene', (47, 60))	('increase', 'PosReg', (35, 43))	('Nutlin-3a', 'Chemical', 'MESH:C482205', (95, 104))	('DMSO', 'Chemical', 'MESH:D004121', (85, 89))	('knocking down', 'Var', (5, 18))	('NR4A2', 'Gene', (19, 24))
69940	27121375	The miR-34 isoforms, predominantly mir-34a, have tumor suppressor functions in multiple cancer types, which is sometimes attributed to their p53 status, though the mechanisms of chromosomal deletion or epigenetic silencing are also major contributors, and miR-34 expression is prognostic for patient outcome or relapse.	('miR-34', 'Gene', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('miR-34', 'Gene', '407040', (4, 10))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('epigenetic silencing', 'Var', (202, 222))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('miR-34', 'Gene', (256, 262))	('patient', 'Species', '9606', (292, 299))	('miR-34', 'Gene', '407040', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mir-34a', 'Var', (35, 42))
69944	27121375	The expression of endogenous miR-34a remained low in 5-FU-resistant cells treated with 5-FU, and the restoration of miR-34a or knockdown of SIRT1 in the resistant cells overcame their resistant phenotype.	('low', 'NegReg', (46, 49))	('overcame', 'PosReg', (169, 177))	('SIRT1', 'Gene', '23411', (140, 145))	('miR-34a', 'Gene', '407040', (29, 36))	('restoration', 'Var', (101, 112))	('5-FU', 'Chemical', 'MESH:D005472', (87, 91))	('expression', 'MPA', (4, 14))	('SIRT1', 'Gene', (140, 145))	('miR-34a', 'Gene', (29, 36))	('miR-34a', 'Gene', '407040', (116, 123))	('miR-34a', 'Gene', (116, 123))	('knockdown', 'Var', (127, 136))	('5-FU', 'Chemical', 'MESH:D005472', (53, 57))
69947	27121375	This regulatory effect was confirmed by using mutagenesis of the predicted miRNA recognition element that is complementary to the miR-34 seed region.	('mutagenesis', 'Var', (46, 57))	('miR-34', 'Gene', (130, 136))	('miR-34', 'Gene', '407040', (130, 136))
69958	27121375	Correspondingly, RKO p53 wild-type cells had higher levels of endogenous NR4A2 and responded better to miR-34 mimics than their p53-deficient counterpart (Supplementary Fig.	('responded', 'MPA', (83, 92))	('miR-34', 'Gene', '407040', (103, 109))	('RKO', 'Var', (17, 20))	('endogenous', 'MPA', (62, 72))	('levels', 'MPA', (52, 58))	('NR4A2', 'Protein', (73, 78))	('higher', 'PosReg', (45, 51))	('better', 'PosReg', (93, 99))	('miR-34', 'Gene', (103, 109))
69960	27121375	To further understand the importance of miR-34 regulation of NR4A2 in the cellular context, we examined the relationship between endogenous miR-34 and endogenous NR4A2 by using our isogenic cell line pairs that possess wild-type or deleted TP53.	('regulation', 'biological_process', 'GO:0065007', ('47', '57'))	('TP53', 'Gene', (240, 244))	('miR-34', 'Gene', (140, 146))	('miR-34', 'Gene', (40, 46))	('deleted', 'Var', (232, 239))	('miR-34', 'Gene', '407040', (40, 46))	('miR-34', 'Gene', '407040', (140, 146))
69979	27121375	Human colorectal carcinoma HCT116 wild-type and TP53-/- isogenic cell lines, which were derived from an adult male harboring a mutation in codon 13 of the ras proto-oncogene, were obtained from the Genetic Resources Core Facility at Johns Hopkins University School of Medicine (Baltimore, MD) and grown in McCoy's 5A medium (ATCC) supplemented with 10% fetal bovine serum (Thermo Fisher Scientific Inc., Rockford, IL) and 1% penicillin-streptomycin (Life Technologies, Carlsbad, CA).	('Human', 'Species', '9606', (0, 5))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (6, 26))	('HCT116', 'CellLine', 'CVCL:0291', (27, 33))	('bovine', 'Species', '9913', (359, 365))	('mutation in', 'Var', (127, 138))	('colorectal carcinoma', 'Disease', (6, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))
