0	33500629	Gastric Cancer Harboring an ERBB3 Mutation Treated with a Pyrotinib-Irinotecan Combo: A Case Study Gastric cancer is common, especially in East Asian countries, and is associated with high recurrence and mortality rates.	('ERBB3', 'Gene', '2065', (28, 33))	('mortality', 'Disease', 'MESH:D003643', (204, 213))	('mortality', 'Disease', (204, 213))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Cancer', 'Phenotype', 'HP:0002664', (8, 14))	('ERBB3', 'Gene', (28, 33))	('Gastric cancer', 'Disease', 'MESH:D013274', (99, 113))	('Mutation', 'Var', (34, 42))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (0, 14))	('Gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))	('Gastric Cancer', 'Disease', (0, 14))	('Gastric Cancer', 'Disease', 'MESH:D013274', (0, 14))	('Irinotecan', 'Chemical', 'MESH:D000077146', (68, 78))	('Pyrotinib', 'Chemical', 'MESH:C000622954', (58, 67))	('Gastric cancer', 'Disease', (99, 113))
3	33500629	Next-generation sequencing performed on paraffin sections of the postoperative tumor samples indicated the presence of the ERBB3 V104L mutation.	('ERBB3', 'Gene', '2065', (123, 128))	('postoperative tumor', 'Disease', (65, 84))	('V104L', 'Var', (129, 134))	('ERBB3', 'Gene', (123, 128))	('paraffin', 'Chemical', 'MESH:D010232', (40, 48))	('postoperative tumor', 'Disease', 'MESH:D010149', (65, 84))	('V104L', 'Mutation', 'rs1057519893', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
5	33500629	Therefore, the combined administration of irinotecan and pyrotinib may improve the clinical condition of patients with gastric cancer harboring an ERBB3 mutation.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('patients', 'Species', '9606', (105, 113))	('pyrotinib', 'Chemical', 'MESH:C000622954', (57, 66))	('ERBB3', 'Gene', '2065', (147, 152))	('gastric cancer', 'Disease', (119, 133))	('ERBB3', 'Gene', (147, 152))	('irinotecan', 'Chemical', 'MESH:D000077146', (42, 52))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('mutation', 'Var', (153, 161))	('improve', 'PosReg', (71, 78))
12	33500629	Herein, we present the case of a patient with advanced gastric cancer harboring the ERBB3 V104L mutation, who received pyrotinib plus irinotecan as a third-line therapy and achieved a progression-free survival (PFS) of 7.6 months with a high quality of life (QOL).	('gastric cancer', 'Disease', (55, 69))	('patient', 'Species', '9606', (33, 40))	('gastric cancer', 'Disease', 'MESH:D013274', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('irinotecan', 'Chemical', 'MESH:D000077146', (134, 144))	('pyrotinib', 'Chemical', 'MESH:C000622954', (119, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (55, 69))	('V104L', 'Mutation', 'rs1057519893', (90, 95))	('ERBB3', 'Gene', '2065', (84, 89))	('V104L', 'Var', (90, 95))	('ERBB3', 'Gene', (84, 89))
23	33500629	The genomic results revealed a mutation in ERBB3 (V104L), accompanied by mutations in TP53 (R273C), KRAS (G12F), and AMER1 (Q577*), as well as amplification of CCNE1/FOS/GATA6/MCL1/MYCN/CIC.	('ERBB3', 'Gene', (43, 48))	('KRAS', 'Gene', (100, 104))	('MYCN', 'Gene', (181, 185))	('CCNE1', 'Gene', (160, 165))	('TP53', 'Gene', (86, 90))	('CCNE1', 'Gene', '898', (160, 165))	('AMER1', 'Gene', (117, 122))	('FOS', 'Gene', (166, 169))	('ERBB3', 'Gene', '2065', (43, 48))	('FOS', 'Gene', '2353', (166, 169))	('V104L', 'Mutation', 'rs1057519893', (50, 55))	('MCL1', 'Gene', (176, 180))	('GATA6', 'Gene', '2627', (170, 175))	('TP53', 'Gene', '7157', (86, 90))	('MYCN', 'Gene', '4613', (181, 185))	('AMER1', 'Gene', '139285', (117, 122))	('MCL1', 'Gene', '4170', (176, 180))	('G12F', 'Mutation', 'p.G12F', (106, 110))	('R273C', 'Mutation', 'rs121913343', (92, 97))	('KRAS', 'Gene', '3845', (100, 104))	('Q577*', 'SUBSTITUTION', 'None', (124, 129))	('Q577*', 'Var', (124, 129))	('mutations', 'Var', (73, 82))	('GATA6', 'Gene', (170, 175))
31	33500629	Considering that his previous NGS test indicated the presence of an ERBB3 mutation, we administered irinotecan (330 mg ivd qd d1 q2w) plus pyrotinib (320 mg qd) starting on December 28, 2018.	('mutation', 'Var', (74, 82))	('pyrotinib', 'Chemical', 'MESH:C000622954', (139, 148))	('ERBB3', 'Gene', (68, 73))	('indicated', 'Reg', (39, 48))	('irinotecan', 'Chemical', 'MESH:D000077146', (100, 110))	('presence', 'Reg', (53, 61))	('ERBB3', 'Gene', '2065', (68, 73))
41	33500629	Herein, we report a patient with HER2-negative gastric cancer harboring an ERBB3 mutation.	('ERBB3', 'Gene', (75, 80))	('HER2', 'Gene', (33, 37))	('gastric cancer', 'Disease', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('HER2', 'Gene', '2064', (33, 37))	('mutation', 'Var', (81, 89))	('gastric cancer', 'Disease', 'MESH:D013274', (47, 61))	('patient', 'Species', '9606', (20, 27))	('gastric cancer', 'Phenotype', 'HP:0012126', (47, 61))	('ERBB3', 'Gene', '2065', (75, 80))
46	33500629	ERBB3 mutations have been identified in some cancers, including colon and gastric cancers, which have ligand-independent and HER2-dependent transformation abilities.	('HER2', 'Gene', (125, 129))	('colon and gastric cancers', 'Disease', 'MESH:D013274', (64, 89))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ERBB3', 'Gene', (0, 5))	('ERBB3', 'Gene', '2065', (0, 5))	('HER2', 'Gene', '2064', (125, 129))	('gastric cancers', 'Phenotype', 'HP:0012126', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('ligand', 'molecular_function', 'GO:0005488', ('102', '108'))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (74, 88))	('identified', 'Reg', (26, 36))	('mutations', 'Var', (6, 15))
47	33500629	The ERBB3 V104L mutation is one of the main hotspot mutations in the extracellular domain and was identified in gallbladder cancer, rectal neuroendocrine tumors, and lung sarcomatoid carcinoma.	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (139, 160))	('ERBB3', 'Gene', '2065', (4, 9))	('V104L', 'Mutation', 'rs1057519893', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('extracellular', 'cellular_component', 'GO:0005576', ('69', '82'))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (139, 159))	('gallbladder cancer', 'Disease', (112, 130))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (139, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('V104L', 'Var', (10, 15))	('lung sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (166, 192))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (171, 192))	('neuroendocrine tumors', 'Disease', (139, 160))	('ERBB3', 'Gene', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('gallbladder cancer', 'Disease', 'MESH:D005706', (112, 130))	('identified', 'Reg', (98, 108))	('lung sarcomatoid carcinoma', 'Disease', (166, 192))
51	33500629	For instance, a patient with a rectal neuroendocrine tumor harboring the ERBB3 V104L mutation was treated with trastuzumab and lapatinib as a third-line therapy, resulting in a stable disease and a PFS of 51 days.	('lapatinib', 'Chemical', 'MESH:D000077341', (127, 136))	('PFS', 'MPA', (198, 201))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (38, 58))	('V104L', 'Mutation', 'rs1057519893', (79, 84))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (38, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('trastuzumab', 'Chemical', 'MESH:D000068878', (111, 122))	('ERBB3', 'Gene', '2065', (73, 78))	('V104L', 'Var', (79, 84))	('neuroendocrine tumor', 'Disease', (38, 58))	('ERBB3', 'Gene', (73, 78))	('patient', 'Species', '9606', (16, 23))
52	33500629	However, HER2-negative breast cancer patients with the ERBB3 G284R mutation, who received trastuzumab with lapatinib as a third-line treatment, showed only a partial response (PR) for more than 40 weeks.	('breast cancer', 'Disease', (23, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('patients', 'Species', '9606', (37, 45))	('HER2', 'Gene', (9, 13))	('lapatinib', 'Chemical', 'MESH:D000077341', (107, 116))	('ERBB3', 'Gene', '2065', (55, 60))	('HER2', 'Gene', '2064', (9, 13))	('trastuzumab', 'Chemical', 'MESH:D000068878', (90, 101))	('ERBB3', 'Gene', (55, 60))	('G284R', 'Mutation', 'rs1057519803', (61, 66))	('G284R', 'Var', (61, 66))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
53	33500629	Additionally, a biliary tract carcinoma patient harboring an ERBB3 mutation achieved a PR after receiving trastuzumab plus lapatinib.	('lapatinib', 'Chemical', 'MESH:D000077341', (123, 132))	('patient', 'Species', '9606', (40, 47))	('ERBB3', 'Gene', (61, 66))	('mutation', 'Var', (67, 75))	('trastuzumab', 'Chemical', 'MESH:D000068878', (106, 117))	('carcinoma', 'Disease', 'MESH:D009369', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('ERBB3', 'Gene', '2065', (61, 66))	('carcinoma', 'Disease', (30, 39))
54	33500629	Additionally, two metastatic urothelial cancers with ERBB3 V104M and G284R mutations achieved 6.3 months and 7 months of PFS, respectively, after treatment with the inhibitor afatinib (Table 1).	('urothelial cancers', 'Disease', 'MESH:D014523', (29, 47))	('urothelial cancers', 'Disease', (29, 47))	('G284R', 'Mutation', 'rs1057519803', (69, 74))	('G284R mutations', 'Var', (69, 84))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('V104M', 'Mutation', 'rs1057519893', (59, 64))	('ERBB3', 'Gene', '2065', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ERBB3', 'Gene', (53, 58))	('afatinib', 'Chemical', 'MESH:D000077716', (175, 183))
57	33500629	In addition, preclinical studies have confirmed that pyrotinib successfully treated non-small-cell lung carcinoma with an HER2 exon 20 mutation and HER2-positive gastric cancer.	('HER2', 'Gene', (148, 152))	('gastric cancer', 'Disease', 'MESH:D013274', (162, 176))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (88, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('HER2', 'Gene', '2064', (148, 152))	('pyrotinib', 'Chemical', 'MESH:C000622954', (53, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (162, 176))	('lung carcinoma', 'Disease', (99, 113))	('lung carcinoma', 'Disease', 'MESH:D008175', (99, 113))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('HER2', 'Gene', (122, 126))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (84, 113))	('HER2', 'Gene', '2064', (122, 126))	('mutation', 'Var', (135, 143))	('gastric cancer', 'Disease', (162, 176))
59	33500629	Here, we showed that a patient with HER2-negative gastric cancer harboring an ERBB3 mutation who received pyrotinib plus irinotecan as a third-line treatment gained a PFS of 7.6 months with a high QOL, indicating the potential of pyrotinib in treating HER2-negative gastric cancer patients with ERBB3 mutations.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('HER2', 'Gene', (36, 40))	('pyrotinib', 'Chemical', 'MESH:C000622954', (106, 115))	('patient', 'Species', '9606', (281, 288))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('HER2', 'Gene', (252, 256))	('irinotecan', 'Chemical', 'MESH:D000077146', (121, 131))	('gastric cancer', 'Phenotype', 'HP:0012126', (266, 280))	('ERBB3', 'Gene', (295, 300))	('pyrotinib', 'Chemical', 'MESH:C000622954', (230, 239))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))	('ERBB3', 'Gene', (78, 83))	('patient', 'Species', '9606', (23, 30))	('HER2', 'Gene', '2064', (36, 40))	('gastric cancer', 'Disease', (266, 280))	('patients', 'Species', '9606', (281, 289))	('HER2', 'Gene', '2064', (252, 256))	('ERBB3', 'Gene', '2065', (295, 300))	('gastric cancer', 'Disease', (50, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (266, 280))	('ERBB3', 'Gene', '2065', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('mutation', 'Var', (84, 92))
62	33500629	In addition, further evaluations are warranted to confirm whether pyrotinib could be widely used in gastric cancer patients with ERBB3 alterations.	('gastric cancer', 'Disease', 'MESH:D013274', (100, 114))	('patients', 'Species', '9606', (115, 123))	('gastric cancer', 'Phenotype', 'HP:0012126', (100, 114))	('alterations', 'Var', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ERBB3', 'Gene', '2065', (129, 134))	('pyrotinib', 'Chemical', 'MESH:C000622954', (66, 75))	('gastric cancer', 'Disease', (100, 114))	('ERBB3', 'Gene', (129, 134))
63	33500629	Collectively, we believe that ERBB3 mutations should be considered a new target for the treatment of gastric cancer.	('ERBB3', 'Gene', (30, 35))	('gastric cancer', 'Disease', (101, 115))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('mutations', 'Var', (36, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ERBB3', 'Gene', '2065', (30, 35))
78	33031325	CRS + HIPEC combined with IP + IV chemotherapy achieved long-term disease-free survival for this patient with gastric signet-ring cell carcinoma and deserve further study.	('CRS', 'Var', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('gastric signet-ring cell carcinoma', 'Disease', 'MESH:D018279', (110, 144))	('patient', 'Species', '9606', (97, 104))	('gastric signet-ring cell carcinoma', 'Disease', (110, 144))
99	33031325	The clinical diagnoses were: GC, at the antrum, signet-ring cell carcinoma, stage cT4NxM0, Borrmann IV; anemia, moderate degree; coronary atherosclerotic heart disease.	('anemia', 'Disease', 'MESH:D000740', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('coronary atherosclerotic heart disease', 'Disease', 'MESH:D003324', (129, 167))	('ring cell carcinoma', 'Disease', 'MESH:D018279', (55, 74))	('ring cell carcinoma', 'Disease', (55, 74))	('anemia', 'Phenotype', 'HP:0001903', (104, 110))	('GC', 'Phenotype', 'HP:0012126', (29, 31))	('stage cT4NxM0', 'Var', (76, 89))	('coronary atherosclerotic heart', 'Phenotype', 'HP:0001677', (129, 159))	('anemia', 'Disease', (104, 110))	('coronary atherosclerotic heart disease', 'Disease', (129, 167))
111	33031325	Therefore, the postoperative TNM stage was pT4aN3M0, IIIC.	('pT4aN3M0', 'Var', (43, 51))	('TNM', 'Gene', '10178', (29, 32))	('TNM', 'Gene', (29, 32))
153	29403459	Thus, deregulation of these intrinsic survival-related responses to H. pylori infection emerge as potential culprits in promoting disease progression.	('infection', 'Disease', 'MESH:D007239', (78, 87))	('H. pylori infection', 'Phenotype', 'HP:0005202', (68, 87))	('deregulation', 'Var', (6, 18))	('H. pylori', 'Species', '210', (68, 77))	('disease', 'Disease', (130, 137))	('promoting', 'PosReg', (120, 129))	('infection', 'Disease', (78, 87))
157	29403459	Helicobacter pylori (H. pylori) is a Gram-negative, flagellated, microaerophilic bacterium that grows in close association with the lining of the stomach and the presence of this infection is identified as the major known risk factor associated with the development of GC (Suerbaum and Michetti,).	('Helicobacter pylori', 'Species', '210', (0, 19))	('infection', 'Disease', (179, 188))	('infection', 'Disease', 'MESH:D007239', (179, 188))	('H. pylori', 'Species', '210', (21, 30))	('presence', 'Var', (162, 170))	('Helicobacter pylori', 'Disease', (0, 19))	('GC', 'Phenotype', 'HP:0012126', (269, 271))
163	29403459	Prospective studies have shown that antibiotic-mediated eradication of H. pylori significantly reduces the incidence of precancerous lesions and thus highlights the role of H. pylori infection in early stages of gastric carcinogenesis (Mera et al.,).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (212, 234))	('H. pylori', 'Species', '210', (71, 80))	('H. pylori', 'Species', '210', (173, 182))	('infection', 'Disease', 'MESH:D007239', (183, 192))	('precancerous lesions', 'Disease', 'MESH:D011230', (120, 140))	('H. pylori infection', 'Phenotype', 'HP:0005202', (173, 192))	('infection', 'Disease', (183, 192))	('precancerous lesions', 'Disease', (120, 140))	('eradication', 'Var', (56, 67))	('gastric carcinogenesis', 'Disease', (212, 234))	('reduces', 'NegReg', (95, 102))
172	29403459	As summarized in Figure 1, deregulation of intrinsic survival-related responses to H. pylori infection may emerge as potential culprits in favoring disease progression.	('deregulation', 'Var', (27, 39))	('H. pylori', 'Species', '210', (83, 92))	('infection', 'Disease', (93, 102))	('H. pylori', 'Disease', (83, 92))	('infection', 'Disease', 'MESH:D007239', (93, 102))	('H. pylori infection', 'Phenotype', 'HP:0005202', (83, 102))	('intrinsic survival-related', 'MPA', (43, 69))
181	29403459	Moreover, silencing of the PERK gene (EIF2AK3) attenuated VacA-mediated phosphorylation of eukaryotic initiation factor-2 alpha (eIF2alpha), expression of BH3-only protein Bim and Bax, as well as cell death induced by VacA (Akazawa et al.,), indicating that ER stress may lead to apoptotic cell death during VacA-induced toxicity (Akazawa et al.,).	('toxicity', 'Disease', (321, 329))	('PERK', 'Gene', (27, 31))	('phosphorylation', 'biological_process', 'GO:0016310', ('72', '87'))	('Bax', 'Gene', (180, 183))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('280', '300'))	('eIF2', 'cellular_component', 'GO:0005850', ('129', '133'))	('apoptotic cell death', 'CPA', (280, 300))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('cell death', 'CPA', (196, 206))	('PERK', 'Gene', '13666', (27, 31))	('cell death', 'biological_process', 'GO:0008219', ('196', '206'))	('toxicity', 'Disease', 'MESH:D064420', (321, 329))	('EIF2', 'cellular_component', 'GO:0005850', ('38', '42'))	('attenuated', 'NegReg', (47, 57))	('lead to', 'Reg', (272, 279))	('silencing', 'Var', (10, 19))
184	29403459	Treatment of dendritic cells with purified H. pylori VacA was shown to induce translocation of cytoplasmic Bax and cytochrome c release from mitochondria and thus bring about apoptosis (Kim et al.,).	('translocation', 'MPA', (78, 91))	('H. pylori', 'Species', '210', (43, 52))	('cytochrome c', 'molecular_function', 'GO:0045155', ('115', '127'))	('apoptosis', 'CPA', (175, 184))	('bring about', 'Reg', (163, 174))	('H. pylori', 'Var', (43, 52))	('cytochrome c release from mitochondria', 'MPA', (115, 153))	('cytochrome c', 'molecular_function', 'GO:0009461', ('115', '127'))	('induce', 'Reg', (71, 77))	('mitochondria', 'cellular_component', 'GO:0005739', ('141', '153'))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))
190	29403459	Overall, these observations support the idea that, besides its classical role in UPR and apoptosis, following H. pylori infection, PERK expression also promotes human gastric cell migration and invasion and thus the acquisition of an aggressive phenotype.	('human', 'Species', '9606', (161, 166))	('infection', 'Disease', 'MESH:D007239', (120, 129))	('PERK', 'Gene', '13666', (131, 135))	('invasion', 'CPA', (194, 202))	('apoptosis', 'biological_process', 'GO:0097194', ('89', '98'))	('expression', 'Var', (136, 146))	('cell migration', 'biological_process', 'GO:0016477', ('175', '189'))	('PERK', 'Gene', (131, 135))	('H. pylori infection', 'Phenotype', 'HP:0005202', (110, 129))	('human gastric cell migration', 'CPA', (161, 189))	('H. pylori', 'Species', '210', (110, 119))	('promotes', 'PosReg', (152, 160))	('apoptosis', 'biological_process', 'GO:0006915', ('89', '98'))	('infection', 'Disease', (120, 129))
191	29403459	The link between ER stress and autophagy is well established, and in the context of H. pylori, it has been demonstrated that the secreted antigen HP0175 can regulate PERK, which in turn activates the transcription of ATF4 and CHOP leading to the induction of autophagy in gastric epithelial cells (Halder et al.,).	('transcription', 'biological_process', 'GO:0006351', ('200', '213'))	('autophagy', 'biological_process', 'GO:0016236', ('259', '268'))	('autophagy', 'biological_process', 'GO:0006914', ('31', '40'))	('activates', 'PosReg', (186, 195))	('CHOP', 'Gene', '1649', (226, 230))	('autophagy', 'CPA', (259, 268))	('PERK', 'Gene', (166, 170))	('PERK', 'Gene', '13666', (166, 170))	('autophagy', 'biological_process', 'GO:0006914', ('259', '268'))	('ATF4', 'Gene', (217, 221))	('transcription', 'MPA', (200, 213))	('CHOP', 'Gene', (226, 230))	('HP0175', 'Var', (146, 152))	('H. pylori', 'Species', '210', (84, 93))	('autophagy', 'biological_process', 'GO:0016236', ('31', '40'))
195	29403459	Moreover, these authors showed that p62, a selective substrate for autophagy-mediated degradation, increased in gastric biopsies of patients infected with the toxic s1m1 VacA strain in comparison with those infected with a nontoxic strain (VacA s2m2).	('autophagy', 'biological_process', 'GO:0006914', ('67', '76'))	('p62', 'Gene', '23636', (36, 39))	('degradation', 'biological_process', 'GO:0009056', ('86', '97'))	('increased', 'PosReg', (99, 108))	('p62', 'Gene', (36, 39))	('patients', 'Species', '9606', (132, 140))	('s1m1', 'Var', (165, 169))	('autophagy', 'biological_process', 'GO:0016236', ('67', '76'))
197	29403459	In line with this, silencing by methylation of the microtubule-associated protein 1 light chain 3 variant 1 (MAP1LC3Av1), an important protein in the autophagy process, was observed in gastric tissue infected with H. pylori (Muhammad et al.,).	('H. pylori', 'Species', '210', (214, 223))	('methylation', 'Var', (32, 43))	('H. pylori', 'Disease', (214, 223))	('autophagy', 'biological_process', 'GO:0006914', ('150', '159'))	('silencing', 'NegReg', (19, 28))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('MAP', 'molecular_function', 'GO:0004239', ('109', '112'))	('autophagy', 'biological_process', 'GO:0016236', ('150', '159'))	('microtubule', 'cellular_component', 'GO:0005874', ('51', '62'))	('MAP1LC3Av1', 'Gene', (109, 119))
203	29403459	Thus, autophagy acts as a quality control system in early stages of cancer, and one may infer that the inhibition of this process at the beginning of the precancerous cascade should increase reactive oxygen species (ROS) production leading to persistent oxidative stress, which in turn causes selective pressure for the acquisition of characteristics, such as increased growth, invasion, and metastasis (Azad et al.,).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('autophagy', 'biological_process', 'GO:0016236', ('6', '15'))	('ROS', 'Chemical', 'MESH:D017382', (216, 219))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('oxidative stress', 'Phenotype', 'HP:0025464', (254, 270))	('causes', 'Reg', (286, 292))	('invasion', 'CPA', (378, 386))	('increase', 'PosReg', (182, 190))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (191, 214))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('autophagy', 'biological_process', 'GO:0006914', ('6', '15'))	('inhibition', 'Var', (103, 113))	('increased', 'PosReg', (360, 369))	('metastasis', 'CPA', (392, 402))	('cancer', 'Disease', (157, 163))	('increase reactive oxygen species', 'Phenotype', 'HP:0025464', (182, 214))	('growth', 'CPA', (370, 376))	('oxidative stress', 'MPA', (254, 270))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', (68, 74))
210	29403459	Accordingly, the promoter region of the tumor suppressor E-Cadherin is frequently hypermethylated in adult patients infected with H. pylori (Perri et al.,).	('Cadherin', 'molecular_function', 'GO:0008014', ('59', '67'))	('E-Cadherin', 'Gene', (57, 67))	('H. pylori', 'Species', '210', (130, 139))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('E-Cadherin', 'Gene', '999', (57, 67))	('hypermethylated', 'Var', (82, 97))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('patients', 'Species', '9606', (107, 115))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))
211	29403459	Also, the demethylating agent 5-azacytidine has been demonstrated to reduce GC incidence in the Mongolian gerbil model of infection (Niwa et al.,).	('5-azacytidine', 'Chemical', 'MESH:D001374', (30, 43))	('infection', 'Disease', (122, 131))	('infection', 'Disease', 'MESH:D007239', (122, 131))	('GC', 'Phenotype', 'HP:0012126', (76, 78))	('5-azacytidine', 'Var', (30, 43))	('reduce', 'NegReg', (69, 75))	('Mongolian gerbil', 'Species', '10047', (96, 112))
216	29403459	In addition, H. pylori secreted peptidyl prolyl cis, trans-isomerase (HP0175) causes a gastric T-cell (Th17) response in patients with GC; leading to the production of IL-17 and IL-21, matrix degradation and the induction of pro-angiogenic pathways in response to HP0175 (Amedei et al.,).	('pro-angiogenic pathways', 'Pathway', (225, 248))	('IL-17', 'Gene', (168, 173))	('IL-17', 'Gene', '3605', (168, 173))	('induction', 'Reg', (212, 221))	('HP0175', 'Gene', (70, 76))	('production', 'MPA', (154, 164))	('IL-21', 'Gene', (178, 183))	('HP0175', 'Var', (264, 270))	('H. pylori', 'Species', '210', (13, 22))	('degradation', 'biological_process', 'GO:0009056', ('192', '203'))	('IL-17', 'molecular_function', 'GO:0030367', ('168', '173'))	('IL-21', 'Gene', '59067', (178, 183))	('GC', 'Phenotype', 'HP:0012126', (135, 137))	('matrix degradation', 'MPA', (185, 203))	('IL-21', 'molecular_function', 'GO:0001531', ('178', '183'))	('patients', 'Species', '9606', (121, 129))
221	29403459	Importantly, certain NF-kappaB target genes such as TNFalpha, IL-1beta, IL-2, and IL-8, present polymorphisms that are associated with increased risk for GC in patients (Valenzuela et al.,; Melchiades et al.,).	('patients', 'Species', '9606', (160, 168))	('IL-8', 'Gene', '3576', (82, 86))	('NF-kappaB', 'Gene', '4790', (21, 30))	('IL-2', 'Gene', '3558', (72, 76))	('TNFalpha', 'Gene', (52, 60))	('IL-8', 'Gene', (82, 86))	('IL-1', 'molecular_function', 'GO:0005149', ('62', '66'))	('IL-8', 'molecular_function', 'GO:0005153', ('82', '86'))	('IL-2', 'Gene', (72, 76))	('IL-2', 'molecular_function', 'GO:0005134', ('72', '76'))	('polymorphisms', 'Var', (96, 109))	('NF-kappaB', 'Gene', (21, 30))	('IL-1beta', 'Gene', (62, 70))	('TNFalpha', 'Gene', '7124', (52, 60))	('IL-1beta', 'Gene', '3553', (62, 70))	('GC', 'Phenotype', 'HP:0012126', (154, 156))
241	29403459	The compound GSK2606414 (GlaxoSmithKline ) was the first reported small molecular inhibitor of PERK, which is highly specific (Axten et al.,).	('GSK2606414', 'Chemical', 'MESH:C576403', (13, 23))	('GSK2606414', 'Var', (13, 23))	('PERK', 'Gene', '13666', (95, 99))	('GSK', 'molecular_function', 'GO:0050321', ('13', '16'))	('PERK', 'Gene', (95, 99))
242	29403459	When administered orally, GSK2606414 inhibits tumor growth in a dose-dependent manner in mice with human pancreatic BxPC3 tumors (Axten et al.,).	('GSK2606414', 'Chemical', 'MESH:C576403', (26, 36))	('GSK', 'molecular_function', 'GO:0050321', ('26', '29'))	('pancreatic BxPC3 tumors', 'Disease', 'MESH:D010190', (105, 128))	('pancreatic BxPC3 tumors', 'Disease', (105, 128))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('GSK2606414', 'Var', (26, 36))	('mice', 'Species', '10090', (89, 93))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('inhibits', 'NegReg', (37, 45))	('tumor', 'Disease', (122, 127))	('human', 'Species', '9606', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
245	29403459	Medulloblastoma cell lines treated with GSK2606414 exhibited a significant reduction in the level of phospho-eIF2alpha and concomitant suppression of cell migration and invasion (Jamison et al.,).	('GSK2606414', 'Chemical', 'MESH:C576403', (40, 50))	('eIF2', 'cellular_component', 'GO:0005850', ('109', '113'))	('phospho-eIF2alpha', 'MPA', (101, 118))	('Medulloblastoma', 'Disease', 'MESH:D008527', (0, 15))	('GSK', 'molecular_function', 'GO:0050321', ('40', '43'))	('Medulloblastoma', 'Disease', (0, 15))	('GSK2606414', 'Var', (40, 50))	('cell migration', 'biological_process', 'GO:0016477', ('150', '164'))	('suppression', 'NegReg', (135, 146))	('reduction', 'NegReg', (75, 84))	('Medulloblastoma', 'Phenotype', 'HP:0002885', (0, 15))	('level', 'MPA', (92, 97))
442	28279063	Examples of studies that have been implemented by CTONG include the INFORM Study, FASTACT 2, and others in the pipeline, including CTONG 1103 on stage III epidermal growth factor receptor (EGFR) mutation positive adenocarcinoma, and CTONG 1104 on adjuvant EGFR tyrosine kinase inhibitor (TKI) in resectable lung cancer with EGFR mutation.	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('155', '178'))	('adenocarcinoma', 'Disease', (213, 227))	('EGFR', 'molecular_function', 'GO:0005006', ('324', '328'))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('EGFR', 'Gene', '1956', (189, 193))	('EGFR', 'Gene', '1956', (324, 328))	('mutation', 'Var', (329, 337))	('epidermal growth factor receptor', 'Gene', (155, 187))	('men', 'Species', '9606', (40, 43))	('lung cancer', 'Disease', (307, 318))	('adenocarcinoma', 'Disease', 'MESH:D000230', (213, 227))	('epidermal growth factor receptor', 'Gene', '1956', (155, 187))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('270', '286'))	('EGFR', 'Gene', (256, 260))	('EGFR', 'molecular_function', 'GO:0005006', ('256', '260'))	('lung cancer', 'Disease', 'MESH:D008175', (307, 318))	('EGFR', 'Gene', (189, 193))	('EGFR', 'Gene', (324, 328))	('EGFR', 'Gene', '1956', (256, 260))	('EGFR', 'molecular_function', 'GO:0005006', ('189', '193'))	('lung cancer', 'Phenotype', 'HP:0100526', (307, 318))
444	28279063	The first study that ATORG will engage in is for stage IV adenocarcinoma EGFR mutation positive resistance to EGFR TKI plasma cell-free DNA positive for T790M.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('T790M', 'Mutation', 'rs121434569', (153, 158))	('IV adenocarcinoma', 'Disease', (55, 72))	('EGFR', 'Gene', '1956', (73, 77))	('mutation', 'Var', (78, 86))	('EGFR', 'Gene', '1956', (110, 114))	('IV adenocarcinoma', 'Disease', 'MESH:D000230', (55, 72))	('EGFR', 'Gene', (110, 114))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('EGFR', 'Gene', (73, 77))	('EGFR', 'molecular_function', 'GO:0005006', ('73', '77'))	('resistance', 'MPA', (96, 106))
488	28152027	Also, the association of H. pylori eradication with a reduced incidence of gastric cancer was demonstrated in a meta-analysis study.	('gastric cancer', 'Disease', (75, 89))	('H. pylori', 'Gene', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('eradication', 'Var', (35, 46))	('reduced', 'NegReg', (54, 61))	('H. pylori', 'Species', '210', (25, 34))	('reduced incidence of gastric cancer', 'Phenotype', 'HP:0006753', (54, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))
531	28152027	The proportion of the proximal tumor location was higher in negative H. pylori infection patients without gastric atrophy than positive H. pylori infection patients (24.0% versus 11.2%, P = 0.004).	('patients', 'Species', '9606', (156, 164))	('H. pylori infection', 'Phenotype', 'HP:0005202', (136, 155))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('pylori infection', 'Disease', (72, 88))	('H. pylori', 'Species', '210', (136, 145))	('pylori infection', 'Disease', (139, 155))	('tumor', 'Disease', (31, 36))	('H. pylori', 'Species', '210', (69, 78))	('H. pylori infection', 'Phenotype', 'HP:0005202', (69, 88))	('patients', 'Species', '9606', (89, 97))	('negative', 'Var', (60, 68))	('gastric atrophy', 'Disease', (106, 121))	('gastric atrophy', 'Disease', 'MESH:D013274', (106, 121))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('pylori infection', 'Disease', 'MESH:D016481', (72, 88))	('pylori infection', 'Disease', 'MESH:D016481', (139, 155))
585	28152027	Previous studies supported that patients with blood group A were more susceptible to atrophic gastritis and in turn the higher risk of subsequent development of HPPGC.	('HPPGC', 'Disease', (161, 166))	('patients', 'Species', '9606', (32, 40))	('GC', 'Phenotype', 'HP:0012126', (164, 166))	('atrophic gastritis', 'Disease', (85, 103))	('atrophic gastritis', 'Disease', 'MESH:D005757', (85, 103))	('gastritis', 'Phenotype', 'HP:0005263', (94, 103))	('HPPGC', 'Phenotype', 'HP:0005202', (161, 166))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (85, 103))	('susceptible', 'Reg', (70, 81))	('blood group A', 'Var', (46, 59))
595	28152027	reported that the effect of negativity H. pylori status was more pronounced in patients with early stage cancer (HR 2.00 CI1.22-3.27, p = 0.0057) but not in patients with stage III or IV disease.	('H. pylori', 'Species', '210', (39, 48))	('stage cancer', 'Disease', 'MESH:D009369', (99, 111))	('negativity', 'Var', (28, 38))	('patients', 'Species', '9606', (157, 165))	('stage cancer', 'Disease', (99, 111))	('patients', 'Species', '9606', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
597	28152027	In our study, we further analyzed the prognostic effect in stage I, II and III cancers which showed worse hazard ratio 1.62 (95% confidence interval, 1.05-2.51; p = 0.026) in the negative H. pylori status than the HR 1.34 (95% confidence interval, 1.04-1.71, p = 0,019) in all stage cancers.	('negative', 'Var', (179, 187))	('cancers', 'Disease', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (283, 290))	('cancers', 'Phenotype', 'HP:0002664', (283, 290))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('stage cancer', 'Disease', 'MESH:D009369', (277, 289))	('cancers', 'Disease', (283, 290))	('III cancers', 'Disease', 'MESH:D009369', (75, 86))	('H. pylori', 'Species', '210', (188, 197))	('negative H. pylori status', 'Phenotype', 'HP:0005202', (179, 204))	('stage cancer', 'Disease', (277, 289))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('stage I', 'Disease', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('III cancers', 'Disease', (75, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
603	28152027	We postulated that the leading genetic or epigenetic alteration in HPNGC such as E-Cadherin (E-CDH) and genetic microsatellite instability (MSI) might be associated with the characteristics of HPNGC which had the manifestation of younger disease onset and diffuse histologic type.	('HPNGC', 'Disease', (193, 198))	('MSI', 'Disease', 'None', (140, 143))	('GC', 'Phenotype', 'HP:0012126', (196, 198))	('E-Cadherin', 'Gene', (81, 91))	('GC', 'Phenotype', 'HP:0012126', (70, 72))	('MSI', 'Disease', (140, 143))	('E-Cadherin', 'Gene', '999', (81, 91))	('Cadherin', 'molecular_function', 'GO:0008014', ('83', '91'))	('HPNGC', 'Gene', (67, 72))	('associated', 'Reg', (154, 164))	('epigenetic alteration', 'Var', (42, 63))
604	28152027	The genetic or epigenetic alteration of E-Cadherin (E-CDH) and genetic microsatellite instability (MSI) might also cause regional or distal metastasis.	('epigenetic alteration', 'Var', (15, 36))	('MSI', 'Disease', (99, 102))	('E-Cadherin', 'Gene', (40, 50))	('regional or distal metastasis', 'CPA', (121, 150))	('E-Cadherin', 'Gene', '999', (40, 50))	('cause', 'Reg', (115, 120))	('Cadherin', 'molecular_function', 'GO:0008014', ('42', '50'))	('MSI', 'Disease', 'None', (99, 102))
631	28143619	Importantly, inhibition of DDR1 is an attractive strategy for gastric carcinoma therapy.	('gastric carcinoma', 'Phenotype', 'HP:0012126', (62, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('inhibition', 'Var', (13, 23))	('gastric carcinoma', 'Disease', 'MESH:D013274', (62, 79))	('gastric carcinoma', 'Disease', (62, 79))	('DDR1', 'Gene', (27, 31))	('rat', 'Species', '10116', (51, 54))
693	28143619	Additional immunofluorescence stains were performed with antibodies against: phosphorylated-DDR1 (Tyr792; 1:100 dilution, #11994, Cell Signaling Technology), phosphorylated-PYK2 (Tyr402; 1:100 dilution, #3291, Cell Signaling Technology), and E-cadherin (1:50 dilution, 610181, BD Biosciences).	('E-cadherin', 'Gene', (242, 252))	('E-cadherin', 'Gene', '999', (242, 252))	('cadherin', 'molecular_function', 'GO:0008014', ('244', '252'))	('Tyr402', 'Chemical', '-', (179, 185))	('Tyr792', 'Chemical', '-', (98, 104))	('Tyr402;', 'Var', (179, 186))	('Signaling', 'biological_process', 'GO:0023052', ('135', '144'))	('Signaling', 'biological_process', 'GO:0023052', ('215', '224'))
698	28143619	Patients with positive DDR1 expression showed a worse prognosis when compared to DDR1-negative patients (P = 0.015; Fig.	('Patients', 'Species', '9606', (0, 8))	('positive', 'Var', (14, 22))	('DDR1', 'Gene', (23, 27))	('patients', 'Species', '9606', (95, 103))
723	28143619	Mice bearing subcutaneous MKN28 tumors were treated with 7rh benzamide or vehicle (Fig.	('MKN28 tumors', 'Disease', 'MESH:D009369', (26, 38))	('7rh', 'Var', (57, 60))	('MKN28 tumors', 'Disease', (26, 38))	('7rh benzamide', 'Chemical', '-', (57, 70))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('Mice', 'Species', '10090', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))
729	28143619	Moreover, we identified that collagen-induced DDR1 activation enhanced aggressive tumor phenotypes, and that a pharmacologic inhibition of DDR1 can suppress cancer progression in vitro and in vivo.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('aggressive tumor', 'Disease', (71, 87))	('suppress', 'NegReg', (148, 156))	('collagen', 'molecular_function', 'GO:0005202', ('29', '37'))	('DDR1', 'Gene', (46, 50))	('DDR1', 'Gene', (139, 143))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancer', 'Disease', (157, 163))	('inhibition', 'Var', (125, 135))	('activation enhanced', 'PosReg', (51, 70))	('aggressive tumor', 'Disease', 'MESH:D001523', (71, 87))
730	28143619	These observations provided strong evidence that DDR1 served as a critical mediator of gastric cancer aggressiveness and that the inhibition of DDR1 can be potentially used as a novel strategy to improve the prognosis of gastric cancer patients.	('gastric cancer aggressiveness', 'Disease', 'MESH:D013274', (87, 116))	('gastric cancer', 'Disease', (221, 235))	('inhibition', 'Var', (130, 140))	('gastric cancer', 'Phenotype', 'HP:0012126', (87, 101))	('rat', 'Species', '10116', (186, 189))	('gastric cancer', 'Disease', 'MESH:D013274', (221, 235))	('improve', 'PosReg', (196, 203))	('patients', 'Species', '9606', (236, 244))	('aggressiveness', 'Phenotype', 'HP:0000718', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('gastric cancer', 'Phenotype', 'HP:0012126', (221, 235))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('gastric cancer aggressiveness', 'Disease', (87, 116))	('gastric cancer', 'Disease', 'MESH:D013274', (87, 101))	('DDR1', 'Gene', (144, 148))
732	28143619	However previous studies have demonstrated a positive association between DDR1 protein expression and poor prognosis in solid tumors, thus supporting the hypothesis that DDR1 expression enhances the aggressiveness of malignant tumors.	('enhances', 'PosReg', (186, 194))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('solid tumors', 'Disease', (120, 132))	('protein', 'Protein', (79, 86))	('aggressiveness of malignant tumors', 'Disease', 'MESH:D018198', (199, 233))	('expression', 'Var', (175, 185))	('DDR1', 'Gene', (170, 174))	('rat', 'Species', '10116', (37, 40))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('DDR1', 'Gene', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('aggressiveness', 'Phenotype', 'HP:0000718', (199, 213))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('solid tumors', 'Disease', 'MESH:D009369', (120, 132))	('poor', 'Disease', (102, 106))	('aggressiveness of malignant tumors', 'Disease', (199, 233))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
748	28143619	Moreover, in a xenograft model, the effect of 7rh benzamide to suppress tumor growth following subcutaneous injection of tumor cells was demonstrated.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (72, 77))	('7rh benzamide', 'Chemical', '-', (46, 59))	('rat', 'Species', '10116', (144, 147))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('7rh', 'Var', (46, 49))	('suppress', 'NegReg', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
753	28143619	We also found that DDR1 inhibition reduced DDR1 activation, EMT, and tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('DDR1', 'Protein', (43, 47))	('reduced', 'NegReg', (35, 42))	('activation', 'MPA', (48, 58))	('tumor', 'Disease', (69, 74))	('inhibition', 'Var', (24, 34))	('EMT', 'CPA', (60, 63))	('EMT', 'biological_process', 'GO:0001837', ('60', '63'))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('DDR1', 'Protein', (19, 23))
756	28143619	We assessed the loss of the epithelial marker E-cadherin as a marker of EMT progression, because E-cadherin loss and/or mutation were shown to associate with progression and poor prognosis of gastric cancers.	('cadherin', 'molecular_function', 'GO:0008014', ('48', '56'))	('cadherin', 'molecular_function', 'GO:0008014', ('99', '107'))	('E-cadherin', 'Gene', (46, 56))	('loss', 'NegReg', (108, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (192, 206))	('E-cadherin', 'Gene', (97, 107))	('gastric cancers', 'Disease', 'MESH:D013274', (192, 207))	('E-cadherin', 'Gene', '999', (97, 107))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('mutation', 'Var', (120, 128))	('gastric cancers', 'Disease', (192, 207))	('E-cadherin', 'Gene', '999', (46, 56))	('gastric cancers', 'Phenotype', 'HP:0012126', (192, 207))	('EMT', 'biological_process', 'GO:0001837', ('72', '75'))	('associate', 'Reg', (143, 152))
775	27172250	Perioperative mFOLFOX6 was a tolerable and effective regimen for gastric cancer.	('mFOLFOX6', 'Var', (14, 22))	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mFOLFOX6', 'Chemical', '-', (14, 22))	('gastric cancer', 'Disease', (65, 79))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))
818	27172250	On the basis of the CT evaluations, T downstaging occurred in 17 (23.6%) of 72 patients, including 2 T2 T1, 2 T3 T1, 8 T3 T2 and 5 T4 T3, and N downstaging occurred in 12 (16.7% N positive or N+ N negative or N-).	('downstaging', 'NegReg', (144, 155))	('T3 T2', 'Var', (119, 124))	('T4 T3', 'Var', (131, 136))	('patients', 'Species', '9606', (79, 87))	('T2 T1', 'Var', (101, 106))	('downstaging', 'NegReg', (38, 49))
850	27172250	When taking 50% as the cut-off value, the 3-year survival rate of patients with a GHR >50% was significantly higher than those with a GHR <50% (69% vs 44%, P=0.01).	('>50%', 'Var', (86, 90))	('higher', 'PosReg', (109, 115))	('GHR', 'Var', (82, 85))	('patients', 'Species', '9606', (66, 74))
854	27172250	Of 73 patients, 91.8% received radical surgery, which was considerably higher than the 69.3% reported by the MAGIC trial using ECF as a neoadjuvant chemotherapy regimen; the FFCD 9703 trial published in 2011 also showed the efficacy of cisplatin+5-FU in gastric cancer, but only 84% of patients received radical surgery.	('5-FU', 'Chemical', 'MESH:D005472', (246, 250))	('FFCD', 'Chemical', '-', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('gastric cancer', 'Disease', (254, 268))	('cisplatin+5-FU', 'Var', (236, 250))	('patients', 'Species', '9606', (6, 14))	('gastric cancer', 'Disease', 'MESH:D013274', (254, 268))	('cisplatin', 'Chemical', 'MESH:D002945', (236, 245))	('patients', 'Species', '9606', (286, 294))	('gastric cancer', 'Phenotype', 'HP:0012126', (254, 268))
886	26877236	Oct1 binding to MOREs is inducible by oxidative and genotoxic stress, through phosphorylation of a conserved Ser385 residue in the POUH DNA binding sub-domain.	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('DNA binding', 'molecular_function', 'GO:0003677', ('136', '147'))	('Ser385', 'Var', (109, 115))	('inducible', 'Reg', (25, 34))	('Ser385', 'Chemical', '-', (109, 115))	('phosphorylation', 'biological_process', 'GO:0016310', ('78', '93'))	('binding', 'molecular_function', 'GO:0005488', ('5', '12'))	('Ser', 'cellular_component', 'GO:0005790', ('109', '112'))	('Oct1', 'Gene', (0, 4))	('binding', 'Interaction', (5, 12))
899	26877236	Oct1 deficient MEFs proliferate normally in standard conditions, while Oct1 deficient hematopoietic progenitors efficiently transplant recipient animals and give rise to stably-engrafted blood cells.	('MEFs', 'CellLine', 'CVCL:9115', (15, 19))	('Oct1', 'Gene', (71, 75))	('deficient', 'NegReg', (76, 85))	('Oct1', 'Gene', (0, 4))	('deficient', 'Var', (5, 14))
901	26877236	Importantly, the early embryonic lethality can be rescued by tetraploid complementation, indicating that it is not embryo-intrinsic.	('embryonic lethality', 'Disease', 'MESH:D020964', (23, 42))	('embryonic lethality', 'Disease', (23, 42))	('tetraploid', 'Var', (61, 71))
904	26877236	Because Oct1 is widely expressed, and because it associates with multiple critically important genes such as histones, U snRNAs, RNA polymerase II subunits and TBP-associated factors (TAFs), a reasonable hypothesis would be that loss of Oct1 is incompatible with cell growth and viability.	('RNA', 'cellular_component', 'GO:0005562', ('129', '132'))	('Oct1', 'Gene', (237, 241))	('Oct1', 'Gene', (8, 12))	('loss', 'Var', (229, 233))	('TBP', 'Gene', (160, 163))	('TBP', 'Gene', '6908', (160, 163))	('cell growth', 'biological_process', 'GO:0016049', ('263', '274'))	('associates', 'Interaction', (49, 59))
905	26877236	Oct1 disruption in mice and cells supports the alternative model.	('Oct1', 'Gene', (0, 4))	('mice', 'Species', '10090', (19, 23))	('disruption', 'Var', (5, 15))
908	26877236	Regarding the third question, one insight came with the discovery that Oct1 deficient cells are hypersensitive to genotoxic and oxidative stress generated using ionizing radiation, doxorubicin or hydrogen peroxide.	('hypersensitive', 'Disease', (96, 110))	('doxorubicin', 'Chemical', 'MESH:D004317', (181, 192))	('Oct1', 'Gene', (71, 75))	('oxidative stress', 'Phenotype', 'HP:0025464', (128, 144))	('deficient', 'Var', (76, 85))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (196, 213))	('hypersensitive', 'Disease', 'MESH:D004342', (96, 110))
909	26877236	Oct1 had already been shown to regulate the induction of Gadd45a in response to DNA damage, suggesting that the hypersensitive phenotype of Oct1 deficient cells may stem from Oct1 responding to stress signals and altering target gene expression.	('gene expression', 'biological_process', 'GO:0010467', ('229', '244'))	('altering', 'Reg', (213, 221))	('expression', 'MPA', (234, 244))	('Gadd45a', 'Gene', '1647', (57, 64))	('DNA', 'cellular_component', 'GO:0005574', ('80', '83'))	('Gadd45a', 'Gene', (57, 64))	('hypersensitive', 'Disease', (112, 126))	('hypersensitive', 'Disease', 'MESH:D004342', (112, 126))	('Oct1', 'Gene', (175, 179))	('responding', 'Reg', (180, 190))	('deficient', 'Var', (145, 154))	('Oct1', 'Gene', (140, 144))
910	26877236	Although Oct1 deficient MEFs grow at normal rates in rich media and are morphologically normal as assessed by light microscopy, they have reduced glucose uptake and increased mitochondrial genome number, membrane potential, respiratory rate and reactive oxygen species (ROS) concentrations.	('reduced', 'NegReg', (138, 145))	('glucose', 'Chemical', 'MESH:D005947', (146, 153))	('glucose uptake', 'biological_process', 'GO:0046323', ('146', '160'))	('mitochondrial genome number', 'CPA', (175, 202))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (245, 268))	('mitochondrial genome', 'cellular_component', 'GO:0000262', ('175', '195'))	('Oct1', 'Gene', (9, 13))	('glucose uptake', 'CPA', (146, 160))	('MEFs', 'CellLine', 'CVCL:9115', (24, 28))	('deficient', 'Var', (14, 23))	('membrane potential', 'MPA', (204, 222))	('respiratory rate', 'MPA', (224, 240))	('ROS', 'Chemical', 'MESH:D017382', (270, 273))	('increased', 'PosReg', (165, 174))	('membrane', 'cellular_component', 'GO:0016020', ('204', '212'))
915	26877236	Oct1 Ser385 phosphorylation in the POUH DNA binding subdomain allows the protein to adopt a configuration that allows it to bind more favorably to genes containing a MORE-like sequence (Fig.	('bind', 'Interaction', (124, 128))	('Ser385', 'Chemical', '-', (5, 11))	('Ser', 'cellular_component', 'GO:0005790', ('5', '8'))	('DNA binding', 'molecular_function', 'GO:0003677', ('40', '51'))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('Ser385', 'Var', (5, 11))	('phosphorylation', 'biological_process', 'GO:0016310', ('12', '27'))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('Oct1', 'Gene', (0, 4))
916	26877236	Phosphorylation at Ser335 in the other DNA binding subdomain, POUS, abrogates DNA binding.	('DNA binding', 'molecular_function', 'GO:0003677', ('39', '50'))	('DNA', 'cellular_component', 'GO:0005574', ('39', '42'))	('Phosphorylation', 'Var', (0, 15))	('DNA', 'MPA', (78, 81))	('Ser335', 'Chemical', '-', (19, 25))	('DNA binding', 'molecular_function', 'GO:0003677', ('78', '89'))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('Ser', 'cellular_component', 'GO:0005790', ('19', '22'))	('abrogates', 'NegReg', (68, 77))	('DNA', 'cellular_component', 'GO:0005574', ('78', '81'))
928	26877236	These modifications repress transcription and thus by removing them Jmjd1a potentiates gene expression (Fig.	('modifications', 'Var', (6, 19))	('gene expression', 'biological_process', 'GO:0010467', ('87', '102'))	('transcription', 'biological_process', 'GO:0006351', ('28', '41'))	('repress', 'NegReg', (20, 27))	('removing', 'NegReg', (54, 62))	('transcription', 'MPA', (28, 41))	('Jmjd1a', 'Gene', '55818', (68, 74))	('potentiates', 'PosReg', (75, 86))	('gene expression', 'MPA', (87, 102))	('Jmjd1a', 'Gene', (68, 74))
931	26877236	H3K9me2 is one such modification, and the H3K9me2 demethylating enzyme Jmjd1a is an Oct1 cofactor.	('Jmjd1a', 'Gene', '55818', (71, 77))	('H3K9me2', 'Var', (0, 7))	('Jmjd1a', 'Gene', (71, 77))
933	26877236	In vivo, loss of Oct1 in CD4+ T cells specifically ablates the memory phase.	('CD4', 'Gene', '920', (25, 28))	('memory', 'biological_process', 'GO:0007613', ('63', '69'))	('loss', 'Var', (9, 13))	('memory phase', 'CPA', (63, 75))	('ablates', 'NegReg', (51, 58))	('Oct1', 'Protein', (17, 21))	('CD4', 'Gene', (25, 28))
937	26877236	The association of Oct1 with the nuclear periphery may be regulated by O-GlcNAcylation, as mutation of O-GlcNAcylated sites within the protein affects both association with the nuclear periphery and association with the stress-responsive Oct1 target gene Gadd45a.	('mutation', 'Var', (91, 99))	('Gadd45a', 'Gene', (255, 262))	('association', 'Interaction', (4, 15))	('affects', 'Reg', (143, 150))	('nuclear periphery', 'cellular_component', 'GO:0034399', ('33', '50'))	('association', 'Interaction', (199, 210))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('Gadd45a', 'Gene', '1647', (255, 262))	('association', 'Interaction', (156, 167))	('nuclear periphery', 'cellular_component', 'GO:0034399', ('177', '194'))
948	26877236	Deletion of tumor suppressor genes is common in cancer.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor suppressor', 'biological_process', 'GO:0051726', ('12', '28'))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('12', '28'))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Disease', (12, 17))	('Deletion', 'Var', (0, 8))
949	26877236	Due to Oct1's pro-tumorigenic functions, in the simplest models recurrent deletion of the Pou2f1 gene encoding Oct1 would not be expected in tumors.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('Pou2f1', 'Gene', (90, 96))	('tumor', 'Disease', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('deletion', 'Var', (74, 82))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumor', 'Disease', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
952	26877236	A common somatic alteration leading to tumorigenesis is the focal amplification of chromosomal regions containing genes encoding oncoproteins.	('focal amplification', 'Var', (60, 79))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('leading', 'Reg', (28, 35))
953	26877236	performed copy number variation analysis in gastric cancer tissues using data from the TCGA, the Singapore dataset and the VU University Medical Center (VUMC) cohorts.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('copy', 'Var', (10, 14))	('gastric cancer', 'Disease', (44, 58))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))
982	26877236	Survival analyses showed that patients with low Oct1 immunoreactivity had better cancer-specific survival compared to patients with high Oct1 immunoreactivity.	('better', 'PosReg', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('Oct1', 'Protein', (48, 52))	('low', 'Var', (44, 47))	('cancer', 'Disease', (81, 87))	('patients', 'Species', '9606', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('patients', 'Species', '9606', (118, 126))
999	26877236	Downregulation of PER2 removes this inhibitory effect and allows for the transcriptional activation of Twst1, Snai1 and Snai2 by Oct1.	('Snai2', 'Gene', (120, 125))	('transcriptional', 'MPA', (73, 88))	('PER2', 'Gene', (18, 22))	('Snai2', 'Gene', '6591', (120, 125))	('Snai1', 'Gene', '6615', (110, 115))	('PER2', 'Gene', '8864', (18, 22))	('Downregulation', 'Var', (0, 14))	('inhibitory effect', 'MPA', (36, 53))	('Snai1', 'Gene', (110, 115))	('activation', 'PosReg', (89, 99))	('Twst1', 'Gene', (103, 108))
1006	26877236	AA promotes binding of mutant but not wild-type BRAF to MEK1, promoting MEK-ERK activation.	('MEK1', 'Gene', '5604', (56, 60))	('ERK', 'molecular_function', 'GO:0004707', ('76', '79'))	('promoting', 'PosReg', (62, 71))	('ERK', 'Gene', (76, 79))	('ERK', 'Gene', '5594', (76, 79))	('MEK1', 'molecular_function', 'GO:0004708', ('56', '60'))	('MEK', 'Gene', (72, 75))	('binding', 'Interaction', (12, 19))	('MEK', 'Gene', (56, 59))	('MEK', 'Gene', '5609', (72, 75))	('MEK', 'Gene', '5609', (56, 59))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('binding', 'molecular_function', 'GO:0005488', ('12', '19'))	('MEK1', 'Gene', (56, 60))	('mutant', 'Var', (23, 29))	('activation', 'PosReg', (80, 90))
1008	26877236	It will be interesting to analyze the expression and activity of Oct1 in other cancer types where BRAF mutation occurs, including breast, lung, ovarian and colorectal cancers.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('BRAF', 'Gene', (98, 102))	('cancer', 'Disease', (167, 173))	('lung', 'Disease', (138, 142))	('BRAF', 'Gene', '673', (98, 102))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('colorectal cancer', 'Phenotype', 'HP:0003003', (156, 173))	('mutation', 'Var', (103, 111))	('ovarian and colorectal cancers', 'Disease', 'MESH:D015179', (144, 174))	('breast', 'Disease', (130, 136))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
1014	26877236	The Sanger Institute Catalogue of Somatic Mutations in Cancer (COSMIC) database reports that out of 22997 samples analyzed, only 120 Oct1 mutations have been identified.	('Oct1', 'Gene', (133, 137))	('Cancer', 'Disease', 'MESH:D009369', (55, 61))	('Cancer', 'Disease', (55, 61))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('mutations', 'Var', (138, 147))
1015	26877236	However there has not been as yet any direct association between these mutations and epithelial cancers.	('epithelial cancers', 'Disease', 'MESH:D000077216', (85, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutations', 'Var', (71, 80))	('epithelial cancer', 'Phenotype', 'HP:0031492', (85, 102))	('epithelial cancers', 'Disease', (85, 103))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))
1029	26877236	When exposed to oxidative stress, Oct1 can be modified by phosphorylation at Ser385.	('modified', 'Reg', (46, 54))	('Ser385', 'Chemical', '-', (77, 83))	('Ser', 'cellular_component', 'GO:0005790', ('77', '80'))	('phosphorylation', 'biological_process', 'GO:0016310', ('58', '73'))	('phosphorylation', 'Var', (58, 73))	('oxidative stress', 'Phenotype', 'HP:0025464', (16, 32))	('Oct1', 'Gene', (34, 38))
1041	26877236	The metabolic activities promoted by Oct1 described in section 4, including the switch from aerobic glycolytic metabolism, are consistent with changes observed in tumor cells, suggesting that Oct1 may have cancer-promoting effects via metabolic mechanisms.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('Oct1', 'Gene', (37, 41))	('metabolic activities', 'MPA', (4, 24))	('tumor', 'Disease', (163, 168))	('metabolism', 'biological_process', 'GO:0008152', ('111', '121'))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('Oct1', 'Var', (192, 196))
1043	26877236	In Tp53 deficient MEFs, Oct1 deletion eliminates soft agar colony formation following transformation with H-Ras.	('deletion', 'Var', (29, 37))	('formation', 'biological_process', 'GO:0009058', ('66', '75'))	('Tp53', 'Gene', (3, 7))	('colon', 'Disease', (59, 64))	('eliminates', 'NegReg', (38, 48))	('H-Ras', 'Gene', '3265', (106, 111))	('Tp53', 'Gene', '7157', (3, 7))	('H-Ras', 'Gene', (106, 111))	('MEFs', 'CellLine', 'CVCL:9115', (18, 22))	('colon', 'Disease', 'MESH:D015179', (59, 64))	('Oct1', 'Gene', (24, 28))
1044	26877236	Loss of Oct1 mimics the effects of dichloroacetate (DCA), a known inhibitor of transformation that promotes oxidative metabolism.	('oxidative metabolism', 'biological_process', 'GO:0045333', ('108', '128'))	('promotes', 'PosReg', (99, 107))	('Oct1', 'Gene', (8, 12))	('oxidative metabolism', 'MPA', (108, 128))	('Loss', 'Var', (0, 4))	('DCA', 'Chemical', 'MESH:D003999', (52, 55))	('dichloroacetate', 'Chemical', 'MESH:D003999', (35, 50))
1047	26877236	Oct1 Ser335 phosphorylation by AMPK dampens its activity and reduces miR-451 expression, resulting in increased expression of repressed miR-451 targets such as CAB39.	('AMPK', 'molecular_function', 'GO:0050405', ('31', '35'))	('dampens', 'NegReg', (36, 43))	('miR-451', 'Gene', '574411', (69, 76))	('CAB39', 'Gene', (160, 165))	('expression', 'MPA', (112, 122))	('activity', 'MPA', (48, 56))	('Ser335', 'Var', (5, 11))	('AMPK', 'molecular_function', 'GO:0004691', ('31', '35'))	('CAB39', 'Gene', '51719', (160, 165))	('Ser', 'cellular_component', 'GO:0005790', ('5', '8'))	('miR-451', 'Gene', (69, 76))	('miR-451', 'Gene', '574411', (136, 143))	('Ser335', 'Chemical', '-', (5, 11))	('AMPK', 'molecular_function', 'GO:0047322', ('31', '35'))	('phosphorylation', 'MPA', (12, 27))	('expression', 'MPA', (77, 87))	('miR-451', 'Gene', (136, 143))	('reduces', 'NegReg', (61, 68))	('phosphorylation', 'biological_process', 'GO:0016310', ('12', '27'))	('increased', 'PosReg', (102, 111))	('Oct1', 'Gene', (0, 4))
1048	26877236	Finally a study focused on melanoma and leukemia identified Oct1 at the center of a pathway linking mutant BRAF and oncogenic MAPK signaling to lipid metabolism, through the direct Oct1 target Hmgcl.	('lipid metabolism', 'MPA', (144, 160))	('lipid metabolism', 'biological_process', 'GO:0006629', ('144', '160'))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('leukemia', 'Disease', (40, 48))	('leukemia', 'Disease', 'MESH:D007938', (40, 48))	('MAPK', 'molecular_function', 'GO:0004707', ('126', '130'))	('Oct1', 'Gene', (60, 64))	('MAPK signaling', 'biological_process', 'GO:0000165', ('126', '140'))	('lipid', 'Chemical', 'MESH:D008055', (144, 149))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', (27, 35))	('BRAF', 'Gene', '673', (107, 111))	('BRAF', 'Gene', (107, 111))	('mutant', 'Var', (100, 106))	('MAPK', 'Gene', (126, 130))	('leukemia', 'Phenotype', 'HP:0001909', (40, 48))	('Hmgcl', 'Gene', (193, 198))	('Hmgcl', 'Gene', '3155', (193, 198))	('MAPK', 'Gene', '5594', (126, 130))
1051	26877236	Loss of Oct1 has been shown to decrease tumor size in xenograft models of colon cancer and lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('colon cancer', 'Phenotype', 'HP:0003003', (74, 86))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('colon cancer', 'Disease', 'MESH:D015179', (74, 86))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Oct1', 'Gene', (8, 12))	('decrease', 'NegReg', (31, 39))	('colon cancer', 'Disease', (74, 86))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('Loss', 'Var', (0, 4))	('lung cancer', 'Disease', (91, 102))
1052	26877236	In the latter model, A549 cells with inducible Oct1 knockout were used to generate subcutaneous tumors in immunodeficient recipients, yielding somewhat smaller tumors that nevertheless grew at the same rate within their hosts.	('knockout', 'Var', (52, 60))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('A549', 'CellLine', 'CVCL:0023', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('immunodeficient', 'Disease', 'MESH:D007153', (106, 121))	('immunodeficient', 'Disease', (106, 121))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('Oct1', 'Gene', (47, 51))	('smaller', 'NegReg', (152, 159))	('tumors', 'Disease', (160, 166))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (83, 102))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
1065	26877236	The authors showed that Oct1 expression correlates with the expression of N-cadherin and ZEB1, which promote EMT, and that Oct1 knockdown in CRC cell lines reduces proliferation, migration and EMT markers.	('promote', 'PosReg', (101, 108))	('N-cadherin', 'Gene', (74, 84))	('cadherin', 'molecular_function', 'GO:0008014', ('76', '84'))	('proliferation', 'CPA', (164, 177))	('EMT', 'biological_process', 'GO:0001837', ('109', '112'))	('N-cadherin', 'Gene', '1000', (74, 84))	('knockdown', 'Var', (128, 137))	('EMT', 'biological_process', 'GO:0001837', ('193', '196'))	('EMT', 'CPA', (109, 112))	('ZEB1', 'Gene', (89, 93))	('reduces', 'NegReg', (156, 163))	('Oct1', 'Gene', (123, 127))	('ZEB1', 'Gene', '6935', (89, 93))	('migration', 'CPA', (179, 188))	('EMT markers', 'CPA', (193, 204))	('Oct1', 'Gene', (24, 28))
1070	26877236	Overexpression of these genes in HNSCC is associated with proliferation and invasion of oral keratinocytes, leading to tumor spread.	('tumor', 'Disease', (119, 124))	('HNSCC', 'Gene', (33, 38))	('proliferation', 'CPA', (58, 71))	('associated with', 'Reg', (42, 57))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('invasion', 'CPA', (76, 84))
1082	26877236	Another largely unexplored area is the role that human polymorphisms in Oct1 target sites may be playing in cancer or other processes.	('human polymorphisms', 'Var', (49, 68))	('human', 'Species', '9606', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('playing', 'Reg', (97, 104))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
1084	26877236	Oct1 binding site polymorphisms associated with bladder cancer and a variety of autoimmune syndromes were identified in this analysis.	('bladder cancer', 'Disease', (48, 62))	('autoimmune syndromes', 'Disease', 'MESH:D001327', (80, 100))	('autoimmune syndromes', 'Disease', (80, 100))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bladder cancer', 'Phenotype', 'HP:0009725', (48, 62))	('Oct1 binding', 'Protein', (0, 12))	('binding', 'molecular_function', 'GO:0005488', ('5', '12'))	('polymorphisms', 'Var', (18, 31))	('associated', 'Reg', (32, 42))	('bladder cancer', 'Disease', 'MESH:D001749', (48, 62))
1098	26540343	The mechanisms of lncRNAs involved in liver disease have widely diverse functions, including DNA imprinting, X inactivation, DNA demethylation, gene transcription, and generation of other RNA molecules.	('liver disease', 'Phenotype', 'HP:0001392', (38, 51))	('DNA', 'cellular_component', 'GO:0005574', ('93', '96'))	('demethylation', 'Var', (129, 142))	('involved', 'Reg', (26, 34))	('liver disease', 'Disease', 'MESH:D008107', (38, 51))	('DNA imprinting', 'biological_process', 'GO:0071514', ('93', '107'))	('DNA demethylation', 'biological_process', 'GO:0080111', ('125', '142'))	('gene', 'MPA', (144, 148))	('RNA', 'cellular_component', 'GO:0005562', ('188', '191'))	('transcription', 'biological_process', 'GO:0006351', ('149', '162'))	('DNA', 'cellular_component', 'GO:0005574', ('125', '128'))	('liver disease', 'Disease', (38, 51))
1122	26540343	Three LINC00152-specific shRNAs were evaluated for their knockdown efficiency, sh152-1 and sh152-3 were found to have higher silencing efficiency than sh152-2 (Supplementary Figure S1E).	('higher', 'PosReg', (118, 124))	('LINC00152', 'Gene', (6, 15))	('LINC00152', 'Gene', '112597', (6, 15))	('sh152-1', 'Var', (79, 86))	('sh152-3', 'Var', (91, 98))	('silencing efficiency', 'MPA', (125, 145))
1141	26540343	Interestingly, we found that silencing LINC00152 by sh152-1 resulted in the down-regulation of EpCAM in HepG2 and MHCC-97H cells at both the mRNA and protein levels (Figure 4E).	('regulation', 'biological_process', 'GO:0065007', ('81', '91'))	('HepG2', 'CellLine', 'CVCL:0027', (104, 109))	('silencing', 'Var', (29, 38))	('LINC00152', 'Gene', '112597', (39, 48))	('MHCC-97H cells', 'CellLine', 'CVCL:4972', (114, 128))	('EpCAM', 'Gene', (95, 100))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('down-regulation', 'NegReg', (76, 91))	('LINC00152', 'Gene', (39, 48))	('EpCAM', 'Gene', '4072', (95, 100))
1143	26540343	Dual luciferase reporter gene assay showed that the knockdown of LINC00152 could decrease the promoter activity of EpCAM in HepG2 and MHCC-97H cells (Figure 4F).	('promoter activity', 'MPA', (94, 111))	('decrease', 'NegReg', (81, 89))	('EpCAM', 'Gene', (115, 120))	('LINC00152', 'Gene', (65, 74))	('EpCAM', 'Gene', '4072', (115, 120))	('LINC00152', 'Gene', '112597', (65, 74))	('MHCC-97H cells', 'CellLine', 'CVCL:4972', (134, 148))	('knockdown', 'Var', (52, 61))	('HepG2', 'CellLine', 'CVCL:0027', (124, 129))
1148	26540343	Luciferase activity after co-transfection of the system indicated that tethering LINC00152 to this reporter gene could stimulate transcription of the reporter to a similar degree as LUNAR1 indicating that LINC00152 could function as a transcription activator (Figure 5C).	('transcription', 'MPA', (129, 142))	('transcription', 'biological_process', 'GO:0006351', ('235', '248'))	('Luciferase activity', 'molecular_function', 'GO:0050397', ('0', '19'))	('LINC00152', 'Gene', (81, 90))	('tethering', 'Var', (71, 80))	('LINC00152', 'Gene', '112597', (205, 214))	('stimulate', 'PosReg', (119, 128))	('Luciferase activity', 'molecular_function', 'GO:0047712', ('0', '19'))	('LUNAR1', 'Gene', (182, 188))	('Luciferase activity', 'molecular_function', 'GO:0047077', ('0', '19'))	('LUNAR1', 'Gene', '104564224', (182, 188))	('Luciferase activity', 'molecular_function', 'GO:0050248', ('0', '19'))	('LINC00152', 'Gene', '112597', (81, 90))	('transcription', 'biological_process', 'GO:0006351', ('129', '142'))	('Luciferase', 'Enzyme', (0, 10))	('LINC00152', 'Gene', (205, 214))	('Luciferase activity', 'molecular_function', 'GO:0045289', ('0', '19'))
1159	26540343	We found that the knockdown of LINC00152 could decrease the promoter activity of EpCAM in HepG2 and MHCC-97H cells.	('LINC00152', 'Gene', '112597', (31, 40))	('knockdown', 'Var', (18, 27))	('promoter activity', 'MPA', (60, 77))	('HepG2', 'CellLine', 'CVCL:0027', (90, 95))	('MHCC-97H cells', 'CellLine', 'CVCL:4972', (100, 114))	('decrease', 'NegReg', (47, 55))	('LINC00152', 'Gene', (31, 40))	('EpCAM', 'Gene', (81, 86))	('EpCAM', 'Gene', '4072', (81, 86))
1167	26540343	Aberrant expression of LINC00152 increases EpCAM levels, resulting in the activation of the mTOR signaling pathway, and afterwards, causing the proliferation of HCC both in vitro and in vivo.	('LINC00152', 'Gene', (23, 32))	('Aberrant expression', 'Var', (0, 19))	('HCC', 'Gene', (161, 164))	('signaling pathway', 'biological_process', 'GO:0007165', ('97', '114'))	('causing', 'Reg', (132, 139))	('LINC00152', 'Gene', '112597', (23, 32))	('increases', 'PosReg', (33, 42))	('activation', 'PosReg', (74, 84))	('EpCAM', 'Gene', (43, 48))	('mTOR', 'Gene', (92, 96))	('HCC', 'Gene', '619501', (161, 164))	('mTOR', 'Gene', '2475', (92, 96))	('EpCAM', 'Gene', '4072', (43, 48))	('proliferation', 'CPA', (144, 157))
1183	26540343	A total of 1.5 x 105 cells were seeded in 35 mm2 tissue culture dishes for 24 h. The knock-down efficiency of the LINC00152 by shRNAs was monitored by qRT-PCR.	('LINC00152', 'Gene', '112597', (114, 123))	('knock-down', 'Var', (85, 95))	('LINC00152', 'Gene', (114, 123))
1198	26540343	Total RNA was extracted from HepG2 and MHCC-97H cells in which LINC00152 was stably knocked down, and control cells were treated with the corresponding empty plasmid, PLL3.7, and was amplified and transcribed into fluorescent cDNA.	('RNA', 'cellular_component', 'GO:0005562', ('6', '9'))	('HepG2', 'CellLine', 'CVCL:0027', (29, 34))	('LINC00152', 'Gene', (63, 72))	('MHCC-97H cells', 'CellLine', 'CVCL:4972', (39, 53))	('PLL', 'biological_process', 'GO:0048915', ('167', '170'))	('LINC00152', 'Gene', '112597', (63, 72))	('knocked down', 'Var', (84, 96))
1209	26310847	Analysis of MALDI-TOF/TOF mass spectrometry and RNA immunoprecipitation-sequencing of interacting proteins and the microRNAs (miRNAs) bound to LIX1L revealed that LIX1L interacts with proteins (RIOK1, nucleolin and PABPC4) and miRNAs (has-miRNA-520a-5p, -300, -216b, -326, -190a, -548b-3p, -7-5p and -1296) in HEK-293 cells.	('PABPC4', 'Gene', (215, 221))	('RNA', 'cellular_component', 'GO:0005562', ('48', '51'))	('interacts', 'Interaction', (169, 178))	('has-miRNA-520a-5p', 'Var', (235, 252))	('nucleolin', 'Gene', '4691', (201, 210))	('HEK-293', 'CellLine', 'CVCL:0045', (310, 317))	('RIOK1', 'Gene', (194, 199))	('293 cells', 'CellLine', 'CVCL:0045', (314, 323))	('RIOK1', 'Gene', '83732', (194, 199))	('nucleolin', 'Gene', (201, 210))	('LIX1L', 'Gene', (163, 168))	('PABPC4', 'Gene', '8761', (215, 221))
1210	26310847	Moreover, the reduction of phosphorylated Tyr136 (pTyr136) in LIX1L through the homeodomain peptide, PY136, inhibited LIX1L-induced cell proliferation in vitro, and PY136 inhibited MKN45 cell proliferation in vivo.	('Tyr136', 'Chemical', '-', (42, 48))	('PY136', 'Chemical', '-', (165, 170))	('Tyr136', 'Chemical', '-', (51, 57))	('PY136', 'Var', (165, 170))	('pTyr136', 'Chemical', '-', (50, 57))	('cell proliferation', 'biological_process', 'GO:0008283', ('187', '205'))	('inhibited', 'NegReg', (171, 180))	('PY136', 'Chemical', '-', (101, 106))	('LIX1L', 'Gene', (62, 67))	('MKN45 cell proliferation in vivo', 'CPA', (181, 213))	('cell proliferation', 'biological_process', 'GO:0008283', ('132', '150'))	('PY136', 'Var', (101, 106))	('reduction', 'NegReg', (14, 23))	('inhibited', 'NegReg', (108, 117))
1212	26310847	Moreover, ROS1, HCK, ABL1, ABL2, JAK3, LCK and TYR03 were identified as candidate kinases responsible for the phosphorylation of Tyr136 of LIX1L.	('JAK3', 'Gene', (33, 37))	('HCK', 'Gene', (16, 19))	('phosphorylation', 'biological_process', 'GO:0016310', ('110', '125'))	('LIX1L', 'Gene', (139, 144))	('ROS1', 'Gene', '6098', (10, 14))	('JAK3', 'Gene', '3718', (33, 37))	('phosphorylation', 'MPA', (110, 125))	('TYR03', 'Chemical', '-', (47, 52))	('LCK', 'Gene', '3932', (39, 42))	('ABL1', 'Gene', (21, 25))	('JAK', 'molecular_function', 'GO:0004713', ('33', '36'))	('HCK', 'Gene', '3055', (16, 19))	('ABL1', 'Gene', '25', (21, 25))	('Tyr136', 'Chemical', '-', (129, 135))	('Tyr136', 'Var', (129, 135))	('ROS1', 'Gene', (10, 14))	('ABL2', 'Gene', (27, 31))	('ABL2', 'Gene', '27', (27, 31))	('LCK', 'Gene', (39, 42))
1229	26310847	Moreover, we identified LIX1L-targeting tyrosine kinases and LIX1-mediated miRNA expression, showing that LIX1L PY136 induced tumor cell apoptosis.	('PY136', 'Var', (112, 117))	('apoptosis', 'biological_process', 'GO:0097194', ('137', '146'))	('LIX1L', 'Var', (106, 111))	('apoptosis', 'biological_process', 'GO:0006915', ('137', '146'))	('tyrosine', 'Chemical', 'MESH:D014443', (40, 48))	('induced', 'PosReg', (118, 125))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('PY136', 'Chemical', '-', (112, 117))	('tumor', 'Disease', (126, 131))
1235	26310847	2A and Supplementary Figure 3), and the effects of the LIX1L knockdown on OCUM-1 proliferation were assessed over 72 h of culture, starting from day 3 post-transfection.	('knockdown', 'Var', (61, 70))	('OCUM-1', 'Gene', (74, 80))	('OCUM-1', 'CellLine', 'CVCL:3084', (74, 80))	('LIX1L', 'Gene', (55, 60))
1237	26310847	When the OCUM-1 cells were transfected with LIX1L shRNA-#1 or -#2, cell proliferation was significantly decreased compared with untreated cells and cells transfected with scrambled shRNA.	('LIX1L', 'Var', (44, 49))	('decreased', 'NegReg', (104, 113))	('cell proliferation', 'biological_process', 'GO:0008283', ('67', '85'))	('OCUM-1', 'CellLine', 'CVCL:3084', (9, 15))	('cell proliferation', 'CPA', (67, 85))
1238	26310847	Moreover, LIX1L knockdown in other gastric cancer cell lines (KATO-III and MKN45) similarly reduced proliferation (data not shown).	('gastric cancer', 'Phenotype', 'HP:0012126', (35, 49))	('proliferation', 'CPA', (100, 113))	('knockdown', 'Var', (16, 25))	('LIX1L', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('reduced', 'NegReg', (92, 99))	('gastric cancer', 'Disease', (35, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (35, 49))
1239	26310847	Next, the incorporation of BrdU was measured, and the rate of DNA synthesis at 24 h was determined after transfection in OCUM-1 cells, showing that BrdU incorporation was significantly reduced after LIX1L knockdown (Fig.	('OCUM-1', 'CellLine', 'CVCL:3084', (121, 127))	('DNA', 'cellular_component', 'GO:0005574', ('62', '65'))	('knockdown', 'Var', (205, 214))	('LIX1L', 'Gene', (199, 204))	('BrdU incorporation', 'MPA', (148, 166))	('DNA synthesis', 'biological_process', 'GO:0071897', ('62', '75'))	('reduced', 'NegReg', (185, 192))
1240	26310847	Moreover, to determine whether the growth inhibition induced through LIX1L knockdown was associated with apoptosis, the caspase activities in OCUM-1 cells were determined at 48 h after transfection with LIX1L shRNA #1 or #2.	('apoptosis', 'biological_process', 'GO:0097194', ('105', '114'))	('apoptosis', 'biological_process', 'GO:0006915', ('105', '114'))	('knockdown', 'Var', (75, 84))	('LIX1L', 'Gene', (69, 74))	('OCUM-1', 'CellLine', 'CVCL:3084', (142, 148))	('growth', 'MPA', (35, 41))
1241	26310847	The results showed that the activities of caspases-3/7 and -9 were significantly increased in LIX1L-knockdown OCUM-1 cells (Fig.	('activities', 'MPA', (28, 38))	('caspases-3/7 and -9', 'Gene', '836;840;842', (42, 61))	('LIX1L-knockdown', 'Var', (94, 109))	('OCUM-1', 'CellLine', 'CVCL:3084', (110, 116))	('LIX1L-knockdown', 'Gene', (94, 109))	('increased', 'PosReg', (81, 90))
1242	26310847	2D,E) compared with control cells, suggesting that OCUM-1 growth suppression through LIX1L knockdown might reflect the induction of apoptosis.	('suppression', 'NegReg', (65, 76))	('LIX1L', 'Gene', (85, 90))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('119', '141'))	('knockdown', 'Var', (91, 100))	('OCUM-1', 'CellLine', 'CVCL:3084', (51, 57))	('growth', 'CPA', (58, 64))
1243	26310847	Similarly, in other gastric cancer cell lines (KATO-III and MKN45), LIX1L knockdown also suppressed BrdU incorporation and induced caspase-3/7 and -9 activities (data not shown).	('induced', 'PosReg', (123, 130))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('suppressed', 'NegReg', (89, 99))	('BrdU incorporation', 'MPA', (100, 118))	('knockdown', 'Var', (74, 83))	('LIX1L', 'Gene', (68, 73))	('gastric cancer', 'Disease', (20, 34))	('caspase-3/7 and -9', 'Gene', '836;840;842', (131, 149))	('gastric cancer', 'Disease', 'MESH:D013274', (20, 34))	('activities', 'MPA', (150, 160))	('gastric cancer', 'Phenotype', 'HP:0012126', (20, 34))
1246	26310847	LIX1L knockdown also induced apoptosis in other gastric cancer cell lines (KATO-III and MKN45) according to a caspase activity assay (data not shown).	('apoptosis', 'CPA', (29, 38))	('gastric cancer', 'Disease', (48, 62))	('caspase activity', 'molecular_function', 'GO:0097153', ('110', '126'))	('gastric cancer', 'Phenotype', 'HP:0012126', (48, 62))	('LIX1L', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('caspase activity', 'molecular_function', 'GO:0030693', ('110', '126'))	('caspase activity', 'molecular_function', 'GO:0004197', ('110', '126'))	('apoptosis', 'biological_process', 'GO:0097194', ('29', '38'))	('induced', 'Reg', (21, 28))	('knockdown', 'Var', (6, 15))	('apoptosis', 'biological_process', 'GO:0006915', ('29', '38'))	('gastric cancer', 'Disease', 'MESH:D013274', (48, 62))
1251	26310847	Upon activation, PKB and MK2 phosphorylate TIS11b at Ser92 and Ser203, and subsequently, TIS11b is prevented from mediating ARE-mediated mRNA decay.	('MK2', 'Gene', '9261', (25, 28))	('MK2', 'Gene', (25, 28))	('prevented', 'NegReg', (99, 108))	('PKB', 'Disease', (17, 20))	('PKB', 'Disease', 'None', (17, 20))	('TIS11b', 'Gene', (89, 95))	('Ser', 'cellular_component', 'GO:0005790', ('63', '66'))	('Ser203', 'Chemical', '-', (63, 69))	('TIS11b', 'Gene', '677', (43, 49))	('Ser', 'cellular_component', 'GO:0005790', ('53', '56'))	('Ser203', 'Var', (63, 69))	('Ser92', 'Chemical', '-', (53, 58))	('mRNA decay', 'biological_process', 'GO:0006402', ('137', '147'))	('mediating ARE-mediated mRNA decay', 'MPA', (114, 147))	('TIS11b', 'Gene', '677', (89, 95))	('Ser92', 'Var', (53, 58))	('TIS11b', 'Gene', (43, 49))
1252	26310847	Similarly, but not at same phosphorylation sites, KSRP is phosphorylated at Ser193 and Thr692 by PKB and p38 respectively.	('phosphorylation', 'biological_process', 'GO:0016310', ('27', '42'))	('Ser193', 'Chemical', '-', (76, 82))	('KSRP', 'Gene', '8570', (50, 54))	('Ser', 'cellular_component', 'GO:0005790', ('76', '79'))	('PKB', 'Disease', (97, 100))	('PKB', 'Disease', 'None', (97, 100))	('Thr692', 'Var', (87, 93))	('p38', 'Gene', (105, 108))	('KSRP', 'Gene', (50, 54))	('Thr692', 'Chemical', '-', (87, 93))	('Ser193', 'Var', (76, 82))	('p38', 'Gene', '1432', (105, 108))
1256	26310847	Surprisingly, only one homeodomain peptide, PY136, inhibited the proliferation of MKN45 cells (Fig.	('PY136', 'Var', (44, 49))	('inhibited', 'NegReg', (51, 60))	('proliferation', 'CPA', (65, 78))	('PY136', 'Chemical', '-', (44, 49))
1259	26310847	We confirmed the internalization of PY136 in NUGC-4 cells (Supplementary Figure 5).	('PY136', 'Chemical', '-', (36, 41))	('PY136', 'Var', (36, 41))	('NUGC-4', 'CellLine', 'CVCL:3082', (45, 51))	('internalization', 'MPA', (17, 32))