69980	27121375	RKO human colon carcinoma (derived from a female harboring mutations in BRAF, NF1 and PIK3CA) and SW48 human colorectal adenocarcinoma (derived from a female harboring mutations in CTNNB1, FBXW7 and EGFR) (wild-type and TP53-/-) and HCT116 (CDKN1A-/- and BBC3-/-) isogenic cell line pairs were obtained from Horizon Discovery (Cambridge, UK) and grown according to the manufacturer's protocol.	('HCT116', 'CellLine', 'CVCL:0291', (233, 239))	('CTNNB1', 'Gene', (181, 187))	('colon carcinoma', 'Disease', (10, 25))	('CDKN1A', 'Gene', (241, 247))	('NF1', 'Gene', '4763', (78, 81))	('colorectal adenocarcinoma', 'Disease', (109, 134))	('CDKN1A', 'Gene', '1026', (241, 247))	('BRAF', 'Gene', '673', (72, 76))	('mutations', 'Var', (168, 177))	('BRAF', 'Gene', (72, 76))	('human', 'Species', '9606', (103, 108))	('colon carcinoma', 'Disease', 'MESH:D015179', (10, 25))	('FBXW7', 'Gene', (189, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('NF1', 'Gene', (78, 81))	('BBC3', 'Gene', '27113', (255, 259))	('PIK3CA', 'Gene', '5290', (86, 92))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (109, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('EGFR', 'Gene', (199, 203))	('mutations', 'Var', (59, 68))	('BBC3', 'Gene', (255, 259))	('CTNNB1', 'Gene', '1499', (181, 187))	('human', 'Species', '9606', (4, 9))	('FBXW7', 'Gene', '55294', (189, 194))	('PIK3CA', 'Gene', (86, 92))	('SW48', 'CellLine', 'CVCL:1724', (98, 102))	('EGFR', 'Gene', '1956', (199, 203))
69988	27121375	Reporter constructs containing either the wild-type (WT 3UTR) or mutated (34mut) 3' UTR were used to demonstrate miR-34 specificity in the NR4A2 3' UTR.	('NR4A2', 'Gene', (139, 144))	('miR-34', 'Gene', (113, 119))	('miR-34', 'Gene', '407040', (113, 119))	('mutated', 'Var', (65, 72))
69989	27121375	We used the primers listed in Supplementary Table S2 to amplify 3xFLAG-NR4A2 cDNA from pEX-3xFLAG-NR4A2 by PCR then subcloned it into a pSin-EF2-IRES-Blast lentiviral expression vector (kindly provided by Dr. Mark E. Hatley).	('pEX-3', 'Gene', (87, 92))	('pEX-3', 'Gene', '8504', (87, 92))	('3xFLAG-NR4A2', 'Var', (64, 76))
69990	27121375	Exogenous expression or inhibition of mature miRNAs was performed with mirVana mimics (CmiR: cat# 446058; miR-34a: cat# 446066; miR-34c: cat# 446066) or inhibitors (Cntrl.	('cat# 446066', 'Var', (137, 148))	('miR-34c', 'Gene', (128, 135))	('CmiR', 'Gene', (87, 91))	('cat', 'molecular_function', 'GO:0004096', ('115', '118'))	('cat', 'molecular_function', 'GO:0004096', ('137', '140'))	('miR-34a', 'Gene', '407040', (106, 113))	('CmiR', 'Gene', '220972', (87, 91))	('cat', 'molecular_function', 'GO:0004096', ('93', '96'))	('miR-34c', 'Gene', '407042', (128, 135))	('cat# 446066', 'Var', (115, 126))	('miR-34a', 'Gene', (106, 113))
70032	25847407	Previous studies have reported that targeted genes may be significantly upregulated by five copies of HREs under hypoxic conditions.	('hypoxic conditions', 'Disease', (113, 131))	('hypoxic conditions', 'Disease', 'MESH:D009135', (113, 131))	('five copies', 'Var', (87, 98))	('upregulated', 'PosReg', (72, 83))	('HREs', 'Gene', (102, 106))
70042	25847407	Subsequently, the 5HRE-hTERTp fragment, which was digested with the restriction endoenzymes BgIII and PstI in buffer at 37 C for 16 h, was cloned into the lentiviral vector pLVX-EGFP-3FLAG (Translational Medical Center, First Affiliated Hospital of Xi'an Jiaotong University) by replacing the CMV promoter in the plasmid to generate the recombinant plasmid pLVX-5HRE-hTERTp-EGFP-3FLAG (designated as 5Hh), into which the amplified CDX2 fragment was cloned by replacing EGFP to produce the recombinant plasmid pLVX-5HRE-hTERTp-CDX2-3FLAG (designated as 5HhC).	('CDX2', 'Gene', '1045', (431, 435))	('replacing', 'Var', (459, 468))	('CDX2', 'Gene', '1045', (526, 530))	('EGFP', 'Gene', (469, 473))	('hTERTp', 'Gene', (519, 525))	('CDX2', 'Gene', (431, 435))	('hTERTp', 'Gene', '7015', (519, 525))	('PstI', 'Gene', (102, 106))	('hTERTp', 'Gene', (23, 29))	('hTERTp', 'Gene', '7015', (23, 29))	('hTERTp', 'Gene', (367, 373))	('hTERTp', 'Gene', '7015', (367, 373))	('5HhC', 'Chemical', '-', (552, 556))	('PstI', 'Gene', '6690', (102, 106))	('CDX2', 'Gene', (526, 530))
70062	25847407	The 5HhC/LoVo cells were cultured under a normoxic (absence of CoCl2) or hypoxic conditions (100, 200, 300, 400 or 500 micromol/l CoCl2) for 24 h and then cultured for 12, 24 or 36 h with the optimal concentration (300 micromol/l) of CoCl2.	('CoCl2', 'Chemical', 'MESH:C018021', (130, 135))	('HhC/LoVo', 'CellLine', 'CVCL:0399', (5, 13))	('100', 'Var', (93, 96))	('5HhC', 'Chemical', '-', (4, 8))	('CoCl2', 'Chemical', 'MESH:C018021', (234, 239))	('hypoxic conditions', 'Disease', (73, 91))	('CoCl2', 'Chemical', 'MESH:C018021', (63, 68))	('hypoxic conditions', 'Disease', 'MESH:D009135', (73, 91))
70076	25847407	It was observed that FLAG was expressed on the membrane and cytoplasm of 5HhC-infected LoVo cells, but not 5HhC-infected HK-2 cells (Fig.	('LoVo', 'CellLine', 'CVCL:0399', (87, 91))	('HK-2', 'Gene', '3099', (121, 125))	('5HhC', 'Chemical', '-', (73, 77))	('5HhC', 'Chemical', '-', (107, 111))	('5HhC-infected', 'Var', (73, 86))	('HK-2', 'Gene', (121, 125))	('cytoplasm', 'cellular_component', 'GO:0005737', ('60', '69'))	('HK-2', 'molecular_function', 'GO:0008256', ('121', '125'))	('membrane', 'cellular_component', 'GO:0016020', ('47', '55'))
70100	25847407	A non-transcriptional function of CDX2 is that it suppresses tumorigenesis via p27Kip1 stabilization, and low levels of CDX2 have been reported to accelerate colon tumorigenesis by reducing p27Kip1 levels.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('p27Kip1', 'Gene', (190, 197))	('reducing', 'NegReg', (181, 189))	('p27Kip1', 'Gene', '1027', (79, 86))	('suppresses', 'NegReg', (50, 60))	('accelerate', 'PosReg', (147, 157))	('CDX2', 'Gene', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('CDX2', 'Gene', (34, 38))	('low', 'Var', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('p27Kip1', 'Gene', (79, 86))	('p27Kip1', 'Gene', '1027', (190, 197))	('CDX2', 'Gene', '1045', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('CDX2', 'Gene', '1045', (120, 124))	('tumor', 'Disease', (61, 66))
70101	25847407	Notably, mutation of a subdomain in the N-terminus of CDX2 has been reported to abrogate the anti-proliferative effects of CDX2, which may be via inhibition of beta-catenin/T-cell factor (TCF) transcriptional activity by disrupting the beta-catenin-TCF protein complex in colon cancer cells.	('beta-catenin/T-cell factor', 'Gene', (160, 186))	('beta-catenin', 'Gene', (160, 172))	('CDX2', 'Gene', (123, 127))	('colon cancer', 'Phenotype', 'HP:0003003', (272, 284))	('TCF', 'Gene', (249, 252))	('beta-catenin', 'Gene', '1499', (160, 172))	('TCF', 'Gene', '3172', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('abrogate', 'NegReg', (80, 88))	('colon cancer', 'Disease', 'MESH:D015179', (272, 284))	('mutation', 'Var', (9, 17))	('disrupting', 'NegReg', (221, 231))	('beta-catenin/T-cell factor', 'Gene', '3172', (160, 186))	('protein complex', 'cellular_component', 'GO:0032991', ('253', '268'))	('CDX2', 'Gene', '1045', (54, 58))	('TCF', 'Gene', '3172', (249, 252))	('beta-catenin', 'Gene', (236, 248))	('colon cancer', 'Disease', (272, 284))	('TCF', 'Gene', (188, 191))	('beta-catenin', 'Gene', '1499', (236, 248))	('inhibition', 'NegReg', (146, 156))	('CDX2', 'Gene', (54, 58))	('CDX2', 'Gene', '1045', (123, 127))	('anti-proliferative effects', 'CPA', (93, 119))