1261	26310847	Similarly, only PY136 inhibited the proliferation of KATO-III and OCUM-1 cells.	('PY136', 'Var', (16, 21))	('KATO-III', 'CPA', (53, 61))	('inhibited', 'NegReg', (22, 31))	('OCUM-1', 'CellLine', 'CVCL:3084', (66, 72))	('PY136', 'Chemical', '-', (16, 21))	('proliferation', 'CPA', (36, 49))	('OCUM-1 cells', 'CPA', (66, 78))
1263	26310847	The results showed that the inhibitory effects of PY136 were independent of the length of the peptide in KATO-III and OCUM-1 cells (using 10-, 20- and 30-aa peptides), and none of these peptides inhibited the proliferation of NUGC-4 cells (Supplementary Figure 7).	('proliferation', 'CPA', (209, 222))	('PY136', 'Var', (50, 55))	('PY136', 'Chemical', '-', (50, 55))	('NUGC-4', 'CellLine', 'CVCL:3082', (226, 232))	('inhibited', 'NegReg', (195, 204))	('OCUM-1', 'CellLine', 'CVCL:3084', (118, 124))
1265	26310847	PY136, PY95 and Pcont internalization and cytoplasmic localization was observed in 92, 95 and 91% of MKN45 cells, respectively, using the flow cytometry at 3 h post-treatment (Fig.	('PY136', 'Chemical', '-', (0, 5))	('PY95', 'Chemical', '-', (7, 11))	('localization', 'biological_process', 'GO:0051179', ('54', '66'))	('PY136', 'Var', (0, 5))	('PY95', 'Var', (7, 11))	('Pcont internalization', 'CPA', (16, 37))
1267	26310847	3E, marked inhibition of tumor growth was observed after the subcutaneous (s.c.) administration of PY136.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('PY136', 'Chemical', '-', (99, 104))	('PY136', 'Var', (99, 104))	('tumor', 'Disease', (25, 30))	('inhibition', 'NegReg', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
1272	26310847	Moreover, PY136 inhibited the phosphorylation of tyrosine residues in both of these fractions, but these effects were not observed with PY95 as a negative control peptide (Fig.	('phosphorylation of tyrosine residues', 'MPA', (30, 66))	('inhibited', 'NegReg', (16, 25))	('PY136', 'Chemical', '-', (10, 15))	('tyrosine', 'Chemical', 'MESH:D014443', (49, 57))	('phosphorylation', 'biological_process', 'GO:0016310', ('30', '45'))	('PY136', 'Var', (10, 15))	('PY95', 'Chemical', '-', (136, 140))
1273	26310847	The results showed that the numbers of HEK-293FLG-LIX1L cells were significantly increased compared with those of FLAG-expressing HEK-293 (HEK-293FLG) cells, and the viable cell counts of HEK-293FLG-LIX1L cells decreased after treatment with PY136 (Fig.	('HEK-293', 'CellLine', 'CVCL:0045', (188, 195))	('viable cell counts', 'CPA', (166, 184))	('PY136', 'Var', (242, 247))	('HEK-293', 'CellLine', 'CVCL:0045', (139, 146))	('HEK-293', 'CellLine', 'CVCL:0045', (130, 137))	('HEK-293', 'CellLine', 'CVCL:0045', (39, 46))	('decreased', 'NegReg', (211, 220))	('PY136', 'Chemical', '-', (242, 247))	('increased', 'PosReg', (81, 90))	('HEK-293FLG-LIX1L', 'Var', (39, 55))
1274	26310847	Moreover, LIX1L transfection also increased the numbers of HEK-293FLG-LIX1L cells, and pY136 inhibited HEK-293FLG-LIX1L colony formation in soft agar (Fig.	('pY136', 'Chemical', '-', (87, 92))	('agar', 'Chemical', 'MESH:D000362', (145, 149))	('LIX1L', 'Gene', (10, 15))	('transfection', 'Var', (16, 28))	('increased', 'PosReg', (34, 43))	('pY136', 'Var', (87, 92))	('formation', 'biological_process', 'GO:0009058', ('127', '136'))	('inhibited', 'NegReg', (93, 102))
1278	26310847	Among these proteins, high immunoreactivity was observed for RIOK1 (C-p89), nucleolin (C-p80) and PABPC4 (C-p80) (Fig.	('RIOK1', 'Gene', '83732', (61, 66))	('PABPC4', 'Gene', '8761', (98, 104))	('nucleolin', 'Gene', '4691', (76, 85))	('C-p80', 'Var', (106, 111))	('PABPC4', 'Gene', (98, 104))	('C-p80', 'Var', (87, 92))	('RIOK1', 'Gene', (61, 66))	('immunoreactivity', 'MPA', (27, 43))	('nucleolin', 'Gene', (76, 85))
1279	26310847	In the nuclear fraction, the differentially expressed proteins identified through MALDI-TOF/TOF mass spectrometry (Supplementary Table 1) were DHX9 (N-p150), nucleolin (N-p100) and hnRNPL (N-p68) (Supplementary Figure 12).	('p68', 'Gene', '10657', (191, 194))	('DHX9', 'Gene', (143, 147))	('hnRNPL', 'Gene', (181, 187))	('hnRNPL', 'Gene', '3191', (181, 187))	('p68', 'Gene', (191, 194))	('nucleolin', 'Gene', (158, 167))	('p150', 'Gene', '25', (151, 155))	('DHX9', 'Gene', '1660', (143, 147))	('N-p100', 'Chemical', '-', (169, 175))	('N-p100', 'Var', (169, 175))	('nucleolin', 'Gene', '4691', (158, 167))	('p150', 'Gene', (151, 155))
1285	26310847	miRNAs play important roles in crucial biological processes, such as cell proliferation, differentiation, and apoptosis, and the dysregulation of miRNAs has been observed in the initiation and progression of a variety of human malignancies.	('dysregulation', 'Var', (129, 142))	('observed', 'Reg', (162, 170))	('apoptosis', 'biological_process', 'GO:0097194', ('110', '119'))	('miRNAs', 'Gene', (146, 152))	('malignancies', 'Disease', 'MESH:D009369', (227, 239))	('apoptosis', 'biological_process', 'GO:0006915', ('110', '119'))	('human', 'Species', '9606', (221, 226))	('cell proliferation', 'CPA', (69, 87))	('malignancies', 'Disease', (227, 239))	('apoptosis', 'CPA', (110, 119))	('differentiation', 'CPA', (89, 104))	('cell proliferation', 'biological_process', 'GO:0008283', ('69', '87'))
1288	26310847	In the AC test, 1,018, 2,226 and 2,798 target genes were upregulated in HEK-293FLG-LIX1L cells compared with HEK-293FLG cells using three databases (PITA, TargetScan and microRNA.org, respectively).	('HEK-293', 'CellLine', 'CVCL:0045', (72, 79))	('HEK-293FLG-LIX1L', 'Var', (72, 88))	('HEK-293', 'CellLine', 'CVCL:0045', (109, 116))	('upregulated', 'PosReg', (57, 68))
1289	26310847	For example, has-miRNA-520a-5p, -300, -216b, and -326 share several common targets [Glycerophosphocholine phosphodiesterase 1 (GPCPD1), Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) and Collagen, type IV, alpha 1 (COL4A1)].	('GPCPD1', 'Gene', (127, 133))	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('COL4A1', 'Gene', (239, 245))	('Leucine-rich repeats and immunoglobulin-like domains protein 1', 'Gene', '26018', (136, 198))	('LRIG1', 'Gene', '26018', (200, 205))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('161', '175'))	('LRIG1', 'Gene', (200, 205))	('has-miRNA-520a-5p', 'Var', (13, 30))	('Collagen, type IV, alpha 1', 'Gene', '1282', (211, 237))	('Collagen', 'molecular_function', 'GO:0005202', ('211', '219'))	('phosphodiesterase', 'molecular_function', 'GO:0008081', ('106', '123'))	('Glycerophosphocholine phosphodiesterase 1', 'Gene', '56261', (84, 125))	('COL4A1', 'Gene', '1282', (239, 245))	('GPCPD1', 'Gene', '56261', (127, 133))	('Glycerophosphocholine phosphodiesterase 1', 'Gene', (84, 125))
1290	26310847	has-miRNA-190a, -548b-3p, -7-5p and -1296 also shared several common targets [Cold shock domain containing E1 (CSDE1), Hyaluronan synthase 2 (HAS2) and Testis development related protein (TDRP)].	('Cold shock domain containing E1', 'Gene', '7812', (78, 109))	('has-miRNA-190a', 'Var', (0, 14))	('CSDE1', 'Gene', (111, 116))	('CSDE1', 'Gene', '7812', (111, 116))	('Testis development', 'biological_process', 'GO:0008584', ('152', '170'))	('Cold shock domain containing E1', 'Gene', (78, 109))	('Testis development related protein', 'Gene', '157695', (152, 186))	('Testis development related protein', 'Gene', (152, 186))	('Hyaluronan synthase 2', 'Gene', '3037', (119, 140))	('shock', 'Phenotype', 'HP:0031273', (83, 88))	('TDRP', 'Gene', '157695', (188, 192))	('HAS2', 'Gene', (142, 146))	('HAS2', 'Gene', '3037', (142, 146))	('Hyaluronan synthase 2', 'Gene', (119, 140))	('TDRP', 'Gene', (188, 192))	('protein', 'cellular_component', 'GO:0003675', ('179', '186'))
1294	26310847	Briefly, Cofilin phosphorylation was increased in HEK-293FLG-LIX1L cells compared with HEK-293FLG cells, while Cofilin phosphorylation was decreased in HEK-293FLG-LIX1L cells treated with PY136 (HEK-293FLG-LIX1L/PY136 cells) compared with HEK-293FLG-LIX1L cells.	('PY136', 'Chemical', '-', (212, 217))	('HEK-293', 'CellLine', 'CVCL:0045', (87, 94))	('PY136', 'Chemical', '-', (188, 193))	('HEK-293', 'CellLine', 'CVCL:0045', (195, 202))	('Cofilin', 'Gene', '1072', (111, 118))	('phosphorylation', 'biological_process', 'GO:0016310', ('17', '32'))	('Cofilin', 'Gene', '1072', (9, 16))	('Cofilin', 'Gene', (111, 118))	('Cofilin', 'Gene', (9, 16))	('PY136', 'Var', (188, 193))	('HEK-293', 'CellLine', 'CVCL:0045', (152, 159))	('HEK-293', 'CellLine', 'CVCL:0045', (50, 57))	('phosphorylation', 'biological_process', 'GO:0016310', ('119', '134'))	('decreased', 'NegReg', (139, 148))	('HEK-293FLG-LIX1L', 'Var', (50, 66))	('HEK-293', 'CellLine', 'CVCL:0045', (239, 246))	('increased', 'PosReg', (37, 46))
1296	26310847	Phosphorylated Cofilin levels were increased in HEK-293FLG-LIX1L cells compared with HEK-293FLG cells, while phosphorylated Cofilin levels decreased after treatment with PY136.	('increased', 'PosReg', (35, 44))	('Cofilin', 'Gene', '1072', (124, 131))	('Cofilin', 'Gene', (124, 131))	('HEK-293', 'CellLine', 'CVCL:0045', (48, 55))	('HEK-293FLG-LIX1L', 'Var', (48, 64))	('Cofilin', 'Gene', '1072', (15, 22))	('HEK-293', 'CellLine', 'CVCL:0045', (85, 92))	('Cofilin', 'Gene', (15, 22))	('PY136', 'Chemical', '-', (170, 175))	('PY136', 'Var', (170, 175))
1298	26310847	5D, LIX1L knockdown decreased Cofilin phosphorylation (Ser3) in MKN45 cells.	('decreased', 'NegReg', (20, 29))	('LIX1L', 'Gene', (4, 9))	('Cofilin', 'Gene', '1072', (30, 37))	('Ser', 'cellular_component', 'GO:0005790', ('55', '58'))	('Cofilin', 'Gene', (30, 37))	('Ser3', 'Chemical', '-', (55, 59))	('phosphorylation', 'biological_process', 'GO:0016310', ('38', '53'))	('knockdown', 'Var', (10, 19))
1300	26310847	We also identified the tyrosine kinase for the phosphorylation of Tyr136 of LIX1L using a protein kinase assay.	('Tyr136', 'Chemical', '-', (66, 72))	('Tyr136', 'Var', (66, 72))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('phosphorylation', 'biological_process', 'GO:0016310', ('47', '62'))	('tyrosine', 'Chemical', 'MESH:D014443', (23, 31))	('LIX1L', 'Gene', (76, 81))
1306	26310847	Because the [Y136] site was mutated to a phenylalanine in this peptide, the counts observed indicate the level of phosphorylation at the [Y139] site only.	('phosphorylation', 'MPA', (114, 129))	('[Y136]', 'Var', (12, 18))	('Y136', 'Chemical', '-', (13, 17))	('phosphorylation', 'biological_process', 'GO:0016310', ('114', '129'))	('phenylalanine', 'Chemical', 'MESH:D010649', (41, 54))
1307	26310847	The difference in counts between the [Y136] WT and [F136] MT indicate the level of phosphorylation of each kinase specifically at the [Y136] site.	('Y136', 'Chemical', '-', (38, 42))	('phosphorylation', 'MPA', (83, 98))	('phosphorylation', 'biological_process', 'GO:0016310', ('83', '98'))	('[F136]', 'Var', (51, 57))	('Y136', 'Chemical', '-', (135, 139))	('[Y136]', 'Var', (37, 43))
1308	26310847	Moreover, the colony-formation counts and the phosphorylation levels were decreased in HEK-293FLG-LIX1L (Y136F) cells (Fig.	('phosphorylation', 'biological_process', 'GO:0016310', ('46', '61'))	('phosphorylation levels', 'MPA', (46, 68))	('Y136F', 'Var', (105, 110))	('Y136F', 'Mutation', 'p.Y136F', (105, 110))	('formation', 'biological_process', 'GO:0009058', ('21', '30'))	('colony-formation counts', 'CPA', (14, 37))	('decreased', 'NegReg', (74, 83))
1309	26310847	The colony counts of HEK-293FLG-LIX1L (Y136F) cells were lower than those of HEK-293FLG and HEK-293FLG-LIX1L (Y136) cells.	('Y136F', 'Var', (39, 44))	('Y136', 'Chemical', '-', (110, 114))	('Y136F', 'Mutation', 'p.Y136F', (39, 44))	('HEK-293', 'CellLine', 'CVCL:0045', (77, 84))	('HEK-293', 'CellLine', 'CVCL:0045', (92, 99))	('Y136', 'Chemical', '-', (39, 43))	('colony counts', 'CPA', (4, 17))	('HEK-293', 'CellLine', 'CVCL:0045', (21, 28))	('lower', 'NegReg', (57, 62))
1310	26310847	The level of phosphorylated LIX1L was also decreased in HEK-293FLG-LIX1L (Y136F) cells compared with HEK-293FLG-LIX1L (Y136) cells.	('level of phosphorylated', 'MPA', (4, 27))	('Y136F', 'Var', (74, 79))	('Y136F', 'Mutation', 'p.Y136F', (74, 79))	('HEK-293FLG-LIX1L (Y136F', 'Var', (56, 79))	('Y136', 'Chemical', '-', (74, 78))	('Y136', 'Chemical', '-', (119, 123))	('decreased', 'NegReg', (43, 52))
1311	26310847	Moreover, the knockdown of ROS1, the putative LIX1L kinase, reduced LIX1L phosphorylation in HEK-293FLG-LIX1L (Y136) cells.	('LIX1L phosphorylation', 'MPA', (68, 89))	('ROS1', 'Gene', (27, 31))	('Y136', 'Chemical', '-', (111, 115))	('ROS1', 'Gene', '6098', (27, 31))	('reduced', 'NegReg', (60, 67))	('knockdown', 'Var', (14, 23))	('phosphorylation', 'biological_process', 'GO:0016310', ('74', '89'))
1312	26310847	Both HEK-293FLG and HEK-293FLG-LIX1L (Y136) cells were transfected with ROS1 shRNA-#1 or -#2, and the phosphorylation level of LIX1L was assessed on day 3 post-transfection.	('Y136', 'Chemical', '-', (38, 42))	('HEK-293', 'CellLine', 'CVCL:0045', (20, 27))	('HEK-293FLG-LIX1L', 'Var', (20, 36))	('ROS1', 'Gene', (72, 76))	('HEK-293', 'CellLine', 'CVCL:0045', (5, 12))	('ROS1', 'Gene', '6098', (72, 76))	('phosphorylation', 'biological_process', 'GO:0016310', ('102', '117'))
1314	26310847	ROS1 knockdown in HEK-293FLG-LIX1L (Y136) cells significantly reduced LIX1L phosphorylation compared with both untreated HEK-293FLG cells and HEK-293FLG-LIX1L cells transfected with scrambled shRNA (Fig.	('HEK-293', 'CellLine', 'CVCL:0045', (18, 25))	('ROS1', 'Gene', (0, 4))	('HEK-293', 'CellLine', 'CVCL:0045', (142, 149))	('knockdown', 'Var', (5, 14))	('HEK-293', 'CellLine', 'CVCL:0045', (121, 128))	('phosphorylation', 'biological_process', 'GO:0016310', ('76', '91'))	('ROS1', 'Gene', '6098', (0, 4))	('Y136', 'Chemical', '-', (36, 40))	('LIX1L phosphorylation', 'MPA', (70, 91))	('reduced', 'NegReg', (62, 69))
1315	26310847	These results showed that ROS1 is the main regulator of Tyr136 phosphorylation in LIX1L, and the phosphorylation of Tyr136 in LIX1L plays an important role in cancer cell proliferation.	('cancer', 'Disease', (159, 165))	('phosphorylation', 'biological_process', 'GO:0016310', ('63', '78'))	('LIX1L', 'Gene', (82, 87))	('ROS1', 'Gene', (26, 30))	('cell proliferation', 'biological_process', 'GO:0008283', ('166', '184'))	('Tyr136', 'Chemical', '-', (56, 62))	('ROS1', 'Gene', '6098', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('plays', 'Reg', (132, 137))	('Tyr136', 'Chemical', '-', (116, 122))	('Tyr136', 'Var', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('phosphorylation', 'biological_process', 'GO:0016310', ('97', '112'))
1332	26310847	miRNA-520a-5p was highly expressed in mature ovarian teratoma tissues, and the function of this molecule remains unknown.	('ovarian teratoma', 'Disease', 'MESH:C562731', (45, 61))	('mature ovarian teratoma', 'Phenotype', 'HP:0025274', (38, 61))	('ovarian teratoma', 'Disease', (45, 61))	('miRNA-520a-5p', 'Var', (0, 13))	('ovarian teratoma', 'Phenotype', 'HP:0012226', (45, 61))	('teratoma', 'Phenotype', 'HP:0009792', (53, 61))
1334	26310847	miRNA-216b inhibits the proliferation, migration and invasion of HCC through the regulation of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2).	('IGF2BP2', 'Gene', (148, 155))	('mRNA-binding', 'molecular_function', 'GO:0003729', ('124', '136'))	('proliferation', 'CPA', (24, 37))	('regulation', 'biological_process', 'GO:0065007', ('81', '91'))	('invasion', 'CPA', (53, 61))	('inhibits', 'NegReg', (11, 19))	('IGF2BP2', 'Gene', '319765', (148, 155))	('migration', 'CPA', (39, 48))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('HCC', 'Disease', (65, 68))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('95', '121'))	('miRNA-216b', 'Var', (0, 10))	('miRNA-216b', 'Chemical', '-', (0, 10))	('insulin-like growth factor 2 mRNA-binding protein 2', 'Gene', '319765', (95, 146))
1338	26310847	miRNA-7-5p, a novel tumor suppressor in melanoma, acts at least in part through the inhibition of IRS-2 expression and oncogenic Akt signaling.	('IRS-2', 'Gene', (98, 103))	('inhibition', 'NegReg', (84, 94))	('tumor suppressor', 'biological_process', 'GO:0051726', ('20', '36'))	('miRNA-7-5p', 'Var', (0, 10))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Disease', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('20', '36'))	('expression', 'MPA', (104, 114))	('Akt signaling', 'biological_process', 'GO:0043491', ('129', '142'))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('IRS-2', 'Gene', '384783', (98, 103))	('oncogenic Akt signaling', 'Pathway', (119, 142))	('miRNA-7-5p', 'Chemical', '-', (0, 10))	('tumor', 'Disease', (20, 25))
1345	26310847	The silencing of the CSDE1 gene significantly increases the sensitivity to platinum based chemotherapy in ovarian cancer cell lines.	('CSDE1', 'Gene', (21, 26))	('CSDE1', 'Gene', '7812', (21, 26))	('ovarian cancer', 'Disease', 'MESH:D010051', (106, 120))	('increases', 'PosReg', (46, 55))	('ovarian cancer', 'Disease', (106, 120))	('platinum', 'Chemical', 'MESH:D010984', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('sensitivity to platinum based chemotherapy', 'MPA', (60, 102))	('silencing', 'Var', (4, 13))	('ovarian cancer', 'Phenotype', 'HP:0100615', (106, 120))
1349	26310847	ROS1 (ROS1 proto-oncogene receptor tyrosine kinase) is activated through chromosomal rearrangement in a variety of human cancers, including glioblastoma multiforme, non-small-cell lung cancer (NSCLC), cholangiocarcinoma, gastric cancer, and ovarian cancer.	('ROS1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ovarian cancer', 'Disease', 'MESH:D010051', (241, 255))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('chromosomal rearrangement', 'Var', (73, 98))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (201, 219))	('cancers', 'Disease', (121, 128))	('gastric cancer', 'Disease', (221, 235))	('ROS1', 'Gene', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('glioblastoma multiforme', 'Disease', (140, 163))	('cholangiocarcinoma', 'Disease', (201, 219))	('glioblastoma', 'Phenotype', 'HP:0012174', (140, 152))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (140, 163))	('lung cancer', 'Disease', (180, 191))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (201, 219))	('ovarian cancer', 'Disease', (241, 255))	('tyrosine', 'Chemical', 'MESH:D014443', (35, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (241, 255))	('gastric cancer', 'Disease', 'MESH:D013274', (221, 235))	('ROS1', 'Gene', '6098', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('NSCLC', 'Disease', 'MESH:D002289', (193, 198))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('lung cancer', 'Disease', 'MESH:D008175', (180, 191))	('ROS1', 'Gene', '6098', (6, 10))	('human', 'Species', '9606', (115, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (221, 235))	('NSCLC', 'Disease', (193, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('activated', 'PosReg', (55, 64))
1356	26310847	We showed that PY136 inhibited cancer cell proliferation by inhibiting the phosphorylation of Tyr136 of the LIX1L protein in vitro and in vivo, and ROS1 phosphorylated LIX1L protein to result in cell proliferation.	('Tyr136', 'Chemical', '-', (94, 100))	('inhibited', 'NegReg', (21, 30))	('PY136', 'Chemical', '-', (15, 20))	('LIX1L', 'Gene', (108, 113))	('cell proliferation', 'biological_process', 'GO:0008283', ('38', '56'))	('PY136', 'Var', (15, 20))	('inhibiting', 'NegReg', (60, 70))	('result in', 'Reg', (185, 194))	('ROS1', 'Gene', (148, 152))	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cell proliferation', 'biological_process', 'GO:0008283', ('195', '213'))	('phosphorylation', 'biological_process', 'GO:0016310', ('75', '90'))	('phosphorylation', 'MPA', (75, 90))	('cell proliferation', 'CPA', (195, 213))	('protein', 'Protein', (114, 121))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('ROS1', 'Gene', '6098', (148, 152))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))
1375	26310847	The knockdown efficiency was consistently 65% to 80%, determined through RT-PCR measurement of LIX1L and ROS1 mRNA.	('knockdown', 'Var', (4, 13))	('ROS1', 'Gene', '6098', (105, 109))	('ROS1', 'Gene', (105, 109))
1422	25993003	In Capan-1 cells, PPIs inhibited recovery of intracellular pH from acidosis.	('acidosis', 'Disease', 'MESH:D000138', (67, 75))	('PPIs', 'Var', (18, 22))	('pH', 'Gene', '2821', (59, 61))	('inhibited', 'NegReg', (23, 32))	('acidosis', 'Disease', (67, 75))	('acidosis', 'Phenotype', 'HP:0001941', (67, 75))	('intracellular', 'cellular_component', 'GO:0005622', ('45', '58'))	('Capan-1', 'CellLine', 'CVCL:0237', (3, 10))
1423	25993003	Furthermore, in rats treated with PPIs, pancreatic secretion was inhibited but concentrations of major ions in secretion follow similar excretory curves in control and PPI treated animals.	('pancreatic secretion', 'Disease', 'MESH:D010195', (40, 60))	('rat', 'Species', '10116', (16, 19))	('secretion', 'biological_process', 'GO:0046903', ('111', '120'))	('PPI', 'biological_process', 'GO:0060134', ('168', '171'))	('secretion', 'biological_process', 'GO:0046903', ('51', '60'))	('rats', 'Species', '10116', (16, 20))	('inhibited', 'NegReg', (65, 74))	('PPIs', 'Var', (34, 38))	('rat', 'Species', '10116', (86, 89))	('pancreatic secretion', 'Disease', (40, 60))
1436	25993003	In addition to NBCs and NHE, earlier studies have shown vacuolar H+ ATPase (V-ATPase) activity on the basolateral membrane of pancreatic ducts by intracellular pH (pHi) measurements and use of the V-ATPase inhibitor bafilomycin A1 Nevertheless, whether the V-ATPase plays a significant role in pancreatic HCO3 - secretion is not clarified, as for example in guinea pig pancreatic ducts bafilomycin A1 could not inhibit agonist-stimulated HCO3 - and fluid secretion.	('V-ATPase', 'cellular_component', 'GO:0008245', ('257', '265'))	('ATPase', 'Gene', (68, 74))	('pancreatic', 'Disease', 'MESH:D010195', (369, 379))	('V-ATPase', 'cellular_component', 'GO:0000219', ('197', '205'))	('bafilomycin A1', 'Var', (386, 400))	('V-ATPase', 'cellular_component', 'GO:0000219', ('257', '265'))	('intracellular', 'cellular_component', 'GO:0005622', ('146', '159'))	('ATPase', 'Gene', '1769', (68, 74))	('V-ATPase', 'cellular_component', 'GO:0000219', ('76', '84'))	('pancreatic duct', 'Disease', 'MESH:D021441', (126, 141))	('pHi', 'Gene', '2821', (164, 167))	('ATPase', 'Gene', (199, 205))	('pancreatic', 'Disease', (369, 379))	('ATPase) activity', 'molecular_function', 'GO:0016887', ('78', '94'))	('V-ATPase', 'cellular_component', 'GO:0008245', ('197', '205'))	('inhibit', 'NegReg', (411, 418))	('pH', 'Gene', '2821', (160, 162))	('ATPase', 'Gene', '1769', (199, 205))	('bafilomycin', 'Chemical', '-', (386, 397))	('pancreatic duct', 'Disease', (126, 141))	('secretion', 'biological_process', 'GO:0046903', ('455', '464'))	('pancreatic', 'Disease', 'MESH:D010195', (126, 136))	('pancreatic', 'Disease', 'MESH:D010195', (294, 304))	('ATPase', 'Gene', (259, 265))	('pancreatic duct', 'Disease', 'MESH:D021441', (369, 384))	('membrane', 'cellular_component', 'GO:0016020', ('114', '122'))	('HCO3', 'Chemical', 'MESH:D001639', (305, 309))	('secretion', 'biological_process', 'GO:0046903', ('312', '321'))	('pH', 'Gene', '2821', (164, 166))	('ATPase', 'Gene', (78, 84))	('bafilomycin', 'Chemical', '-', (216, 227))	('ATPase', 'Gene', '1769', (259, 265))	('pHi', 'Gene', (164, 167))	('HCO3', 'Chemical', 'MESH:D001639', (438, 442))	('guinea pig', 'Species', '10141', (358, 368))	('V-ATPase', 'cellular_component', 'GO:0008245', ('76', '84'))	('pancreatic duct', 'Disease', (369, 384))	('ATPase', 'Gene', '1769', (78, 84))	('pancreatic', 'Disease', (126, 136))	('pancreatic', 'Disease', (294, 304))
1460	25993003	Briefly, Capan-1 cells grown on standard Ibidi mu-Dish35mm were loaded with 2 muM BCECF/AM (Invitrogen) for 20-30 min; thereafter they were superfused at 2 ml/min, at 37 C. Control perfusate had the following composition (in mM): Na+ 145, Cl- 145, K+ 4, Ca2+ 1.5, Mg2+ 1, phosphate 2, HEPES 10 glucose 5; pH was 7.4.	('muM', 'Gene', (78, 81))	('Ca2+', 'Chemical', 'MESH:D000069285', (254, 258))	('Capan-1', 'CellLine', 'CVCL:0237', (9, 16))	('Na+ 145', 'Var', (230, 237))	('BCECF', 'Chemical', 'MESH:C043829', (82, 87))	('glucose', 'Chemical', 'MESH:D005947', (294, 301))	('pH', 'Gene', '2821', (305, 307))	('Mg2', 'Chemical', '-', (264, 267))	('HEPES', 'Chemical', 'MESH:D006531', (285, 290))	('muM', 'Gene', '56925', (78, 81))	('K+ 4', 'Var', (248, 252))	('phosphate', 'Chemical', 'MESH:D010710', (272, 281))
1466	25993003	Tissues were exposed to ammonium pulses (2-3 min), then ammonium was removed, and pHi recovery rates from acidosis were determined from the initial slopes of pHi changes and expressed as dpH/dt (i.e.	('pHi', 'Gene', '2821', (158, 161))	('ammonium', 'Chemical', 'MESH:D064751', (24, 32))	('ammonium', 'Chemical', 'MESH:D064751', (56, 64))	('pHi', 'Gene', (158, 161))	('acidosis', 'Disease', 'MESH:D000138', (106, 114))	('rat', 'Species', '10116', (95, 98))	('pHi', 'Gene', (82, 85))	('dpH', 'Chemical', 'MESH:D010672', (187, 190))	('dt', 'Chemical', 'MESH:D013936', (191, 193))	('acidosis', 'Phenotype', 'HP:0001941', (106, 114))	('acidosis', 'Disease', (106, 114))	('changes', 'Var', (162, 169))	('pHi', 'Gene', '2821', (82, 85))
1512	25993003	Capan-1 and PANC-1 cells express functional CFTR, while CFPAC-1 cells have F508 deletion in CFTR and thus the protein expression and function are defect.	('function', 'MPA', (133, 141))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('protein', 'Protein', (110, 117))	('PANC-1', 'CellLine', 'CVCL:0480', (12, 18))	('F508 deletion', 'Var', (75, 88))	('CFTR', 'Gene', '1080', (44, 48))	('CFTR', 'Gene', '1080', (92, 96))	('CFPAC-1', 'CellLine', 'CVCL:1119', (56, 63))	('defect', 'NegReg', (146, 152))	('Capan-1', 'CellLine', 'CVCL:0237', (0, 7))	('CFTR', 'Gene', (44, 48))	('CFTR', 'Gene', (92, 96))
1535	25993003	The gastric H+/K+ pump inhibitor omeprazole inhibited 75% of the Na+ independent pHi recovery (n = 6), while SCH28080 reduced the Na+ independent pHi recovery by 52% (n = 5).	('SCH28080', 'Var', (109, 117))	('pHi', 'Gene', (81, 84))	('SCH28080', 'Chemical', 'MESH:C035235', (109, 117))	('inhibited', 'NegReg', (44, 53))	('pHi', 'Gene', '2821', (146, 149))	('omeprazole', 'Chemical', 'MESH:D009853', (33, 43))	('pHi', 'Gene', '2821', (81, 84))	('pHi', 'Gene', (146, 149))
1536	25993003	In addition, PPIs also reduced pHi recovery when cells were returned to control Na+ containing buffer (Fig 4 phase III vs.	('reduced', 'NegReg', (23, 30))	('pHi', 'Gene', '2821', (31, 34))	('PPIs', 'Var', (13, 17))	('pHi', 'Gene', (31, 34))
1552	25993003	In order to check the possible contribution of non-gastric H+/K+ pump to pancreatic secretion, the acute effects of SCH28080 were tested.	('SCH28080', 'Var', (116, 124))	('SCH28080', 'Chemical', 'MESH:C035235', (116, 124))	('pancreatic secretion', 'Disease', 'MESH:D010195', (73, 93))	('pancreatic secretion', 'Disease', (73, 93))	('secretion', 'biological_process', 'GO:0046903', ('84', '93'))
1553	25993003	SCH28080 inhibits gastric pump and it has been reported that in high doses it can also inhibit non-gastric H+/K+ pumps.	('SCH28080', 'Var', (0, 8))	('non-gastric H+/K+ pumps', 'MPA', (95, 118))	('gastric pump', 'MPA', (18, 30))	('inhibits', 'NegReg', (9, 17))	('SCH28080', 'Chemical', 'MESH:C035235', (0, 8))	('inhibit', 'NegReg', (87, 94))
1555	25993003	There seems to be more pronounced inhibition of secretion with SCH28080 than with omeprazole compared to their respective controls.	('inhibition of secretion', 'biological_process', 'GO:0051048', ('34', '57'))	('omeprazole', 'Chemical', 'MESH:D009853', (82, 92))	('secretion', 'MPA', (48, 57))	('inhibition', 'NegReg', (34, 44))	('SCH28080', 'Var', (63, 71))	('SCH28080', 'Chemical', 'MESH:C035235', (63, 71))
1556	25993003	Interestingly, given the dose of inhibitors used in our studies, we would have expected weaker inhibition by SCH28080, due to higher expected ED50 values.	('SCH28080', 'Var', (109, 117))	('SCH28080', 'Chemical', 'MESH:C035235', (109, 117))	('higher', 'PosReg', (126, 132))	('ED50 values', 'MPA', (142, 153))	('weaker', 'NegReg', (88, 94))
1568	25993003	Also with SCH28080, HCO3 - concentrations decreased in low secretory rates.	('rat', 'Species', '10116', (34, 37))	('decreased', 'NegReg', (42, 51))	('SCH28080', 'Var', (10, 18))	('low secretory rates', 'MPA', (55, 74))	('SCH28080', 'Chemical', 'MESH:C035235', (10, 18))	('rat', 'Species', '10116', (69, 72))	('HCO3', 'Chemical', 'MESH:D001639', (20, 24))	('HCO3 - concentrations', 'MPA', (20, 41))
1603	25993003	Additionally, several mucin genes have been identified in pancreatic duct cells and pancreatic mucins would be relevant in epithelial protection, and altered expression pattern of mucins is one of the important factors in development and drug resistance in pancreatic cancer.	('pancreatic', 'Disease', 'MESH:D010195', (84, 94))	('pancreatic cancer', 'Disease', (257, 274))	('expression', 'MPA', (158, 168))	('pancreatic', 'Disease', (84, 94))	('pancreatic cancer', 'Disease', 'MESH:D010190', (257, 274))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('drug resistance', 'Phenotype', 'HP:0020174', (238, 253))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (257, 274))	('pancreatic', 'Disease', 'MESH:D010195', (58, 68))	('pancreatic', 'Disease', 'MESH:D010195', (257, 267))	('drug resistance', 'biological_process', 'GO:0009315', ('238', '253'))	('altered', 'Var', (150, 157))	('drug resistance', 'biological_process', 'GO:0042493', ('238', '253'))	('pancreatic', 'Disease', (58, 68))	('pancreatic duct', 'Disease', (58, 73))	('pancreatic duct', 'Disease', 'MESH:D021441', (58, 73))	('pancreatic', 'Disease', (257, 267))
1606	25993003	The observation that PPIs and P-CABs inhibit secretin-evoked pancreatic secretion in in vivo rat studies shows that H+/K+-pumps are in general involved in pancreatic duct secretion.	('secretin', 'molecular_function', 'GO:0008565', ('45', '53'))	('pancreatic secretion', 'Disease', 'MESH:D010195', (61, 81))	('secretion', 'biological_process', 'GO:0046903', ('171', '180'))	('P-CABs', 'Var', (30, 36))	('pancreatic secretion', 'Disease', (61, 81))	('inhibit', 'NegReg', (37, 44))	('pancreatic duct secretion', 'Disease', 'MESH:D021441', (155, 180))	('secretin', 'molecular_function', 'GO:0046659', ('45', '53'))	('secretion', 'biological_process', 'GO:0046903', ('72', '81'))	('PPIs', 'Var', (21, 25))	('pancreatic duct secretion', 'Disease', (155, 180))	('rat', 'Species', '10116', (93, 96))
1608	25993003	Omeprazole, the acid-activated pro-drug, would inhibit the gastric pump, while SCH28080, which competitively binds to the K+ site, could, most likely, inhibit both gastric and non-gastric pumps and seems more effective given the dose used in our experiments and published ED50 values.	('Omeprazole', 'Chemical', 'MESH:D009853', (0, 10))	('gastric pump', 'MPA', (59, 71))	('inhibit', 'NegReg', (47, 54))	('SCH28080', 'Var', (79, 87))	('SCH28080', 'Chemical', 'MESH:C035235', (79, 87))	('inhibit', 'NegReg', (151, 158))
1609	25993003	In pHi studies, we acidified the pro-drug and thus the activated form of omeprazole would be formed.	('pHi', 'Gene', (3, 6))	('pHi', 'Gene', '2821', (3, 6))	('omeprazole', 'Chemical', 'MESH:D009853', (73, 83))	('acidified', 'Var', (19, 28))
1612	25993003	Clearly, the first was the case and pancreatic secretion was further reduced by long-term PPI treatment.	('reduced', 'NegReg', (69, 76))	('secretion', 'biological_process', 'GO:0046903', ('47', '56'))	('PPI', 'Var', (90, 93))	('pancreatic secretion', 'Disease', 'MESH:D010195', (36, 56))	('pancreatic secretion', 'Disease', (36, 56))	('PPI', 'biological_process', 'GO:0060134', ('90', '93'))
1626	25993003	Our acute and long-term experiments on rats show that pancreatic secretion is significantly inhibited by PPIs.	('rats', 'Species', '10116', (39, 43))	('inhibited', 'NegReg', (92, 101))	('PPIs', 'Var', (105, 109))	('pancreatic secretion', 'Disease', 'MESH:D010195', (54, 74))	('secretion', 'biological_process', 'GO:0046903', ('65', '74'))	('pancreatic secretion', 'Disease', (54, 74))
1779	33512745	lncRNA NKX2-1-AS1 (NKX2-1 antisense RNA 1) plays a pivotal role in cancer progression and metastasis; however, the contribution of aberrant expression of NKX2-1-AS1 and the mechanism by which it functions as a competing endogenous RNA (ceRNA) in gastric cancer (GC) remains elusive.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Disease', (67, 73))	('GC', 'Gene', '14473', (262, 264))	('RNA', 'cellular_component', 'GO:0005562', ('36', '39'))	('NKX2-1 antisense RNA 1', 'Gene', (19, 41))	('gastric cancer', 'Disease', (246, 260))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('NKX2-1 antisense RNA 1', 'Gene', '100506237', (19, 41))	('gastric cancer', 'Disease', 'MESH:D013274', (246, 260))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('GC', 'Phenotype', 'HP:0012126', (262, 264))	('cancer', 'Disease', (254, 260))	('aberrant', 'Var', (131, 139))	('RNA', 'cellular_component', 'GO:0005562', ('231', '234'))	('antisense RNA', 'molecular_function', 'GO:0009388', ('26', '39'))	('gastric cancer', 'Phenotype', 'HP:0012126', (246, 260))
1782	33512745	Overexpression of NKX2-1-AS1 was significantly associated with tumor progression and enhanced angiogenesis.	('tumor', 'Disease', (63, 68))	('angiogenesis', 'CPA', (94, 106))	('angiogenesis', 'biological_process', 'GO:0001525', ('94', '106'))	('enhanced', 'PosReg', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('NKX2-1-AS1', 'Var', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('associated', 'Reg', (47, 57))
1784	33512745	RIP and dual-luciferase assays revealed that the microRNA miR-145-5p is a direct target of NKX2-1-AS1 and that NKX2-1-AS1 serves as a ceRNA to sponge miRNA and regulate angiogenesis in GC.	('regulate', 'Reg', (160, 168))	('GC', 'Phenotype', 'HP:0012126', (185, 187))	('angiogenesis', 'CPA', (169, 181))	('angiogenesis', 'biological_process', 'GO:0001525', ('169', '181'))	('miR-145-5p', 'Chemical', '-', (58, 68))	('NKX2-1-AS1', 'Var', (111, 121))	('GC', 'Gene', '14473', (185, 187))
1787	33512745	Collectively, NKX2-1-AS1 functions as a ceRNA to miR-145-5p and promotes tumor progression and angiogenesis by activating the VEGFR-2 signaling pathway via SERPINE1.	('VEGFR-2 signaling pathway', 'biological_process', 'GO:0036324', ('126', '151'))	('promotes', 'PosReg', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('angiogenesis', 'biological_process', 'GO:0001525', ('95', '107'))	('angiogenesis', 'CPA', (95, 107))	('VEGFR-2', 'Gene', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('activating', 'PosReg', (111, 121))	('tumor', 'Disease', (73, 78))	('NKX2-1-AS1', 'Var', (14, 24))	('miR-145-5p', 'Chemical', '-', (49, 59))	('VEGFR-2', 'Gene', '3791', (126, 133))
1788	33512745	This study revealed that NKX2-1-AS1 might serve as an independent prognostic biomarker in gastric cancer (GC).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('GC', 'Phenotype', 'HP:0012126', (106, 108))	('NKX2-1-AS1', 'Var', (25, 35))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('GC', 'Gene', '14473', (106, 108))	('gastric cancer', 'Disease', (90, 104))
1789	33512745	NKX2-1-AS1 promotes cell proliferation and tumor angiogenesis in GC.	('GC', 'Gene', '14473', (65, 67))	('cell proliferation', 'CPA', (20, 38))	('GC', 'Phenotype', 'HP:0012126', (65, 67))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('angiogenesis', 'biological_process', 'GO:0001525', ('49', '61'))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('NKX2-1-AS1', 'Var', (0, 10))	('cell proliferation', 'biological_process', 'GO:0008283', ('20', '38'))	('promotes', 'PosReg', (11, 19))	('tumor', 'Disease', (43, 48))
1798	33512745	Moreover, the dysregulated expression of lncRNAs has been implicated in multiple cancer types and shown to be differentially expressed across various tumor differentiation stages.	('dysregulated', 'Var', (14, 26))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('expression', 'MPA', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('implicated', 'Reg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('lncRNAs', 'Gene', (41, 48))
1801	33512745	However, the contribution of aberrant expression of NKX2-1-AS1 in GC tumorigenesis and its prognostic relevance in GC remains elusive.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('GC', 'Phenotype', 'HP:0012126', (66, 68))	('GC', 'Gene', '14473', (115, 117))	('tumor', 'Disease', (69, 74))	('GC', 'Phenotype', 'HP:0012126', (115, 117))	('aberrant', 'Var', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('GC', 'Gene', '14473', (66, 68))	('NKX2-1-AS1', 'Gene', (52, 62))
1804	33512745	Aberrant expression of SERPINE1 has been observed in numerous cancer types and is associated with poor prognosis.	('Aberrant expression', 'Var', (0, 19))	('associated', 'Reg', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('observed', 'Reg', (41, 49))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('SERPINE1', 'Gene', (23, 31))
1807	33512745	Emerging studies have demonstrated that the inhibition of SERPINE1 with SK-216 (a specific PAL-1 inhibitor) can reduce the extent of angiogenesis in the tumors and suppress progression in vivo angiogenesis.	('inhibition', 'Var', (44, 54))	('PAL', 'molecular_function', 'GO:0004598', ('91', '94'))	('reduce', 'NegReg', (112, 118))	('SERPINE1', 'Protein', (58, 66))	('angiogenesis', 'biological_process', 'GO:0001525', ('133', '145'))	('SK-216', 'Gene', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('angiogenesis', 'biological_process', 'GO:0001525', ('193', '205'))	('SK-216', 'Chemical', 'MESH:C000589255', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('suppress', 'NegReg', (164, 172))
1809	33512745	Based on these findings, it was speculated that the aberrant expression of SERPINE1 might be associated with GC progression due to increased tumor angiogenesis promoted by SERPINE1.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('increased', 'PosReg', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('associated', 'Reg', (93, 103))	('aberrant expression', 'Var', (52, 71))	('GC', 'Gene', '14473', (109, 111))	('angiogenesis', 'biological_process', 'GO:0001525', ('147', '159'))	('SERPINE1', 'Gene', (75, 83))	('GC', 'Phenotype', 'HP:0012126', (109, 111))
1845	33512745	At 48 h post-transfection, cells were incubated in 2 mug/mL puromycin for 2 weeks for selecting transfected cells with stable knockdown or overexpression of NKX2-1-AS1.	('knockdown', 'Var', (126, 135))	('puromycin', 'Chemical', 'MESH:D011691', (60, 69))	('overexpression', 'PosReg', (139, 153))	('mug', 'molecular_function', 'GO:0043739', ('53', '56'))
1869	33512745	The mutant NKX2-1-AS1 containing point mutations of the miR-145-5p seed region binding site was specifically synthesized and inserted into the above-mentioned vector, which was designated as pmirGLO-NKX2-1-AS1-Mut.	('miR-145-5p', 'Chemical', '-', (56, 66))	('point mutations', 'Var', (33, 48))	('miR-145-5p', 'Gene', (56, 66))	('binding', 'molecular_function', 'GO:0005488', ('79', '86'))	('NKX2-1-AS1', 'Gene', (11, 21))
1871	33512745	To confirm the direct interaction of miR-145-5p and SERPINE1, wild-type and mutant SERPINE1 3'-UTR fragments were amplified by qRT-PCR and cloned into the pmirGLO vector (Promega) using the one-step directed cloning kit (Novoprotein, Shanghai, China); the resultant vectors were designated as SERPINE1-WT and SERPINE1-Mut, respectively.	('SERPINE1', 'Gene', (83, 91))	('mutant', 'Var', (76, 82))	('miR-145-5p', 'Chemical', '-', (37, 47))
1882	33512745	Following primary antibodies were used: anti-SERPINE1 (cat.11907, CST; 1 : 1000), anti-VEGFR-2 (cat.9698, CST; 1 : 1000), anti-p-VEGFR-2 (cat.2478, CST; 1 : 1000), anti-PLC-lambda (cat.5690, CST; 1 : 1000), anti-p-PLC-lambda (cat.8713, CST; 1 : 1000), anti-Erk1/2 (cat.4695, CST; 1 : 1000), anti-p-Erk1/2 (cat.4370, CST; 1 : 1000), anti-P38 (cat.8690, CST; 1 : 1000), anti-p-P38 (cat.4511, CST; 1 : 1000), anti-FAK (cat.71433, CST; 1 : 1000), anti-p-FAK (cat.8556, CST; 1 : 1000), anti-Src (cat.2109, CST; 1 : 1000), anti-p-Src (cat.6943, CST; 1 : 1000), anti-Akt (cat.4685, CST; 1 : 1000), anti-p-Akt (cat.4060, CST; 1 : 1000), anti-GAPDH (cat.51332, CST; 1 : 1000), and HRP-conjugated goat anti-rabbit (cat.7074, CST; 1 : 3000) or anti-mouse IgG (cat.7076, CST; 1 : 3000) antibodies.	('Src', 'Gene', (524, 527))	('cat', 'molecular_function', 'GO:0004096', ('380', '383'))	('CST; 1', 'Gene', (613, 619))	('VEGFR-2', 'Gene', (87, 94))	('cat.7076', 'Var', (749, 757))	('CST; 1', 'Gene', '1469', (613, 619))	('CST; 1', 'Gene', (106, 112))	('Erk1/2', 'Gene', '5595;5594', (257, 263))	('CST; 1', 'Gene', '1469', (106, 112))	('P38', 'Gene', (337, 340))	('CST; 1', 'Gene', (539, 545))	('CST; 1', 'Gene', '1469', (191, 197))	('cat', 'molecular_function', 'GO:0004096', ('96', '99'))	('GAPDH', 'Gene', (634, 639))	('Akt', 'Gene', '207', (598, 601))	('Erk1/2', 'Gene', (298, 304))	('CST; 1', 'Gene', (759, 765))	('VEGFR-2', 'Gene', '3791', (87, 94))	('cat', 'molecular_function', 'GO:0004096', ('603', '606'))	('CST; 1', 'Gene', '1469', (759, 765))	('cat', 'molecular_function', 'GO:0004096', ('342', '345'))	('CST; 1', 'Gene', (465, 471))	('P38', 'Gene', '5594', (337, 340))	('CST; 1', 'Gene', '1469', (465, 471))	('FAK', 'Gene', '5747', (450, 453))	('FAK', 'Gene', '5747', (411, 414))	('CST; 1', 'Gene', (652, 658))	('Akt', 'Gene', (560, 563))	('CST; 1', 'Gene', (501, 507))	('CST; 1', 'Gene', '1469', (652, 658))	('CST; 1', 'Gene', (715, 721))	('CST; 1', 'Gene', '1469', (501, 507))	('CST; 1', 'Gene', '1469', (715, 721))	('cat', 'molecular_function', 'GO:0004096', ('55', '58'))	('cat', 'molecular_function', 'GO:0004096', ('641', '644'))	('CST; 1', 'Gene', '1469', (539, 545))	('CST; 1', 'Gene', (316, 322))	('CST; 1', 'Gene', '1469', (316, 322))	('CST; 1', 'Gene', (427, 433))	('cat', 'molecular_function', 'GO:0004096', ('491', '494'))	('VEGFR-2', 'Gene', (129, 136))	('cat', 'molecular_function', 'GO:0004096', ('416', '419'))	('CST; 1', 'Gene', (148, 154))	('cat', 'molecular_function', 'GO:0004096', ('705', '708'))	('cat.4060', 'Var', (603, 611))	('Src', 'Gene', '6714', (486, 489))	('CST; 1', 'Gene', (66, 72))	('Erk1', 'molecular_function', 'GO:0004707', ('298', '302'))	('CST; 1', 'Gene', '1469', (66, 72))	('CST; 1', 'Gene', (352, 358))	('PLC', 'cellular_component', 'GO:0042824', ('169', '172'))	('Erk1/2', 'Gene', '5595;5594', (298, 304))	('cat', 'molecular_function', 'GO:0004096', ('306', '309'))	('CST; 1', 'Gene', '1469', (352, 358))	('cat', 'molecular_function', 'GO:0004096', ('749', '752'))	('P38', 'Gene', (375, 378))	('Akt', 'Gene', '207', (560, 563))	('cat', 'molecular_function', 'GO:0004096', ('265', '268'))	('VEGFR-2', 'Gene', '3791', (129, 136))	('CST; 1', 'Gene', (390, 396))	('CST; 1', 'Gene', '1469', (390, 396))	('cat', 'molecular_function', 'GO:0004096', ('226', '229'))	('CST; 1', 'Gene', '1469', (427, 433))	('FAK', 'molecular_function', 'GO:0004717', ('411', '414'))	('CST; 1', 'Gene', (275, 281))	('Erk1/2', 'Gene', (257, 263))	('CST; 1', 'Gene', '1469', (275, 281))	('FAK', 'Gene', (411, 414))	('CST; 1', 'Gene', '1469', (148, 154))	('P38', 'Gene', '5594', (375, 378))	('PLC', 'cellular_component', 'GO:0042824', ('214', '217'))	('cat', 'molecular_function', 'GO:0004096', ('181', '184'))	('Erk1', 'molecular_function', 'GO:0004707', ('257', '261'))	('cat', 'molecular_function', 'GO:0004096', ('138', '141'))	('Src', 'Gene', '6714', (524, 527))	('cat', 'molecular_function', 'GO:0004096', ('455', '458'))	('GAPDH', 'Gene', '2597', (634, 639))	('CST; 1', 'Gene', (191, 197))	('cat', 'molecular_function', 'GO:0004096', ('565', '568'))	('Akt', 'Gene', (598, 601))	('CST; 1', 'Gene', (236, 242))	('Src', 'Gene', (486, 489))	('CST; 1', 'Gene', '1469', (236, 242))	('cat', 'molecular_function', 'GO:0004096', ('529', '532'))	('CST; 1', 'Gene', (575, 581))	('FAK', 'molecular_function', 'GO:0004717', ('450', '453'))	('FAK', 'Gene', (450, 453))	('CST; 1', 'Gene', '1469', (575, 581))	('cat.51332', 'Var', (641, 650))
1891	33512745	Although NKX2-1-AS1 expression was positively correlated with increased tumor size, higher infiltration of peritumoral tissues, peritoneum dissemination, and presence of distant metastasis, no statistically significant differences were observed among these subgroups (Additional file 2: Fig.	('distant metastasis', 'CPA', (170, 188))	('increased', 'PosReg', (62, 71))	('NKX2-1-AS1', 'Gene', (9, 19))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (72, 77))	('peritoneum dissemination', 'CPA', (128, 152))	('expression', 'Var', (20, 30))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('higher', 'PosReg', (84, 90))
1895	33512745	The Kaplan-Meier analysis revealed that patients with high expression of NKX2-1-AS1 in tumor tissues exhibited significantly shorter 5-year OS (40.52% vs. 58.89%, P = 0.0051) and 5-year PFS (36.67% vs. 59.93%, P = 0.0019), than patients with low NKX-2-1AS1 expression (Fig.	('NKX2-1-AS1', 'Gene', (73, 83))	('PFS', 'CPA', (186, 189))	('high expression', 'Var', (54, 69))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('patients', 'Species', '9606', (40, 48))	('tumor', 'Disease', (87, 92))	('patients', 'Species', '9606', (228, 236))	('NKX-2-1AS1', 'Gene', '100506237', (246, 256))	('shorter', 'NegReg', (125, 132))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('NKX-2-1AS1', 'Gene', (246, 256))
1901	33512745	Taken together, the results suggested that NKX2-1-AS1 and SERPINE1 may serve as potential prognostic predictors in GC patients.	('SERPINE1', 'Gene', (58, 66))	('GC', 'Gene', '14473', (115, 117))	('GC', 'Phenotype', 'HP:0012126', (115, 117))	('patients', 'Species', '9606', (118, 126))	('NKX2-1-AS1', 'Var', (43, 53))
1905	33512745	Cell count and colony formation assays indicated that NKX2-1-AS1 knockdown inhibited GC cell growth and colony formation (Fig.	('GC', 'Phenotype', 'HP:0012126', (85, 87))	('formation', 'biological_process', 'GO:0009058', ('22', '31'))	('cell growth', 'biological_process', 'GO:0016049', ('88', '99'))	('formation', 'biological_process', 'GO:0009058', ('111', '120'))	('inhibited', 'NegReg', (75, 84))	('NKX2-1-AS1', 'Gene', (54, 64))	('GC', 'Gene', '14473', (85, 87))	('knockdown', 'Var', (65, 74))	('colony formation', 'CPA', (104, 120))
1906	33512745	Furthermore, NKX2-1-AS1 knockdown suppressed the migratory and invasive characteristics of GC cells (Fig.	('suppressed', 'NegReg', (34, 44))	('GC', 'Gene', '14473', (91, 93))	('NKX2-1-AS1', 'Gene', (13, 23))	('GC', 'Phenotype', 'HP:0012126', (91, 93))	('knockdown', 'Var', (24, 33))
1907	33512745	Interestingly, there were no significant changes in the cell cycle and apoptosis rate of GC cells after NKX2-1-AS1 knockdown (Fig.	('NKX2-1-AS1', 'Gene', (104, 114))	('apoptosis rate', 'CPA', (71, 85))	('cell cycle', 'CPA', (56, 66))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('GC', 'Gene', '14473', (89, 91))	('cell cycle', 'biological_process', 'GO:0007049', ('56', '66'))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('GC', 'Phenotype', 'HP:0012126', (89, 91))	('knockdown', 'Var', (115, 124))
1910	33512745	As anticipated, xenograft tumors were significantly larger and heavier in the AGS-NKX2-1-AS1 group than in the negative control (NC) group (Fig.	('AGS', 'Chemical', 'MESH:D012834', (78, 81))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('heavier', 'PosReg', (63, 70))	('AGS-NKX2-1-AS1', 'Var', (78, 92))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('larger', 'PosReg', (52, 58))	('tumors', 'Disease', (26, 32))
1911	33512745	Similarly, NKX2-1-AS1 shRNA-transfected AGS cells were also injected subcutaneously in female nude mice, and it was observed that the tumors were significantly smaller and lighter in the shNKX2-1-AS1-1 group as compared to the shRNA-NC group (Fig.	('nude mice', 'Species', '10090', (94, 103))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('AGS', 'Chemical', 'MESH:D012834', (40, 43))	('lighter', 'NegReg', (172, 179))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('smaller', 'NegReg', (160, 167))	('shNKX2-1-AS1-1', 'Var', (187, 201))
1912	33512745	During necropsy, tumors appeared paler in the shNKX2-1-AS1-1 group than in the shRNA-NC group; based on this observation, we hypothesized that NKX2-1-AS1 expression might be associated with angiogenesis in GC tissue that may affect tumor growth and progression.	('GC', 'Gene', '14473', (206, 208))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('progression', 'CPA', (249, 260))	('angiogenesis', 'CPA', (190, 202))	('associated', 'Reg', (174, 184))	('tumor', 'Disease', (17, 22))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('GC', 'Phenotype', 'HP:0012126', (206, 208))	('angiogenesis', 'biological_process', 'GO:0001525', ('190', '202'))	('NKX2-1-AS1', 'Var', (143, 153))	('affect', 'Reg', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
1914	33512745	These findings strongly suggested that NKX2-1-AS1 was associated with enhanced growth and increased angiogenesis in GC in vivo.	('NKX2-1-AS1', 'Var', (39, 49))	('increased', 'PosReg', (90, 99))	('growth', 'CPA', (79, 85))	('angiogenesis', 'biological_process', 'GO:0001525', ('100', '112'))	('GC', 'Gene', '14473', (116, 118))	('enhanced', 'PosReg', (70, 78))	('angiogenesis', 'CPA', (100, 112))	('GC', 'Phenotype', 'HP:0012126', (116, 118))
1916	33512745	Based on our TCGA data analysis and validation of clinical samples, we hypothesized that NKX2-1-AS1, miR-145-5p, and SERPINE1 might be involved in a regulatory ceRNA network.	('miR-145-5p', 'Var', (101, 111))	('involved', 'Reg', (135, 143))	('miR-145-5p', 'Chemical', '-', (101, 111))	('NKX2-1-AS1', 'Var', (89, 99))
1921	33512745	Notably, NKX2-1-AS1 knockdown significantly upregulated the expression of miR-145-5p.	('expression', 'MPA', (60, 70))	('NKX2-1-AS1', 'Gene', (9, 19))	('upregulated', 'PosReg', (44, 55))	('miR-145-5p', 'Chemical', '-', (74, 84))	('miR-145-5p', 'Gene', (74, 84))	('knockdown', 'Var', (20, 29))
1922	33512745	Conversely, under- and overexpression of miR-145-5p markedly up- and downregulated the expression of NKX2-1-AS1, respectively (Fig.	('overexpression', 'PosReg', (23, 37))	('up-', 'PosReg', (61, 64))	('NKX2-1-AS1', 'Gene', (101, 111))	('downregulated', 'NegReg', (69, 82))	('expression', 'MPA', (87, 97))	('miR-145-5p', 'Var', (41, 51))	('miR-145-5p', 'Chemical', '-', (41, 51))
1924	33512745	To identify the direct evidence of interaction between NKX2-1-AS1 and miR-145-5p, NKX2-1-AS1 was subcloned with a wild-type (NKX2-1-AS1-WT) or mutated (NKX2-1-AS1-Mut) miR-145-5p binding site into a dual-luciferase reporter.	('miR-145-5p', 'Chemical', '-', (70, 80))	('binding', 'molecular_function', 'GO:0005488', ('179', '186'))	('binding', 'Interaction', (179, 186))	('interaction', 'Interaction', (35, 46))	('mutated', 'Var', (143, 150))	('miR-145-5p', 'Chemical', '-', (168, 178))
1927	33512745	Based on our RNAseq analysis and binding site predictions, miR-145-5p is predicted to bind to both SERPINE1 and MEST (Fig.	('miR-145-5p', 'Chemical', '-', (59, 69))	('MEST', 'Gene', (112, 116))	('MEST', 'Gene', '4232', (112, 116))	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('bind', 'Interaction', (86, 90))	('SERPINE1', 'Protein', (99, 107))	('miR-145-5p', 'Var', (59, 69))
1929	33512745	Luciferase assay revealed that miR-145-5p could directly bind to complementary sequences in the 3'-UTR of SERPINE1 (Fig.	('miR-145-5p', 'Chemical', '-', (31, 41))	('miR-145-5p', 'Var', (31, 41))	('bind', 'Interaction', (57, 61))	('SERPINE1', 'Gene', (106, 114))
1930	33512745	Consistently, the miR-145-5p inhibitor could partially rescue the inhibitory effect of NKX2-1-AS1 on SERPINE1 expression (Fig.	('SERPINE1', 'Gene', (101, 109))	('miR-145-5p', 'Chemical', '-', (18, 28))	('miR-145-5p', 'Var', (18, 28))	('inhibitory effect', 'MPA', (66, 83))
1932	33512745	At the same time, rescue of SERPINE1 expression in NKX2-1-AS1 knockdown GC cells is able to restore, or even to promote, the ability of growth, migration, invasion in GC cells (Additional file 3: Fig.	('restore', 'PosReg', (92, 99))	('SERPINE1', 'Gene', (28, 36))	('promote', 'PosReg', (112, 119))	('rescue', 'Var', (18, 24))	('GC', 'Phenotype', 'HP:0012126', (72, 74))	('invasion', 'CPA', (155, 163))	('GC', 'Gene', '14473', (167, 169))	('GC', 'Phenotype', 'HP:0012126', (167, 169))	('growth', 'CPA', (136, 142))	('migration', 'CPA', (144, 153))	('GC', 'Gene', '14473', (72, 74))
1937	33512745	Furthermore, HUVECs co-cultured with AGS exhibited enhanced proliferation compared with HUVECs in a single culture (Fig.	('proliferation', 'CPA', (60, 73))	('AGS', 'Chemical', 'MESH:D012834', (37, 40))	('enhanced', 'PosReg', (51, 59))	('AGS', 'Var', (37, 40))	('HUVEC', 'CellLine', 'CVCL:2959', (88, 93))	('HUVEC', 'CellLine', 'CVCL:2959', (13, 18))
1938	33512745	Besides, HUVECs co-cultured with AGS that overexpressed both NKX2-1-AS1 and SERPINE exhibited higher proliferative capabilities than those co-cultured with NKX2-1-AS1 knockdown (Fig.	('SERPINE', 'Chemical', '-', (76, 83))	('overexpressed', 'PosReg', (42, 55))	('proliferative capabilities', 'CPA', (101, 127))	('NKX2-1-AS1', 'Var', (61, 71))	('AGS', 'Chemical', 'MESH:D012834', (33, 36))	('HUVEC', 'CellLine', 'CVCL:2959', (9, 14))	('higher', 'PosReg', (94, 100))
1939	33512745	Collectively, these findings demonstrated that the effect of NKX2-1-AS1 in GC angiogenesis was predominantly mediated through the miR-145-5p/SERPINE1 axis.	('miR-145-5p/SERPINE1', 'Gene', (130, 149))	('mediated', 'Reg', (109, 117))	('NKX2-1-AS1', 'Var', (61, 71))	('GC', 'Gene', '14473', (75, 77))	('miR-145-5p', 'Chemical', '-', (130, 140))	('angiogenesis', 'biological_process', 'GO:0001525', ('78', '90'))	('GC', 'Phenotype', 'HP:0012126', (75, 77))
1942	33512745	In contrast, NKX2-1-AS1 knockdown caused reduced protein phosphorylation, whereas NKX2-1-AS1 overexpression resulted in increased protein phosphorylation, suggesting an active role of NKX2-1-AS1 in the regulation of VEGFR-2 signaling (Fig.	('VEGFR-2', 'Gene', '3791', (216, 223))	('reduced', 'NegReg', (41, 48))	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('protein phosphorylation', 'biological_process', 'GO:0006468', ('49', '72'))	('protein', 'cellular_component', 'GO:0003675', ('49', '56'))	('protein phosphorylation', 'MPA', (49, 72))	('protein phosphorylation', 'biological_process', 'GO:0006468', ('130', '153'))	('VEGFR-2', 'Gene', (216, 223))	('regulation', 'biological_process', 'GO:0065007', ('202', '212'))	('protein phosphorylation', 'MPA', (130, 153))	('signaling', 'biological_process', 'GO:0023052', ('224', '233'))	('NKX2-1-AS1', 'Gene', (13, 23))	('increased', 'PosReg', (120, 129))	('knockdown', 'Var', (24, 33))
1946	33512745	Dysregulation of lncRNA expression has been recently associated with GC and other gastrointestinal cancers [34].	('lncRNA expression', 'Protein', (17, 34))	('GC', 'Gene', '14473', (69, 71))	('Dysregulation', 'Var', (0, 13))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('gastrointestinal cancers', 'Disease', (82, 106))	('GC', 'Phenotype', 'HP:0012126', (69, 71))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (82, 106))	('associated', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
1948	33512745	Evidence indicates that NKX2-1-AS1, a lncRNA, suppresses the migration of human carcinoma cells by negatively regulating CD274/PD-L1 and cell-cell interaction genes [13].	('CD274', 'Gene', (121, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('suppresses', 'NegReg', (46, 56))	('NKX2-1-AS1', 'Var', (24, 34))	('negatively regulating', 'NegReg', (99, 120))	('carcinoma', 'Disease', (80, 89))	('CD274', 'Gene', '29126', (121, 126))	('PD-L1', 'Gene', (127, 132))	('human', 'Species', '9606', (74, 79))	('carcinoma', 'Disease', 'MESH:D009369', (80, 89))	('PD-L1', 'Gene', '29126', (127, 132))
1951	33512745	Taken together, the results suggested that NKX2-1-AS1 promotes GC progression and may serve as a potential candidate diagnostic and prognostic biomarker for GC.	('GC', 'Gene', '14473', (63, 65))	('GC', 'Phenotype', 'HP:0012126', (63, 65))	('GC', 'Gene', '14473', (157, 159))	('NKX2-1-AS1', 'Var', (43, 53))	('GC', 'Phenotype', 'HP:0012126', (157, 159))	('promotes', 'PosReg', (54, 62))
1954	33512745	The under-expression of miR-145-5p, due to the ceRNA nature of NKX2-1-AS1, alleviated the downregulation of SERPINE1, thereby promoted GC progression.	('downregulation', 'MPA', (90, 104))	('GC', 'Gene', '14473', (135, 137))	('promoted', 'PosReg', (126, 134))	('alleviated', 'NegReg', (75, 85))	('SERPINE1', 'Protein', (108, 116))	('GC', 'Phenotype', 'HP:0012126', (135, 137))	('miR-145-5p', 'Chemical', '-', (24, 34))	('miR-145-5p', 'Var', (24, 34))	('under-expression', 'NegReg', (4, 20))	('NKX2-1-AS1', 'Gene', (63, 73))
1960	33512745	Moreover, inhibition of miRNA-mediated SERPINE1 suppresses tumor angiogenesis, regardless of the angiogenic stimuli, in malignant pleural mesothelioma [42].	('angiogenesis', 'biological_process', 'GO:0001525', ('65', '77'))	('malignant pleural mesothelioma', 'Disease', (120, 150))	('tumor', 'Disease', (59, 64))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (130, 150))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('miRNA-mediated SERPINE1', 'Protein', (24, 47))	('suppresses', 'NegReg', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('inhibition', 'Var', (10, 20))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (120, 150))
1961	33512745	In the present study, we found that SERPINE1 as a direct target of miR-145-5p.	('SERPINE1', 'Protein', (36, 44))	('miR-145-5p', 'Chemical', '-', (67, 77))	('miR-145-5p', 'Var', (67, 77))
1962	33512745	Further analysis revealed that the loss of SERPINE1 inhibition by miR-145-5p significantly enhanced the activity of the VEGFR-2 pathway.	('activity', 'MPA', (104, 112))	('VEGFR-2', 'Gene', (120, 127))	('miR-145-5p', 'Chemical', '-', (66, 76))	('miR-145-5p', 'Var', (66, 76))	('enhanced', 'PosReg', (91, 99))	('SERPINE1', 'Protein', (43, 51))	('VEGFR-2', 'Gene', '3791', (120, 127))	('inhibition', 'NegReg', (52, 62))
1963	33512745	Similarly, the VEGFR-2 pathway was significantly activated in GC cells overexpressing NKX2-1-AS1.	('GC', 'Phenotype', 'HP:0012126', (62, 64))	('VEGFR-2', 'Gene', '3791', (15, 22))	('NKX2-1-AS1', 'Var', (86, 96))	('GC', 'Gene', '14473', (62, 64))	('activated', 'PosReg', (49, 58))	('VEGFR-2', 'Gene', (15, 22))
1966	33512745	Thus, we hypothesized that miR-145-5p regulated SERPINE1 expression in GC.	('expression', 'MPA', (57, 67))	('SERPINE1', 'Gene', (48, 56))	('GC', 'Gene', '14473', (71, 73))	('regulated', 'Reg', (38, 47))	('miR-145-5p', 'Var', (27, 37))	('GC', 'Phenotype', 'HP:0012126', (71, 73))	('miR-145-5p', 'Chemical', '-', (27, 37))
1968	33512745	During the proliferation of GC cells, we also observed that GC cells with high expression of NKX2-1-AS1 exhibited stronger proliferation activity.	('GC', 'Gene', '14473', (28, 30))	('GC', 'Phenotype', 'HP:0012126', (60, 62))	('NKX2-1-AS1', 'Gene', (93, 103))	('high expression', 'Var', (74, 89))	('GC', 'Phenotype', 'HP:0012126', (28, 30))	('proliferation activity', 'CPA', (123, 145))	('stronger', 'PosReg', (114, 122))	('GC', 'Gene', '14473', (60, 62))
1973	33512745	Collectively, the present study highlighted the significance of NKX2-1-AS1 as a ceRNA for miR-145-5p to upregulate SERPINE1, leading to increased activation of the VEGFR-2 signaling pathway, thereby promoting tumor angiogenesis, proliferation, and metastasis in GC.	('angiogenesis', 'biological_process', 'GO:0001525', ('215', '227'))	('miR-145-5p', 'Chemical', '-', (90, 100))	('miR-145-5p', 'Var', (90, 100))	('promoting', 'PosReg', (199, 208))	('tumor', 'Disease', (209, 214))	('increased activation', 'PosReg', (136, 156))	('metastasis', 'CPA', (248, 258))	('GC', 'Gene', '14473', (262, 264))	('VEGFR-2', 'Gene', (164, 171))	('proliferation', 'CPA', (229, 242))	('GC', 'Phenotype', 'HP:0012126', (262, 264))	('SERPINE1', 'Gene', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('VEGFR-2 signaling pathway', 'biological_process', 'GO:0036324', ('164', '189'))	('VEGFR-2', 'Gene', '3791', (164, 171))	('upregulate', 'PosReg', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
1976	33512745	Furthermore, NKX2-1-AS1 promoted cell proliferation and tumor angiogenesis in GC both in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cell proliferation', 'biological_process', 'GO:0008283', ('33', '51'))	('NKX2-1-AS1', 'Var', (13, 23))	('tumor', 'Disease', (56, 61))	('GC', 'Gene', '14473', (78, 80))	('promoted', 'PosReg', (24, 32))	('cell proliferation', 'CPA', (33, 51))	('angiogenesis', 'biological_process', 'GO:0001525', ('62', '74'))	('GC', 'Phenotype', 'HP:0012126', (78, 80))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
1982	32545395	Effect of Astaxanthin on Activation of Autophagy and Inhibition of Apoptosis in Helicobacter pylori-Infected Gastric Epithelial Cell Line AGS Helicobacter pylori (H. pylori) infection leads to the massive apoptosis of the gastric epithelial cells, causing gastric ulcers, gastritis, and gastric adenocarcinoma.	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (287, 309))	('gastritis', 'Phenotype', 'HP:0005263', (272, 281))	('Autophagy', 'biological_process', 'GO:0016236', ('39', '48'))	('Helicobacter pylori', 'Species', '210', (142, 161))	('apoptosis', 'biological_process', 'GO:0097194', ('205', '214'))	('apoptosis', 'CPA', (205, 214))	('apoptosis', 'biological_process', 'GO:0006915', ('205', '214'))	('gastritis', 'Disease', 'MESH:D005756', (272, 281))	('gastritis', 'Disease', (272, 281))	('Infected', 'Disease', (100, 108))	('gastric adenocarcinoma', 'Disease', (287, 309))	('infection', 'Disease', (174, 183))	('gastric ulcers', 'Disease', 'MESH:D013276', (256, 270))	('Inhibition of Apoptosis', 'biological_process', 'GO:0043066', ('53', '76'))	('infection', 'Disease', 'MESH:D007239', (174, 183))	('Autophagy', 'biological_process', 'GO:0006914', ('39', '48'))	('H. pylori', 'Species', '210', (163, 172))	('gastric ulcers', 'Phenotype', 'HP:0002592', (256, 270))	('Infected', 'Disease', 'MESH:D007239', (100, 108))	('Helicobacter', 'Var', (142, 154))	('causing', 'Reg', (248, 255))	('gastric ulcers', 'Disease', (256, 270))	('Helicobacter pylori', 'Species', '210', (80, 99))	('Astaxanthin', 'Chemical', 'MESH:C005948', (10, 21))
2001	32545395	If hyperproliferation from the dysregulation of apoptosis is uncontrolled, neoplasia can occur.	('hyperproliferation', 'Disease', (3, 21))	('apoptosis', 'biological_process', 'GO:0006915', ('48', '57'))	('neoplasia', 'Disease', (75, 84))	('dysregulation', 'Var', (31, 44))	('neoplasia', 'Phenotype', 'HP:0002664', (75, 84))	('neoplasia', 'Disease', 'MESH:D009369', (75, 84))	('apoptosis', 'biological_process', 'GO:0097194', ('48', '57'))
2008	32545395	The AMP/ATP ratio, Ca2+ levels, oxidative stress, and other factors can lead to the activation of AMPK, which is phosphorylated at Thr 172 in a catalytic alpha-subunit through the transfer of reversible phosphate groups by upstream kinases.	('AMPK', 'molecular_function', 'GO:0047322', ('98', '102'))	('Thr', 'Chemical', 'MESH:D013912', (131, 134))	('AMP', 'Chemical', 'MESH:D000249', (4, 7))	('activation', 'PosReg', (84, 94))	('AMPK', 'Gene', '5562', (98, 102))	('AMPK', 'Gene', (98, 102))	('AMP/ATP', 'Var', (4, 11))	('AMP', 'Chemical', 'MESH:D000249', (98, 101))	('AMPK', 'molecular_function', 'GO:0004691', ('98', '102'))	('ATP', 'Chemical', 'MESH:D000255', (8, 11))	('AMPK', 'molecular_function', 'GO:0050405', ('98', '102'))	('Ca2+', 'Chemical', 'MESH:D000069285', (19, 23))	('phosphate', 'Chemical', 'MESH:D010710', (203, 212))	('oxidative stress', 'Phenotype', 'HP:0025464', (32, 48))
2011	32545395	The direct pathway involves phosphorylating and activating ULK1, and the indirect pathway involves activating ULK1 by inhibiting the mammalian target of rapamycin (mTOR).	('ULK1', 'Gene', (110, 114))	('activating', 'PosReg', (99, 109))	('mammalian target of rapamycin', 'Gene', '2475', (133, 162))	('mammalian target of rapamycin', 'Gene', (133, 162))	('activating', 'PosReg', (48, 58))	('phosphorylating', 'Var', (28, 43))	('ULK1', 'Gene', (59, 63))	('inhibiting', 'NegReg', (118, 128))	('mTOR', 'Gene', (164, 168))	('mTOR', 'Gene', '2475', (164, 168))
2031	32545395	Autophagy activation was determined by levels of mTOR, p-mTOR, AMPK, p-AMPK, Akt, p-Akt, ULK1, p-ULK1, p62, LC3 protein expression, and the number of LC3 puncta.	('p62', 'Gene', '23636', (103, 106))	('Akt', 'Gene', (77, 80))	('Autophagy activation', 'CPA', (0, 20))	('p62', 'Gene', (103, 106))	('AMPK', 'Gene', '5562', (63, 67))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('AMPK', 'molecular_function', 'GO:0047322', ('63', '67'))	('mTOR', 'Gene', (49, 53))	('Akt', 'Gene', '207', (77, 80))	('AMPK', 'Gene', '5562', (71, 75))	('Autophagy', 'biological_process', 'GO:0016236', ('0', '9'))	('AMPK', 'molecular_function', 'GO:0050405', ('71', '75'))	('LC3', 'Gene', (108, 111))	('Akt', 'Gene', (84, 87))	('mTOR', 'Gene', (57, 61))	('LC3', 'Gene', '84557', (150, 153))	('p-ULK1', 'Var', (95, 101))	('mTOR', 'Gene', '2475', (49, 53))	('Akt', 'Gene', '207', (84, 87))	('AMPK', 'molecular_function', 'GO:0050405', ('63', '67'))	('AMPK', 'molecular_function', 'GO:0004691', ('71', '75'))	('mTOR', 'Gene', '2475', (57, 61))	('AMPK', 'Gene', (63, 67))	('Autophagy', 'biological_process', 'GO:0006914', ('0', '9'))	('LC3', 'Gene', '84557', (108, 111))	('AMPK', 'Gene', (71, 75))	('AMPK', 'molecular_function', 'GO:0047322', ('71', '75'))	('AMPK', 'molecular_function', 'GO:0004691', ('63', '67'))	('LC3', 'Gene', (150, 153))	('ULK1', 'Gene', (89, 93))
2065	32545395	The densitometric analysis was performed for the ratio of p-mTOR/TOR, p-AMPK/AMPK, p-Akt/Akt, p-ULK1/ULK1, p62/actin, cytochrome C/actin, and LC3B-II/LC3B-1.	('AMPK', 'molecular_function', 'GO:0050405', ('72', '76'))	('AMPK', 'Gene', (77, 81))	('mTOR', 'Gene', '2475', (60, 64))	('Akt', 'Gene', (85, 88))	('AMPK', 'molecular_function', 'GO:0004691', ('77', '81'))	('AMPK', 'Gene', '5562', (72, 76))	('AMPK', 'molecular_function', 'GO:0004691', ('72', '76'))	('p-ULK1/ULK1', 'Var', (94, 105))	('Akt', 'Gene', '207', (85, 88))	('cytochrome C', 'molecular_function', 'GO:0009461', ('118', '130'))	('AMPK', 'molecular_function', 'GO:0047322', ('77', '81'))	('AMPK', 'Gene', '5562', (77, 81))	('AMPK', 'molecular_function', 'GO:0047322', ('72', '76'))	('p62', 'Gene', '23636', (107, 110))	('p62', 'Gene', (107, 110))	('Akt', 'Gene', (89, 92))	('AMPK', 'Gene', (72, 76))	('Akt', 'Gene', '207', (89, 92))	('AMPK', 'molecular_function', 'GO:0050405', ('77', '81'))	('mTOR', 'Gene', (60, 64))	('cytochrome C', 'molecular_function', 'GO:0045155', ('118', '130'))
2072	32545395	H. pylori-induced cell death was enhanced by compound C, but was inhibited by metformin (Figure 1B).	('H. pylori-induced', 'Disease', (0, 17))	('H. pylori', 'Species', '210', (0, 9))	('metformin', 'Chemical', 'MESH:D008687', (78, 87))	('cell death', 'biological_process', 'GO:0008219', ('18', '28'))	('compound C', 'Var', (45, 55))	('cell death', 'CPA', (18, 28))	('enhanced', 'PosReg', (33, 41))
2119	32545395	Dephosphorylated mTOR has been found to separate ULK1 from mTORC1, and phosphorylated ULK1 has been shown to augment autophagy.	('ULK1', 'Gene', (49, 53))	('ULK1', 'Gene', (86, 90))	('autophagy', 'biological_process', 'GO:0006914', ('117', '126'))	('autophagy', 'CPA', (117, 126))	('mTOR', 'Gene', '2475', (59, 63))	('autophagy', 'biological_process', 'GO:0016236', ('117', '126'))	('phosphorylated', 'Var', (71, 85))	('mTORC1', 'Gene', '382056', (59, 65))	('mTORC1', 'cellular_component', 'GO:0031931', ('59', '65'))	('augment', 'PosReg', (109, 116))	('mTOR', 'Gene', (17, 21))	('mTORC1', 'Gene', (59, 65))	('mTOR', 'Gene', '2475', (17, 21))	('mTOR', 'Gene', (59, 63))
2138	32545395	The mice that were fed 0.08% astaxanthin had higher cardiac mitochondrial membrane potential and contractility index compared with control animals.	('mitochondrial membrane', 'cellular_component', 'GO:0031966', ('60', '82'))	('mice', 'Species', '10090', (4, 8))	('0.08%', 'Var', (23, 28))	('cardiac mitochondrial membrane potential', 'MPA', (52, 92))	('contractility index', 'CPA', (97, 116))	('higher', 'PosReg', (45, 51))	('astaxanthin', 'Chemical', 'MESH:C005948', (29, 40))
2143	32545395	Caspase-8 directly activates caspase-3 and Bid (BH3 interacting-domain death agonist), and tBid (truncated Bid) (as a result of the cleavage of Bid by caspase-8) stimulates cytochrome c release from the mitochondria.	('caspase-3', 'Gene', (29, 38))	('cytochrome c', 'molecular_function', 'GO:0045155', ('173', '185'))	('activates', 'PosReg', (19, 28))	('cleavage', 'Var', (132, 140))	('tBid', 'Chemical', '-', (91, 95))	('BH3', 'Chemical', 'MESH:C006008', (48, 51))	('cytochrome c release from the mitochondria', 'MPA', (173, 215))	('Bid', 'Gene', (144, 147))	('stimulates', 'PosReg', (162, 172))	('cytochrome c', 'molecular_function', 'GO:0009461', ('173', '185'))	('caspase-3', 'Gene', '12367', (29, 38))	('mitochondria', 'cellular_component', 'GO:0005739', ('203', '215'))
2164	32545395	They compared the autophagy using AGS cells, HEK293T cells (human embryonic kidney), and NCI-N87 (human gastric epithelial, male), infected at MOI of 100 with either wild type H. pylori (ATCC 11,637, cagA+, vacA+) and VM02 (isogenic to 11,637 except to deletion of vacA).	('infected', 'Disease', (131, 139))	('vacA', 'Gene', (265, 269))	('autophagy', 'biological_process', 'GO:0016236', ('18', '27'))	('deletion', 'Var', (253, 261))	('embryonic kidney', 'Disease', (66, 82))	('NCI-N87', 'CellLine', 'CVCL:1603', (89, 96))	('infected', 'Disease', 'MESH:D007239', (131, 139))	('embryonic kidney', 'Disease', 'MESH:D007674', (66, 82))	('HEK293T', 'CellLine', 'CVCL:0063', (45, 52))	('H. pylori', 'Species', '210', (176, 185))	('autophagy', 'biological_process', 'GO:0006914', ('18', '27'))	('human', 'Species', '9606', (98, 103))	('human', 'Species', '9606', (60, 65))
2167	32545395	In the present study, we used AGS cells infected with ATCC 1137 at a MOI of 50 for 1 h. We found that H. pylori decreased p-Akt and p-mTOR, while increasing total forms of mTOR and Akt, thus leading to a reduction in the ratios of p-mTOR/mTOR and p-Akt/Akt in AGS cells at 1 h of culture.	('reduction', 'NegReg', (204, 213))	('mTOR', 'Gene', (172, 176))	('Akt', 'Gene', (253, 256))	('decreased', 'NegReg', (112, 121))	('Akt', 'Gene', (181, 184))	('mTOR', 'Gene', '2475', (172, 176))	('mTOR', 'Gene', (233, 237))	('Akt', 'Gene', '207', (253, 256))	('Akt', 'Gene', (124, 127))	('H. pylori', 'Species', '210', (102, 111))	('Akt', 'Gene', '207', (181, 184))	('H. pylori', 'Var', (102, 111))	('Akt', 'Gene', '207', (124, 127))	('mTOR', 'Gene', '2475', (233, 237))	('mTOR', 'Gene', (238, 242))	('Akt', 'Gene', (249, 252))	('mTOR', 'Gene', (134, 138))	('infected', 'Disease', 'MESH:D007239', (40, 48))	('infected', 'Disease', (40, 48))	('increasing', 'PosReg', (146, 156))	('Akt', 'Gene', '207', (249, 252))	('mTOR', 'Gene', '2475', (238, 242))	('ratios', 'MPA', (221, 227))	('mTOR', 'Gene', '2475', (134, 138))
2169	32545395	At 6 h of culture, we found that H. pylori increased p-mTOR and p-Akt, but decreased total forms of mTOR and Akt in AGS cells.	('Akt', 'Gene', (66, 69))	('mTOR', 'Gene', (55, 59))	('mTOR', 'Gene', '2475', (100, 104))	('Akt', 'Gene', '207', (109, 112))	('mTOR', 'Gene', '2475', (55, 59))	('H. pylori', 'Var', (33, 42))	('Akt', 'Gene', '207', (66, 69))	('increased', 'PosReg', (43, 52))	('Akt', 'Gene', (109, 112))	('H. pylori', 'Species', '210', (33, 42))	('mTOR', 'Gene', (100, 104))	('decreased', 'NegReg', (75, 84))
2201	31547640	In regard to the clinical studies, the results of meta-analyses and randomized control trials differ from those of retrospective studies: the former trials show that H. pylori eradication has a preventive effect on MGC, while the latter studies do not.	('H. pylori', 'Species', '210', (166, 175))	('GC', 'Phenotype', 'HP:0012126', (216, 218))	('preventive', 'NegReg', (194, 204))	('H. pylori', 'Gene', (166, 175))	('eradication', 'Var', (176, 187))	('MGC', 'Disease', (215, 218))
2202	31547640	This discrepancy may be at least partly attributable to differences in the follow-up periods: H. pylori eradication is more likely to prevent MGC over a long-term follow-up period (>=5 years) than over a short-term follow-up period.	('GC', 'Phenotype', 'HP:0012126', (143, 145))	('eradication', 'Var', (104, 115))	('MGC', 'Disease', (142, 145))	('H. pylori', 'Species', '210', (94, 103))	('prevent', 'Reg', (134, 141))
2209	31547640	To date, both meta-analyses and randomized controlled trials (RCTs) have found that H. pylori eradication appears to reduce the risk of GC.	('H. pylori', 'Species', '210', (84, 93))	('reduce', 'NegReg', (117, 123))	('GC', 'Phenotype', 'HP:0012126', (136, 138))	('eradication', 'Var', (94, 105))
2214	31547640	It has been widely reported that many of the molecular alterations of tumor-suppressor and tumor-related genes involve the development or progression of precancerous conditions, that is, atrophic mucosa (atrophy) and IM, as well as GC.	('atrophic mucosa', 'Disease', 'MESH:D020966', (187, 202))	('tumor', 'Disease', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('atrophic mucosa', 'Disease', (187, 202))	('atrophy', 'Disease', 'MESH:D001284', (204, 211))	('atrophy', 'Disease', (204, 211))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('involve', 'Reg', (111, 118))	('IM', 'Chemical', '-', (217, 219))	('alterations', 'Var', (55, 66))	('cancer', 'Disease', (156, 162))	('tumor', 'Disease', (70, 75))	('GC', 'Phenotype', 'HP:0012126', (232, 234))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
2236	31547640	H. pylori eradication significantly reduces the prevalence of primary GC by approximately one-third, as many investigators have mentioned.	('primary GC', 'Disease', (62, 72))	('H. pylori', 'Species', '210', (0, 9))	('GC', 'Phenotype', 'HP:0012126', (70, 72))	('eradication', 'Var', (10, 21))	('reduces', 'NegReg', (36, 43))
2237	31547640	Some of the possible reasons for the reduction of GC by H. pylori eradication include: (1) eradication therapy inhibits new occurrence of GC; (2) eradication regresses or inhibits the growth of GC; and (3) eradication interferes with the discovery of GC.	('inhibits', 'NegReg', (171, 179))	('GC', 'Phenotype', 'HP:0012126', (251, 253))	('eradication', 'Var', (66, 77))	('reduction', 'NegReg', (37, 46))	('H. pylori', 'Gene', (56, 65))	('inhibits', 'NegReg', (111, 119))	('GC', 'Phenotype', 'HP:0012126', (138, 140))	('H. pylori', 'Species', '210', (56, 65))	('GC', 'Phenotype', 'HP:0012126', (50, 52))	('regresses', 'NegReg', (158, 167))	('GC', 'Phenotype', 'HP:0012126', (194, 196))	('growth', 'MPA', (184, 190))
2238	31547640	Therefore, when discussing reports on the reduction of GC risk by H. pylori eradication, the above-mentioned possible mechanisms should be considered.	('H. pylori', 'Species', '210', (66, 75))	('eradication', 'Var', (76, 87))	('GC', 'Phenotype', 'HP:0012126', (55, 57))	('H. pylori', 'Gene', (66, 75))
2242	31547640	With regard to primary GC development after H. pylori eradication, the reduction of GC after eradication was significantly greater (p=0.01) in the groups with long-term (>=5 years) follow-up (OR, 0.32; 95% CI, 0.24 to 0.43) as compared to those with shorter follow-up (<5 years) (OR, 0.55; 95% CI, 0.41 to 0.72).	('H. pylori', 'Species', '210', (44, 53))	('reduction', 'NegReg', (71, 80))	('primary GC development', 'CPA', (15, 37))	('eradication', 'Var', (93, 104))	('GC', 'Phenotype', 'HP:0012126', (84, 86))	('GC', 'Phenotype', 'HP:0012126', (23, 25))
2243	31547640	changed their previous negative conclusion after a long-term follow-up (median follow-up: 71.6 months) and ultimately found that H. pylori eradication significantly reduced the incidence of MGC.	('H. pylori', 'Gene', (129, 138))	('GC', 'Phenotype', 'HP:0012126', (191, 193))	('MGC', 'Disease', (190, 193))	('H. pylori', 'Species', '210', (129, 138))	('eradication', 'Var', (139, 150))	('reduced', 'NegReg', (165, 172))
2245	31547640	Taken together, these results suggest that H. pylori eradication may reduce MGC development in patients who are followed-up for a long term (at least >=5 years), but may not show a reduction in MGC development over a short-term follow-up (<5 years).	('H. pylori', 'Species', '210', (43, 52))	('patients', 'Species', '9606', (95, 103))	('MGC development', 'CPA', (76, 91))	('eradication', 'Var', (53, 64))	('reduce', 'NegReg', (69, 75))	('H. pylori', 'Gene', (43, 52))	('GC', 'Phenotype', 'HP:0012126', (77, 79))	('GC', 'Phenotype', 'HP:0012126', (195, 197))
2246	31547640	To date, most meta-analyses have demonstrated that H. pylori eradication reduces the risk of MGC (Table 1).	('reduces', 'NegReg', (73, 80))	('GC', 'Phenotype', 'HP:0012126', (94, 96))	('MGC', 'Disease', (93, 96))	('H. pylori', 'Protein', (51, 60))	('H. pylori', 'Species', '210', (51, 60))	('eradication', 'Var', (61, 72))
2282	31547640	The strong influence of methylation accumulation on GC risk is considered to be due to the major contribution to gastric carcinogenesis, along with mutations, of aberrant DNA methylation that is induced by H. pylori infection in gastric epithelial cells.	('DNA', 'Gene', (171, 174))	('pylori infection', 'Disease', (209, 225))	('GC', 'Phenotype', 'HP:0012126', (52, 54))	('pylori infection', 'Disease', 'MESH:D016481', (209, 225))	('H. pylori infection', 'Phenotype', 'HP:0005202', (206, 225))	('methylation', 'Var', (175, 186))	('H. pylori', 'Species', '210', (206, 215))	('DNA', 'cellular_component', 'GO:0005574', ('171', '174'))	('aberrant', 'Var', (162, 170))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('gastric carcinogenesis', 'Disease', (113, 135))	('DNA methylation', 'biological_process', 'GO:0006306', ('171', '186'))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (113, 135))
2283	31547640	It has been considered, however, that tumor-suppressor genes are more inactivated by DNA methylation than by mutations in gastric carcinogenesis, thus indicating that GC is an epigenetic disease.	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (122, 144))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('DNA', 'cellular_component', 'GO:0005574', ('85', '88'))	('inactivated', 'NegReg', (70, 81))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('38', '54'))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('38', '54'))	('GC', 'Phenotype', 'HP:0012126', (167, 169))	('DNA methylation', 'Var', (85, 100))	('DNA methylation', 'biological_process', 'GO:0006306', ('85', '100'))	('gastric carcinogenesis', 'Disease', (122, 144))
2285	31547640	microRNAs (miRNAs), such as the methylation of several tumor-suppressor miRNAs, is also considered to play important roles in the pathogenesis of GC.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('methylation', 'Var', (32, 43))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('55', '71'))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('pathogenesis', 'biological_process', 'GO:0009405', ('130', '142'))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('tumor', 'Disease', (55, 60))	('GC', 'Phenotype', 'HP:0012126', (146, 148))	('roles', 'Reg', (117, 122))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('55', '71'))
2289	31547640	Over 10 years ago, it was reported that H. pylori eradication can significantly reduce gene methylation in the chronic gastritis mucosa, thereby delaying or reversing H. pylori-induced gastric carcinogenesis.	('H. pylori', 'Species', '210', (167, 176))	('H. pylori-induced', 'Disease', (167, 184))	('gastritis mucosa', 'Disease', (119, 135))	('H. pylori', 'Species', '210', (40, 49))	('reversing', 'NegReg', (157, 166))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (185, 207))	('chronic gastritis', 'Phenotype', 'HP:0005231', (111, 128))	('chronic gastritis', 'Disease', 'MESH:D005756', (111, 128))	('gastritis', 'Phenotype', 'HP:0005263', (119, 128))	('gastritis mucosa', 'Disease', 'MESH:D005756', (119, 135))	('gene methylation', 'MPA', (87, 103))	('reduce', 'NegReg', (80, 86))	('methylation', 'biological_process', 'GO:0032259', ('92', '103'))	('gastric carcinogenesis', 'Disease', (185, 207))	('delaying', 'NegReg', (145, 153))	('chronic gastritis', 'Disease', (111, 128))	('eradication', 'Var', (50, 61))
2290	31547640	first showed that methylation of the E-cadherin (CDH1) promoter was reversed after H. pylori eradication, and that the disappearance of E-cadherin methylation may be important for preventing the future development of GC.	('CDH1', 'Gene', (49, 53))	('GC', 'Phenotype', 'HP:0012126', (217, 219))	('cadherin', 'molecular_function', 'GO:0008014', ('138', '146'))	('cadherin', 'molecular_function', 'GO:0008014', ('39', '47'))	('H. pylori', 'Species', '210', (83, 92))	('CDH1', 'Gene', '999', (49, 53))	('disappearance', 'NegReg', (119, 132))	('methylation', 'Var', (147, 158))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('E-cadherin', 'Protein', (136, 146))	('methylation', 'biological_process', 'GO:0032259', ('147', '158'))
2301	31547640	We analyzed the KRAS mutation in IM, and showed that (1) the prevalence of KRAS mutation in patients with IM without cancer was significantly higher than that in patients with intestinal-type GC; (2) KRAS mutations significantly declined in patients with chronic gastritis; (3) KRAS mutations in IM were related to lymphocyte infiltration caused by the bacteria; (4) AGT transformation in the mutation pattern was not affected by the treatment, and some mutations in KRAS may be selected by the eradication; and (5) H. pylori eradication before the development of stable mutations will likely halt the risk of GC.	('GC', 'Phenotype', 'HP:0012126', (192, 194))	('IM', 'Chemical', '-', (106, 108))	('KRAS', 'Gene', (467, 471))	('H. pylori', 'Species', '210', (516, 525))	('gastritis', 'Phenotype', 'HP:0005263', (263, 272))	('KRAS', 'Gene', '3845', (75, 79))	('declined', 'NegReg', (229, 237))	('chronic gastritis', 'Phenotype', 'HP:0005231', (255, 272))	('patients', 'Species', '9606', (92, 100))	('KRAS', 'Gene', '3845', (200, 204))	('KRAS', 'Gene', (75, 79))	('GC', 'Phenotype', 'HP:0012126', (610, 612))	('cancer', 'Disease', (117, 123))	('patients', 'Species', '9606', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('KRAS', 'Gene', (200, 204))	('chronic gastritis', 'Disease', 'MESH:D005756', (255, 272))	('KRAS', 'Gene', '3845', (278, 282))	('mutations', 'Var', (283, 292))	('KRAS', 'Gene', '3845', (16, 20))	('AGT', 'Gene', '183', (367, 370))	('patients', 'Species', '9606', (241, 249))	('KRAS', 'Gene', (278, 282))	('IM', 'Chemical', '-', (296, 298))	('KRAS', 'Gene', '3845', (467, 471))	('IM', 'Chemical', '-', (33, 35))	('AG', 'Phenotype', 'HP:0002582', (367, 369))	('chronic gastritis', 'Disease', (255, 272))	('KRAS', 'Gene', (16, 20))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('AGT', 'Gene', (367, 370))	('halt', 'NegReg', (593, 597))
2306	31547640	Interestingly, CIMP in IM, which is a surrogate marker of GC, decreased in patients with chronic gastritis who regularly took aspirin for more than three years.	('chronic gastritis', 'Disease', 'MESH:D005756', (89, 106))	('CIMP', 'Chemical', '-', (15, 19))	('decreased', 'NegReg', (62, 71))	('aspirin', 'Chemical', 'MESH:D001241', (126, 133))	('chronic gastritis', 'Disease', (89, 106))	('GC', 'Phenotype', 'HP:0012126', (58, 60))	('patients', 'Species', '9606', (75, 83))	('IM', 'Chemical', '-', (16, 18))	('gastritis', 'Phenotype', 'HP:0005263', (97, 106))	('chronic gastritis', 'Phenotype', 'HP:0005231', (89, 106))	('CIMP', 'Var', (15, 19))	('IM', 'Chemical', '-', (23, 25))
2313	31547640	Although it has been reported that miR-124a-3 and miR-34b/c methylations in the background mucosa were associated with an increased risk of developing MGCs, in our previous study the methylations of miR-124a-3 and miR-34c were mostly observed in IM, and only rarely in atrophy.	('atrophy', 'Disease', (269, 276))	('MGCs', 'Disease', (151, 155))	('miR-124a-3', 'Gene', (199, 209))	('methylations', 'Var', (60, 72))	('miR-34c', 'Var', (214, 221))	('miR-124a-3', 'Gene', (35, 45))	('miR-34b/c', 'Gene', (50, 59))	('associated with', 'Reg', (103, 118))	('GC', 'Phenotype', 'HP:0012126', (152, 154))	('observed', 'Reg', (234, 242))	('methylations', 'Var', (183, 195))	('atrophy', 'Disease', 'MESH:D001284', (269, 276))	('IM', 'Chemical', '-', (246, 248))
2314	31547640	Thus, these results indicate that the methylation of these miRNA genes might be a specific marker expressed in IM and might not necessarily be a risk marker for GC.	('GC', 'Phenotype', 'HP:0012126', (161, 163))	('methylation', 'Var', (38, 49))	('miRNA genes', 'Gene', (59, 70))	('IM', 'Chemical', '-', (111, 113))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))
2319	31547640	Interestingly, the decrease in the methylation level in MOS after H. pylori eradication was significant among controls (cases without organic gastric or esophageal diseases) without IM; however, it was not observed among patients with IM or those with dysplasia or GC.	('patients', 'Species', '9606', (221, 229))	('decrease', 'NegReg', (19, 27))	('esophageal diseases', 'Disease', (153, 172))	('H. pylori', 'Gene', (66, 75))	('IM', 'Chemical', '-', (182, 184))	('methylation level', 'MPA', (35, 52))	('organic gastric', 'Disease', (134, 149))	('GC', 'Phenotype', 'HP:0012126', (265, 267))	('eradication', 'Var', (76, 87))	('MOS', 'Gene', (56, 59))	('dysplasia', 'Disease', 'MESH:C536170', (252, 261))	('H. pylori', 'Species', '210', (66, 75))	('dysplasia', 'Disease', (252, 261))	('organic gastric', 'Disease', 'MESH:D013274', (134, 149))	('esophageal diseases', 'Disease', 'MESH:D004935', (153, 172))	('IM', 'Chemical', '-', (235, 237))	('MOS', 'Gene', '4342', (56, 59))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))
2323	31547640	Meta-analyses and RCTs show that H. pylori eradication reduces the risk of MGC development in patients who were followed-up for a long term after the eradication (>=5 years).	('eradication', 'Var', (43, 54))	('patients', 'Species', '9606', (94, 102))	('GC', 'Phenotype', 'HP:0012126', (76, 78))	('MGC development', 'Disease', (75, 90))	('reduces', 'NegReg', (55, 62))	('H. pylori', 'Species', '210', (33, 42))
2351	30901943	The benefit of FLOT was shown in all the subgroups analyzed, such as proximal versus distal tumors, well versus poorly differentiated as well as in the early stages (cT1,2), in which FLOT showed greater survival benefit than ECF/X.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('FLOT', 'Var', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
2364	30901943	Noteworthy, adjuvant treatment was shown to be an independent prognostic factor related to survival at multivariate analysis, observing the largest benefit in pts with node-positive disease or sub-optimal histological tumor regression grade (TRG).	('TRG', 'Chemical', '-', (242, 245))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (218, 223))	('pts', 'Species', '9606', (159, 162))	('sub-optimal', 'Var', (193, 204))
2400	30901943	Another German analysis confirmed that signet ring cell histology was significantly associated with lower probability of R0 resection and worse histopathological response (16.3 versus 28.9 %, p < 0.001) in pts affected by resectable gastric and GEJ cancer and treated with preoperative chemotherapy (CF-based, with taxans or epirubicin).	('gastric', 'Disease', (233, 240))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('signet ring cell histology', 'Var', (39, 65))	('lower', 'NegReg', (100, 105))	('cancer', 'Disease', (249, 255))	('pts', 'Species', '9606', (206, 209))	('epirubicin', 'Chemical', 'MESH:D015251', (325, 335))	('taxans', 'Chemical', '-', (315, 321))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
2401	30901943	It is noteworthy that the prognosis of these pts was significantly worse in comparison with other adenocarcinomas, making the presence of signet ring cell an independent prognostic factor.	('adenocarcinomas', 'Disease', 'MESH:D000230', (98, 113))	('adenocarcinomas', 'Disease', (98, 113))	('pts', 'Species', '9606', (45, 48))	('presence', 'Var', (126, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
2422	30901943	The prognostic and predictive role of microsatellites and mismatch repair proteins (MMR) is well defined in colon cancer.	('colon cancer', 'Disease', (108, 120))	('colon cancer', 'Phenotype', 'HP:0003003', (108, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mismatch repair', 'biological_process', 'GO:0006298', ('58', '73'))	('colon cancer', 'Disease', 'MESH:D015179', (108, 120))	('MMR', 'biological_process', 'GO:0006298', ('84', '87'))	('microsatellites', 'Var', (38, 53))
2425	30901943	Moreover, pts with MSI status showed a better OS than pts with microsatellite stability (MSS) (HR: 0.69, 95% CI: 0.56-0.86; p < 0.001).	('pts', 'Species', '9606', (54, 57))	('MSS', 'Disease', 'MESH:D013132', (89, 92))	('MSS', 'Disease', (89, 92))	('MSI', 'Var', (19, 22))	('pts', 'Species', '9606', (10, 13))	('OS', 'Gene', '17451', (46, 48))	('better', 'PosReg', (39, 45))
2433	30901943	However, we should consider that in this post hoc study, only GC showed an MSI or MMRD status compared to the GEJ tumors (0%), which is in accordance with low prevalence of the deficiency in proximal gastric or esophageal cancers.	('MMRD', 'CPA', (82, 86))	('GC', 'Phenotype', 'HP:0012126', (62, 64))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('MSI', 'Var', (75, 78))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('deficiency in proximal gastric or esophageal cancers', 'Disease', 'MESH:D013274', (177, 229))
2436	30901943	On the other hand, pts with MSI-L, MSS and/or MMRP may have a better outcome when treated with chemotherapy first.	('pts', 'Species', '9606', (19, 22))	('MMRP', 'Disease', (46, 50))	('MSS', 'Disease', 'MESH:D013132', (35, 38))	('MSS', 'Disease', (35, 38))	('MSI-L', 'Var', (28, 33))
2458	30901943	Among other studies that investigated the predictive value of molecular markers expression for treatment response and survival, great interest has been garnered by Phase II randomized trial FLOT4-AIO with a significantly higher proportion of pts achieving pCR (according to Becker's classification, 16% versus 6% in the group treated with docetaxel-based versus epirubicin-based triplet, respectively).	('docetaxel', 'Chemical', 'MESH:D000077143', (339, 348))	('higher', 'PosReg', (221, 227))	('epirubicin', 'Chemical', 'MESH:D015251', (362, 372))	('FLOT4-AIO', 'Var', (190, 199))	('pCR', 'Disease', (256, 259))	('pts', 'Species', '9606', (242, 245))
2519	29979376	She was treated with paclitaxel (175 mg/m2 d1 q21d) and carboplatin (AUC 5 d1 q21d) as second-line chemotherapy for 6 cycles again from July 3, 2015, to January 22, 2016.	('AUC 5 d1 q21d', 'Var', (69, 82))	('175', 'Var', (33, 36))	('carboplatin', 'Chemical', 'MESH:D016190', (56, 67))	('paclitaxel', 'Chemical', 'MESH:D017239', (21, 31))
2661	29434637	In conclusion, serum AFP-elevated GCLM had a poorer prognosis.	('serum', 'Var', (15, 20))	('AFP', 'Gene', '174', (21, 24))	('AFP', 'Gene', (21, 24))	('GCLM', 'Gene', (34, 38))
2667	29434637	reported that the dismal prognosis of serum AFP-elevated gastric cancer was mainly due to high incidence of synchronous and metachronous liver metastasis, even when radical operation was done.	('serum', 'Var', (38, 43))	('AFP-elevated gastric cancer', 'Disease', 'MESH:D013274', (44, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (57, 71))	('synchronous and metachronous liver metastasis', 'Disease', 'MESH:D009362', (108, 153))	('AFP-elevated gastric cancer', 'Disease', (44, 71))
2668	29434637	Therefore, systemic chemotherapy became the predominant treatment method for serum AFP-elevated gastric cancer with liver metastasis (GCLM).	('liver metastasis', 'Disease', (116, 132))	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('AFP-elevated gastric cancer', 'Disease', (83, 110))	('serum', 'Var', (77, 82))	('AFP-elevated gastric cancer', 'Disease', 'MESH:D013274', (83, 110))	('liver metastasis', 'Disease', 'MESH:D009362', (116, 132))
2673	29434637	As the precise underlying mechanism of serum AFP-elevated GC remains to be elucidated, the optimal treatment approach requires further consideration.	('AFP', 'Gene', '174', (45, 48))	('AFP', 'Gene', (45, 48))	('serum', 'Var', (39, 44))
2713	29434637	Median serum AFP level was 480.9 ng/ml and 3.1 ng/ml in the AFP >= 20 ng/ml group and AFP < 20 ng/ml group, respectively.	('>= 20 ng/ml', 'Var', (64, 75))	('AFP', 'Gene', (60, 63))	('AFP', 'Gene', '174', (13, 16))	('AFP', 'Gene', (13, 16))	('AFP', 'Gene', '174', (60, 63))	('AFP', 'Gene', (86, 89))	('AFP', 'Gene', '174', (86, 89))
2750	29434637	We noted that there were two patients complicated with PVTT, which is a special characteristic of AFP-related gastric cancer; a high rate of PVTT in AFP-producing gastric cancer (14.9% in our study) may indicate high intendancy of vascular invasion and angiogenesis.	('gastric cancer', 'Disease', (110, 124))	('gastric cancer', 'Disease', (163, 177))	('patients', 'Species', '9606', (29, 37))	('AFP', 'Gene', '174', (149, 152))	('PVTT', 'Var', (141, 145))	('gastric cancer', 'Disease', 'MESH:D013274', (163, 177))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('angiogenesis', 'biological_process', 'GO:0001525', ('253', '265'))	('angiogenesis', 'CPA', (253, 265))	('AFP', 'Gene', (98, 101))	('vascular invasion', 'CPA', (231, 248))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (163, 177))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('AFP', 'Gene', '174', (98, 101))	('AFP', 'Gene', (149, 152))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
2751	29434637	It was reported that silencing AFP inhibits VEGF production in human HCC cells.	('human', 'Species', '9606', (63, 68))	('inhibits', 'NegReg', (35, 43))	('HCC', 'Gene', (69, 72))	('VEGF', 'Gene', (44, 48))	('AFP', 'Gene', '174', (31, 34))	('VEGF production', 'biological_process', 'GO:0010573', ('44', '59'))	('AFP', 'Gene', (31, 34))	('VEGF', 'Gene', '7422', (44, 48))	('silencing', 'Var', (21, 30))	('HCC', 'Gene', '619501', (69, 72))
2771	28930841	TLTG for gastric cancer is technically safe, feasible, and minimally invasive compared with OTG.	('TLTG', 'Var', (0, 4))	('gastric cancer', 'Disease', (9, 23))	('gastric cancer', 'Disease', 'MESH:D013274', (9, 23))	('gastric cancer', 'Phenotype', 'HP:0012126', (9, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
2894	27756337	In addition, the recent phase III study of apatinib, an oral small molecule VEGFR-2 TKI, in Chinese patients with advanced GC, demonstrated prolonged median OS in the apatinib arm of 195 versus 140 days in the placebo arm (HR 0.71, 95 % CI 0.54-0.94, P < 0.0001).	('GC', 'Phenotype', 'HP:0012126', (123, 125))	('apatinib', 'Chemical', 'MESH:C553458', (43, 51))	('apatinib', 'Var', (167, 175))	('VEGFR-2', 'Gene', '3791', (76, 83))	('patients', 'Species', '9606', (100, 108))	('apatinib', 'Chemical', 'MESH:C553458', (167, 175))	('VEGFR-2', 'Gene', (76, 83))
2908	27756337	This analysis showed that the biologics are more likely to lead to hypertension (RR 5.87, 95 % CI 3.34-10.34, P < 0.0001, Additional file 3: Table S4), neutropenia (RR 1.56, 95 % CI 1.27-1.93, P < 0.0001, Additional file 3: Table S4), diarrhea (RR 1.83, 95 % CI 1.14-2.94, P = 0.01, Additional file 3: Table S4), and gastrointestinal perforation (RR 4.14, 95 % CI 1.14-10.09, P = 0.03, Additional file 3: Table S4), while small molecule TKIs are more likely to lead to hand-foot syndrome (RR 7.70, 95 % CI 1.83-32.39, P = 0.005, Additional file 4: Table S3) and thrombocytopenia (RR 0.68, 95 % CI 0.46-1.00, P = 0.04, Additional file 4: Table S3).	('RR 1', 'Gene', '6240', (245, 249))	('RR 1', 'Gene', '6240', (165, 169))	('hypertension', 'Disease', 'MESH:D006973', (67, 79))	('diarrhea', 'Disease', (235, 243))	('thrombocytopenia', 'Disease', (562, 578))	('hypertension', 'Disease', (67, 79))	('lead', 'Reg', (59, 63))	('RR 1', 'Gene', (245, 249))	('diarrhea', 'Disease', 'MESH:D003967', (235, 243))	('RR 1', 'Gene', (165, 169))	('hand-foot syndrome', 'Disease', (469, 487))	('hypertension', 'Phenotype', 'HP:0000822', (67, 79))	('neutropenia', 'Disease', (152, 163))	('thrombocytopenia', 'Disease', 'MESH:D013921', (562, 578))	('small molecule', 'Var', (422, 436))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (562, 578))	('gastrointestinal', 'Disease', (317, 333))	('gastrointestinal', 'Disease', 'MESH:D005767', (317, 333))	('hand-foot syndrome', 'Disease', 'MESH:D060831', (469, 487))	('neutropenia', 'Disease', 'MESH:D009503', (152, 163))	('lead to', 'Reg', (461, 468))	('neutropenia', 'Phenotype', 'HP:0001875', (152, 163))	('diarrhea', 'Phenotype', 'HP:0002014', (235, 243))
2956	27733135	Briefly, cells are treated with Apelin (50 and 100 ng/mL) and seeded (cell density of 5 x 103 per well) in 96-well microplates and cultured in the hypoxic incubator for 8 h, followed by addition of 10 ul WST-8 solution to each well.	('Apelin', 'Gene', (32, 38))	('Apelin', 'Gene', '8862', (32, 38))	('50', 'Var', (40, 42))
2990	27733135	When these cells are transfected with Apelin receptor APJ si-RNA, an 85 % reduction of APJ was observed and Apelin expression was not affected (Fig.	('APJ', 'Gene', (54, 57))	('Apelin', 'Gene', '8862', (38, 44))	('Apelin', 'Gene', (108, 114))	('si-RNA', 'Var', (58, 64))	('reduction', 'NegReg', (74, 83))	('APJ', 'Gene', '187', (87, 90))	('Apelin', 'Gene', '8862', (108, 114))	('APJ', 'Gene', (87, 90))	('APJ', 'Gene', '187', (54, 57))	('Apelin', 'Gene', (38, 44))	('RNA', 'cellular_component', 'GO:0005562', ('61', '64'))
3027	27733135	in vitro study indicated in GC cell lines inhibition of APJ reduced cellular proliferation rate, migration and invasion ability in vitro, suggesting the involvement of Apelin/APJ pathway in GC progression.	('Apelin', 'Gene', '8862', (168, 174))	('migration', 'CPA', (97, 106))	('cellular proliferation rate', 'CPA', (68, 95))	('APJ', 'Gene', (175, 178))	('APJ', 'Gene', '187', (56, 59))	('inhibition', 'Var', (42, 52))	('reduced', 'NegReg', (60, 67))	('Apelin', 'Gene', (168, 174))	('invasion ability', 'CPA', (111, 127))	('APJ', 'Gene', (56, 59))	('APJ', 'Gene', '187', (175, 178))
3029	26443527	Prophylactic Laparoscopic Total Gastrectomy with Jejunal Pouch Reconstruction in Patients Carrying a CDH1 Germline Mutation For patients with an identified germline E-cadherin-1 (CDH1) mutation, prophylactic gastrectomy is the treatment of choice to eliminate the high risk of developing diffuse gastric cancer.	('CDH1', 'Gene', (179, 183))	('Jejunal Pouch', 'Phenotype', 'HP:0004786', (49, 62))	('CDH1', 'Gene', '999', (179, 183))	('gastric cancer', 'Phenotype', 'HP:0012126', (296, 310))	('E-cadherin-1', 'Gene', '999', (165, 177))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('CDH1', 'Gene', (101, 105))	('mutation', 'Var', (185, 193))	('CDH1', 'Gene', '999', (101, 105))	('Patients', 'Species', '9606', (81, 89))	('cadherin', 'molecular_function', 'GO:0008014', ('167', '175'))	('gastric cancer', 'Disease', (296, 310))	('patients', 'Species', '9606', (128, 136))	('E-cadherin-1', 'Gene', (165, 177))	('Mutation', 'Var', (115, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (296, 310))
3031	26443527	Patients with a germline CDH1 mutation who underwent prophylactic laparoscopic total gastrectomy with jejunal pouch were included in our prospective database.	('jejunal pouch', 'Phenotype', 'HP:0004786', (102, 115))	('CDH1', 'Gene', '999', (25, 29))	('mutation', 'Var', (30, 38))	('Patients', 'Species', '9606', (0, 8))	('CDH1', 'Gene', (25, 29))
3038	26443527	Prophylactic laparoscopic total gastrectomy with jejunal pouch reconstruction in patients with a CDH1 germline mutation is feasible and safe.	('germline', 'Var', (102, 110))	('CDH1', 'Gene', (97, 101))	('patients', 'Species', '9606', (81, 89))	('jejunal pouch', 'Phenotype', 'HP:0004786', (49, 62))	('CDH1', 'Gene', '999', (97, 101))
3045	26443527	Patients who carry CDH1 germline mutations have a lifetime risk of >70 % of developing diffuse gastric cancer with a 5-year survival of less than 20 %.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('gastric cancer', 'Disease', 'MESH:D013274', (95, 109))	('CDH1', 'Gene', (19, 23))	('gastric cancer', 'Disease', (95, 109))	('germline', 'Var', (24, 32))	('Patients', 'Species', '9606', (0, 8))	('CDH1', 'Gene', '999', (19, 23))	('gastric cancer', 'Phenotype', 'HP:0012126', (95, 109))
3047	26443527	Surgery eliminates the high risk of developing diffuse gastric cancer in patients with germline CDH1 mutations and therefore is the treatment of choice.	('CDH1', 'Gene', (96, 100))	('gastric cancer', 'Disease', (55, 69))	('mutations', 'Var', (101, 110))	('gastric cancer', 'Disease', 'MESH:D013274', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('CDH1', 'Gene', '999', (96, 100))	('gastric cancer', 'Phenotype', 'HP:0012126', (55, 69))	('eliminates', 'NegReg', (8, 18))	('patients', 'Species', '9606', (73, 81))
3049	26443527	In this article, we describe our initial experience with prophylactic laparoscopic total gastrectomy with jejunal pouch in a case series of patients carrying a CDH1 germline mutation.	('jejunal pouch', 'Phenotype', 'HP:0004786', (106, 119))	('germline', 'Var', (165, 173))	('CDH1', 'Gene', (160, 164))	('patients', 'Species', '9606', (140, 148))	('CDH1', 'Gene', '999', (160, 164))
3050	26443527	Patients (n = 11) with identified germline CDH1 mutations who were referred to the University Medical Centre Utrecht for prophylactic total gastrectomy between April 2006 and May 2015 were included in this study.	('Patients', 'Species', '9606', (0, 8))	('CDH1', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))	('CDH1', 'Gene', '999', (43, 47))
3061	26443527	A total of 11 patients (eight females, three males) who carried the CDH1 gene mutation were included and underwent prophylactic laparoscopic total gastrectomy.	('patients', 'Species', '9606', (14, 22))	('CDH1', 'Gene', (68, 72))	('mutation', 'Var', (78, 86))	('CDH1', 'Gene', '999', (68, 72))
3072	26443527	In this article, we report our initial experience with prophylactic laparoscopic total gastrectomy with jejunal pouch in patients with a CDH1 germline mutation.	('jejunal pouch', 'Phenotype', 'HP:0004786', (104, 117))	('CDH1', 'Gene', (137, 141))	('patients', 'Species', '9606', (121, 129))	('CDH1', 'Gene', '999', (137, 141))	('germline mutation', 'Var', (142, 159))
3078	26443527	The high percentage of intramucosal gastric cancer in both our series and the series from literature emphasizes the need for prophylactic gastrectomy for patients with germline CDH1 mutations.	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('intramucosal gastric cancer', 'Disease', (23, 50))	('intramucosal gastric cancer', 'Disease', 'MESH:D013274', (23, 50))	('patients', 'Species', '9606', (154, 162))	('CDH1', 'Gene', (177, 181))	('gastric cancer', 'Phenotype', 'HP:0012126', (36, 50))	('CDH1', 'Gene', '999', (177, 181))	('mutations', 'Var', (182, 191))
3079	26443527	In a meta-analysis, we demonstrated that laparoscopic total gastrectomy is associated with reduced intraoperative blood loss, lower risk at postoperative complications, and shorter hospital stay compared to open total gastrectomy in patients with gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('gastric cancer', 'Phenotype', 'HP:0012126', (247, 261))	('laparoscopic', 'Var', (41, 53))	('intraoperative blood loss', 'Disease', (99, 124))	('gastric cancer', 'Disease', (247, 261))	('reduced', 'NegReg', (91, 98))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (99, 124))	('patients', 'Species', '9606', (233, 241))	('gastric cancer', 'Disease', 'MESH:D013274', (247, 261))
3080	26443527	These benefits are especially relevant for patients with a CDH1 germline mutation.	('patients', 'Species', '9606', (43, 51))	('CDH1', 'Gene', '999', (59, 63))	('germline mutation', 'Var', (64, 81))	('CDH1', 'Gene', (59, 63))
3081	26443527	We expect that the outcomes of prophylactic laparoscopic total gastrectomy will approximate the results for laparoscopic total gastrectomy for gastric cancer in larger series of patients with a CDH1 germline mutation.	('gastric cancer', 'Phenotype', 'HP:0012126', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('patients', 'Species', '9606', (178, 186))	('CDH1', 'Gene', (194, 198))	('gastric cancer', 'Disease', (143, 157))	('germline mutation', 'Var', (199, 216))	('gastric cancer', 'Disease', 'MESH:D013274', (143, 157))	('CDH1', 'Gene', '999', (194, 198))
3094	26443527	In conclusion, we showed that prophylactic laparoscopic total gastrectomy with jejunal pouch for patients with germline CDH1 mutation is feasible and safe.	('CDH1', 'Gene', '999', (120, 124))	('jejunal pouch', 'Phenotype', 'HP:0004786', (79, 92))	('CDH1', 'Gene', (120, 124))	('mutation', 'Var', (125, 133))	('patients', 'Species', '9606', (97, 105))
3095	26443527	Laparoscopic total gastrectomy is associated with less intraoperative blood loss, fewer postoperative complications, and shorter hospital admission time in comparison to open total gastrectomy.	('Laparoscopic', 'Var', (0, 12))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (55, 80))	('less', 'NegReg', (50, 54))	('intraoperative blood loss', 'Disease', (55, 80))
3096	26443527	These benefits may be especially relevant to patients with germline CDH1 mutation.	('germline', 'Var', (59, 67))	('patients', 'Species', '9606', (45, 53))	('CDH1', 'Gene', (68, 72))	('mutation', 'Var', (73, 81))	('CDH1', 'Gene', '999', (68, 72))
3172	25221363	HIK1083-reactive mucin was detected in all cases with focal expression observed in one (5.9%), multifocal expression observed in four cases (23.5%), and diffuse expression observed in 12 cases (70.6%).	('HIK1083-reactive', 'Var', (0, 16))	('mucin', 'Gene', (17, 22))	('mucin', 'Gene', '100508689', (17, 22))
3174	25221363	In flat lesions, MUC5AC expression was inversely related to the expression of MUC6 and HIK1083-reactive mucin (Fig.	('mucin', 'Gene', (104, 109))	('MUC6', 'Gene', '4588', (78, 82))	('MUC5AC', 'Gene', '4586', (17, 23))	('expression', 'MPA', (24, 34))	('mucin', 'Gene', '100508689', (104, 109))	('MUC6', 'Gene', (78, 82))	('HIK1083-reactive', 'Var', (87, 103))	('MUC5AC', 'Gene', (17, 23))
3210	25221363	The mechanisms responsible for the aberrant MUC5AC expression in IPMNs are unknown.	('MUC5AC', 'Gene', (44, 50))	('IPMNs', 'Disease', (65, 70))	('aberrant', 'Var', (35, 43))	('MUC5AC', 'Gene', '4586', (44, 50))
3216	25221363	This hypothesis was confirmed in our study, where gastric type was characterized by branch duct-type lesions often associated with pyloric gland-like structures, whereas the intestinal type was characterized by main duct-type lesions often associated with atrophy and fibrosis of the surrounding parenchyma.	('branch duct-type', 'Disease', (84, 100))	('pyloric gland-like structures', 'Disease', (131, 160))	('atrophy', 'Disease', 'MESH:D001284', (256, 263))	('associated', 'Reg', (240, 250))	('atrophy', 'Disease', (256, 263))	('fibrosis', 'Disease', (268, 276))	('associated', 'Reg', (115, 125))	('fibrosis', 'Disease', 'MESH:D005355', (268, 276))	('gastric', 'Disease', (50, 57))	('lesions', 'Var', (101, 108))
3217	25221363	In our immunohistochemical analyses, HIK1083-reactive mucin was observed in gastric and mixed phenotype, but not in intestinal type IPMN.	('mucin', 'Gene', (54, 59))	('mucin', 'Gene', '100508689', (54, 59))	('HIK1083-reactive', 'Var', (37, 53))	('gastric', 'Disease', (76, 83))
3228	24396472	In addition, the overall survival rate was greater in NICD- and P21+ patients than in NICD+ and P21- patients, respectively (P<0.05).	('P21', 'Gene', (96, 99))	('patients', 'Species', '9606', (101, 109))	('P21', 'Gene', '1026', (64, 67))	('patients', 'Species', '9606', (69, 77))	('P21', 'Gene', '1026', (96, 99))	('NICD-', 'Var', (54, 59))	('P21', 'Gene', (64, 67))	('overall survival', 'CPA', (17, 33))	('greater', 'PosReg', (43, 50))
3229	24396472	The COX regression multivariate analysis revealed that NICD+, p21-, depth of tumor invasion and lymph node metastasis were all independent prognostic factors for patients with gastric cancer.	('patients', 'Species', '9606', (162, 170))	('gastric cancer', 'Phenotype', 'HP:0012126', (176, 190))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('NICD+', 'Var', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('gastric cancer', 'Disease', 'MESH:D013274', (176, 190))	('tumor', 'Disease', (77, 82))	('p21', 'Gene', '1026', (62, 65))	('gastric cancer', 'Disease', (176, 190))	('p21', 'Gene', (62, 65))
3230	24396472	NICD and p21 proteins are differentially expressed in gastric cancer and the aberrant expression of these proteins is associated with an advanced tumor stage, tumor metastasis and overall patient survival.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('patient', 'Species', '9606', (188, 195))	('p21', 'Gene', '1026', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('gastric cancer', 'Disease', (54, 68))	('tumor', 'Disease', (146, 151))	('tumor metastasis', 'Disease', 'MESH:D009362', (159, 175))	('expression', 'MPA', (86, 96))	('tumor', 'Disease', (159, 164))	('p21', 'Gene', (9, 12))	('gastric cancer', 'Disease', 'MESH:D013274', (54, 68))	('tumor metastasis', 'Disease', (159, 175))	('associated', 'Reg', (118, 128))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('gastric cancer', 'Phenotype', 'HP:0012126', (54, 68))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('aberrant', 'Var', (77, 85))
3240	24396472	However, alterations of this gene pathway contribute to the development of various human cancers and their progression.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('human', 'Species', '9606', (83, 88))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('alterations', 'Var', (9, 20))	('cancers', 'Disease', (89, 96))	('contribute to', 'Reg', (42, 55))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
3243	24396472	However, dysregulation of Notch1 or the expression of its functional domain, NICD, may be involved in tumorigenesis.	('Notch1', 'Gene', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('involved', 'Reg', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('dysregulation', 'Var', (9, 22))
3244	24396472	A previous study has shown that abnormal Notch1 signaling contributes to the development and occurrence of gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('contributes', 'Reg', (58, 69))	('signaling', 'biological_process', 'GO:0023052', ('48', '57'))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Notch1', 'Protein', (41, 47))	('abnormal', 'Var', (32, 40))	('gastric cancer', 'Disease', (107, 121))	('gastric cancer', 'Disease', 'MESH:D013274', (107, 121))
3248	24396472	Specifically, a previous study has shown that Notch signaling induced cell cycle arrest in small cell lung cancer cells.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (70, 87))	('signaling', 'biological_process', 'GO:0023052', ('52', '61'))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('Notch signaling', 'Var', (46, 61))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('arrest', 'Disease', 'MESH:D006323', (81, 87))	('small cell lung cancer', 'Disease', 'MESH:D055752', (91, 113))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (91, 113))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('70', '87'))	('arrest', 'Disease', (81, 87))	('small cell lung cancer', 'Disease', (91, 113))
3286	24396472	The two- and three-year survival rates of NICD+ (58.7 and 28.9%, respectively) gastric cancer patients were significantly lower than those that were NICD- (74.30 and 48.70%, respectively; chi2, 6.01; P<0.05; Fig.	('lower', 'NegReg', (122, 127))	('patients', 'Species', '9606', (94, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('NICD+', 'Var', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('gastric cancer', 'Disease', (79, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))
3291	24396472	Among the 11 factors that were analyzed (age, gender, tumor location, tumor size, tumor differentiation, depth of tumor invasion, vascular invasion, lymph node and distant metastasis, and NICD and p21 protein expression; Table IV), the univariate analysis showed that tumor differentiation, depth of tumor invasion, vascular invasion, lymph node metastasis, and NICD+ and p21+ protein expression were eligible for the multivariate analysis (Table V).	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('protein', 'cellular_component', 'GO:0003675', ('377', '384'))	('p21', 'Gene', (372, 375))	('tumor', 'Disease', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('p21', 'Gene', (197, 200))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('NICD+', 'Var', (362, 367))	('p21', 'Gene', '1026', (372, 375))	('protein', 'cellular_component', 'GO:0003675', ('201', '208'))	('tumor', 'Disease', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (268, 273))	('p21', 'Gene', '1026', (197, 200))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
3292	24396472	The multivariate analysis revealed that only NICD+ or p21+ protein expression, depth of tumor invasion and lymph node metastasis had statistical significance.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('p21', 'Gene', '1026', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('NICD+', 'Var', (45, 50))	('p21', 'Gene', (54, 57))	('tumor', 'Disease', (88, 93))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
3293	24396472	NICD+ or p21- protein expression, depth of tumor invasion and lymph node metastasis were independent prognostic factors of gastric cancer (Tables III and IV).	('NICD+', 'Var', (0, 5))	('p21', 'Gene', '1026', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('gastric cancer', 'Disease', (123, 137))	('p21', 'Gene', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('gastric cancer', 'Disease', 'MESH:D013274', (123, 137))	('tumor', 'Disease', (43, 48))	('protein', 'cellular_component', 'GO:0003675', ('14', '21'))	('gastric cancer', 'Phenotype', 'HP:0012126', (123, 137))
3299	24396472	The COX-regression multivariate analysis showed that NICD+, p21-, depth of tumor invasion and lymph node metastasis were all independent prognostic factors for gastric cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('gastric cancer', 'Disease', (160, 174))	('gastric cancer', 'Disease', 'MESH:D013274', (160, 174))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('p21', 'Gene', '1026', (60, 63))	('patients', 'Species', '9606', (175, 183))	('gastric cancer', 'Phenotype', 'HP:0012126', (160, 174))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('NICD+', 'Var', (53, 58))	('p21', 'Gene', (60, 63))	('tumor', 'Disease', (75, 80))
3320	24396472	However, the majority of studies support that Notch1 expression inhibits p21 expression and activation or vice versa.	('p21', 'Gene', '1026', (73, 76))	('expression', 'Var', (53, 63))	('p21', 'Gene', (73, 76))	('Notch1', 'Gene', (46, 52))	('inhibits', 'NegReg', (64, 72))	('activation', 'MPA', (92, 102))
3323	24396472	Silencing of SKP2 by RNA interference in G1 stabilizes p27 and p21 but abolishes the Notch1 effect on G1-S progression.	('RNA interference', 'biological_process', 'GO:0016246', ('21', '37'))	('RNA', 'cellular_component', 'GO:0005562', ('21', '24'))	('G1-S progression', 'CPA', (102, 118))	('p21', 'Gene', (63, 66))	('SKP2', 'Gene', '6502', (13, 17))	('p27', 'Gene', '5715', (55, 58))	('abolishes', 'NegReg', (71, 80))	('stabilizes', 'NegReg', (44, 54))	('p27', 'Gene', (55, 58))	('RNA interference', 'MPA', (21, 37))	('SKP2', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))	('p21', 'Gene', '1026', (63, 66))
3327	24396472	The present study demonstrated that a combination of aberrant expression of NICD and p21 proteins was able to predict overall survival of gastric cancer patients, which is more efficient than that of an individual protein.	('gastric cancer', 'Disease', (138, 152))	('gastric cancer', 'Disease', 'MESH:D013274', (138, 152))	('NICD', 'Gene', (76, 80))	('predict', 'Reg', (110, 117))	('patients', 'Species', '9606', (153, 161))	('gastric cancer', 'Phenotype', 'HP:0012126', (138, 152))	('p21', 'Gene', '1026', (85, 88))	('protein', 'cellular_component', 'GO:0003675', ('214', '221'))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('aberrant expression', 'Var', (53, 72))	('p21', 'Gene', (85, 88))
3348	23039019	They reported that D2 dissection was associated with lower loco-regional recurrence and GC-related death rates than D1.	('death', 'Disease', 'MESH:D003643', (99, 104))	('death', 'Disease', (99, 104))	('D2 dissection', 'Var', (19, 32))	('loco-regional recurrence', 'CPA', (59, 83))	('lower', 'NegReg', (53, 58))
3402	23039019	Our study also showed that Borrmann type (III/IV versus I/II) and depth of invasion (pT4 versus pT2/pT3) were associated with 11.1- and 5.6-fold increases, respectively, for risk of No.	('pT3', 'Gene', (100, 103))	('increases', 'PosReg', (145, 154))	('pT3', 'Gene', '7694', (100, 103))	('pT4', 'Var', (85, 88))
3425	21242262	A multi-faceted amino-acid, cysteine can modulate the immune response by inhibiting activation of nuclear factor-kappaB (NF-kappaB) and the expression of several NF-kappaB dependent genes.	('cysteine', 'Chemical', 'MESH:D003545', (28, 36))	('expression', 'MPA', (140, 150))	('immune response', 'CPA', (54, 69))	('activation', 'PosReg', (84, 94))	('immune response', 'biological_process', 'GO:0006955', ('54', '69'))	('cysteine', 'Var', (28, 36))	('modulate', 'Reg', (41, 49))	('inhibiting', 'NegReg', (73, 83))	('NF-kappaB', 'Gene', (162, 171))	('nuclear factor-kappaB', 'Pathway', (98, 119))
3427	21242262	Evidence from both human and animal studies suggests that cysteine also exerts direct anti-carcinogenic properties, since it can bind to and detoxify acetaldehyde, a known mutagen and carcinogen.	('bind to', 'Interaction', (129, 136))	('carcinogenic', 'Disease', (91, 103))	('cysteine', 'Chemical', 'MESH:D003545', (58, 66))	('acetaldehyde', 'Chemical', 'MESH:D000079', (150, 162))	('detoxify acetaldehyde', 'MPA', (141, 162))	('cysteine', 'Var', (58, 66))	('human', 'Species', '9606', (19, 24))	('carcinogenic', 'Disease', 'MESH:D063646', (91, 103))
3428	21242262	A recent study involving rats exposed to environmental cigarette smoke showed that orally administered N-acetylcysteine effectively modulated smoke-induced alterations of microRNA expression in rat lungs; specifically, N-acetylcysteine modulated microRNAs involved in NF-kappaB-mediated stress and P53 functions.	('microRNAs', 'MPA', (246, 255))	('P53', 'Gene', (298, 301))	('men', 'Species', '9606', (48, 51))	('rats', 'Species', '10116', (25, 29))	('rat', 'Species', '10116', (160, 163))	('rat', 'Species', '10116', (194, 197))	('modulated', 'Reg', (236, 245))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (219, 235))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (103, 119))	('N-acetylcysteine', 'Var', (219, 235))	('microRNA expression', 'MPA', (171, 190))	('rat', 'Species', '10116', (25, 28))	('P53', 'Gene', '301300', (298, 301))
3507	21242262	The single study that we have identified which related to gastric cancer reported that N-acetylcysteine inhibited human gastric cancer SJ-89 cell growth by inducing apoptosis and DNA synthesis arrest.	('apoptosis', 'biological_process', 'GO:0097194', ('165', '174'))	('apoptosis', 'biological_process', 'GO:0006915', ('165', '174'))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('apoptosis', 'CPA', (165, 174))	('gastric cancer', 'Disease', 'MESH:D013274', (120, 134))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (87, 103))	('human', 'Species', '9606', (114, 119))	('DNA', 'cellular_component', 'GO:0005574', ('179', '182'))	('gastric cancer', 'Phenotype', 'HP:0012126', (58, 72))	('DNA synthesis', 'biological_process', 'GO:0071897', ('179', '192'))	('synthesis arrest', 'Disease', (183, 199))	('cell growth', 'biological_process', 'GO:0016049', ('141', '152'))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('gastric cancer', 'Phenotype', 'HP:0012126', (120, 134))	('N-acetylcysteine', 'Var', (87, 103))	('synthesis arrest', 'Disease', 'MESH:D006323', (183, 199))	('human', 'CPA', (114, 119))	('gastric cancer', 'Disease', (58, 72))	('inhibited', 'NegReg', (104, 113))	('gastric cancer', 'Disease', (120, 134))	('inducing', 'PosReg', (156, 164))	('gastric cancer', 'Disease', 'MESH:D013274', (58, 72))	('SJ-89', 'CellLine', 'CVCL:S860', (135, 140))
3513	21242262	There is always a concern that pre-clinical disease could lead to alterations in serum measurements, thus creating a misleading association, but we found no difference in the exposure-disease associations between those with cancers diagnosed within the first 2 years of the study and those diagnosed after 2 years.	('rat', 'Species', '10116', (70, 73))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('men', 'Species', '9606', (94, 97))	('lead', 'Reg', (58, 62))	('pre', 'molecular_function', 'GO:0003904', ('31', '34'))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('serum measurements', 'MPA', (81, 99))	('cancers', 'Disease', (224, 231))	('alterations', 'Var', (66, 77))
3646	33530540	Acid suppression increases blood levels of gastrin in most patients.	('Acid', 'Var', (0, 4))	('increases', 'PosReg', (17, 26))	('blood levels of gastrin', 'Phenotype', 'HP:0500167', (27, 50))	('patients', 'Species', '9606', (59, 67))	('blood levels of gastrin', 'MPA', (27, 50))
3676	33530540	Indomethacin caused high-grade inflammation of the gastric mucosa, as manifested by the significant increments in gastric mucosal inflammatory cell infiltration, and elevated TNF-alpha and IL-6 content, compared to the intact gastric mucosa in control rats.	('Indomethacin', 'Var', (0, 12))	('TNF-alpha', 'Gene', (175, 184))	('rats', 'Species', '10116', (252, 256))	('inflammation of the gastric mucosa', 'Disease', 'MESH:D013272', (31, 65))	('IL-6', 'molecular_function', 'GO:0005138', ('189', '193'))	('increments', 'PosReg', (100, 110))	('rat', 'Species', '10116', (252, 255))	('Indomethacin', 'Chemical', 'MESH:D007213', (0, 12))	('TNF-alpha', 'Gene', '24835', (175, 184))	('inflammation of the gastric mucosa', 'Disease', (31, 65))	('rat', 'Species', '10116', (154, 157))	('gastric mucosal', 'Disease', 'MESH:D013272', (114, 129))	('inflammation', 'biological_process', 'GO:0006954', ('31', '43'))	('IL-6', 'Gene', (189, 193))	('gastric mucosal', 'Disease', (114, 129))	('IL-6', 'Gene', '24498', (189, 193))	('elevated', 'PosReg', (166, 174))
3694	33530540	; methodology, software, formal analysis, data curation and validation, M.N., M.A.E.R., W.A., M.A.O.A., A.M.E.-S., M.S.	('rat', 'Species', '10116', (49, 52))	('M.A.E.R.', 'Var', (78, 86))	('M.A.O.A.', 'Var', (94, 102))
3695	33530540	writing:original draft preparation, M.N., M.A.E.R., W.A., M.A.O.A., A.M.E.-S., M.S.	('M.A.O.A.', 'Var', (58, 66))	('M.A.E.R.', 'Var', (42, 50))	('rat', 'Species', '10116', (28, 31))
3725	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))	('satiety', 'MPA', (255, 262))	('red', 'Gene', (267, 270))	('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))
3739	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))	('chronic diseases', 'Disease', (123, 139))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('chronic diseases', 'Disease', 'MESH:D002908', (123, 139))	('improves', 'PosReg', (51, 59))	('fiber', 'Chemical', 'MESH:D004043', (38, 43))	('satiety', 'MPA', (89, 96))	('high dietary fiber', 'Var', (25, 43))
3776	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))
3793	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))
3799	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))
3801	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))
3829	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.	('modification', 'Var', (50, 62))	('gastroesophageal reflux', 'MPA', (66, 89))	('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', (239, 245))	('cancer', 'Disease', (178, 184))	('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))
3833	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))
3839	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))
3865	30879091	The modulation of lncRNAs by phytochemicals can produce therapeutic effects in some cancer types (Table 2).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('modulation', 'Var', (4, 14))	('cancer', 'Disease', (84, 90))
3868	30879091	Moreover, the modulation of lncRNAs by phytochemicals can lead to the inhibition of survival, proliferation, migration, invasion, metastasis, and epithelial-to-mesenchymal transition (Fig.	('inhibition', 'NegReg', (70, 80))	('rat', 'Species', '10116', (101, 104))	('modulation', 'Var', (14, 24))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('146', '182'))	('epithelial-to-mesenchymal transition', 'CPA', (146, 182))	('invasion', 'CPA', (120, 128))	('metastasis', 'CPA', (130, 140))	('proliferation', 'CPA', (94, 107))	('migration', 'CPA', (109, 118))	('rat', 'Species', '10116', (112, 115))	('survival', 'CPA', (84, 92))
3869	30879091	The modulation of lncRNAs expression by phytochemicals can also lead to chemosensitization and radiosensitization of cancer cells (Fig.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('modulation', 'Var', (4, 14))	('lead to', 'Reg', (64, 71))	('radiosensitization', 'CPA', (95, 113))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('chemosensitization', 'CPA', (72, 90))	('cancer', 'Disease', (117, 123))	('lncRNAs', 'Protein', (18, 25))
3875	30879091	The common lncRNAs modulated by curcumin include AF086415, AK056098, AK095147, AK294004, FLJ36000, GUCY2GP, H19, H2BFXP, HOTAIR, LINC00623, LOC100506835, MEG3, MUDENG, PANDAR, PVT1, RP1-179N16.3, and ZRANB2-AS2.	('AK095147', 'Var', (69, 77))	('PVT1', 'Gene', '5820', (176, 180))	('HOTAIR', 'Gene', '100124700', (121, 127))	('LINC00623', 'Gene', '728855', (129, 138))	('ZRANB2-AS2', 'Gene', (200, 210))	('HOTAIR', 'Gene', (121, 127))	('MEG3', 'Gene', '55384', (154, 158))	('ZRANB2-AS2', 'Gene', '100852410;9406', (200, 210))	('PANDAR', 'Gene', '101154753', (168, 174))	('PANDAR', 'Gene', (168, 174))	('RA', 'Phenotype', 'HP:0001370', (201, 203))	('LINC00623', 'Gene', (129, 138))	('curcumin', 'Chemical', 'MESH:D003474', (32, 40))	('AK056098', 'Var', (59, 67))	('H19', 'Gene', (108, 111))	('MUDENG', 'Gene', '55745', (160, 166))	('GUCY2GP', 'Gene', '390003', (99, 106))	('MUDENG', 'Gene', (160, 166))	('AK294004', 'Var', (79, 87))	('RP1', 'Gene', (182, 185))	('H19', 'Gene', '283120', (108, 111))	('GUCY2GP', 'Gene', (99, 106))	('AF086415', 'Var', (49, 57))	('H2BFXP', 'Gene', (113, 119))	('MEG3', 'Gene', (154, 158))	('FLJ36000', 'Var', (89, 97))	('PVT1', 'Gene', (176, 180))	('RP1', 'Gene', '6101', (182, 185))	('H2BFXP', 'Gene', '767811', (113, 119))	('LOC100506835', 'Var', (140, 152))
3892	30879091	The promoter of CDKN1A antisense DNA damage-activated RNA (PANDAR) is an lncRNA with 1506 nucleotides in length.	('antisense DNA', 'Var', (23, 36))	('CDKN1A', 'Gene', (16, 22))	('CDKN1A', 'Gene', '1026', (16, 22))	('PANDAR', 'Gene', '101154753', (59, 65))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('PANDAR', 'Gene', (59, 65))	('RNA', 'cellular_component', 'GO:0005562', ('54', '57'))
3896	30879091	The proliferation of CRC DLD-1 cells was not affected by the knockdown of PANDAR.	('knockdown', 'Var', (61, 70))	('PANDAR', 'Gene', (74, 80))	('rat', 'Species', '10116', (11, 14))	('PANDAR', 'Gene', '101154753', (74, 80))
3899	30879091	The silencing of PANDAR enhanced apoptosis and attenuated senescence in curcumin-treated DLD-1 cells.	('apoptosis', 'biological_process', 'GO:0097194', ('33', '42'))	('PANDAR', 'Gene', '101154753', (17, 23))	('apoptosis', 'CPA', (33, 42))	('PANDAR', 'Gene', (17, 23))	('senescence', 'MPA', (58, 68))	('apoptosis', 'biological_process', 'GO:0006915', ('33', '42'))	('senescence', 'biological_process', 'GO:0010149', ('58', '68'))	('enhanced', 'PosReg', (24, 32))	('attenuated', 'NegReg', (47, 57))	('curcumin', 'Chemical', 'MESH:D003474', (72, 80))	('silencing', 'Var', (4, 13))
3901	30879091	Furthermore, PANDAR silencing can also switch cells from senescence to apoptosis partly by stimulating the expression of the p53-up-regulated modulator of apoptosis (PUMA).	('PUMA', 'Gene', (166, 170))	('apoptosis', 'biological_process', 'GO:0006915', ('155', '164'))	('stimulating', 'Reg', (91, 102))	('PANDAR', 'Gene', (13, 19))	('expression', 'MPA', (107, 117))	('p53-up-regulated modulator of apoptosis', 'Gene', (125, 164))	('apoptosis', 'biological_process', 'GO:0097194', ('71', '80'))	('PUMA', 'Gene', '27113', (166, 170))	('p53-up-regulated modulator of apoptosis', 'Gene', '27113', (125, 164))	('apoptosis', 'biological_process', 'GO:0006915', ('71', '80'))	('silencing', 'Var', (20, 29))	('senescence', 'biological_process', 'GO:0010149', ('57', '67'))	('apoptosis', 'biological_process', 'GO:0097194', ('155', '164'))	('switch', 'Reg', (39, 45))	('PANDAR', 'Gene', '101154753', (13, 19))
3910	30879091	It was concluded that induction of DNA hypomethylation and MEG3 by DNC could be an effective choice for epigenetic therapy of HCC.	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('MEG3', 'Gene', (59, 63))	('HCC', 'Disease', (126, 129))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('35', '54'))	('hypomethylation', 'Var', (39, 54))	('HCC', 'Phenotype', 'HP:0001402', (126, 129))	('DNC', 'Chemical', '-', (67, 70))	('MEG3', 'Gene', '55384', (59, 63))
3924	30879091	The EVs were found to induce drug resistance in ovarian cancer cells that were weakened by curcumin treatment.	('curcumin', 'Chemical', 'MESH:D003474', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('ovarian cancer', 'Disease', 'MESH:D010051', (48, 62))	('drug resistance', 'CPA', (29, 44))	('EVs', 'Var', (4, 7))	('drug resistance', 'biological_process', 'GO:0009315', ('29', '44'))	('drug resistance', 'biological_process', 'GO:0042493', ('29', '44'))	('induce', 'Reg', (22, 28))	('drug resistance', 'Phenotype', 'HP:0020174', (29, 44))	('ovarian cancer', 'Disease', (48, 62))
3929	30879091	Furthermore, curcumin significantly up-regulated the expression of lncRNAs such as GUCY2GP, H2BFXP, and LINC00623, while the expression of ZRANB2-AS2, LOC100506835, and FLJ36000 IncRNA was down-regulated.	('ZRANB2-AS2', 'Gene', '100852410;9406', (139, 149))	('down-regulated', 'NegReg', (189, 203))	('H2BFXP', 'Gene', (92, 98))	('RA', 'Phenotype', 'HP:0001370', (140, 142))	('LINC00623', 'Gene', '728855', (104, 113))	('curcumin', 'Chemical', 'MESH:D003474', (13, 21))	('FLJ36000', 'Var', (169, 177))	('up-regulated', 'PosReg', (36, 48))	('GUCY2GP', 'Gene', '390003', (83, 90))	('ZRANB2-AS2', 'Gene', (139, 149))	('H2BFXP', 'Gene', '767811', (92, 98))	('LINC00623', 'Gene', (104, 113))	('GUCY2GP', 'Gene', (83, 90))	('expression', 'MPA', (53, 63))	('LOC100506835', 'Var', (151, 163))
3930	30879091	In another study, curcumin-induced radiosensitization of nasopharyngeal carcinoma cells was mediated partly through modulation of lncRNAs such as AF086415, AK056098, AK095147, AK294004, MUDENG, and RP1-179N16.3.	('AK294004', 'Var', (176, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('AK095147', 'Var', (166, 174))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (57, 81))	('carcinoma', 'Disease', (72, 81))	('AK056098', 'Var', (156, 164))	('MUDENG', 'Gene', '55745', (186, 192))	('MUDENG', 'Gene', (186, 192))	('RP1', 'Gene', '6101', (198, 201))	('curcumin', 'Chemical', 'MESH:D003474', (18, 26))	('AF086415', 'Var', (146, 154))	('radiosensitization', 'CPA', (35, 53))	('RP1', 'Gene', (198, 201))	('carcinoma', 'Disease', 'MESH:D009369', (72, 81))
3951	30879091	Furthermore, the knockdown of AK001796 was associated with a significant reduction in the viability of lung cancer cells and reduced tumor growth.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('AK001796', 'Gene', (30, 38))	('reduced', 'NegReg', (125, 132))	('AK001796', 'Gene', '541471', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('viability', 'CPA', (90, 99))	('lung cancer', 'Disease', (103, 114))	('tumor', 'Disease', (133, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('knockdown', 'Var', (17, 26))	('reduction', 'NegReg', (73, 82))
3970	30879091	Furthermore, H19 suppressed the promoter activity of BIK by recruiting EZH2 and by trimethylating the histone H3 at lysine 27.	('EZH2', 'Gene', (71, 75))	('trimethylating', 'Var', (83, 97))	('recruiting', 'PosReg', (60, 70))	('BIK', 'Gene', '638', (53, 56))	('EZH2', 'Gene', '2146', (71, 75))	('promoter activity', 'MPA', (32, 49))	('lysine', 'Chemical', 'MESH:D008239', (116, 122))	('suppressed', 'NegReg', (17, 27))	('BIK', 'Gene', (53, 56))	('H19', 'Gene', '283120', (13, 16))	('H19', 'Gene', (13, 16))
3980	30879091	The genetic polymorphisms of GAS5 can also predict the response of nasopharyngeal carcinoma patients to paclitaxel.	('carcinoma', 'Disease', 'MESH:D009369', (82, 91))	('predict', 'Reg', (43, 50))	('paclitaxel', 'Chemical', 'MESH:D017239', (104, 114))	('patients', 'Species', '9606', (92, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (67, 91))	('genetic polymorphisms', 'Var', (4, 25))	('GAS', 'molecular_function', 'GO:0034005', ('29', '32'))	('response', 'MPA', (55, 63))	('carcinoma', 'Disease', (82, 91))	('GAS5', 'Gene', (29, 33))
3981	30879091	The inhibition of MA-linc1 enhances cell death in cancer cells induced by paclitaxel.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('MA-linc1', 'Gene', '100505636', (18, 26))	('cell death', 'biological_process', 'GO:0008219', ('36', '46'))	('inhibition', 'Var', (4, 14))	('death', 'Disease', 'MESH:D003643', (41, 46))	('death', 'Disease', (41, 46))	('paclitaxel', 'Chemical', 'MESH:D017239', (74, 84))	('enhances', 'PosReg', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('MA-linc1', 'Gene', (18, 26))
3991	30879091	The knockdown of ZFAS1 can suppress the growth, proliferation, cell-cycle progression, migration, and invasion.	('ZFAS1', 'Gene', (17, 22))	('migration', 'CPA', (87, 96))	('invasion', 'CPA', (102, 110))	('ZFAS1', 'Gene', '441951', (17, 22))	('cell-cycle', 'biological_process', 'GO:0007049', ('63', '73'))	('cell-cycle progression', 'CPA', (63, 85))	('growth', 'CPA', (40, 46))	('suppress', 'NegReg', (27, 35))	('knockdown', 'Var', (4, 13))	('rat', 'Species', '10116', (55, 58))	('rat', 'Species', '10116', (90, 93))
3999	30879091	Some other lncRNAs associated with paclitaxel resistance include H19 in breast cancer; SNHG12 in NSCLC; XR_938728, XR_947831, XR_938392, XR_948297, NR_036503, NR_073113, and NR_103801 in ovarian cancer; LINC00672 in endometrial cancer; n375709 in nasopharyngeal carcinoma ; HIF1AAS2 and AK124454 in triple-negative breast cancer; linc-ROR in breast cancer; KCNQ1OT1 and ANRIL in lung adenocarcinoma; and RP11-381N20.2 in cervical cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (187, 201))	('breast cancer', 'Disease', (342, 355))	('endometrial cancer', 'Disease', (216, 234))	('SNHG12', 'Gene', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('H19', 'Gene', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (379, 398))	('endometrial cancer', 'Disease', 'MESH:D016889', (216, 234))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (379, 398))	('cancer', 'Disease', (430, 436))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('LINC00672', 'Gene', (203, 212))	('ANRIL', 'Gene', '100048912', (370, 375))	('HIF1AAS2', 'Gene', '100750247', (274, 282))	('H19', 'Gene', '283120', (65, 68))	('paclitaxel', 'Chemical', 'MESH:D017239', (35, 45))	('ovarian cancer', 'Disease', (187, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (315, 328))	('carcinoma', 'Phenotype', 'HP:0030731', (389, 398))	('carcinoma', 'Disease', (262, 271))	('cancer', 'Disease', (349, 355))	('SNHG12', 'Gene', '85028', (87, 93))	('carcinoma', 'Disease', (389, 398))	('HIF1AAS2', 'Gene', (274, 282))	('n375709', 'Var', (236, 243))	('RP11', 'Gene', '26121', (404, 408))	('ovarian cancer', 'Phenotype', 'HP:0100615', (187, 201))	('cancer', 'Disease', (79, 85))	('breast cancer', 'Disease', 'MESH:D001943', (315, 328))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('breast cancer', 'Disease', (315, 328))	('cancer', 'Disease', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (247, 271))	('cancer', 'Disease', (322, 328))	('cancer', 'Disease', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('ANRIL', 'Gene', (370, 375))	('carcinoma', 'Disease', 'MESH:D009369', (262, 271))	('ROR', 'Gene', (335, 338))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (430, 436))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('carcinoma', 'Disease', 'MESH:D009369', (389, 398))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('KCNQ1OT1', 'Gene', '10984', (357, 365))	('ROR', 'Gene', '100885779', (335, 338))	('LINC00672', 'Gene', '100505576', (203, 212))	('breast cancer', 'Phenotype', 'HP:0003002', (342, 355))	('NSCLC', 'Disease', (97, 102))	('endometrial cancer', 'Phenotype', 'HP:0012114', (216, 234))	('lung adenocarcinoma', 'Disease', (379, 398))	('cancer', 'Disease', 'MESH:D009369', (349, 355))	('RP11', 'Gene', (404, 408))	('KCNQ1OT1', 'Gene', (357, 365))	('AK124454', 'Var', (287, 295))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('breast cancer', 'Disease', 'MESH:D001943', (342, 355))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
4004	30879091	EGCG can modulate multiple cell signaling pathways in tumor cells.	('modulate', 'Reg', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('signaling', 'biological_process', 'GO:0023052', ('32', '41'))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('EGCG', 'Var', (0, 4))	('tumor', 'Disease', (54, 59))
4007	30879091	The identification of lncRNA AT102202 and its potential mRNA target, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) was of particular importance.	('3-hydroxy-3-methylglutaryl coenzyme A reductase', 'Gene', (69, 116))	('AT102202', 'Var', (29, 37))	('HMGCR', 'Gene', (118, 123))	('3-hydroxy-3-methylglutaryl coenzyme A reductase', 'Gene', '3156', (69, 116))	('HMGCR', 'Gene', '3156', (118, 123))
4008	30879091	The quantitative PCR analyses revealed a down-regulation in the mRNA level of HMGCR and an up-regulation in AT102202.	('HMGCR', 'Gene', '3156', (78, 83))	('AT102202', 'Var', (108, 116))	('regulation', 'biological_process', 'GO:0065007', ('94', '104'))	('regulation', 'biological_process', 'GO:0065007', ('46', '56'))	('up-regulation', 'PosReg', (91, 104))	('down-regulation', 'NegReg', (41, 56))	('HMGCR', 'Gene', (78, 83))	('mRNA level', 'MPA', (64, 74))
4009	30879091	Furthermore, silencing of AT102202 was associated with an increased expression of HMGCR.	('increased', 'PosReg', (58, 67))	('expression', 'MPA', (68, 78))	('HMGCR', 'Gene', '3156', (82, 87))	('HMGCR', 'Gene', (82, 87))	('AT102202', 'Var', (26, 34))	('silencing', 'Var', (13, 22))
4010	30879091	The authors of this study concluded that AT102202 is involved in the improvement of cholesterol metabolism by EGCG.	('improvement', 'PosReg', (69, 80))	('EGCG', 'Gene', (110, 114))	('cholesterol', 'Chemical', 'MESH:D002784', (84, 95))	('EGCG', 'Chemical', 'MESH:C045651', (110, 114))	('cholesterol metabolism', 'biological_process', 'GO:0008203', ('84', '106'))	('AT102202', 'Var', (41, 49))	('cholesterol metabolism', 'MPA', (84, 106))
4016	30879091	EGCG can also enhance the sensitivity of ovarian cancer cells to cDDP.	('ovarian cancer', 'Disease', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ovarian cancer', 'Phenotype', 'HP:0100615', (41, 55))	('enhance', 'PosReg', (14, 21))	('cDDP', 'Chemical', '-', (65, 69))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('ovarian cancer', 'Disease', 'MESH:D010051', (41, 55))	('EGCG', 'Var', (0, 4))	('sensitivity', 'MPA', (26, 37))
4037	30879091	Furthermore, the gene silencing of HOTAIR was associated with a decrease in the proliferation, migration and invasion, while an induction in cell-cycle arrest and apoptosis was observed.	('apoptosis', 'biological_process', 'GO:0006915', ('163', '172'))	('apoptosis', 'CPA', (163, 172))	('apoptosis', 'biological_process', 'GO:0097194', ('163', '172'))	('HOTAIR', 'Gene', (35, 41))	('invasion', 'CPA', (109, 117))	('HOTAIR', 'Gene', '100124700', (35, 41))	('decrease', 'NegReg', (64, 72))	('arrest', 'Disease', 'MESH:D006323', (152, 158))	('gene silencing', 'Var', (17, 31))	('rat', 'Species', '10116', (98, 101))	('gene silencing', 'biological_process', 'GO:0016458', ('17', '31'))	('induction', 'Reg', (128, 137))	('arrest', 'Disease', (152, 158))	('cell-cycle arrest', 'biological_process', 'GO:0007050', ('141', '158'))	('rat', 'Species', '10116', (87, 90))
4078	30879091	Interestingly, GA-induced apoptosis in bladder cancer cells was suppressed by knockdown of GAS5.	('GAS', 'molecular_function', 'GO:0034005', ('91', '94'))	('bladder cancer', 'Phenotype', 'HP:0009725', (39, 53))	('bladder cancer', 'Disease', 'MESH:D001749', (39, 53))	('apoptosis', 'CPA', (26, 35))	('GAS5', 'Gene', (91, 95))	('suppressed', 'NegReg', (64, 74))	('knockdown', 'Var', (78, 87))	('bladder cancer', 'Disease', (39, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('26', '35'))	('apoptosis', 'biological_process', 'GO:0006915', ('26', '35'))	('GA', 'Chemical', 'MESH:C052659', (91, 93))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('GA', 'Chemical', 'MESH:C052659', (15, 17))
4117	30879091	The alkaloid also induced the expression of cancer susceptibility candidate 2 (CASC2) lncRNA, the silencing of which reversed the effects of sanguinarine.	('expression', 'MPA', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('silencing', 'Var', (98, 107))	('cancer susceptibility candidate 2', 'Gene', (44, 77))	('lncRNA', 'Protein', (86, 92))	('cancer susceptibility candidate 2', 'Gene', '255082', (44, 77))	('CASC2', 'Gene', '255082', (79, 84))	('CASC2', 'Gene', (79, 84))	('sanguinarine', 'Chemical', 'MESH:C005705', (141, 153))
4119	30879091	EIF4A3 could bind to CASC2; the knockdown of EIF4A3 reversed the effects of sanguinarine plus CASC2 silencing.	('CASC2', 'Gene', '255082', (21, 26))	('CASC2', 'Gene', (94, 99))	('sanguinarine', 'Chemical', 'MESH:C005705', (76, 88))	('EIF4', 'cellular_component', 'GO:0008304', ('45', '49'))	('CASC2', 'Gene', '255082', (94, 99))	('EIF4A3', 'Gene', (0, 6))	('EIF4A3', 'Gene', (45, 51))	('knockdown', 'Var', (32, 41))	('EIF4A3', 'Gene', '9775', (45, 51))	('EIF4A3', 'Gene', '9775', (0, 6))	('CASC2', 'Gene', (21, 26))	('EIF4', 'cellular_component', 'GO:0008304', ('0', '4'))
4131	30879091	The disruption of LINC01116 using CRISPR/CAS9 method suppressed the colony-forming ability of PC-3 cells by fourfold.	('PC-3', 'CellLine', 'CVCL:0035', (94, 98))	('LINC01116', 'Gene', (18, 27))	('colony-forming ability of PC-3 cells', 'CPA', (68, 104))	('LINC01116', 'Gene', '375295', (18, 27))	('disruption', 'Var', (4, 14))	('suppressed', 'NegReg', (53, 63))	('CAS', 'cellular_component', 'GO:0005650', ('41', '44'))
4133	30879091	Overall, these results suggest that the modulation of lncRNAs by SFN may contribute to its activities against prostate cancer.	('SFN', 'Chemical', 'MESH:C016766', (65, 68))	('prostate cancer', 'Disease', 'MESH:D011471', (110, 125))	('SFN', 'Gene', (65, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (110, 125))	('activities', 'MPA', (91, 101))	('modulation', 'Var', (40, 50))	('prostate cancer', 'Disease', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
4152	30879091	Because most chronic diseases are caused by dysregulation of multiple genes, phytochemicals possess promise against these diseases.	('caused by', 'Reg', (34, 43))	('chronic diseases', 'Disease', 'MESH:D002908', (13, 29))	('chronic diseases', 'Disease', (13, 29))	('dysregulation', 'Var', (44, 57))
4160	32635246	The most prominent proteins present in milk are the caseins consisting of alpha-s1, alpha-s2, and beta and kappa-caseins, and the whey proteins alpha-lactalbumin and beta-lactoglobulin.	('alpha-s1', 'Var', (74, 82))	('alpha-lactalbumin', 'Gene', '281894', (144, 161))	('alpha-lactalbumin', 'Gene', (144, 161))	('kappa-casein', 'Gene', '281728', (107, 119))	('alpha-s2', 'Var', (84, 92))	('beta-lactoglobulin', 'Protein', (166, 184))	('kappa-casein', 'Gene', (107, 119))	('beta', 'Protein', (98, 102))
4178	32635246	The native molecule contains two intramolecular disulfide bonds (Cys106-Cys119 and Cys66-Cys160) and one free thiol group (Cys121).	('Cys66', 'Chemical', '-', (83, 88))	('Cys119', 'Chemical', '-', (72, 78))	('disulfide', 'Chemical', 'MESH:D004220', (48, 57))	('Cys106', 'Chemical', '-', (65, 71))	('Cys121', 'Chemical', '-', (123, 129))	('Cys66-Cys160', 'Var', (83, 95))	('Cys160', 'Chemical', '-', (89, 95))	('thiol', 'Chemical', 'MESH:D013438', (110, 115))	('Cys106-Cys119', 'Var', (65, 78))
4179	32635246	The free thiol group, Cys121, and the disulfide bond Cys106-Cys 119, are buried, whereas the other disulfide bond, Cys66-Cys160, is positioned on the outer surface in a mobile region of the molecule.	('Cys106-Cys 119', 'Var', (53, 67))	('Cys121', 'Chemical', '-', (22, 28))	('thiol', 'Chemical', 'MESH:D013438', (9, 14))	('disulfide', 'Chemical', 'MESH:D004220', (38, 47))	('Cys', 'Chemical', 'MESH:D003545', (115, 118))	('Cys66', 'Chemical', '-', (115, 120))	('Cys', 'Chemical', 'MESH:D003545', (22, 25))	('Cys', 'Chemical', 'MESH:D003545', (60, 63))	('Cys66-Cys160', 'Var', (115, 127))	('Cys', 'Chemical', 'MESH:D003545', (53, 56))	('Cys106', 'Chemical', '-', (53, 59))	('Cys121', 'Var', (22, 28))	('Cys160', 'Chemical', '-', (121, 127))	('disulfide', 'Chemical', 'MESH:D004220', (99, 108))	('Cys', 'Chemical', 'MESH:D003545', (121, 124))
4183	32635246	For example, bovine beta-lactoglobulin variants B and C, but not variant A, were observed to form high molecular weight aggregates at pH 6.7, and variant B was found to be more thermostable than variant A.	('bovine', 'Species', '9913', (13, 19))	('high molecular weight aggregates', 'MPA', (98, 130))	('variants', 'Var', (39, 47))	('more', 'PosReg', (172, 176))
4208	32635246	Many of the lactosylation sites of beta-lactoglobulin in commercially available pasteurized milk have now been identified and include K8, K14, K47, K60, K69, K75, K77, K83, K91, K100, K101, and K135.	('K14', 'Gene', (138, 141))	('K77', 'Var', (163, 166))	('K14', 'Gene', '404111', (138, 141))	('K75', 'Gene', '539683', (158, 161))	('K69', 'Var', (153, 156))	('K91', 'Var', (173, 176))	('K60', 'Var', (148, 151))	('K47', 'Var', (143, 146))	('K83', 'Gene', (168, 171))	('K100', 'Var', (178, 182))	('K135', 'Var', (194, 198))	('K83', 'Gene', '507421', (168, 171))	('K101', 'Var', (184, 188))	('K75', 'Gene', (158, 161))
4211	32635246	In extension to this observation, conjugation of beta-lactoglobulin with alpha-dicarbonyl compounds, a Maillard reaction intermediate, or glucose, was shown to inhibit fibril growth.	('glucose', 'Chemical', 'MESH:D005947', (138, 145))	('conjugation', 'Var', (34, 45))	('inhibit', 'NegReg', (160, 167))	('alpha-dicarbonyl compounds', 'Chemical', '-', (73, 99))	('fibril', 'cellular_component', 'GO:0099512', ('168', '174'))	('conjugation', 'biological_process', 'GO:0000746', ('34', '45'))	('beta-lactoglobulin', 'Protein', (49, 67))	('fibril growth', 'CPA', (168, 181))
4253	32635246	At the same time, prediction of cleavage sites using the ExPASy tool PeptideCutter suggests that trypsin preferentially targets arginine and lysine groups, indicating that lysine modification may well affect the digestibility of proteins.	('digestibility of proteins', 'MPA', (212, 237))	('lysine', 'Chemical', 'MESH:D008239', (141, 147))	('lysine', 'Var', (172, 178))	('affect', 'Reg', (201, 207))	('arginine', 'Chemical', 'MESH:D001120', (128, 136))	('lysine', 'Chemical', 'MESH:D008239', (172, 178))	('arginine', 'MPA', (128, 136))
4255	32635246	It was indeed experimentally validated that lysine modification impairs susceptibility of proteins to enzymatic digestion (reviewed in).	('lysine modification', 'Var', (44, 63))	('digestion', 'biological_process', 'GO:0007586', ('112', '121'))	('impairs', 'NegReg', (64, 71))	('proteins', 'Protein', (90, 98))	('lysine', 'Chemical', 'MESH:D008239', (44, 50))	('susceptibility of', 'MPA', (72, 89))
4256	32635246	Various mechanisms to explain impaired digestion have been suggested, including direct protection of lysine as a proteolytic target site, prevention of docking of proteolytic enzymes as a result of a modified lysine residue located immediately adjacent to an intended cleavage site, or by means of cross-linking with target residues.	('modified', 'Var', (200, 208))	('lysine', 'Chemical', 'MESH:D008239', (209, 215))	('digestion', 'biological_process', 'GO:0007586', ('39', '48'))	('lysine', 'Chemical', 'MESH:D008239', (101, 107))	('docking', 'MPA', (152, 159))	('lysine', 'Protein', (209, 215))
4266	32635246	Uptake of aggregated beta-lactoglobulin by Peyer's patches was associated with an increased production of Th2-associated antibodies and cytokines such as IL-5, IL-13, and IFN-gamma.	('IFN-gamma', 'Gene', (171, 180))	('IFN-gamma', 'Gene', '281237', (171, 180))	('Uptake', 'MPA', (0, 6))	('IL-5', 'Gene', (154, 158))	('Th2-associated antibodies', 'Protein', (106, 131))	('IL-5', 'Gene', '280825', (154, 158))	('IL-13', 'molecular_function', 'GO:0005144', ('160', '165'))	('Uptake', 'biological_process', 'GO:0098739', ('0', '6'))	('IL-13', 'Gene', '281247', (160, 165))	('Uptake', 'biological_process', 'GO:0098657', ('0', '6'))	('beta-lactoglobulin', 'Protein', (21, 39))	('increased', 'PosReg', (82, 91))	('IL-5', 'molecular_function', 'GO:0005137', ('154', '158'))	('IL-13', 'Gene', (160, 165))	('aggregated', 'Var', (10, 20))	('production', 'MPA', (92, 102))
4270	32635246	The involvement of APCs was demonstrated as antibodies against CD2 or its ligand CD58 reduced beta-lactoglobulin-mediated proliferation of lymphocytes.	('CD58', 'Gene', '782186', (81, 85))	('ligand', 'molecular_function', 'GO:0005488', ('74', '80'))	('reduced', 'NegReg', (86, 93))	('beta-lactoglobulin-mediated proliferation', 'MPA', (94, 135))	('CD2', 'Gene', '497022', (63, 66))	('CD58', 'Gene', (81, 85))	('CD2', 'Gene', (63, 66))	('antibodies', 'Var', (44, 54))
4273	32635246	beta-Lactoglobulin was also found to induce neutrophilic superoxide production and induce translocation of p47phox subunit of cytosolic NADPH-oxidase to the plasma membrane which is required for activation of NADPH-oxidase-mediated superoxide production.	('NADPH-oxidase', 'molecular_function', 'GO:0008753', ('209', '222'))	('superoxide', 'Chemical', 'MESH:D013481', (232, 242))	('induce', 'Reg', (83, 89))	('NADPH-oxidase', 'molecular_function', 'GO:0016174', ('136', '149'))	('p47phox', 'Var', (107, 114))	('neutrophilic superoxide production', 'MPA', (44, 78))	('beta-Lactoglobulin', 'Gene', (0, 18))	('superoxide', 'Chemical', 'MESH:D013481', (57, 67))	('NADPH-oxidase', 'molecular_function', 'GO:0016174', ('209', '222'))	('NADPH-oxidase', 'molecular_function', 'GO:0008753', ('136', '149'))	('translocation', 'MPA', (90, 103))	('plasma membrane', 'cellular_component', 'GO:0005886', ('157', '172'))	('beta-Lactoglobulin', 'Gene', '280838', (0, 18))	('induce', 'PosReg', (37, 43))
4317	30931134	Whilst it is not known whether our patient exhibited any weaknesses in the fixation of his gastric ligaments, we would suggest that the presence of a hiatus hernia could still predispose individuals to gastrogastric intussusception via a similar mechanism, without simultaneous involvement of the oesophagus.	('hiatus hernia', 'Disease', 'MESH:D006551', (150, 163))	('predispose', 'Reg', (176, 186))	('hernia', 'Phenotype', 'HP:0100790', (157, 163))	('patient', 'Species', '9606', (35, 42))	('weakness', 'Disease', 'MESH:D018908', (57, 65))	('weakness', 'Disease', (57, 65))	('hiatus hernia', 'Phenotype', 'HP:0002036', (150, 163))	('intussusception', 'Phenotype', 'HP:0002576', (216, 231))	('presence', 'Var', (136, 144))	('hiatus hernia', 'Disease', (150, 163))	('gastrogastric intussusception', 'Disease', (202, 231))
4476	29954326	H. pylori infection has been shown to increase the production of reactive oxygen metabolites, which often cause extensive tissue damage and DNA damage, leading to mutations of oncogenes and tumor suppressors.	('oncogenes', 'Gene', (176, 185))	('increase', 'PosReg', (38, 46))	('leading to', 'Reg', (152, 162))	('mutations', 'Var', (163, 172))	('oxygen', 'Chemical', 'MESH:D010100', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('H. pylori', 'Species', '210', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('H. pylori infection', 'Phenotype', 'HP:0005202', (0, 19))	('tumor', 'Disease', (190, 195))	('DNA', 'cellular_component', 'GO:0005574', ('140', '143'))	('production of reactive oxygen metabolites', 'MPA', (51, 92))
4524	29946149	While half of the world's population harbors H. pylori, only 15-20% of them show symptoms of gastritis, gastric ulcers and cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('H. pylori', 'Species', '210', (45, 54))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('gastric ulcers', 'Phenotype', 'HP:0002592', (104, 118))	('gastritis', 'Phenotype', 'HP:0005263', (93, 102))	('gastritis', 'Disease', 'MESH:D005756', (93, 102))	('gastric ulcers', 'Disease', (104, 118))	('cancer', 'Disease', (123, 129))	('gastric ulcers', 'Disease', 'MESH:D013276', (104, 118))	('gastritis', 'Disease', (93, 102))	('H. pylori', 'Var', (45, 54))
4551	29946149	As these mucins also varied in binding to H. pylori adhesins, we compared the motility of the wild type J99 with an adhesin deletion mutant J99DeltababADeltasabA lacking the blood group binding adhesin (BabA) and the sialic acid binding adhesin (SabA) that bind the Leb and SLex/a respectively.	('Leb', 'Gene', '4586', (266, 269))	('sialic acid binding', 'molecular_function', 'GO:0033691', ('217', '236'))	('mucin', 'Gene', '100508689', (9, 14))	('J99DeltababADeltasabA', 'Var', (140, 161))	('H. pylori', 'Species', '210', (42, 51))	('Leb', 'Gene', (266, 269))	('SabA', 'Chemical', '-', (246, 250))	('sialic acid', 'Chemical', 'MESH:D019158', (217, 228))	('binding', 'molecular_function', 'GO:0005488', ('31', '38'))	('binding', 'molecular_function', 'GO:0005488', ('186', '193'))	('lacking', 'NegReg', (162, 169))	('mucin', 'Gene', (9, 14))