70111	25527197	The identification of dominant oncogenic mutations, and our ability to specifically inhibit these genetic abnormalities with targeted inhibitors has altered the therapeutic approach for many cancer patients, particularly those with non-small cell lung cancer (NSCLC).	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (232, 258))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('patients', 'Species', '9606', (198, 206))	('NSCLC', 'Disease', 'MESH:D002289', (260, 265))	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (191, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (247, 258))	('non-small cell lung cancer', 'Disease', (232, 258))	('altered', 'Reg', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('NSCLC', 'Disease', (260, 265))	('cancer', 'Disease', (252, 258))	('NSCLC', 'Phenotype', 'HP:0030358', (260, 265))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (232, 258))	('genetic abnormalities', 'Disease', 'MESH:D030342', (98, 119))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('genetic abnormalities', 'Disease', (98, 119))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (236, 258))
70112	25527197	Activating point mutations, in-frame insertions/deletions, gene amplification, and gene rearrangements can serve as predictive biomarkers for oncogene-targeted therapies and thus help select patients that have a high likelihood of benefiting from a particular therapy.	('patients', 'Species', '9606', (191, 199))	('gene amplification', 'Var', (59, 77))	('point mutations', 'Var', (11, 26))	('in-frame insertions/deletions', 'Var', (28, 57))	('rearrangements', 'Var', (88, 102))
70114	25527197	The treatment of epidermal growth factor receptor (EGFR) mutation positive NSCLC patients (comprising approximately 18% of lung adenocarcinomas) and anaplastic lymphoma kinase, ALK, gene rearrangement positive NSCLC patients (encompassing approximately 5% of lung adenocarcinomas), respond significantly better to the targeted therapies erlotinib and crizotinib, respectively, compared with the standard-of-care chemotherapy.	('EGFR', 'Gene', (51, 55))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (259, 278))	('lymphoma', 'Phenotype', 'HP:0002665', (160, 168))	('ALK', 'Gene', '238', (177, 180))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (259, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (123, 143))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('crizotinib', 'Chemical', 'MESH:D000077547', (351, 361))	('ALK', 'Gene', (177, 180))	('EGFR', 'Gene', '1956', (51, 55))	('mutation', 'Var', (57, 65))	('better', 'PosReg', (304, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('17', '40'))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (123, 142))	('patients', 'Species', '9606', (216, 224))	('NSCLC', 'Disease', 'MESH:D002289', (210, 215))	('NSCLC', 'Disease', (75, 80))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (259, 279))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (149, 168))	('lymphoma', 'Disease', (160, 168))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (123, 143))	('lymphoma', 'Disease', 'MESH:D008223', (160, 168))	('epidermal growth factor receptor', 'Gene', (17, 49))	('lung adenocarcinomas', 'Disease', (259, 279))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('NSCLC', 'Disease', (210, 215))	('epidermal growth factor receptor', 'Gene', '1956', (17, 49))	('patients', 'Species', '9606', (81, 89))	('lung adenocarcinomas', 'Disease', (123, 143))	('EGFR', 'molecular_function', 'GO:0005006', ('51', '55'))	('erlotinib', 'Chemical', 'MESH:D000069347', (337, 346))	('NSCLC', 'Phenotype', 'HP:0030358', (210, 215))