4565	29946149	The MSD as a function of time for individual particles tracked in HM5T, HM1NS, and HM3NG mucin solutions (15 mg/ml) as well as in mucin solutions containing bacteria (J99 WT or J99DeltababADeltasabA) are presented in the Supplementary Information Fig.	('J99DeltababADeltasabA', 'Var', (177, 198))	('mucin', 'Gene', (130, 135))	('MSD', 'Disease', (4, 7))	('MSD', 'Disease', 'MESH:D052517', (4, 7))	('HM1NS', 'Chemical', '-', (72, 77))	('mucin', 'Gene', (89, 94))	('HM5T', 'CellLine', 'CVCL:M679', (66, 70))	('mucin', 'Gene', '100508689', (130, 135))	('mucin', 'Gene', '100508689', (89, 94))
4573	29946149	Whether the decrease of viscosity of the tumor mucin solution is related to the presence of sialic acid in HM5T, which is not seen in the other mucins (see Table 1), or other differences is not clear.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('sialic acid', 'Protein', (92, 103))	('mucin', 'Gene', (47, 52))	('tumor', 'Disease', (41, 46))	('mucin', 'Gene', (144, 149))	('sialic acid', 'Chemical', 'MESH:D019158', (92, 103))	('mucin', 'Gene', '100508689', (47, 52))	('HM5T', 'CellLine', 'CVCL:M679', (107, 111))	('HM5T', 'Var', (107, 111))	('viscosity', 'MPA', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('decrease', 'NegReg', (12, 20))	('mucin', 'Gene', '100508689', (144, 149))
4574	29946149	Truncated glycans is a common feature of cancer cells, and this could be a potential cause of the decreased viscosity.	('viscosity', 'MPA', (108, 117))	('glycans', 'Chemical', 'MESH:D011134', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('glycans', 'Protein', (10, 17))	('cancer', 'Disease', (41, 47))	('Truncated', 'Var', (0, 9))	('decreased', 'NegReg', (98, 107))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
4577	29946149	More specifically, in the tumor sample, HM5T, the J99 WT was much more motile than the J99DeltababADeltasabA which were mostly immobile, and the highly active bacteria motion led to an enhanced diffusivity (Table 2).	('J99 WT', 'Var', (50, 56))	('diffusivity', 'MPA', (194, 205))	('enhanced', 'PosReg', (185, 193))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('more', 'PosReg', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('HM5T', 'CellLine', 'CVCL:M679', (40, 44))	('motile', 'CPA', (71, 77))
4585	29946149	In cases where highly mobile bacteria were present - such as J99 WT in HM5T or J99DeltababADeltasabA in HM3NG - we detected super-diffusivity with alpha > 1 and enhanced diffusivity D+bac/D0 > 1 (Table 2).	('J99 WT', 'Var', (61, 67))	('enhanced', 'PosReg', (161, 169))	('super-diffusivity', 'MPA', (124, 141))	('HM5T', 'CellLine', 'CVCL:M679', (71, 75))	('diffusivity D+bac/D0 > 1', 'MPA', (170, 194))	('J99DeltababADeltasabA', 'Var', (79, 100))	('alpha > 1', 'MPA', (147, 156))
4586	29946149	The values of alpha ranged from 1 to 1.2 for particles diffusing in the presence of J99 WT in the HM3NG and HM5T mucins.	('mucin', 'Gene', (113, 118))	('HM5T', 'CellLine', 'CVCL:M679', (108, 112))	('mucin', 'Gene', '100508689', (113, 118))	('J99 WT', 'Var', (84, 90))
4587	29946149	The alpha values for particles diffusing in presence of J99 WT and J99DeltababADeltasabA in PGM were 1.3 and 1.4, respectively, higher than those in the human mucins, which is due to the higher viscoelasticity of PGM.	('J99DeltababADeltasabA', 'Var', (67, 88))	('mucin', 'Gene', '100508689', (159, 164))	('J99', 'Var', (56, 59))	('PGM', 'molecular_function', 'GO:0004619', ('92', '95'))	('alpha', 'MPA', (4, 9))	('PGM', 'Chemical', '-', (92, 95))	('PGM', 'Chemical', '-', (213, 216))	('human', 'Species', '9606', (153, 158))	('particles diffusing', 'MPA', (21, 40))	('mucin', 'Gene', (159, 164))	('PGM', 'molecular_function', 'GO:0004619', ('213', '216'))	('higher', 'PosReg', (128, 134))
4588	29946149	Furthermore, these alpha values for the J99 strain are higher than those obtained in the presence of the LSH100 strain of H. pylori in PGM.	('PGM', 'molecular_function', 'GO:0004619', ('135', '138'))	('H. pylori', 'Species', '210', (122, 131))	('PGM', 'Chemical', '-', (135, 138))	('J99', 'Var', (40, 43))	('higher', 'PosReg', (55, 61))
4589	29946149	no super-diffusivity, in HM1NS, where the bacteria were much less motile than in HM5T, HM3NG, or PGM.	('super-diffusivity', 'MPA', (3, 20))	('PGM', 'Chemical', '-', (97, 100))	('HM1NS', 'Chemical', '-', (25, 30))	('HM1NS', 'Var', (25, 30))	('PGM', 'molecular_function', 'GO:0004619', ('97', '100'))	('HM5T', 'CellLine', 'CVCL:M679', (81, 85))	('less', 'NegReg', (61, 65))	('motile', 'CPA', (66, 72))
4593	29946149	The same analysis for mucin solutions in the presence of J99 WT (middle panel) and J99DeltababADeltasabA (right panel) are shown in Fig.	('J99 WT', 'Var', (57, 63))	('mucin', 'Gene', '100508689', (22, 27))	('mucin', 'Gene', (22, 27))	('J99DeltababADeltasabA', 'Var', (83, 104))
4594	29946149	We note that in presence of active bacteria motions - specifically, J99WT in HM5T solution and J99DeltababADeltasabA in HM3NG solution - there is a noticeable decrease in the viscous modulus.	('HM5T', 'CellLine', 'CVCL:M679', (77, 81))	('J99DeltababADeltasabA', 'Var', (95, 116))	('viscous modulus', 'MPA', (175, 190))	('J99WT', 'Var', (68, 73))	('decrease', 'NegReg', (159, 167))
4595	29946149	The elastic modulus (G') was detectable in HM1NS solution in presence of either J99 WT or J99DeltababADeltasabA, while in HM5T we only found G' in presence of J99 WT at low frequency.	('HM5T', 'CellLine', 'CVCL:M679', (122, 126))	('detectable', 'Reg', (29, 39))	('HM1NS', 'Chemical', '-', (43, 48))	('elastic modulus', 'MPA', (4, 19))	('J99 WT', 'Var', (80, 86))	('J99DeltababADeltasabA', 'Var', (90, 111))
4596	29946149	The gland mucin solutions HM3NG did not exhibit an elastic response in presence of either J99 WT or J99DeltababADeltasabA bacteria.	('mucin', 'Gene', (10, 15))	('mucin', 'Gene', '100508689', (10, 15))	('J99DeltababADeltasabA', 'Var', (100, 121))	('elastic response', 'MPA', (51, 67))
4611	29946149	We found that both J99 WT and J99DeltababADeltasabA were motile in broth and PGM, implying that the mutation does not alter motility in these two media.	('PGM', 'molecular_function', 'GO:0004619', ('77', '80'))	('J99DeltababADeltasabA', 'Var', (30, 51))	('PGM', 'Chemical', '-', (77, 80))	('J99', 'Var', (19, 22))
4613	29946149	Moreover, in contrast to experiments in broth or PGM where J99 WT and J99DeltababADeltasabA always behaved in a similar manner, the individual human mucins differed both in their overall effect on swimming and in that some of them affected the J99 WT and J99DeltababADeltasabA differently.	('swimming', 'CPA', (197, 205))	('human', 'Species', '9606', (143, 148))	('swimming', 'biological_process', 'GO:0036268', ('197', '205'))	('J99', 'Var', (244, 247))	('mucin', 'Gene', '100508689', (149, 154))	('PGM', 'molecular_function', 'GO:0004619', ('49', '52'))	('PGM', 'Chemical', '-', (49, 52))	('mucin', 'Gene', (149, 154))	('affected', 'Reg', (231, 239))
4618	29946149	In this section we present a detailed analysis of the trajectories of J99 WT in HM1NS, HM3NG and HM5T, and J99DeltababADeltasabA in HM3NG, as well as compare to their swimming in broth and PGM.	('swimming', 'biological_process', 'GO:0036268', ('167', '175'))	('HM1NS', 'Chemical', '-', (80, 85))	('PGM', 'molecular_function', 'GO:0004619', ('189', '192'))	('eta', 'Gene', '1909', (30, 33))	('PGM', 'Chemical', '-', (189, 192))	('J99 WT', 'Var', (70, 76))	('HM5T', 'CellLine', 'CVCL:M679', (97, 101))	('J99DeltababADeltasabA', 'Var', (107, 128))	('eta', 'Gene', (30, 33))
4622	29946149	The run speed distributions of both J99 WT and J99DeltababADeltasabA in broth and in PGM are comparable (P = 0.5 in PGM and P = 0.49 in BB10) (see Fig.	('PGM', 'molecular_function', 'GO:0004619', ('85', '88'))	('BB10', 'Chemical', '-', (136, 140))	('J99 WT', 'Var', (36, 42))	('J99DeltababADeltasabA', 'Var', (47, 68))	('PGM', 'molecular_function', 'GO:0004619', ('116', '119'))	('PGM', 'Chemical', '-', (85, 88))	('PGM', 'Chemical', '-', (116, 119))
4623	29946149	Figure 4a shows that the run speed distribution of J99 WT in HM1NS and broth are very similar, whereas in HM3NG and PGM there is a larger proportion of faster swimmers compared to broth.	('PGM', 'molecular_function', 'GO:0004619', ('116', '119'))	('PGM', 'Chemical', '-', (116, 119))	('HM1NS', 'Chemical', '-', (61, 66))	('J99 WT', 'Var', (51, 57))	('faster swimmers', 'CPA', (152, 167))
4624	29946149	On the other hand J99 WT in HM5T differs from all other mucin solutions by exhibiting a more or less uniform distribution of run speeds.	('mucin', 'Gene', '100508689', (56, 61))	('J99 WT', 'Var', (18, 24))	('mucin', 'Gene', (56, 61))	('HM5T', 'CellLine', 'CVCL:M679', (28, 32))
4625	29946149	As mentioned earlier, J99DeltababADeltasabA only swam in HM3NG out of the human mucin samples and showed a broader run speed distribution with a larger fraction of faster swimmers than in broth or PGM.	('PGM', 'Chemical', '-', (197, 200))	('mucin', 'Gene', '100508689', (80, 85))	('J99DeltababADeltasabA', 'Var', (22, 43))	('PGM', 'molecular_function', 'GO:0004619', ('197', '200'))	('mucin', 'Gene', (80, 85))	('human', 'Species', '9606', (74, 79))
4626	29946149	S5) to the run speed distribution of J99 WT and J99DeltababADeltasabA in BB10, PGM, and human mucins we found no differences between the two distributions in all cases, with K-S tests of all giving P >= 0.05 (Supplementary Information Table S6).	('PGM', 'molecular_function', 'GO:0004619', ('79', '82'))	('mucin', 'Gene', '100508689', (94, 99))	('BB10', 'Chemical', '-', (73, 77))	('PGM', 'Chemical', '-', (79, 82))	('mucin', 'Gene', (94, 99))	('human', 'Species', '9606', (88, 93))	('J99DeltababADeltasabA', 'Var', (48, 69))	('J99 WT', 'Var', (37, 43))
4628	29946149	Figure 4c,d show distributions of the reorientation angle (thetare) of J99 WT and J99DeltababADeltasabA in various media.	('J99 WT', 'Var', (71, 77))	('reorientation', 'MPA', (38, 51))	('eta', 'Gene', (61, 64))	('J99DeltababADeltasabA', 'Var', (82, 103))	('eta', 'Gene', '1909', (61, 64))
4632	29946149	To address whether the motility is altered over a period of 24 hours, we measured the motility of J99 WT in HM5T mucin and J99DeltababADeltasabA in HM3NG mucin at three different times and present these results in Fig.	('mucin', 'Gene', (154, 159))	('mucin', 'Gene', (113, 118))	('J99 WT', 'Var', (98, 104))	('motility', 'CPA', (86, 94))	('J99DeltababADeltasabA', 'Var', (123, 144))	('HM5T', 'CellLine', 'CVCL:M679', (108, 112))	('mucin', 'Gene', '100508689', (154, 159))	('mucin', 'Gene', '100508689', (113, 118))
4633	29946149	We note that J99 WT in HM5T gained a swimming advantage from 45 minutes to 2 hours (see Fig.	('swimming', 'biological_process', 'GO:0036268', ('37', '45'))	('HM5T', 'CellLine', 'CVCL:M679', (23, 27))	('swimming advantage', 'CPA', (37, 55))	('J99 WT', 'Var', (13, 19))
4637	29946149	Figure 5g shows that the percent of reversals calculated by counting over all trajectories for J99 WT is less in human mucins as compared to PGM.	('PGM', 'Chemical', '-', (141, 144))	('J99 WT', 'Var', (95, 101))	('PGM', 'molecular_function', 'GO:0004619', ('141', '144'))	('mucin', 'Gene', (119, 124))	('mucin', 'Gene', '100508689', (119, 124))	('human', 'Species', '9606', (113, 118))
4643	29946149	The detection of an elastic response in HM1NS solution in presence of J99 WT or J99DeltababADeltasabA, and in HM5T in presence of J99 WT at low frequency is further suggestive of the influence of bacteria motion on medium rheology.	('elastic response', 'MPA', (20, 36))	('HM5T', 'CellLine', 'CVCL:M679', (110, 114))	('J99 WT', 'Var', (70, 76))	('HM1NS', 'Chemical', '-', (40, 45))	('J99DeltababADeltasabA', 'Var', (80, 101))
4644	29946149	We observed that while both J99 WT and J99DeltababADeltasabA were motile in PGM solutions and broth, their ability to swim in human mucins varied considerably with bacteria being immotile in some of the human mucin solutions.	('human', 'Species', '9606', (126, 131))	('J99', 'Var', (28, 31))	('J99DeltababADeltasabA', 'Var', (39, 60))	('PGM', 'Chemical', '-', (76, 79))	('human', 'Species', '9606', (203, 208))	('mucin', 'Gene', (209, 214))	('mucin', 'Gene', '100508689', (132, 137))	('mucin', 'Gene', (132, 137))	('PGM', 'molecular_function', 'GO:0004619', ('76', '79'))	('mucin', 'Gene', '100508689', (209, 214))
4645	29946149	The motility of J99 WT and adhesin mutant were impacted differently by different mucins.	('motility', 'CPA', (4, 12))	('mucin', 'Gene', (81, 86))	('mutant', 'Var', (35, 41))	('adhesin', 'Protein', (27, 34))	('mucin', 'Gene', '100508689', (81, 86))	('impacted', 'Reg', (47, 55))
4647	29946149	The speed distributions of both WT and adhesion deletion mutant of J99 in human mucin solutions are broader and have a larger fraction of faster swimmers and less reversals in comparison to PGM or broth.	('human', 'Species', '9606', (74, 79))	('PGM', 'molecular_function', 'GO:0004619', ('190', '193'))	('J99', 'Gene', (67, 70))	('reversals', 'MPA', (163, 172))	('mucin', 'Gene', '100508689', (80, 85))	('PGM', 'Chemical', '-', (190, 193))	('mucin', 'Gene', (80, 85))	('faster swimmers', 'CPA', (138, 153))	('deletion', 'Var', (48, 56))
4650	29946149	This immotility is not due to a general toxic effect, since either the J99 WT or J99DeltababADeltasabA swam in all tested mucins and both types of bacteria swam well in broth and PGM.	('mucin', 'Gene', (122, 127))	('J99DeltababADeltasabA', 'Var', (81, 102))	('J99', 'Var', (71, 74))	('PGM', 'Chemical', '-', (179, 182))	('PGM', 'molecular_function', 'GO:0004619', ('179', '182'))	('mucin', 'Gene', '100508689', (122, 127))
4657	29946149	H. pylori strain J99 WT and its isogenic knockout mutant J99DeltababADeltasabA lacking blood group antigen binding adhesins (BabA), which binds primarily to Leb and related mucin structures, and sialic acid binding adhesins (SabA), which bind mainly to sialyl-Lewis x (SLex) and sialyl-Lewis a (SLea) were kindly provided by Prof. Thomas Boren, Umea University, Sweden.	('mucin', 'Gene', (173, 178))	('SLea', 'Disease', 'None', (295, 299))	('SabA', 'Chemical', '-', (225, 229))	('J99DeltababADeltasabA', 'Var', (57, 78))	('antigen binding', 'molecular_function', 'GO:0003823', ('99', '114'))	('sialic acid binding', 'molecular_function', 'GO:0033691', ('195', '214'))	('Leb', 'Gene', '4586', (157, 160))	('mucin', 'Gene', '100508689', (173, 178))	('lacking', 'NegReg', (79, 86))	('SLea', 'Disease', (295, 299))	('sialic acid', 'Chemical', 'MESH:D019158', (195, 206))	('blood group antigen', 'molecular_function', 'GO:0005555', ('87', '106'))	('H. pylori str', 'Species', '85963', (0, 13))	('Leb', 'Gene', (157, 160))
4658	29946149	Both J99 WT and J99DeltababADeltasabA were cultured on Brucella agar (Brucella Medium Base, Oxoid, Basingstoke, Hampshire, England) supplemented with 10% sheep blood, 1% IsoVitox (Oxoid), 4 mg/L amphotericin B, 10 mg/L vancomycin and 5 mg/L trimethoprim, then inoculated in liquid media containing 10% fetal bovine serum and 90% Brucella broth.	('bovine', 'Species', '9913', (308, 314))	('trimethoprim', 'Chemical', 'MESH:D014295', (241, 253))	('J99DeltababADeltasabA', 'Var', (16, 37))	('eta', 'Gene', '1909', (303, 306))	('eta', 'Gene', (303, 306))	('amphotericin B', 'Chemical', 'MESH:D000666', (195, 209))	('vancomycin', 'Chemical', 'MESH:D014640', (219, 229))	('sheep', 'Species', '9940', (154, 159))
4694	29721046	The association between the polymorphisms of the TOB1 gene and gastric cancer (GC) risk is still unclear.	('gastric cancer', 'Disease', (63, 77))	('gastric cancer', 'Disease', 'MESH:D013274', (63, 77))	('GC', 'Phenotype', 'HP:0012126', (79, 81))	('gastric cancer', 'Phenotype', 'HP:0012126', (63, 77))	('polymorphisms', 'Var', (28, 41))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('TOB1', 'Gene', (49, 53))	('TOB1', 'Gene', '10140', (49, 53))
4695	29721046	In this study, 506 GC cases and 548 healthy controls (HCs) were collected to evaluate the association between the eleven SNPs (rs35220381, rs12950561, rs7221352, rs61482741, rs9303568, rs34700818, rs12949115, rs9903822, rs12601477, rs11656976 and rs4626) of the TOB1 gene and GC risk in the population of northeast China.	('rs34700818', 'Var', (185, 195))	('rs12949115', 'Var', (197, 207))	('rs12949115', 'Mutation', 'rs12949115', (197, 207))	('rs7221352', 'Mutation', 'rs7221352', (151, 160))	('HCs', 'molecular_function', 'GO:0004077', ('54', '57'))	('rs12601477', 'Mutation', 'rs12601477', (220, 230))	('rs12601477', 'Var', (220, 230))	('rs34700818', 'Mutation', 'rs34700818', (185, 195))	('rs61482741', 'Mutation', 'rs61482741', (162, 172))	('rs11656976', 'Var', (232, 242))	('GC', 'Phenotype', 'HP:0012126', (276, 278))	('rs12950561', 'Mutation', 'rs12950561', (139, 149))	('TOB1', 'Gene', '10140', (262, 266))	('rs9903822', 'Var', (209, 218))	('rs9303568', 'Var', (174, 183))	('rs9303568', 'Mutation', 'rs9303568', (174, 183))	('rs12950561', 'Var', (139, 149))	('rs9903822', 'Mutation', 'rs9903822', (209, 218))	('rs4626', 'Var', (247, 253))	('rs7221352', 'Var', (151, 160))	('rs4626', 'Mutation', 'rs4626', (247, 253))	('TOB1', 'Gene', (262, 266))	('rs11656976', 'Mutation', 'rs11656976', (232, 242))	('rs35220381', 'Var', (127, 137))	('GC', 'Phenotype', 'HP:0012126', (19, 21))	('rs35220381', 'Mutation', 'rs35220381', (127, 137))	('rs61482741', 'Var', (162, 172))
4696	29721046	The results showed that there were significant associations of haplotype GCCTTGC, haplotype ATCTTGG, and haplotype GCCACGC with GC risk (P < 0.05, P < 0.001, and P <0.001, respectively).	('haplotype', 'Var', (82, 91))	('GCC', 'Gene', '2984', (115, 118))	('CG', 'Chemical', 'MESH:C028505', (119, 121))	('GC', 'Phenotype', 'HP:0012126', (78, 80))	('GCC', 'Gene', (115, 118))	('GCC', 'Gene', (73, 76))	('GC', 'Phenotype', 'HP:0012126', (128, 130))	('haplotype', 'Var', (63, 72))	('GC', 'Phenotype', 'HP:0012126', (73, 75))	('GC', 'Phenotype', 'HP:0012126', (115, 117))	('ATCTTGG', 'Gene', (92, 99))	('CT', 'Chemical', 'MESH:D002251', (94, 96))	('associations', 'Interaction', (47, 59))	('GCC', 'Gene', '2984', (73, 76))	('GC', 'Phenotype', 'HP:0012126', (120, 122))	('CT', 'Chemical', 'MESH:D002251', (75, 77))
4699	29721046	The rs34700818 CT+TT genotypes were associated with a significantly increased risk of T3-T4 (CT+TT vs CC, adjusted OR=1.71, 95% CI= 1.01-2.88, P<0.05) and TNM stage II (CT+TT vs CC, adjusted OR=2.40, 95% CI =1.27-4.52, P<0.01).	('CT', 'Chemical', 'MESH:D002251', (15, 17))	('TNM', 'Gene', '10178', (155, 158))	('rs34700818', 'Var', (4, 14))	('T3-T4', 'Disease', (86, 91))	('rs34700818', 'Mutation', 'rs34700818', (4, 14))	('TNM', 'Gene', (155, 158))	('CT', 'Chemical', 'MESH:D002251', (169, 171))	('CT', 'Chemical', 'MESH:D002251', (93, 95))
4700	29721046	The rs61482741 CG+GG genotypes were also associated with a significantly increased risk of T3-T4 (CG+GG vs CC, adjusted OR=1.71, 95% CI = 1.01-2.88, P<0.05) and TNM stage II (CG+GG vs CC, adjusted OR=2.40, 95% CI=1.27-4.52, P<0.01).	('TNM', 'Gene', '10178', (161, 164))	('CG', 'Chemical', 'MESH:C028505', (98, 100))	('rs61482741', 'Mutation', 'rs61482741', (4, 14))	('CG', 'Chemical', 'MESH:C028505', (175, 177))	('CG', 'Chemical', 'MESH:C028505', (15, 17))	('TNM', 'Gene', (161, 164))	('rs61482741', 'Var', (4, 14))	('T3-T4', 'Disease', (91, 96))
4701	29721046	The results suggest that four SNPs (rs12601477, rs4626, rs34700818 and rs61482741) of the TOB1 gene play an important role in the occurrence and development of GC in the Chinese Han population of northeast China.	('TOB1', 'Gene', '10140', (90, 94))	('rs61482741', 'Var', (71, 81))	('rs61482741', 'Mutation', 'rs61482741', (71, 81))	('rs34700818', 'Var', (56, 66))	('role', 'Reg', (118, 122))	('rs12601477', 'Mutation', 'rs12601477', (36, 46))	('rs12601477', 'Var', (36, 46))	('rs4626', 'Mutation', 'rs4626', (48, 54))	('rs34700818', 'Mutation', 'rs34700818', (56, 66))	('development', 'CPA', (145, 156))	('GC', 'Phenotype', 'HP:0012126', (160, 162))	('TOB1', 'Gene', (90, 94))	('rs4626', 'Var', (48, 54))
4712	29721046	Recently, increasing numbers of studies have identified that genetic variation plays an important role in the development of most diseases, especially in tumors.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('role', 'Reg', (98, 102))	('diseases', 'Disease', (130, 138))	('genetic variation', 'Var', (61, 78))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))
4713	29721046	Increasingly more studies have been performed to investigate the association between tumor suppressor gene polymorphisms and GC risk.	('tumor', 'Disease', (85, 90))	('tumor suppressor', 'biological_process', 'GO:0051726', ('85', '101'))	('GC', 'Phenotype', 'HP:0012126', (125, 127))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('85', '101'))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('polymorphisms', 'Var', (107, 120))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
4714	29721046	A GWAS (genome wide association study) revealed that two SNPs in the PSCA gene were associated with an increased diffuse-type GC risk in a Korean and Japanese population.	('PSCA', 'Gene', '8000', (69, 73))	('SNPs', 'Var', (57, 61))	('PSCA', 'Gene', (69, 73))	('diffuse-type GC', 'Disease', (113, 128))	('GC', 'Phenotype', 'HP:0012126', (126, 128))
4715	29721046	A meta-analysis indicated that in the P53 codon, 72 polymorphisms might be associated with GC among Asians.	('P53', 'Gene', '7157', (38, 41))	('polymorphisms', 'Var', (52, 65))	('associated', 'Reg', (75, 85))	('P53', 'Gene', (38, 41))	('GC', 'Phenotype', 'HP:0012126', (91, 93))
4716	29721046	However, the association of the SNPs in the TOB1 gene with the risk in malignant tumors (including GC) has not been reported.	('SNPs', 'Var', (32, 36))	('TOB1', 'Gene', (44, 48))	('malignant tumors', 'Disease', (71, 87))	('malignant tumors', 'Disease', 'MESH:D018198', (71, 87))	('TOB1', 'Gene', '10140', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('GC', 'Phenotype', 'HP:0012126', (99, 101))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
4718	29721046	However, it is not clear what role the TOB1 gene polymorphisms play in GC risk.	('GC', 'Phenotype', 'HP:0012126', (71, 73))	('polymorphisms', 'Var', (49, 62))	('TOB1', 'Gene', (39, 43))	('TOB1', 'Gene', '10140', (39, 43))
4719	29721046	Here, we investigated the association between some SNPs in the TOB1 gene and GC risk in a set of 506 GC patients and 548 healthy controls (HCs).	('investigated', 'Reg', (9, 21))	('SNPs', 'Var', (51, 55))	('GC', 'Phenotype', 'HP:0012126', (101, 103))	('HCs', 'molecular_function', 'GO:0004077', ('139', '142'))	('TOB1', 'Gene', (63, 67))	('TOB1', 'Gene', '10140', (63, 67))	('GC', 'Phenotype', 'HP:0012126', (77, 79))	('patients', 'Species', '9606', (104, 112))
4720	29721046	Our results suggested that SNPs (rs12601477, rs4626, rs34700818, and rs61482741) in the TOB1 gene are important markers for GC risk in the Chinese Han population.	('rs34700818', 'Mutation', 'rs34700818', (53, 63))	('TOB1', 'Gene', (88, 92))	('rs61482741', 'Mutation', 'rs61482741', (69, 79))	('rs12601477', 'Mutation', 'rs12601477', (33, 43))	('TOB1', 'Gene', '10140', (88, 92))	('rs12601477', 'Var', (33, 43))	('GC', 'Phenotype', 'HP:0012126', (124, 126))	('rs4626', 'Mutation', 'rs4626', (45, 51))	('rs34700818', 'Var', (53, 63))	('rs4626', 'Var', (45, 51))	('rs61482741', 'Var', (69, 79))
4728	29721046	Ultimately, thirteen SNPs (rs78420930, rs35220381, rs12950561, rs7221352, rs61482741, rs9303568, rs34700818, rs12949115, rs9903822, rs12601477, rs11656976, rs9898809 and rs4626) were selected in our study.	('rs11656976', 'Mutation', 'rs11656976', (144, 154))	('rs12949115', 'Var', (109, 119))	('rs12949115', 'Mutation', 'rs12949115', (109, 119))	('rs12601477', 'Var', (132, 142))	('rs12601477', 'Mutation', 'rs12601477', (132, 142))	('rs61482741', 'Var', (74, 84))	('rs34700818', 'Var', (97, 107))	('rs11656976', 'Var', (144, 154))	('rs7221352', 'Var', (63, 72))	('rs4626', 'Var', (170, 176))	('rs78420930', 'Mutation', 'rs78420930', (27, 37))	('rs9303568', 'Var', (86, 95))	('rs9903822', 'Var', (121, 130))	('rs9898809', 'Mutation', 'rs9898809', (156, 165))	('rs9303568', 'Mutation', 'rs9303568', (86, 95))	('rs12950561', 'Mutation', 'rs12950561', (51, 61))	('rs78420930', 'Var', (27, 37))	('rs9898809', 'Var', (156, 165))	('rs61482741', 'Mutation', 'rs61482741', (74, 84))	('rs34700818', 'Mutation', 'rs34700818', (97, 107))	('rs9903822', 'Mutation', 'rs9903822', (121, 130))	('rs4626', 'Mutation', 'rs4626', (170, 176))	('rs12950561', 'Var', (51, 61))	('rs7221352', 'Mutation', 'rs7221352', (63, 72))	('rs35220381', 'Var', (39, 49))	('rs35220381', 'Mutation', 'rs35220381', (39, 49))
4729	29721046	Ultimately, eleven SNPs (rs35220381, rs12950561, rs7221352, rs61482741, rs9303568, rs34700818, rs12949115, rs9903822, rs12601477, rs11656976 and rs4626) were successfully genotyped in 1054 subjects (506 GCs and 548 HCs) and were available for analysis.	('rs12601477', 'Var', (118, 128))	('rs12601477', 'Mutation', 'rs12601477', (118, 128))	('rs61482741', 'Var', (60, 70))	('rs34700818', 'Var', (83, 93))	('rs12950561', 'Mutation', 'rs12950561', (37, 47))	('rs11656976', 'Var', (130, 140))	('rs9303568', 'Var', (72, 81))	('rs9903822', 'Var', (107, 116))	('rs12950561', 'Var', (37, 47))	('rs9303568', 'Mutation', 'rs9303568', (72, 81))	('rs34700818', 'Mutation', 'rs34700818', (83, 93))	('rs61482741', 'Mutation', 'rs61482741', (60, 70))	('rs4626', 'Var', (145, 151))	('rs9903822', 'Mutation', 'rs9903822', (107, 116))	('GC', 'Phenotype', 'HP:0012126', (203, 205))	('rs7221352', 'Var', (49, 58))	('rs11656976', 'Mutation', 'rs11656976', (130, 140))	('rs35220381', 'Var', (25, 35))	('rs4626', 'Mutation', 'rs4626', (145, 151))	('rs35220381', 'Mutation', 'rs35220381', (25, 35))	('rs12949115', 'Var', (95, 105))	('rs12949115', 'Mutation', 'rs12949115', (95, 105))	('rs7221352', 'Mutation', 'rs7221352', (49, 58))	('HCs', 'molecular_function', 'GO:0004077', ('215', '218'))
4740	29721046	The results showed that there were significant associations of haplotype GCCTTGC, haplotype ATCTTGG, and haplotype GCCACGC with GC risk (P= 0.028, P< 0.001, and P<0.001, respectively).	('haplotype', 'Var', (82, 91))	('GCC', 'Gene', '2984', (115, 118))	('CG', 'Chemical', 'MESH:C028505', (119, 121))	('GC', 'Phenotype', 'HP:0012126', (78, 80))	('GCC', 'Gene', (115, 118))	('GCC', 'Gene', (73, 76))	('GC', 'Phenotype', 'HP:0012126', (128, 130))	('haplotype', 'Var', (63, 72))	('GC', 'Phenotype', 'HP:0012126', (73, 75))	('GC', 'Phenotype', 'HP:0012126', (115, 117))	('ATCTTGG', 'Gene', (92, 99))	('CT', 'Chemical', 'MESH:D002251', (94, 96))	('associations', 'Interaction', (47, 59))	('GCC', 'Gene', '2984', (73, 76))	('GC', 'Phenotype', 'HP:0012126', (120, 122))	('CT', 'Chemical', 'MESH:D002251', (75, 77))
4745	29721046	As shown in Table 4, the rs34700818 CT+TT genotypes were associated with a significant increase in T3-T4 compared with T1-T2 (CT+TT vs CC adjusted OR=1.71, 95% CI=1.01-2.88, P=0.046) and with a significant increase in TNM stage II compared with stage I (adjusted OR=2.40, 95% CI=1.27-4.52, P=0.007).	('CT', 'Chemical', 'MESH:D002251', (126, 128))	('T3-T4', 'MPA', (99, 104))	('increase', 'PosReg', (87, 95))	('rs34700818', 'Var', (25, 35))	('TNM', 'Gene', (218, 221))	('CT', 'Chemical', 'MESH:D002251', (36, 38))	('rs34700818', 'Mutation', 'rs34700818', (25, 35))	('TNM', 'Gene', '10178', (218, 221))	('increase', 'PosReg', (206, 214))
4746	29721046	The rs61482741 CG+GG genotypes were also associated with a significant increase in T3-T4 compared with T1-T2 (CG+GG vs CC, adjusted OR=1.71, 95% CI = 1.01-2.88, P=0.046) and with a significant increase in TNM stage II compared with stage I (CG+GG vs CC, adjusted OR=2.40, 95% CI = 1.27-4.52, P=0.007).	('TNM', 'Gene', (205, 208))	('increase', 'PosReg', (193, 201))	('rs61482741', 'Mutation', 'rs61482741', (4, 14))	('T3-T4', 'MPA', (83, 88))	('CG', 'Chemical', 'MESH:C028505', (241, 243))	('CG', 'Chemical', 'MESH:C028505', (110, 112))	('increase', 'PosReg', (71, 79))	('TNM', 'Gene', '10178', (205, 208))	('rs61482741', 'Var', (4, 14))	('CG', 'Chemical', 'MESH:C028505', (15, 17))
4754	29721046	demonstrated that the CT+TT genotypes of the DACT1 rs863091 polymorphism were significantly associated with a decreased risk of GC in the Chinese Han population, especially in younger individuals and males.	('DACT1', 'Gene', '51339', (45, 50))	('CT', 'Chemical', 'MESH:D002251', (47, 49))	('rs863091', 'Mutation', 'rs863091', (51, 59))	('DACT1', 'Gene', (45, 50))	('decreased', 'NegReg', (110, 119))	('GC', 'Phenotype', 'HP:0012126', (128, 130))	('rs863091', 'Var', (51, 59))	('CT', 'Chemical', 'MESH:D002251', (22, 24))
4758	29721046	In the present study, we investigated the associations between the polymorphisms of the TOB1 gene and GC risk in the Chinese Han population.	('GC', 'Phenotype', 'HP:0012126', (102, 104))	('associations', 'Interaction', (42, 54))	('TOB1', 'Gene', (88, 92))	('TOB1', 'Gene', '10140', (88, 92))	('polymorphisms', 'Var', (67, 80))
4759	29721046	However, we found that several SNPs of the TOB1 gene were in strong linkage disequilibrium, and haplotype GCCTTGC, haplotype ATCTTGG, and haplotype GCCACGC were significantly associated with GC risk.	('GCC', 'Gene', '2984', (148, 151))	('GC', 'Phenotype', 'HP:0012126', (106, 108))	('associated with', 'Reg', (175, 190))	('TOB1', 'Gene', (43, 47))	('CT', 'Chemical', 'MESH:D002251', (127, 129))	('GCC', 'Gene', (148, 151))	('GC', 'Phenotype', 'HP:0012126', (153, 155))	('CT', 'Chemical', 'MESH:D002251', (108, 110))	('TOB1', 'Gene', '10140', (43, 47))	('CG', 'Chemical', 'MESH:C028505', (152, 154))	('GC', 'Phenotype', 'HP:0012126', (191, 193))	('GC', 'Phenotype', 'HP:0012126', (148, 150))	('GCC', 'Gene', '2984', (106, 109))	('haplotype', 'Var', (96, 105))	('haplotype', 'Var', (138, 147))	('GC', 'Phenotype', 'HP:0012126', (111, 113))	('haplotype', 'Var', (115, 124))	('GCC', 'Gene', (106, 109))
4761	29721046	Several studies suggest that haplotypes are associated with tumors, such as in TP53, for which the haplotype CCA decreases the risk for GC in a Spanish population.	('decreases', 'NegReg', (113, 122))	('TP53', 'Gene', '7157', (79, 83))	('CCA', 'Gene', (109, 112))	('TP53', 'Gene', (79, 83))	('haplotype', 'Var', (99, 108))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('GC', 'Phenotype', 'HP:0012126', (136, 138))	('tumors', 'Disease', (60, 66))
4762	29721046	The polymorphisms included in block 2 were upstream variants of the TOB1 gene, and for the first time, they were associated with cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('associated with', 'Reg', (113, 128))	('TOB1', 'Gene', (68, 72))	('TOB1', 'Gene', '10140', (68, 72))	('polymorphisms', 'Var', (4, 17))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', (129, 135))
4764	29721046	We also found that the rs12601477 GA+AA genotypes and the rs4626 AG+GG genotypes were associated with a significantly increased risk of GC among individuals older than 58.	('rs12601477', 'Mutation', 'rs12601477', (23, 33))	('rs12601477', 'Var', (23, 33))	('rs4626', 'Mutation', 'rs4626', (58, 64))	('rs4626', 'Var', (58, 64))	('GC', 'Phenotype', 'HP:0012126', (136, 138))
4769	29721046	Low levels of TOB1 may promote an aberrant immune response and affect disease progression.	('affect', 'Reg', (63, 69))	('promote', 'PosReg', (23, 30))	('immune response', 'biological_process', 'GO:0006955', ('43', '58'))	('TOB1', 'Gene', (14, 18))	('TOB1', 'Gene', '10140', (14, 18))	('Low levels', 'Var', (0, 10))	('disease progression', 'CPA', (70, 89))
4770	29721046	The rs34700818 CT+TT genotypes and the rs61482741 CG+GG genotypes were associated with a significant increase in T3-T4 and TNM stage II.	('T3-T4', 'CPA', (113, 118))	('CT', 'Chemical', 'MESH:D002251', (15, 17))	('rs61482741', 'Var', (39, 49))	('rs34700818', 'Var', (4, 14))	('TNM', 'Gene', (123, 126))	('increase', 'PosReg', (101, 109))	('rs34700818', 'Mutation', 'rs34700818', (4, 14))	('rs61482741', 'Mutation', 'rs61482741', (39, 49))	('CG', 'Chemical', 'MESH:C028505', (50, 52))	('TNM', 'Gene', '10178', (123, 126))
4772	29721046	Two GWASs demonstrated that the genetic variant loci in PLCE1 at 10q23 and, for non-cardia GC, at 3q13.31 and 5p13.1 increase the risk of tumors in the stomach.	('increase', 'PosReg', (117, 125))	('non-cardia', 'Disease', 'MESH:D004938', (80, 90))	('variant', 'Var', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (138, 144))	('non-cardia', 'Disease', (80, 90))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors in the stomach', 'Phenotype', 'HP:0006753', (138, 159))	('GC', 'Phenotype', 'HP:0012126', (91, 93))	('PLCE1', 'Gene', (56, 61))	('PLCE1', 'Gene', '51196', (56, 61))
4773	29721046	A SNP (rs41274221) in miR-25 regulates the expression of TOB1 by binding with its 3'-UTR region in GC.	('miR-25', 'Gene', '407014', (22, 28))	('miR-25', 'Gene', (22, 28))	('TOB1', 'Gene', (57, 61))	('binding', 'Interaction', (65, 72))	('rs41274221', 'Mutation', 'rs41274221', (7, 17))	('TOB1', 'Gene', '10140', (57, 61))	('rs41274221', 'Var', (7, 17))	('binding', 'molecular_function', 'GO:0005488', ('65', '72'))	('GC', 'Phenotype', 'HP:0012126', (99, 101))	('expression', 'MPA', (43, 53))	('regulates', 'Reg', (29, 38))
4777	29721046	Our study is an expansion of the previous work, and it is the first time to investigate the association between TOB1 gene polymorphism and GC susceptibility with molecular markers in peripheral blood.	('polymorphism', 'Var', (122, 134))	('GC', 'Phenotype', 'HP:0012126', (139, 141))	('TOB1', 'Gene', (112, 116))	('TOB1', 'Gene', '10140', (112, 116))
4778	29721046	Our results showed that the genotypes of the two SNPs (rs34700818 and rs61482741) have significant association with the increased invasion and severity, which suggesting that they impair the inhibition of TOB1.	('TOB1', 'Gene', '10140', (205, 209))	('rs34700818', 'Mutation', 'rs34700818', (55, 65))	('rs61482741', 'Mutation', 'rs61482741', (70, 80))	('impair', 'NegReg', (180, 186))	('rs34700818', 'Var', (55, 65))	('severity', 'CPA', (143, 151))	('inhibition', 'MPA', (191, 201))	('rs61482741', 'Var', (70, 80))	('increased', 'PosReg', (120, 129))	('TOB1', 'Gene', (205, 209))
4783	29721046	Despite these limitations, this is the first study to examine the role of TOB1 gene polymorphisms in the susceptibility to GC.	('TOB1', 'Gene', (74, 78))	('TOB1', 'Gene', '10140', (74, 78))	('GC', 'Phenotype', 'HP:0012126', (123, 125))	('polymorphisms', 'Var', (84, 97))
4784	29721046	Our findings provide a novel clue for the associations between the SNPs of the TOB1 gene and GC risk in the population of northeast China.	('associations', 'Interaction', (42, 54))	('SNPs', 'Var', (67, 71))	('GC', 'Phenotype', 'HP:0012126', (93, 95))	('TOB1', 'Gene', (79, 83))	('TOB1', 'Gene', '10140', (79, 83))
4786	29721046	In conclusion these results indicated, for the first time, that the four SNPs (rs12601477, rs4626, rs34700818 and rs61482741) of the TOB1 gene are related with GC risk in the Chinese Han population of northeast China.	('GC', 'Phenotype', 'HP:0012126', (160, 162))	('rs34700818', 'Var', (99, 109))	('rs61482741', 'Var', (114, 124))	('rs4626', 'Mutation', 'rs4626', (91, 97))	('TOB1', 'Gene', (133, 137))	('rs4626', 'Var', (91, 97))	('rs34700818', 'Mutation', 'rs34700818', (99, 109))	('TOB1', 'Gene', '10140', (133, 137))	('related', 'Reg', (147, 154))	('rs61482741', 'Mutation', 'rs61482741', (114, 124))	('rs12601477', 'Mutation', 'rs12601477', (79, 89))	('rs12601477', 'Var', (79, 89))
4844	29434446	A deletion in the miR-202-3p binding site of the DUSP1 gene 3'-UTR was introduced using a Quik-Change Site-Directed Mutagenesis Kit (Stratagene, United States) following the manufacturer's instructions.	('binding', 'molecular_function', 'GO:0005488', ('29', '36'))	('DUSP1', 'Gene', (49, 54))	('deletion', 'Var', (2, 10))	('miR-202', 'Gene', (18, 25))	('Mutagenesis', 'biological_process', 'GO:0006280', ('116', '127'))	('DUSP1', 'Gene', '1843', (49, 54))	('miR-202', 'Gene', '574448', (18, 25))
4845	29434446	In accordance with the manufacturer's instructions, Lipofectamine 2000 was used to cotransfect 293T cells with the miR-202-3p/non-targeting control mimic (purchased from Hanbio, Shanghai) using a psiCHECK2 vector containing either the wild-type or mutant-type 3'-UTR of DUSP1.	('mutant-type', 'Var', (248, 259))	('miR-202', 'Gene', (115, 122))	('miR-202', 'Gene', '574448', (115, 122))	('DUSP1', 'Gene', (270, 275))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (52, 70))	('DUSP1', 'Gene', '1843', (270, 275))	('293T', 'CellLine', 'CVCL:0063', (95, 99))
4861	29434446	However, 293T cells cotransfected with the miR-202-3p mimic and mutant-type 3'-UTR of DUSP1 had the same luciferase activity as the control group.	('luciferase activity', 'molecular_function', 'GO:0047712', ('105', '124'))	('miR-202', 'Gene', '574448', (43, 50))	('luciferase activity', 'molecular_function', 'GO:0050248', ('105', '124'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('105', '124'))	('luciferase activity', 'molecular_function', 'GO:0050397', ('105', '124'))	('DUSP1', 'Gene', (86, 91))	('luciferase', 'Enzyme', (105, 115))	('DUSP1', 'Gene', '1843', (86, 91))	('293T', 'CellLine', 'CVCL:0063', (9, 13))	('luciferase activity', 'molecular_function', 'GO:0047077', ('105', '124'))	('activity', 'MPA', (116, 124))	('mutant-type', 'Var', (64, 75))	('miR-202', 'Gene', (43, 50))
4863	29434446	miR-202 is located at 10q26 (position 135061015 -135061124 on chromosome 10), and its mature single-stranded miRNA sequence is 5'-UUCCUAUGCAUAUAC UUCUUUG-3'.	('miR-202', 'Gene', (0, 7))	('miR', 'Gene', '220972', (109, 112))	('miR', 'Gene', (109, 112))	('miR-202', 'Gene', '574448', (0, 7))	('chromosome', 'cellular_component', 'GO:0005694', ('62', '72'))	('position 135061015 -135061124', 'Var', (29, 58))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))
4902	29434446	Thus, many factors that may contribute to tumour formation have been proposed, such as mutations in BCL-2, Reg, Mcl-2, and MEN-1 genes, growth factor regulation, and bacterial infection.	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('BCL-2', 'molecular_function', 'GO:0015283', ('100', '105'))	('regulation', 'biological_process', 'GO:0065007', ('150', '160'))	('BCL-2', 'Gene', '596', (100, 105))	('Reg', 'Gene', '5967', (107, 110))	('bacterial infection', 'Phenotype', 'HP:0002718', (166, 185))	('MEN-1', 'Gene', '4221', (123, 128))	('MEN-1', 'Gene', (123, 128))	('Reg', 'Gene', (107, 110))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('BCL-2', 'Gene', (100, 105))	('tumour', 'Disease', (42, 48))	('bacterial infection', 'Disease', 'MESH:D001424', (166, 185))	('bacterial infection', 'Disease', (166, 185))	('formation', 'biological_process', 'GO:0009058', ('49', '58'))	('Mcl-2', 'Gene', (112, 117))	('mutations', 'Var', (87, 96))
4911	29434446	However, when DUSP1 is downregulated by high miR-202 expression, ECL cells will have more opportunities to develop type 1 g-NETs.	('high', 'Var', (40, 44))	('downregulated', 'NegReg', (23, 36))	('DUSP1', 'Gene', (14, 19))	('miR-202', 'Gene', (45, 52))	('DUSP1', 'Gene', '1843', (14, 19))	('miR-202', 'Gene', '574448', (45, 52))
4961	28912915	Immediately after UGI treatment, his consciousness level dropped to Glasgow coma scale E1V1M1 with a systolic blood pressure of 60 mm Hg.	('coma', 'Disease', 'MESH:D003128', (76, 80))	('coma', 'Disease', (76, 80))	('consciousness level dropped', 'Phenotype', 'HP:0004372', (37, 64))	('dropped', 'NegReg', (57, 64))	('E1V1M1', 'Var', (87, 93))	('consciousness level', 'MPA', (37, 56))	('coma', 'Phenotype', 'HP:0001259', (76, 80))
4974	28912915	Laboratory analysis revealed severe anemia (RBC 199 x 104/microL and hemoglobin level 6.7 g/dL), abnormal renal function (creatinine 3.25 mg/dL and blood urea nitrogen 175.6 mg/dL), and abnormal electrolytes (Na+ 156 mEq/L, K+ 7.4 mEq/L, and Cl- 122 mEq/L).	('Na+ 156', 'Var', (209, 216))	('abnormal renal function', 'Disease', (97, 120))	('abnormal electrolytes', 'Phenotype', 'HP:0003111', (186, 207))	('anemia', 'Disease', (36, 42))	('anemia', 'Disease', 'MESH:D000740', (36, 42))	('RBC', 'Var', (44, 47))	('abnormal renal function', 'Phenotype', 'HP:0012211', (97, 120))	('blood urea nitrogen', 'Phenotype', 'HP:0003138', (148, 167))	('nitrogen', 'Chemical', 'MESH:D009584', (159, 167))	('Cl- 122 mEq/L', 'MPA', (242, 255))	('K+ 7.4', 'MPA', (224, 230))	('electrolytes', 'MPA', (195, 207))	('urea', 'Chemical', 'MESH:D014508', (154, 158))	('anemia', 'Phenotype', 'HP:0001903', (36, 42))	('creatinine', 'Chemical', 'MESH:D003404', (122, 132))	('abnormal renal function', 'Disease', 'MESH:D007674', (97, 120))
5017	28912915	On the other hand, TAE in the lower GI tract may cause intestinal infarction unless TAE was performed in the vasa recta.	('intestinal infarction', 'Disease', (55, 76))	('TAE', 'Var', (19, 22))	('TAE', 'Chemical', '-', (19, 22))	('TAE', 'Chemical', '-', (84, 87))	('cause', 'Reg', (49, 54))	('intestinal infarction', 'Disease', 'MESH:D007238', (55, 76))	('intestinal infarction', 'Phenotype', 'HP:0005244', (55, 76))
5031	28144424	Results showed that A) gastric distention increased the level of mRNA expressions of NBC1, TFF1 and TFF2; B) these levels in NaHS-treated rats were significantly higher than those in Distention group; and C) PAG decreased the expression levels of NBC1 and TFF1.	('increased', 'PosReg', (42, 51))	('decreased', 'NegReg', (212, 221))	('PAG', 'Chemical', 'MESH:C009055', (208, 211))	('higher', 'PosReg', (162, 168))	('mRNA expressions', 'MPA', (65, 81))	('NBC1', 'Gene', (247, 251))	('gastric distention', 'Phenotype', 'HP:0003270', (23, 41))	('TFF1', 'Gene', (91, 95))	('NBC1', 'Gene', (85, 89))	('NBC1', 'Gene', '84484', (85, 89))	('NBC1', 'Gene', '84484', (247, 251))	('rats', 'Species', '10116', (138, 142))	('NaHS', 'Chemical', 'MESH:C025451', (125, 129))	('expression levels', 'MPA', (226, 243))	('PAG', 'Var', (208, 211))	('TFF2', 'Gene', (100, 104))
5037	28144424	The H2S has been shown to contribute in sub-epithelial barrier by increasing gastric mucosal blood flow and also promote the pre-epithelial barrier by stimulation of mucus and bicarbonate secretion.	('pre', 'molecular_function', 'GO:0003904', ('125', '128'))	('H2S', 'Chemical', 'MESH:D006862', (4, 7))	('gastric mucosal blood flow', 'Disease', (77, 103))	('promote', 'PosReg', (113, 120))	('stimulation', 'PosReg', (151, 162))	('secretion', 'biological_process', 'GO:0046903', ('188', '197'))	('mucus', 'cellular_component', 'GO:0070701', ('166', '171'))	('pre-epithelial barrier', 'CPA', (125, 147))	('increasing', 'PosReg', (66, 76))	('H2S', 'Var', (4, 7))	('bicarbonate', 'Chemical', 'MESH:D001639', (176, 187))	('gastric mucosal blood flow', 'Disease', 'MESH:D013274', (77, 103))
5082	28144424	The PAG treatment significantly decreased the level of gene expression of TFF1 compared to distention (p < 0.05).	('gene expression', 'biological_process', 'GO:0010467', ('55', '70'))	('TFF1', 'Gene', (74, 78))	('PAG', 'Var', (4, 7))	('level of gene expression', 'MPA', (46, 70))	('PAG', 'Chemical', 'MESH:C009055', (4, 7))	('decreased', 'NegReg', (32, 41))
5083	28144424	NaHS significantly increased the level of gene expression of TFF2 compared to distention group (p < 0.001).	('NaHS', 'Var', (0, 4))	('NaHS', 'Chemical', 'MESH:C025451', (0, 4))	('level of gene expression', 'MPA', (33, 57))	('increased', 'PosReg', (19, 28))	('gene expression', 'biological_process', 'GO:0010467', ('42', '57'))	('TFF2', 'Gene', (61, 65))
5085	28144424	As indicated in Table 1, the total acid content of gastric contents in NaHS-treated rats was significantly lower than in D, and PAG-treated groups (p < 0.05 and p < 0.01, respectively).	('lower', 'NegReg', (107, 112))	('acid content of gastric contents', 'MPA', (35, 67))	('NaHS-treated', 'Var', (71, 83))	('PAG', 'Chemical', 'MESH:C009055', (128, 131))	('rats', 'Species', '10116', (84, 88))	('NaHS', 'Chemical', 'MESH:C025451', (71, 75))
5087	28144424	As shown in Figure1, the level of mRNA expression of NBC1 in distention group was significantly higher than in control rats.	('NBC1', 'Gene', (53, 57))	('distention', 'Var', (61, 71))	('mRNA expression', 'MPA', (34, 49))	('NBC1', 'Gene', '84484', (53, 57))	('level', 'MPA', (25, 30))	('higher', 'PosReg', (96, 102))	('rats', 'Species', '10116', (119, 123))
5094	28144424	According to Table 1, the total acid content of gastric washout in NaHS-treated rats was significantly lower than in distention and PAG-treated rats.	('total acid content', 'MPA', (26, 44))	('rats', 'Species', '10116', (144, 148))	('rats', 'Species', '10116', (80, 84))	('lower', 'NegReg', (103, 108))	('NaHS-treated', 'Var', (67, 79))	('NaHS', 'Chemical', 'MESH:C025451', (67, 71))	('PAG', 'Chemical', 'MESH:C009055', (132, 135))
5100	28144424	In this study, we for the first time showed that exogenous H2S upregulated mucosal mRNA expression of TFF1 and TFF2 in response to gastric distention.	('gastric distention', 'Phenotype', 'HP:0003270', (131, 149))	('TFF2', 'Gene', (111, 115))	('H2S', 'Protein', (59, 62))	('exogenous', 'Var', (49, 58))	('TFF1', 'Gene', (102, 106))	('mucosal mRNA expression', 'MPA', (75, 98))	('upregulated', 'PosReg', (63, 74))	('response to gastric distention', 'MPA', (119, 149))	('H2S', 'Chemical', 'MESH:D006862', (59, 62))
5112	28144424	In conclusion, the findings of the present study showed that exogenous H2S upregulated the mucosal levels of mRNA expressions of NBC1, TFF1 and TFF2, and the mucosal levels of mRNA expressions of NBC1 and TFF1 were induced by endogenous hydrogen sulfide.	('upregulated', 'PosReg', (75, 86))	('hydrogen sulfide', 'Chemical', 'MESH:D006862', (237, 253))	('NBC1', 'Gene', (129, 133))	('NBC1', 'Gene', '84484', (129, 133))	('mRNA expressions', 'MPA', (176, 192))	('NBC1', 'Gene', (196, 200))	('H2S', 'Chemical', 'MESH:D006862', (71, 74))	('NBC1', 'Gene', '84484', (196, 200))	('exogenous', 'Var', (61, 70))	('mucosal levels', 'MPA', (158, 172))	('TFF2', 'Gene', (144, 148))	('TFF1', 'Gene', (135, 139))	('mucosal levels of mRNA expressions', 'MPA', (91, 125))
5113	27819260	Combination of OipA, BabA, and SabA as candidate biomarkers for predicting Helicobacter pylori-related gastric cancer Helicobacter pylori (H. pylori ) infection is a major cause of chronic gastritis and is highly related to duodenal ulcer (DU) and gastric cancer (GC).	('gastric cancer', 'Disease', (248, 262))	('GC', 'Phenotype', 'HP:0012126', (264, 266))	('Helicobacter pylori', 'Species', '210', (118, 137))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('ulcer', 'Disease', 'MESH:D014456', (233, 238))	('gastric cancer', 'Disease', 'MESH:D013274', (248, 262))	('duodenal ulcer', 'Phenotype', 'HP:0002588', (224, 238))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('DU', 'Phenotype', 'HP:0002588', (240, 242))	('Helicobacter pylori', 'Species', '210', (75, 94))	('chronic gastritis', 'Phenotype', 'HP:0005231', (181, 198))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('ulcer', 'Disease', (233, 238))	('infection', 'Disease', (151, 160))	('gastritis', 'Phenotype', 'HP:0005263', (189, 198))	('infection', 'Disease', 'MESH:D007239', (151, 160))	('OipA', 'Chemical', '-', (15, 19))	('gastric cancer', 'Phenotype', 'HP:0012126', (248, 262))	('cause', 'Reg', (172, 177))	('H. pylori', 'Species', '210', (139, 148))	('SabA', 'Chemical', '-', (31, 35))	('gastritis', 'Disease', 'MESH:D005756', (189, 198))	('Helicobacter', 'Var', (118, 130))	('related', 'Reg', (213, 220))	('gastric cancer', 'Disease', (103, 117))	('gastritis', 'Disease', (189, 198))
5150	27819260	2B (left panel), the RT-PCR data showed that expression of AlpA, OipA, BabA, and SabA was higher in GC strain H. pylori than in DU strain H. pylori.	('GC', 'Phenotype', 'HP:0012126', (100, 102))	('H. pylori', 'Species', '210', (138, 147))	('GC strain H. pylori', 'Var', (100, 119))	('expression', 'MPA', (45, 55))	('expression', 'Species', '1526930', (45, 55))	('SabA', 'Chemical', '-', (81, 85))	('H. pylori', 'Species', '210', (110, 119))	('DU', 'Phenotype', 'HP:0002588', (128, 130))	('higher', 'PosReg', (90, 96))
5160	27819260	The prevalence of AlpA seropositivity in patients with GC, DU, non-GC was 46.1, 15, and 14%; which was higher in GC samples than in DU samples (OR = 4.84; 95% CI, 2.26-10.36; p < 0.0001) or the non-GC samples (OR = 5.24; 95% CI, 2.55-10.80; p < 0.0001).	('seropositivity', 'Var', (23, 37))	('DU', 'Phenotype', 'HP:0002588', (59, 61))	('AlpA', 'Protein', (18, 22))	('GC', 'Phenotype', 'HP:0012126', (55, 57))	('patients', 'Species', '9606', (41, 49))	('GC', 'Phenotype', 'HP:0012126', (67, 69))	('higher', 'PosReg', (103, 109))	('DU', 'Phenotype', 'HP:0002588', (132, 134))	('GC', 'Phenotype', 'HP:0012126', (113, 115))	('GC', 'Phenotype', 'HP:0012126', (198, 200))
5163	27819260	The prevalence of SabA seropositivity in GC patients was also significantly higher than in DU patients (48.7% versus 12.5%; OR = 6.64; 95% CI, 2.98-14.79; p < 0.0001) or the non-GC groups (48.7% versus 15%; OR = 5.38; 95% CI, 2.64-10.93; p < 0.0001).	('seropositivity', 'Var', (23, 37))	('GC', 'Phenotype', 'HP:0012126', (178, 180))	('patients', 'Species', '9606', (44, 52))	('patients', 'Species', '9606', (94, 102))	('GC', 'Phenotype', 'HP:0012126', (41, 43))	('DU', 'Phenotype', 'HP:0002588', (91, 93))	('higher', 'PosReg', (76, 82))	('SabA', 'Gene', (18, 22))	('SabA', 'Chemical', '-', (18, 22))
5164	27819260	These results show that the prevalence of AlpA, OipA, BabA, and SabA seropositivity was significantly higher in GC patients than in non-GC patients, with a higher OR and p < 0.0001 and these 4 proteins were therefore considered as GC-related antigens.	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (139, 147))	('AlpA', 'Disease', (42, 46))	('SabA', 'Chemical', '-', (64, 68))	('higher', 'PosReg', (102, 108))	('BabA', 'Disease', (54, 58))	('GC', 'Phenotype', 'HP:0012126', (112, 114))	('GC', 'Phenotype', 'HP:0012126', (136, 138))	('GC', 'Phenotype', 'HP:0012126', (231, 233))	('seropositivity', 'Var', (69, 83))
5198	27819260	In our study, we found that the number of bacteria attached to each gastric epithelial cell was considerably higher for GC strain H. pylori, which shows higher expression of these adhesins, than for DU strain H. pylori.	('expression', 'MPA', (160, 170))	('higher', 'PosReg', (153, 159))	('H. pylori', 'Species', '210', (130, 139))	('expression', 'Species', '1526930', (160, 170))	('H. pylori', 'Species', '210', (209, 218))	('DU', 'Phenotype', 'HP:0002588', (199, 201))	('higher', 'PosReg', (109, 115))	('GC strain H. pylori', 'Var', (120, 139))	('GC', 'Phenotype', 'HP:0012126', (120, 122))
5205	27819260	The presence of OipA gene correlates to the risk of H. pylori associated GC in the population of Japan, China, Dutch and Colombian with odds ratio from 2.43 to 5.69, while it has little effect on the Iran population.	('OipA gene', 'Gene', (16, 25))	('GC', 'Phenotype', 'HP:0012126', (73, 75))	('H. pylori', 'Species', '210', (52, 61))	('H. pylori', 'Disease', (52, 61))	('presence', 'Var', (4, 12))
5206	27819260	Furthermore, the presence of SabA gene is associated with the risk of GC in the population of Columbia with OR of 2.8.	('SabA gene', 'Gene', (29, 38))	('associated', 'Reg', (42, 52))	('SabA', 'Chemical', '-', (29, 33))	('GC', 'Phenotype', 'HP:0012126', (70, 72))	('presence', 'Var', (17, 25))
5213	27819260	Overall, the three antigens of the 5 GC strains are all genetically positive with some strain specific variable mutations which is commonly found in H. pylori genes and has long been thought to contribute to host adaption.	('mutations', 'Var', (112, 121))	('GC', 'Phenotype', 'HP:0012126', (37, 39))	('positive', 'Reg', (68, 76))	('H. pylori', 'Species', '210', (149, 158))
5224	27819260	Based on our results, we suggest considering seropositivity of three antigens as a high risk of developing GC, and seropositivity of all four antigens should be examined in a larger sample of H. pylori-infected patients to verify and to optimize the discrimination of GC from other gastric diseases.	('patients', 'Species', '9606', (211, 219))	('gastric diseases', 'Disease', (282, 298))	('GC', 'Phenotype', 'HP:0012126', (107, 109))	('gastric diseases', 'Disease', 'MESH:D013274', (282, 298))	('H. pylori', 'Species', '210', (192, 201))	('GC', 'Phenotype', 'HP:0012126', (268, 270))	('seropositivity', 'Var', (45, 59))	('pylori-infected', 'Disease', 'MESH:D016481', (195, 210))	('pylori-infected', 'Disease', (195, 210))
5280	27127880	Here, we report that FOXO3a overexpression promoted migration and invasion of gastric cancer cells by upregulating cathepsin L. FOXO3a knockdown suppressed migration and invasion and also downregulated cathepsin L expression in gastric cancer cells.	('downregulated', 'NegReg', (188, 201))	('gastric cancer', 'Disease', 'MESH:D013274', (228, 242))	('knockdown', 'Var', (135, 144))	('gastric cancer', 'Disease', (228, 242))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('migration', 'CPA', (156, 165))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('gastric cancer', 'Disease', (78, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (228, 242))	('gastric cancer', 'Disease', 'MESH:D013274', (78, 92))	('suppressed', 'NegReg', (145, 155))	('cathepsin L', 'Gene', (202, 213))	('FOXO3a', 'Gene', (128, 134))	('invasion', 'CPA', (170, 178))	('expression', 'MPA', (214, 224))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))
5290	27127880	In human cancers, FOXO3a was initially categorized as a tumor suppressor because inhibition of FOXO3a transcription promoted cell transformation, tumor progression, and angiogenesis, and our previous study also showed that activation of FOXO3a was correlated with good prognosis in human gastric cancer.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('human', 'Species', '9606', (3, 8))	('tumor', 'Disease', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('gastric cancer', 'Disease', 'MESH:D013274', (288, 302))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('angiogenesis', 'CPA', (169, 181))	('cancers', 'Disease', (9, 16))	('inhibition', 'Var', (81, 91))	('FOXO3a', 'Gene', (95, 101))	('angiogenesis', 'biological_process', 'GO:0001525', ('169', '181'))	('gastric cancer', 'Phenotype', 'HP:0012126', (288, 302))	('activation', 'PosReg', (223, 233))	('cell transformation', 'CPA', (125, 144))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('promoted', 'PosReg', (116, 124))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('transcription', 'biological_process', 'GO:0006351', ('102', '115'))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('56', '72'))	('human', 'Species', '9606', (282, 287))	('gastric cancer', 'Disease', (288, 302))	('tumor suppressor', 'biological_process', 'GO:0051726', ('56', '72'))
5299	27127880	FOXO3a overexpression promoted migration and invasion of gastric cancer cells, whereas FOXO3a knockdown suppressed migration and invasion in gastric cancer cells.	('knockdown', 'Var', (94, 103))	('gastric cancer', 'Disease', (57, 71))	('migration', 'CPA', (31, 40))	('migration', 'CPA', (115, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (141, 155))	('promoted', 'PosReg', (22, 30))	('invasion', 'CPA', (129, 137))	('gastric cancer', 'Disease', 'MESH:D013274', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('FOXO3a', 'Gene', (0, 6))	('gastric cancer', 'Phenotype', 'HP:0012126', (57, 71))	('invasion', 'CPA', (45, 53))	('suppressed', 'NegReg', (104, 114))	('gastric cancer', 'Disease', (141, 155))	('FOXO3a', 'Gene', (87, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (141, 155))
5316	27127880	To explore the effects of FOXO3a and cathepsin L on tumor metastasis in vivo, FOXO3a-OE SGC7901, FOXO3a-OE and cathepsin L KD SGC7901 and their corresponding control cells were injected into nude mice through the tail vein.	('SGC7901', 'CellLine', 'CVCL:0520', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('SGC7901', 'CellLine', 'CVCL:0520', (126, 133))	('nude mice', 'Species', '10090', (191, 200))	('tumor metastasis', 'Disease', 'MESH:D009362', (52, 68))	('FOXO3a-OE', 'Var', (78, 87))	('tumor metastasis', 'Disease', (52, 68))
5318	27127880	Silencing cathepsin L in FOXO3a-OE cells inhibited metastatic capability, as determined by the number of metastatic foci in the lungs of each mouse.	('mouse', 'Species', '10090', (142, 147))	('metastatic capability', 'CPA', (51, 72))	('cathepsin', 'Protein', (10, 19))	('inhibited', 'NegReg', (41, 50))	('Silencing', 'Var', (0, 9))
5323	27127880	However, when cathepsin L was knockdown in FOXO3a-OE cells, expression of E-cadherin was increased, indicating that cathepsin L cleaves E-cadherin and participates in EMT of gastric cancer cells during the metastatic process.	('expression', 'MPA', (60, 70))	('metastatic', 'CPA', (206, 216))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('gastric cancer', 'Phenotype', 'HP:0012126', (174, 188))	('cadherin', 'molecular_function', 'GO:0008014', ('76', '84'))	('cadherin', 'molecular_function', 'GO:0008014', ('138', '146'))	('E-cadherin', 'Gene', (74, 84))	('increased', 'PosReg', (89, 98))	('E-cadherin', 'Gene', (136, 146))	('E-cadherin', 'Gene', '999', (74, 84))	('E-cadherin', 'Gene', '999', (136, 146))	('gastric cancer', 'Disease', (174, 188))	('EMT', 'biological_process', 'GO:0001837', ('167', '170'))	('knockdown', 'Var', (30, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (174, 188))	('EMT', 'CPA', (167, 170))	('participates', 'Reg', (151, 163))
5324	27127880	To confirm that cathepsin L is a transcriptional target of FOXO3a, we cloned three cathepsin L promoter fragments containing the wild type or mutant FOXO3a putative target site into pGL3-control vector.	('pGL3', 'Gene', (182, 186))	('pGL', 'molecular_function', 'GO:0004598', ('182', '185'))	('pGL3', 'Gene', '6391', (182, 186))	('mutant', 'Var', (142, 148))	('FOXO3a', 'Gene', (149, 155))
5336	27127880	found that antisense inhibition of cathepsin L completely abolished the invasiveness of human melanoma clones in vitro and inhibited metastasis in vivo.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('metastasis in vivo', 'CPA', (133, 151))	('abolished', 'NegReg', (58, 67))	('melanoma', 'Disease', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('inhibited', 'NegReg', (123, 132))	('antisense inhibition', 'Var', (11, 31))	('human', 'Species', '9606', (88, 93))	('cathepsin', 'Protein', (35, 44))
5338	27127880	In addition to degrading the extracellular matrix directly, cathepsin L also reduces cell-cell adhesion through cleavage of E-cadherin.	('cleavage', 'MPA', (112, 120))	('E-cadherin', 'Gene', '999', (124, 134))	('cathepsin', 'Var', (60, 69))	('extracellular matrix', 'CPA', (29, 49))	('degrading', 'NegReg', (15, 24))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('29', '49'))	('cadherin', 'molecular_function', 'GO:0008014', ('126', '134'))	('cell-cell adhesion', 'biological_process', 'GO:0098609', ('85', '103'))	('reduces', 'NegReg', (77, 84))	('E-cadherin', 'Gene', (124, 134))	('cell-cell adhesion', 'CPA', (85, 103))
5341	27127880	This result is consistent with our finding that cell migration in SGC7901 and MKN28 cathepsin L knockdown cells was significantly decreased compared with the control shRNA cells.	('knockdown', 'Var', (96, 105))	('cell migration', 'CPA', (48, 62))	('cell migration', 'biological_process', 'GO:0016477', ('48', '62'))	('SGC7901', 'CellLine', 'CVCL:0520', (66, 73))	('MKN28', 'Gene', (78, 83))	('cathepsin L', 'Enzyme', (84, 95))	('decreased', 'NegReg', (130, 139))	('SGC7901', 'Gene', (66, 73))
5342	27127880	However, cell growth in SGC7901 and MKN28 cathepsin L knockdown cells was not significantly different compared with the control shRNA cells.	('cathepsin L', 'Gene', (42, 53))	('SGC7901', 'Gene', (24, 31))	('knockdown', 'Var', (54, 63))	('cell growth', 'biological_process', 'GO:0016049', ('9', '20'))	('SGC7901', 'CellLine', 'CVCL:0520', (24, 31))
5345	27127880	The inactivation of FOXO3a in the early stage of tumor growth by increased signaling through growth factors may offer a proliferative advantage to cancer.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('increased', 'PosReg', (65, 74))	('signaling', 'MPA', (75, 84))	('inactivation', 'Var', (4, 16))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('FOXO3a', 'Gene', (20, 26))	('proliferative advantage', 'CPA', (120, 143))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('tumor', 'Disease', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
5372	25437333	Effects of EGFR Inhibitor on Helicobacter pylori Induced Gastric Epithelial Pathology in Vivo Helicobacter pylori transactivates the Epidermal Growth Factor Receptor (EGFR) and predisposes to gastric cancer development in humans and animal models.	('Helicobacter pylori', 'Species', '210', (94, 113))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('humans', 'Species', '9606', (222, 228))	('Helicobacter pylori', 'Species', '210', (29, 48))	('Epidermal Growth Factor', 'molecular_function', 'GO:0005154', ('133', '156'))	('gastric cancer', 'Disease', 'MESH:D013274', (192, 206))	('EGFR', 'Gene', (11, 15))	('EGFR', 'Gene', (167, 171))	('gastric cancer', 'Phenotype', 'HP:0012126', (192, 206))	('EGFR', 'molecular_function', 'GO:0005006', ('11', '15'))	('Epidermal Growth Factor Receptor', 'Gene', (133, 165))	('Helicobacter pylori', 'Var', (94, 113))	('EGFR', 'Gene', '1956', (11, 15))	('transactivates', 'MPA', (114, 128))	('EGFR', 'molecular_function', 'GO:0005006', ('167', '171'))	('EGFR', 'Gene', '1956', (167, 171))	('gastric cancer', 'Disease', (192, 206))	('predisposes to', 'Reg', (177, 191))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (133, 165))
5378	25437333	EKB-569 increased gastric epithelial apoptosis in H. pylori-infected gerbils which counteracted some of the consequences of increased gastric epithelial cell proliferation.	('EKB-569', 'Var', (0, 7))	('EKB-569', 'Chemical', 'MESH:C413879', (0, 7))	('epithelial cell proliferation', 'biological_process', 'GO:0050673', ('142', '171'))	('increased gastric', 'Phenotype', 'HP:0005207', (124, 141))	('H. pylori-infected', 'Disease', (50, 68))	('apoptosis', 'biological_process', 'GO:0006915', ('37', '46'))	('apoptosis', 'biological_process', 'GO:0097194', ('37', '46'))	('increased gastric', 'Phenotype', 'HP:0005207', (8, 25))	('increased', 'PosReg', (8, 17))	('gastric epithelial apoptosis', 'CPA', (18, 46))	('rat', 'Species', '10116', (165, 168))	('H. pylori', 'Species', '210', (50, 59))
5385	25437333	EGFR transactivation has been strongly implicated in epithelial hyperproliferation and cancer.	('cancer', 'Disease', (87, 93))	('transactivation', 'Var', (5, 20))	('EGFR', 'Gene', (0, 4))	('implicated', 'Reg', (39, 49))	('epithelial hyperproliferation', 'Disease', (53, 82))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('EGFR', 'molecular_function', 'GO:0005006', ('0', '4'))	('epithelial hyperproliferation', 'Disease', 'MESH:D002277', (53, 82))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('transactivation', 'biological_process', 'GO:2000144', ('5', '20'))
5396	25437333	Whilst the chemotherapeutic effects of EGFR-kinase inhibitors on intestinal neoplasia is established in mice, their potential for preventing H. pylori-induced hyperproliferative disease is unknown.	('mice', 'Species', '10090', (104, 108))	('neoplasia', 'Phenotype', 'HP:0002664', (76, 85))	('hyperproliferative disease', 'Disease', (159, 185))	('intestinal neoplasia', 'Disease', (65, 85))	('H. pylori', 'Species', '210', (141, 150))	('EGFR', 'molecular_function', 'GO:0005006', ('39', '43'))	('EGFR-kinase', 'Gene', (39, 50))	('hyperproliferative disease', 'Disease', 'MESH:D004194', (159, 185))	('intestinal neoplasia', 'Disease', 'MESH:D009369', (65, 85))	('inhibitors', 'Var', (51, 61))
5401	25437333	Previous in vitro studies using "In Cell Western" analysis identified that EKB-569 significantly inhibited H. pylori-stimulated ERK1/2 phosphorylation (pERK1/2) in A-431 cells.	('ERK1/2', 'Protein', (128, 134))	('EKB-569', 'Var', (75, 82))	('H. pylori-stimulated', 'Disease', (107, 127))	('H. pylori', 'Species', '210', (107, 116))	('inhibited', 'NegReg', (97, 106))	('EKB-569', 'Chemical', 'MESH:C413879', (75, 82))	('A-431', 'CellLine', 'CVCL:0037', (164, 169))
5402	25437333	ERK1/2 phosphorylation in A-431 cells was examined as a readout of EGFR signalling rather than phosphorylated EGFR due to cross reactivity of pEGFR antibodies with H. pylori.	('EGFR', 'MPA', (67, 71))	('rat', 'Species', '10116', (83, 86))	('signalling', 'biological_process', 'GO:0023052', ('72', '82'))	('ERK1', 'molecular_function', 'GO:0004707', ('0', '4'))	('H. pylori', 'Species', '210', (164, 173))	('A-431', 'CellLine', 'CVCL:0037', (26, 31))	('H. pylori', 'Disease', (164, 173))	('EGFR', 'molecular_function', 'GO:0005006', ('67', '71'))	('phosphorylation', 'biological_process', 'GO:0016310', ('7', '22'))	('pEGFR', 'Var', (142, 147))	('EGFR', 'molecular_function', 'GO:0005006', ('110', '114'))	('cross reactivity', 'Reg', (122, 138))
5403	25437333	Initial in vitro studies determined whether EKB-569 inhibited SS1-induced pERK1/2 in A431 cells.	('A431', 'CellLine', 'CVCL:0037', (85, 89))	('EKB-569', 'Var', (44, 51))	('inhibited', 'NegReg', (52, 61))	('SS1', 'Species', '102617', (62, 65))	('EKB-569', 'Chemical', 'MESH:C413879', (44, 51))	('SS1-induced pERK1/2', 'Enzyme', (62, 81))
5407	25437333	Additionally, all inoculated gerbils on EKB-569 and control diet were classified histologically as H. pylori infected.	('EKB-569', 'Var', (40, 47))	('EKB-569', 'Chemical', 'MESH:C413879', (40, 47))	('H. pylori', 'Species', '210', (99, 108))	('H. pylori', 'Disease', (99, 108))
5421	25437333	Treatment of H. pylori infected gerbils with EKB-569 resulted in a significant reduction in phospho-ERK positive epithelial cells compared to H. pylori infected gerbils on control diet (Figure 3D).	('ERK', 'molecular_function', 'GO:0004707', ('100', '103'))	('EKB-569', 'Var', (45, 52))	('phospho-ERK positive epithelial cells', 'MPA', (92, 129))	('H. pylori', 'Species', '210', (13, 22))	('EKB-569', 'Chemical', 'MESH:C413879', (45, 52))	('H. pylori', 'Disease', (13, 22))	('H. pylori', 'Species', '210', (142, 151))	('reduction', 'NegReg', (79, 88))
5425	25437333	The results indicate that EKB-569 significantly reduces H. pylori induced gastric phospho-Erk signalling in gastric epithelial cells in vivo (p < 0.002) (Figure 3F) as well as in vitro (Table 1).	('Erk', 'molecular_function', 'GO:0004707', ('90', '93'))	('H. pylori', 'Species', '210', (56, 65))	('EKB-569', 'Var', (26, 33))	('reduces', 'NegReg', (48, 55))	('signalling', 'biological_process', 'GO:0023052', ('94', '104'))	('H. pylori', 'Disease', (56, 65))	('EKB-569', 'Chemical', 'MESH:C413879', (26, 33))	('gastric phospho-Erk signalling', 'MPA', (74, 104))
5427	25437333	At 38 weeks post-infection there was a significant increase in antral (p < 0.001) and corpus (p < 0.001) epithelial cell proliferation in EKB-569 treated and untreated gerbils compared to uninfected controls (Figure 4A-B).	('increase', 'PosReg', (51, 59))	('antral', 'CPA', (63, 69))	('EKB-569', 'Var', (138, 145))	('infection', 'Disease', (17, 26))	('infection', 'Disease', 'MESH:D007239', (17, 26))	('EKB-569', 'Chemical', 'MESH:C413879', (138, 145))	('epithelial cell proliferation', 'biological_process', 'GO:0050673', ('105', '134'))	('rat', 'Species', '10116', (128, 131))
5446	25437333	Analysis of Adam-17, Egfr and Cox-2 in the gastric mucosa of uninfected control gerbils showed that EKB-569 had no significant effect on transcript abundance of these genes (Figure 6A-C).	('transcript abundance', 'MPA', (137, 157))	('EKB-569', 'Var', (100, 107))	('EKB-569', 'Chemical', 'MESH:C413879', (100, 107))	('Adam-17', 'Gene', (12, 19))	('Cox-2', 'Gene', '4513', (30, 35))	('Cox-2', 'Gene', (30, 35))	('Egfr', 'Gene', (21, 25))	('Egfr', 'molecular_function', 'GO:0005006', ('21', '25'))
5449	25437333	HB-EGF expression is upregulated in cultured human gastric epithelial cells by H. pylori and HB-EGF is also present in parietal cells.	('HB-EGF', 'Gene', (0, 6))	('EGF', 'molecular_function', 'GO:0005154', ('96', '99'))	('upregulated', 'PosReg', (21, 32))	('EGF', 'molecular_function', 'GO:0005154', ('3', '6'))	('expression', 'MPA', (7, 17))	('human', 'Species', '9606', (45, 50))	('H. pylori', 'Species', '210', (79, 88))	('H. pylori', 'Var', (79, 88))
5459	25437333	In the present study EKB-569 significantly reduced H. pylori phosphorylation of ERK1/2 in gastric epithelial cells both in vitro and in vivo.	('phosphorylation', 'biological_process', 'GO:0016310', ('61', '76'))	('ERK1/2', 'Protein', (80, 86))	('EKB-569', 'Chemical', 'MESH:C413879', (21, 28))	('ERK1', 'molecular_function', 'GO:0004707', ('80', '84'))	('H. pylori', 'Species', '210', (51, 60))	('reduced', 'NegReg', (43, 50))	('H. pylori phosphorylation', 'MPA', (51, 76))	('EKB-569', 'Var', (21, 28))
5471	25437333	Earlier studies on murine airway epithelium have shown EKB-569 interrupts viral induced anti-apoptotic pathways and partially inhibits goblet cell metaplasia.	('inhibits', 'NegReg', (126, 134))	('goblet cell metaplasia', 'CPA', (135, 157))	('metaplasia', 'biological_process', 'GO:0036074', ('147', '157'))	('EKB-569', 'Var', (55, 62))	('anti-apoptotic pathways', 'Pathway', (88, 111))	('murine', 'Species', '10090', (19, 25))	('EKB-569', 'Chemical', 'MESH:C413879', (55, 62))	('interrupts', 'NegReg', (63, 73))
5482	25437333	Although antral mucosa was used to avoid Hb-egf positive parietal cells, possible parietal cells in the transition zone in two control gerbils with high Hb-egf transcripts may have precluded the expected increase in Hb-egf transcripts with H. pylori infection.	('transcripts', 'Var', (160, 171))	('egf', 'molecular_function', 'GO:0005154', ('156', '159'))	('Hb-egf', 'Gene', '15200', (41, 47))	('increase in Hb', 'Phenotype', 'HP:0001900', (204, 218))	('H. pylori', 'Species', '210', (240, 249))	('infection', 'Disease', 'MESH:D007239', (250, 259))	('Hb-egf', 'Gene', '15200', (216, 222))	('H. pylori infection', 'Phenotype', 'HP:0005202', (240, 259))	('egf', 'molecular_function', 'GO:0005154', ('219', '222'))	('Hb-egf', 'Gene', '15200', (153, 159))	('Hb-egf', 'Gene', (216, 222))	('Hb-egf', 'Gene', (41, 47))	('egf', 'molecular_function', 'GO:0005154', ('44', '47'))	('infection', 'Disease', (250, 259))	('high Hb', 'Phenotype', 'HP:0001900', (148, 155))	('Hb-egf', 'Gene', (153, 159))
5484	25437333	EGF stimulated upregulation of COX-2 and HB-EGF, but not ADAM17, in human MKN-28 gastric epithelial cells are also downregulated by EKB-569 treatment.	('EGF', 'molecular_function', 'GO:0005154', ('0', '3'))	('EGF', 'Gene', (44, 47))	('human', 'Species', '9606', (68, 73))	('EKB-569', 'Var', (132, 139))	('upregulation', 'PosReg', (15, 27))	('EGF', 'Gene', '1950', (44, 47))	('EGF', 'Gene', (0, 3))	('EGF', 'molecular_function', 'GO:0005154', ('44', '47'))	('EKB-569', 'Chemical', 'MESH:C413879', (132, 139))	('EGF', 'Gene', '1950', (0, 3))	('downregulated', 'NegReg', (115, 128))	('COX-2', 'Gene', '4513', (31, 36))	('COX-2', 'Gene', (31, 36))
5487	25437333	The significant decrease in Egfr transcripts in the gastric mucosa of infected gerbils with EKB-569 treatment probably reflects an overall reduction in gastric epithelial cells.	('decrease', 'NegReg', (16, 24))	('reduction', 'NegReg', (139, 148))	('EKB-569', 'Chemical', 'MESH:C413879', (92, 99))	('transcripts', 'MPA', (33, 44))	('EKB-569', 'Var', (92, 99))	('Egfr', 'molecular_function', 'GO:0005006', ('28', '32'))	('Egfr', 'Gene', (28, 32))	('gastric', 'MPA', (152, 159))
5488	25437333	These in vivo observations in gerbils concur with previous studies in an immortalised gastric epithelial cell line in which EGFR knockdown by siRNA enhanced H. pylori stimulated apoptosis.	('H. pylori', 'Species', '210', (157, 166))	('H. pylori', 'Disease', (157, 166))	('knockdown', 'Var', (129, 138))	('EGFR', 'Gene', (124, 128))	('apoptosis', 'CPA', (178, 187))	('EGFR', 'molecular_function', 'GO:0005006', ('124', '128'))	('apoptosis', 'biological_process', 'GO:0097194', ('178', '187'))	('apoptosis', 'biological_process', 'GO:0006915', ('178', '187'))
5492	25437333	Although no significant reduction in gastric epithelial proliferation was identified with EKB-569 treatment in infected gerbils, in vivo rodent studies with other carcinogens such as asbestos, which also transactivates the EGFR, indicate bronchial hyperproliferative responses are dependent on EGFR activation.	('transactivates', 'Var', (204, 218))	('EGFR', 'molecular_function', 'GO:0005006', ('294', '298'))	('EGFR', 'Gene', (223, 227))	('EKB-569', 'Chemical', 'MESH:C413879', (90, 97))	('rat', 'Species', '10116', (260, 263))	('EGFR', 'molecular_function', 'GO:0005006', ('223', '227'))	('EKB-569', 'Gene', (90, 97))	('asbestos', 'Disease', 'MESH:D001195', (183, 191))	('bronchial hyperproliferative', 'Disease', (238, 266))	('rat', 'Species', '10116', (63, 66))	('asbestos', 'Disease', (183, 191))
5493	25437333	Asbestos induced inflammation alone in transgenic mice with mutant EGFR was not associated with epithelial hyperproliferative responses nor proto-oncogene activation.	('Asbestos', 'Chemical', 'MESH:D001194', (0, 8))	('rat', 'Species', '10116', (119, 122))	('transgenic mice', 'Species', '10090', (39, 54))	('EGFR', 'molecular_function', 'GO:0005006', ('67', '71'))	('inflammation', 'Disease', 'MESH:D007249', (17, 29))	('inflammation', 'biological_process', 'GO:0006954', ('17', '29'))	('EGFR', 'Gene', (67, 71))	('mutant', 'Var', (60, 66))	('inflammation', 'Disease', (17, 29))
5526	25437333	In conclusion, this study demonstrates that treatment of H. pylori infected gerbils with a selective EGFR inhibitor improves gastric corpus pathology and precancerous lesions and substantially decreases both the antral and corpus epithelial to apoptosis ratios to those of uninfected gerbils.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('inhibitor', 'Var', (106, 115))	('apoptosis', 'biological_process', 'GO:0006915', ('244', '253'))	('gastric corpus pathology', 'CPA', (125, 149))	('precancerous lesions', 'Disease', 'MESH:D011230', (154, 174))	('apoptosis', 'biological_process', 'GO:0097194', ('244', '253'))	('EGFR', 'molecular_function', 'GO:0005006', ('101', '105'))	('improves', 'PosReg', (116, 124))	('EGFR', 'Gene', (101, 105))	('rat', 'Species', '10116', (33, 36))	('precancerous lesions', 'Disease', (154, 174))	('decreases', 'NegReg', (193, 202))	('H. pylori', 'Gene', (57, 66))	('H. pylori', 'Species', '210', (57, 66))	('rat', 'Species', '10116', (254, 257))
5645	23953708	HDGC family history has been associated with breast cancer, the etiology of which may involve germline mutations in the cadherin-1 (CDH1) gene.	('HDGC', 'Disease', 'MESH:D013274', (0, 4))	('mutations', 'Var', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cadherin', 'molecular_function', 'GO:0008014', ('120', '128'))	('CDH1', 'Gene', (132, 136))	('HDGC', 'Disease', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Disease', (45, 58))	('CDH1', 'Gene', '999', (132, 136))	('GC', 'Phenotype', 'HP:0012126', (2, 4))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('family', 'Var', (5, 11))	('associated', 'Reg', (29, 39))	('cadherin-1', 'Gene', '999', (120, 130))	('cadherin-1', 'Gene', (120, 130))
5675	20237463	Fourth, H. pylori induces maturation, activation, and inflammatory cytokine secretion by human monocyte-derived DCs (MoDCs) and murine bone marrow DCs (BM-DCs) in vitro, "licensing" the DCs for T-cell priming.	('murine', 'Species', '10090', (128, 134))	('inflammatory cytokine secretion', 'MPA', (54, 85))	('human', 'Species', '9606', (89, 94))	('H. pylori', 'Var', (8, 17))	('activation', 'MPA', (38, 48))	('maturation', 'CPA', (26, 36))	('induces', 'Reg', (18, 25))	('H. pylori', 'Species', '210', (8, 17))	('cytokine secretion', 'biological_process', 'GO:0050663', ('67', '85'))
5700	20237463	Importantly, H. pylori infection resulted in a more activated phenotype in the gastric HLADR+ DCs, reflected in increased expression of CD11c (P <0.001), CD83 (P =0.02), CD86 (P =0.002), CD80, DC-SIGN, and CD14 compared with cells isolated from noninfected subjects (Figure 1b; Table 1).	('expression', 'MPA', (122, 132))	('CD11c', 'Gene', '3687', (136, 141))	('CD11c', 'Gene', (136, 141))	('CD80', 'Var', (187, 191))	('H. pylori infection', 'Phenotype', 'HP:0005202', (13, 32))	('activated', 'PosReg', (52, 61))	('CD83', 'Gene', (154, 158))	('H. pylori', 'Disease', (13, 22))	('infection', 'Disease', (23, 32))	('infection', 'Disease', 'MESH:D007239', (23, 32))	('phenotype', 'MPA', (62, 71))	('CD83', 'Gene', '9308', (154, 158))	('gastric', 'Disease', (79, 86))	('H. pylori', 'Species', '210', (13, 22))	('increased', 'PosReg', (112, 121))	('CD14', 'Gene', (206, 210))	('CD14', 'Gene', '929', (206, 210))	('CD86', 'Gene', '942', (170, 174))	('CD86', 'Gene', (170, 174))
5713	20237463	Following exposure to H. pylori, increased proportions of MoDCs expressed CD83 and CD80, similar to previously reported studies (Figure 3c).	('H. pylori', 'Species', '210', (22, 31))	('CD83', 'Gene', (74, 78))	('CD80', 'Var', (83, 87))	('CD83', 'Gene', '9308', (74, 78))
5722	20237463	Gastric CD13+ cells displayed poor phagocytic activity for GFP- H. pylori and reduced endocytic activity for DQ-ovalbumin, and MoDCs avidly took up both GFP- H. pylori and DQ-ovalbumin.	('GFP- H.', 'Var', (59, 66))	('CD13', 'Gene', '290', (8, 12))	('endocytic activity', 'MPA', (86, 104))	('CD13', 'Gene', (8, 12))	('phagocytic activity', 'CPA', (35, 54))	('H. pylori', 'Species', '210', (64, 73))	('H. pylori', 'Species', '210', (158, 167))	('CD13', 'molecular_function', 'GO:0004179', ('8', '12'))	('reduced', 'NegReg', (78, 85))
5727	20237463	Pulsed gastric CD13+ cells were unable to induce detectable T-cell cytokine production, whereas MoDCs induced T-cells to secrete levels of IFN-gamma and IL-10 similar to those induced by gastric DCs.	('IL-10', 'Gene', (153, 158))	('CD13', 'Gene', (15, 19))	('CD13', 'molecular_function', 'GO:0004179', ('15', '19'))	('T-cell cytokine production', 'MPA', (60, 86))	('IL-10', 'Gene', '3586', (153, 158))	('IL-10', 'molecular_function', 'GO:0005141', ('153', '158'))	('MoDCs', 'Var', (96, 101))	('secrete levels of IFN-gamma', 'MPA', (121, 148))	('T-cell cytokine production', 'biological_process', 'GO:0002369', ('60', '86'))	('CD13', 'Gene', '290', (15, 19))
5729	20237463	We report here the first characterization and isolation of DCs from human gastric mucosa and provide evidence that gastric DCs induce the adaptive T-cell response to H. pylori.	('human', 'Species', '9606', (68, 73))	('induce', 'PosReg', (127, 133))	('DCs', 'Var', (123, 126))	('gastric', 'Disease', (115, 122))	('adaptive T-cell response', 'CPA', (138, 162))	('H. pylori', 'Species', '210', (166, 175))
5744	20237463	The apparent inability of gastric HLA-DR+ DCs to produce IL-12 raises the possibility that gastric DCs induce T-cell IFN-gamma secretion through macrophage inhibitory factor, a protein that has recently emerged as a Th1- stimulating cytokine in H. pylori gastritis.	('T-cell IFN-gamma secretion', 'MPA', (110, 136))	('Th1', 'Gene', (216, 219))	('gastric', 'Var', (91, 98))	('IFN-gamma secretion', 'biological_process', 'GO:0072643', ('117', '136'))	('IL-12', 'molecular_function', 'GO:0005143', ('57', '62'))	('H. pylori gastritis', 'Phenotype', 'HP:0005202', (245, 264))	('Th1', 'Gene', '57314', (216, 219))	('induce', 'Reg', (103, 109))	('gastritis', 'Disease', 'MESH:D005756', (255, 264))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('gastritis', 'Phenotype', 'HP:0005263', (255, 264))	('H. pylori', 'Species', '210', (245, 254))	('gastritis', 'Disease', (255, 264))
5759	20237463	The following monoclonal anti-human antibodies were used for immunohistology and flow cytometry: CD1a (clone HI149), CD3 (HIT3a), CD11c (Bly6), CD13 (WM15), CD14 (M5E2), CD20 (2H7), CD56 (B159), CD80 (BB1), CD83 (HB15e), CD86 (FUN-1), CD116 (M5D12), CD123 (7G3), HLA-DR (L243), DC-SIGN (19.2), CD206 (mannose receptor, DCN46) and CCR3 (5E8).	('CD14', 'Gene', (157, 161))	('CD14', 'Gene', '929', (157, 161))	('CD20', 'Gene', (170, 174))	('CD83', 'Gene', (207, 211))	('CD13', 'Gene', '290', (144, 148))	('CD20', 'Gene', '54474', (170, 174))	('CD13', 'molecular_function', 'GO:0004179', ('144', '148'))	('mannose receptor', 'molecular_function', 'GO:0005532', ('301', '317'))	('CD86', 'Gene', '942', (221, 225))	('CD86', 'Gene', (221, 225))	('CCR', 'molecular_function', 'GO:0043880', ('330', '333'))	('CD20', 'Gene', (294, 298))	('CD83', 'Gene', '9308', (207, 211))	('CD116', 'Var', (235, 240))	('CD20', 'Gene', '54474', (294, 298))	('human', 'Species', '9606', (30, 35))	('CD11c', 'Gene', '3687', (130, 135))	('CD11c', 'Gene', (130, 135))	('CD13', 'Gene', (144, 148))
5794	32649523	Many miRNAs contribute to cancer development, and the ectopic expression of miRNAs is associated with tumor initiation and progression, such as proliferation, invasion, and other malignant phenotypes.	('contribute', 'Reg', (12, 22))	('miR', 'Gene', (5, 8))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('miR', 'Gene', '751557', (76, 79))	('associated', 'Reg', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('ectopic expression', 'Var', (54, 72))	('miR', 'Gene', '751557', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('invasion', 'CPA', (159, 167))	('miR', 'Gene', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('proliferation', 'CPA', (144, 157))
5809	32649523	Hayashi et al showed that CagA induced the epigenetic silence of let-7 expression, which triggered the up-regulation of Ras expression in Helicobacter pylori-related tumorigenesis of GC.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('regulation', 'biological_process', 'GO:0065007', ('106', '116'))	('up-regulation', 'PosReg', (103, 116))	('CagA', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('Ras', 'Protein', (120, 123))	('CagA', 'Gene', '6279', (26, 30))	('Helicobacter pylori', 'Species', '210', (138, 157))	('tumor', 'Disease', (166, 171))	('GC', 'Phenotype', 'HP:0012126', (183, 185))	('let-7', 'Gene', (65, 70))	('expression', 'MPA', (124, 134))	('epigenetic silence', 'Var', (43, 61))	('Helicobacter pylori-related', 'Disease', (138, 165))
5812	32649523	For example, miR-508-3p directly targets NF-kappaB1 and RELA (p65), and the inactivation of miR-508-3p may activate the canonical NF-kappaB signaling pathway in GC.	('p65', 'Gene', '5970', (62, 65))	('NF-kappaB', 'Gene', '4790', (130, 139))	('signaling pathway', 'biological_process', 'GO:0007165', ('140', '157'))	('GC', 'Phenotype', 'HP:0012126', (161, 163))	('NF-kappaB', 'Gene', (130, 139))	('p65', 'Gene', (62, 65))	('NF-kappaB', 'Gene', '4790', (41, 50))	('activate', 'PosReg', (107, 115))	('RELA', 'Gene', '5970', (56, 60))	('NF-kappaB', 'Gene', (41, 50))	('inactivation', 'Var', (76, 88))	('miR-508-3p', 'Chemical', '-', (92, 102))	('miR-508-3p', 'Chemical', '-', (13, 23))	('RELA', 'Gene', (56, 60))	('miR-508-3p', 'Gene', (92, 102))
5820	32649523	MiR-371a-3p is also a positive force in tumorigenesis via the targeting of transducer of human epidermal growth factor receptor 2, 1 (TOB1).	('epidermal growth factor receptor 2', 'Gene', (95, 129))	('human', 'Species', '9606', (89, 94))	('371a', 'Chemical', '-', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('95', '118'))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('TOB1', 'Gene', (134, 138))	('TOB1', 'Gene', '10140', (134, 138))	('MiR-371a-3p', 'Var', (0, 11))	('tumor', 'Disease', (40, 45))	('epidermal growth factor receptor 2', 'Gene', '2064', (95, 129))
5825	32649523	MiR-203 over-expression and knockdown of its target PIBF1 suppressed tumor cell proliferation, and the knockdown of miR-203 promoted the growth of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (69, 74))	('PIBF1', 'Gene', '10464', (52, 57))	('over-expression', 'PosReg', (8, 23))	('suppressed', 'NegReg', (58, 68))	('miR-203', 'Gene', (116, 123))	('MiR-203', 'Gene', (0, 7))	('promoted', 'PosReg', (124, 132))	('PIBF1', 'Gene', (52, 57))	('miR-203', 'Gene', '406986', (116, 123))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('MiR-203', 'Gene', '406986', (0, 7))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('knockdown', 'Var', (103, 112))
5832	32649523	Jiang et al showed that miR-1254 inhibited the PI3K/AKT signaling pathway via the targeting of Smurf1, which led to the suppression of tumor cell proliferation, migration, and invasion.	('miR-1254', 'Gene', '100302273', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('targeting', 'Var', (82, 91))	('inhibited', 'NegReg', (33, 42))	('AKT signaling', 'biological_process', 'GO:0043491', ('52', '65'))	('AKT', 'Gene', (52, 55))	('Smurf1', 'Gene', '57154', (95, 101))	('tumor', 'Disease', (135, 140))	('cell proliferation', 'biological_process', 'GO:0008283', ('141', '159'))	('signaling pathway', 'biological_process', 'GO:0007165', ('56', '73'))	('miR-1254', 'Gene', (24, 32))	('Smurf1', 'Gene', (95, 101))	('migration', 'CPA', (161, 170))	('AKT', 'Gene', '207', (52, 55))	('suppression', 'NegReg', (120, 131))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))	('invasion', 'CPA', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
5835	32649523	Silence of TRPM2-AS suppressed GC cell proliferation, metastasis, and radio-resistance, and ectopic expression showed an obvious opposite effect.	('TRPM2-AS', 'Gene', '101928607', (11, 19))	('GC cell proliferation', 'CPA', (31, 52))	('suppressed', 'NegReg', (20, 30))	('GC', 'Phenotype', 'HP:0012126', (31, 33))	('TRPM2-AS', 'Gene', (11, 19))	('radio-resistance', 'CPA', (70, 86))	('metastasis', 'CPA', (54, 64))	('cell proliferation', 'biological_process', 'GO:0008283', ('34', '52'))	('Silence', 'Var', (0, 7))
5838	32649523	Anomalous apoptosis is an important reason for cancer occurrence, development, and therapeutic inefficiency.	('Anomalous', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('apoptosis', 'CPA', (10, 19))	('apoptosis', 'biological_process', 'GO:0097194', ('10', '19'))	('apoptosis', 'biological_process', 'GO:0006915', ('10', '19'))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
5842	32649523	The ectopic expression of miR-24 triggered tumor cell cycle blockade and apoptosis.	('miR-24', 'Gene', (26, 32))	('apoptosis', 'biological_process', 'GO:0097194', ('73', '82'))	('apoptosis', 'biological_process', 'GO:0006915', ('73', '82'))	('miR-24', 'Chemical', '-', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cell cycle', 'biological_process', 'GO:0007049', ('49', '59'))	('apoptosis', 'CPA', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('ectopic expression', 'Var', (4, 22))	('tumor', 'Disease', (43, 48))
5843	32649523	Except for cancer cell proliferation, miR-17-5p/20a also exerted a pro-apoptotic effect in this experiment.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('miR-17-5p/20a', 'Var', (38, 51))	('pro-apoptotic effect', 'CPA', (67, 87))	('cell proliferation', 'biological_process', 'GO:0008283', ('18', '36'))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))
5844	32649523	Knockdown of miR-17-5p/20a promoted cancer cell apoptosis and resulted in cell cycle blockade.	('miR-17-5p/20a', 'Var', (13, 26))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('apoptosis', 'biological_process', 'GO:0006915', ('48', '57'))	('cancer', 'Disease', (36, 42))	('promoted', 'PosReg', (27, 35))	('cell cycle', 'biological_process', 'GO:0007049', ('74', '84'))	('cell cycle blockade', 'CPA', (74, 93))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('apoptosis', 'biological_process', 'GO:0097194', ('48', '57'))
5846	32649523	Early experiments revealed that poor expression of miR-106b enhanced apoptosis of GC cells via inhibition of the JAK1/STAT3 signaling pathway, and arm protein lost in epithelial cancers on chromosome X 1 was a direct target of miR-106b.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('inhibition', 'NegReg', (95, 105))	('apoptosis', 'CPA', (69, 78))	('apoptosis', 'biological_process', 'GO:0097194', ('69', '78'))	('arm protein lost in epithelial cancers on chromosome X 1', 'Gene', '51309', (147, 203))	('apoptosis', 'biological_process', 'GO:0006915', ('69', '78'))	('JAK', 'molecular_function', 'GO:0004713', ('113', '116'))	('JAK1', 'Gene', '3716', (113, 117))	('STAT3', 'Gene', (118, 123))	('miR-106b', 'Gene', '406900', (51, 59))	('miR-106b', 'Gene', '406900', (227, 235))	('chromosome', 'cellular_component', 'GO:0005694', ('189', '199'))	('STAT3', 'Gene', '6774', (118, 123))	('miR-106b', 'Gene', (51, 59))	('poor expression', 'Var', (32, 47))	('miR-106b', 'Gene', (227, 235))	('enhanced', 'PosReg', (60, 68))	('JAK1', 'Gene', (113, 117))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('protein', 'cellular_component', 'GO:0003675', ('151', '158'))	('signaling pathway', 'biological_process', 'GO:0007165', ('124', '141'))	('GC', 'Phenotype', 'HP:0012126', (82, 84))
5848	32649523	MiR-324-3p over-expression contributed to the loss of drosophila protein, mothers against decapentaplegic homolog 4 and activated the Wnt/beta-catenin signaling pathway, which resulted in tumor cell growth and apoptosis inhibition.	('tumor', 'Disease', (188, 193))	('cell growth', 'biological_process', 'GO:0016049', ('194', '205'))	('MiR-324-3p', 'Var', (0, 10))	('apoptosis', 'biological_process', 'GO:0097194', ('210', '219'))	('drosophila protein', 'Protein', (54, 72))	('signaling pathway', 'biological_process', 'GO:0007165', ('151', '168'))	('over-expression', 'PosReg', (11, 26))	('loss', 'NegReg', (46, 50))	('activated', 'PosReg', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('drosophila', 'Species', '7227', (54, 64))	('apoptosis inhibition', 'CPA', (210, 230))	('apoptosis', 'biological_process', 'GO:0006915', ('210', '219'))	('MiR-324-3p', 'Chemical', '-', (0, 10))	('Wnt/beta-catenin signaling pathway', 'Pathway', (134, 168))
5857	32649523	MiR-29c-3p mediated an inner ear-specific protein, cell migration inducing hyaluronan binding protein (KIAA1199 or CEMIP), expression and activated the fibroblast growth factor receptor 4/Wnt/beta-catenin and EGFR signaling pathways, which induced metastasis behavior.	('fibroblast growth factor receptor 4', 'Gene', '2264', (152, 187))	('EGFR', 'molecular_function', 'GO:0005006', ('209', '213'))	('cell migration', 'biological_process', 'GO:0016477', ('51', '65'))	('CEMIP', 'Gene', '57214', (115, 120))	('induced', 'Reg', (240, 247))	('activated', 'PosReg', (138, 147))	('protein', 'cellular_component', 'GO:0003675', ('94', '101'))	('EGFR', 'Gene', (209, 213))	('MiR-29c-3p', 'Var', (0, 10))	('cell migration', 'CPA', (51, 65))	('metastasis behavior', 'Disease', (248, 267))	('hyaluronan binding', 'molecular_function', 'GO:0005540', ('75', '93'))	('metastasis behavior', 'Disease', 'MESH:D009362', (248, 267))	('fibroblast growth factor', 'molecular_function', 'GO:0005104', ('152', '176'))	('CEMIP', 'Gene', (115, 120))	('EGFR', 'Gene', '1956', (209, 213))	('fibroblast growth factor receptor 4', 'Gene', (152, 187))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('KIAA1199', 'Gene', '57214', (103, 111))	('signaling', 'biological_process', 'GO:0023052', ('214', '223'))	('KIAA1199', 'Gene', (103, 111))
5872	32649523	Mousa et al showed that miR-4316 inhibited vascular endothelial growth factor A (VEGF-A) expression and induced the suppression of migration and colony formation in tumor cell lines.	('miR-4316', 'Var', (24, 32))	('miR-4316', 'Chemical', '-', (24, 32))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('43', '77'))	('VEGF', 'Gene', '7422', (81, 85))	('expression', 'MPA', (89, 99))	('formation', 'biological_process', 'GO:0009058', ('152', '161'))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('VEGF', 'Gene', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('inhibited', 'NegReg', (33, 42))	('suppression', 'NegReg', (116, 127))	('tumor', 'Disease', (165, 170))
5876	32649523	Ye et al discovered that the low expression of miR-7 activated p65-mediated abnormal NF-kappaB expression and promoted metastasis, which ultimately led to a poor prognosis.	('miR-7', 'Gene', '10859', (47, 52))	('NF-kappaB', 'Gene', '4790', (85, 94))	('activated', 'PosReg', (53, 62))	('NF-kappaB', 'Gene', (85, 94))	('p65', 'Gene', (63, 66))	('miR-7', 'Gene', (47, 52))	('low expression', 'Var', (29, 43))	('metastasis', 'CPA', (119, 129))	('p65', 'Gene', '5970', (63, 66))	('promoted', 'PosReg', (110, 118))	('expression', 'MPA', (95, 105))
5878	32649523	Zhang et al demonstrated that low miR-29a/c expression promoted the release of VEGF in GC cells, which enhanced vascular cell growth and angiogenesis.	('miR-29a/c', 'Gene', '407021', (34, 43))	('miR-29a/c', 'Gene', (34, 43))	('vascular cell growth', 'CPA', (112, 132))	('VEGF', 'Gene', '7422', (79, 83))	('GC', 'Phenotype', 'HP:0012126', (87, 89))	('low', 'Var', (30, 33))	('angiogenesis', 'CPA', (137, 149))	('enhanced', 'PosReg', (103, 111))	('promoted', 'PosReg', (55, 63))	('angiogenesis', 'biological_process', 'GO:0001525', ('137', '149'))	('cell growth', 'biological_process', 'GO:0016049', ('121', '132'))	('VEGF', 'Gene', (79, 83))
5883	32649523	MiR-150-5p and its sponge circLMTK2 showed a positive effect on proliferation and metastasis in GC via the regulation of c-Myc expression.	('c-Myc', 'Gene', '4609', (121, 126))	('positive effect', 'PosReg', (45, 60))	('GC', 'Phenotype', 'HP:0012126', (96, 98))	('regulation', 'Reg', (107, 117))	('expression', 'MPA', (127, 137))	('MiR-150-5p', 'Var', (0, 10))	('MiR-150-5p', 'Chemical', '-', (0, 10))	('regulation', 'biological_process', 'GO:0065007', ('107', '117'))	('c-Myc', 'Gene', (121, 126))	('proliferation', 'CPA', (64, 77))	('metastasis', 'CPA', (82, 92))
5886	32649523	However, multi-drug resistance generally leads to treatment failure and a poor prognosis of patients.	('drug resistance', 'biological_process', 'GO:0009315', ('15', '30'))	('drug resistance', 'biological_process', 'GO:0042493', ('15', '30'))	('leads to', 'Reg', (41, 49))	('patients', 'Species', '9606', (92, 100))	('multi-drug resistance', 'Var', (9, 30))	('drug resistance', 'Phenotype', 'HP:0020174', (15, 30))
5892	32649523	MiR-148a-3p conferred mitochondrial fission and suppressed cyto-protective autophagy by enhancing cisplatin cytotoxicity in experiments.	('MiR-148a-3p', 'Chemical', '-', (0, 11))	('MiR-148a-3p', 'Var', (0, 11))	('cytotoxicity', 'Disease', 'MESH:D064420', (108, 120))	('conferred', 'PosReg', (12, 21))	('autophagy', 'biological_process', 'GO:0016236', ('75', '84'))	('cyto-protective autophagy', 'CPA', (59, 84))	('suppressed', 'NegReg', (48, 58))	('autophagy', 'biological_process', 'GO:0006914', ('75', '84'))	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('cytotoxicity', 'Disease', (108, 120))	('mitochondrial fission', 'CPA', (22, 43))	('enhancing', 'PosReg', (88, 97))	('mitochondrial fission', 'biological_process', 'GO:0000266', ('22', '43'))
5899	32649523	Shao et al found that a high level of miR-135b-5p suppressed apoptosis and induced cisplatin resistance.	('apoptosis', 'biological_process', 'GO:0006915', ('61', '70'))	('suppressed', 'NegReg', (50, 60))	('apoptosis', 'CPA', (61, 70))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('cisplatin resistance', 'MPA', (83, 103))	('miR-135b-5p', 'Var', (38, 49))	('induced', 'PosReg', (75, 82))	('miR-135b-5p', 'Chemical', '-', (38, 49))	('apoptosis', 'biological_process', 'GO:0097194', ('61', '70'))
5906	32649523	They found that gradually injecting exo-anti-214 in nude mice reduced GC cell growth and restored sensitivity to DDP.	('GC cell growth', 'CPA', (70, 84))	('restored', 'PosReg', (89, 97))	('GC', 'Phenotype', 'HP:0012126', (70, 72))	('sensitivity to DDP', 'MPA', (98, 116))	('exo-anti-214', 'Var', (36, 48))	('nude mice', 'Species', '10090', (52, 61))	('cell growth', 'biological_process', 'GO:0016049', ('73', '84'))	('reduced', 'NegReg', (62, 69))	('DDP', 'Chemical', '-', (113, 116))
5909	32649523	Li et al demonstrated that treatment with 5-fluorouracil increased the expression of miR-204 and inhibited the transforming growth factor-beta (TGF-beta) pathway, and high miR-204 expression may reverse the chemotherapy resistance via the targeting of TGF-beta receptors 1.	('reverse', 'NegReg', (195, 202))	('expression', 'MPA', (71, 81))	('miR-204', 'Gene', (85, 92))	('transforming growth factor-beta', 'Gene', (111, 142))	('TGF-beta', 'Gene', '7039', (252, 260))	('miR-204', 'Gene', '406987', (172, 179))	('high', 'Var', (167, 171))	('transforming growth factor-beta', 'Gene', '7124', (111, 142))	('TGF-beta', 'Gene', '7039', (144, 152))	('chemotherapy resistance', 'CPA', (207, 230))	('miR-204', 'Gene', (172, 179))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (42, 56))	('TGF-beta', 'Gene', (252, 260))	('increased', 'PosReg', (57, 66))	('inhibited', 'NegReg', (97, 106))	('transforming growth factor-beta', 'molecular_function', 'GO:0005160', ('111', '142'))	('TGF-beta', 'Gene', (144, 152))	('miR-204', 'Gene', '406987', (85, 92))
5914	32649523	Notably, Wei et al found that a well-known neurotransmitter related to stress, isoproterenol, also led to chemo-resistance in GC cells, and transfection with miR-373 inhibited the effects of isoproterenol on drug sensitivity.	('isoproterenol', 'Chemical', 'MESH:D007545', (191, 204))	('drug sensitivity', 'Phenotype', 'HP:0020174', (208, 224))	('drug sensitivity', 'MPA', (208, 224))	('transfection', 'Var', (140, 152))	('miR-373', 'Gene', '442918', (158, 165))	('GC', 'Phenotype', 'HP:0012126', (126, 128))	('isoproterenol', 'Var', (79, 92))	('led to', 'Reg', (99, 105))	('miR-373', 'Gene', (158, 165))	('isoproterenol', 'Chemical', 'MESH:D007545', (79, 92))	('effects', 'MPA', (180, 187))	('inhibited', 'NegReg', (166, 175))	('chemo-resistance', 'MPA', (106, 122))
5917	32649523	The silencing of an endogenous sponge for miR-3657, circRACGAP1, suppressed apatinib-induced autophagy.	('apatinib', 'Chemical', 'MESH:C553458', (76, 84))	('miR-3657', 'Gene', '100500889', (42, 50))	('miR-3657', 'Gene', (42, 50))	('circRACGAP1', 'Gene', (52, 63))	('suppressed', 'NegReg', (65, 75))	('autophagy', 'biological_process', 'GO:0016236', ('93', '102'))	('apatinib-induced', 'MPA', (76, 92))	('autophagy', 'biological_process', 'GO:0006914', ('93', '102'))	('silencing', 'Var', (4, 13))
5926	32649523	Mounting evidence shows that the ectopic expression of CD44 also influences the stemness of cancer cells.	('ectopic expression', 'Var', (33, 51))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('influences', 'Reg', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('CD44', 'Gene', (55, 59))
5928	32649523	Jang et al designed nanovesicles containing poly L-lysine-graft-imidazole (PLI)/miR, PLI-condensing miRs, and found that the application of this PLI/miR-34a-containing nanovesicle to nude mice suppressed the expression of CD44.	('PLI', 'Gene', (85, 88))	('poly', 'Var', (44, 48))	('miR', 'Gene', (80, 83))	('miR', 'Gene', '751557', (100, 103))	('miR', 'Gene', '751557', (149, 152))	('CD44', 'Protein', (222, 226))	('nude mice', 'Species', '10090', (183, 192))	('PLI', 'Gene', '18816', (75, 78))	('miR', 'Gene', '751557', (80, 83))	('PLI', 'Gene', '18816', (85, 88))	('miR', 'Gene', (100, 103))	('PLI', 'Gene', (145, 148))	('poly L-lysine-graft-imidazole', 'Chemical', '-', (44, 73))	('miR', 'Gene', (149, 152))	('expression', 'MPA', (208, 218))	('PLI', 'Gene', (75, 78))	('PLI', 'Gene', '18816', (145, 148))	('suppressed', 'NegReg', (193, 203))
5950	32649523	For example, high miR-15 expression down-regulated the expression of some genes that are involved in a defective DNA mismatch repair system, which leads to gastric pathologies.	('DNA', 'cellular_component', 'GO:0005574', ('113', '116'))	('miR', 'Gene', '751557', (18, 21))	('leads to', 'Reg', (147, 155))	('high', 'Var', (13, 17))	('mismatch repair', 'biological_process', 'GO:0006298', ('117', '132'))	('gastric pathologies', 'Disease', (156, 175))	('expression', 'MPA', (55, 65))	('miR', 'Gene', (18, 21))	('down-regulated', 'NegReg', (36, 50))
5953	32649523	CagA-induced MiR-223-3p directly targeted AT-rich interactive domain 1A to play a role in cell proliferation and migration, which provided an explanation of carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (157, 171))	('CagA', 'Gene', (0, 4))	('play', 'Reg', (75, 79))	('MiR-223-3p', 'Var', (13, 23))	('cell proliferation', 'CPA', (90, 108))	('CagA', 'Gene', '6279', (0, 4))	('role', 'Reg', (82, 86))	('carcinogenesis', 'Disease', (157, 171))	('cell proliferation', 'biological_process', 'GO:0008283', ('90', '108'))
5988	32649523	The expression of miR-153 in tumor tissues was associated with worse overall survival (HR = 0.253) and disease-free survival (HR = 0.228) in patients with GC.	('overall survival', 'CPA', (69, 85))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('worse', 'NegReg', (63, 68))	('miR-153', 'Var', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('GC', 'Phenotype', 'HP:0012126', (155, 157))	('disease-free survival', 'CPA', (103, 124))	('tumor', 'Disease', (29, 34))	('patients', 'Species', '9606', (141, 149))	('miR-153', 'Chemical', '-', (18, 25))
5989	32649523	Guo et al found that high hsa-mir-3923 expression in patients with GC may be an independent prognosis element for poor survival.	('patients', 'Species', '9606', (53, 61))	('high', 'Var', (21, 25))	('hsa-mir-3923', 'Gene', '100500877', (26, 38))	('expression', 'MPA', (39, 49))	('GC', 'Phenotype', 'HP:0012126', (67, 69))	('hsa-mir-3923', 'Gene', (26, 38))
5992	32649523	MiR-1236-3p expression in tumor tissues was significantly declined, which was an independent prognostic factor for overall survival in patients with GC.	('patients', 'Species', '9606', (135, 143))	('MiR-1236-3p', 'Chemical', '-', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('GC', 'Phenotype', 'HP:0012126', (149, 151))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('MiR-1236-3p', 'Var', (0, 11))	('tumor', 'Disease', (26, 31))	('declined', 'NegReg', (58, 66))
6035	32575584	Whole-genome sequencing of the 23S rRNA genes detected 42 mutations on 40 nonidentical loci, including 2147A>G (formerly 2143A>G) and 2146A>G (formerly 2142A>G).	('2146A>G', 'Var', (134, 141))	('2147A>G', 'Mutation', 'c.2147A>G', (103, 110))	('2143A>G', 'Mutation', 'c.2143A>G', (121, 128))	('2147A>G', 'Var', (103, 110))	('2146A>G', 'Mutation', 'c.2146A>G', (134, 141))	('2142A>G', 'Mutation', 'c.2142A>G', (152, 159))
6036	32575584	All strains with clarithromycin-resistant phenotype had either 2147A>G or 2146A>G mutation.	('2147A>G', 'Mutation', 'c.2147A>G', (63, 70))	('2146A>G', 'Var', (74, 81))	('2147A>G', 'Var', (63, 70))	('clarithromycin', 'Chemical', 'MESH:D017291', (17, 31))	('2146A>G', 'Mutation', 'c.2146A>G', (74, 81))
6037	32575584	When comparing genotype and phenotype for clarithromycin resistance, there was a significant association between 2147A>G mutation and clarithromycin-resistant phenotype.	('clarithromycin', 'Chemical', 'MESH:D017291', (134, 148))	('clarithromycin-resistant phenotype', 'MPA', (134, 168))	('clarithromycin', 'Chemical', 'MESH:D017291', (42, 56))	('2147A>G', 'Mutation', 'c.2147A>G', (113, 120))	('2147A>G', 'Var', (113, 120))
6038	32575584	Conclusions: All clarithromycin-resistant strains had either 2146A>G or 2147A>G mutation, suggesting that tests targeting these two mutations may be enough for the prediction of clarithromycin resistance in this population.	('2147A>G', 'Var', (72, 79))	('2146A>G', 'Var', (61, 68))	('clarithromycin', 'Chemical', 'MESH:D017291', (178, 192))	('clarithromycin', 'Chemical', 'MESH:D017291', (17, 31))	('2146A>G', 'Mutation', 'c.2146A>G', (61, 68))	('2147A>G', 'Mutation', 'c.2147A>G', (72, 79))
6046	32575584	Point mutations in the peptidyl transferase region encoded in domain V of 23S ribosomal subunit (23S rRNA) are responsible for clarithromycin resistance.	('responsible', 'Reg', (111, 122))	('clarithromycin', 'Chemical', 'MESH:D017291', (127, 141))	('Point mutations', 'Var', (0, 15))	('ribosomal subunit', 'cellular_component', 'GO:0044391', ('78', '95'))	('clarithromycin', 'MPA', (127, 141))
6047	32575584	These mutations inhibit binding between clarithromycin and the ribosomal subunit dedicated to bacterial peptide translation.	('ribosomal', 'Protein', (63, 72))	('clarithromycin', 'Chemical', 'MESH:D017291', (40, 54))	('inhibit', 'NegReg', (16, 23))	('binding', 'Interaction', (24, 31))	('translation', 'biological_process', 'GO:0006412', ('112', '123'))	('binding', 'molecular_function', 'GO:0005488', ('24', '31'))	('ribosomal subunit', 'cellular_component', 'GO:0044391', ('63', '80'))	('mutations', 'Var', (6, 15))
6048	32575584	Point mutations in one of two adjacent nucleotides in 23S rRNA, namely 2143A>G, 2142A>G, or 2142A>C, are the most commonly reported mutations in H. pylori with clarithromycin resistance.	('2142A>C', 'Mutation', 'c.2142A>C', (92, 99))	('2142A>C', 'Var', (92, 99))	('2143A>G', 'Var', (71, 78))	('2143A>G', 'Mutation', 'c.2143A>G', (71, 78))	('2142A>G', 'Mutation', 'c.2142A>G', (80, 87))	('Point mutations', 'Var', (0, 15))	('H. pylori', 'Species', '210', (145, 154))	('clarithromycin', 'Chemical', 'MESH:D017291', (160, 174))
6049	32575584	Several other point mutations in the 23S rRNA are also reportedly involved in clarithromycin resistance.	('clarithromycin resistance', 'MPA', (78, 103))	('involved', 'Reg', (66, 74))	('clarithromycin', 'Chemical', 'MESH:D017291', (78, 92))	('point mutations', 'Var', (14, 29))
6068	32575584	Among 42 mutations, 1691T>C, 1825A>G, 1830G>A, and 1834T>C were found in all patients regardless of antimicrobial susceptibility.	('1834T>C', 'Mutation', 'c.1834T>C', (51, 58))	('1825A>G', 'Mutation', 'c.1825A>G', (29, 36))	('patients', 'Species', '9606', (77, 85))	('1825A>G', 'Var', (29, 36))	('1691T>C', 'Mutation', 'c.1691T>C', (20, 27))	('1830G>A', 'Mutation', 'c.1830G>A', (38, 45))	('1834T>C', 'Var', (51, 58))	('1830G>A', 'Var', (38, 45))	('1691T>C', 'Var', (20, 27))
6069	32575584	Mutations of 387G>A, 1582C>T, 1583G>A, 2227A>G, and 2292C>T were observed only in primary strains and were considered variations that existed before the acquisition of clarithromycin resistance.	('1583G>A', 'Mutation', 'c.1583G>A', (30, 37))	('1583G>A', 'Var', (30, 37))	('387G>A', 'Mutation', 'c.387G>A', (13, 19))	('clarithromycin', 'Chemical', 'MESH:D017291', (168, 182))	('2292C>T', 'Var', (52, 59))	('2227A>G', 'Mutation', 'c.2227A>G', (39, 46))	('1582C>T', 'Mutation', 'c.1582C>T', (21, 28))	('2292C>T', 'Mutation', 'c.2292C>T', (52, 59))
6071	32575584	All 38 clarithromycin-resistant strains had either 2147A>G or 2146A>G mutation, equivalent to location 2143 and 2142 in domain V of the 23S rRNA genes proposed by Taylor et al.	('2147A>G', 'Mutation', 'c.2147A>G', (51, 58))	('2147A>G', 'Var', (51, 58))	('clarithromycin', 'Chemical', 'MESH:D017291', (7, 21))	('2146A>G', 'Var', (62, 69))	('2146A>G', 'Mutation', 'c.2146A>G', (62, 69))
6072	32575584	The 2147A>G mutation was found in 94.7% (36/38) of strains with clarithromycin resistance and was observed in both primary and secondary strains with MIC ranging from 4 to 32 mug/mL (Table 1 and Supplementary Figure S2).	('2147A>G', 'Mutation', 'c.2147A>G', (4, 11))	('clarithromycin', 'Chemical', 'MESH:D017291', (64, 78))	('clarithromycin resistance', 'MPA', (64, 89))	('2147A>G', 'Var', (4, 11))	('mug', 'molecular_function', 'GO:0043739', ('175', '178'))
6075	32575584	The association between 2147A>G and phenotypic antimicrobial resistance was found in 95.7% (44/46) of strains; the presence of G allele was associated with clarithromycin resistance in 94.7% (36/38) of strains, and A allele was associated with clarithromycin susceptibility in 100% (8/8) of strains.	('clarithromycin', 'Chemical', 'MESH:D017291', (156, 170))	('clarithromycin resistance', 'MPA', (156, 181))	('associated', 'Reg', (140, 150))	('2147A>G', 'Mutation', 'c.2147A>G', (24, 31))	('2147A>G', 'Var', (24, 31))	('presence', 'Var', (115, 123))	('clarithromycin', 'Chemical', 'MESH:D017291', (244, 258))
6076	32575584	In the present study, we investigated the prevalence of mutations in the 23S rRNA genes conferring clarithromycin resistance, using next-generation sequencing of H. pylori strains.	('H. pylori strai', 'Species', '85962', (162, 177))	('mutations', 'Var', (56, 65))	('clarithromycin', 'Chemical', 'MESH:D017291', (99, 113))	('23S rRNA', 'Gene', (73, 81))	('conferring', 'Reg', (88, 98))
6077	32575584	A total of 42 mutations, including 2146A>G and 2147A>G (formerly 2142A>G and 2143A>G), were found in 40 loci.	('2147A>G', 'Var', (47, 54))	('2142A>G', 'Mutation', 'c.2142A>G', (65, 72))	('2146A>G', 'Var', (35, 42))	('2143A>G', 'Var', (77, 84))	('2143A>G', 'Mutation', 'c.2143A>G', (77, 84))	('2146A>G', 'Mutation', 'c.2146A>G', (35, 42))	('2147A>G', 'Mutation', 'c.2147A>G', (47, 54))
6078	32575584	All clarithromycin-resistant strains had either 2146A>G or 2147A>G mutation.	('2147A>G', 'Mutation', 'c.2147A>G', (59, 66))	('2146A>G', 'Mutation', 'c.2146A>G', (48, 55))	('2147A>G', 'Var', (59, 66))	('clarithromycin', 'Chemical', 'MESH:D017291', (4, 18))	('2146A>G', 'Var', (48, 55))
6079	32575584	That is, the combination of mutations 2146A>G and 2147A>G can predict resistant phenotype in all strains.	('mutations 2146A>G', 'Var', (28, 45))	('2147A>G', 'Mutation', 'c.2147A>G', (50, 57))	('resistant phenotype', 'MPA', (70, 89))	('2146A>G', 'Mutation', 'c.2146A>G', (38, 45))	('2147A>G', 'Var', (50, 57))	('predict', 'Reg', (62, 69))
6082	32575584	Various molecular methods, including next-generation sequencing, have enabled the detection of genetic mutations of H. pylori and suggested association between genotype and phenotype for antimicrobial resistance.	('association', 'Interaction', (140, 151))	('H. pylori', 'Gene', (116, 125))	('genetic mutations', 'Var', (95, 112))	('H. pylori', 'Species', '210', (116, 125))
6083	32575584	Each genotype was compared with phenotypic resistance to clarithromycin, and there was a clear association between the presence of 2147A>G mutation (formerly 2143A>G) and clarithromycin resistance.	('clarithromycin', 'Chemical', 'MESH:D017291', (171, 185))	('clarithromycin', 'Chemical', 'MESH:D017291', (57, 71))	('presence of 2147A>G', 'Var', (119, 138))	('2147A>G', 'Mutation', 'c.2147A>G', (131, 138))	('clarithromycin resistance', 'MPA', (171, 196))	('2143A>G', 'Mutation', 'c.2143A>G', (158, 165))
6084	32575584	The antimicrobial resistance mechanism of H. pylori is mainly based on point mutations in the bacterial chromosome.	('based', 'Reg', (62, 67))	('H. pylori', 'Species', '210', (42, 51))	('H. pylori', 'Disease', (42, 51))	('chromosome', 'cellular_component', 'GO:0005694', ('104', '114'))	('point mutations', 'Var', (71, 86))
6085	32575584	Clarithromycin resistance is mediated by mutations in the 23S rRNA gene that reduce the affinity of clarithromycin for the 23S ribosomal component and inhibit clarithromycin activity against H. pylori.	('mutations', 'Var', (41, 50))	('23S rRNA', 'Gene', (58, 66))	('reduce', 'NegReg', (77, 83))	('Clarithromycin', 'Chemical', 'MESH:D017291', (0, 14))	('affinity', 'Interaction', (88, 96))	('mediated by', 'Reg', (29, 40))	('clarithromycin', 'Chemical', 'MESH:D017291', (100, 114))	('inhibit', 'NegReg', (151, 158))	('clarithromycin activity', 'MPA', (159, 182))	('clarithromycin', 'Chemical', 'MESH:D017291', (159, 173))	('H. pylori', 'Species', '210', (191, 200))
6086	32575584	The most commonly reported mutations include 2143A>G, 2142A>G, and 2142A>C.	('2143A>G', 'Var', (45, 52))	('2143A>G', 'Mutation', 'c.2143A>G', (45, 52))	('2142A>C', 'Var', (67, 74))	('2142A>G', 'Var', (54, 61))	('2142A>G', 'Mutation', 'c.2142A>G', (54, 61))	('2142A>C', 'Mutation', 'c.2142A>C', (67, 74))
6087	32575584	Several other mutations have been recognized, such as 2182T>C, 2183T>C, 2223A>G, 2717T>C, 2245T>C, and 2116A>G (corresponding to nucleotide locations at 2186, 2187, 2227, 2722, 2249, and 2120 in this study), but their clinical relevance remains controversial.	('2223A>G', 'Mutation', 'c.2223A>G', (72, 79))	('2116A>G', 'Var', (103, 110))	('2182T>C', 'Var', (54, 61))	('2182T>C', 'Mutation', 'c.2182T>C', (54, 61))	('2717T>C', 'Mutation', 'c.2717T>C', (81, 88))	('2116A>G', 'Mutation', 'c.2116A>G', (103, 110))	('2183T>C', 'Mutation', 'c.2183T>C', (63, 70))	('2227', 'Var', (165, 169))	('2245T>C', 'Mutation', 'c.2245T>C', (90, 97))	('2722', 'Var', (171, 175))
6088	32575584	Several reports suggested that 2143A>G is responsible for clarithromycin resistance and is associated with eradication failure.	('eradication failure', 'Disease', 'MESH:D006333', (107, 126))	('eradication failure', 'Disease', (107, 126))	('2143A>G', 'Var', (31, 38))	('2143A>G', 'Mutation', 'c.2143A>G', (31, 38))	('clarithromycin', 'Chemical', 'MESH:D017291', (58, 72))	('clarithromycin resistance', 'MPA', (58, 83))	('responsible', 'Reg', (42, 53))
6089	32575584	In a previous study, 2143A>G mutation was found only in clarithromycin-resistant strains, and the presence of 2143A>G was correlated with the efficacy of eradication therapy.	('2143A>G', 'Mutation', 'c.2143A>G', (110, 117))	('clarithromycin', 'Chemical', 'MESH:D017291', (56, 70))	('correlated', 'Reg', (122, 132))	('2143A>G', 'Var', (21, 28))	('2143A>G', 'Mutation', 'c.2143A>G', (21, 28))
6090	32575584	Recent studies using whole-genome sequencing also found that clarithromycin resistance is associated with the presence of mutations 2146A>C (formerly 2142A>C), 2146A>G (formerly 2142A>G), or 2147A>G (formerly 2143A>G) in the 23S rRNA genes.	('2142A>C', 'Mutation', 'c.2142A>C', (150, 157))	('2142A>G', 'Mutation', 'c.2142A>G', (178, 185))	('2146A>C', 'Mutation', 'c.2146A>C', (132, 139))	('2147A>G', 'Mutation', 'c.2147A>G', (191, 198))	('2146A>G', 'Mutation', 'c.2146A>G', (160, 167))	('clarithromycin resistance', 'MPA', (61, 86))	('23S rRNA', 'Gene', (225, 233))	('associated', 'Reg', (90, 100))	('2143A>G', 'Mutation', 'c.2143A>G', (209, 216))	('mutations 2146A>C', 'Var', (122, 139))	('2146A>G', 'Var', (160, 167))	('clarithromycin', 'Chemical', 'MESH:D017291', (61, 75))
6091	32575584	In the present study, clarithromycin resistance was primarily associated with 2147A>G, and clarithromycin-resistant strains without 2147G allele had the mutation 2146A>G.	('2146A>G', 'Mutation', 'c.2146A>G', (162, 169))	('associated', 'Reg', (62, 72))	('clarithromycin resistance', 'MPA', (22, 47))	('2147A>G', 'Mutation', 'c.2147A>G', (78, 85))	('2147A>G', 'Var', (78, 85))	('clarithromycin', 'Chemical', 'MESH:D017291', (91, 105))	('clarithromycin', 'Chemical', 'MESH:D017291', (22, 36))
6093	32575584	The prevalence of 2142A>G is reportedly lower than that of 2143A>G and is considered to be associated with clarithromycin resistance.	('2143A>G', 'Mutation', 'c.2143A>G', (59, 66))	('clarithromycin', 'MPA', (107, 121))	('2142A>G', 'Mutation', 'c.2142A>G', (18, 25))	('2142A>G', 'Var', (18, 25))	('clarithromycin', 'Chemical', 'MESH:D017291', (107, 121))	('lower', 'NegReg', (40, 45))	('associated', 'Reg', (91, 101))
6095	32575584	Previous studies showed a similar eradication rate for 2142A>G mutants and wild-type strains, while the rate significantly decreased with 2143A>G mutation.	('2143A>G', 'Var', (138, 145))	('2143A>G', 'Mutation', 'c.2143A>G', (138, 145))	('decreased', 'NegReg', (123, 132))	('eradication', 'MPA', (34, 45))	('2142A>G', 'Var', (55, 62))	('2142A>G', 'Mutation', 'c.2142A>G', (55, 62))
6096	32575584	According to a more recent report from the same group, the eradication rate of 2142A>G or 2142A>C mutants decreased to 57.1% compared to 96.4% of strains with genotypic and phenotypic susceptibility, suggesting that mutations at A2142 seemed to have a marginal role in conferring clarithromycin-resistant phenotype.	('decreased', 'NegReg', (106, 115))	('clarithromycin', 'Chemical', 'MESH:D017291', (280, 294))	('mutations at A2142', 'Var', (216, 234))	('clarithromycin-resistant phenotype', 'MPA', (280, 314))	('2142A>G', 'Var', (79, 86))	('2142A>G', 'Mutation', 'c.2142A>G', (79, 86))	('2142A>C mutants', 'Var', (90, 105))	('2142A>C', 'Mutation', 'c.2142A>C', (90, 97))
6098	32575584	These discrepancies between studies may be due to the relatively low prevalence of 2142A>G, which makes it difficult to draw clear conclusions regarding the clinical impact of 2142A>G or 2142A>C mutations on eradication therapy.	('2142A>C', 'Var', (187, 194))	('2142A>G', 'Var', (83, 90))	('2142A>G', 'Var', (176, 183))	('2142A>G', 'Mutation', 'c.2142A>G', (83, 90))	('2142A>G', 'Mutation', 'c.2142A>G', (176, 183))	('2142A>C', 'Mutation', 'c.2142A>C', (187, 194))
6102	32575584	However, microbiologic evidence revealed that 2182T>C mutation was not responsible for clarithromycin resistance, which mainly depends on the presence of the 2143G allele.	('2143G', 'Var', (158, 163))	('2182T>C', 'Var', (46, 53))	('clarithromycin', 'Chemical', 'MESH:D017291', (87, 101))	('2182T>C', 'Mutation', 'c.2182T>C', (46, 53))
6107	32575584	To overcome this limitation, we compared each genotype with phenotypes determined by using a culture-based method to elucidate the clinical relevance of genotypic mutations in the 23S rRNA genes of H. pylori.	('H. pylori', 'Species', '210', (198, 207))	('mutations', 'Var', (163, 172))	('H. pylori', 'Gene', (198, 207))
6110	32575584	Recent studies reported mutations in multidrug efflux transporter genes involved in the development of resistance to clarithromycin.	('efflux', 'biological_process', 'GO:0140352', ('47', '53'))	('multidrug efflux transporter genes', 'Gene', (37, 71))	('clarithromycin', 'Chemical', 'MESH:D017291', (117, 131))	('mutations', 'Var', (24, 33))	('efflux', 'biological_process', 'GO:0140115', ('47', '53'))
6111	32575584	In addition, mutations in other target genes, such as rpl22 (encodes ribosomal protein that interacts with 23S rRNA domains) and infB (encodes translation initiation factor), have been shown to induce clarithromycin resistance, particularly in combination with mutations at A2146 and A2147 (equivalent to the location 2142 and 2143).	('A2147', 'Var', (284, 289))	('ribosomal protein', 'molecular_function', 'GO:0003735', ('69', '86'))	('induce', 'PosReg', (194, 200))	('A2146', 'Var', (274, 279))	('rpl22', 'Gene', (54, 59))	('protein', 'cellular_component', 'GO:0003675', ('79', '86'))	('mutations', 'Var', (13, 22))	('clarithromycin', 'Chemical', 'MESH:D017291', (201, 215))	('infB', 'Gene', (129, 133))	('clarithromycin resistance', 'MPA', (201, 226))	('translation initiation', 'biological_process', 'GO:0006413', ('143', '165'))
6113	32575584	Despite these limitations, this study investigated genotypic resistance before and after clarithromycin-based triple therapy through whole-genome sequencing and suggested the clinical impact of mutations in 23S rRNA genes on phenotypic resistance, determined using agar dilution tests.	('clarithromycin', 'Chemical', 'MESH:D017291', (89, 103))	('investigated', 'Reg', (38, 50))	('mutations', 'Var', (194, 203))	('23S rRNA', 'Gene', (207, 215))	('agar', 'Chemical', 'MESH:D000362', (265, 269))	('phenotypic resistance', 'MPA', (225, 246))
6114	32575584	All clarithromycin-resistant strains had either 2146A>G or 2147A>G mutation (formerly 2142A>G and 2143A>G).	('2147A>G', 'Mutation', 'c.2147A>G', (59, 66))	('2146A>G', 'Mutation', 'c.2146A>G', (48, 55))	('2147A>G', 'Var', (59, 66))	('2142A>G', 'Mutation', 'c.2142A>G', (86, 93))	('clarithromycin', 'Chemical', 'MESH:D017291', (4, 18))	('2143A>G', 'Mutation', 'c.2143A>G', (98, 105))	('2146A>G', 'Var', (48, 55))	('2143A>G', 'Var', (98, 105))
6116	32575584	Figure S1: Visually depicted location of mutations in 23S rRNA genes of 46 H. pylori strains.	('mutations', 'Var', (41, 50))	('H. pylori strai', 'Species', '85962', (75, 90))	('23S rRNA genes', 'Gene', (54, 68))
6117	32575584	Mutations in 23S rRNA genes at each nucleotide position and distribution of minimum inhibitory concentrations (MIC) for clarithromycin before and after unsuccessful clarithromycin-containing triple therapy.	('clarithromycin', 'Chemical', 'MESH:D017291', (120, 134))	('clarithromycin', 'Chemical', 'MESH:D017291', (165, 179))	('Mutations', 'Var', (0, 9))	('23S rRNA genes', 'Gene', (13, 27))
6118	32575584	Of note, 2147A>G mutation is found only in clarithromycin-resistant phenotype, with median MIC of 16 mug/mL (range, from 4 to 32 mug/mL).	('mug', 'molecular_function', 'GO:0043739', ('101', '104'))	('clarithromycin', 'Chemical', 'MESH:D017291', (43, 57))	('mug', 'molecular_function', 'GO:0043739', ('129', '132'))	('2147A>G', 'Mutation', 'c.2147A>G', (9, 16))	('2147A>G', 'Var', (9, 16))	('MIC', 'MPA', (91, 94))	('clarithromycin-resistant', 'Disease', (43, 67))
6121	32575584	Assessment of linkage disequilibrium between mutations 2147A>G and 2186T>C in 23S rRNA genes.	('2147A>G', 'Mutation', 'c.2147A>G', (55, 62))	('23S rRNA genes', 'Gene', (78, 92))	('2186T>C', 'Var', (67, 74))	('2186T>C', 'Mutation', 'c.2186T>C', (67, 74))	('mutations 2147A>G', 'Var', (45, 62))
6128	32114387	Overexpression of Nurr1 was directly related to the poor prognosis of GC patients.	('GC', 'Disease', 'MESH:D013274', (70, 72))	('GC', 'Phenotype', 'HP:0012126', (70, 72))	('related', 'Reg', (37, 44))	('Nurr1', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (73, 81))
6133	32114387	This work was supported by the  (Nos 81801983, 81871620, 81971901, 81772151 and 81571960), and the Department of Science and Technology of  (2018CXGC1208).	('GC', 'Phenotype', 'HP:0012126', (147, 149))	('81571960', 'Var', (80, 88))	('81772151', 'Var', (67, 75))	('81971901', 'Var', (57, 65))	('GC', 'Disease', 'MESH:D013274', (147, 149))
6188	32114387	BGC-823 cells were transduced with lenti-Nurr1 shRNA, lenti-CDK4 shRNA or a lenti-negative control.	('BGC-823', 'CellLine', 'CVCL:3360', (0, 7))	('lenti-CDK4 shRNA', 'Var', (54, 70))	('lenti-Nurr1', 'Var', (35, 46))	('GC', 'Phenotype', 'HP:0012126', (1, 3))	('CDK', 'molecular_function', 'GO:0004693', ('60', '63'))
6203	32114387	The overexpression of Nurr1 predicted poor prognosis in three cohorts of GC patients (GSE51105, GSE62254, GSE14210) (Fig.	('GC', 'Disease', 'MESH:D013274', (73, 75))	('patients', 'Species', '9606', (76, 84))	('poor', 'NegReg', (38, 42))	('GSE14210', 'Var', (106, 114))	('GC', 'Phenotype', 'HP:0012126', (73, 75))	('overexpression', 'PosReg', (4, 18))	('GSE62254', 'Var', (96, 104))	('Nurr1', 'Gene', (22, 27))	('GSE51105', 'Var', (86, 94))
6207	32114387	Colony formation, CCK8 and EdU assays suggested that knockdown of Nurr1 by siRNA inhibited GC cells proliferation, while overexpression of Nurr1 had the opposite effects (Fig.	('GC', 'Disease', 'MESH:D013274', (91, 93))	('knockdown', 'Var', (53, 62))	('inhibited', 'NegReg', (81, 90))	('Nurr1', 'Gene', (66, 71))	('formation', 'biological_process', 'GO:0009058', ('7', '16'))	('GC', 'Phenotype', 'HP:0012126', (91, 93))
6217	32114387	We found that CDK4 knockdown could impair GC cells proliferation by colony formation and CCK8 assays (Supplementary Fig.	('GC', 'Phenotype', 'HP:0012126', (42, 44))	('knockdown', 'Var', (19, 28))	('formation', 'biological_process', 'GO:0009058', ('75', '84'))	('colony formation', 'CPA', (68, 84))	('impair', 'NegReg', (35, 41))	('CDK4', 'Gene', (14, 18))	('GC', 'Disease', 'MESH:D013274', (42, 44))	('CDK', 'molecular_function', 'GO:0004693', ('14', '17'))
6220	32114387	Tumors formed in CDK4 shRNA group were smaller than that in control group, with regard to size and weight (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('CDK4 shRNA', 'Var', (17, 27))	('CDK', 'molecular_function', 'GO:0004693', ('17', '20'))	('smaller', 'NegReg', (39, 46))
6224	32114387	4c) levels with infection of two H. pylori strains (Hp11637 and Hp26695).	('Hp11637', 'Var', (52, 59))	('Hp26695', 'Var', (64, 71))	('H. pylori', 'Species', '210', (33, 42))
6228	32114387	The upregulation of Nurr1 protein expression induced by H. pylori infection was blocked by PI3K/AKT inhibitor (LY294002) strongly (Fig.	('AKT', 'Gene', (96, 99))	('AKT', 'Gene', '207', (96, 99))	('Nurr1', 'Gene', (20, 25))	('LY294002', 'Var', (111, 119))	('H. pylori infection', 'Disease', 'MESH:D016481', (56, 75))	('H. pylori infection', 'Phenotype', 'HP:0005202', (56, 75))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('H. pylori infection', 'Disease', (56, 75))	('protein', 'Protein', (26, 33))	('LY294002', 'Chemical', 'MESH:C085911', (111, 119))	('PI3K', 'molecular_function', 'GO:0016303', ('91', '95'))	('upregulation', 'PosReg', (4, 16))
6229	32114387	In addition, induction of Nurr1 mRNA expression by H. pylori was also blocked by LY294002 treatment (Fig 5b and c).	('Nurr1', 'Gene', (26, 31))	('LY294002', 'Chemical', 'MESH:C085911', (81, 89))	('H. pylori', 'Species', '210', (51, 60))	('blocked', 'NegReg', (70, 77))	('LY294002', 'Var', (81, 89))	('H. pylori', 'Var', (51, 60))
6231	32114387	Treatment alone with LY294002 attenuated the induction of Nurr1 by H. pylori in GC cells.	('H. pylori', 'Species', '210', (67, 76))	('GC', 'Disease', 'MESH:D013274', (80, 82))	('LY294002', 'Var', (21, 29))	('GC', 'Phenotype', 'HP:0012126', (80, 82))	('Nurr1', 'Gene', (58, 63))	('LY294002', 'Chemical', 'MESH:C085911', (21, 29))	('H. pylori', 'Gene', (67, 76))	('induction', 'MPA', (45, 54))	('attenuated', 'NegReg', (30, 40))
6236	32114387	We found that H. pylori infection increased the expression of Sp1 and Nurr1 simultaneously, and the LY294002 relieved the upregulation of these proteins induced by H. pylori at the same time (Fig.	('Sp1', 'Gene', (62, 65))	('LY294002', 'Var', (100, 108))	('relieved', 'NegReg', (109, 117))	('expression', 'MPA', (48, 58))	('H. pylori', 'Species', '210', (164, 173))	('H. pylori', 'Species', '210', (14, 23))	('H. pylori infection', 'Phenotype', 'HP:0005202', (14, 33))	('H. pylori infection', 'Disease', 'MESH:D016481', (14, 33))	('Nurr1', 'Gene', (70, 75))	('LY294002', 'Chemical', 'MESH:C085911', (100, 108))	('upregulation', 'PosReg', (122, 134))	('H. pylori infection', 'Disease', (14, 33))	('increased', 'PosReg', (34, 43))
6254	32114387	In our study, we proved that the aberrant upregulation of Nurr1 accelerated GC cells proliferation.	('GC', 'Disease', 'MESH:D013274', (76, 78))	('accelerated', 'PosReg', (64, 75))	('GC', 'Phenotype', 'HP:0012126', (76, 78))	('Nurr1', 'Gene', (58, 63))	('aberrant', 'Var', (33, 41))	('upregulation', 'PosReg', (42, 54))
6273	32114387	Different from the above reports, we primarily focused on the signaling pathways associated with H. pylori infection and found that H. pylori could induce Nurr1 expression via PI3K/AKT signaling pathway.	('H. pylori', 'Var', (132, 141))	('AKT', 'Gene', (181, 184))	('expression', 'MPA', (161, 171))	('PI3K', 'molecular_function', 'GO:0016303', ('176', '180'))	('signaling', 'biological_process', 'GO:0023052', ('62', '71'))	('AKT signaling', 'biological_process', 'GO:0043491', ('181', '194'))	('H. pylori', 'Species', '210', (97, 106))	('Nurr1', 'Gene', (155, 160))	('H. pylori infection', 'Disease', 'MESH:D016481', (97, 116))	('AKT', 'Gene', '207', (181, 184))	('induce', 'PosReg', (148, 154))	('signaling pathway', 'biological_process', 'GO:0007165', ('185', '202'))	('H. pylori infection', 'Phenotype', 'HP:0005202', (97, 116))	('H. pylori infection', 'Disease', (97, 116))	('H. pylori', 'Species', '210', (132, 141))
6274	32114387	What's more, it has also been reported that Nurr1 expression is upregulated by COX-2 and high expression of Nurr1 can block apoptosis in colorectal cancer.	('Nurr1', 'Gene', (44, 49))	('colorectal cancer', 'Phenotype', 'HP:0003003', (137, 154))	('apoptosis', 'biological_process', 'GO:0097194', ('124', '133'))	('apoptosis', 'biological_process', 'GO:0006915', ('124', '133'))	('colorectal cancer', 'Disease', (137, 154))	('high expression', 'Var', (89, 104))	('upregulated', 'PosReg', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('colorectal cancer', 'Disease', 'MESH:D015179', (137, 154))	('block', 'NegReg', (118, 123))	('Nurr1', 'Gene', (108, 113))	('apoptosis', 'CPA', (124, 133))	('expression', 'MPA', (50, 60))
6275	32114387	Down-regulation of Nurr1 can reduce cells proliferation and elevate cells apoptosis in Hela cells.	('cells apoptosis', 'CPA', (68, 83))	('Hela', 'CellLine', 'CVCL:0030', (87, 91))	('Down-regulation', 'Var', (0, 15))	('cells proliferation', 'CPA', (36, 55))	('apoptosis', 'biological_process', 'GO:0097194', ('74', '83'))	('regulation', 'biological_process', 'GO:0065007', ('5', '15'))	('apoptosis', 'biological_process', 'GO:0006915', ('74', '83'))	('Nurr1', 'Gene', (19, 24))	('reduce', 'NegReg', (29, 35))	('elevate', 'PosReg', (60, 67))
6277	32114387	In our study, we found that the apoptosis of GC cells didn't change significantly after silencing of Nurr1, while the proliferation of GC cells was significantly inhibited (Supplementary Fig.	('GC', 'Disease', 'MESH:D013274', (45, 47))	('GC', 'Disease', 'MESH:D013274', (135, 137))	('apoptosis', 'biological_process', 'GO:0097194', ('32', '41'))	('apoptosis', 'biological_process', 'GO:0006915', ('32', '41'))	('inhibited', 'NegReg', (162, 171))	('GC', 'Phenotype', 'HP:0012126', (45, 47))	('proliferation', 'CPA', (118, 131))	('silencing', 'Var', (88, 97))	('GC', 'Phenotype', 'HP:0012126', (135, 137))	('Nurr1', 'Gene', (101, 106))
6363	31689766	However, fluorouracil can lead to different degrees of adverse reactions, such as bone marrow suppression, gastrointestinal reaction, liver and kidney function damage, which can reduce the quality of life and survival of patients and even lead to the premature termination of chemotherapy.	('bone marrow suppression', 'Disease', 'MESH:D001855', (82, 105))	('patients', 'Species', '9606', (221, 229))	('fluorouracil', 'Chemical', 'MESH:D005472', (9, 21))	('fluorouracil', 'Var', (9, 21))	('bone marrow suppression', 'Disease', (82, 105))	('survival', 'CPA', (209, 217))	('lead to', 'Reg', (239, 246))	('reduce', 'NegReg', (178, 184))	('gastrointestinal reaction', 'Disease', 'MESH:D005767', (107, 132))	('bone marrow suppression', 'Phenotype', 'HP:0005528', (82, 105))	('gastrointestinal reaction', 'Disease', (107, 132))	('gastrointestinal reaction', 'Phenotype', 'HP:0004386', (107, 132))	('quality of life', 'CPA', (189, 204))	('liver and kidney function damage', 'Disease', 'MESH:D007674', (134, 166))
6565	30697615	In the current study, poor PS was an independent factor associated with anastomotic stenosis.	('poor PS', 'Var', (22, 29))	('anastomotic stenosis', 'Disease', (72, 92))	('anastomotic stenosis', 'Disease', 'MESH:D057868', (72, 92))
6566	30697615	Results showed that poor PS tended to be associated with the presence of cardiovascular disease (P = 0.097).	('associated', 'Reg', (41, 51))	('cardiovascular disease', 'Disease', (73, 95))	('poor PS', 'Var', (20, 27))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (73, 95))	('cardiovascular disease', 'Disease', 'MESH:D002318', (73, 95))
6583	29954358	The MAGIC trial showed that three cycles of epirubicin, cisplatin and continuous 5-fluorouracil (5-Fu) infusion (ECF) before and after surgery led to a significant improvement in OS in advanced gastroesophageal adenocarcinoma in western countries.	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('5-Fu', 'Chemical', 'MESH:D005472', (97, 101))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (81, 95))	('epirubicin', 'Chemical', 'MESH:D015251', (44, 54))	('gastroesophageal adenocarcinoma', 'Disease', 'MESH:D005764', (194, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('improvement', 'PosReg', (164, 175))	('cisplatin', 'Var', (56, 65))	('gastroesophageal adenocarcinoma', 'Disease', (194, 225))	('OS', 'Chemical', '-', (179, 181))
6691	29675100	Using the population-based database, we identified patients with primary GC (International Classification of Diseases for Oncology, Third Edition [ICD-O-3], codes C16.1-16.6, C16.8-16.9) who were 18 or older at diagnosis between 1 January 2004 and 31 December 2012.	('C16.8-16.9', 'CellLine', 'CVCL:2322', (175, 185))	('primary GC', 'Disease', (65, 75))	('Oncology', 'Phenotype', 'HP:0002664', (122, 130))	('GC', 'Phenotype', 'HP:0012126', (73, 75))	('C16.1-16.6', 'CellLine', 'CVCL:2322', (163, 173))	('C16.8-16.9', 'Var', (175, 185))	('patients', 'Species', '9606', (51, 59))
6727	29675100	(Figure 1A) Then, we used Kaplan-Meier curve to determine the CSS of patients with M0 GC in Figure 1B.	('GC', 'Phenotype', 'HP:0012126', (86, 88))	('CSS', 'Gene', '55907', (62, 65))	('patients', 'Species', '9606', (69, 77))	('CSS', 'Gene', (62, 65))	('M0 GC', 'Var', (83, 88))
6756	29675100	Genetically, it was reported that age at breast cancer diagnosis adds a layer of genomic complexity beyond pathological and clinical variables, including the pattern of somatic mutations, chromosomal copy number variations (CNVs) and transcriptomic profiles.	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('chromosomal copy number variations', 'Var', (188, 222))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))
6765	29675100	After adjustment, young patients with M0 GC still had an independently better prognosis, especially for those who underwent total gastrectomy.	('better', 'PosReg', (71, 77))	('GC', 'Phenotype', 'HP:0012126', (41, 43))	('M0 GC', 'Var', (38, 43))	('patients', 'Species', '9606', (24, 32))
6772	29675100	Although these factors, including delayed stage and poor histologic grade, were defined as independent poor prognostic factors in our multivariate Cox analysis, young patients with M0 GC had a better 3-year CSS.	('CSS', 'Gene', '55907', (207, 210))	('Cox', 'Gene', '1351', (147, 150))	('Cox', 'Gene', (147, 150))	('patients', 'Species', '9606', (167, 175))	('CSS', 'Gene', (207, 210))	('GC', 'Phenotype', 'HP:0012126', (184, 186))	('better', 'PosReg', (193, 199))	('M0 GC', 'Var', (181, 186))
6796	29675100	Based on data from multiple Chinese centers, it is validated that the conclusion, that young patients with M0 GC tend to survive longer than the elderly after gastrectomy despite poorer tumor behavior, can be also applicable in China.	('M0 GC', 'Var', (107, 112))	('tumor behavior', 'Disease', 'MESH:D001523', (186, 200))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('GC', 'Phenotype', 'HP:0012126', (110, 112))	('tumor behavior', 'Disease', (186, 200))	('patients', 'Species', '9606', (93, 101))
6799	29675100	Considering that unique genetic changes including MSI, LOH and germ-line truncation play a vital part in this phenomenon, it is necessary to instill great importance to take preventive measure of early onset of gastric cancer, including detailed family surveys, genetic testing for high-risk populations, early detection of CDH1 mutations, and preventive gastrectomy for stomachs with canceration tendencies.	('MSI', 'Disease', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (385, 391))	('gastric cancer', 'Disease', (211, 225))	('gastric cancer', 'Disease', 'MESH:D013274', (211, 225))	('CDH1', 'Gene', (324, 328))	('mutations', 'Var', (329, 338))	('gastric cancer', 'Phenotype', 'HP:0012126', (211, 225))	('CDH1', 'Gene', '999', (324, 328))	('MSI', 'Disease', 'None', (50, 53))	('canceration tendencies', 'Disease', (385, 407))	('canceration tendencies', 'Disease', 'MESH:C536965', (385, 407))
6812	25081232	These differences were reflected in better disease-specific outcomes of min-mix-IPMN compared with ex-mix-IPMN (P = .046).	('ex-mix-IPMN', 'Chemical', '-', (99, 110))	('IPMN', 'Phenotype', 'HP:0031496', (106, 110))	('min-mix-IPMN', 'Chemical', '-', (72, 84))	('min-mix-IPMN', 'Var', (72, 84))	('IPMN', 'Phenotype', 'HP:0031496', (80, 84))	('better', 'PosReg', (36, 42))
6854	25081232	Conversely, patients with ex-mix-IPMN, similar to MD-IPMNs, more frequently presented with related symptoms including weight loss (30% vs 11%; P = .009) and jaundice (14% vs 0%; P = .007) than those with min-mix-IPMN.	('patients', 'Species', '9606', (12, 20))	('ex-mix-IPMN', 'Chemical', '-', (26, 37))	('jaundice', 'Disease', 'MESH:D007565', (157, 165))	('IPMN', 'Phenotype', 'HP:0031496', (53, 57))	('weight loss', 'Disease', 'MESH:D015431', (118, 129))	('MD-IPMNs', 'Chemical', '-', (50, 58))	('IPMN', 'Phenotype', 'HP:0031496', (212, 216))	('jaundice', 'Disease', (157, 165))	('jaundice', 'Phenotype', 'HP:0000952', (157, 165))	('min-mix-IPMN', 'Chemical', '-', (204, 216))	('weight loss', 'Disease', (118, 129))	('ex-mix-IPMN', 'Var', (26, 37))	('weight loss', 'Phenotype', 'HP:0001824', (118, 129))	('IPMN', 'Phenotype', 'HP:0031496', (33, 37))
6855	25081232	The pancreatic head was the predominant location for all IPMNs followed by the pancreatic body (Table II), but min-mix-IPMNs were more likely to involve the tail compared with ex-mix-IPMNs (22% vs 8%; P = .008).	('IPMN', 'Phenotype', 'HP:0031496', (57, 61))	('pancreatic body', 'Disease', (79, 94))	('IPMN', 'Phenotype', 'HP:0031496', (119, 123))	('pancreatic body', 'Disease', 'MESH:D010195', (79, 94))	('min-mix-IPMNs', 'Var', (111, 124))	('IPMN', 'Chemical', '-', (57, 61))	('pancreatic', 'Disease', 'MESH:D010195', (79, 89))	('IPMN', 'Chemical', '-', (119, 123))	('IPMN', 'Phenotype', 'HP:0031496', (183, 187))	('ex-mix-IPMNs', 'Chemical', '-', (176, 188))	('pancreatic', 'Disease', 'MESH:D010195', (4, 14))	('min-mix-IPMNs', 'Chemical', '-', (111, 124))	('pancreatic', 'Disease', (79, 89))	('IPMN', 'Chemical', '-', (183, 187))	('pancreatic', 'Disease', (4, 14))
6862	25081232	Patients with min-mix-IPMN were more likely to have an observation period before operation compared with ex-mix-IPMN (41% vs 10%; P < .0001) and an increase in cyst size was the leading indication for resection in this group.	('min-mix-IPMN', 'Chemical', '-', (14, 26))	('increase', 'PosReg', (148, 156))	('min-mix-IPMN', 'Var', (14, 26))	('ex-mix-IPMN', 'Chemical', '-', (105, 116))	('IPMN', 'Phenotype', 'HP:0031496', (22, 26))	('IPMN', 'Phenotype', 'HP:0031496', (112, 116))	('Patients', 'Species', '9606', (0, 8))	('cyst', 'Disease', (160, 164))
6864	25081232	There was no difference in operative indications between min-mix-IPMN and BD-IPMN, whereas all patients with MD-IPMN underwent operation for dilation of the MPD (Table III).	('MD-IPMN', 'Chemical', '-', (109, 116))	('BD-IPMN', 'Disease', (74, 81))	('IPMN', 'Phenotype', 'HP:0031496', (77, 81))	('patients', 'Species', '9606', (95, 103))	('IPMN', 'Phenotype', 'HP:0031496', (112, 116))	('min-mix-IPMN', 'Var', (57, 69))	('IPMN', 'Phenotype', 'HP:0031496', (65, 69))	('BD-IPMN', 'Chemical', '-', (74, 81))	('min-mix-IPMN', 'Chemical', '-', (57, 69))
6868	25081232	Most importantly, the prevalence of high-grade dysplasia (37% vs 11%) and invasive carcinoma (33% vs 6.5%) was greater in ex-mix-IPMN compared with min-mix-IPMN (P < .0001), whereas the grades of dysplasia in min-mix-IPMN and BD-IPMN were comparable.	('ex-mix-IPMN', 'Var', (122, 133))	('dysplasia', 'Disease', (196, 205))	('IPMN', 'Phenotype', 'HP:0031496', (129, 133))	('IPMN', 'Phenotype', 'HP:0031496', (229, 233))	('BD-IPMN', 'Chemical', '-', (226, 233))	('dysplasia', 'Disease', 'MESH:D004476', (196, 205))	('min-mix-IPMN', 'Chemical', '-', (148, 160))	('ex-mix-IPMN', 'Chemical', '-', (122, 133))	('dysplasia', 'Disease', (47, 56))	('invasive carcinoma', 'Disease', 'MESH:D009361', (74, 92))	('IPMN', 'Phenotype', 'HP:0031496', (217, 221))	('IPMN', 'Phenotype', 'HP:0031496', (156, 160))	('dysplasia', 'Disease', 'MESH:D004476', (47, 56))	('invasive carcinoma', 'Disease', (74, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('min-mix-IPMN', 'Chemical', '-', (209, 221))
6872	25081232	Similarly, all invasive carcinomas arising in min-mix-IPMN and the vast majority of those arising in BD-IPMN were of the tubular type, whereas 26% of those arising in ex-mix-IPMN and 45% of those arising in MD-IPMN were of the colloid type.	('IPMN', 'Phenotype', 'HP:0031496', (54, 58))	('min-mix-IPMN', 'Chemical', '-', (46, 58))	('ex-mix-IPMN', 'Chemical', '-', (167, 178))	('min-mix-IPMN', 'Var', (46, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('BD-IPMN', 'Chemical', '-', (101, 108))	('IPMN', 'Phenotype', 'HP:0031496', (210, 214))	('IPMN', 'Phenotype', 'HP:0031496', (104, 108))	('IPMN', 'Phenotype', 'HP:0031496', (174, 178))	('invasive carcinomas', 'Disease', (15, 34))	('invasive carcinomas', 'Disease', 'MESH:D009361', (15, 34))	('MD-IPMN', 'Chemical', '-', (207, 214))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))
6881	25081232	In accordance with the greater incidence of invasive carcinoma in patients with ex-mix-IPMN, 10% of them died owing to recurrent pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('ex-mix-IPMN', 'Chemical', '-', (80, 91))	('invasive carcinoma', 'Disease', 'MESH:D009361', (44, 62))	('ex-mix-IPMN', 'Var', (80, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('IPMN', 'Phenotype', 'HP:0031496', (87, 91))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('pancreatic cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('invasive carcinoma', 'Disease', (44, 62))	('patients', 'Species', '9606', (66, 74))
6896	25081232	In our cohort, invasive carcinoma was observed only in 6% of min-mix-IPMNs compared with 33% of ex-mix-IPMN (P = .001).	('invasive carcinoma', 'Disease', 'MESH:D009361', (15, 33))	('min-mix-IPMNs', 'Chemical', '-', (61, 74))	('IPMN', 'Phenotype', 'HP:0031496', (69, 73))	('invasive carcinoma', 'Disease', (15, 33))	('IPMN', 'Phenotype', 'HP:0031496', (103, 107))	('ex-mix-IPMN', 'Chemical', '-', (96, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('min-mix-IPMNs', 'Var', (61, 74))
6900	25081232	Furthermore, the main-duct components of min-mix-IPMNs consisted exclusively of the gastric-type epithelium, even in those with the branch-duct component exhibiting the intestinal (16%) or pancreatobiliary (4%) epithelium.	('min-mix-IPMNs', 'Chemical', '-', (41, 54))	('consisted', 'Reg', (55, 64))	('min-mix-IPMNs', 'Var', (41, 54))	('IPMN', 'Phenotype', 'HP:0031496', (49, 53))
6905	25081232	In our cohort, all patients with MD-IPMN presented with IPMN-related symptoms, whereas the half of BD-IPMNs were incidental findings, the figures similar to those of the previous reports.	('IPMN', 'Chemical', '-', (36, 40))	('BD-IPMNs', 'Chemical', '-', (99, 107))	('patients', 'Species', '9606', (19, 27))	('IPMN', 'Phenotype', 'HP:0031496', (36, 40))	('IPMN', 'Phenotype', 'HP:0031496', (102, 106))	('IPMN', 'Chemical', '-', (102, 106))	('IPMN', 'Phenotype', 'HP:0031496', (56, 60))	('presented', 'Reg', (41, 50))	('IPMN-related symptoms', 'Disease', (56, 77))	('MD-IPMN', 'Var', (33, 40))	('MD-IPMN', 'Chemical', '-', (33, 40))	('IPMN', 'Chemical', '-', (56, 60))
6908	25081232	Conversely, 61% of ex-mix-IPMNs presented with related symptoms, and the incidence of weight loss and jaundice in ex-mix-IPMNs was similar to that of MD-IPMNs, but was significantly greater than min-mix-IPMNs and BD-IPMNs.	('greater', 'PosReg', (182, 189))	('IPMN', 'Phenotype', 'HP:0031496', (216, 220))	('jaundice', 'Disease', (102, 110))	('ex-mix-IPMNs', 'Chemical', '-', (114, 126))	('IPMN', 'Phenotype', 'HP:0031496', (121, 125))	('IPMN', 'Phenotype', 'HP:0031496', (153, 157))	('ex-mix-IPMNs', 'Chemical', '-', (19, 31))	('jaundice', 'Disease', 'MESH:D007565', (102, 110))	('IPMN', 'Phenotype', 'HP:0031496', (26, 30))	('ex-mix-IPMNs', 'Disease', (19, 31))	('weight loss', 'Disease', 'MESH:D015431', (86, 97))	('BD-IPMNs', 'Chemical', '-', (213, 221))	('weight loss', 'Phenotype', 'HP:0001824', (86, 97))	('ex-mix-IPMNs', 'Var', (114, 126))	('jaundice', 'Phenotype', 'HP:0000952', (102, 110))	('weight loss', 'Disease', (86, 97))	('min-mix-IPMNs', 'Chemical', '-', (195, 208))	('IPMN', 'Phenotype', 'HP:0031496', (203, 207))	('MD-IPMNs', 'Chemical', '-', (150, 158))
6915	25081232	Conversely, given that the vast majority of min-mix-IPMNs exhibited low- or intermediate-grade dysplasia of the gastric type, especially those resected only owing to MPD dilation by imaging studies and/or an increase in size (38%) could have been followed without operative intervention.	('exhibited', 'Reg', (58, 67))	('MPD dilation', 'Disease', (166, 178))	('MPD dilation', 'Disease', 'MESH:D002311', (166, 178))	('min-mix-IPMNs', 'Chemical', '-', (44, 57))	('dysplasia of the gastric type', 'Disease', (95, 124))	('dysplasia of the gastric type', 'Disease', 'MESH:D013274', (95, 124))	('IPMN', 'Phenotype', 'HP:0031496', (52, 56))	('min-mix-IPMNs', 'Var', (44, 57))
6917	25081232	We did not observe a difference in the median age of diagnosis between min-mix-IPMN (65 years) versus ex-mix-IPMN (67 years; P = .75) in our cohort; however, in some min-mix-IPMNs, MPD with focal involvement by mucinous epithelium was associated immediately with a large branch duct that was involved circumferentially by mucinous epithelium with a greater grade of dysplasia (data not shown), raising the possibility of IPMN extending from peripheral ducts to MPD.	('mucin', 'Gene', (211, 216))	('mucin', 'Gene', '100508689', (211, 216))	('IPMN', 'Phenotype', 'HP:0031496', (421, 425))	('IPMN', 'Chemical', '-', (79, 83))	('IPMN', 'Chemical', '-', (109, 113))	('min-mix-IPMNs', 'Var', (166, 179))	('dysplasia', 'Disease', (366, 375))	('IPMN', 'Chemical', '-', (174, 178))	('IPMN', 'Phenotype', 'HP:0031496', (79, 83))	('dysplasia', 'Disease', 'MESH:D004476', (366, 375))	('min-mix-IPMNs', 'Chemical', '-', (166, 179))	('IPMN', 'Phenotype', 'HP:0031496', (109, 113))	('IPMN', 'Phenotype', 'HP:0031496', (174, 178))	('mucin', 'Gene', (322, 327))	('ex-mix-IPMN', 'Chemical', '-', (102, 113))	('min-mix-IPMN', 'Chemical', '-', (166, 178))	('mucin', 'Gene', '100508689', (322, 327))	('min-mix-IPMN', 'Chemical', '-', (71, 83))	('IPMN', 'Chemical', '-', (421, 425))
6930	28460635	In order to identify therapeutic leads selective for the HDGC subtype of gastric cancer, we compared gene expression profiles and drug phenotype derived from an oncology library of 1912 compounds between gastric cancer cells established from a patient with metastatic HDGC harboring a c.1380delA CDH1 germline variant and sporadic gastric cancer cells.	('gastric cancer', 'Phenotype', 'HP:0012126', (331, 345))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('gastric cancer', 'Disease', (204, 218))	('sporadic gastric cancer', 'Disease', (322, 345))	('c.1380delA', 'Mutation', 'c.1380delA', (285, 295))	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('HDGC', 'Disease', 'MESH:D013274', (268, 272))	('c.1380delA', 'Var', (285, 295))	('oncology', 'Phenotype', 'HP:0002664', (161, 169))	('sporadic gastric cancer', 'Disease', 'MESH:D013274', (322, 345))	('gene expression', 'biological_process', 'GO:0010467', ('101', '116'))	('HDGC', 'Disease', (57, 61))	('gastric cancer', 'Disease', 'MESH:D013274', (204, 218))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('patient', 'Species', '9606', (244, 251))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('CDH1', 'Gene', (296, 300))	('gastric cancer', 'Disease', 'MESH:D013274', (331, 345))	('gastric cancer', 'Phenotype', 'HP:0012126', (204, 218))	('HDGC', 'Disease', (268, 272))	('HDGC', 'Disease', 'MESH:D013274', (57, 61))	('gastric cancer', 'Disease', (73, 87))
6934	28460635	Upon additional drug response testing, dual PI3K (Phosphatidylinositol 3-Kinase)/mTOR and topoisomerase 2A inhibitors displayed up to >100-fold increased activity in hereditary c.1380delA CDH1 gastric cancer cells inducing apoptosis most effectively in cells with deficient CDH1 function.	('gastric cancer', 'Disease', 'MESH:D013274', (193, 207))	('PI3', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('CDH1', 'Gene', (188, 192))	('topoisomerase', 'molecular_function', 'GO:0003918', ('90', '103'))	('hereditary c.1380delA', 'Var', (166, 187))	('Phosphatidylinositol 3-Kinase', 'Gene', '5290', (50, 79))	('apoptosis', 'biological_process', 'GO:0006915', ('223', '232'))	('gastric cancer', 'Phenotype', 'HP:0012126', (193, 207))	('mTOR', 'Gene', (81, 85))	('Phosphatidylinositol 3-Kinase', 'Gene', (50, 79))	('mTOR', 'Gene', '2475', (81, 85))	('PI3', 'Gene', '5266', (44, 47))	('increased', 'PosReg', (144, 153))	('gastric cancer', 'Disease', (193, 207))	('c.1380delA', 'Mutation', 'c.1380delA', (177, 187))	('apoptosis', 'CPA', (223, 232))	('topoisomerase', 'molecular_function', 'GO:0003917', ('90', '103'))	('activity', 'MPA', (154, 162))	('apoptosis', 'biological_process', 'GO:0097194', ('223', '232'))	('PI3K', 'molecular_function', 'GO:0016303', ('44', '48'))
6935	28460635	Integrated pharmacological and transcriptomic profiling of hereditary diffuse gastric cancer cells with a loss-of-function c.1380delA CDH1 mutation implies various pharmacological vulnerabilities selective to CDH1-deficient familial gastric cancer cells and suggests novel treatment leads for future preclinical and clinical treatment studies of familial gastric cancer.	('hereditary diffuse gastric cancer', 'Disease', (59, 92))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('gastric cancer', 'Phenotype', 'HP:0012126', (233, 247))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (59, 92))	('loss-of-function', 'NegReg', (106, 122))	('familial gastric cancer', 'Disease', 'MESH:D013274', (346, 369))	('gastric cancer', 'Phenotype', 'HP:0012126', (355, 369))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CDH1-deficient familial gastric cancer', 'Disease', 'MESH:D013274', (209, 247))	('c.1380delA', 'Mutation', 'c.1380delA', (123, 133))	('familial gastric cancer', 'Disease', 'MESH:D013274', (224, 247))	('familial gastric cancer', 'Disease', (346, 369))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))	('c.1380delA', 'Var', (123, 133))	('CDH1-deficient familial gastric cancer', 'Disease', (209, 247))	('CDH1', 'Gene', (134, 138))
6936	28460635	Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer susceptibility syndrome due to germline mutations within the E-cadherin (CDH1) gene locus cadherin (CDH1; NM_004360).	('diffuse gastric cancer', 'Disease', 'MESH:D013274', (11, 33))	('due', 'Reg', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cadherin', 'molecular_function', 'GO:0008014', ('163', '171'))	('CDH1', 'Gene', (146, 150))	('cadherin', 'molecular_function', 'GO:0008014', ('136', '144'))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('HDGC', 'Disease', 'MESH:D013274', (35, 39))	('autosomal dominant cancer', 'Disease', (47, 72))	('gastric cancer', 'Phenotype', 'HP:0012126', (19, 33))	('mutations', 'Var', (113, 122))	('autosomal dominant cancer', 'Disease', 'MESH:D009369', (47, 72))	('HDGC', 'Disease', (35, 39))	('diffuse gastric cancer', 'Disease', (11, 33))
6938	28460635	Of the 26,370 cases of gastric cancer expected to be diagnosed in the United States in 2016, 5 to 10 percent arise in a familiar context and about 34-45% of these are due to CDH1 germline mutations.	('due to', 'Reg', (167, 173))	('CDH1', 'Gene', (174, 178))	('gastric cancer', 'Disease', (23, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('gastric cancer', 'Disease', 'MESH:D013274', (23, 37))	('germline mutations', 'Var', (179, 197))	('gastric cancer', 'Phenotype', 'HP:0012126', (23, 37))
6939	28460635	Male CDH1 mutation carriers have by the age 80 a cumulative incidence of gastric cancer of 70%, female mutation carriers a risk of 56% of gastric and 42% for lobular breast cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('lobular breast cancer', 'Disease', (158, 179))	('gastric', 'Disease', (138, 145))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('lobular breast cancer', 'Disease', 'MESH:D013274', (158, 179))	('mutation', 'Var', (10, 18))	('CDH1', 'Gene', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('lobular breast cancer', 'Phenotype', 'HP:0006625', (158, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('gastric cancer', 'Disease', (73, 87))
6940	28460635	Risk-reducing gastrectomy and breast MRI surveillance is currently advised for all patients with CDH1 germline gene mutations.	('patients', 'Species', '9606', (83, 91))	('CDH1', 'Gene', (97, 101))	('mutations', 'Var', (116, 125))
6944	28460635	Clinically, patients with advanced familial gastric cancer and a genetic loss of CDH1 have a worse clinical outcome compared to patients with epigenetic silencing or no CDH1 alteration.	('loss', 'NegReg', (73, 77))	('patients', 'Species', '9606', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('familial gastric cancer', 'Disease', (35, 58))	('genetic', 'Var', (65, 72))	('familial gastric cancer', 'Disease', 'MESH:D013274', (35, 58))	('CDH1', 'Gene', (81, 85))	('patients', 'Species', '9606', (128, 136))	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))
6946	28460635	In contrast, recent differential gene expression, synthetic lethality, and high throughput drug screening studies in isogenic E-cadherin deficient (-/-) breast MCF10A cells identified several select genetic and pharmacological vulnerabilities in CDH1(-/-) mutant cells.	('deficient', 'NegReg', (137, 146))	('MCF10A', 'CellLine', 'CVCL:0598', (160, 166))	('CDH1', 'Gene', (246, 250))	('mutant', 'Var', (256, 262))	('cadherin', 'molecular_function', 'GO:0008014', ('128', '136'))	('gene expression', 'biological_process', 'GO:0010467', ('33', '48'))	('synthetic', 'Species', '2086595', (50, 59))
6947	28460635	While some of the observed activity profiles in CDH1-deficient cells, like select sensitivities to Src kinase in the CDH1(-/-) mutant MCF10A isoform, were in line with early signaling perturbations observed in T1a cancers of gastrectomy specimens of HDGC patients, other signaling aberrations observed in clinical specimens later in the transition of invasion beyond the gastric mucosa, like FAK and STAT3 kinase activation, were not found to be associated with select drug sensitivities in the MCF10A CDH1(-/-) in vitro system.	('MCF10A', 'CellLine', 'CVCL:0598', (495, 501))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('FAK', 'Gene', (392, 395))	('HDGC', 'Disease', (250, 254))	('CDH1', 'Gene', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('MCF10A', 'CellLine', 'CVCL:0598', (134, 140))	('FAK', 'molecular_function', 'GO:0004717', ('392', '395'))	('FAK', 'Gene', '5747', (392, 395))	('mutant', 'Var', (127, 133))	('Src', 'Gene', (99, 102))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('gastric mucosa', 'Disease', 'MESH:D013274', (371, 385))	('STAT3', 'Gene', (400, 405))	('cancers', 'Disease', (214, 221))	('gastric mucosa', 'Disease', (371, 385))	('signaling', 'biological_process', 'GO:0023052', ('174', '183'))	('patients', 'Species', '9606', (255, 263))	('HDGC', 'Disease', 'MESH:D013274', (250, 254))	('STAT3', 'Gene', '6774', (400, 405))	('signaling', 'biological_process', 'GO:0023052', ('271', '280'))	('Src', 'Gene', '6714', (99, 102))