70115	25527197	EGFR mutation positive patients who are treated with an EGFR tyrosine kinase inhibitor (TKI) have an objective response rate (ORR) of about 70%, and a progression free survival (PFS) time of approximately 10 months, both of which are superior to chemotherapy.	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (23, 31))	('EGFR', 'Gene', '1956', (56, 60))	('EGFR', 'Gene', (56, 60))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('70', '86'))	('EGFR', 'molecular_function', 'GO:0005006', ('56', '60'))	('rat', 'Species', '10116', (120, 123))	('tyrosine', 'Chemical', 'MESH:D014443', (61, 69))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
70124	25527197	It was estimated in 2007 that gene fusions were reported in approximately 20% of all cancers accounting for a significant proportion of cancer morbidity and mortality.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('reported', 'Reg', (48, 56))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('gene fusions', 'Var', (30, 42))
70125	25527197	The emergence of high-throughput genomics technologies and programmatic sequencing efforts such as the NCI/NHGRI Cancer Genome Atlas Network and the Sanger Cancer Genome Project have generated the molecular profiles of numerous cancers, and this emergent technology has enabled the identification of many additional gene fusions that are putative oncogenes and predicted to be conserved as drivers across breast, glioblastoma, lung, colorectal cancer, and others tumors.	('Cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Disease', 'MESH:D009369', (463, 469))	('colorectal cancer', 'Phenotype', 'HP:0003003', (433, 450))	('Cancer', 'Phenotype', 'HP:0002664', (113, 119))	('gene fusions', 'Var', (316, 328))	('numerous cancers', 'Disease', 'MESH:D009369', (219, 235))	('NHGRI Cancer Genome Atlas Network and the Sanger Cancer', 'Disease', 'MESH:D009369', (107, 162))	('cancer', 'Phenotype', 'HP:0002664', (444, 450))	('glioblastoma', 'Disease', 'MESH:D005909', (413, 425))	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('tumors', 'Phenotype', 'HP:0002664', (463, 469))	('rat', 'Species', '10116', (187, 190))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('lung', 'Disease', (427, 431))	('glioblastoma', 'Disease', (413, 425))	('breast', 'Disease', (405, 411))	('numerous cancers', 'Disease', (219, 235))	('tumor', 'Phenotype', 'HP:0002664', (463, 468))	('colorectal cancer', 'Disease', 'MESH:D015179', (433, 450))	('glioblastoma', 'Phenotype', 'HP:0012174', (413, 425))	('tumors', 'Disease', (463, 469))	('colorectal cancer', 'Disease', (433, 450))
70133	25527197	The binding of each of these ligands to its cognate receptor, such as binding of NGF to TrkA, induces receptor homodimerization and transphosphorylation of five critical tyrosine (Y) residues (Y496, Y676, Y680, Y681, and Y791).	('Y791', 'Var', (221, 225))	('receptor homodimerization', 'MPA', (102, 127))	('TrkA', 'Gene', (88, 92))	('NGF', 'Gene', '4803', (81, 84))	('binding', 'Interaction', (70, 77))	('binding', 'Interaction', (4, 11))	('NGF', 'Gene', (81, 84))	('TrkA', 'Gene', '4914', (88, 92))	('Y681', 'Var', (211, 215))	('Y496', 'Var', (193, 197))	('Y676', 'Var', (199, 203))	('tyrosine', 'Chemical', 'MESH:D014443', (170, 178))	('induces', 'Reg', (94, 101))	('Y680', 'Var', (205, 209))	('transphosphorylation', 'MPA', (132, 152))