6948	28460635	As the MCF10A CDH1(-/-) isogenic system captures predominantly early vulnerabilities with predominantly chemopreventative translational value, it is thus not known if the synthetic lethalities and drug sensitivities discovered to selectively occur in the CDH1(-/-) mutants capture vulnerabilities of E-cadherin deficient gastric cancers in a more evolved stage which might harbor greater therapeutic value.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('CDH1', 'Gene', (255, 259))	('gastric cancers', 'Phenotype', 'HP:0012126', (321, 336))	('mutants', 'Var', (265, 272))	('CDH1', 'Gene', (14, 18))	('deficient gastric cancers', 'Disease', (311, 336))	('cancers', 'Phenotype', 'HP:0002664', (329, 336))	('deficient gastric cancers', 'Disease', 'MESH:D013274', (311, 336))	('synthetic', 'Species', '2086595', (171, 180))	('cadherin', 'molecular_function', 'GO:0008014', ('302', '310'))	('gastric cancer', 'Phenotype', 'HP:0012126', (321, 335))	('MCF10A', 'CellLine', 'CVCL:0598', (7, 13))
6949	28460635	To develop new therapeutic strategies for HDGC patients, we compared drug sensitivity profiles derived from a dose response quantitative high throughput drug (qHTS) screens of 1912 oncology compounds between c.del1380A CDH1 gastric cancer cells derived from a HDGC patient, and wild type CDH1 gastric cancer cells derived from a sporadic gastric cancer patient.	('HDGC', 'Disease', (260, 264))	('patients', 'Species', '9606', (47, 55))	('gastric cancer', 'Phenotype', 'HP:0012126', (338, 352))	('type CDH1 gastric cancer', 'Disease', (283, 307))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('gastric cancer', 'Disease', 'MESH:D013274', (224, 238))	('sporadic gastric cancer', 'Disease', (329, 352))	('type CDH1 gastric cancer', 'Disease', 'MESH:D013274', (283, 307))	('c.del1380A', 'Var', (208, 218))	('HDGC', 'Disease', (42, 46))	('sporadic gastric cancer', 'Disease', 'MESH:D013274', (329, 352))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('drug sensitivity', 'Phenotype', 'HP:0020174', (69, 85))	('HDGC', 'Disease', 'MESH:D013274', (260, 264))	('CDH1', 'Gene', (219, 223))	('gastric cancer', 'Disease', 'MESH:D013274', (293, 307))	('patient', 'Species', '9606', (47, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (224, 238))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('HDGC', 'Disease', 'MESH:D013274', (42, 46))	('gastric cancer', 'Disease', 'MESH:D013274', (338, 352))	('patient', 'Species', '9606', (353, 360))	('gastric cancer', 'Phenotype', 'HP:0012126', (293, 307))	('patient', 'Species', '9606', (265, 272))	('oncology', 'Phenotype', 'HP:0002664', (181, 189))	('gastric cancer', 'Disease', (224, 238))
6950	28460635	We combined the differential pharmacological responses with gene expression profiles between c.del1380A CDH1 and a cohort of sporadic gastric cancer cells.	('CDH1', 'Gene', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('c.del1380A', 'Var', (93, 103))	('sporadic gastric cancer', 'Disease', (125, 148))	('gene expression', 'biological_process', 'GO:0010467', ('60', '75'))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))	('sporadic gastric cancer', 'Disease', 'MESH:D013274', (125, 148))
6951	28460635	Increased ERK1/2 and phosphatidylinositol 4,5-bisphosphate (PIP2)-mediated signaling in c.1380delA CDH1 cells was accompanied by increased sensitivities to mTOR, AKT, MEK, protein kinase C (PKC) and topoisomerase II (TOPO2) signaling inhibition.	('MEK', 'Gene', (167, 170))	('AKT', 'Gene', '207', (162, 165))	('ERK1', 'molecular_function', 'GO:0004707', ('10', '14'))	('signaling', 'biological_process', 'GO:0023052', ('75', '84'))	('mTOR', 'Gene', '2475', (156, 160))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('ERK1/2', 'Gene', (10, 16))	('ERK1/2', 'Gene', '5595;5594', (10, 16))	('increased', 'PosReg', (129, 138))	('PIP2', 'Chemical', 'MESH:D019269', (60, 64))	('PKC', 'molecular_function', 'GO:0004697', ('190', '193'))	('signaling', 'biological_process', 'GO:0023052', ('224', '233'))	('sensitivities', 'MPA', (139, 152))	('protein kinase C', 'Gene', '112476', (172, 188))	('AKT', 'Gene', (162, 165))	('Increased', 'PosReg', (0, 9))	('phosphatidylinositol 4,5-bisphosphate', 'Chemical', 'MESH:D019269', (21, 58))	('protein kinase C', 'Gene', (172, 188))	('PKC', 'Gene', '112476', (190, 193))	('CDH1', 'Gene', (99, 103))	('MEK', 'Gene', '5609', (167, 170))	('c.1380delA', 'Mutation', 'c.1380delA', (88, 98))	('topoisomerase II', 'molecular_function', 'GO:0003918', ('199', '215'))	('mTOR', 'Gene', (156, 160))	('c.1380delA', 'Var', (88, 98))	('PKC', 'Gene', (190, 193))
6953	28460635	Together, this study integrates transcriptomic aberrations with drug cytotoxic responses in patient-derived c.del1380A CDH1 HDGC versus CDH1 wild type sporadic gastric cancer cells providing new therapeutic leads for the difficult to treat CDH1 mutant familial subtype of gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('gastric cancer', 'Phenotype', 'HP:0012126', (272, 286))	('HDGC', 'Disease', 'MESH:D013274', (124, 128))	('patient', 'Species', '9606', (92, 99))	('gastric cancer', 'Disease', 'MESH:D013274', (160, 174))	('sporadic gastric cancer', 'Disease', (151, 174))	('c.del1380A', 'Var', (108, 118))	('HDGC', 'Disease', (124, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (160, 174))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('CDH1', 'Gene', (119, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (272, 286))	('sporadic gastric cancer', 'Disease', 'MESH:D013274', (151, 174))	('gastric cancer', 'Disease', (272, 286))
6957	28460635	The patient, and other family members, previously underwent germline CDH1 mutation testing and found to harbor a heterozygous c.1380delA variant in the CDH1 locus.	('CDH1', 'Gene', (69, 73))	('patient', 'Species', '9606', (4, 11))	('CDH1', 'Gene', (152, 156))	('c.1380delA', 'Mutation', 'c.1380delA', (126, 136))	('c.1380delA', 'Var', (126, 136))
6983	28460635	For phospho-immunoblotting using p-ERK Thr202/Tyr204 (Cat#4376), p-AKT T308 (Cat#9275), p-PDK1 Ser241 (Cat#3438) approximately 50ug of protein was loaded, for total anti-ERK (Cat#9101), AKT (Cat#C67E7), PDK1 (Cat#3062), and actin (Cat#4967, all Cell Signaling, Danvers, USA) 5-10 microg, onto 4-20% SDS/Polyacrylamide gels.	('ERK', 'molecular_function', 'GO:0004707', ('35', '38'))	('ERK', 'Gene', '5594', (170, 173))	('AKT', 'Gene', '207', (186, 189))	('Cat#3062', 'Var', (209, 217))	('Cat', 'molecular_function', 'GO:0004096', ('77', '80'))	('PDK1', 'molecular_function', 'GO:0004740', ('90', '94'))	('PDK1', 'Gene', '5163', (90, 94))	('ERK', 'Gene', (35, 38))	('Cat', 'molecular_function', 'GO:0004096', ('191', '194'))	('Ser', 'cellular_component', 'GO:0005790', ('95', '98'))	('AKT', 'Gene', (67, 70))	('ERK', 'Gene', (170, 173))	('PDK1', 'Gene', (203, 207))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('Cat', 'molecular_function', 'GO:0004096', ('175', '178'))	('Cat', 'molecular_function', 'GO:0004096', ('231', '234'))	('Cat', 'molecular_function', 'GO:0004096', ('103', '106'))	('Cat#C67E7', 'Var', (191, 200))	('AKT', 'Gene', (186, 189))	('Signaling', 'biological_process', 'GO:0023052', ('250', '259'))	('Cat', 'molecular_function', 'GO:0004096', ('209', '212'))	('PDK1', 'Gene', (90, 94))	('AKT', 'Gene', '207', (67, 70))	('ERK', 'molecular_function', 'GO:0004707', ('170', '173'))	('Cat', 'molecular_function', 'GO:0004096', ('54', '57'))	('Cat#9101', 'Var', (175, 183))	('PDK1', 'Gene', '5163', (203, 207))	('PDK1', 'molecular_function', 'GO:0004740', ('203', '207'))	('ERK', 'Gene', '5594', (35, 38))
6997	28460635	The patient, and other family members had been previously tested for germline CDH1 mutations and found to harbor a heterozygous c.1380delA variant in exon 10 of the CDH1 locus.	('CDH1', 'Gene', (165, 169))	('mutations', 'Var', (83, 92))	('c.1380delA', 'Mutation', 'c.1380delA', (128, 138))	('patient', 'Species', '9606', (4, 11))	('c.1380delA', 'Var', (128, 138))	('CDH1', 'Gene', (78, 82))
6998	28460635	The protein product is a 480-amino acid long (P461Lfs*20) variant of CDH1 (Additional file 3: Figure S1), and is predicted to be disease causing and subject to nonsense-mediated RNA decay by MutationTaster and SIFT prediction leading to loss of expression.	('CDH1', 'Gene', (69, 73))	('P461Lfs*20', 'Var', (46, 56))	('SIFT', 'Disease', (210, 214))	('disease causing', 'Reg', (129, 144))	('P461Lfs*20', 'Mutation', 'p.P461LfsX20', (46, 56))	('SIFT', 'Disease', 'None', (210, 214))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))	('expression', 'MPA', (245, 255))	('RNA', 'cellular_component', 'GO:0005562', ('178', '181'))	('loss', 'NegReg', (237, 241))
7001	28460635	Multiple SKY karyotyping shows a diploid karyotype with frequent chromosomal aberrations including losses, duplications, and translocations typically observed in cancer (Fig.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('translocations', 'Var', (125, 139))	('cancer', 'Disease', (162, 168))	('losses', 'NegReg', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (65, 88))	('duplications', 'Var', (107, 119))
7003	28460635	We assessed next the ability of mono-dispersed c.1380delA CDH1 SB.mhdgc-1 gastric cancer cells to self-assemble and form multicellular spheroids (MCS), both as a measure of their self-renewal ability and tumorigenicity as well as to investigate the possible impact the loss of CDH1 might have on self-aggregation and the ability to form cell-to-cell contact.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('c.1380delA', 'Mutation', 'c.1380delA', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('loss', 'Var', (269, 273))	('gastric cancer', 'Disease', (74, 88))	('SB', 'Chemical', 'MESH:D000965', (63, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (74, 88))	('tumor', 'Disease', (204, 209))	('SB.mhdgc-1', 'Gene', (63, 73))	('CDH1', 'Gene', (277, 281))	('MCS', 'cellular_component', 'GO:0044232', ('146', '149'))	('self-aggregation', 'CPA', (296, 312))	('gastric cancer', 'Phenotype', 'HP:0012126', (74, 88))
7005	28460635	To confirm that MCS and 2D monolayer cells maintained the same CDH1 genotype, we performed deep sequencing using the CLIA-approved OncoVar assay in both spheroids as well as monolayer c.1380delA CDH1 SB.mhdgc-1 cells confirming the unique c.1380delA CDH1 variant in both subpopulations (Fig.	('c.1380delA', 'Mutation', 'c.1380delA', (184, 194))	('MCS', 'cellular_component', 'GO:0044232', ('16', '19'))	('SB', 'Chemical', 'MESH:D000965', (200, 202))	('c.1380delA', 'Mutation', 'c.1380delA', (239, 249))	('CDH1', 'Gene', (250, 254))	('c.1380delA', 'Var', (239, 249))
7008	28460635	The detection of the previously affirmed germline c.1380delA CDH1 germline variant in the derived cells, the loss of E-cadherin in combination with features of malignant transformation suggests the establishment of a de novo primary cell culture line from a patient with HDGC.	('c.1380delA', 'Mutation', 'c.1380delA', (50, 60))	('HDGC', 'Disease', (271, 275))	('loss', 'NegReg', (109, 113))	('patient', 'Species', '9606', (258, 265))	('cadherin', 'molecular_function', 'GO:0008014', ('119', '127'))	('CDH1', 'Gene', (61, 65))	('c.1380delA', 'Var', (50, 60))	('HDGC', 'Disease', 'MESH:D013274', (271, 275))	('E-cadherin', 'Protein', (117, 127))
7035	28460635	Using potency (logAC50) as a measure of compound activity, fewer drug classes were significantly different between c.1380delA CDH1 SB.mhdgc-1 and SB.msgc-1 cells: while topoisomerase II and AKT inhibiting agents were identified as preferentially active, some of the previously differently observed drug classes like MEK, protein kinase C, or ALK inhibitors were not measured as different activity profiles in the two cell lines (Additional file 7: Figure S5B) when using logAC50.	('c.1380delA', 'Mutation', 'c.1380delA', (115, 125))	('AKT', 'Gene', '207', (190, 193))	('ALK', 'Gene', (342, 345))	('MEK', 'Gene', (316, 319))	('protein kinase C', 'Gene', '112476', (321, 337))	('SB', 'Chemical', 'MESH:D000965', (131, 133))	('logAC50', 'Var', (471, 478))	('MEK', 'Gene', '5609', (316, 319))	('topoisomerase II', 'molecular_function', 'GO:0003918', ('169', '185'))	('protein', 'cellular_component', 'GO:0003675', ('321', '328'))	('SB', 'Chemical', 'MESH:D000965', (146, 148))	('AKT', 'Gene', (190, 193))	('ALK', 'Gene', '238', (342, 345))	('protein kinase C', 'Gene', (321, 337))
7039	28460635	Only 52 of the direct targets of compounds in the MIPE collection showed greater than twofold difference in expression levels between c.1380delA CDH1 SB.mhdgc-1 and SB.msgc-1 cells.	('SB', 'Chemical', 'MESH:D000965', (150, 152))	('SB', 'Chemical', 'MESH:D000965', (165, 167))	('CDH1', 'Gene', (145, 149))	('expression levels', 'MPA', (108, 125))	('c.1380delA', 'Mutation', 'c.1380delA', (134, 144))	('c.1380delA', 'Var', (134, 144))
7047	28460635	Figure 5a shows full 10-point dose response curves of PI-103, etoposide, and mitoxantrone confirming select sensitivity of hereditary c.1380delA CDH1 mutant SB.mhdgc-1 gastric cancer cells compared to most sporadic gastric cancer cells (up to 100- to 1000-fold lower GI50 measurements compared to SNU-16 or SB.msgc-1 cells).	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('c.1380delA', 'Mutation', 'c.1380delA', (134, 144))	('gastric cancer', 'Disease', 'MESH:D013274', (168, 182))	('PI-103', 'Chemical', 'MESH:C522973', (54, 60))	('etoposide', 'Chemical', 'MESH:D005047', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('gastric cancer', 'Disease', 'MESH:D013274', (215, 229))	('mutant', 'Var', (150, 156))	('SB', 'Chemical', 'MESH:D000965', (157, 159))	('gastric cancer', 'Phenotype', 'HP:0012126', (168, 182))	('GI50 measurements', 'MPA', (267, 284))	('SB', 'Chemical', 'MESH:D000965', (307, 309))	('mitoxantrone', 'Chemical', 'MESH:D008942', (77, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (215, 229))	('CDH1', 'Gene', (145, 149))	('lower', 'NegReg', (261, 266))	('sporadic gastric cancer', 'Disease', (206, 229))	('gastric cancer', 'Disease', (168, 182))	('sporadic gastric cancer', 'Disease', 'MESH:D013274', (206, 229))
7048	28460635	Next, we examined apoptosis levels upon treatment in c.1380delA CDH1 SB.mhdgc-1 and sporadic gastric cancer lines.	('c.1380delA', 'Mutation', 'c.1380delA', (53, 63))	('apoptosis', 'biological_process', 'GO:0006915', ('18', '27'))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('SB', 'Chemical', 'MESH:D000965', (69, 71))	('sporadic gastric cancer', 'Disease', 'MESH:D013274', (84, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('c.1380delA', 'Var', (53, 63))	('apoptosis', 'MPA', (18, 27))	('CDH1', 'Gene', (64, 68))	('examined', 'Reg', (9, 17))	('sporadic gastric cancer', 'Disease', (84, 107))	('apoptosis', 'biological_process', 'GO:0097194', ('18', '27'))
7050	28460635	Flow cytometry analysis of cell death measured by labeling DNA breaks with FITC-dUTP confirmed increased fraction of BrU positive cells in mitoxantrone, etoposide, and PI-103-treated hereditary c.1380delA CDH1 mutant SB.mhdgc-1 gastric cancer cells showed increased cell death compared to sporadic gastric cancer cells (Fig.	('cell death', 'CPA', (266, 276))	('cell death', 'biological_process', 'GO:0008219', ('266', '276'))	('gastric cancer', 'Phenotype', 'HP:0012126', (298, 312))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('SB.mhdgc-1', 'Var', (217, 227))	('gastric cancer', 'Disease', (228, 242))	('sporadic gastric cancer', 'Disease', (289, 312))	('FITC-dUTP', 'Chemical', '-', (75, 84))	('c.1380delA', 'Mutation', 'c.1380delA', (194, 204))	('sporadic gastric cancer', 'Disease', 'MESH:D013274', (289, 312))	('gastric cancer', 'Disease', 'MESH:D013274', (228, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('SB', 'Chemical', 'MESH:D000965', (217, 219))	('PI-103', 'Chemical', 'MESH:C522973', (168, 174))	('mitoxantrone', 'Chemical', 'MESH:D008942', (139, 151))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('etoposide', 'Chemical', 'MESH:D005047', (153, 162))	('gastric cancer', 'Phenotype', 'HP:0012126', (228, 242))	('gastric cancer', 'Disease', 'MESH:D013274', (298, 312))	('cell death', 'biological_process', 'GO:0008219', ('27', '37'))
7055	28460635	In contrast, leads for drug sensitivities unique to familial gastric cancer due to germline CDH1 mutations are to date largely derived from a synthetic lethality and drug screen in an isogenic CDH1 knockout breast fibroblast model (MCF10A CDH1(-/-)), CDH1-negative systems overexpressing wild type versus mutant forms of CDH1, or correlative tissue studies of the early unique T1a lesions of prophylactic gastrectomy specimens.	('mutations', 'Var', (97, 106))	('mutant', 'Var', (305, 311))	('synthetic', 'Species', '2086595', (142, 151))	('familial gastric cancer', 'Disease', (52, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('familial gastric cancer', 'Disease', 'MESH:D013274', (52, 75))	('CDH1', 'Gene', (92, 96))	('MCF10A', 'CellLine', 'CVCL:0598', (232, 238))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))	('CDH1', 'Gene', (321, 325))
7056	28460635	That hereditary diffuse gastric cancer (HDGC) due to germline CDH1 variants, and sporadic gastric cancers with somatic CDH1 perturbations are unique subtypes of gastric cancer, likely to harbor different drug sensitivity profiles and hence offer opportunities for genotype-directed personalized treatment approaches, is supported by a number of observations; for example, in a detailed CDH1 profiling effort of 174 sporadic and 72 familial gastric cancer specimens Corso et al.	('gastric cancer', 'Disease', 'MESH:D013274', (440, 454))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('gastric cancers', 'Disease', 'MESH:D013274', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('gastric cancers', 'Disease', (90, 105))	('gastric cancers', 'Phenotype', 'HP:0012126', (90, 105))	('gastric cancer', 'Disease', 'MESH:D013274', (24, 38))	('gastric cancer', 'Disease', 'MESH:D013274', (161, 175))	('variants', 'Var', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('CDH1', 'Gene', (62, 66))	('gastric cancer', 'Phenotype', 'HP:0012126', (440, 454))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('hereditary diffuse gastric cancer', 'Disease', (5, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('sporadic gastric cancer', 'Disease', (81, 104))	('HDGC', 'Disease', (40, 44))	('gastric cancer', 'Phenotype', 'HP:0012126', (24, 38))	('gastric cancer', 'Phenotype', 'HP:0012126', (161, 175))	('drug sensitivity', 'Phenotype', 'HP:0020174', (204, 220))	('hereditary diffuse gastric cancer', 'Disease', 'MESH:D013274', (5, 38))	('sporadic gastric cancer', 'Disease', 'MESH:D013274', (81, 104))	('familial gastric cancer', 'Disease', 'MESH:D013274', (431, 454))	('HDGC', 'Disease', 'MESH:D013274', (40, 44))	('gastric cancer', 'Disease', (161, 175))	('CDH1', 'Gene', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (448, 454))	('familial gastric cancer', 'Disease', (431, 454))
7058	28460635	Or, eleven percent of the 205 primary gastric adenocarcinoma, examined as part of the TCGA effort, harbored somatic mutations in the CDH1 gene, which occurred nearly exclusively in the genomically stable (GS) gastric cancer subtype (37% of GS cases) which, by far, comprised of the largest number of cancers with diffuse histology.	('GS', 'Disease', 'MESH:D011125', (240, 242))	('cancers', 'Disease', 'MESH:D009369', (300, 307))	('GS', 'Disease', 'MESH:D011125', (205, 207))	('gastric adenocarcinoma', 'Disease', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (38, 60))	('gastric cancer', 'Disease', (209, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('mutations', 'Var', (116, 125))	('gastric cancer', 'Disease', 'MESH:D013274', (209, 223))	('CDH1', 'Gene', (133, 137))	('gastric cancer', 'Phenotype', 'HP:0012126', (209, 223))	('occurred', 'Reg', (150, 158))	('cancers', 'Phenotype', 'HP:0002664', (300, 307))	('cancers', 'Disease', (300, 307))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
7059	28460635	In order to identify treatment leads selective for the HDGC subtype due to CDH1 germline mutations of gastric cancer, we derived a primary tissue culture line from an HDGC patient with a c.1380delA CDH1 truncating germline mutation leading to loss of CDH1 expression, and compared the transcriptomic profile and drug sensitivity profile of these cells to a panel of sporadic gastric cancer cells.	('gastric cancer', 'Disease', 'MESH:D013274', (375, 389))	('HDGC', 'Disease', 'MESH:D013274', (55, 59))	('gastric cancer', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (383, 389))	('CDH1', 'Gene', (198, 202))	('loss', 'NegReg', (243, 247))	('expression', 'MPA', (256, 266))	('CDH1', 'Gene', (251, 255))	('gastric cancer', 'Phenotype', 'HP:0012126', (375, 389))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('sporadic gastric cancer', 'Disease', (366, 389))	('HDGC', 'Disease', (167, 171))	('c.1380delA', 'Mutation', 'c.1380delA', (187, 197))	('patient', 'Species', '9606', (172, 179))	('HDGC', 'Disease', (55, 59))	('c.1380delA', 'Var', (187, 197))	('sporadic gastric cancer', 'Disease', 'MESH:D013274', (366, 389))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('CDH1', 'Gene', (75, 79))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('drug sensitivity', 'Phenotype', 'HP:0020174', (312, 328))	('HDGC', 'Disease', 'MESH:D013274', (167, 171))
7066	28460635	Overall, drug sensitivities with overlap to Telford and colleagues' findings in the CDH1(-/-) isogenic mutant MCF10A model include inhibitors of the PI3K/mTOR axis, including PI-103 followed up in our validation studies, mTOR, aurora kinase inhibitors as well as inhibitors of c-Src kinase.	('PI3K', 'molecular_function', 'GO:0016303', ('149', '153'))	('PI-103', 'Chemical', 'MESH:C522973', (175, 181))	('MCF10A', 'CellLine', 'CVCL:0598', (110, 116))	('mTOR', 'Gene', (221, 225))	('mTOR', 'Gene', '2475', (221, 225))	('mutant', 'Var', (103, 109))	('c-Src kinase', 'Gene', '1445', (277, 289))	('PI3', 'Gene', '5266', (149, 152))	('MCF10A', 'Gene', (110, 116))	('mTOR', 'Gene', (154, 158))	('mTOR', 'Gene', '2475', (154, 158))	('c-Src kinase', 'Gene', (277, 289))	('PI3', 'Gene', (149, 152))
7070	28460635	These tumors were frequently hyper-methylated and of high grade and appear to be most similar to the genomically stable (GS) subtype by TCGA which consists of 75% Lauren classification type diffuse tumors, which has the highest rate of CDH1 mutations, as well as frequent variants involving genes of cytoskeletal, cell polarity, and cellular component organization, both findings in line with the GO process analysis and drug phenotype in the c.1380delA CDH1 SB.mhdgc-1 cells.	('cellular component', 'cellular_component', 'GO:0005575', ('333', '351'))	('variants', 'Var', (272, 280))	('hyper-methylated', 'Var', (29, 45))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('cellular component organization', 'biological_process', 'GO:0016043', ('333', '364'))	('cell polarity', 'biological_process', 'GO:0007163', ('314', '327'))	('tumors', 'Disease', (6, 12))	('c.1380delA', 'Mutation', 'c.1380delA', (443, 453))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('SB', 'Chemical', 'MESH:D000965', (459, 461))	('CDH1', 'Gene', (236, 240))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('GS', 'Disease', 'MESH:D011125', (121, 123))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('mutations', 'Var', (241, 250))
7071	28460635	On the other, there were also significant differences between the pharmacological profile of MCF10A CDH1 (-/-) mutant cells reported by Telford and coworkers and the drug phenotype of c.1380delA CDH1 SB.mhdgc-1 in our study.	('CDH1', 'Gene', (100, 104))	('c.1380delA', 'Mutation', 'c.1380delA', (184, 194))	('mutant', 'Var', (111, 117))	('MCF10A', 'CellLine', 'CVCL:0598', (93, 99))	('SB', 'Chemical', 'MESH:D000965', (200, 202))	('MCF10A CDH1', 'Gene', (93, 104))	('differences', 'Reg', (42, 53))
7075	28460635	In the sentinel studies of Humar and colleagues, who examined signal transduction aberrations of the T1a stage with phospho-immunohistochemistry in a family with a c.1008G>T CDH1 germline mutation, detailed pathology analysis showed that deficiency in E-cadherin is sufficient to initiate diffuse gastric cancer in the absence of hyperproliferation and that early intramucosal signet-ring cell carcinoma (SRRC) is initially slow proliferating in the upper neck of the gastric glands with loss of expression of junctional molecules including actin, p120, or Lin-7 homologue A of the cell polarity complex.	('E-cadherin', 'Gene', (252, 262))	('diffuse gastric cancer', 'Disease', 'MESH:D013274', (289, 311))	('gastric cancer', 'Phenotype', 'HP:0012126', (297, 311))	('absence of hyperproliferation', 'Disease', (319, 348))	('CDH1', 'Gene', (174, 178))	('p120', 'Gene', '1500', (548, 552))	('c.1008G>T', 'Var', (164, 173))	('cell polarity', 'biological_process', 'GO:0007163', ('582', '595'))	('cell carcinoma', 'Disease', (389, 403))	('diffuse gastric cancer', 'Disease', (289, 311))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('neck', 'cellular_component', 'GO:0044326', ('456', '460'))	('p120', 'Gene', (548, 552))	('absence of hyperproliferation', 'Disease', 'MESH:D004832', (319, 348))	('signal transduction', 'biological_process', 'GO:0007165', ('62', '81'))	('carcinoma', 'Phenotype', 'HP:0030731', (394, 403))	('Lin-7', 'Gene', (557, 562))	('Lin-7', 'Gene', '8825', (557, 562))	('loss of', 'NegReg', (488, 495))	('initiate', 'PosReg', (280, 288))	('cell carcinoma', 'Disease', 'MESH:C538614', (389, 403))	('cadherin', 'molecular_function', 'GO:0008014', ('254', '262'))	('c.1008G>T', 'Mutation', 'rs267606712', (164, 173))	('actin', 'Protein', (541, 546))	('deficiency', 'Var', (238, 248))	('expression', 'MPA', (496, 506))
7076	28460635	Expansion and progression beyond the early HDGC base is associated with c-Src kinase activation, including activation of downstream effectors FAK and signal transducer and activator of transcription 3 (STAT3), and described as one of the sentinel events of progression beyond the gastric mucosa and transformation to poorly differentiated cells and the development of an EMT phenotype.	('gastric mucosa', 'Disease', (280, 294))	('transcription', 'biological_process', 'GO:0006351', ('185', '198'))	('FAK', 'molecular_function', 'GO:0004717', ('142', '145'))	('EMT', 'biological_process', 'GO:0001837', ('371', '374'))	('HDGC', 'Disease', (43, 47))	('c-Src kinase', 'Gene', (72, 84))	('signal transducer and activator of transcription 3', 'Gene', '6774', (150, 200))	('poorly differentiated cells', 'CPA', (317, 344))	('FAK', 'Gene', (142, 145))	('HDGC', 'Disease', 'MESH:D013274', (43, 47))	('Expansion', 'Var', (0, 9))	('EMT', 'Gene', (371, 374))	('STAT3', 'Gene', (202, 207))	('EMT', 'Gene', '3702', (371, 374))	('activation', 'PosReg', (85, 95))	('FAK', 'Gene', '5747', (142, 145))	('STAT3', 'Gene', '6774', (202, 207))	('c-Src kinase', 'Gene', '1445', (72, 84))	('activation', 'PosReg', (107, 117))	('gastric mucosa', 'Disease', 'MESH:D013274', (280, 294))
7083	28460635	Hereditary diffuse gastric cancer due to CDH1 germline mutations has to date largely escaped the benefits of the personalized medicine approach.	('diffuse gastric cancer', 'Disease', 'MESH:D013274', (11, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('germline mutations', 'Var', (46, 64))	('gastric cancer', 'Phenotype', 'HP:0012126', (19, 33))	('diffuse gastric cancer', 'Disease', (11, 33))	('CDH1', 'Gene', (41, 45))
7092	27572307	Microarray analysis indicated that expression of WWOX and CADM1, tumor suppressor genes, was significantly enhanced in MKN74 cells after SETDB2 knockdown.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('CADM1', 'Gene', (58, 63))	('tumor suppressor', 'biological_process', 'GO:0051726', ('65', '81'))	('CADM1', 'Gene', '23705', (58, 63))	('enhanced', 'PosReg', (107, 115))	('expression', 'MPA', (35, 45))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('65', '81'))	('knockdown', 'Var', (144, 153))	('WWOX', 'Gene', '51741', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('SETDB2', 'Gene', (137, 143))	('WWOX', 'Gene', (49, 53))
7096	27572307	Genetic and epigenetic alterations are involved in gastric carcinogenesis; for example, mutations of the CDH1 and p53 tumor suppressor genes (TSGs), and hypermethylation at the CpG island promoter region of TSGs have been detected in GCs.	('gastric carcinogenesis', 'Disease', (51, 73))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('118', '134'))	('GC', 'Phenotype', 'HP:0012126', (234, 236))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('GCs', 'Disease', (234, 237))	('mutations', 'Var', (88, 97))	('tumor suppressor', 'biological_process', 'GO:0051726', ('118', '134'))	('CDH1', 'Gene', (105, 109))	('hypermethylation', 'Var', (153, 169))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (51, 73))	('tumor', 'Disease', (118, 123))	('detected', 'Reg', (222, 230))	('GCs', 'Phenotype', 'HP:0012126', (234, 237))	('CDH1', 'Gene', '999', (105, 109))
7104	27572307	Moreover, it was reported that knockdown of Setdb2 in zebrafish embryo induced abnormal convergence and extension movements during gastrulation, resulting in anterior-posterior shortening, indicating an essential role in embryonic development.	('convergence', 'CPA', (88, 99))	('induced', 'Reg', (71, 78))	('gastrulation', 'biological_process', 'GO:0007369', ('131', '143'))	('anterior-posterior shortening', 'CPA', (158, 187))	('abnormal convergence', 'Phenotype', 'HP:0000619', (79, 99))	('zebrafish', 'Species', '7955', (54, 63))	('knockdown', 'Var', (31, 40))	('Setdb2', 'Gene', (44, 50))
7112	27572307	Scratch assay also demonstrated that cell migration was significantly faster in AGS and NUGC3 cells with SETDB2 overexpression than those with empty vector transfection (P<0.05, Supplementary Figure S1A).	('AGS', 'Disease', (80, 83))	('AGS', 'Disease', 'MESH:C535607', (80, 83))	('faster', 'PosReg', (70, 76))	('GC', 'Phenotype', 'HP:0012126', (90, 92))	('cell migration', 'biological_process', 'GO:0016477', ('37', '51'))	('SETDB2', 'Gene', (105, 111))	('overexpression', 'Var', (112, 126))	('cell migration', 'CPA', (37, 51))
7114	27572307	Global H3K9me3 at the protein levels were decreased in both of these cell lines with knockdown of SETDB2 by Western blotting, although global di- (H3K9me2, Figure 3A) and mono-methylation (H3K9me1, data not shown) levels were not changed.	('H3', 'Chemical', 'MESH:C012616', (189, 191))	('decreased', 'NegReg', (42, 51))	('methylation', 'biological_process', 'GO:0032259', ('176', '187'))	('knockdown', 'Var', (85, 94))	('protein', 'cellular_component', 'GO:0003675', ('22', '29'))	('H3', 'Chemical', 'MESH:C012616', (7, 9))	('H3', 'Chemical', 'MESH:C012616', (147, 149))	('me3', 'Gene', '10873', (11, 14))	('SETDB2', 'Gene', (98, 104))	('me3', 'Gene', (11, 14))
7116	27572307	The mRNA expression of SETDB1 and SUV39H1 was not changed in MKN74 and MKN45 cells after SETDB2 knockdown (Supplementary Figure S2), suggesting that SETDB2 itself is correlated with global H3K9me3 levels in these two GC cell lines.	('knockdown', 'Var', (96, 105))	('H3', 'Chemical', 'MESH:C012616', (189, 191))	('GC', 'Phenotype', 'HP:0012126', (217, 219))	('SETDB1', 'Gene', (23, 29))	('SUV39H1', 'Gene', '6839', (34, 41))	('me3', 'Gene', '10873', (193, 196))	('me3', 'Gene', (193, 196))	('SETDB1', 'Gene', '9869', (23, 29))	('SETDB2', 'Gene', (89, 95))	('SUV39H1', 'Gene', (34, 41))
7117	27572307	Because SETDB2 knockdown led to significant inhibition of cell growth, migration and invasion, we further selected six tumor- or differentiation-related genes (WWOX, CADM1/TSLC1, CCDC80, NDRG1, CA9 and FZD9) that have been reported to show altered expression in several cancers including GCs.	('FZD9', 'Gene', (202, 206))	('WWOX', 'Gene', (160, 164))	('migration', 'CPA', (71, 80))	('CADM1', 'Gene', '23705', (166, 171))	('invasion', 'CPA', (85, 93))	('CA9', 'Gene', '768', (194, 197))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('TSLC1', 'Gene', (172, 177))	('cancers', 'Phenotype', 'HP:0002664', (270, 277))	('cancers', 'Disease', (270, 277))	('NDRG1', 'Gene', (187, 192))	('expression', 'MPA', (248, 258))	('FZD9', 'Gene', '8326', (202, 206))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('WWOX', 'Gene', '51741', (160, 164))	('inhibition', 'NegReg', (44, 54))	('CCDC80', 'Gene', (179, 185))	('GCs', 'Disease', (288, 291))	('tumor', 'Disease', (119, 124))	('TSLC1', 'Gene', '23705', (172, 177))	('cell growth', 'CPA', (58, 69))	('knockdown', 'Var', (15, 24))	('cancers', 'Disease', 'MESH:D009369', (270, 277))	('SETDB2', 'Gene', (8, 14))	('CADM1', 'Gene', (166, 171))	('GCs', 'Phenotype', 'HP:0012126', (288, 291))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('CCDC80', 'Gene', '151887', (179, 185))	('inhibition of cell growth', 'biological_process', 'GO:0030308', ('44', '69'))	('CA9', 'Gene', (194, 197))	('NDRG1', 'Gene', '10397', (187, 192))	('GC', 'Phenotype', 'HP:0012126', (288, 290))
7119	27572307	SETDB2 knockdown in MKN45 cells resulted in similar gene expression patterns except for expression of FZD9 (Figure 3B and Supplementary Figure S3A).	('SETDB2', 'Gene', (0, 6))	('FZD9', 'Gene', '8326', (102, 106))	('knockdown', 'Var', (7, 16))	('FZD9', 'Gene', (102, 106))	('gene expression', 'biological_process', 'GO:0010467', ('52', '67'))
7121	27572307	We therefore focused on the three genes (WWOX, CADM1 and CCDC80) whose expression was elevated by SETDB2 knockdown, and we examined how SETDB2 expression inhibited the expression of these genes in GC cells.	('CCDC80', 'Gene', (57, 63))	('expression', 'MPA', (71, 81))	('elevated', 'PosReg', (86, 94))	('CCDC80', 'Gene', '151887', (57, 63))	('CADM1', 'Gene', '23705', (47, 52))	('expression', 'MPA', (168, 178))	('knockdown', 'Var', (105, 114))	('WWOX', 'Gene', '51741', (41, 45))	('GC', 'Phenotype', 'HP:0012126', (197, 199))	('WWOX', 'Gene', (41, 45))	('SETDB2', 'Gene', (98, 104))	('CADM1', 'Gene', (47, 52))
7122	27572307	ChIP assays showed that H3K9me3 levels at the promoter regions of WWOX and CADM1 were greatly decreased in MKN74 and MKN45 cells with SETDB2 siRNA transfection compared with negative control (Figures 4A-4D).	('CADM1', 'Gene', '23705', (75, 80))	('me3', 'Gene', '10873', (28, 31))	('H3', 'Chemical', 'MESH:C012616', (24, 26))	('me3', 'Gene', (28, 31))	('transfection', 'Var', (147, 159))	('decreased', 'NegReg', (94, 103))	('SETDB2', 'Gene', (134, 140))	('WWOX', 'Gene', '51741', (66, 70))	('CADM1', 'Gene', (75, 80))	('WWOX', 'Gene', (66, 70))
7123	27572307	In contrast, the H3K9me3 levels at a region approximately +3 kb downstream of the transcriptional start site (TSS) were not changed by SETDB2 siRNA transfection compared with negative control transfection (Figures 4B and 4D, right panels).	('me3', 'Gene', (21, 24))	('SETDB2', 'Gene', (135, 141))	('H3', 'Chemical', 'MESH:C012616', (17, 19))	('transfection', 'Var', (148, 160))	('me3', 'Gene', '10873', (21, 24))
7128	27572307	The expression levels of WWOX in GC cell lines with high SETDB2 expression were lower than those with low SETDB2 expression, thereby displaying a tendency of WWOX expression to inversely correlate with SETDB2 expression (P=0.058), (Figure 5A and Supplementary Figure S3B).	('expression levels', 'MPA', (4, 21))	('WWOX', 'Gene', '51741', (158, 162))	('SETDB2', 'Gene', (57, 63))	('WWOX', 'Gene', '51741', (25, 29))	('WWOX', 'Gene', (25, 29))	('lower', 'NegReg', (80, 85))	('expression', 'Var', (64, 74))	('high', 'Var', (52, 56))	('GC', 'Phenotype', 'HP:0012126', (33, 35))	('WWOX', 'Gene', (158, 162))
7131	27572307	SETDB2 knockdown up-regulated WWOX protein expression in MKN74 and MKN45 cells, and, conversely, SETDB2 overexpression in AGS and NUGC3 cells repressed the protein expression of WWOX (Figure 5B).	('SETDB2', 'Gene', (0, 6))	('SETDB2', 'Gene', (97, 103))	('AGS', 'Disease', (122, 125))	('expression', 'MPA', (43, 53))	('WWOX', 'Gene', '51741', (30, 34))	('WWOX', 'Gene', (30, 34))	('GC', 'Phenotype', 'HP:0012126', (132, 134))	('protein', 'cellular_component', 'GO:0003675', ('35', '42'))	('WWOX', 'Gene', '51741', (178, 182))	('WWOX', 'Gene', (178, 182))	('knockdown', 'Var', (7, 16))	('AGS', 'Disease', 'MESH:C535607', (122, 125))	('up-regulated', 'PosReg', (17, 29))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))
7132	27572307	To assess whether or not the effects of SETDB2 overexpression in GC cells were mediated by reduced expression of WWOX, we performed knockdown of WWOX by transfection of its siRNA into AGS and NUGC3 GC cells (Figure 6A).	('expression', 'MPA', (99, 109))	('AGS', 'Disease', (184, 187))	('knockdown', 'Var', (132, 141))	('WWOX', 'Gene', (145, 149))	('AGS', 'Disease', 'MESH:C535607', (184, 187))	('WWOX', 'Gene', '51741', (113, 117))	('WWOX', 'Gene', (113, 117))	('GC', 'Phenotype', 'HP:0012126', (65, 67))	('SETDB2', 'Gene', (40, 46))	('GC', 'Phenotype', 'HP:0012126', (194, 196))	('GC', 'Phenotype', 'HP:0012126', (198, 200))	('WWOX', 'Gene', '51741', (145, 149))
7133	27572307	The abilities of cell proliferation, migration and invasion were promoted after knockdown of WWOX in AGS and NUGC3 cells (P<0.05, Figure 6B-6D, Supplementary Figure S1B).	('knockdown', 'Var', (80, 89))	('WWOX', 'Gene', (93, 97))	('cell proliferation', 'CPA', (17, 35))	('AGS', 'Disease', 'MESH:C535607', (101, 104))	('migration', 'CPA', (37, 46))	('promoted', 'PosReg', (65, 73))	('cell proliferation', 'biological_process', 'GO:0008283', ('17', '35'))	('GC', 'Phenotype', 'HP:0012126', (111, 113))	('invasion', 'CPA', (51, 59))	('WWOX', 'Gene', '51741', (93, 97))	('AGS', 'Disease', (101, 104))
7139	27572307	It has been reported that SETDB1 promoter region contains multiple SP1-binding sites and SETDB1 expression was enhanced by SP1, suggesting a significant relation between SETDB1 and TF bindings.	('SETDB1', 'Gene', (89, 95))	('SETDB1', 'Gene', '9869', (170, 176))	('expression', 'MPA', (96, 106))	('bindings', 'Interaction', (184, 192))	('enhanced', 'PosReg', (111, 119))	('SETDB1', 'Gene', '9869', (26, 32))	('SP1', 'Var', (123, 126))	('SETDB1', 'Gene', '9869', (89, 95))	('SETDB1', 'Gene', (170, 176))	('SETDB1', 'Gene', (26, 32))	('binding', 'molecular_function', 'GO:0005488', ('71', '78'))
7141	27572307	Besides, amplification of the SETDB1 gene was found in lung and liver cancers, and SETDB1 and SUV39H1 were negatively regulated by miR-29 and miR-125b, respectively.	('SETDB1', 'Gene', (30, 36))	('SETDB1', 'Gene', '9869', (83, 89))	('SUV39H1', 'Gene', (94, 101))	('lung and liver cancers', 'Disease', 'MESH:D006528', (55, 77))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SUV39H1', 'Gene', '6839', (94, 101))	('negatively', 'NegReg', (107, 117))	('miR-125b', 'Var', (142, 150))	('SETDB1', 'Gene', (83, 89))	('SETDB1', 'Gene', '9869', (30, 36))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('liver cancers', 'Phenotype', 'HP:0002896', (64, 77))	('miR-29', 'Var', (131, 137))
7142	27572307	The H3K9 methyltransferase genes mediated global and promoter/enhancer region of H3K9 tri- di- and mono- methylation.	('tri-', 'Var', (86, 90))	('H3K9', 'Gene', (81, 85))	('H3', 'Chemical', 'MESH:C012616', (81, 83))	('methylation', 'biological_process', 'GO:0032259', ('105', '116'))	('H3K9', 'Gene', (4, 8))	('mono- methylation', 'Var', (99, 116))	('H3', 'Chemical', 'MESH:C012616', (4, 6))
7146	27572307	In addition, we observed that knockdown of SETDB2 resulted in a decrease in H3K9me3 levels at the promoter regions of WWOX and CADM1 genes, both of whose expression were increased by SETDB2 knockdown.	('decrease', 'NegReg', (64, 72))	('WWOX', 'Gene', '51741', (118, 122))	('CADM1', 'Gene', (127, 132))	('WWOX', 'Gene', (118, 122))	('CADM1', 'Gene', '23705', (127, 132))	('me3', 'Gene', '10873', (80, 83))	('SETDB2', 'Gene', (43, 49))	('me3', 'Gene', (80, 83))	('knockdown', 'Var', (30, 39))	('H3', 'Chemical', 'MESH:C012616', (76, 78))
7147	27572307	Ectopic SETDB2 in GC cells was recruited to the promoters of these two genes and increased H3K9me3 levels at the regions.	('H3', 'Chemical', 'MESH:C012616', (91, 93))	('SETDB2', 'Gene', (8, 14))	('GC', 'Phenotype', 'HP:0012126', (18, 20))	('me3', 'Gene', '10873', (95, 98))	('me3', 'Gene', (95, 98))	('Ectopic', 'Var', (0, 7))	('increased', 'PosReg', (81, 90))	('recruited', 'PosReg', (31, 40))
7152	27572307	It is known that WWOX and CADM1 but not CCDC80 have dense CpG islands in their promoter regions and hypermethylation at the promoter regions of WWOX and CADM1 has been reported in cancer cells.	('CADM1', 'Gene', (26, 31))	('hypermethylation', 'Var', (100, 116))	('CADM1', 'Gene', '23705', (26, 31))	('CCDC80', 'Gene', '151887', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('WWOX', 'Gene', '51741', (17, 21))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('WWOX', 'Gene', '51741', (144, 148))	('WWOX', 'Gene', (17, 21))	('CpG', 'Protein', (58, 61))	('CADM1', 'Gene', (153, 158))	('WWOX', 'Gene', (144, 148))	('CADM1', 'Gene', '23705', (153, 158))	('cancer', 'Disease', (180, 186))	('CCDC80', 'Gene', (40, 46))
7166	27572307	Western blotting was conducted with mouse monoclonal anti-SETDB2 (1:500; M17, Abnova, Taipei, Taiwan), and anti-WWOX (1:300; sc-374449, Santa Cruz Biotechnology, Santa Cruz, CA): and rabbit polyclonal anti-H3 (1:4000; Active Motif, Carlsbad, CA), anti-H3K9me3 (1:2000; Active Motif) and anti-H3K9me2 (1:2000; Active Motif).	('H3', 'Chemical', 'MESH:C012616', (292, 294))	('H3', 'Chemical', 'MESH:C012616', (252, 254))	('anti-H3K9me2', 'Var', (287, 299))	('rabbit', 'Species', '9986', (183, 189))	('WWOX', 'Gene', '51741', (112, 116))	('WWOX', 'Gene', (112, 116))	('me3', 'Gene', '10873', (256, 259))	('me3', 'Gene', (256, 259))	('H3', 'Chemical', 'MESH:C012616', (206, 208))	('mouse', 'Species', '10090', (36, 41))
7183	27572307	Antibodies used were anti-H3 (Active Motif), anti-H3K9me3 (Active Motif), Normal Rabbit IgG (No.	('H3', 'Chemical', 'MESH:C012616', (26, 28))	('H3', 'Chemical', 'MESH:C012616', (50, 52))	('me3', 'Gene', '10873', (54, 57))	('Rabbit', 'Species', '9986', (81, 87))	('me3', 'Gene', (54, 57))	('anti-H3', 'Var', (21, 28))
7239	27119558	Tumor Content Chart-Assisted HER2/CEP17 Digital PCR Analysis of Gastric Cancer Biopsy Specimens Evaluating HER2 gene amplification is an essential component of therapeutic decision-making for advanced or metastatic gastric cancer.	('HER2', 'Gene', '2064', (107, 111))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('CEP', 'molecular_function', 'GO:0047849', ('34', '37'))	('HER2', 'Gene', (29, 33))	('gastric cancer', 'Disease', (215, 229))	('gastric cancer', 'Disease', 'MESH:D013274', (215, 229))	('HER2', 'Gene', '2064', (29, 33))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (64, 78))	('Gastric Cancer', 'Disease', (64, 78))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Gastric Cancer', 'Disease', 'MESH:D013274', (64, 78))	('gene amplification', 'Var', (112, 130))	('gastric cancer', 'Phenotype', 'HP:0012126', (215, 229))	('HER2', 'Gene', (107, 111))
7241	27119558	In this study, we developed a microfluidics-based digital PCR method for determining HER2 and chromosome 17 centromere (CEP17) copy numbers and estimating tumor content ratio (TCR).	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('centromere', 'cellular_component', 'GO:0000775', ('108', '118'))	('CEP17', 'Gene', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('TCR', 'cellular_component', 'GO:0042101', ('176', '179'))	('CEP', 'molecular_function', 'GO:0047849', ('120', '123'))	('chromosome', 'cellular_component', 'GO:0005694', ('94', '104'))	('tumor', 'Disease', (155, 160))	('HER2', 'Gene', (85, 89))	('copy numbers', 'Var', (127, 139))	('HER2', 'Gene', '2064', (85, 89))	('TCR', 'biological_process', 'GO:0006283', ('176', '179'))	('centromere', 'cellular_component', 'GO:0005698', ('108', '118'))
7249	27119558	This is usually caused by HER2 gene amplification, which has been reported in several types of malignant tumor including breast cancer, salivary gland adenocarcinoma, urinary bladder cancer, and gastric cancer.	('malignant tumor', 'Disease', 'MESH:D018198', (95, 110))	('HER2', 'Gene', '2064', (26, 30))	('bladder cancer', 'Phenotype', 'HP:0009725', (175, 189))	('gene amplification', 'Var', (31, 49))	('urinary bladder cancer', 'Disease', (167, 189))	('gastric cancer', 'Disease', (195, 209))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('caused by', 'Reg', (16, 25))	('HER2', 'Gene', (26, 30))	('gastric cancer', 'Disease', 'MESH:D013274', (195, 209))	('salivary gland adenocarcinoma', 'Disease', 'MESH:D012468', (136, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (167, 189))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('salivary gland adenocarcinoma', 'Disease', (136, 165))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('breast cancer', 'Disease', (121, 134))	('malignant tumor', 'Disease', (95, 110))	('gastric cancer', 'Phenotype', 'HP:0012126', (195, 209))
7301	27119558	unpublished data), CEP17 copy number is 1.0-5.7, median 2.5, and monosomy, defined as [A < 1.5], is quite rare in only two cases (1.2%).	('A < 1', 'Gene', (87, 92))	('A < 1', 'Gene', '597', (87, 92))	('copy number', 'Var', (25, 36))	('CEP', 'molecular_function', 'GO:0047849', ('19', '22'))	('CEP17', 'Gene', (19, 24))
7348	27119558	In the present study, we used image analysis to obtain a semi-automated estimation of tumor cell content and developed the TC chart to classify data into three categories:i.e., amplified, non-amplified, and equivocal.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('non-amplified', 'Var', (188, 201))	('tumor', 'Disease', (86, 91))	('amplified', 'Var', (177, 186))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
7351	27119558	The frequency of HER2 amplification varies across gastric cancer histological types, from 20%-30% in the intestinal to < 10% in the diffuse type.	('intestinal', 'Disease', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('gastric cancer', 'Disease', (50, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('HER2', 'Gene', (17, 21))	('amplification', 'Var', (22, 35))	('HER2', 'Gene', '2064', (17, 21))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))
7363	27119558	Aneusomy of chromosome 17 (monosomy and polysomy) may affect HER2 amplification measurements by the HER2/CEP17 ratio, although its clinical importance is unknown in the absence of HER2 overexpression on IHC.	('HER2', 'Gene', (180, 184))	('HER2', 'Gene', '2064', (180, 184))	('clinical', 'Species', '191496', (131, 139))	('CEP', 'molecular_function', 'GO:0047849', ('105', '108'))	('polysomy', 'Var', (40, 48))	('monosomy', 'Var', (27, 35))	('HER2', 'Gene', (61, 65))	('affect', 'Reg', (54, 60))	('HER2', 'Gene', '2064', (61, 65))	('HER2', 'Gene', (100, 104))	('Aneusomy', 'Var', (0, 8))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))	('HER2', 'Gene', '2064', (100, 104))
7364	27119558	Polysomy may be more common in gastric cancer, but the average CEP17 copy number [A] did not exceed 6.0.	('CEP17', 'Gene', (63, 68))	('gastric cancer', 'Phenotype', 'HP:0012126', (31, 45))	('Polysomy', 'Var', (0, 8))	('CEP', 'molecular_function', 'GO:0047849', ('63', '66'))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('gastric cancer', 'Disease', (31, 45))	('gastric cancer', 'Disease', 'MESH:D013274', (31, 45))	('common', 'Reg', (21, 27))
7366	27119558	The histological heterogeneity of tumors is a major problem associated with HER2 amplification measurements, especially in gastric cancer.	('tumors', 'Disease', (34, 40))	('HER2', 'Gene', (76, 80))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('HER2', 'Gene', '2064', (76, 80))	('amplification measurements', 'Var', (81, 107))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('gastric cancer', 'Disease', (123, 137))	('gastric cancer', 'Disease', 'MESH:D013274', (123, 137))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (123, 137))
7368	27119558	Several studies have suggested that patients showing a higher copy number of HER2 respond better to anti-HER2 monoclonal antibody treatment.	('higher copy number', 'Var', (55, 73))	('HER2', 'Gene', (105, 109))	('patients', 'Species', '9606', (36, 44))	('antibody', 'cellular_component', 'GO:0019814', ('121', '129'))	('HER2', 'Gene', '2064', (105, 109))	('HER2', 'Gene', (77, 81))	('antibody', 'molecular_function', 'GO:0003823', ('121', '129'))	('HER2', 'Gene', '2064', (77, 81))	('better', 'PosReg', (90, 96))	('antibody', 'cellular_component', 'GO:0042571', ('121', '129'))	('antibody', 'cellular_component', 'GO:0019815', ('121', '129'))
7384	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))
7385	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))
7390	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))
7395	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))
7422	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))
7428	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))	('PD-L1', 'Var', (152, 157))	('tumor', 'Disease', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Disease', (10, 15))	('patients', 'Species', '9606', (123, 131))	('esophageal cancer', 'Disease', (33, 50))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('high levels', 'Var', (137, 148))
7432	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))
7443	25656989	There are few data directly comparing the frequencies of single nucleotide mutations in cancer-related genes between the two sites.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('single nucleotide mutations', 'Var', (57, 84))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
7448	25656989	TP53 mutations were the most common abnormality detected, and were more common in gastroesophageal junction carcinomas (42% vs. 27%, p = 0.036).	('gastroesophageal junction carcinomas', 'Disease', (82, 118))	('gastroesophageal junction carcinomas', 'Disease', 'MESH:D008309', (82, 118))	('TP53', 'Gene', '7157', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('TP53', 'Gene', (0, 4))	('common', 'Reg', (72, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('mutations', 'Var', (5, 14))
7449	25656989	Mutations in the Wnt pathway components APC and CTNNB1 were more common among gastric carcinomas (16% vs. 3%, p = 0.006), and gastric carcinomas were more likely to have >=3 driver mutations detected (11% vs. 2%, p = 0.044).	('common', 'Reg', (65, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('APC', 'Gene', '324', (40, 43))	('Wnt pathway', 'Pathway', (17, 28))	('CTNNB1', 'Gene', (48, 54))	('gastric carcinomas', 'Disease', 'MESH:D013274', (78, 96))	('Mutations', 'Var', (0, 9))	('gastric carcinomas', 'Disease', (78, 96))	('gastric carcinomas', 'Disease', (126, 144))	('gastric carcinomas', 'Disease', 'MESH:D013274', (126, 144))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (78, 95))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (126, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('APC', 'cellular_component', 'GO:0005680', ('40', '43'))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('CTNNB1', 'Gene', '1499', (48, 54))	('APC', 'Gene', (40, 43))
7450	25656989	R132H and R132C missense mutations in the IDH1 gene were observed, and are the first reported mutations of their kind in gastric carcinoma.	('R132H', 'Mutation', 'rs121913500', (0, 5))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (121, 138))	('IDH1', 'Gene', '3417', (42, 46))	('R132C', 'Mutation', 'rs121913499', (10, 15))	('R132C missense mutations', 'Var', (10, 34))	('gastric carcinoma', 'Disease', 'MESH:D013274', (121, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('gastric carcinoma', 'Disease', (121, 138))	('IDH1', 'Gene', (42, 46))	('R132H', 'Var', (0, 5))
7459	25656989	TP53 mutations are more frequent in the GEJ than in the distal stomach, while loss of heterozygosity of the TP53 locus is also more common in GEJ tumors.	('GEJ tumors', 'Disease', (142, 152))	('TP53', 'Gene', '7157', (0, 4))	('GEJ', 'Disease', (40, 43))	('TP53', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('mutations', 'Var', (5, 14))	('GEJ tumors', 'Disease', 'MESH:D009369', (142, 152))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('frequent', 'Reg', (24, 32))
7462	25656989	Testing of amplifications of the ERBB2 (also known as HER2) gene in gastric and gastroesophageal junction cancers is now routine practice in many institutions.	('ERBB2', 'Gene', '2064', (33, 38))	('HER2', 'Gene', (54, 58))	('gastric and gastroesophageal junction cancers', 'Disease', 'MESH:D013274', (68, 113))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('HER2', 'Gene', '2064', (54, 58))	('amplifications', 'Var', (11, 25))	('ERBB2', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
7463	25656989	Similarly, testing for driver mutations, particularly single nucleotide substitutions, in oncogenes and tumour suppressor genes currently informs treatment in adenocarcinomas of other sites such as the lung and colon.	('colon', 'Disease', (211, 216))	('oncogenes', 'Gene', (90, 99))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('adenocarcinomas', 'Disease', 'MESH:D000230', (159, 174))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('colon', 'Disease', 'MESH:D015179', (211, 216))	('adenocarcinomas', 'Disease', (159, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('single nucleotide substitutions', 'Var', (54, 85))	('tumour', 'Disease', (104, 110))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
7497	25656989	Among all cases, 145 mutations were detected in 31 genes, with 75 mutations detected among 57 of the tumors from the GEJ, and 70 mutations detected among 43 gastric tumors (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('gastric tumors', 'Disease', (157, 171))	('gastric tumors', 'Disease', 'MESH:D013274', (157, 171))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('gastric tumors', 'Phenotype', 'HP:0006753', (157, 171))	('tumors', 'Disease', (101, 107))	('mutations', 'Var', (21, 30))
7499	25656989	TP53 was the most commonly mutated genes, with variants identified in 59 of 167 cases (35%).	('TP53', 'Gene', '7157', (0, 4))	('variants', 'Var', (47, 55))	('TP53', 'Gene', (0, 4))
7503	25656989	TP53 mutations were identified in 39 of 92 (42%) of GEJ tumors, and in 20 of 75 (27%) gastric tumors (p = 0.036).	('TP53', 'Gene', '7157', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('TP53', 'Gene', (0, 4))	('gastric tumors', 'Phenotype', 'HP:0006753', (86, 100))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('GEJ tumors', 'Disease', 'MESH:D009369', (52, 62))	('mutations', 'Var', (5, 14))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('gastric tumors', 'Disease', (86, 100))	('gastric tumors', 'Disease', 'MESH:D013274', (86, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('GEJ tumors', 'Disease', (52, 62))
7504	25656989	When subdivided into the 3 subtypes suggested by Shah et al., TP53 mutations occurred more frequently in proximal nondiffuse cancers (44%) than in diffuse cancers (37%) and distal nondiffuse cancers (20%; p = 0.024).	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('TP53', 'Gene', '7157', (62, 66))	('cancers', 'Disease', (125, 132))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancers', 'Disease', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('TP53', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))	('occurred', 'Reg', (77, 85))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('cancers', 'Disease', (155, 162))
7505	25656989	This classification also showed more frequent mutations in KRAS within distal nondiffuse cancers (12%) versus proximal nondiffuse (3%) and diffuse (0%) carcinomas (p = 0.12).	('KRAS', 'Gene', '3845', (59, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('mutations', 'Var', (46, 55))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('carcinomas', 'Disease', (152, 162))	('cancers', 'Disease', (89, 96))	('carcinomas', 'Disease', 'MESH:D002277', (152, 162))	('KRAS', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
7506	25656989	Two components of the Wnt pathway, APC and CTNNB1, were in aggregate mutated more frequently in gastric carcinomas than in GEJ tumors (16% vs. 3%, p = 0.006).	('GEJ tumors', 'Disease', 'MESH:D009369', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('Wnt pathway', 'Pathway', (22, 33))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (96, 113))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (104, 114))	('mutated', 'Var', (69, 76))	('APC', 'Gene', (35, 38))	('APC', 'cellular_component', 'GO:0005680', ('35', '38'))	('GEJ tumors', 'Disease', (123, 133))	('CTNNB1', 'Gene', '1499', (43, 49))	('APC', 'Gene', '324', (35, 38))	('gastric carcinomas', 'Disease', 'MESH:D013274', (96, 114))	('gastric carcinomas', 'Disease', (96, 114))	('CTNNB1', 'Gene', (43, 49))
7507	25656989	Gastric carcinomas more frequently had mutations in 3 or more genes (11% vs. 2%, p = 0.044; Figure 4).	('Gastric carcinomas', 'Disease', (0, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('carcinomas', 'Phenotype', 'HP:0030731', (8, 18))	('mutations', 'Var', (39, 48))	('Gastric carcinomas', 'Disease', 'MESH:D013274', (0, 18))
7508	25656989	Targeted therapies are available or in development for mutations occurring in the following genes: AKT, BRAF, ERBB2, ERBB4, FGFR1, FGFR3, FLT3, IDH1, JAK3, KDR, KRAS, MET, PDGFRA, PIK3CA, PTEN, PTPN11, RET, SMO.	('FGFR', 'molecular_function', 'GO:0005007', ('131', '135'))	('KDR', 'Gene', (156, 159))	('RET', 'Gene', (202, 205))	('PTEN', 'Gene', '5728', (188, 192))	('IDH1', 'Gene', (144, 148))	('KRAS', 'Gene', '3845', (161, 165))	('FGFR1', 'Gene', '2260', (124, 129))	('PDGFRA', 'Gene', (172, 178))	('MET', 'Gene', (167, 170))	('FLT3', 'Gene', (138, 142))	('PDGFRA', 'Gene', '5156', (172, 178))	('ERBB4', 'Gene', '2066', (117, 122))	('FGFR', 'molecular_function', 'GO:0005007', ('124', '128'))	('ERBB4', 'Gene', (117, 122))	('JAK3', 'Gene', (150, 154))	('AKT', 'Gene', (99, 102))	('FGFR3', 'Gene', (131, 136))	('PTPN11', 'Gene', (194, 200))	('KRAS', 'Gene', (161, 165))	('FLT3', 'Gene', '2322', (138, 142))	('ERBB2', 'Gene', (110, 115))	('PIK3CA', 'Gene', '5290', (180, 186))	('IDH1', 'Gene', '3417', (144, 148))	('KDR', 'Gene', '3791', (156, 159))	('mutations', 'Var', (55, 64))	('FGFR3', 'Gene', '2261', (131, 136))	('SMO', 'Gene', '6608', (207, 210))	('PTPN11', 'Gene', '5781', (194, 200))	('JAK3', 'Gene', '3718', (150, 154))	('ERBB2', 'Gene', '2064', (110, 115))	('FGFR1', 'Gene', (124, 129))	('RET', 'Gene', '5979', (202, 205))	('JAK', 'molecular_function', 'GO:0004713', ('150', '153'))	('AKT', 'Gene', '207', (99, 102))	('PTEN', 'Gene', (188, 192))	('PIK3CA', 'Gene', (180, 186))	('BRAF', 'Gene', '673', (104, 108))	('SMO', 'Gene', (207, 210))	('BRAF', 'Gene', (104, 108))
7510	25656989	ERBB4 mutations were associated with worse disease-free survival (p = 0.018), while there was a trend towards worse disease-free survival associated with mutations in ABL1 (p = 0.063) and JAK3 (p = 0.059).	('disease-free survival', 'CPA', (43, 64))	('ERBB4', 'Gene', '2066', (0, 5))	('ERBB4', 'Gene', (0, 5))	('mutations', 'Var', (154, 163))	('JAK', 'molecular_function', 'GO:0004713', ('188', '191'))	('JAK3', 'Gene', (188, 192))	('worse', 'NegReg', (110, 115))	('ABL1', 'Gene', '25', (167, 171))	('JAK3', 'Gene', '3718', (188, 192))	('worse', 'NegReg', (37, 42))	('ABL1', 'Gene', (167, 171))	('mutations', 'Var', (6, 15))
7511	25656989	Mutations in BRAF (p < 0.001), FGFR3 (p < 0.001), FLT3 (p < 0.001) were associated with worse overall survival on univariate analysis as a result of a single case with mutations in all three of these genes.).	('FGFR', 'molecular_function', 'GO:0005007', ('31', '35'))	('FLT3', 'Gene', '2322', (50, 54))	('FGFR3', 'Gene', '2261', (31, 36))	('BRAF', 'Gene', '673', (13, 17))	('FLT3', 'Gene', (50, 54))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('FGFR3', 'Gene', (31, 36))
7512	25656989	BRAF mutation remained prognostically significant after accounting for age, sex, Lauren subtype, stage, grade and margin status (p = 0.002).	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (0, 4))	('mutation', 'Var', (5, 13))
7514	25656989	The overall frequency of TP53 mutations was not different between the study cohort and the TCGA cohort (p = 0.230).	('TP53', 'Gene', (25, 29))	('mutations', 'Var', (30, 39))	('TP53', 'Gene', '7157', (25, 29))
7516	25656989	Regarding the mutations with possible prognostic significance identified in our cohort, there was a trend towards worse overall survival associated with BRAF mutations (p = 0.079), while no prognostic association was found in the TCGA cohort in association with mutations in ERBB4, ABL1, JAK3, FLT3 or FGFR3.	('ABL1', 'Gene', '25', (282, 286))	('BRAF', 'Gene', (153, 157))	('FGFR', 'molecular_function', 'GO:0005007', ('302', '306'))	('FLT3', 'Gene', '2322', (294, 298))	('ABL1', 'Gene', (282, 286))	('FGFR3', 'Gene', '2261', (302, 307))	('JAK3', 'Gene', (288, 292))	('ERBB4', 'Gene', '2066', (275, 280))	('JAK3', 'Gene', '3718', (288, 292))	('FLT3', 'Gene', (294, 298))	('FGFR3', 'Gene', (302, 307))	('worse', 'NegReg', (114, 119))	('overall survival', 'MPA', (120, 136))	('ERBB4', 'Gene', (275, 280))	('JAK', 'molecular_function', 'GO:0004713', ('288', '291'))	('mutations', 'Var', (158, 167))	('mutations', 'Var', (262, 271))	('BRAF', 'Gene', '673', (153, 157))
7520	25656989	In gastric carcinoma, deep sequencing of single nucleotide polymorphism and RNA expression arrays have recently revealed abnormalities in several pathways including WNT, Hedgehog, cell cycling, DNA damage repair and the epithelial-to-mesenchymal transition.	('DNA', 'MPA', (194, 197))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (3, 20))	('abnormalities', 'Var', (121, 134))	('DNA', 'cellular_component', 'GO:0005574', ('194', '197'))	('WNT', 'Pathway', (165, 168))	('cell cycling', 'CPA', (180, 192))	('gastric carcinoma', 'Disease', 'MESH:D013274', (3, 20))	('RNA', 'cellular_component', 'GO:0005562', ('76', '79'))	('single nucleotide polymorphism', 'Var', (41, 71))	('Hedgehog', 'Gene', (170, 178))	('gastric carcinoma', 'Disease', (3, 20))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('220', '256'))	('epithelial-to-mesenchymal transition', 'CPA', (220, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
7521	25656989	Targeted panel sequencing can detect aberrations in cancer-related genes in early gastric cancers and precursors lesions, and its deep coverage could be particularly useful in gastric cancer by providing adequate results despite scant biopsy material and the admixture of tumor cells with desmoplasia and inflammatory cells.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('detect', 'Reg', (30, 36))	('gastric cancers', 'Disease', 'MESH:D013274', (82, 97))	('tumor', 'Disease', (272, 277))	('gastric cancers', 'Disease', (82, 97))	('gastric cancers', 'Phenotype', 'HP:0012126', (82, 97))	('gastric cancer', 'Phenotype', 'HP:0012126', (176, 190))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('desmoplasia', 'Disease', 'None', (289, 300))	('cancer', 'Disease', (90, 96))	('aberrations', 'Var', (37, 48))	('cancer', 'Disease', (52, 58))	('gastric cancer', 'Disease', (176, 190))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('desmoplasia', 'Disease', (289, 300))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (176, 190))
7522	25656989	Putative driver mutations were identified in a majority of GEJ and gastric carcinomas investigated in this study.	('gastric carcinomas', 'Disease', 'MESH:D013274', (67, 85))	('gastric carcinomas', 'Disease', (67, 85))	('mutations', 'Var', (16, 25))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (67, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('GEJ', 'Disease', (59, 62))
7525	25656989	A case with a mutation in BRAF (as well as FLT3 and FGFR3) was associated with poor overall survival on both univariate and multivariable analysis.	('BRAF', 'Gene', '673', (26, 30))	('FGFR3', 'Gene', '2261', (52, 57))	('FGFR', 'molecular_function', 'GO:0005007', ('52', '56'))	('BRAF', 'Gene', (26, 30))	('FLT3', 'Gene', '2322', (43, 47))	('overall survival', 'MPA', (84, 100))	('mutation', 'Var', (14, 22))	('FGFR3', 'Gene', (52, 57))	('FLT3', 'Gene', (43, 47))	('poor', 'NegReg', (79, 83))
7527	25656989	For example, although TP53 mutations occur throughout the gene, the panel primarily covers exons 5-8, and some of the gene segments that were not sequenced are more frequently associated with loss of p53 on immunohistochemistry.	('mutations', 'Var', (27, 36))	('p53', 'Gene', (200, 203))	('p53', 'Gene', '7157', (200, 203))	('TP53', 'Gene', '7157', (22, 26))	('loss', 'Var', (192, 196))	('TP53', 'Gene', (22, 26))
7528	25656989	This fact may potentially explain both the differences in the rates of TP53 mutations and patterns of immunohistochemical expression observed in the GEJ and stomach.	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('mutations', 'Var', (76, 85))
7529	25656989	An unexpected result of the cancer hotspot panel sequencing approach was the identification of mutations in genes usually associated with non-epithelial malignancies, such as IDH1 R132H/R132C, JAK3 V722I, and FLT3 A680V.	('R132H', 'Var', (180, 185))	('JAK3', 'Gene', '3718', (193, 197))	('IDH1', 'Gene', (175, 179))	('A680V', 'Var', (214, 219))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('A680V', 'Mutation', 'rs372303125', (214, 219))	('malignancies', 'Disease', 'MESH:D009369', (153, 165))	('malignancies', 'Disease', (153, 165))	('JAK', 'molecular_function', 'GO:0004713', ('193', '196'))	('R132H', 'SUBSTITUTION', 'None', (180, 185))	('FLT3', 'Gene', (209, 213))	('IDH1', 'Gene', '3417', (175, 179))	('V722I', 'Mutation', 'rs3213409', (198, 203))	('FLT3', 'Gene', '2322', (209, 213))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (142, 165))	('R132C', 'Mutation', 'rs121913499', (186, 191))	('cancer', 'Disease', (28, 34))	('associated', 'Reg', (122, 132))	('JAK3', 'Gene', (193, 197))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))
7530	25656989	The IDH1 variants identified occur primarily in glial and hematologic malignancies, and result in altered cancer cell metabolism.	('IDH1', 'Gene', '3417', (4, 8))	('glial', 'Disease', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('altered', 'Reg', (98, 105))	('hematologic malignancies', 'Disease', 'MESH:D019337', (58, 82))	('cancer', 'Disease', (106, 112))	('IDH1', 'Gene', (4, 8))	('metabolism', 'biological_process', 'GO:0008152', ('118', '128'))	('variants', 'Var', (9, 17))	('hematologic malignancies', 'Disease', (58, 82))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
7531	25656989	To the best of our knowledge, these cases constitute the first report of pathogenic IDH1 mutations in gastric cancer.	('IDH1', 'Gene', (84, 88))	('gastric cancer', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('IDH1', 'Gene', '3417', (84, 88))	('mutations', 'Var', (89, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))
7532	25656989	Recently IDH1 mutations have been targeted, and mutation-specific treatments are currently the aim of a phase I clinical trial that includes cholantiocarcinomas (http://clinicaltrial.gov/ct2/show/NCT02073994).	('cholantiocarcinomas', 'Disease', 'None', (141, 160))	('IDH1', 'Gene', (9, 13))	('IDH1', 'Gene', '3417', (9, 13))	('cholantiocarcinomas', 'Disease', (141, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('carcinomas', 'Phenotype', 'HP:0030731', (150, 160))	('mutations', 'Var', (14, 23))
7533	25656989	FLT3 mutations occur in a third of cases of acute myelogenous leukemia, and the point mutation resulting in the A680V substitution has not been previously described in gastric cancer, while being observed occasionally in AML.	('AML', 'Disease', 'MESH:D015470', (221, 224))	('A680V', 'Mutation', 'rs372303125', (112, 117))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (44, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (168, 182))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (44, 70))	('AML', 'Disease', (221, 224))	('leukemia', 'Phenotype', 'HP:0001909', (62, 70))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (50, 70))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('A680V', 'Var', (112, 117))	('FLT3', 'Gene', '2322', (0, 4))	('gastric cancer', 'Disease', (168, 182))	('FLT3', 'Gene', (0, 4))	('gastric cancer', 'Disease', 'MESH:D013274', (168, 182))	('acute myelogenous leukemia', 'Disease', (44, 70))
7534	25656989	Similarly, activating JAK3 mutations such as V722I have been identified in acute megakaryoblastic leukemia and NK/T-cell lymphoma, and only in a few cases of gastric and breast cancer.	('JAK', 'molecular_function', 'GO:0004713', ('22', '25'))	('leukemia', 'Phenotype', 'HP:0001909', (98, 106))	('JAK3', 'Gene', '3718', (22, 26))	('acute megakaryoblastic leukemia', 'Disease', 'MESH:D007947', (75, 106))	('V722I', 'Var', (45, 50))	('activating', 'PosReg', (11, 21))	('JAK3', 'Gene', (22, 26))	('V722I', 'Mutation', 'rs3213409', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('lymphoma', 'Phenotype', 'HP:0002665', (121, 129))	('NK/T-cell lymphoma', 'Disease', 'MESH:D054391', (111, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (114, 129))	('NK/T-cell lymphoma', 'Disease', (111, 129))	('acute megakaryoblastic leukemia', 'Phenotype', 'HP:0006733', (75, 106))	('gastric and breast cancer', 'Disease', 'MESH:D013274', (158, 183))	('acute megakaryoblastic leukemia', 'Disease', (75, 106))	('cell lymphoma', 'Phenotype', 'HP:0012191', (116, 129))
7537	25656989	As in other series, the rates of p53 overexpression were higher in the GEJ, as were the rates of TP53 mutation, while Wnt abnormalities were more common in the gastric carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('overexpression', 'PosReg', (37, 51))	('GEJ', 'Disease', (71, 74))	('TP53', 'Gene', '7157', (97, 101))	('gastric carcinomas', 'Disease', (160, 178))	('mutation', 'Var', (102, 110))	('gastric carcinomas', 'Disease', 'MESH:D013274', (160, 178))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (160, 177))	('TP53', 'Gene', (97, 101))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))
7538	25656989	In addition, more frequently there were mutations across >=3 genes in gastric carcinomas, suggesting a higher mutational load and/or a bias towards genes included in the panel compared to GEJ lesions.	('gastric carcinomas', 'Disease', (70, 88))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (70, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('mutations', 'Var', (40, 49))	('mutational load', 'MPA', (110, 125))	('higher', 'PosReg', (103, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('gastric carcinomas', 'Disease', 'MESH:D013274', (70, 88))
7541	25656989	The detection of more frequent KRAS mutations within distal non-diffuse carcinomas in our dataset when using this subclassification further supports pathologic classification of gastric cancers based on location and histotype.	('KRAS', 'Gene', (31, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('gastric cancers', 'Disease', 'MESH:D013274', (178, 193))	('carcinomas', 'Disease', 'MESH:D002277', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('gastric cancers', 'Disease', (178, 193))	('carcinomas', 'Disease', (72, 82))	('mutations', 'Var', (36, 45))	('KRAS', 'Gene', '3845', (31, 35))	('gastric cancers', 'Phenotype', 'HP:0012126', (178, 193))	('gastric cancer', 'Phenotype', 'HP:0012126', (178, 192))
7547	25656989	worse prognosis and rates of TP53 mutations).	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))
7550	25656989	GEJ and gastric tumors differ in several clinicopathologic respects, including the frequencies of mutations in certain caner-related genes.	('caner-related genes', 'Gene', (119, 138))	('gastric tumors', 'Phenotype', 'HP:0006753', (8, 22))	('GEJ', 'Disease', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutations', 'Var', (98, 107))	('gastric tumors', 'Disease', (8, 22))	('gastric tumors', 'Disease', 'MESH:D013274', (8, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))
7563	25588809	Nrf2 positivity was closely associated with tumor size, tumor depth, lymph node metastases, lymphovascular invasion, histology and stage (p < 0.05 for all).	('positivity', 'Var', (5, 15))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Nrf2', 'Gene', '4780', (0, 4))	('associated', 'Reg', (28, 38))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('lymphovascular invasion', 'CPA', (92, 115))	('Nrf2', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('lymph node metastases', 'Disease', 'MESH:D009362', (69, 90))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('lymph node metastases', 'Disease', (69, 90))
7565	25588809	And, positive Nrf2 expression was significantly associated with resistance to 5FU-based adjuvant chemotherapy (p = 0.024).	('expression', 'MPA', (19, 29))	('resistance to 5FU-based adjuvant chemotherapy', 'CPA', (64, 109))	('Nrf2', 'Gene', '4780', (14, 18))	('associated with', 'Reg', (48, 63))	('Nrf2', 'Gene', (14, 18))	('5FU', 'Chemical', 'MESH:D005472', (78, 81))	('positive', 'Var', (5, 13))
7597	25588809	Subsequently, to confirm nuclear and cytoplasmic fractions, the membrane was washed with WB Stripping Solution (Nakalai Tesque, Tokyo, Japan) for 15 minutes and re-probed for nuclear and cytoplasmic markers using the anti-Lamin B1 antibody (ab16048, Abcam, Cambridge, USA, 1:1000) and the anti-alpha-Tubulin antibody (CP06, Calbiochem, MA, USA, 1:1000) respectively.	('antibody', 'molecular_function', 'GO:0003823', ('231', '239'))	('Lamin B1', 'Gene', '4001', (222, 230))	('antibody', 'cellular_component', 'GO:0019814', ('308', '316'))	('CP06', 'Var', (318, 322))	('membrane', 'cellular_component', 'GO:0016020', ('64', '72'))	('antibody', 'molecular_function', 'GO:0003823', ('308', '316'))	('Lamin B1', 'Gene', (222, 230))	('antibody', 'cellular_component', 'GO:0042571', ('231', '239'))	('antibody', 'cellular_component', 'GO:0019814', ('231', '239'))	('antibody', 'cellular_component', 'GO:0019815', ('231', '239'))	('alpha-Tubulin', 'Gene', (294, 307))	('antibody', 'cellular_component', 'GO:0042571', ('308', '316'))	('alpha-Tubulin', 'Gene', '10376', (294, 307))	('antibody', 'cellular_component', 'GO:0019815', ('308', '316'))
7643	25588809	Out of the 59 Nfr2 positive patients, 43 (72.9%) patients were 5FU resistant, whereas only 5 (38.5%) of the 13 Nrf2 negative patients were 5FU resistant.	('5FU', 'Chemical', 'MESH:D005472', (63, 66))	('patients', 'Species', '9606', (125, 133))	('Nrf2', 'Gene', '4780', (111, 115))	('5FU', 'Chemical', 'MESH:D005472', (139, 142))	('patients', 'Species', '9606', (49, 57))	('patients', 'Species', '9606', (28, 36))	('Nrf2', 'Gene', (111, 115))	('positive', 'Var', (19, 27))	('Nfr2', 'Gene', (14, 18))
7645	25588809	Kaplan Meier analysis indicated that the overall survival of the Nrf2 positive group was significantly poorer than that of the Nrf2 negative group (61% vs. 79% respectively) (p < 0.01) (Figure 3).	('Nrf2', 'Gene', '4780', (65, 69))	('Nrf2', 'Gene', (127, 131))	('poorer', 'NegReg', (103, 109))	('positive', 'Var', (70, 78))	('Nrf2', 'Gene', (65, 69))	('Nrf2', 'Gene', '4780', (127, 131))
7657	25588809	It can therefore be theoretically proposed that the gastric cancer cell lines with nuclear Nrf2 expression would have a higher malignant potential through this mechanism.	('Nrf2', 'Gene', '4780', (91, 95))	('Nrf2', 'Gene', (91, 95))	('malignant potential', 'CPA', (127, 146))	('gastric cancer', 'Phenotype', 'HP:0012126', (52, 66))	('higher', 'PosReg', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('gastric cancer', 'Disease', (52, 66))	('nuclear', 'Var', (83, 90))	('gastric cancer', 'Disease', 'MESH:D013274', (52, 66))
7671	25588809	similarly reported that Nrf2 expression was associated with poor overall survival in non-small cell lung carcinoma and in gallbladder cancer, respectively.	('Nrf2', 'Gene', '4780', (24, 28))	('expression', 'Var', (29, 39))	('cell lung carcinoma', 'Disease', (95, 114))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (89, 114))	('poor', 'NegReg', (60, 64))	('Nrf2', 'Gene', (24, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('gallbladder cancer', 'Disease', (122, 140))	('gallbladder cancer', 'Disease', 'MESH:D005706', (122, 140))	('cell lung carcinoma', 'Disease', 'MESH:D055752', (95, 114))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (85, 114))	('overall survival', 'MPA', (65, 81))
7673	25588809	It has recently been reported that high Nrf2 expression may facilitate and prolong cancer cell survival following anticancer chemotherapy and radiation therapy.	('Nrf2', 'Gene', (40, 44))	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('prolong', 'PosReg', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('expression', 'MPA', (45, 55))	('Nrf2', 'Gene', '4780', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('facilitate', 'PosReg', (60, 70))	('high', 'Var', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Disease', (83, 89))
7676	25588809	Genetic or functional inhibition of Nrf2 has been shown to result in the repression of cellular Nrf2 -regulated antioxidant enzymes, including cellular glutathione, thioredoxin and non-protein thiols.	('thioredoxin', 'Gene', '7295', (165, 176))	('Nrf2', 'Gene', '4780', (96, 100))	('inhibition', 'NegReg', (22, 32))	('thiols', 'Chemical', 'MESH:D013438', (193, 199))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('Genetic', 'Var', (0, 7))	('thioredoxin', 'molecular_function', 'GO:0030508', ('165', '176'))	('cellular glutathione', 'MPA', (143, 163))	('thioredoxin', 'Gene', (165, 176))	('non-protein thiols', 'MPA', (181, 199))	('Nrf2', 'Gene', (96, 100))	('Nrf2', 'Gene', (36, 40))	('Nrf2', 'Gene', '4780', (36, 40))	('glutathione', 'Chemical', 'MESH:D005978', (152, 163))	('thioredoxin', 'molecular_function', 'GO:0000008', ('165', '176'))	('repression', 'NegReg', (73, 83))
7677	25588809	Ultimately, these alterations may restore the sensitivity of cancer cells to anticancer drugs and radiation therapy.	('alterations', 'Var', (18, 29))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', (81, 87))	('restore', 'PosReg', (34, 41))	('sensitivity', 'MPA', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
7679	25588809	reported that the combination of cisplatin and knockdown of Nrf2 dramatically and significantly inhibited tumor growth in vivo.	('Nrf2', 'Gene', (60, 64))	('knockdown', 'Var', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('inhibited', 'NegReg', (96, 105))	('Nrf2', 'Gene', '4780', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
7769	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))
7772	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))
7774	25038797	Western blotting analysis revealed that silencing of ANXA1 leaded to up-regulation of COX-2 (Figure 6B), while forced expression of ANXA1 decreased COX-2 production (Figure 6C).	('up-regulation', 'PosReg', (69, 82))	('COX-2 production', 'MPA', (148, 164))	('decreased', 'NegReg', (138, 147))	('COX-2', 'Enzyme', (86, 91))	('ANXA1', 'Gene', (53, 58))	('expression', 'Species', '29278', (118, 128))	('silencing', 'Var', (40, 49))	('regulation', 'biological_process', 'GO:0065007', ('72', '82'))
7806	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))
7815	25038797	Notably, knockdown ANXA1 expression with ANXA1-specific shRNA leads to an increase of COX-2 expression, suggesting ANXA1 mediating many diverse cellular functions, such as inflammation and proliferation.	('inflammation', 'Disease', 'MESH:D007249', (172, 184))	('expression', 'Species', '29278', (25, 35))	('knockdown', 'Var', (9, 18))	('proliferation', 'CPA', (189, 202))	('inflammation', 'Disease', (172, 184))	('increase', 'PosReg', (74, 82))	('ANXA1', 'Gene', (19, 24))	('COX-2', 'Protein', (86, 91))	('inflammation', 'biological_process', 'GO:0006954', ('172', '184'))	('expression', 'Species', '29278', (92, 102))	('expression', 'MPA', (92, 102))
7817	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))
7863	25061538	Interestingly, in patients with differentiated carcinoma, the 5-year survival rate was significantly associated with the number of LNs retrieved (15~25 and >25) (Fig.	('15~25', 'Var', (146, 151))	('carcinoma', 'Disease', 'MESH:D002277', (47, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('patients', 'Species', '9606', (18, 26))	('carcinoma', 'Disease', (47, 56))
7890	23383271	microRNA-9 Suppresses the Proliferation, Invasion and Metastasis of Gastric Cancer Cells through Targeting Cyclin D1 and Ets1 Recent evidence shows that altered microRNA-9 (miR-9) expression is implicated in the progression of gastric cancer.	('Cyclin', 'molecular_function', 'GO:0016538', ('107', '113'))	('Cyclin D1', 'Gene', (107, 116))	('implicated', 'Reg', (194, 204))	('miR', 'Gene', '22877', (173, 176))	('Metastasis of Gastric Cancer', 'Disease', (54, 82))	('gastric cancer', 'Phenotype', 'HP:0012126', (227, 241))	('Invasion', 'CPA', (41, 49))	('altered', 'Var', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('Metastasis of Gastric Cancer', 'Disease', 'MESH:D009362', (54, 82))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (68, 82))	('Suppresses', 'NegReg', (11, 21))	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('gastric cancer', 'Disease', (227, 241))	('Cyclin D1', 'Gene', '595', (107, 116))	('gastric cancer', 'Disease', 'MESH:D013274', (227, 241))	('miR', 'Gene', (173, 176))
7894	23383271	Ectopic expression or knockdown of miR-9 resulted in responsively altered expression of cyclin D1, Ets1 and their downstream targets phosphorylated retinoblastoma and matrix metalloproteinase 9 in cultured gastric cancer cell lines SGC-7901 and AGS.	('Ets1', 'Gene', '2113', (99, 103))	('Ets1', 'Gene', (99, 103))	('retinoblastoma', 'Disease', 'MESH:D012175', (148, 162))	('cyclin D1', 'Gene', (88, 97))	('knockdown', 'Var', (22, 31))	('gastric cancer', 'Disease', (206, 220))	('expression', 'MPA', (74, 84))	('cyclin D1', 'Gene', '595', (88, 97))	('matrix metalloproteinase 9', 'Gene', (167, 193))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('miR', 'Gene', (35, 38))	('retinoblastoma', 'Phenotype', 'HP:0009919', (148, 162))	('SGC-7901', 'CellLine', 'CVCL:0520', (232, 240))	('gastric cancer', 'Disease', 'MESH:D013274', (206, 220))	('matrix metalloproteinase 9', 'Gene', '4318', (167, 193))	('retinoblastoma', 'Disease', (148, 162))	('miR', 'Gene', '22877', (35, 38))	('gastric cancer', 'Phenotype', 'HP:0012126', (206, 220))	('altered', 'Reg', (66, 73))	('cyclin', 'molecular_function', 'GO:0016538', ('88', '94'))
7895	23383271	In the luciferase reporter system, miR-9 directly targeted the 3'-UTR of cyclin D1 and Ets1, and these effects were abolished by mutating the miR-9 binding sites.	('cyclin D1', 'Gene', (73, 82))	('miR', 'Gene', '22877', (142, 145))	('binding', 'molecular_function', 'GO:0005488', ('148', '155'))	('Ets1', 'Gene', '2113', (87, 91))	('cyclin', 'molecular_function', 'GO:0016538', ('73', '79'))	('Ets1', 'Gene', (87, 91))	('mutating', 'Var', (129, 137))	('miR', 'Gene', (35, 38))	('miR', 'Gene', (142, 145))	('cyclin D1', 'Gene', '595', (73, 82))	('miR', 'Gene', '22877', (35, 38))
7898	23383271	Furthermore, anti-miR-9 inhibitor promoted the proliferation, migration and invasion of gastric cancer cells, while knocking down of cyclin D1 or Ets1 partially phenocopied the effects of miR-9 over-expression.	('migration', 'CPA', (62, 71))	('miR', 'Gene', '22877', (18, 21))	('miR', 'Gene', (188, 191))	('gastric cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cyclin D1', 'Gene', '595', (133, 142))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('Ets1', 'Gene', '2113', (146, 150))	('cyclin D1', 'Gene', (133, 142))	('Ets1', 'Gene', (146, 150))	('miR', 'Gene', (18, 21))	('promoted', 'PosReg', (34, 42))	('knocking down', 'Var', (116, 129))	('miR', 'Gene', '22877', (188, 191))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('proliferation', 'CPA', (47, 60))	('cyclin', 'molecular_function', 'GO:0016538', ('133', '139'))	('invasion', 'CPA', (76, 84))
7912	23383271	A series of subsequent studies have shown that altered miR-9 expression is associated with the development and progression of cancers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('miR', 'Gene', (55, 58))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('progression', 'CPA', (111, 122))	('associated', 'Reg', (75, 85))	('miR', 'Gene', '22877', (55, 58))	('expression', 'MPA', (61, 71))	('altered', 'Var', (47, 54))
7931	23383271	Potential binding sites of miR-9 with high complementarity were noted at bases 2974-2995 of the cyclin D1 3'-UTR and 2648-2670 of the Ets1 3'-UTR (Fig.	('cyclin D1', 'Gene', (96, 105))	('Ets1', 'Gene', '2113', (134, 138))	('Ets1', 'Gene', (134, 138))	('binding', 'Interaction', (10, 17))	('miR', 'Gene', '22877', (27, 30))	('cyclin', 'molecular_function', 'GO:0016538', ('96', '102'))	('miR', 'Gene', (27, 30))	('binding', 'molecular_function', 'GO:0005488', ('10', '17'))	('cyclin D1', 'Gene', '595', (96, 105))	('2648-2670', 'Var', (117, 126))
7941	23383271	To determine whether miR-9 could repress the expression of cyclin D1 and Ets1 by targeting its binding sites in the 3'-UTR, the PCR products containing intact target sites or mutation of miR-9 seed recognition sequences (Fig.	('miR', 'Gene', '22877', (187, 190))	('mutation', 'Var', (175, 183))	('Ets1', 'Gene', '2113', (73, 77))	('cyclin', 'molecular_function', 'GO:0016538', ('59', '65'))	('miR', 'Gene', (21, 24))	('Ets1', 'Gene', (73, 77))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('cyclin D1', 'Gene', '595', (59, 68))	('miR', 'Gene', (187, 190))	('cyclin D1', 'Gene', (59, 68))	('miR', 'Gene', '22877', (21, 24))
7944	23383271	3B), and these effects were abolished by mutating the putative miR-9 binding sites within the 3'-UTR of cyclin D1 and Ets1 (Fig.	('cyclin D1', 'Gene', '595', (104, 113))	('cyclin D1', 'Gene', (104, 113))	('binding', 'molecular_function', 'GO:0005488', ('69', '76'))	('binding', 'Interaction', (69, 76))	('miR', 'Gene', (63, 66))	('cyclin', 'molecular_function', 'GO:0016538', ('104', '110'))	('Ets1', 'Gene', '2113', (118, 122))	('miR', 'Gene', '22877', (63, 66))	('mutating', 'Var', (41, 49))	('Ets1', 'Gene', (118, 122))
7945	23383271	Moreover, knockdown of miR-9 with anti-miR-9 inhibitor increased the luciferase activities in GES-1, SGC-7901 and AGS cells (Fig.	('miR', 'Gene', (39, 42))	('miR', 'Gene', (23, 26))	('increased', 'PosReg', (55, 64))	('activities', 'MPA', (80, 90))	('miR', 'Gene', '22877', (23, 26))	('SGC-7901', 'CellLine', 'CVCL:0520', (101, 109))	('miR', 'Gene', '22877', (39, 42))	('knockdown', 'Var', (10, 19))	('luciferase', 'Enzyme', (69, 79))
7946	23383271	S4C), while mutation of miR-9 recognition site abolished these effects (Fig.	('mutation', 'Var', (12, 20))	('miR', 'Gene', '22877', (24, 27))	('miR', 'Gene', (24, 27))
7953	23383271	On the other hand, we examined the effects of miR-9 knockdown on GES-1, SGC-7901 and AGS cells.	('miR', 'Gene', (46, 49))	('SGC-7901', 'CellLine', 'CVCL:0520', (72, 80))	('knockdown', 'Var', (52, 61))	('miR', 'Gene', '22877', (46, 49))
7960	23383271	In addition, transfection of Ets1, but not of cyclin D1, into SGC-7901 and AGS cell lines restored the miR-9-meditaed inhibition on the migration and invasion (Fig.	('cyclin D1', 'Gene', '595', (46, 55))	('miR', 'Gene', '22877', (103, 106))	('SGC-7901', 'CellLine', 'CVCL:0520', (62, 70))	('transfection', 'Var', (13, 25))	('cyclin D1', 'Gene', (46, 55))	('miR', 'Gene', (103, 106))	('cyclin', 'molecular_function', 'GO:0016538', ('46', '52'))	('Ets1', 'Gene', '2113', (29, 33))	('Ets1', 'Gene', (29, 33))
7961	23383271	Furthermore, we examined the effects of miR-9 knockdown on GES-1, SGC-7901 and AGS cells.	('SGC-7901', 'CellLine', 'CVCL:0520', (66, 74))	('miR', 'Gene', '22877', (40, 43))	('miR', 'Gene', (40, 43))	('knockdown', 'Var', (46, 55))
7970	23383271	Since above results indicated the negative regulation of cyclin D1 and Ets1 expression by miR-9, we hypothesized that knockdown of cyclin D1 and Ets1 might exert similar effects on cultured gastric cancer cells.	('knockdown', 'Var', (118, 127))	('cyclin D1', 'Gene', (57, 66))	('Ets1', 'Gene', '2113', (145, 149))	('Ets1', 'Gene', (145, 149))	('gastric cancer', 'Disease', 'MESH:D013274', (190, 204))	('cyclin', 'molecular_function', 'GO:0016538', ('131', '137'))	('cyclin D1', 'Gene', '595', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('Ets1', 'Gene', '2113', (71, 75))	('miR', 'Gene', (90, 93))	('Ets1', 'Gene', (71, 75))	('regulation', 'biological_process', 'GO:0065007', ('43', '53'))	('negative', 'NegReg', (34, 42))	('gastric cancer', 'Phenotype', 'HP:0012126', (190, 204))	('miR', 'Gene', '22877', (90, 93))	('cyclin D1', 'Gene', (131, 140))	('cyclin', 'molecular_function', 'GO:0016538', ('57', '63'))	('gastric cancer', 'Disease', (190, 204))	('cyclin D1', 'Gene', '595', (131, 140))
7974	23383271	In addition, knockdown of Ets1 in SGC-7901 and AGS cells resulted in decreased capabilities of migration and invasion (Fig.	('Ets1', 'Gene', (26, 30))	('decreased', 'NegReg', (69, 78))	('knockdown', 'Var', (13, 22))	('SGC-7901', 'CellLine', 'CVCL:0520', (34, 42))	('Ets1', 'Gene', '2113', (26, 30))
7986	23383271	Similarly, aberrant hypermethylation of miR-9 family genes is also reported in some primary tumors with lymph node metastasis, such as colon cancer, lung cancer, breast cancer, and melanoma.	('colon cancer', 'Disease', (135, 147))	('miR', 'Gene', '22877', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('lung cancer', 'Disease', (149, 160))	('reported', 'Reg', (67, 75))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('melanoma', 'Disease', (181, 189))	('colon cancer', 'Phenotype', 'HP:0003003', (135, 147))	('aberrant hypermethylation', 'Var', (11, 36))	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('primary tumors', 'Disease', (84, 98))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Disease', (162, 175))	('colon cancer', 'Disease', 'MESH:D015179', (135, 147))	('miR', 'Gene', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('primary tumors', 'Disease', 'MESH:D009369', (84, 98))	('melanoma', 'Disease', 'MESH:D008545', (181, 189))
7994	23383271	indicated that miR-9 might be involved in gastric carcinogenesis through down-regulating CDX2, and knockdown of miR-9 decreased the in vitro proliferation of gastric cancer MKN-45 cells, while their findings need be further strengthened with miR-9 over-expression, target gene rescue, and in vivo studies.	('CDX2', 'Gene', '1045', (89, 93))	('down-regulating', 'NegReg', (73, 88))	('involved', 'Reg', (30, 38))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (42, 64))	('miR', 'Gene', '22877', (242, 245))	('miR', 'Gene', (112, 115))	('miR', 'Gene', '22877', (15, 18))	('miR', 'Gene', '22877', (112, 115))	('CDX2', 'Gene', (89, 93))	('knockdown', 'Var', (99, 108))	('gastric cancer', 'Disease', (158, 172))	('decreased', 'NegReg', (118, 127))	('gastric cancer', 'Disease', 'MESH:D013274', (158, 172))	('gastric cancer', 'Phenotype', 'HP:0012126', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('gastric carcinogenesis', 'Disease', (42, 64))	('miR', 'Gene', (242, 245))	('miR', 'Gene', (15, 18))
8012	23383271	Knockdown of Ets1 partially phenocopied the effects of miR-9 over-expression in gastric cancer cell lines, while restoration of Ets1 expression rescued the cancer cells from miR-9-mediated inhibition on the migration and invasion, revealing a novel post-transcriptional regulation mechanism of Ets1 by miR-9 and its clinical potentials in gastric cancer.	('gastric cancer', 'Disease', (80, 94))	('cancer', 'Disease', (88, 94))	('gastric cancer', 'Phenotype', 'HP:0012126', (339, 353))	('migration', 'CPA', (207, 216))	('Ets1', 'Gene', '2113', (128, 132))	('regulation', 'biological_process', 'GO:0065007', ('270', '280'))	('miR', 'Gene', '22877', (174, 177))	('Ets1', 'Gene', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Ets1', 'Gene', '2113', (294, 298))	('miR', 'Gene', '22877', (55, 58))	('Ets1', 'Gene', (294, 298))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('miR', 'Gene', '22877', (302, 305))	('gastric cancer', 'Disease', (339, 353))	('cancer', 'Disease', (347, 353))	('restoration', 'Var', (113, 124))	('Ets1', 'Gene', '2113', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('Ets1', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('gastric cancer', 'Disease', 'MESH:D013274', (339, 353))	('invasion', 'CPA', (221, 229))	('cancer', 'Disease', (156, 162))	('miR', 'Gene', (174, 177))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('miR', 'Gene', (55, 58))	('cancer', 'Disease', 'MESH:D009369', (347, 353))	('miR', 'Gene', (302, 305))	('over-expression', 'PosReg', (61, 76))
8042	23383271	Their mutant constructs with a mutation of the miR-9 seed sequence were generated with the mutagenic oligonucleotide primers (Table S3), according to the manual of GeneTailor Site-Directed Mutagenesis System (Invitrogen).	('Mutagenesis', 'biological_process', 'GO:0006280', ('189', '200'))	('miR', 'Gene', (47, 50))	('mutation', 'Var', (31, 39))	('miR', 'Gene', '22877', (47, 50))
8076	21318155	Chromosomal trisomies are commonly detected in gastrointestinal marginal zone lymphomas but are nonspecific.	('gastrointestinal marginal zone lymphomas', 'Disease', (47, 87))	('detected', 'Reg', (35, 43))	('lymphoma', 'Phenotype', 'HP:0002665', (78, 86))	('Chromosomal trisomies', 'Var', (0, 21))	('gastrointestinal marginal zone lymphomas', 'Disease', 'MESH:D018442', (47, 87))	('lymphomas', 'Phenotype', 'HP:0002665', (78, 87))
8077	21318155	Trisomy 3q27 is the most common chromosomal abnormality in gastrointestinal lymphomas.	('common', 'Reg', (25, 31))	('gastrointestinal lymphomas', 'Disease', 'MESH:D005767', (59, 85))	('lymphoma', 'Phenotype', 'HP:0002665', (76, 84))	('abnormality in gastrointestinal', 'Phenotype', 'HP:0011024', (44, 75))	('Trisomy 3q27', 'Var', (0, 12))	('lymphomas', 'Phenotype', 'HP:0002665', (76, 85))	('gastrointestinal lymphomas', 'Disease', (59, 85))	('chromosomal abnormality in gastrointestinal lymphomas', 'Disease', 'MESH:D005767', (32, 85))
8079	21318155	Trisomy 18 can be seen independently or in association with trisomy 3 and has also been correlated with more aggressive disease, especially in gastrointestinal lymphomas classified as diffuse large B-cell lymphoma.	('correlated with', 'Reg', (88, 103))	('lymphoma', 'Phenotype', 'HP:0002665', (205, 213))	('aggressive disease', 'Disease', 'MESH:D001523', (109, 127))	('lymphoma', 'Phenotype', 'HP:0002665', (160, 168))	('diffuse large B-cell lymphoma', 'Disease', (184, 213))	('aggressive disease', 'Disease', (109, 127))	('more', 'Disease', (104, 108))	('lymphomas', 'Phenotype', 'HP:0002665', (160, 169))	('gastrointestinal lymphomas', 'Disease', (143, 169))	('Trisomy 18', 'Var', (0, 10))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (198, 213))
8090	21318155	Several cytogenetic abnormalities, including chromosomal translocations and trisomies, have been described in MALT lymphoma, and two translocations [t(11;18)(q21;q21) and t(1;14)(p22;q32)] are associated with resistance to conservative treatment.	('lymphoma', 'Phenotype', 'HP:0002665', (115, 123))	('t(1;14)(p22;q32)]', 'Var', (171, 188))	('t(11;18)(q21;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (149, 166))	('t(1;14)(p22;q32)', 'STRUCTURAL_ABNORMALITY', 'None', (171, 187))	('MALT lymphoma', 'Disease', (110, 123))	('associated', 'Reg', (193, 203))
8100	20670946	Anti-FGFR2 mAbs GAL-FR21 and GAL-FR22 have potential for the treatment of gastric and other tumors.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('GAL-FR22', 'Var', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('GAL-FR21', 'Var', (16, 24))	('FGFR', 'molecular_function', 'GO:0005007', ('5', '9'))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('Anti-FGFR2', 'Gene', (0, 10))	('tumors', 'Disease', (92, 98))	('gastric', 'Disease', 'MESH:D013274', (74, 81))	('gastric', 'Disease', (74, 81))
8110	20670946	Thus, FGF3 and FGF7 are expressed in mesenchymal tissues so may be paracrine effectors of epithelial cells expressing FGFR2IIIb, while the FGF4 subfamily members FGF4-6 bind to FGFR2IIIc and are expressed in both epithelial and mesenchymal lineages so may have either autocrine or paracrine functions.	('FGF4', 'Gene', '2249', (162, 166))	('FGF4-6', 'Gene', '2249;2250;2251', (162, 168))	('FGF3', 'Gene', '2248', (6, 10))	('FGF7', 'Gene', '2252', (15, 19))	('FGFR', 'molecular_function', 'GO:0005007', ('118', '122'))	('FGF7', 'Gene', (15, 19))	('FGFR2IIIb', 'Var', (118, 127))	('FGF4-6', 'Gene', (162, 168))	('FGF4', 'Gene', '2249', (139, 143))	('FGF4', 'Gene', (162, 166))	('FGFR', 'molecular_function', 'GO:0005007', ('177', '181'))	('FGF3', 'Gene', (6, 10))	('FGF4', 'Gene', (139, 143))
8111	20670946	Because of the expression patterns of the isoforms of FGFR2 and their ligands, FGFR2 plays a role in epithelial-mesenchymal interactions, so it is not surprising that knock-out of FGFR2IIIb in mice leads to embryonic defects and lethality.	('FGFR2', 'Gene', (79, 84))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('FGFR2IIIb', 'Gene', (180, 189))	('knock-out', 'Var', (167, 176))	('lethality', 'CPA', (229, 238))	('FGFR', 'molecular_function', 'GO:0005007', ('180', '184'))	('mice', 'Species', '10090', (193, 197))	('FGFR2', 'Gene', (54, 59))	('FGFR', 'molecular_function', 'GO:0005007', ('54', '58'))	('embryonic defects', 'Disease', (207, 224))	('embryonic defects', 'Disease', 'MESH:D009373', (207, 224))
8116	20670946	One of the most common mutations found, a Ser-252   Trp substitution, is known to also be associated with the congenital skeletal disorder Apert syndrome and increases ligand binding and receptor activation.	('congenital skeletal disorder Apert syndrome', 'Disease', (110, 153))	('Ser-252   Trp', 'Var', (42, 55))	('receptor', 'Interaction', (187, 195))	('associated', 'Reg', (90, 100))	('Ser-252   Trp', 'Mutation', 'rs79184941', (42, 55))	('congenital skeletal disorder Apert syndrome', 'Disease', 'MESH:D000168', (110, 153))	('ligand', 'molecular_function', 'GO:0005488', ('168', '174'))	('activation', 'PosReg', (196, 206))	('binding', 'molecular_function', 'GO:0005488', ('175', '182'))	('Ser', 'cellular_component', 'GO:0005790', ('42', '45'))	('increases', 'PosReg', (158, 167))	('skeletal disorder', 'Phenotype', 'HP:0000924', (121, 138))	('ligand binding', 'Interaction', (168, 182))
8119	20670946	Of particular interest, amplification and overexpression of FGFR2 is strongly associated with the poorly differentiated, diffuse type of gastric cancer, which has an especially unfavorable prognosis.	('associated', 'Reg', (78, 88))	('poorly differentiated', 'Disease', (98, 119))	('FGFR', 'molecular_function', 'GO:0005007', ('60', '64'))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('gastric cancer', 'Disease', (137, 151))	('amplification', 'Var', (24, 37))	('overexpression', 'PosReg', (42, 56))	('FGFR2', 'Gene', (60, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (137, 151))	('gastric cancer', 'Phenotype', 'HP:0012126', (137, 151))
8120	20670946	The association of FGFR2 overexpression or mutation with many types of cancer suggests that FGFR2 may be an excellent therapeutic target.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('association', 'Interaction', (4, 15))	('cancer', 'Disease', (71, 77))	('mutation', 'Var', (43, 51))	('FGFR2', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('overexpression', 'PosReg', (25, 39))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))
8126	20670946	The alpha isoform (D1, D2 and D3 domains) and beta isoform (D2 and D3 domains) of human FGFR2IIIb and FGFR2IIIc were expressed as immunoadhesin molecules by respectively fusing the extracellular domain residues 1-378 (alpha isoform) and 152-378 (beta isoform) of FGFR2IIIb or 1-377 (alpha isoform) and 152-377 (beta isoform) of FGFR2IIIc to the human Ig Fc region (residues 216 to 446) in the pDisplay vector (Invitrogen).	('FGFR', 'molecular_function', 'GO:0005007', ('328', '332'))	('152-377', 'Var', (302, 309))	('FGFR', 'molecular_function', 'GO:0005007', ('102', '106'))	('1-377', 'Var', (276, 281))	('FGFR2IIIc', 'Gene', (328, 337))	('FGFR', 'molecular_function', 'GO:0005007', ('263', '267'))	('human', 'Species', '9606', (345, 350))	('FGFR', 'molecular_function', 'GO:0005007', ('88', '92'))	('extracellular', 'cellular_component', 'GO:0005576', ('181', '194'))	('human', 'Species', '9606', (82, 87))
8128	20670946	Fc fusion proteins of the other FGFRs as well as FGFR2IIIb(S252W)-Fc with the S252W mutation were similarly generated and produced.	('FGF', 'Gene', (32, 35))	('FGF', 'Gene', '2246;2247;2248;2249;2250;2251;2252;14178;2255', (49, 52))	('S252W', 'Mutation', 'rs79184941', (59, 64))	('S252W', 'Var', (78, 83))	('FGF', 'Gene', '2246;2247;2248;2249;2250;2251;2252;14178;2255', (32, 35))	('FGF', 'Gene', (49, 52))	('FGFR', 'molecular_function', 'GO:0005007', ('49', '53'))	('S252W', 'Mutation', 'rs79184941', (78, 83))
8130	20670946	Female 6-week old Balb/c mice (Charles River Laboratories) were immunized with human FGFR2IIIb-Fc or FGFR2IIIc-Fc in monophosphoryl lipid A/ trehalose dicorynomycolate (MPL/TDM, Sigma) in their rear footpads about 20 times, once per week.	('FGFR2IIIc-Fc', 'Var', (101, 113))	('trehalose dicorynomycolate', 'Chemical', 'MESH:C043399', (141, 167))	('human', 'Species', '9606', (79, 84))	('mice', 'Species', '10090', (25, 29))	('FGFR2IIIb-Fc', 'Var', (85, 97))	('FGFR', 'molecular_function', 'GO:0005007', ('85', '89'))	('MPL', 'Gene', '4352', (169, 172))	('FGFR', 'molecular_function', 'GO:0005007', ('101', '105'))	('lipid A', 'Chemical', 'MESH:D008050', (132, 139))	('MPL', 'Gene', (169, 172))	('monophosphoryl', 'Chemical', '-', (117, 131))
8136	20670946	The plates were then incubated with the alpha and beta isoforms of FGFR2IIIb-Fc and FGFR2IIIc-Fc or control human IgG, followed by incubation with various concentrations of mAbs.	('FGFR2IIIb-Fc', 'Var', (67, 79))	('FGFR', 'molecular_function', 'GO:0005007', ('67', '71'))	('IgG', 'Gene', '16059', (114, 117))	('IgG', 'Gene', (114, 117))	('human', 'Species', '9606', (108, 113))	('FGFR', 'molecular_function', 'GO:0005007', ('84', '88'))
8150	20670946	The FGFR2IIIb band was detected by incubation with 0.2 mug/ml of GAL-FR21 mAb, followed by HRP-goat anti-mouse IgG.	('GAL-FR21', 'Var', (65, 73))	('IgG', 'Gene', '16059', (111, 114))	('FGFR', 'molecular_function', 'GO:0005007', ('4', '8'))	('goat', 'Species', '9925', (95, 99))	('mug', 'molecular_function', 'GO:0043739', ('55', '58'))	('IgG', 'Gene', (111, 114))	('FGFR2IIIb', 'Gene', (4, 13))	('mouse', 'Species', '10090', (105, 110))
8154	20670946	After screening several thousand hybridomas from 5 fusions in an FGFR2IIIb-Fc binding ELISA followed by flow cytometry on SNU-16 cells, we selected three mAbs (GAL-FR21, GAL-FR22 and GAL-FR23) for further analysis.	('SNU-16', 'CellLine', 'CVCL:0076', (122, 128))	('GAL-FR23', 'Var', (183, 191))	('FGFR', 'molecular_function', 'GO:0005007', ('65', '69'))	('GAL-FR22', 'Var', (170, 178))	('GAL-FR21', 'Var', (160, 168))	('binding', 'molecular_function', 'GO:0005488', ('78', '85'))
8155	20670946	GAL-FR21 is of the IgG1 isotype while GAL-FR22 and GAL-FR23 are of the IgG2b isotype.	('IgG2b', 'cellular_component', 'GO:0071735', ('71', '76'))	('IgG1', 'cellular_component', 'GO:0071735', ('19', '23'))	('IgG', 'Gene', '16059', (71, 74))	('IgG', 'Gene', '16059', (19, 22))	('IgG', 'Gene', (71, 74))	('IgG', 'Gene', (19, 22))	('GAL-FR21', 'Var', (0, 8))
8156	20670946	While the binding affinities of the mAbs have not been determined precisely by BioCore or similar methods, the low EC50s for binding in the ELISA (approximately 20 pM, 5 pM and 10 pM for GAL-FR21, GAL-FR22 and GAL-FR23 respectively) suggest the affinities are very high.	('50s', 'Species', '1214577', (117, 120))	('GAL-FR21', 'Var', (187, 195))	('GAL-FR22', 'Var', (197, 205))	('binding', 'Interaction', (125, 132))	('binding', 'molecular_function', 'GO:0005488', ('125', '132'))	('binding', 'molecular_function', 'GO:0005488', ('10', '17'))	('GAL-FR23', 'Var', (210, 218))
8162	20670946	Finally, when FGFR2IIIb containing the S252W mutation associated with Apert syndrome and certain tumors was expressed on 293F cells by transfection, all the mAbs bound the mutant FGFR2IIIb as well as normal FGFR2IIIb (Fig.	('mutant', 'Var', (172, 178))	('Apert syndrome', 'Disease', 'MESH:D000168', (70, 84))	('Apert syndrome', 'Disease', (70, 84))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('FGFR', 'molecular_function', 'GO:0005007', ('14', '18'))	('S252W', 'Var', (39, 44))	('bound', 'Interaction', (162, 167))	('FGFR', 'molecular_function', 'GO:0005007', ('179', '183'))	('293F', 'CellLine', 'CVCL:6642', (121, 125))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('FGFR', 'molecular_function', 'GO:0005007', ('207', '211'))	('FGFR2IIIb', 'Gene', (179, 188))	('S252W', 'Mutation', 'rs79184941', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('associated', 'Reg', (54, 64))
8163	20670946	In order to help interpret the results of the xenograft experiments described below, we determined the ability of GAL-FR21 and GAL-FR22 to bind to mouse FGFR2IIIb.	('mouse', 'Species', '10090', (147, 152))	('FGFR', 'molecular_function', 'GO:0005007', ('153', '157'))	('FGFR2IIIb', 'Gene', (153, 162))	('bind', 'Interaction', (139, 143))	('GAL-FR22', 'Var', (127, 135))
8175	20670946	In this experiment, SNU-16 cells were serum starved overnight and treated with 10 mug/ml of mAb for 30 min, followed by the addition of FGF2 (100 ng/ml) or FGF7 (10 ng/ml) in the presence of heparin for 10 min.	('FGF2', 'Gene', (136, 140))	('FGF7', 'Gene', '2252', (156, 160))	('heparin', 'Chemical', 'MESH:D006493', (191, 198))	('mug', 'molecular_function', 'GO:0043739', ('82', '85'))	('FGF7', 'Gene', (156, 160))	('SNU-16', 'CellLine', 'CVCL:0076', (20, 26))	('100 ng/ml', 'Var', (142, 151))	('FGF2', 'Gene', '2247', (136, 140))
8181	20670946	However, both GAL-FR21 and GAL-FR22 significantly inhibited FGF2-induced phosphorylation of FGFR2IIIb (Fig.	('FGF2', 'Gene', (60, 64))	('FGFR2IIIb', 'Gene', (92, 101))	('FGFR', 'molecular_function', 'GO:0005007', ('92', '96'))	('FGF2', 'Gene', '2247', (60, 64))	('phosphorylation', 'MPA', (73, 88))	('phosphorylation', 'biological_process', 'GO:0016310', ('73', '88'))	('GAL-FR22', 'Var', (27, 35))	('inhibited', 'NegReg', (50, 59))
8188	20670946	The GAL-FR21 and GAL-FR22 mAbs inhibited growth of the SNU-16 xenografts essentially completely at a dose level of 1 mg/kg and in some cases tumor regression was observed (Fig.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('GAL-FR21', 'Var', (4, 12))	('growth of the SNU-16 xenografts', 'CPA', (41, 72))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('SNU-16', 'CellLine', 'CVCL:0076', (55, 61))	('GAL-FR22', 'Var', (17, 25))	('inhibited', 'NegReg', (31, 40))
8189	20670946	6A; p = 0.0014 for GAL-FR21 vs mIgG and p = 0.0005 for GAL-FR22 vs mIgG).	('GAL-FR22', 'Var', (55, 63))	('IgG', 'Gene', '16059', (32, 35))	('GAL-FR21', 'Var', (19, 27))	('IgG', 'Gene', (32, 35))	('IgG', 'Gene', '16059', (68, 71))	('IgG', 'Gene', (68, 71))
8190	20670946	6C; p = 0.003 for GAL-FR21 or GAL-FR22 vs mIgG).	('GAL-FR21', 'Var', (18, 26))	('IgG', 'Gene', '16059', (43, 46))	('GAL-FR22', 'Var', (30, 38))	('IgG', 'Gene', (43, 46))
8210	20670946	The small molecule FGFR2 inhibitor PD173074 potently inhibited this phosphorylation and the growth of the SNU-16, OCUM-2M and KATO-III cell lines in vitro and induced apoptosis of SNU-16 and OCUM-2M cells.	('inhibited', 'NegReg', (53, 62))	('phosphorylation', 'MPA', (68, 83))	('apoptosis', 'CPA', (167, 176))	('SNU-16', 'CellLine', 'CVCL:0076', (106, 112))	('PD173074', 'Chemical', 'MESH:C115711', (35, 43))	('FGFR2', 'Gene', (19, 24))	('apoptosis', 'biological_process', 'GO:0097194', ('167', '176'))	('growth', 'CPA', (92, 98))	('PD173074', 'Var', (35, 43))	('SNU-16', 'CellLine', 'CVCL:0076', (180, 186))	('apoptosis', 'biological_process', 'GO:0006915', ('167', '176'))	('phosphorylation', 'biological_process', 'GO:0016310', ('68', '83'))	('induced', 'Reg', (159, 166))	('FGFR', 'molecular_function', 'GO:0005007', ('19', '23'))
8211	20670946	Similarly, the small molecule FGFR2 inhibitor Ki23057 suppressed proliferation of the scirrhous gastric carcinoma cell lines OCUM-2MD3 and OCUM-8 overexpressing FGFR2, but not proliferation of three nonscirrhous gastric cancer lines, and strongly inhibited growth of OCUM-2MD3 xenografts in mice.	('growth', 'CPA', (257, 263))	('Ki23057', 'Chemical', 'MESH:C515425', (46, 53))	('gastric cancer', 'Phenotype', 'HP:0012126', (212, 226))	('inhibitor Ki23057', 'Var', (36, 53))	('FGFR', 'molecular_function', 'GO:0005007', ('161', '165'))	('nonscirrhous gastric cancer', 'Disease', 'MESH:D013274', (199, 226))	('FGFR2', 'Gene', (161, 166))	('scirrhous gastric carcinoma', 'Disease', 'MESH:D002293', (86, 113))	('FGFR', 'molecular_function', 'GO:0005007', ('30', '34'))	('mice', 'Species', '10090', (291, 295))	('nonscirrhous gastric cancer', 'Disease', (199, 226))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (96, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('suppressed', 'NegReg', (54, 64))	('scirrhous gastric carcinoma', 'Disease', (86, 113))	('inhibited', 'NegReg', (247, 256))	('proliferation', 'CPA', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('FGFR2', 'Gene', (30, 35))	('Ki23057', 'Var', (46, 53))
8215	20670946	Importantly, the ability of the GAL-FR21 and GAL-FR22 mAbs, which are highly specific for FGFR2, to almost completely inhibit the growth of SNU-16 and OCUM-2M xenografts provides decisive additional evidence for the causative role of FGFR2.	('inhibit', 'NegReg', (118, 125))	('FGFR2', 'Gene', (90, 95))	('SNU-16', 'CellLine', 'CVCL:0076', (140, 146))	('GAL-FR21', 'Var', (32, 40))	('growth', 'CPA', (130, 136))	('FGFR', 'molecular_function', 'GO:0005007', ('90', '94'))	('FGFR', 'molecular_function', 'GO:0005007', ('234', '238'))	('GAL-FR22', 'Var', (45, 53))
8218	20670946	For example, the L2G7 mAb to hepatocyte growth factor strongly inhibits growth of xenografts from several tumor cell lines against which it has little direct effect in vitro (our unpublished data).	('hepatocyte growth factor', 'Gene', '3082', (29, 53))	('inhibits', 'NegReg', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('L2G7', 'Var', (17, 21))	('hepatocyte growth factor', 'Gene', (29, 53))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('29', '53'))	('tumor', 'Disease', (106, 111))
8221	20670946	ADCC is unlikely to be an important factor because GAL-FR21, which is of the IgG1 isotype that mediates ADCC poorly, inhibits tumor growth as well as GAL-FR22, which is of the IgG2b isotype known to mediate ADCC well.	('ADCC', 'biological_process', 'GO:0001788', ('207', '211'))	('GAL-FR21', 'Var', (51, 59))	('inhibits', 'NegReg', (117, 125))	('IgG', 'Gene', '16059', (176, 179))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('IgG', 'Gene', '16059', (77, 80))	('IgG2b', 'cellular_component', 'GO:0071735', ('176', '181'))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('ADCC', 'biological_process', 'GO:0001788', ('0', '4'))	('ADCC', 'biological_process', 'GO:0001788', ('104', '108'))	('GAL-FR22', 'Var', (150, 158))	('IgG', 'Gene', (176, 179))	('IgG', 'Gene', (77, 80))	('IgG1', 'cellular_component', 'GO:0071735', ('77', '81'))	('tumor', 'Disease', (126, 131))
8224	20670946	In addition, although tested in different xenograft models, the anti-tumor effects of GAL-FR21 and GAL-FR22 are stronger than those generally seen with the murine precursor antibody of bevacizumab, an anti-angiogenic mAb that inhibits VEGF.	('antibody', 'cellular_component', 'GO:0019814', ('173', '181'))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('antibody', 'molecular_function', 'GO:0003823', ('173', '181'))	('stronger', 'PosReg', (112, 120))	('antibody', 'cellular_component', 'GO:0019815', ('173', '181'))	('murine', 'Species', '10090', (156, 162))	('tumor', 'Disease', (69, 74))	('GAL-FR21', 'Var', (86, 94))	('VEGF', 'Gene', (235, 239))	('antibody', 'cellular_component', 'GO:0042571', ('173', '181'))	('VEGF', 'Gene', '7422', (235, 239))	('bevacizumab', 'Chemical', 'MESH:D000068258', (185, 196))	('GAL-FR22', 'Var', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
8231	20670946	While small-molecule antagonists of FGFR2 have previously been shown to inhibit certain tumors, especially gastric tumors overexpressing FGFR2, the lack of specificity of the inhibitors made it difficult to draw definitive conclusions regarding the role of FGFR2.	('gastric tumors', 'Disease', (107, 121))	('small-molecule', 'Var', (6, 20))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('FGFR', 'molecular_function', 'GO:0005007', ('257', '261'))	('FGFR2', 'Gene', (36, 41))	('FGFR', 'molecular_function', 'GO:0005007', ('137', '141'))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('antagonists', 'Var', (21, 32))	('FGFR', 'molecular_function', 'GO:0005007', ('36', '40'))	('FGFR2', 'Gene', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('gastric tumors', 'Disease', 'MESH:D013274', (107, 121))	('tumors', 'Disease', (115, 121))	('overexpressing', 'PosReg', (122, 136))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('gastric tumors', 'Phenotype', 'HP:0006753', (107, 121))	('gastric tumor', 'Phenotype', 'HP:0006753', (107, 120))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('inhibit', 'NegReg', (72, 79))	('tumors', 'Disease', (88, 94))
8233	20670946	In addition, after humanization to reduce immunogenicity, one of the anti-FGFR2 antibodies will itself be a viable clinical candidate for the treatment of gastric and possibly other cancers.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('anti-FGFR2', 'Var', (69, 79))	('gastric', 'Disease', 'MESH:D013274', (155, 162))	('gastric', 'Disease', (155, 162))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('cancers', 'Disease', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('human', 'Species', '9606', (19, 24))	('FGFR', 'molecular_function', 'GO:0005007', ('74', '78'))
8235	20670946	The ability of the GAL-FR21 and GAL-FR22 mAbs to inhibit growth of xenografts from two gastric tumor cell lines without apparent toxicity suggests that it will be worthwhile to humanize one of these mAbs, and then test the humanized mAb in clinical trials for the treatment of the poorly differentiated form of gastric carcinoma and potentially other types of cancer.	('toxicity', 'Disease', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (360, 366))	('gastric carcinoma', 'Disease', 'MESH:D013274', (311, 328))	('gastric carcinoma', 'Disease', (311, 328))	('GAL-FR22', 'Var', (32, 40))	('growth', 'CPA', (57, 63))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (311, 328))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('human', 'Species', '9606', (177, 182))	('gastric tumor', 'Disease', (87, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('gastric tumor', 'Disease', 'MESH:D013274', (87, 100))	('gastric tumor', 'Phenotype', 'HP:0006753', (87, 100))	('human', 'Species', '9606', (223, 228))	('cancer', 'Disease', 'MESH:D009369', (360, 366))	('toxicity', 'Disease', 'MESH:D064420', (129, 137))	('cancer', 'Disease', (360, 366))	('GAL-FR21', 'Var', (19, 27))	('inhibit', 'NegReg', (49, 56))
8238	33824332	Concordantly, Vangl2 inhibition causes fewer and shorter cytonemes to be formed and reduces paracrine Wnt/beta-catenin signaling.	('paracrine Wnt/beta-catenin signaling', 'MPA', (92, 128))	('ntl', 'Gene', (8, 11))	('cytonemes', 'CPA', (57, 66))	('shorter', 'NegReg', (49, 56))	('ntl', 'Gene', '30399', (8, 11))	('inhibition', 'Var', (21, 31))	('reduces', 'NegReg', (84, 91))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))	('Vangl2', 'Gene', (14, 20))
8251	33824332	Subsequently, CK1delta/epsilon activates Vangl2 by phosphorylation, similarly CK1 phosphorylates Vangl2/strabismus in Drosophila.	('Drosophila', 'Species', '7227', (118, 128))	('activates', 'PosReg', (31, 40))	('strabismus', 'Phenotype', 'HP:0000486', (104, 114))	('CK1', 'Species', '2498238', (78, 81))	('phosphorylation', 'biological_process', 'GO:0016310', ('51', '66'))	('CK1delta/epsilon', 'Var', (14, 30))	('ntl', 'Gene', (8, 11))	('ntl', 'Gene', '30399', (8, 11))	('CK1', 'Species', '2498238', (14, 17))	('phosphorylation', 'MPA', (51, 66))	('Vangl2', 'Gene', (41, 47))
8273	33824332	We find that in the presence of over-expressed untagged Vangl2, Ror2-mCherry accumulated more strongly at the cytoneme tip (Fig.	('cytoneme', 'cellular_component', 'GO:0035230', ('110', '118'))	('strongly', 'PosReg', (94, 102))	('untagged', 'Var', (47, 55))	('accumulated', 'PosReg', (77, 88))	('over-expressed untagged', 'Var', (32, 55))	('mCh', 'Gene', (69, 72))	('mCh', 'Gene', '104242', (69, 72))	('Vangl2', 'Gene', (56, 62))
8278	33824332	Activation of Vangl2 caused the average cytoneme length to increase significantly by 187.3% (Fig.	('cytoneme length', 'CPA', (40, 55))	('cytoneme', 'cellular_component', 'GO:0035230', ('40', '48'))	('ntl', 'Gene', '30399', (77, 80))	('Activation', 'Var', (0, 10))	('ntl', 'Gene', (77, 80))	('Vangl2', 'Gene', (14, 20))	('increase', 'PosReg', (59, 67))
8279	33824332	So we used an N-terminal deletion mutant of Vangl2 (DeltaN-Vangl2) lacking the two Ser/Thr phosphorylation clusters and the all-phospho Vangl2 mutant S5-17A::S76-84A, in which 10 Ser/Thr are replaced by Ala (Vangl210A) to block Vangl2-mediated signaling.	('Ala', 'Chemical', 'MESH:D000409', (203, 206))	('Ser', 'Chemical', 'MESH:D012694', (179, 182))	('10 Ser/Thr', 'Var', (176, 186))	('DeltaN-Vangl2', 'Gene', '245949', (52, 65))	('DeltaN-Vangl2', 'Gene', (52, 65))	('Ser', 'cellular_component', 'GO:0005790', ('83', '86'))	('signaling', 'biological_process', 'GO:0023052', ('244', '253'))	('Ser', 'Chemical', 'MESH:D012694', (83, 86))	('block', 'NegReg', (222, 227))	('phosphorylation', 'biological_process', 'GO:0016310', ('91', '106'))	('Ser', 'cellular_component', 'GO:0005790', ('179', '182'))	('lacking', 'NegReg', (67, 74))	('Thr', 'Chemical', 'MESH:D013912', (183, 186))	('10 Ser/Thr', 'SUBSTITUTION', 'None', (176, 186))	('Thr', 'Chemical', 'MESH:D013912', (87, 90))	('Vangl2-mediated signaling', 'MPA', (228, 253))
8280	33824332	Ectopic expression of the Vangl210A led to a significant reduction in the number of cytonemes and DeltaN-Vangl2 and Vangl210A to a reduction in the number of long cytonemes, and an increase in the number of short cytonemes (Fig.	('reduction', 'NegReg', (131, 140))	('reduction', 'NegReg', (57, 66))	('DeltaN-Vangl2', 'Gene', '245949', (98, 111))	('Vangl210A', 'Gene', (26, 35))	('short cytonemes', 'Phenotype', 'HP:0000941', (207, 222))	('Vangl210A', 'Var', (116, 125))	('DeltaN-Vangl2', 'Gene', (98, 111))	('increase', 'PosReg', (181, 189))
8281	33824332	Vangl210A also showed significant reduction in all filopodia numbers and DeltaN-Vangl2 and Vangl210A showed reduction in all filopodia length compared to control (Supplementary Figs.	('DeltaN-Vangl2', 'Gene', '245949', (73, 86))	('DeltaN-Vangl2', 'Gene', (73, 86))	('reduction', 'NegReg', (34, 43))	('Vangl210A', 'Var', (91, 100))	('Vangl210A', 'Var', (0, 9))	('reduction', 'NegReg', (108, 117))
8284	33824332	IRSp534K has four lysine residues in the actin-binding sites mutated to glutamic acid, which strongly reduce filopodia formation.	('IRSp53', 'Gene', (0, 6))	('glutamic acid', 'Chemical', 'MESH:D018698', (72, 85))	('filopodia formation', 'biological_process', 'GO:0046847', ('109', '128'))	('lysine', 'Chemical', 'MESH:D008239', (18, 24))	('reduce', 'NegReg', (102, 108))	('IRSp53', 'Gene', '108100', (0, 6))	('actin-binding', 'molecular_function', 'GO:0003779', ('41', '54'))	('mutated', 'Var', (61, 68))	('actin', 'Gene', '35526', (41, 46))	('filopodia formation', 'CPA', (109, 128))	('actin', 'Gene', (41, 46))
8293	33824332	We found that, like what occurred in cultured PAC2 cells, expression of vangl2 mRNA led to significantly longer cytonemes per cell compared to control (Fig.	('ntl', 'Gene', '30399', (100, 103))	('longer', 'PosReg', (105, 111))	('PAC2', 'Gene', '56984', (46, 50))	('ntl', 'Gene', (100, 103))	('cytonemes per cell', 'CPA', (112, 130))	('PAC2', 'Gene', (46, 50))	('expression', 'Var', (58, 68))	('vangl2', 'Gene', (72, 78))
8295	33824332	Expression of DeltaN-vangl2 or vangl210A did not significantly change the length of cytonemes compared to control however, it significantly reduced the number (Fig.	('ntl', 'Gene', '30399', (58, 61))	('vangl210A', 'Var', (31, 40))	('DeltaN-vangl2', 'Var', (14, 27))	('ntl', 'Gene', (135, 138))	('ntl', 'Gene', '30399', (135, 138))	('ntl', 'Gene', (58, 61))	('reduced', 'NegReg', (140, 147))
8319	33824332	In vertebrates SP600125 specifically inhibits all three JNKs (JNK1-3) within minutes without inhibition of ERK1 or ERK2, phospho-p38, or ATF2.	('JNK1-3', 'Gene', '65236;100149273;569698', (62, 68))	('SP600125', 'Chemical', 'MESH:C432165', (15, 23))	('JNK1-3', 'Gene', (62, 68))	('ERK2', 'molecular_function', 'GO:0004707', ('115', '119'))	('ERK1', 'molecular_function', 'GO:0004707', ('107', '111'))	('p38', 'Gene', '65237', (129, 132))	('SP600125', 'Var', (15, 23))	('JNK', 'molecular_function', 'GO:0004705', ('62', '65'))	('ERK1', 'Gene', '399480', (107, 111))	('ATF2', 'Gene', (137, 141))	('p38', 'Gene', (129, 132))	('ATF2', 'Gene', '100006516', (137, 141))	('ERK1', 'Gene', (107, 111))	('inhibits', 'NegReg', (37, 45))	('ERK2', 'Gene', '360144', (115, 119))	('ERK2', 'Gene', (115, 119))	('JNKs', 'Disease', 'None', (56, 60))	('JNKs', 'Disease', (56, 60))
8320	33824332	We found that Wnt cytonemes collapse and retracted following the addition of SP600125 (Fig.	('Wnt cytonemes', 'CPA', (14, 27))	('collapse', 'NegReg', (28, 36))	('SP600125', 'Chemical', 'MESH:C432165', (77, 85))	('retracted', 'CPA', (41, 50))	('SP600125', 'Var', (77, 85))
8322	33824332	2L) prior to the addition of SP600125, also had a significant change in the number and length of cytonemes compared to untreated Vangl2-expressing fibroblasts.	('change', 'Reg', (62, 68))	('SP600125', 'Var', (29, 37))	('SP600125', 'Chemical', 'MESH:C432165', (29, 37))
8324	33824332	While JNK inhibition had a significant effect at 60 min, Y-27632 treatment produced only a modest and non-significant reduction of protrusion length after 5 h (Supplementary Fig.	('Y-27632', 'Chemical', 'MESH:C108830', (57, 64))	('reduction', 'NegReg', (118, 127))	('protrusion length', 'MPA', (131, 148))	('Y-27632', 'Var', (57, 64))	('JNK', 'molecular_function', 'GO:0004705', ('6', '9'))
8326	33824332	We co-cultivated AGS cells transiently expressing combinations of Wnt8a, Vangl2, Ror2, and DeltaN-Vangl2 together with the STF-mCherry reporter cells (Fig.	('ntl', 'Gene', '30399', (34, 37))	('Vangl2', 'Gene', (73, 79))	('mCh', 'Gene', (127, 130))	('Wnt8a', 'Gene', (66, 71))	('mCh', 'Gene', '104242', (127, 130))	('DeltaN-Vangl2', 'Gene', '245949', (91, 104))	('DeltaN-Vangl2', 'Gene', (91, 104))	('combinations', 'Var', (50, 62))	('ntl', 'Gene', (34, 37))
8332	33824332	We find that blockage of filopodia formation in these cells reduces significantly the paracrine signaling activity by Vangl2/Wnt8a expressing cells.	('filopodia', 'CPA', (25, 34))	('paracrine signaling', 'biological_process', 'GO:0038001', ('86', '105'))	('filopodia formation', 'biological_process', 'GO:0046847', ('25', '44'))	('Vangl2/Wnt8a', 'Gene', (118, 130))	('paracrine signaling activity', 'MPA', (86, 114))	('ntl', 'Gene', '30399', (77, 80))	('ntl', 'Gene', (77, 80))	('blockage', 'Var', (13, 21))	('reduces', 'NegReg', (60, 67))
8338	33824332	VANGL1 and VANGL2 expression in telocytes was reduced by siRNA-mediated knockdown (Supplementary Fig.	('VANGL2', 'Gene', (11, 17))	('VANGL1', 'Gene', '403076', (0, 6))	('VANGL1', 'Gene', (0, 6))	('reduced', 'NegReg', (46, 53))	('expression', 'MPA', (18, 28))	('knockdown', 'Var', (72, 81))
8339	33824332	The number of filopodia was significantly reduced after Vangl1 knockdown and even more markedly reduced after double knockdown of Vangl1/Vangl2 (Fig.	('reduced', 'NegReg', (42, 49))	('Vangl1', 'Gene', (56, 62))	('Vangl1', 'Gene', '403076', (56, 62))	('ntl', 'Gene', '30399', (37, 40))	('Vangl1', 'Gene', (130, 136))	('Vangl1', 'Gene', '403076', (130, 136))	('ntl', 'Gene', (37, 40))	('knockdown', 'Var', (63, 72))	('reduced', 'NegReg', (96, 103))
8344	33824332	Notably, we were not able to observe long filopodia in telocytes upon knockdown of Vangl1/Vangl2 or IRSp53 (Fig.	('IRSp53', 'Gene', (100, 106))	('knockdown', 'Var', (70, 79))	('Vangl1', 'Gene', '403076', (83, 89))	('Vangl1', 'Gene', (83, 89))	('IRSp53', 'Gene', '108100', (100, 106))
8345	33824332	After simultaneous knockdown of Vangl1 and Vangl2 in the WNT-producing telocytes, we further observed a strong decrease in the number of organoids (Fig.	('number of organoids', 'CPA', (127, 146))	('Vangl2', 'Gene', (43, 49))	('knockdown', 'Var', (19, 28))	('Vangl1', 'Gene', '403076', (32, 38))	('Vangl1', 'Gene', (32, 38))	('decrease', 'NegReg', (111, 119))
8346	33824332	In addition, knockdown of IRSp53 led to a similar reduction in organoid counts (Fig.	('IRSp53', 'Gene', '108100', (26, 32))	('reduction', 'NegReg', (50, 59))	('organoid counts', 'CPA', (63, 78))	('IRSp53', 'Gene', (26, 32))	('knockdown', 'Var', (13, 22))
8352	33824332	To test our prediction from the simulation, we analysed the consequences of Vangl2 function on the Wnt signaling range in zebrafish embryogenesis.	('Vangl2', 'Gene', (76, 82))	('embryogenesis', 'biological_process', 'GO:0009793', ('132', '145'))	('function', 'Var', (83, 91))	('Wnt signaling range', 'MPA', (99, 118))	('embryogenesis', 'biological_process', 'GO:0009790', ('132', '145'))	('signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('embryogenesis', 'biological_process', 'GO:0009792', ('132', '145'))	('zebrafish', 'Species', '7955', (122, 131))
8358	33824332	At 60% epiboly, the overexpression of vangl2; and more drastically, wnt8a with vangl2, caused an abnormal broadening and ectopic expression pattern of ntl (Fig.	('ntl', 'Gene', (151, 154))	('vangl2', 'Var', (79, 85))	('epiboly', 'biological_process', 'GO:0090504', ('7', '14'))	('broadening', 'MPA', (106, 116))	('ectopic expression pattern', 'MPA', (121, 147))	('ntl', 'Gene', '30399', (151, 154))
8368	33824332	As predicted from our simulation, in synergy, Wnt8a and Vangl2 leads to a broadening and less sharp gbx1 expression domain, suggesting that the increase in cytoneme length and contact points may affect the signaling range and capability to signal to further cells.	('signaling range', 'MPA', (206, 221))	('gbx1', 'Gene', '142985', (100, 104))	('signaling', 'biological_process', 'GO:0023052', ('206', '215'))	('gbx1', 'Gene', (100, 104))	('cytoneme', 'cellular_component', 'GO:0035230', ('156', '164'))	('Wnt8a', 'Var', (46, 51))	('less', 'NegReg', (89, 93))	('contact', 'Interaction', (176, 183))	('expression domain', 'MPA', (105, 122))	('affect', 'Reg', (195, 201))	('increase', 'PosReg', (144, 152))	('Vangl2', 'Gene', (56, 62))
8374	33824332	Overall, Vangl2 alterations leads to changes in early neural plate patterning, as outlined by changes to ntl and gbx1 expression.	('early neural plate patterning', 'CPA', (48, 77))	('Vangl2', 'Gene', (9, 15))	('alterations', 'Var', (16, 27))	('changes', 'Reg', (37, 44))	('ntl', 'Gene', '30399', (105, 108))	('gbx1', 'Gene', '142985', (113, 117))	('changes', 'Reg', (94, 101))	('ntl', 'Gene', (105, 108))	('gbx1', 'Gene', (113, 117))	('expression', 'MPA', (118, 128))
8383	33824332	In mouse, mutants for the core PCP component Vangl2 exhibit open neural tubes (craniorachischisis).	('mouse', 'Species', '10090', (3, 8))	('PCP', 'molecular_function', 'GO:0004188', ('31', '34'))	('mutants', 'Var', (10, 17))	('PCP', 'molecular_function', 'GO:1904091', ('31', '34'))	('craniorachischisis', 'Phenotype', 'HP:0030770', (79, 97))	('Vangl2', 'Gene', (45, 51))	('core', 'cellular_component', 'GO:0019013', ('26', '30'))	('open neural tubes', 'CPA', (60, 77))
8384	33824332	Similarly, human mutations in both VANGL1/2 are associated with spina bifida.	('human', 'Species', '9606', (11, 16))	('associated', 'Reg', (48, 58))	('VANGL1/2', 'Gene', '81839;57216', (35, 43))	('spina bifida', 'Disease', (64, 76))	('spina bifida', 'Phenotype', 'HP:0002414', (64, 76))	('VANGL1/2', 'Gene', (35, 43))	('mutations', 'Var', (17, 26))
8385	33824332	In zebrafish, the vangl2 mutant trilobite exhibits a broadened body axis, owing to similar defects in convergent extension (CE) movements during development.	('convergent extension', 'biological_process', 'GO:0060026', ('102', '122'))	('mutant', 'Var', (25, 31))	('vangl2', 'Gene', (18, 24))	('zebrafish', 'Species', '7955', (3, 12))	('defects', 'NegReg', (91, 98))	('convergent extension', 'CPA', (102, 122))	('broadened body axis', 'CPA', (53, 72))	('trilobite', 'Chemical', '-', (32, 41))
8394	33824332	We decided against the usage of the zebrafish vangl2 mutant trilobite or a Morpholino-based knock-down approach, because our experimental strategy demanded the analysis of the cytoneme-generating cells without interfering with the cytoneme-receiving cells.	('Morpholino', 'Chemical', 'MESH:D060172', (75, 85))	('vangl2', 'Gene', (46, 52))	('cytoneme', 'cellular_component', 'GO:0035230', ('176', '184'))	('cytoneme', 'cellular_component', 'GO:0035230', ('231', '239'))	('mutant', 'Var', (53, 59))	('zebrafish', 'Species', '7955', (36, 45))	('trilobite', 'Chemical', '-', (60, 69))
8395	33824332	To complement our analysis in zebrafish embryos, we knocked-down Vangl1/2 in mouse telocytes by an siRNA approach (Fig.	('mouse', 'Species', '10090', (77, 82))	('Vangl1/2', 'Gene', (65, 73))	('knocked-down', 'Var', (52, 64))	('zebrafish', 'Species', '7955', (30, 39))
8398	33824332	In Drosophila, knock-down of vangl and prickle lead to the formation of very few and short Fgf cytonemes.	('formation', 'biological_process', 'GO:0009058', ('59', '68'))	('lead to', 'Reg', (47, 54))	('Fgf', 'Gene', '42356', (91, 94))	('Drosophila', 'Species', '7227', (3, 13))	('knock-down', 'Var', (15, 25))	('vangl', 'Gene', (29, 34))	('Fgf', 'Gene', (91, 94))
8399	33824332	In Vangl2-/-/Loop-tail mouse mutants, filopodia were unable to extend.	('filopodia', 'CPA', (38, 47))	('mutants', 'Var', (29, 36))	('unable', 'NegReg', (53, 59))	('mouse', 'Species', '10090', (23, 28))	('Vangl2-/-/Loop-tail', 'Gene', (3, 22))
8400	33824332	In hippocampal neurons, Vangl2 was found to regulate dendritic branching, with Vangl2 knockdown leading to reduced spine density and dendritic branching.	('Vangl2', 'Gene', (79, 85))	('dendritic branching', 'Disease', 'MESH:D007635', (53, 72))	('knockdown', 'Var', (86, 95))	('dendritic branching', 'Disease', (53, 72))	('reduced', 'NegReg', (107, 114))	('dendritic branching', 'Disease', 'MESH:D007635', (133, 152))	('dendritic branching', 'Disease', (133, 152))	('spine', 'cellular_component', 'GO:0044309', ('115', '120'))	('spine density', 'CPA', (115, 128))
8420	33824332	In the zebrafish vangl2 mutant trilobite, longer and thicker protrusions were observed.	('mutant', 'Var', (24, 30))	('zebrafish', 'Species', '7955', (7, 16))	('trilobite', 'Chemical', '-', (31, 40))	('observed', 'Reg', (78, 86))	('vangl2', 'Gene', (17, 23))
8453	33824332	As confluence of cultured cells was reaching 80%, they were transfected with Vangl1 and Vangl2 siRNAs (Dharmacon Cat# J-057276-09-0002 and Cat# J-059396-09-0002 respectively, at 10 nM) using siRNAmax reagent (Invitrogen Cat#13778-030).	('Vangl2', 'Gene', (88, 94))	('Cat# J-059396-09-0002', 'Var', (139, 160))	('Cat', 'molecular_function', 'GO:0004096', ('139', '142'))	('Cat', 'molecular_function', 'GO:0004096', ('220', '223'))	('Vangl1', 'Gene', (77, 83))	('Vangl1', 'Gene', '403076', (77, 83))	('Cat', 'molecular_function', 'GO:0004096', ('113', '116'))
8458	33824332	The following plasmids were used: GPI-anchored mCherry in pCS2+(Mem-mCh); zfGap43-GFP in pCS2, xRor2 in pCS2+, XRor23i in pCS2+ and xRor2-mCherry in PCS2+; zfWnt8a ORF1-mCherry in pCS2+; zfWnt8a ORF1-GFP in pCS2+; meGFP-Vangl2 in pcDNA3.1; zfStbm (Vangl2), in pCS2+, (Addgene, #17067); Stbm-DeltaN-6myc in pCS2+; IRSp534K; Vangl2 S5~17A::S76~84A; JNK KTR-mCherry; 7xTRE Super TOPFlash-NLS-mCherry (STF-mCherry); Lrp6-GFP.	('zfWnt8a', 'Gene', (187, 194))	('Stbm', 'Gene', (286, 290))	('Stbm', 'Gene', '245949', (242, 246))	('mCh', 'Gene', '104242', (47, 50))	('TOPFlash-NLS-mCherry', 'Disease', (376, 396))	('zfWnt8a', 'Gene', (156, 163))	('GPI-anchored mCherry', 'Disease', 'MESH:C537277', (34, 54))	('IRSp53', 'Gene', '108100', (313, 319))	('Ror23i', 'Gene', (112, 118))	('mCh', 'Gene', '104242', (402, 405))	('GPI-anchored mCherry', 'Disease', (34, 54))	(':S76~84A', 'Var', (337, 345))	('mCh', 'Gene', '104242', (355, 358))	('zfWnt8a', 'Gene', '30122', (187, 194))	('zfWnt8a', 'Gene', '30122', (156, 163))	('mCh', 'Gene', '104242', (68, 71))	('mCh', 'Gene', (47, 50))	('zfGap43', 'Gene', '30608', (74, 81))	('mCh', 'Gene', (402, 405))	('mCh', 'Gene', '104242', (138, 141))	('mCh', 'Gene', (355, 358))	('zfGap43', 'Gene', (74, 81))	('Lrp6', 'Gene', (412, 416))	('mCh', 'Gene', '104242', (169, 172))	('Ror23i', 'Gene', '561183', (112, 118))	('Stbm', 'Gene', '245949', (286, 290))	('mCh', 'Gene', (68, 71))	('mCh', 'molecular_function', 'GO:0043881', ('68', '71'))	('JNK', 'molecular_function', 'GO:0004705', ('347', '350'))	('Stbm', 'Gene', (242, 246))	('mCh', 'Gene', (138, 141))	('mCh', 'Gene', '104242', (389, 392))	('TOPFlash-NLS-mCherry', 'Disease', 'MESH:C536405', (376, 396))	('mCh', 'Gene', (169, 172))	('IRSp53', 'Gene', (313, 319))	('Lrp6', 'Gene', '100003877', (412, 416))	('mCh', 'Gene', (389, 392))
8499	33692946	Moreover, TIM-3 expression was found to be related to worse OS in 9491 TCGA patients (HR = 1.2, P < 0.001), but was not associated with DFS.	('TIM-3', 'Gene', (10, 15))	('patients', 'Species', '9606', (76, 84))	('expression', 'Var', (16, 26))	('TCGA', 'Disease', (71, 75))	('TIM-3', 'Gene', '84868', (10, 15))	('worse OS', 'Disease', (54, 62))
8521	33692946	reported a significant association between TIM-3 expression and worse OS in esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (76, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('worse OS', 'Disease', (64, 72))	('esophageal squamous cell carcinoma', 'Disease', (76, 110))	('TIM-3', 'Gene', '84868', (43, 48))	('TIM-3', 'Gene', (43, 48))	('expression', 'Var', (49, 59))
8542	33692946	Of these eligible studies, only three articles reported that TIM-3 expression was correlated with worse OS in cervical cancer (n= 43 cases), gastric cancer (n=305 cases), and colorectal cancer (n=201 cases).	('correlated with', 'Reg', (82, 97))	('gastric cancer', 'Disease', (141, 155))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))	('worse OS', 'Disease', (98, 106))	('TIM-3', 'Gene', '84868', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('expression', 'Var', (67, 77))	('colorectal cancer', 'Disease', (175, 192))	('cancer', 'Disease', (119, 125))	('TIM-3', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('gastric cancer', 'Disease', 'MESH:D013274', (141, 155))	('cancer', 'Disease', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', (186, 192))	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('gastric cancer', 'Phenotype', 'HP:0012126', (141, 155))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
8543	33692946	The result from 22 studies indicated that the expression of TIM-3 led to poorer OS (HR= 1.54, 95% CI = 1.19-1.98, P = 0.001) (Figure 2), including 3317 malignant tumor patients.	('TIM-3', 'Gene', '84868', (60, 65))	('expression', 'Var', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('malignant tumor', 'Disease', (152, 167))	('poorer', 'NegReg', (73, 79))	('malignant tumor', 'Disease', 'MESH:D009369', (152, 167))	('patients', 'Species', '9606', (168, 176))	('TIM-3', 'Gene', (60, 65))
8546	33692946	The results by age group showed that TIM-3 expression was correlated with worse OS in the elder age group (> 60 years: n = 8 studies with 1600 cases: HR = 2.10, 95% CI = 1.34-3.31, P = 0.001) and the younger group (<= 60 years: n = 10 studies with 1348 cases: HR = 1.45, 95% CI = 1.01-2.08, P = 0.046).	('TIM-3', 'Gene', '84868', (37, 42))	('expression', 'Var', (43, 53))	('TIM-3', 'Gene', (37, 42))
8547	33692946	The results grouped by ethnicity showed that TIM-3 expression was associated with poor OS in Asian populations (n = 16 studies with 2452 cases: HR = 1.64, 95% CI = 1.14-2.35, P = 0.007), but not in European populations (n = 6 studies with 865 cases: P = 0.203).	('poor OS', 'Disease', (82, 89))	('TIM-3', 'Gene', '84868', (45, 50))	('TIM-3', 'Gene', (45, 50))	('expression', 'Var', (51, 61))
8551	33692946	The re-calculated result from the remaining studies showed that TIM-3 expression was still significantly correlated with shorter OS (HR= 1.71, 95% CI = 1.44-2.04, P < 0.001), with no heterogeneity (P = 0.102).	('shorter OS', 'Disease', (121, 131))	('expression', 'Var', (70, 80))	('TIM-3', 'Gene', '84868', (64, 69))	('TIM-3', 'Gene', (64, 69))
8565	33692946	TIM-3 expression is related to worse prognosis in some cancers, such as gastric cancer and ovarian cancer, but is not correlated with prognosis in some cancers, such as renal cell carcinoma and sarcoma.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('ovarian cancer', 'Disease', 'MESH:D010051', (91, 105))	('expression', 'Var', (6, 16))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('cancers', 'Disease', (152, 159))	('gastric cancer', 'Disease', (72, 86))	('renal cell carcinoma', 'Disease', (169, 189))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (169, 189))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ovarian cancer', 'Disease', (91, 105))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (91, 105))	('cancers', 'Disease', (55, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('sarcoma', 'Disease', 'MESH:D012509', (194, 201))	('sarcoma', 'Disease', (194, 201))	('TIM-3', 'Gene', '84868', (0, 5))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (169, 189))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('TIM-3', 'Gene', (0, 5))
8568	33692946	reported that TIM-3 single nucleotide polymorphisms (SNPs) were correlated with an increased cancer risk (case-control studies with 4852 participants).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('TIM-3', 'Gene', (14, 19))	('participants', 'Species', '9606', (137, 149))	('TIM-3', 'Gene', '84868', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('single nucleotide polymorphisms', 'Var', (20, 51))
8569	33692946	reported that TIM-3 expression was associated with shorter OS in solid tumors (n=869 patients).	('TIM-3', 'Gene', (14, 19))	('TIM-3', 'Gene', '84868', (14, 19))	('expression', 'Var', (20, 30))	('patients', 'Species', '9606', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
8583	33692946	These analyses suggest that TIM-3 could become an independent prognostic marker for predicting worse OS, and targeting TIM-3 is a potentially effective approach for cancer immunotherapy.	('TIM-3', 'Gene', '84868', (119, 124))	('TIM-3', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('targeting', 'Var', (109, 118))	('TIM-3', 'Gene', '84868', (28, 33))	('worse OS', 'Disease', (95, 103))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('TIM-3', 'Gene', (119, 124))
8585	33692946	reported that TIM-3 expression was correlated with worse CSS in clear cell renal cell carcinoma (n=137 cases), but Burugu 2018 et al.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('TIM-3', 'Gene', (14, 19))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (75, 95))	('TIM-3', 'Gene', '84868', (14, 19))	('expression', 'Var', (20, 30))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (64, 95))	('clear cell renal cell carcinoma', 'Disease', (64, 95))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (64, 95))
8586	33692946	reported that TIM-3 expression was related to favorable CSS in a large cohort of breast cancer (> 3000 cases).	('TIM-3', 'Gene', (14, 19))	('breast cancer', 'Disease', (81, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('TIM-3', 'Gene', '84868', (14, 19))	('expression', 'Var', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
8592	33692946	Subgroup analysis by ethnicity demonstrated that TIM-3 expression was related to worse OS in Asian populations, but not in European populations.	('TIM-3', 'Gene', (49, 54))	('worse OS', 'Disease', (81, 89))	('TIM-3', 'Gene', '84868', (49, 54))	('expression', 'Var', (55, 65))
8605	33692946	The present study provided more evidence that TIM-3 expression was significantly associated with worse OS, and it might be a useful prognosticator in malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('malignant tumors', 'Disease', (150, 166))	('malignant tumors', 'Disease', 'MESH:D009369', (150, 166))	('worse OS', 'Disease', (97, 105))	('TIM-3', 'Gene', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('TIM-3', 'Gene', '84868', (46, 51))	('expression', 'Var', (52, 62))	('associated', 'Reg', (81, 91))
8649	33262461	This is further supported by the findings that depletion of NK cells by performing antibody-mediated methods or using transgenic mice model (Nfil3-/- mice) vastly exacerbated tumorigenesis in mouse models developing malignant diseases.	('antibody', 'molecular_function', 'GO:0003823', ('83', '91'))	('mice', 'Species', '10090', (150, 154))	('tumor', 'Disease', (175, 180))	('mouse', 'Species', '10090', (192, 197))	('exacerbated', 'PosReg', (163, 174))	('Nfil3', 'Gene', '18030', (141, 146))	('transgenic mice', 'Species', '10090', (118, 133))	('antibody', 'cellular_component', 'GO:0019814', ('83', '91'))	('depletion', 'Var', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('malignant diseases', 'Disease', 'MESH:D009369', (216, 234))	('antibody', 'cellular_component', 'GO:0042571', ('83', '91'))	('antibody', 'cellular_component', 'GO:0019815', ('83', '91'))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('Nfil3', 'Gene', (141, 146))	('mice', 'Species', '10090', (129, 133))	('malignant diseases', 'Disease', (216, 234))
8658	33262461	Similarly, in MC38 (murine primary colon carcinoma cell line)-based liver metastasis of CRC mice model, Nlrp3 inflammasome can increase the IL-18 secretion and promote the maturation of hepatic NK cells with increasing FasL expression, the Fas/FasL interaction can exert cytotoxicity towards tumor cells.	('Nlrp3', 'Gene', '216799', (104, 109))	('IL-18 secretion', 'MPA', (140, 155))	('cytotoxicity', 'Disease', (271, 283))	('cytotoxicity', 'Disease', 'MESH:D064420', (271, 283))	('mice', 'Species', '10090', (92, 96))	('colon carcinoma', 'Disease', 'MESH:D003110', (35, 50))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('promote', 'PosReg', (160, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('IL-18 secretion', 'biological_process', 'GO:0072616', ('140', '155'))	('murine', 'Species', '10090', (20, 26))	('inflammasome', 'Var', (110, 122))	('hepatic', 'Enzyme', (186, 193))	('Nlrp3', 'Gene', (104, 109))	('IL-18', 'molecular_function', 'GO:0045515', ('140', '145'))	('FasL', 'Protein', (219, 223))	('interaction', 'Interaction', (249, 260))	('tumor', 'Disease', (292, 297))	('colon carcinoma', 'Disease', (35, 50))	('increase', 'PosReg', (127, 135))	('maturation', 'CPA', (172, 182))	('tumor', 'Disease', 'MESH:D009369', (292, 297))
8717	33262461	Combining FT500 and immune checkpoint inhibitors are presumed to combat drug resistance for cancer patients.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('drug resistance', 'biological_process', 'GO:0042493', ('72', '87'))	('drug resistance', 'Phenotype', 'HP:0020174', (72, 87))	('patients', 'Species', '9606', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('FT500', 'Var', (10, 15))	('drug resistance', 'biological_process', 'GO:0009315', ('72', '87'))
8728	33262461	Both in vitro and in vivo experiment confirmed the improved cytotoxicity of the modified NK cells.	('cytotoxicity', 'Disease', 'MESH:D064420', (60, 72))	('improved', 'PosReg', (51, 59))	('modified', 'Var', (80, 88))	('cytotoxicity', 'Disease', (60, 72))
8730	33262461	Compared with the CAR-T therapy, recent investigation found that CAR-NK does not cause serious GVHD (graft-versus-host disease) and CRS (cytokine release syndrome), as NK cells have initial cytotoxicity to transformed cells without pre-immunization.	('cytotoxicity', 'Disease', (190, 202))	('CAR-NK', 'Var', (65, 71))	('pre', 'molecular_function', 'GO:0003904', ('232', '235'))	('CAR-NK', 'Chemical', '-', (65, 71))	('graft-versus-host disease', 'Disease', (101, 126))	('cytotoxicity', 'Disease', 'MESH:D064420', (190, 202))	('CAR-T', 'Chemical', '-', (18, 23))	('GVHD', 'Disease', 'MESH:D006086', (95, 99))	('GVHD', 'Disease', (95, 99))	('CAR', 'cellular_component', 'GO:0005826', ('65', '68'))	('graft-versus-host disease', 'Disease', 'MESH:D006086', (101, 126))	('CAR', 'cellular_component', 'GO:0005826', ('18', '21'))
8740	33262461	The results demonstrated that blocking of inhibitory receptors can enhance NK cells' cytotoxicity towards the tumor cells.	('blocking', 'Var', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('cytotoxicity', 'Disease', (85, 97))	('inhibitory receptors', 'Protein', (42, 62))	('NK cells', 'CPA', (75, 83))	('enhance', 'PosReg', (67, 74))	('cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
8757	33262461	From the antibody-dependent cell-mediated cytotoxicity (ADCC) of NK cell function mechanism, specially designed bi- and tri-specific killer engagers (BiKEs and TriKEs), the small molecules linking a single-chain Fv against CD16 that is expressed on the NK cell with one (BiKE) or two (TriKE) tumor-associated antigens, were developed to improve the formation of immunological synapses between NK cells and tumor cells.	('antibody', 'cellular_component', 'GO:0019814', ('9', '17'))	('cytotoxicity', 'Disease', (42, 54))	('CD16', 'Gene', (223, 227))	('BiKE', 'Gene', '55589', (271, 275))	('cytotoxicity', 'Disease', 'MESH:D064420', (42, 54))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('antibody', 'molecular_function', 'GO:0003823', ('9', '17'))	('tumor', 'Disease', (406, 411))	('BiKE', 'Gene', (150, 154))	('antibody', 'cellular_component', 'GO:0042571', ('9', '17'))	('TriKE', 'Chemical', '-', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (406, 411))	('ADCC', 'biological_process', 'GO:0001788', ('56', '60'))	('formation', 'biological_process', 'GO:0009058', ('349', '358'))	('TriKE', 'Chemical', '-', (285, 290))	('improve', 'PosReg', (337, 344))	('BiKE', 'Gene', '55589', (150, 154))	('antibody', 'cellular_component', 'GO:0019815', ('9', '17'))	('single-chain', 'Var', (199, 211))	('tumor', 'Disease', (292, 297))	('tumor', 'Phenotype', 'HP:0002664', (406, 411))	('CD16', 'Gene', '2214', (223, 227))	('BiKE', 'Gene', (271, 275))	('tumor', 'Disease', 'MESH:D009369', (292, 297))
8878	26715559	Epithelial injury and disruption of intercellular tight junctions leading to DIS formation as well as loss of barrier function has been well characterized in rabbit as well as human esophagus using ex vivo culture systems.	('formation', 'biological_process', 'GO:0009058', ('81', '90'))	('disruption', 'Var', (22, 32))	('intercellular tight junctions', 'Protein', (36, 65))	('human', 'Species', '9606', (176, 181))	('Epithelial injury', 'Disease', 'MESH:D002277', (0, 17))	('DIS', 'Chemical', '-', (77, 80))	('DIS formation', 'Disease', (77, 90))	('Epithelial injury', 'Disease', (0, 17))
8916	26715559	Bile acid, possible by activating EGFR pathway and downstream Akt phosphorylation, might cause beta-catenin phosphorylation at Ser552 residue triggering its release and subsequent disruption of the adherens junction complex.	('EGFR', 'Gene', (34, 38))	('cause', 'Reg', (89, 94))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('Akt', 'Gene', '207', (62, 65))	('release', 'MPA', (157, 164))	('EGFR', 'Gene', '1956', (34, 38))	('beta-catenin', 'Gene', (95, 107))	('phosphorylation', 'biological_process', 'GO:0016310', ('108', '123'))	('adherens junction', 'cellular_component', 'GO:0005912', ('198', '215'))	('Bile acid', 'Chemical', 'MESH:D001647', (0, 9))	('Ser', 'cellular_component', 'GO:0005790', ('127', '130'))	('Ser552', 'Chemical', '-', (127, 133))	('phosphorylation', 'biological_process', 'GO:0016310', ('66', '81'))	('beta-catenin', 'Gene', '1499', (95, 107))	('Akt', 'Gene', (62, 65))	('Ser552', 'Var', (127, 133))	('activating', 'PosReg', (23, 33))
8927	32346610	Efficacy of a Third-Generation Oncolytic Herpes Virus G47Delta in Advanced Stage Models of Human Gastric Cancer Advanced gastric cancer, especially scirrhous gastric cancer with peritoneal dissemination, remains refractory to conventional therapies.	('Cancer', 'Disease', (105, 111))	('scirrhous gastric cancer', 'Disease', (148, 172))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('G47Delta', 'Var', (54, 62))	('Cancer', 'Disease', 'MESH:D009369', (105, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (97, 111))	('Cancer', 'Phenotype', 'HP:0002664', (105, 111))	('scirrhous gastric cancer', 'Disease', 'MESH:D013274', (148, 172))	('gastric cancer', 'Disease', 'MESH:D013274', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('gastric cancer', 'Disease', (121, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (158, 172))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))	('Human', 'Species', '9606', (91, 96))
8928	32346610	G47Delta, a third-generation oncolytic herpes simplex virus type 1, is an attractive novel therapeutic agent for solid cancer.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('herpes simplex', 'Phenotype', 'HP:0012302', (39, 53))	('G47Delta', 'Var', (0, 8))	('cancer', 'Disease', (119, 125))	('herpes simplex virus type 1', 'Species', '10298', (39, 66))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
8929	32346610	In this study, we investigated the therapeutic potential of G47Delta for human gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('G47Delta', 'Var', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('human', 'Species', '9606', (73, 78))	('gastric cancer', 'Disease', (79, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))
8930	32346610	In vitro, G47Delta showed good cytopathic effects and replication capabilities in nine human gastric cancer cell lines tested.	('cytopathic effects', 'CPA', (31, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('human', 'Species', '9606', (87, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('G47Delta', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('replication capabilities', 'CPA', (54, 78))	('gastric cancer', 'Disease', (93, 107))
8931	32346610	In vivo, intratumoral inoculations with G47Delta (2 x 105 or 1 x 106 plaque-forming units [PFU]) significantly inhibited the growth of subcutaneous tumors (MKN45, MKN74, and 44As3).	('subcutaneous tumors', 'Disease', 'MESH:D013352', (135, 154))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('growth', 'CPA', (125, 131))	('G47Delta', 'Var', (40, 48))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (135, 153))	('tumor', 'Disease', (148, 153))	('subcutaneous tumors', 'Disease', (135, 154))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('inhibited', 'NegReg', (111, 120))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (135, 154))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
8933	32346610	G47Delta (1 x 106 PFU) was constantly efficacious whether administered intratumorally or intraperitoneally in the clinically relevant models.	('G47Delta', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
8934	32346610	Notably, G47Delta injected intraperitoneally readily distributed to, and selectively replicated in, disseminated tumors.	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('G47Delta', 'Var', (9, 17))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
8935	32346610	Furthermore, flow cytometric analyses of tumor-infiltrating cells in subcutaneous tumors revealed that intratumoral G47Delta injections markedly decreased M2 macrophages while increasing M1 macrophages and natural killer (NK) cells.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('M1 macrophages', 'CPA', (187, 201))	('tumor', 'Disease', (108, 113))	('decreased', 'NegReg', (145, 154))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (69, 88))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (69, 88))	('G47Delta', 'Var', (116, 124))	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('M2 macrophages', 'CPA', (155, 169))	('subcutaneous tumors', 'Disease', (69, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('increasing', 'PosReg', (176, 186))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (69, 87))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))
8936	32346610	These findings indicate the usefulness of G47Delta for treating human gastric cancer, including scirrhous gastric cancer and the ones in advanced stages.	('scirrhous gastric cancer', 'Disease', (96, 120))	('human', 'Species', '9606', (64, 69))	('gastric cancer', 'Disease', 'MESH:D013274', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('gastric cancer', 'Phenotype', 'HP:0012126', (70, 84))	('gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('scirrhous gastric cancer', 'Disease', 'MESH:D013274', (96, 120))	('G47Delta', 'Var', (42, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('gastric cancer', 'Disease', (70, 84))
8937	32346610	G47Delta, a third-generation oncolytic herpes simplex virus type 1, is efficacious in various advanced-stage models of human gastric cancer with features mimicking intractable patients, when injected intratumorally or intraperitoneally.	('gastric cancer', 'Disease', 'MESH:D013274', (125, 139))	('patients', 'Species', '9606', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))	('herpes simplex', 'Phenotype', 'HP:0012302', (39, 53))	('G47Delta', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('herpes simplex virus type 1', 'Species', '10298', (39, 66))	('gastric cancer', 'Disease', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('human', 'Species', '9606', (119, 124))
8938	32346610	G47Delta should be useful for treating human gastric cancer, including the scirrhous type and the ones in advanced stages.	('gastric cancer', 'Phenotype', 'HP:0012126', (45, 59))	('human', 'Species', '9606', (39, 44))	('G47Delta', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('scirrhous type', 'Disease', (75, 89))	('gastric cancer', 'Disease', (45, 59))	('gastric cancer', 'Disease', 'MESH:D013274', (45, 59))