70134	25527197	Y496 and Y791 serve as phosphorylation-dependent binding sites for various adaptor proteins that contain SH2 or PTB domains, primarily SHC1, PLCgamma, and GAB1, but others include FRS2, GRB2, IRS-1, IRS-2, SH2B (Fig.	('GRB2', 'Gene', (186, 190))	('Y496', 'Var', (0, 4))	('SH2B', 'Gene', (206, 210))	('Y791', 'Var', (9, 13))	('GAB1', 'Gene', (155, 159))	('IRS-2', 'Gene', '8660', (199, 204))	('binding', 'Interaction', (49, 56))	('SHC1', 'Gene', '6464', (135, 139))	('IRS-2', 'Gene', (199, 204))	('SHC1', 'Gene', (135, 139))	('GRB2', 'Gene', '2885', (186, 190))	('FRS2', 'Gene', (180, 184))	('SH2B', 'Gene', '25970', (206, 210))	('GAB1', 'Gene', '2549', (155, 159))	('IRS-1', 'Gene', '3667', (192, 197))	('IRS-1', 'Gene', (192, 197))	('FRS2', 'Gene', '10818', (180, 184))
70136	25527197	Once activated, the three wild-type Trk family members most frequently signal through several downstream signaling pathways including SHC/RAS/MAPK, PI3K/AKT, or PLC-gamma/PKC, depending on which docking protein(s) bind to the critical phosphorylated tyrosines Y496, and Y791.	('Y496', 'Var', (260, 264))	('SHC', 'Gene', (134, 137))	('downstream signaling pathways', 'Pathway', (94, 123))	('Y791', 'Var', (270, 274))	('AKT', 'Gene', '207', (153, 156))	('docking protein', 'molecular_function', 'GO:0005047', ('195', '210'))	('PKC', 'molecular_function', 'GO:0004697', ('171', '174'))	('signal', 'Reg', (71, 77))	('protein', 'cellular_component', 'GO:0003675', ('203', '210'))	('SHC', 'Gene', '6464', (134, 137))	('PLC-gamma/PKC', 'Enzyme', (161, 174))	('PLC', 'cellular_component', 'GO:0042824', ('161', '164'))	('AKT', 'Gene', (153, 156))	('MAPK', 'molecular_function', 'GO:0004707', ('142', '146'))	('signaling', 'biological_process', 'GO:0023052', ('105', '114'))	('PI3K', 'molecular_function', 'GO:0016303', ('148', '152'))	('tyrosines', 'Chemical', 'MESH:D014443', (250, 259))
70146	25527197	The TPM3-NTRK1, MPRIP-NTRK1, and CD74-NTRK1 fusions seem to signal predominantly through the SHC/RAS/MAPK pathway in endogenous colorectal and lung cancer cell lines, but can engage PI3K/AKT or STAT3 signaling in certain cell-types.	('CD74', 'Gene', '972', (33, 37))	('colorectal and lung cancer', 'Disease', 'MESH:D015179', (128, 154))	('PI3K', 'molecular_function', 'GO:0016303', ('182', '186'))	('engage', 'Reg', (175, 181))	('TPM3', 'Gene', (4, 8))	('MPRIP', 'Gene', (16, 21))	('MAPK', 'molecular_function', 'GO:0004707', ('101', '105'))	('fusions', 'Var', (44, 51))	('AKT', 'Gene', (187, 190))	('CD74', 'Gene', (33, 37))	('signal', 'Reg', (60, 66))	('STAT3', 'Gene', (194, 199))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('SHC', 'Gene', (93, 96))	('TPM3', 'Gene', '7170', (4, 8))	('AKT', 'Gene', '207', (187, 190))	('STAT3', 'Gene', '6774', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('signaling', 'biological_process', 'GO:0023052', ('200', '209'))	('SHC', 'Gene', '6464', (93, 96))	('MPRIP', 'Gene', '23164', (16, 21))
70147	25527197	Studies of the ETV6-NTRK3 fusion have demonstrated oncogenic signaling is engaged through IRS-1, but due to the limited availability of cell lines expressing the ETV6-NTRK3, most studies were conducted using a cDNA of the fusion expressed in various cell-lines, such as fibroblasts, resulting predominantly in activation of the RAS-MAPK signaling pathway, but also PI3K/AKT, often simultaneously (Fig.	('ETV6-NTRK3', 'Gene', (162, 172))	('activation', 'PosReg', (310, 320))	('ETV6-NTRK3', 'Gene', (15, 25))	('ETV6-NTRK3 fusion', 'Gene', (15, 32))	('ETV6-NTRK3', 'Gene', '2120;4916', (15, 25))	('IRS-1', 'Gene', (90, 95))	('AKT', 'Gene', '207', (370, 373))	('IRS-1', 'Gene', '3667', (90, 95))	('RAS-MAPK signaling pathway', 'Pathway', (328, 354))	('ETV6-NTRK3', 'Gene', '2120;4916', (162, 172))	('fusion', 'Var', (222, 228))	('ETV6-NTRK3 fusion', 'Gene', '4916;2120', (15, 32))	('rat', 'Species', '10116', (45, 48))	('AKT', 'Gene', (370, 373))
70150	25527197	Studies in mice in select NTRK1 and NTRK3 fusions have suggested these fusions likely play an important, early role in tumor progression.	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('mice', 'Species', '10090', (11, 15))	('fusions', 'Var', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('NTRK3', 'Gene', (36, 41))	('NTRK1', 'Gene', (26, 31))
70152	25527197	The deletion in DeltaTrkA results in the loss of 75 amino acids in the extra-cellular domain of TrkA, removes four glycosylation sites adjacent to the transmembrane domain, and transforms both fibroblasts and epithelial cells.	('four glycosylation sites adjacent', 'MPA', (110, 143))	('TrkA', 'Gene', '4914', (21, 25))	('removes', 'NegReg', (102, 109))	('TrkA', 'Gene', (21, 25))	('75 amino acids in the extra-cellular domain', 'MPA', (49, 92))	('transforms', 'Reg', (177, 187))	('deletion', 'Var', (4, 12))	('TrkA', 'Gene', '4914', (96, 100))	('TrkA', 'Gene', (96, 100))	('loss', 'NegReg', (41, 45))
70155	25527197	Although not yet identified in human tumors samples to date, mutations in the extra-cellular domain of TrkA, P203A and C345S, have both been characterized as transforming.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('P203A', 'Mutation', 'p.P203A', (109, 114))	('P203A', 'Var', (109, 114))	('C345S', 'Var', (119, 124))	('human', 'Species', '9606', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('TrkA', 'Gene', '4914', (103, 107))	('TrkA', 'Gene', (103, 107))	('C345S', 'Mutation', 'p.C345S', (119, 124))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
70156	25527197	These studies may point to regions of interest where mutations have been identified in human tumors; for example, a relative cluster of mutations occur in NTRK1 at the R342 position in close proximity to the C345 site identified by mutagenesis.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('human', 'Species', '9606', (87, 92))	('NTRK1', 'Gene', (155, 160))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('mutations', 'Var', (136, 145))	('tumors', 'Disease', (93, 99))
70158	25527197	Interestingly, all of these different mechanisms of oncogenic activation of TrkA (gene rearrangements, deletion, and splice variant) contain the loss of some of the extracellular domain of TrkA.	('extracellular', 'cellular_component', 'GO:0005576', ('165', '178'))	('TrkA', 'Gene', '4914', (76, 80))	('loss', 'NegReg', (145, 149))	('of the extracellular domain', 'MPA', (158, 185))	('TrkA', 'Gene', (189, 193))	('TrkA', 'Gene', '4914', (189, 193))	('TrkA', 'Gene', (76, 80))	('deletion', 'Var', (103, 111))
70165	25527197	The incidence and therapeutic potential of TPM3-NTRK1 in colorectal cancer was recently revisited after 32 years by Isacchi and colleagues, reaffirming that this NTRK1 fusion is indeed a recurrent, albeit infrequent, oncogene in colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (229, 241))	('colorectal cancer', 'Disease', (57, 74))	('colon cancer', 'Disease', 'MESH:D015179', (229, 241))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('NTRK1', 'Gene', (162, 167))	('TPM3', 'Gene', (43, 47))	('fusion', 'Var', (168, 174))	('colon cancer', 'Disease', (229, 241))	('colorectal cancer', 'Disease', 'MESH:D015179', (57, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('TPM3', 'Gene', '7170', (43, 47))
70166	25527197	Each of the identified colorectal cases harboring NTRK1 fusions identified thus far express the TPM3-NTRK1 oncogene, suggestin