8948	32346610	In preclinical studies, G47Delta exhibited robust antitumor efficacy while retaining excellent safety features.	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('G47Delta', 'Var', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))
8949	32346610	The first-in-man clinical trial in patients with glioblastoma (UMIN-CTR: UMIN000002661) demonstrated the safety of G47Delta inoculated into the human brain.	('human', 'Species', '9606', (144, 149))	('glioblastoma', 'Disease', (49, 61))	('glioblastoma', 'Disease', 'MESH:D005909', (49, 61))	('patients', 'Species', '9606', (35, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (49, 61))	('G47Delta', 'Var', (115, 123))
8951	32346610	Not only for brain tumors, but G47Delta should also be applicable to various types of solid cancer.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('brain tumors', 'Disease', 'MESH:D001932', (13, 25))	('brain tumors', 'Phenotype', 'HP:0030692', (13, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('G47Delta', 'Var', (31, 39))	('brain tumors', 'Disease', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
8953	32346610	In this study, we investigate the efficacy of G47Delta for human gastric cancer, including scirrhous gastric cancer in vitro and in vivo.	('G47Delta', 'Var', (46, 54))	('human', 'Species', '9606', (59, 64))	('scirrhous gastric cancer', 'Disease', 'MESH:D013274', (91, 115))	('scirrhous gastric cancer', 'Disease', (91, 115))	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('gastric cancer', 'Disease', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))
8954	32346610	We further examine the usefulness of G47Delta for advanced-stage gastric cancer using an orthotopic tumor model and peritoneal dissemination models.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('G47Delta', 'Var', (37, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (65, 79))	('tumor', 'Disease', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('gastric cancer', 'Disease', (65, 79))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('gastric cancer', 'Disease', 'MESH:D013274', (65, 79))
8955	32346610	In addition, immune responses accompanying G47Delta treatment are investigated by analyzing tumor-infiltrating immune cells.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('G47Delta', 'Var', (43, 51))	('tumor', 'Disease', (92, 97))
8956	32346610	To characterize the oncolytic activity of G47Delta in gastric cancer, we studied its cytopathic effects and replication capabilities in nine human gastric cancer cell lines in vitro.	('gastric cancer', 'Phenotype', 'HP:0012126', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('died', 'Disease', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('died', 'Disease', 'MESH:D003643', (76, 80))	('gastric cancer', 'Disease', (54, 68))	('gastric cancer', 'Disease', 'MESH:D013274', (54, 68))	('human', 'Species', '9606', (141, 146))	('gastric cancer', 'Disease', (147, 161))	('G47Delta', 'Var', (42, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (147, 161))	('gastric cancer', 'Phenotype', 'HP:0012126', (54, 68))
8957	32346610	In the cell lines tested, with the exceptions of 44As3 and HSC-39, G47Delta at a multiplicity of infection (MOI) of 0.1 showed >70% cell destruction within 4 days after infection (Figure 1A).	('HSC', 'cellular_component', 'GO:0035301', ('59', '62'))	('G47Delta', 'Var', (67, 75))	('infection', 'Disease', (97, 106))	('infection', 'Disease', 'MESH:D007239', (97, 106))	('infection', 'Disease', (169, 178))	('cell destruction', 'CPA', (132, 148))	('infection', 'Disease', 'MESH:D007239', (169, 178))
8958	32346610	44As3 cells and HSC-39 cells, both of which are established from scirrhous gastric cancer, were relatively resistant to killing by G47Delta at an MOI of 0.1, although both were effectively killed by G47Delta at an MOI of 1 by day 4 (Figure 1A).	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('HSC', 'cellular_component', 'GO:0035301', ('16', '19'))	('G47Delta', 'Var', (199, 207))	('scirrhous gastric cancer', 'Disease', 'MESH:D013274', (65, 89))	('scirrhous gastric cancer', 'Disease', (65, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('G47Delta', 'Var', (131, 139))
8960	32346610	These observations indicate that good cytopathic effect and replication capability of G47Delta are shown in the majority of human gastric cell lines, whereas some cell lines can be relatively resistant.	('human', 'Species', '9606', (124, 129))	('replication capability', 'CPA', (60, 82))	('G47Delta', 'Var', (86, 94))
8961	32346610	To study the antitumor efficacy of G47Delta in vivo, we used three mouse models with subcutaneous tumors of gastric cancer.	('subcutaneous tumors', 'Disease', (85, 104))	('tumors of gastric cancer', 'Disease', 'MESH:D013274', (98, 122))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', (17, 22))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (85, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (108, 122))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('mouse', 'Species', '10090', (67, 72))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (85, 103))	('tumors of gastric', 'Phenotype', 'HP:0006753', (98, 115))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (85, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('G47Delta', 'Var', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumors of gastric cancer', 'Disease', (98, 122))	('tumor', 'Disease', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
8962	32346610	Athymic mice harboring MNK45, MKN74, and 44As3 tumors of approximately 6 mm in diameter were inoculated intratumorally with G47Delta (2 x 105 or 1 x 106 plaque-forming units [PFU]) or mock twice (days 0 and 3).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('MNK45', 'Var', (23, 28))	('G47Delta', 'Var', (124, 132))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('mice', 'Species', '10090', (8, 12))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', (109, 114))
8963	32346610	In all subcutaneous tumor models, G47Delta treatment significantly inhibited tumor growth compared with mock treatment (MKN45, p < 0.01 on day 24; MKN74, p < 0.01 on day 31; 44As3, p < 0.01 on day 15; Figure 2A).	('subcutaneous tumor', 'Disease', 'MESH:D013352', (7, 25))	('inhibited', 'NegReg', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('G47Delta', 'Var', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (7, 25))	('subcutaneous tumor', 'Disease', (7, 25))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', (20, 25))
8964	32346610	Furthermore, in all tumor models, G47Delta used at a low dose (2 x 105 PFU) was as effective as G47Delta at a high dose (1 x 106 PFU).	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('G47Delta', 'Var', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
8965	32346610	We further investigated the efficacy of G47Delta treatment for large subcutaneous tumors.	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (69, 87))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('G47Delta', 'Var', (40, 48))	('subcutaneous tumors', 'Disease', (69, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (69, 88))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (69, 88))
8966	32346610	G47Delta treatment significantly inhibited tumor growth compared with mock treatment even for large subcutaneous tumors (>=200 mm3) (MKN45, p < 0.01 on day 19; 44As3, p < 0.01 on day 31; Figure 2B).	('tumor', 'Disease', (113, 118))	('subcutaneous tumors', 'Disease', (100, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('G47Delta', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (100, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (43, 48))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (100, 118))	('inhibited', 'NegReg', (33, 42))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (100, 119))
8967	32346610	To determine whether G47Delta can inhibit the growth of orthotopic tumors, we used an orthotopic tumor model of 44As3Luc.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('G47Delta', 'Var', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('growth', 'CPA', (46, 52))	('tumor', 'Disease', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', (67, 72))	('inhibit', 'NegReg', (34, 41))	('tumors', 'Disease', (67, 73))
8972	32346610	Intratumoral inoculations with G47Delta (1 x 106 PFU, on days 8 and 11) significantly inhibited the growth of orthotopic tumors (p = 0.04 on day 27, Figure 3C), resulting in improved survival of tumor-bearing mice (median survival time [MST], 68 days versus 55 days; p = 0.004; Figure 3D).	('mice', 'Species', '10090', (209, 213))	('tumor', 'Disease', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('G47Delta', 'Var', (31, 39))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('survival', 'CPA', (183, 191))	('tumor', 'Disease', (5, 10))	('inhibited', 'NegReg', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('improved', 'PosReg', (174, 182))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
8975	32346610	Athymic mice bearing MKN45-luc peritoneal tumors were divided into two groups on day 3, at which time total photon counts did not differ between the two groups (data not shown).	('peritoneal tumors', 'Disease', (31, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('peritoneal tumors', 'Disease', 'MESH:D010534', (31, 48))	('MKN45-luc', 'Var', (21, 30))	('mice', 'Species', '10090', (8, 12))
8976	32346610	Two intraperitoneal injections with G47Delta (1 x 106 PFU, on days 4 and 7) significantly inhibited the growth of peritoneal tumors (p < 0.01 on day 24, Figure 4A) and prolonged the survival of tumor-bearing mice (MST, 57 days versus 30 days; p < 0.01; Figure 4B).	('peritoneal tumors', 'Disease', 'MESH:D010534', (114, 131))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('G47Delta', 'Var', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('peritoneal tumors', 'Disease', (114, 131))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('prolonged', 'PosReg', (168, 177))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', (125, 130))	('survival', 'CPA', (182, 190))	('tumor', 'Disease', (194, 199))	('inhibited', 'NegReg', (90, 99))	('mice', 'Species', '10090', (208, 212))
8977	32346610	Another peritoneal dissemination model of scirrhous gastric cancer (44As3Luc) similarly showed that two intraperitoneal injections with G47Delta (1 x 106 PFU, on days 4 and 7) significantly suppressed the growth of peritoneal tumors (p < 0.01 on day 7, Figure 4D) and prolonged the survival of tumor-bearing mice (MST, 40 days versus 13 days; p < 0.01; Figure 4E).	('peritoneal tumors', 'Disease', 'MESH:D010534', (215, 232))	('gastric cancer', 'Phenotype', 'HP:0012126', (52, 66))	('G47Delta', 'Var', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('suppressed', 'NegReg', (190, 200))	('scirrhous gastric cancer', 'Disease', 'MESH:D013274', (42, 66))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('scirrhous gastric cancer', 'Disease', (42, 66))	('prolonged', 'PosReg', (268, 277))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('growth', 'CPA', (205, 211))	('survival', 'CPA', (282, 290))	('tumor', 'Disease', (294, 299))	('peritoneal tumors', 'Disease', (215, 232))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('mice', 'Species', '10090', (308, 312))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', (226, 231))
8978	32346610	Furthermore, we studied the efficacy of intraperitoneal injections with G47Delta for mice bearing 44As3Luc peritoneal tumors using a virus dose (5 x 106 PFU, on days 3, 5 and 7; Figure 4G) and treatment timing (1 x 106 PFU, on days 1, 3 and 5; Figure 4J) different from the original experiment.	('mice', 'Species', '10090', (85, 89))	('peritoneal tumors', 'Disease', (107, 124))	('died', 'Disease', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('died', 'Disease', 'MESH:D003643', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('peritoneal tumors', 'Disease', 'MESH:D010534', (107, 124))	('G47Delta', 'Var', (72, 80))
8980	32346610	Results from both models indicate that G47Delta exerts strong therapeutic efficacy for peritoneal dissemination of gastric cancer, including scirrhous gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('G47Delta', 'Var', (39, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('gastric cancer', 'Phenotype', 'HP:0012126', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('peritoneal dissemination', 'CPA', (87, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('scirrhous gastric cancer', 'Disease', 'MESH:D013274', (141, 165))	('therapeutic efficacy', 'CPA', (62, 82))	('scirrhous gastric cancer', 'Disease', (141, 165))	('gastric cancer', 'Disease', 'MESH:D013274', (151, 165))	('gastric cancer', 'Disease', (115, 129))
8985	32346610	To study the immune responses in tumors treated by G47Delta, athymic mice bearing MKN45 subcutaneous tumors were inoculated intratumorally with G47Delta (1 x 106 PFU) or mock.	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (88, 106))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (88, 107))	('G47Delta', 'Var', (144, 152))	('mice', 'Species', '10090', (69, 73))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (88, 107))	('tumor', 'Disease', (129, 134))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('subcutaneous tumors', 'Disease', (88, 107))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (101, 107))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
8987	32346610	G47Delta treatment significantly increased the absolute number of intratumoral CD45+ cells compared with mock treatment (p = 0.007, Figure 6A).	('CD45', 'Gene', (79, 83))	('CD45', 'Gene', '5788', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('G47Delta', 'Var', (0, 8))	('increased', 'PosReg', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
8988	32346610	The total number of intratumoral macrophages (CD45+CD11b+F4/80+) did not differ significantly between the two groups (p = 0.10, Figure 6B), whereas NK cells (CD45+CD49b+) were significantly increased in the G47Delta treatment group (p < 0.001, Figure 6C).	('NK cells', 'CPA', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('CD45', 'Gene', (46, 50))	('CD45', 'Gene', '5788', (158, 162))	('tumor', 'Disease', (25, 30))	('CD11b', 'Gene', (51, 56))	('CD49b', 'Gene', '3673', (163, 168))	('CD11b', 'Gene', '3684', (51, 56))	('increased', 'PosReg', (190, 199))	('CD49b', 'Gene', (163, 168))	('CD45', 'Gene', '5788', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('CD45', 'Gene', (158, 162))	('G47Delta', 'Var', (207, 215))
8989	32346610	The ratio of M2 macrophages (CD206+CD86- macrophages) to total macrophages was significantly reduced in the G47Delta treatment group (p < 0.001, Figure 6D), whereas the ratio of M1 macrophages (CD206-CD86+ macrophages) to total macrophages was significantly increased in the G47Delta treatment group (p = 0.02, Figure 6E), resulting in a significant increase in the M1-to-M2 ratio in the G47Delta treatment group (p = 0.03, Figure 6F).	('increase', 'PosReg', (350, 358))	('reduced', 'NegReg', (93, 100))	('CD206', 'Gene', '4360', (29, 34))	('CD206', 'Gene', '4360', (194, 199))	('CD206', 'Gene', (29, 34))	('CD206', 'Gene', (194, 199))	('G47Delta', 'Var', (388, 396))	('M1-to-M2 ratio', 'MPA', (366, 380))	('CD86', 'Gene', '942', (200, 204))	('G47Delta', 'Var', (108, 116))	('CD86', 'Gene', '942', (35, 39))	('CD86', 'Gene', (35, 39))	('CD86', 'Gene', (200, 204))
8990	32346610	Gene expression analysis of MKN45 subcutaneous tumors revealed a significant increase in a gene related to macrophages (Cd68) after G47Delta treatment (Figure 7A, p < 0.01).	('subcutaneous tumors', 'Disease', (34, 53))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (34, 53))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('Cd68', 'Gene', '968', (120, 124))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (34, 53))	('increase', 'PosReg', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (34, 52))	('Cd68', 'Gene', (120, 124))	('G47Delta treatment', 'Var', (132, 150))
8991	32346610	Notably, a significant increase in Cd86, an M1 macrophage marker, was observed in the G47Delta group (Figure 7B, p < 0.001).	('Cd86', 'Gene', '942', (35, 39))	('increase', 'PosReg', (23, 31))	('G47Delta', 'Var', (86, 94))	('Cd86', 'Gene', (35, 39))
8992	32346610	In contrast, gene expressions of Arg1 and Mrc1, both M2 macrophage markers, were significantly downregulated in G47Delta-treated tumors (Figure 7D, p < 0.01; Figure 7E, p = 0.04, respectively).	('gene expressions', 'MPA', (13, 29))	('Mrc1', 'Gene', '4360', (42, 46))	('tumors', 'Disease', (129, 135))	('Arg1', 'Gene', (33, 37))	('downregulated', 'NegReg', (95, 108))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('Mrc1', 'Gene', (42, 46))	('G47Delta-treated', 'Var', (112, 128))	('Arg1', 'Gene', '383', (33, 37))
8994	32346610	In the present study, G47Delta, a third-generation oncolytic HSV-1, shows a high therapeutic potential for human gastric cancer, even in advanced stages, such that a robust efficacy of G47Delta was observed in an orthotopic tumor model as well as in peritoneal dissemination models.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('G47Delta', 'Var', (22, 30))	('human', 'Species', '9606', (107, 112))	('gastric cancer', 'Disease', (113, 127))	('tumor', 'Disease', (224, 229))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('HSV-1', 'Species', '10298', (61, 66))	('G47Delta', 'Var', (185, 193))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
8997	32346610	The antitumor activity of G47Delta is attributable to several different mechanisms, including selective replication in tumor cells and direct cytotoxicity, induction of both innate and adaptive antitumor immune responses, and modification of the tumor microenvironment.	('tumor', 'Disease', (119, 124))	('cytotoxicity', 'Disease', 'MESH:D064420', (142, 154))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('modification', 'Reg', (226, 238))	('cytotoxicity', 'Disease', (142, 154))	('G47Delta', 'Var', (26, 34))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', (8, 13))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
8998	32346610	In addition, G47Delta efficiently kills cancer stem cells, counteracts the angiogenesis induced by oncolytic HSV-1, and can be engineered to express therapeutic genes that further enhance the efficacy.	('G47Delta', 'Var', (13, 21))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('HSV-1', 'Species', '10298', (109, 114))	('angiogenesis', 'biological_process', 'GO:0001525', ('75', '87'))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
8999	32346610	Good cytopathic effects and replication capabilities of G47Delta were demonstrated in all gastric cancer cell lines tested in vitro, including scirrhous gastric cancer cell lines (Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('demonstrated', 'Reg', (70, 82))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('gastric cancer', 'Disease', 'MESH:D013274', (153, 167))	('replication capabilities', 'CPA', (28, 52))	('scirrhous gastric cancer', 'Disease', 'MESH:D013274', (143, 167))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('scirrhous gastric cancer', 'Disease', (143, 167))	('gastric cancer', 'Phenotype', 'HP:0012126', (153, 167))	('G47Delta', 'Var', (56, 64))	('gastric cancer', 'Disease', (90, 104))
9000	32346610	Subsequent in vivo studies revealed that intratumoral inoculation with G47Delta markedly inhibited tumor growth in subcutaneous tumor models (Figure 2).	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (115, 133))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('subcutaneous tumor', 'Disease', 'MESH:D013352', (115, 133))	('inhibited', 'NegReg', (89, 98))	('G47Delta', 'Var', (71, 79))	('tumor', 'Disease', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('subcutaneous tumor', 'Disease', (115, 133))
9002	32346610	In clinical settings, intratumoral G47Delta inoculation into gastric tumors using endoscopic devices is likely to become a principal means of treating the disease.	('gastric tumors', 'Disease', 'MESH:D013274', (61, 75))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('gastric tumors', 'Phenotype', 'HP:0006753', (61, 75))	('G47Delta inoculation', 'Var', (35, 55))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('gastric tumors', 'Disease', (61, 75))
9003	32346610	We showed the efficacy and feasibility of intratumoral G47Delta inoculation in an orthotopic scirrhous gastric cancer model, which mimics the clinical situation of refractory gastric cancer (Figure 3).	('gastric cancer', 'Phenotype', 'HP:0012126', (175, 189))	('tumor', 'Disease', (47, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('refractory gastric cancer', 'Disease', (164, 189))	('refractory gastric cancer', 'Disease', 'MESH:D013274', (164, 189))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('G47Delta inoculation', 'Var', (55, 75))	('scirrhous gastric cancer', 'Disease', 'MESH:D013274', (93, 117))	('scirrhous gastric cancer', 'Disease', (93, 117))
9007	32346610	Of note, G47Delta treatment remarkably prolonged the survival of mice bearing 44As3Luc peritoneal tumors that were rapidly fatal without G47Delta treatment owing to aggressive tumor progression.	('survival', 'CPA', (53, 61))	('aggressive tumor', 'Disease', 'MESH:D001523', (165, 181))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('peritoneal tumors', 'Disease', (87, 104))	('aggressive tumor', 'Disease', (165, 181))	('mice', 'Species', '10090', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('peritoneal tumors', 'Disease', 'MESH:D010534', (87, 104))	('G47Delta treatment', 'Var', (9, 27))	('prolonged', 'PosReg', (39, 48))
9008	32346610	These findings together with the results from orthotopic models support the usefulness of G47Delta treatment for gastric cancer patients in advanced stages.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('gastric cancer', 'Disease', (113, 127))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('patients', 'Species', '9606', (128, 136))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('G47Delta', 'Var', (90, 98))
9009	32346610	A selective replication of intraperitoneally injected G47Delta in metastatic tumors of the peritoneum was further confirmed in this study (Figure 5).	('tumors', 'Disease', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('G47Delta', 'Var', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))
9010	32346610	An intratumoral inoculation is a reliable way to deliver G47Delta to target tumors; however, in practice, it is difficult to inoculate tumor nodules scattered in the peritoneum with G47Delta without an invasive procedure.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('G47Delta', 'Var', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', (76, 82))	('G47Delta', 'Var', (182, 190))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
9011	32346610	The present results suggest that G47Delta injected intraperitoneally can readily distribute to, and selectively replicate in, disseminated tumors without needing to inject the virus into each tumor nodule.	('G47Delta', 'Var', (33, 41))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
9012	32346610	Because ascites can contain a high concentration of antibodies, a possibility remains that intraperitoneally injected G47Delta can be attenuated in patients pre-exposed to HSV-1, as reported in a phase I study of oncolytic vaccinia virus for patients with peritoneal carcinomatosis.	('patients', 'Species', '9606', (148, 156))	('high concentration of antibodies', 'Phenotype', 'HP:0010702', (30, 62))	('HSV-1', 'Species', '10298', (172, 177))	('pre', 'molecular_function', 'GO:0003904', ('157', '160'))	('attenuated', 'NegReg', (134, 144))	('peritoneal carcinomatosis', 'Disease', (256, 281))	('ascites', 'Phenotype', 'HP:0001541', (8, 15))	('ascites', 'Disease', (8, 15))	('G47Delta', 'Var', (118, 126))	('peritoneal carcinomatosis', 'Disease', 'MESH:D010534', (256, 281))	('vaccinia virus', 'Species', '10245', (223, 237))	('ascites', 'Disease', 'MESH:D001201', (8, 15))	('patients', 'Species', '9606', (242, 250))
9016	32346610	G47Delta treatment elicits specific antitumor immunity that is further augmented by local expressions of immunostimulatory molecules such as soluble B7-1 and IL-12.	('IL-12', 'molecular_function', 'GO:0005143', ('158', '163'))	('elicits', 'Reg', (19, 26))	('B7-1', 'Gene', (149, 153))	('soluble', 'cellular_component', 'GO:0005625', ('141', '148'))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('B7-1', 'Gene', '941', (149, 153))	('G47Delta treatment', 'Var', (0, 18))	('expressions', 'MPA', (90, 101))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('augmented', 'PosReg', (71, 80))
9017	32346610	In addition, G47Delta treatment modifies immunosuppressive components of the tumor microenvironment such as regulatory T cells or immunosuppressive tumor-associated macrophages, resulting in facilitated trafficking of effector immune cells.	('modifies', 'Reg', (32, 40))	('facilitated', 'PosReg', (191, 202))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('G47Delta treatment', 'Var', (13, 31))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('trafficking', 'CPA', (203, 214))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
9018	32346610	Our study reveals that G47Delta treatment significantly increases the infiltration of inflammatory M1 macrophages and NK cells into the tumor, while markedly decreasing the number of intratumoral immunosuppressive M2 macrophages, resulting in an increase in the M1-to-M2 ratio (Figures 6 and 7).	('tumor', 'Disease', (188, 193))	('infiltration', 'CPA', (70, 82))	('G47Delta treatment', 'Var', (23, 41))	('increases', 'PosReg', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('increase', 'PosReg', (246, 254))	('decreasing', 'NegReg', (158, 168))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', (136, 141))	('M1-to-M2 ratio', 'MPA', (262, 276))
9021	32346610	M1-polarized macrophages induced by oncolytic HSV-1 reportedly produce tumor necrosis factor (TNF)-alpha, which inhibits viral replication.	('HSV-1', 'Species', '10298', (46, 51))	('necrosis', 'biological_process', 'GO:0070265', ('77', '85'))	('viral replication', 'biological_process', 'GO:0008166', ('121', '138'))	('necrosis', 'biological_process', 'GO:0008219', ('77', '85'))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('71', '92'))	('necrosis', 'biological_process', 'GO:0019835', ('77', '85'))	('viral replication', 'CPA', (121, 138))	('necrosis', 'biological_process', 'GO:0008220', ('77', '85'))	('necrosis', 'biological_process', 'GO:0001906', ('77', '85'))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor necrosis factor (TNF)-alpha', 'Gene', '7124', (71, 104))	('oncolytic', 'Var', (36, 45))	('viral replication', 'biological_process', 'GO:0019079', ('121', '138'))	('viral replication', 'biological_process', 'GO:0019058', ('121', '138'))	('HSV-1', 'Gene', (46, 51))	('inhibits', 'NegReg', (112, 120))
9028	32346610	Whether the decrease of M2 macrophages in G47Delta-treated tumors is relevant to the improved efficacy needs further elucidation.	('G47Delta-treated', 'Var', (42, 58))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
9029	32346610	In summary, our results demonstrate that G47Delta is useful for treating human gastric cancer, including scirrhous gastric cancer and the ones in advanced stages.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('scirrhous gastric cancer', 'Disease', 'MESH:D013274', (105, 129))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('scirrhous gastric cancer', 'Disease', (105, 129))	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('G47Delta', 'Var', (41, 49))	('human', 'Species', '9606', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('gastric cancer', 'Disease', (79, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))
9030	32346610	Further scrutiny is merited as to whether the innate immunity stimulated by G47Delta treatment can facilitate the antitumor effect of G47Delta.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('G47Delta', 'Var', (134, 142))	('tumor', 'Disease', (118, 123))	('innate immunity', 'biological_process', 'GO:0045087', ('46', '61'))	('facilitate', 'PosReg', (99, 109))	('G47Delta', 'Var', (76, 84))
9037	32346610	Briefly, cells were seeded onto six-well plates at 2 x 105 cells/well and incubated overnight at 37 C. The following day, the cells were infected with G47Delta at various MOIs (0.01, 0.1, or 1) or mock, and further incubated in growth medium containing 1% heat-inactivated fetal calf serum (FCS) at 34.5 C. The number of surviving cells was counted daily with a Coulter Counter (Beckman Coulter, Fullerton, CA, USA) and expressed as a percentage of mock-infected controls.	('infected', 'Disease', (137, 145))	('infected', 'Disease', 'MESH:D007239', (454, 462))	('G47Delta', 'Var', (151, 159))	('infected', 'Disease', (454, 462))	('infected', 'Disease', 'MESH:D007239', (137, 145))
9038	32346610	Briefly, the cells were seeded onto 96-well plates at the optimal cell density (OCUM-1, 1 x 104 cells/well; Kato III, 5 x 103 cells/well; HSC-39, 9 x 103 cells/well) and were then infected with G47Delta (MOIs of 0.01, 0.1 or 1) or mock.	('G47Delta', 'Var', (194, 202))	('infected', 'Disease', 'MESH:D007239', (180, 188))	('HSC', 'cellular_component', 'GO:0035301', ('138', '141'))	('infected', 'Disease', (180, 188))
9040	32346610	Cells were seeded onto six-well plates at 3 x 105 cells/well and incubated overnight at 37 C. The following day, triplicate wells were infected with G47Delta at an MOI of 0.01.	('G47Delta', 'Var', (149, 157))	('infected', 'Disease', 'MESH:D007239', (135, 143))	('infected', 'Disease', (135, 143))
9045	32346610	When tumors reached approximately 5-7 mm in diameter, the animals were randomized, and mock or G47Delta (2 x 105 or 1 x 106 PFU) in 20 muL of phosphate-buffered saline (PBS) containing 10% glycerol was inoculated into the left-flank tumors.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Disease', (5, 11))	('PBS', 'Chemical', '-', (169, 172))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('G47Delta', 'Var', (95, 103))	('left-flank tumors', 'Disease', (222, 239))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Disease', (233, 239))	('left-flank tumors', 'Disease', 'MESH:D021501', (222, 239))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('phosphate-buffered saline', 'Chemical', '-', (142, 167))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('glycerol', 'Chemical', 'MESH:D005990', (189, 197))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
9048	32346610	For evaluating the efficacy of G47Delta for large tumors, athymic mice harboring MNK45 and 44As3 tumors were inoculated intratumorally with G47Delta (1 x 106 PFU) or mock three times (days 0, 2, and 4) when the tumor volumes exceeded 200 mm3.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumors', 'Disease', (97, 103))	('tumor', 'Disease', (211, 216))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('MNK45', 'Gene', (81, 86))	('tumor', 'Disease', (97, 102))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('mice', 'Species', '10090', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('G47Delta', 'Var', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))
9051	32346610	For in vivo flow cytometry experiments, mice with established MKN45 subcutaneous tumors were given a single intratumoral inoculation with mock or G47Delta (1 x 106 PFU).	('subcutaneous tumors', 'Disease', (68, 87))	('tumor', 'Disease', (113, 118))	('MKN45', 'Gene', (62, 67))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (68, 87))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (68, 87))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (68, 86))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mice', 'Species', '10090', (40, 44))	('G47Delta', 'Var', (146, 154))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (81, 86))
9056	32346610	On days 8 and 11, the mice were inoculated intratumorally with mock or G47Delta (2 x 106 PFU) in 20 muL of PBS containing 10% glycerol.	('PBS', 'Chemical', '-', (107, 110))	('tumor', 'Disease', (48, 53))	('glycerol', 'Chemical', 'MESH:D005990', (126, 134))	('G47Delta', 'Var', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mice', 'Species', '10090', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
9070	32346610	Athymic mice bearing MKN45 subcutaneous tumors were treated with a single intratumoral inoculation with mock or G47Delta (1 x 106 PFU).	('subcutaneous tumors', 'Disease', 'MESH:D013352', (27, 46))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('subcutaneous tumors', 'Disease', (27, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('G47Delta', 'Var', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (27, 46))	('MKN45', 'Var', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (40, 45))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (27, 45))	('mice', 'Species', '10090', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
9076	32175271	On the other hand, a high level of METTL3 was significantly associated with several clinicopathological features and poor survival in patients with GC.	('GC', 'Disease', 'MESH:D013274', (148, 150))	('patients', 'Species', '9606', (134, 142))	('GC', 'Phenotype', 'HP:0012126', (148, 150))	('METTL3', 'Gene', (35, 41))	('high level', 'Var', (21, 31))	('associated', 'Reg', (60, 70))
9084	32175271	N6-methyladenosine (m6A) modification is the most prominent and conservative RNA modification in both prokaryotes and eukaryotes.	('m6A', 'Gene', '56339', (20, 23))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('N6-methyladenosine', 'Var', (0, 18))	('RNA', 'cellular_component', 'GO:0005562', ('77', '80'))	('RNA modification', 'biological_process', 'GO:0009451', ('77', '93'))	('m6A', 'Gene', (20, 23))
9085	32175271	Recent studies have shown that m6A modifications in mRNA play critical roles in cell meiosis, circadian clock control, and cell fate decisions, even in viral infections and immune responses.	('circadian', 'MPA', (94, 103))	('viral infections', 'Disease', 'MESH:D014777', (152, 168))	('m6A', 'Gene', '56339', (31, 34))	('cell fate decisions', 'CPA', (123, 142))	('meiosis', 'biological_process', 'GO:0051321', ('85', '92'))	('modifications', 'Var', (35, 48))	('roles', 'Reg', (71, 76))	('cell meiosis', 'CPA', (80, 92))	('m6A', 'Gene', (31, 34))	('viral infections', 'Disease', (152, 168))
9086	32175271	M6A modifications are dynamic and reversible processes catalyzed by methyltransferases (writers) and demethylases (erasers).	('demethylase', 'Gene', '8932', (101, 112))	('methyltransferases', 'Enzyme', (68, 86))	('M6A', 'Gene', '56339', (0, 3))	('M6A', 'Gene', (0, 3))	('modifications', 'Var', (4, 17))	('demethylase', 'Gene', (101, 112))
9093	32175271	In this study, we identified aberrant METTL3 expression and its prognostic value in GC.	('METTL3', 'Gene', (38, 44))	('GC', 'Phenotype', 'HP:0012126', (84, 86))	('GC', 'Disease', 'MESH:D013274', (84, 86))	('aberrant', 'Var', (29, 37))
9129	32175271	Gene set enrichment analysis (GSEA) was performed to evaluate the pathway differences in expression and m6A modification patterns between the sh#METTL3 and control groups.	('expression', 'MPA', (89, 99))	('m6A', 'Gene', '56339', (104, 107))	('sh#', 'Var', (142, 145))	('GSEA', 'Chemical', '-', (30, 34))	('m6A', 'Gene', (104, 107))
9154	32175271	In addition, in the tumor size <=5 cm group and grade III group, high METTL3 expression was associated with worse OS and DFS (Supplementary Figure 2).	('expression', 'MPA', (77, 87))	('worse OS', 'Disease', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('METTL3', 'Gene', (70, 76))	('high', 'Var', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('DFS', 'Disease', (121, 124))	('tumor', 'Disease', (20, 25))
9155	32175271	Collectively, these findings suggested that high METTL3 expression was an independent prognostic factor of poor overall survival in GC patients.	('patients', 'Species', '9606', (135, 143))	('high', 'Var', (44, 48))	('GC', 'Disease', 'MESH:D013274', (132, 134))	('METTL3', 'Protein', (49, 55))	('expression', 'MPA', (56, 66))	('GC', 'Phenotype', 'HP:0012126', (132, 134))	('overall', 'MPA', (112, 119))
9157	32175271	As expected, once successfully knocking down METTL3, m6A levels in SGC7901 and AGS sharply reduced (Figure 3A).	('knocking down', 'Var', (31, 44))	('m6A', 'Gene', '56339', (53, 56))	('METTL3', 'Gene', (45, 51))	('SGC7901', 'Gene', (67, 74))	('m6A', 'Gene', (53, 56))	('reduced', 'NegReg', (91, 98))	('SGC7901', 'CellLine', 'CVCL:0520', (67, 74))	('AGS', 'Disease', (79, 82))	('AGS', 'Disease', 'MESH:C535607', (79, 82))	('GC', 'Phenotype', 'HP:0012126', (68, 70))
9159	32175271	The results of the MTS assays and colony-forming assays indicated that depletion of METTL3 could obviously suppress proliferation and colony-forming abilities of GC cells (Figures 3B,C).	('suppress', 'NegReg', (107, 115))	('GC', 'Disease', 'MESH:D013274', (162, 164))	('depletion', 'Var', (71, 80))	('GC', 'Phenotype', 'HP:0012126', (162, 164))	('colony-forming abilities', 'CPA', (134, 158))	('proliferation', 'CPA', (116, 129))	('METTL3', 'Gene', (84, 90))
9160	32175271	In the migration and invasion assays, the silencing of METTL3 significantly inhibited the migratory and invasive abilities of SGC7901 and AGS cells (Figure 3D).	('GC', 'Phenotype', 'HP:0012126', (127, 129))	('silencing', 'Var', (42, 51))	('SGC7901', 'CellLine', 'CVCL:0520', (126, 133))	('METTL3', 'Gene', (55, 61))	('AGS', 'Disease', (138, 141))	('inhibited', 'NegReg', (76, 85))	('migration', 'CPA', (7, 16))	('AGS', 'Disease', 'MESH:C535607', (138, 141))
9162	32175271	We observed xenograft growth for 3 weeks and found that METTL3 silencing could suppress tumor growth in vivo (Figure 3E).	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('METTL3', 'Gene', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('suppress', 'NegReg', (79, 87))	('silencing', 'Var', (63, 72))
9166	32175271	In addition, we observed elevated m6A levels in cells overexpressing METTL3 (Figure 4A).	('m6A', 'Gene', '56339', (34, 37))	('overexpressing', 'Var', (54, 68))	('elevated', 'PosReg', (25, 33))	('METTL3', 'Gene', (69, 75))	('m6A', 'Gene', (34, 37))
9174	32175271	MYC target genes had a significant decrease at both the m6A and mRNA levels after METTL3 knockdown (Figure 5D).	('MYC', 'Gene', (0, 3))	('m6A', 'Gene', (56, 59))	('METTL3', 'Gene', (82, 88))	('m6A', 'Gene', '56339', (56, 59))	('decrease', 'NegReg', (35, 43))	('mRNA levels', 'MPA', (64, 75))	('MYC', 'Gene', '4609', (0, 3))	('knockdown', 'Var', (89, 98))
9176	32175271	In addition, the protein levels of MYC, MCM5, and MCM6 were decreased with METTL3 knockdown in SGC7901 cells (Figure 5F).	('decreased', 'NegReg', (60, 69))	('METTL3', 'Gene', (75, 81))	('MYC', 'Gene', (35, 38))	('GC', 'Phenotype', 'HP:0012126', (96, 98))	('MCM5', 'Gene', '4174', (40, 44))	('MCM6', 'Gene', '4175', (50, 54))	('knockdown', 'Var', (82, 91))	('SGC7901', 'CellLine', 'CVCL:0520', (95, 102))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('MYC', 'Gene', '4609', (35, 38))	('MCM5', 'Gene', (40, 44))	('protein levels', 'MPA', (17, 31))	('MCM6', 'Gene', (50, 54))
9181	32175271	Several studies have identified that METTL3 can promote cancer cell proliferation and invasion by upregulating downstream key oncogenes via post-transcriptional modification.	('upregulating', 'PosReg', (98, 110))	('post-transcriptional modification', 'Var', (140, 173))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('promote', 'PosReg', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('METTL3', 'Gene', (37, 43))	('cancer', 'Disease', (56, 62))	('invasion', 'CPA', (86, 94))	('cell proliferation', 'biological_process', 'GO:0008283', ('63', '81'))
9186	32175271	The results of Liu and coworkers indicated that METTL3 knockdown reduces alpha-smooth muscle actin and that METTL3 is an adverse factor in patients with GC.	('knockdown', 'Var', (55, 64))	('GC', 'Disease', 'MESH:D013274', (153, 155))	('patients', 'Species', '9606', (139, 147))	('alpha-smooth muscle actin', 'MPA', (73, 98))	('reduces', 'NegReg', (65, 72))	('METTL3', 'Gene', (48, 54))	('GC', 'Phenotype', 'HP:0012126', (153, 155))
9191	32175271	Then, we confirmed the carcinogenesis of METTL3 by silencing or overexpressing METTL3 in cells.	('silencing', 'Var', (51, 60))	('carcinogenesis', 'Disease', (23, 37))	('METTL3', 'Gene', (41, 47))	('METTL3', 'Gene', (79, 85))	('overexpressing', 'PosReg', (64, 78))	('carcinogenesis', 'Disease', 'MESH:D063646', (23, 37))
9196	32175271	Several studies have indicated that METTL3, METTL14, or FTO could affect the stability of MYC mRNA via the alteration of m6A abundance.	('alteration', 'Reg', (107, 117))	('FTO', 'Gene', (56, 59))	('affect', 'Reg', (66, 72))	('m6A', 'Gene', (121, 124))	('MYC', 'Gene', (90, 93))	('m6A', 'Gene', '56339', (121, 124))	('FTO', 'Gene', '79068', (56, 59))	('MYC', 'Gene', '4609', (90, 93))	('METTL14', 'Gene', (44, 51))	('METTL14', 'Gene', '57721', (44, 51))	('METTL3', 'Var', (36, 42))
9197	32175271	However, in the current research, we did not observe influences on the relative m6A abundance of MYC transcripts by METTL3 depletion.	('METTL3', 'Gene', (116, 122))	('m6A', 'Gene', (80, 83))	('MYC', 'Gene', (97, 100))	('depletion', 'Var', (123, 132))	('m6A', 'Gene', '56339', (80, 83))	('MYC', 'Gene', '4609', (97, 100))
9198	32175271	Indeed, MYC and its downstream proteins were degraded upon METTL3 depletion.	('degraded', 'NegReg', (45, 53))	('MYC', 'Gene', (8, 11))	('METTL3', 'Gene', (59, 65))	('depletion', 'Var', (66, 75))	('MYC', 'Gene', '4609', (8, 11))	('proteins', 'Protein', (31, 39))
9202	32175271	It was reported that high MCM5 expression was associated with poor clinicopathological parameters and poor survival in GC.	('GC', 'Phenotype', 'HP:0012126', (119, 121))	('MCM5', 'Gene', (26, 30))	('high', 'Var', (21, 25))	('MCM5', 'Gene', '4174', (26, 30))	('GC', 'Disease', 'MESH:D013274', (119, 121))
9206	32175271	Thus, we presumed that the possible regulatory mechanisms were a decrease in the stability of MCM5 and MCM6 transcripts mediated by METTL3 depletion.	('MCM6', 'Gene', '4175', (103, 107))	('MCM5', 'Gene', '4174', (94, 98))	('MCM5', 'Gene', (94, 98))	('decrease', 'NegReg', (65, 73))	('MCM6', 'Gene', (103, 107))	('METTL3', 'Gene', (132, 138))	('depletion', 'Var', (139, 148))	('stability', 'MPA', (81, 90))
9209	32175271	In conclusion, our study highlights a new pathway of METTL3-mediated m6A modification in the epigenetic silencing of MYC downstream molecules in GC, which can provide a new strategy for more careful surveillance and aggressive therapeutic intervention.	('m6A', 'Gene', (69, 72))	('epigenetic silencing', 'MPA', (93, 113))	('GC', 'Disease', 'MESH:D013274', (145, 147))	('m6A', 'Gene', '56339', (69, 72))	('MYC', 'Gene', (117, 120))	('GC', 'Phenotype', 'HP:0012126', (145, 147))	('METTL3-mediated', 'Gene', (53, 68))	('modification', 'Var', (73, 85))	('MYC', 'Gene', '4609', (117, 120))
9210	32175271	The RNA-seq and m6A-seq data from METTL3 knockdown or non-treated SGC7901 have been deposited in BioProject under accession PRJNA595769.	('METTL3', 'Gene', (34, 40))	('m6A', 'Gene', (16, 19))	('SGC7901', 'CellLine', 'CVCL:0520', (66, 73))	('RNA', 'cellular_component', 'GO:0005562', ('4', '7'))	('m6A', 'Gene', '56339', (16, 19))	('GC', 'Phenotype', 'HP:0012126', (67, 69))	('knockdown', 'Var', (41, 50))	('SGC7901', 'Gene', (66, 73))
9260	32099809	Any deferment - delay in gastric output which leads to accumulation of food debris associated with low gastric pH provides an ideal environment for Sarcina spp.	('spp', 'molecular_function', 'GO:0042499', ('156', '159'))	('deferment - delay', 'Var', (4, 21))	('gastric output', 'MPA', (25, 39))	('accumulation of food debris', 'MPA', (55, 82))	('Sarcina', 'Species', '35785', (148, 155))
9265	32099809	There are even cases of Sarcina ventriculi isolated from the blood of the patients with suffering from congenital chloride diarrhea a rare inherited disease that belongs to the Finnish disease heritage caused by mutations in the SLC26A3 gene on the chromosome 7 leading to the function disruption of the major anion exchanger on the surface of intestinal epithelial cells.	('function disruption', 'MPA', (277, 296))	('inherited disease', 'Disease', 'MESH:D030342', (139, 156))	('SLC26A3', 'Gene', (229, 236))	('patients', 'Species', '9606', (74, 82))	('congenital chloride diarrhea', 'Disease', (103, 131))	('SLC26A3', 'Gene', '1811', (229, 236))	('Sarcina ventriculi', 'Species', '1267', (24, 42))	('congenital chloride diarrhea', 'Disease', 'MESH:C536210', (103, 131))	('exchanger', 'molecular_function', 'GO:0015297', ('316', '325'))	('inherited disease', 'Disease', (139, 156))	('chromosome', 'cellular_component', 'GO:0005694', ('249', '259'))	('mutations', 'Var', (212, 221))	('caused by', 'Reg', (202, 211))	('diarrhea', 'Phenotype', 'HP:0002014', (123, 131))
9393	29209116	On this basis, ROS can cause DNA damage and associated oncogenic changes, thus lead to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('DNA', 'cellular_component', 'GO:0005574', ('29', '32'))	('DNA damage', 'MPA', (29, 39))	('tumor', 'Disease', (87, 92))	('ROS', 'Chemical', 'MESH:D017382', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('ROS', 'Var', (15, 18))	('lead to', 'Reg', (79, 86))	('cause', 'Reg', (23, 28))	('oncogenic changes', 'CPA', (55, 72))
9415	29209116	Logistic regression revealed role of fasting plasma glucose, neutrophil, and CEA as independent risk factors in xanthelasma.	('xanthelasma', 'Disease', (112, 123))	('xanthelasma', 'Phenotype', 'HP:0001114', (112, 123))	('neutrophil', 'Var', (61, 71))	('glucose', 'Chemical', 'MESH:D005947', (52, 59))
9437	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))	('apoptosis', 'biological_process', 'GO:0097194', ('188', '197'))	('proliferation', 'CPA', (151, 164))	('apoptosis', 'biological_process', 'GO:0006915', ('188', '197'))	('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))	('drug resistance', 'biological_process', 'GO:0009315', ('208', '223'))	('drug resistance', 'biological_process', 'GO:0042493', ('208', '223'))	('cancer', 'Disease', (108, 114))	('metastasis', 'CPA', (176, 186))	('invasion', 'CPA', (166, 174))	('regulation', 'biological_process', 'GO:0065007', ('94', '104'))	('regulation', 'MPA', (94, 104))	('multi-drug resistance', 'CPA', (202, 223))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (58, 64))
9439	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))
9460	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))
9499	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))	('breast cancer', 'Disease', (350, 363))	('bladder cancer', 'Disease', (208, 222))	('increases', 'PosReg', (170, 179))	('promotes', 'PosReg', (387, 395))	('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))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('310', '346'))	('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))
9508	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))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cell proliferation', 'CPA', (75, 93))	('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))	('colon cancer', 'Disease', (3, 15))
9511	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))
9512	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))
9515	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))
9525	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))
9558	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))
9640	27591765	Mutations in the tumor suppressor genes TP53 and p16/CDKN2A have also been shown to occur commonly in IPMNs  although mostly in regions of high grade dysplasia.	('tumor suppressor', 'biological_process', 'GO:0051726', ('17', '33'))	('tumor', 'Disease', (17, 22))	('CDKN2A', 'Gene', (53, 59))	('CDKN2A', 'Gene', '1029', (53, 59))	('p16', 'Gene', (49, 52))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('17', '33'))	('TP53', 'Gene', '7157', (40, 44))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', (40, 44))	('occur', 'Reg', (84, 89))	('dysplasia', 'Disease', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('dysplasia', 'Disease', 'MESH:D004476', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('p16', 'Gene', '1029', (49, 52))	('IPMNs', 'Disease', (102, 107))
9642	27591765	In addition, activating mutations in GNAS  and inactivating mutations in RNF43  have been identified in at least half of IPMNs, especially intestinal-type, and are relatively specific for the "IPMN pathway" .	('RNF43', 'Gene', (73, 78))	('GNAS', 'Gene', (37, 41))	('activating', 'PosReg', (13, 23))	('identified', 'Reg', (90, 100))	('IPMNs', 'Disease', (121, 126))	('GNAS', 'Gene', '2778', (37, 41))	('inactivating mutations', 'Var', (47, 69))	('RNF43', 'Gene', '54894', (73, 78))
9644	27591765	Several other studies have investigated mucin expression and selected gene mutations in IOPNs and showed that IOPNs generally do not have specific patterns of mucin protein expression (except for MUC6 ), and they do not harbor the same genetic alterations commonly seen in DAs and IPMNs .	('investigated', 'Reg', (27, 39))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('DAs', 'Disease', (273, 276))	('MUC6', 'Gene', '4588', (196, 200))	('mucin', 'Gene', (40, 45))	('mucin', 'Gene', '100508689', (159, 164))	('mucin', 'Gene', (159, 164))	('mutations', 'Var', (75, 84))	('MUC6', 'Gene', (196, 200))	('IPMNs', 'Disease', (281, 286))	('mucin', 'Gene', '100508689', (40, 45))
9646	27591765	identified mutations in codon 12 of the KRAS gene in three of eighteen (17%) IOPNs.	('mutations in', 'Var', (11, 23))	('KRAS', 'Gene', '3845', (40, 44))	('KRAS', 'Gene', (40, 44))
9647	27591765	Therefore, it is quite possible that the three cases they reported as KRAS mutated may have exhibited heterogeneity in differentiation, and that the oncocytic features were a morphologic variation within a non-oncocytic IPMN.	('mutated', 'Var', (75, 82))	('KRAS', 'Gene', (70, 74))	('KRAS', 'Gene', '3845', (70, 74))
9648	27591765	reported that twelve of twelve (100%) intestinal-type, five of seven (71%) pancreatobiliary-type, and twenty-seven of fifty-three (51%) gastric-type IPMNs harbored a codon 201 GNAS mutation, while two of two (100%) IOPNs in their series were found to be GNAS wild type .	('GNAS', 'Gene', '2778', (254, 258))	('GNAS', 'Gene', '2778', (176, 180))	('codon 201', 'Var', (166, 175))	('harbored', 'Reg', (155, 163))	('GNAS', 'Gene', (254, 258))	('gastric-type IPMN', 'Disease', 'MESH:D000077779', (136, 153))	('GNAS', 'Gene', (176, 180))	('gastric-type IPMN', 'Disease', (136, 153))
9650	27591765	Instead, ARHGAP26, ASXL1, EPHA8, and ERBB4 genes were mutated in more than one IOPN .	('ERBB4', 'Gene', (37, 42))	('ASXL1', 'Gene', '171023', (19, 24))	('EPHA8', 'Gene', '2046', (26, 31))	('EPHA8', 'Gene', (26, 31))	('ASXL1', 'Gene', (19, 24))	('ARHGAP26', 'Gene', '23092', (9, 17))	('ARHGAP26', 'Gene', (9, 17))	('mutated', 'Var', (54, 61))	('ERBB4', 'Gene', '2066', (37, 42))
9683	27591765	A higher proportion of IOPNs labeled with antibodies to mesothelin [21/24 (87.5%) of IOPNs vs 6/22 (27%) of IPMNs, p<0.001], while the reverse was true for claudin-4 [2/23 (9%) of IOPNs vs 9/22 (41%) of IPMNs, p=0.01].	('claudin-4', 'Gene', '1364', (156, 165))	('mesothelin', 'Gene', '10232', (56, 66))	('claudin-4', 'Gene', (156, 165))	('higher proportion of IOPNs', 'Phenotype', 'HP:0007906', (2, 28))	('antibodies', 'Var', (42, 52))	('mesothelin', 'Gene', (56, 66))
9697	27591765	6), but only 6/21(29%) IPMNs revealed MUC6 expression (p=0.002) in their papillae and the degree of expression was much stronger in IOPNs compared to IPMNs.	('MUC6', 'Gene', (38, 42))	('stronger', 'PosReg', (120, 128))	('MUC6', 'Gene', '4588', (38, 42))	('IOPNs', 'Var', (132, 137))	('expression', 'MPA', (43, 53))
9721	27591765	Alterations in the adenomatous polyposis coli (APC)/ beta-catenin pathway have been reported in non-ductal pancreatic lesions such as acinar cell carcinoma, solid-pseudopapillary neoplasm and pancreatoblastoma but are only rarely found in DA .	('Alterations', 'Var', (0, 11))	('pancreatic lesions', 'Disease', 'MESH:D010182', (107, 125))	('APC)', 'Gene', '324', (47, 51))	('APC', 'Phenotype', 'HP:0005227', (47, 50))	('solid-pseudopapillary neoplasm and pancreatoblastoma', 'Disease', 'MESH:C537162', (157, 209))	('APC', 'cellular_component', 'GO:0005680', ('47', '50'))	('neoplasm', 'Phenotype', 'HP:0002664', (179, 187))	('pancreatoblastoma', 'Phenotype', 'HP:0100757', (192, 209))	('APC', 'Gene', (47, 50))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (19, 45))	('beta-catenin', 'Gene', (53, 65))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (19, 45))	('adenomatous polyposis coli', 'Disease', (19, 45))	('beta-catenin', 'Gene', '1499', (53, 65))	('acinar cell carcinoma', 'Disease', (134, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('pancreatic lesions', 'Disease', (107, 125))	('acinar cell carcinoma', 'Disease', 'MESH:D018267', (134, 155))	('reported', 'Reg', (84, 92))
9725	27591765	In previous studies, TP53 gene mutations have been identified in 0-38% (weighted mean, 21%) of IPMNs, with most cases showing mutation only in high-grade dysplasia and invasive carcinoma .	('TP53', 'Gene', (21, 25))	('mutations', 'Var', (31, 40))	('invasive carcinoma', 'Disease', (168, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('invasive carcinoma', 'Disease', 'MESH:D009361', (168, 186))	('dysplasia', 'Disease', (154, 163))	('IPMNs', 'Disease', (95, 100))	('dysplasia', 'Disease', 'MESH:D004476', (154, 163))	('TP53', 'Gene', '7157', (21, 25))
9726	27591765	In pancreatic DA and PanIN, abnormalities in p53 expression are detected more often in invasive carcinomas (60%) and PanIN3 and rarely in lower-grade lesions .	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('p53', 'Gene', (45, 48))	('abnormalities', 'Var', (28, 41))	('p53', 'Gene', '7157', (45, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('invasive carcinomas', 'Disease', (87, 106))	('invasive carcinomas', 'Disease', 'MESH:D009361', (87, 106))	('expression', 'MPA', (49, 59))	('detected', 'Reg', (64, 72))	('pancreatic', 'Disease', 'MESH:D010195', (3, 13))	('PanIN3', 'Disease', (117, 123))	('pancreatic', 'Disease', (3, 13))
9741	27591765	Also, in accordance with previous findings was a high proportion of MUC2 positivity in intestinal-type IPMN versus than in pancreatobiliary-type IPMN or gastric-type IPMN.	('intestinal-type IPMN', 'Disease', (87, 107))	('gastric-type IPMN', 'Disease', 'MESH:D000077779', (153, 170))	('pancreatobiliary-type IPMN', 'Disease', (123, 149))	('pancreatobiliary-type IPMN', 'Disease', 'MESH:D000077779', (123, 149))	('positivity', 'Var', (73, 83))	('gastric-type IPMN', 'Disease', (153, 170))	('MUC2', 'Gene', (68, 72))	('MUC2', 'Gene', '4583', (68, 72))
9742	27591765	The unexpected finding was that a high percentage (52%) of IOPNs labeled with antibodies to MUC1 (Fig.	('antibodies', 'Var', (78, 88))	('MUC1', 'Gene', (92, 96))	('MUC1', 'Gene', '4582', (92, 96))
9778	27504109	Subsequently, a huge number of studies confirmed the role of H. pylori virulence factors in peptic ulcer and gastric cancer and H. pylori was classified as a type I carcinogen by WHO.	('H. pylori', 'Species', '210', (61, 70))	('virulence', 'biological_process', 'GO:0009405', ('71', '80'))	('peptic ulcer', 'Disease', 'MESH:D010437', (92, 104))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('H. pylori', 'Var', (128, 137))	('gastric cancer', 'Disease', (109, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('peptic ulcer', 'Disease', (92, 104))	('peptic ulcer', 'Phenotype', 'HP:0004398', (92, 104))	('virulence', 'biological_process', 'GO:0009406', ('71', '80'))	('virulence', 'biological_process', 'GO:0016032', ('71', '80'))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('H. pylori', 'Species', '210', (128, 137))
9781	27504109	The phospho-CagA interacts and deregulates the SHP-2 protein, which leads to cancer, but the CagA can hijack cellular pathways also by phosphorylation independent manner.	('hijack', 'Reg', (102, 108))	('cellular pathways', 'Pathway', (109, 126))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('protein', 'cellular_component', 'GO:0003675', ('53', '60'))	('phosphorylation', 'biological_process', 'GO:0016310', ('135', '150'))	('protein', 'Protein', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('SHP-2', 'Gene', (47, 52))	('leads to', 'Reg', (68, 76))	('deregulates', 'Var', (31, 42))
9782	27504109	For example, polymorphisms in interleukin-1 (IL1) and tumour necrosis factor (TNF) genes have been shown to play important roles in progression of gastric diseases among Scottish, Japanese, American, and Indian populations.	('tumour necrosis', 'Disease', (54, 69))	('gastric diseases', 'Disease', 'MESH:D013274', (147, 163))	('necrosis', 'biological_process', 'GO:0070265', ('61', '69'))	('necrosis', 'biological_process', 'GO:0008219', ('61', '69'))	('necrosis', 'biological_process', 'GO:0019835', ('61', '69'))	('IL1', 'molecular_function', 'GO:0005149', ('45', '48'))	('necrosis', 'biological_process', 'GO:0008220', ('61', '69'))	('polymorphisms', 'Var', (13, 26))	('necrosis', 'biological_process', 'GO:0001906', ('61', '69'))	('IL1', 'Gene', (45, 48))	('roles', 'Reg', (123, 128))	('TNF', 'Gene', (78, 81))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumour necrosis', 'Disease', 'MESH:D009336', (54, 69))	('gastric diseases', 'Disease', (147, 163))
9784	27504109	A study using Swedish patients showed that the presence of H. pylori in stomach may significantly alter the relative abundance of other bacteria.	('H. pylori', 'Gene', (59, 68))	('alter', 'Reg', (98, 103))	('H. pylori', 'Species', '210', (59, 68))	('presence of H. pylori in stomach', 'Phenotype', 'HP:0005202', (47, 79))	('patients', 'Species', '9606', (22, 30))	('relative abundance of other bacteria', 'MPA', (108, 144))	('presence', 'Var', (47, 55))
9795	27504109	Also, eradication of H. pylori may lead to esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('H. pylori', 'Species', '210', (21, 30))	('eradication', 'Var', (6, 17))	('lead to', 'Reg', (35, 42))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
9854	26716899	Compared with the reference EBV strain GD1, they harbored 961 variations in total, including 919 substitutions, 23 insertions, and 19 deletions.	('strain GD1', 'Species', '1176482', (32, 42))	('EBV strain', 'Species', '10376', (28, 38))	('substitutions', 'Var', (97, 110))	('insertions', 'Var', (115, 125))
9855	26716899	Single nucleotide polymorphism (SNP) density varied substantially across all known open reading frames and was highest in latency-associated genes.	('highest', 'Reg', (111, 118))	('latency-associated', 'Gene', (122, 140))	('Single nucleotide polymorphism', 'Var', (0, 30))	('P', 'Chemical', 'MESH:D010758', (34, 35))
9858	26716899	In conclusion, we reported the first genome-wide view of sequence variation of EBV isolated from primary EBVaGC biopsy specimens, which might serve as an effective method for further understanding the genomic variations contribute to EBVaGC carcinogenesis and treatment.	('EBV', 'Species', '10376', (105, 108))	('EBV', 'Gene', (79, 82))	('carcinogenesis', 'Disease', 'MESH:D063646', (241, 255))	('EBVaGC', 'Disease', (234, 240))	('carcinogenesis', 'Disease', (241, 255))	('EBV', 'Species', '10376', (234, 237))	('sequence variation', 'Var', (57, 75))	('EBV', 'Species', '10376', (79, 82))
9861	26716899	Furthermore, the presence of EBV in tumor cells represents a potential "tumor-specific" target for therapeutic approaches.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('EBV', 'Species', '10376', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('presence', 'Var', (17, 25))	('EBV', 'Protein', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('pro', 'Chemical', 'MESH:D011392', (113, 116))	('tumor', 'Disease', (36, 41))
9865	26716899	Up to now, 19 complete or partial EBV genomes, EBV-wild type, B95-8, AG876, Akata, Mutu, K4413-Mi, K4123-Mi, C666-1, GD1, GD2, and HKNPC1 to 9, have been reported.	('K4413-Mi', 'Var', (89, 97))	('P', 'Chemical', 'MESH:D010758', (134, 135))	('GD1', 'Species', '929558', (117, 120))	('NPC', 'Phenotype', 'HP:0100630', (133, 136))	('K4123-Mi', 'Var', (99, 107))	('C666-1', 'Var', (109, 115))	('EBV', 'Species', '10376', (47, 50))	('to 9', 'Species', '1214577', (138, 142))	('EBV', 'Species', '10376', (34, 37))	('GD2', 'Species', '929558', (122, 125))
9870	26716899	K4413-Mi and K4123-Mi were sequenced from immortalized human B lymphocyte cell lines.	('K4413-Mi', 'Var', (0, 8))	('human', 'Species', '9606', (55, 60))	('K4123-Mi', 'Var', (13, 21))
9871	26716899	C666-1 was derived from a nasopharyngeal carcinoma (NPC) xenograft cell line of southern Chinese origin.	('C666-1', 'Var', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('NPC', 'Phenotype', 'HP:0100630', (52, 55))	('P', 'Chemical', 'MESH:D010758', (53, 54))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (26, 50))	('NPC', 'cellular_component', 'GO:0005643', ('52', '55'))	('nasopharyngeal carcinoma', 'Disease', (26, 50))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (26, 50))
9897	26716899	The genome sizes, estimated based on the reference EBV GD1 sequence, were as follows: EBVaGC1 (171,957 bp), EBVaGC2 (171,759 bp), EBVaGC3 (171,615 bp), EBVaGC4 (171,661 bp), EBVaGC5 (171,759 bp), EBVaGC6 (171,612 bp), EBVaGC7 (171,673 bp), EBVaGC8 (171,664 bp), and EBVaGC9 (171,858 bp).	('EBV', 'Species', '10376', (86, 89))	('EBVaGC5', 'Chemical', '-', (174, 181))	('171,664', 'Var', (249, 256))	('EBV', 'Species', '10376', (196, 199))	('EBV', 'Species', '10376', (108, 111))	('GD1', 'Species', '929558', (55, 58))	('EBV', 'Species', '10376', (266, 269))	('EBVaGC6', 'Chemical', '-', (196, 203))	('EBV', 'Species', '10376', (51, 54))	('171,673', 'Var', (227, 234))	('171,612', 'Var', (205, 212))	('EBV', 'Species', '10376', (218, 221))	('EBVaGC2', 'Chemical', '-', (108, 115))	('EBV', 'Species', '10376', (130, 133))	('EBVaGC4', 'Chemical', '-', (152, 159))	('EBV', 'Species', '10376', (240, 243))	('EBV', 'Species', '10376', (152, 155))	('EBVaGC1', 'Chemical', '-', (86, 93))	('EBV', 'Species', '10376', (174, 177))
9898	26716899	961 variations were observed in the EBVaGC1 to 9 genomes in comparison to the reference EBV GD1, including 919 substitutions, 23 insertions, and 19 deletions.	('insertions', 'Var', (129, 139))	('substitutions', 'Var', (111, 124))	('EBVaGC1', 'Chemical', '-', (36, 43))	('EBV', 'Species', '10376', (36, 39))	('to 9', 'Species', '1214577', (44, 48))	('EBV', 'Species', '10376', (88, 91))	('GD1', 'Species', '929558', (92, 95))
9901	26716899	The pattern of distribution of variations among the genomes of EBVaGC2, 4, 7 and 9 was rather similar, showing relative fewer variations.	('variations', 'Var', (31, 41))	('EBVaGC2', 'Gene', (63, 70))	('EBVaGC2', 'Chemical', '-', (63, 70))
9904	26716899	Nonsynonymous mutations in the 9 GC-EBV genomes were classified into 9 categories, according to the function of EBV-encoded proteins defined by Tarbouriech et al..	('GC-EBV', 'Gene', (33, 39))	('EBV', 'Species', '10376', (36, 39))	('pro', 'Chemical', 'MESH:D011392', (124, 127))	('Nonsynonymous mutations', 'Var', (0, 23))	('EBV', 'Species', '10376', (112, 115))	('to 9', 'Species', '1214577', (66, 70))
9906	26716899	The remaining nonsynonymous mutations were located in membrane glycoproteins, capsid, and proteins for replication, transcription, nucleotide metabolism, or packaging, or in proteins of unknown function.	('pro', 'Chemical', 'MESH:D011392', (174, 177))	('pro', 'Chemical', 'MESH:D011392', (68, 71))	('nonsynonymous mutations', 'Var', (14, 37))	('pro', 'Chemical', 'MESH:D011392', (90, 93))	('gly', 'Chemical', '-', (63, 66))	('membrane', 'cellular_component', 'GO:0016020', ('54', '62'))	('transcription', 'biological_process', 'GO:0006351', ('116', '129'))	('located', 'Reg', (43, 50))	('nucleotide metabolism', 'biological_process', 'GO:0009117', ('131', '152'))
9909	26716899	Additionally, analysis on LMP-1 genes of EBVaGC1 to 9 revealed that EBVaGC6 was distant to other GC-EBV strains, indicating that EBVaGC6 might harbor many mutations that were not present in the other GC-EBV strains.	('mutations', 'Var', (155, 164))	('EBV strain', 'Species', '10376', (100, 110))	('EBV strain', 'Species', '10376', (203, 213))	('EBVaGC6', 'Chemical', '-', (129, 136))	('P', 'Chemical', 'MESH:D010758', (28, 29))	('EBVaGC6', 'Chemical', '-', (68, 75))	('LMP-1', 'Gene', (26, 31))	('EBVaGC1', 'Chemical', '-', (41, 48))	('harbor', 'Reg', (143, 149))	('to 9', 'Species', '1214577', (49, 53))
9914	26716899	Figure S2 in the Supplementary Materials illustrates the nonsynonymous mutations that resulted in amino acid changes in EBNA1 in at least 1 of the 9 GC-EBV strains relative to the reference GD1 EBNA1 sequence.	('resulted', 'Reg', (86, 94))	('amino', 'MPA', (98, 103))	('EBNA1', 'Gene', (120, 125))	('GD1', 'Species', '929558', (190, 193))	('mutations', 'Var', (71, 80))	('EBV strain', 'Species', '10376', (152, 162))
9915	26716899	and Gutierrez et al., 5 EBNA1 subtypes were determined, including P-ala, P-thr, V-pro, V-leu, and V-val.	('V-leu', 'Var', (87, 92))	('P-thr', 'Var', (73, 78))	('pro', 'Chemical', 'MESH:D011392', (82, 85))	('V', 'Chemical', 'MESH:D014639', (98, 99))	('V-val', 'Chemical', '-', (98, 103))	('leu', 'Chemical', 'MESH:D007930', (89, 92))	('V-val', 'Var', (98, 103))	('V-pro', 'Var', (80, 85))	('V', 'Chemical', 'MESH:D014639', (87, 88))	('P-thr', 'Chemical', '-', (73, 78))	('V', 'Chemical', 'MESH:D014639', (80, 81))	('P-ala', 'Var', (66, 71))
9922	26716899	EBNA-1 N-terminus changes, though generally linked to variations in the C-terminus, have revealed additional variants that were not evident by evaluating the C-terminus alone.	('changes', 'Var', (18, 25))	('C-terminus', 'MPA', (72, 82))	('EBNA-1', 'Gene', '17494214', (0, 6))	('N-terminus', 'MPA', (7, 17))	('linked', 'Reg', (44, 50))	('variants', 'Var', (109, 117))	('EBNA-1', 'Gene', (0, 6))	('variations', 'Var', (54, 64))
9927	26716899	However, a small number of isolates displayed a different combination, for example, EBVaGC5 may arise from recombination of EBVaGC1 and EBVaGC2, and EBVaGC4 may arise from recombination of AG876 and EBVaGC1 (Figure 5 and Figure S3).	('EBVaGC1', 'Gene', (124, 131))	('recombination', 'Var', (107, 120))	('arise from', 'Reg', (161, 171))	('EBVaGC2', 'Chemical', '-', (136, 143))	('arise from', 'Reg', (96, 106))	('EBVaGC1', 'Chemical', '-', (124, 131))	('EBVaGC1', 'Chemical', '-', (199, 206))	('EBVaGC5', 'Disease', (84, 91))	('EBVaGC4', 'Chemical', '-', (149, 156))	('EBVaGC5', 'Chemical', '-', (84, 91))
9929	26716899	The extensive genetic diversity within EBNA1 and LMP2A can have a significant impact on immune recognition of these antigens.	('extensive genetic diversity', 'Var', (4, 31))	('EBNA1', 'Gene', (39, 44))	('impact', 'Reg', (78, 84))	('LMP2A', 'Gene', '17494231', (49, 54))	('LMP2A', 'Gene', (49, 54))	('immune', 'MPA', (88, 94))
9931	26716899	According to the epitopes specific for both CD4+ and CD8+ T cells defined and reviewed in previous publications, amino acid changes were found in 5 CD8+ epitopes and 28 CD4+ epitopes of EBNA1, 14 CD8+ epitopes and 8 CD4+ epitopes of LMP2A.	('CD8', 'Gene', '925', (148, 151))	('CD8', 'Gene', (53, 56))	('CD4', 'Gene', (216, 219))	('CD8', 'Gene', '925', (53, 56))	('CD4', 'Gene', '920', (216, 219))	('CD4', 'Gene', (169, 172))	('CD8', 'Gene', (196, 199))	('CD8', 'Gene', '925', (196, 199))	('amino acid changes', 'Var', (113, 131))	('LMP2A', 'Gene', '17494231', (233, 238))	('LMP2A', 'Gene', (233, 238))	('CD4', 'Gene', '920', (169, 172))	('found', 'Reg', (137, 142))	('CD8', 'Gene', (148, 151))	('CD4', 'Gene', (44, 47))	('CD4', 'Gene', '920', (44, 47))	('EBNA1', 'Gene', (186, 191))
9932	26716899	For example, a G-to-A substitution at coordinate 97120 (NC_007605) resulted in the change of residue 487 (A T) in EBNA1 in EBVaGC1 and EBVaGC4, and a C-to-T substitution at coordinate 97121 resulted in the change of residue 487 (A V) in EBNA1 in the other 7 GC-EBV strains, where CD4+ epitopes SNP, NPK, ENI, IAE, and LRA were located.	('EBVaGC4', 'Chemical', '-', (135, 142))	('V', 'Chemical', 'MESH:D014639', (263, 264))	('V', 'Chemical', 'MESH:D014639', (137, 138))	('change', 'Reg', (206, 212))	('residue 487', 'MPA', (216, 227))	('substitution', 'Var', (22, 34))	('P', 'Chemical', 'MESH:D010758', (296, 297))	('P', 'Chemical', 'MESH:D010758', (300, 301))	('change', 'Reg', (83, 89))	('EBV strain', 'Species', '10376', (261, 271))	('V', 'Chemical', 'MESH:D014639', (125, 126))	('CD4', 'Gene', (280, 283))	('EBVaGC1', 'Chemical', '-', (123, 130))	('CD4', 'Gene', '920', (280, 283))	('residue 487', 'MPA', (93, 104))	('EBNA1', 'Gene', (114, 119))	('V', 'Chemical', 'MESH:D014639', (231, 232))
9933	26716899	A C-to-T substitution at coordinate 97232 resulted in the change of residue 524 (T I) in EBNA1 in all 9 GC-EBV strains, where CD4+ epitopes VYG, TSL, YNL, NLR, and EEG were located.	('CD4', 'Gene', (126, 129))	('V', 'Chemical', 'MESH:D014639', (109, 110))	('residue', 'MPA', (68, 75))	('EBNA1', 'Gene', (89, 94))	('CD4', 'Gene', '920', (126, 129))	('change', 'Reg', (58, 64))	('EBV strain', 'Species', '10376', (107, 117))	('V', 'Chemical', 'MESH:D014639', (140, 141))	('substitution', 'Var', (9, 21))
9934	26716899	Another G-to-T substitution at coordinate 97250 resulted in the change of residue 563 (M I) in EBNA1 in only EBVaGC1 and EBVaGC4, where CD4+ epitopes APG, PQP, PGP, LRE, YFM, and MVF were located.	('change', 'Reg', (64, 70))	('P', 'Chemical', 'MESH:D010758', (157, 158))	('P', 'Chemical', 'MESH:D010758', (160, 161))	('residue', 'MPA', (74, 81))	('substitution', 'Var', (15, 27))	('CD4', 'Gene', '920', (136, 139))	('EBVaGC1', 'Chemical', '-', (109, 116))	('EBNA1', 'Gene', (95, 100))	('V', 'Chemical', 'MESH:D014639', (123, 124))	('P', 'Chemical', 'MESH:D010758', (151, 152))	('EBVaGC4', 'Chemical', '-', (121, 128))	('PGP', 'Gene', '283871', (160, 163))	('P', 'Chemical', 'MESH:D010758', (162, 163))	('P', 'Chemical', 'MESH:D010758', (155, 156))	('V', 'Chemical', 'MESH:D014639', (111, 112))	('PGP', 'Gene', (160, 163))	('V', 'Chemical', 'MESH:D014639', (180, 181))	('CD4', 'Gene', (136, 139))
9949	26716899	Consistent with previous reports, there is clear evidence (Figure 3) for a higher frequency of SNPs in latent genes, followed by the genes encoding tegument and membrane glycoproteins.	('latent genes', 'Gene', (103, 115))	('gly', 'Chemical', '-', (170, 173))	('pro', 'Chemical', 'MESH:D011392', (175, 178))	('membrane', 'cellular_component', 'GO:0016020', ('161', '169'))	('SNPs', 'Var', (95, 99))	('P', 'Chemical', 'MESH:D010758', (97, 98))
9951	26716899	V-val and P-thrV were observed in our study based on the amino acid changes at position 487 in the COOH-terminal region in EBNA1 relative to B95-8 (P-ala).	('changes', 'Var', (68, 75))	('thrV', 'Chemical', '-', (12, 16))	('amino', 'Var', (57, 62))	('V-val', 'Chemical', '-', (0, 5))	('EBNA1', 'Gene', (123, 128))
9957	26716899	A comprehensive investigation into the functional and immunological impact of the naturally occurred EBNA1 sequence variations and interstrain recombinants is required to evaluate their possible significance, which may also be helpful for clarifying the association of EBNA1 subtypes and EBVaGC.	('variations', 'Var', (116, 126))	('EBVaGC', 'Disease', (288, 294))	('association', 'Interaction', (254, 265))	('EBV', 'Species', '10376', (288, 291))	('EBNA1', 'Gene', (101, 106))
9988	26716899	6 available EBV reference genomes included EBV-wild type (NC_007605.1), AG876 (DQ279927.1), B95-8 (V01555.2), GD1 (AY961628.3), GD2 (HQ020558.1), and HKNPC1 (JQ009376).	('AY961628.3', 'Var', (115, 125))	('NPC', 'Phenotype', 'HP:0100630', (152, 155))	('GD2', 'Species', '929558', (128, 131))	('GD1', 'Species', '929558', (110, 113))	('HQ020558.1', 'Var', (133, 143))	('EBV', 'Species', '10376', (12, 15))	('V', 'Chemical', 'MESH:D014639', (99, 100))	('EBV', 'Species', '10376', (43, 46))	('V', 'Chemical', 'MESH:D014639', (14, 15))	('DQ279927.1', 'Var', (79, 89))	('V01555.2', 'Var', (99, 107))	('P', 'Chemical', 'MESH:D010758', (153, 154))	('V', 'Chemical', 'MESH:D014639', (45, 46))
10002	26716899	Classification of nonsynonymous mutations was based on the 9 categories of EBV-encoded proteins, as defined by Tarbouriech et al.. More attention was paid to those that resulted in amino acid changes in CD8+ and CD4+ T-cell epitopes of EBNA1 and LMP2A.	('CD4', 'Gene', (212, 215))	('LMP2A', 'Gene', '17494231', (246, 251))	('LMP2A', 'Gene', (246, 251))	('CD4', 'Gene', '920', (212, 215))	('EBNA1', 'Gene', (236, 241))	('pro', 'Chemical', 'MESH:D011392', (87, 90))	('CD8', 'Gene', (203, 206))	('changes', 'Var', (192, 199))	('EBV', 'Species', '10376', (75, 78))	('CD8', 'Gene', '925', (203, 206))	('resulted in', 'Reg', (169, 180))
10006	26716899	Sequence data for the 9 GC biopsy specimen-derived EBV (GC-EBV) genomes were submitted to GenBank under accession numbers KT273942 (EBVaGC1), KT273943 (EBVaGC2), KT254013 (EBVaGC3), KT273944 (EBVaGC4), KT273945 (EBVaGC5), KT273946 (EBVaGC6), KT273947 (EBVaGC7), KT273948 (EBVaGC8), and KT273949 (EBVaGC9).	('KT273945', 'Var', (202, 210))	('EBV', 'Species', '10376', (252, 255))	('EBV', 'Species', '10376', (172, 175))	('EBVaGC1', 'Chemical', '-', (132, 139))	('EBV', 'Species', '10376', (212, 215))	('EBVaGC2', 'Chemical', '-', (152, 159))	('KT273947', 'Var', (242, 250))	('KT273946', 'Var', (222, 230))	('EBV', 'Species', '10376', (132, 135))	('EBVaGC5', 'Chemical', '-', (212, 219))	('KT273943', 'Var', (142, 150))	('EBV', 'Species', '10376', (59, 62))	('EBV', 'Species', '10376', (51, 54))	('EBV', 'Species', '10376', (296, 299))	('KT273948', 'Var', (262, 270))	('EBVaGC4', 'Chemical', '-', (192, 199))	('KT273949', 'Var', (286, 294))	('EBV', 'Species', '10376', (232, 235))	('EBV', 'Species', '10376', (192, 195))	('KT273942', 'Var', (122, 130))	('EBV', 'Species', '10376', (272, 275))	('EBV', 'Species', '10376', (152, 155))	('EBVaGC6', 'Chemical', '-', (232, 239))	('KT254013', 'Var', (162, 170))	('KT273944', 'Var', (182, 190))
10051	26878019	Although the advantage of LCTG has not been established relative to the open procedure, we expect that LCTG has general advantages, such as reduced pain and faster recovery, without compromising oncologic safety.	('pain', 'Phenotype', 'HP:0012531', (148, 152))	('reduced pain', 'Phenotype', 'HP:0007328', (140, 152))	('pain', 'Disease', 'MESH:D010146', (148, 152))	('pain', 'Disease', (148, 152))	('LCTG', 'Chemical', '-', (26, 30))	('LCTG', 'Var', (103, 107))	('LCTG', 'Chemical', '-', (103, 107))	('reduced', 'NegReg', (140, 147))
10094	26354049	In addition, the use of PPIs and histamine-2 receptor antagonists (H2RAs) can also cause false-negative results by reducing gastric acid secretion and inhibiting the growth of H. pylori.	('growth', 'MPA', (166, 172))	('gastric acid secretion', 'biological_process', 'GO:0001696', ('124', '146'))	('inhibiting', 'NegReg', (151, 161))	('false', 'biological_process', 'GO:0071878', ('89', '94'))	('H. pylori', 'Species', '210', (176, 185))	('reducing', 'NegReg', (115, 123))	('H. pylori', 'Disease', (176, 185))	('gastric acid secretion', 'MPA', (124, 146))	('PPIs', 'Var', (24, 28))	('false', 'biological_process', 'GO:0071877', ('89', '94'))
10097	26354049	also demonstrated that both PPIs and H2RAs could affect the sensitivity of UBT, with an equivocal or false-negative result of 61% and 18%, respectively.	('PPIs', 'Var', (28, 32))	('affect', 'Reg', (49, 55))	('false', 'biological_process', 'GO:0071878', ('101', '106'))	('false', 'biological_process', 'GO:0071877', ('101', '106'))	('UBT', 'Chemical', '-', (75, 78))	('UBT', 'Disease', (75, 78))	('H2RAs', 'Var', (37, 42))	('sensitivity', 'MPA', (60, 71))
10105	26354049	Another study based on 1,000 biopsy specimens has shown that the area of H. pylori colonization was larger than the area of active chronic gastritis, suggesting that H. pylori colonization may precede the development of active chronic gastritis.	('chronic gastritis', 'Disease', 'MESH:D005756', (227, 244))	('chronic gastritis', 'Phenotype', 'HP:0005231', (131, 148))	('H. pylori', 'Var', (166, 175))	('chronic gastritis', 'Disease', 'MESH:D005756', (131, 148))	('H. pylori', 'Species', '210', (73, 82))	('chronic gastritis', 'Disease', (227, 244))	('H. pylori', 'Species', '210', (166, 175))	('gastritis', 'Phenotype', 'HP:0005263', (139, 148))	('chronic gastritis', 'Phenotype', 'HP:0005231', (227, 244))	('chronic gastritis', 'Disease', (131, 148))	('gastritis', 'Phenotype', 'HP:0005263', (235, 244))
10136	26354049	Molecular changes in gastric protective factors, such as mucin, are also hypothesized to be associated with risk of ulcers.	('mucin', 'Protein', (57, 62))	('ulcers', 'Disease', (116, 122))	('Molecular changes', 'Var', (0, 17))	('ulcers', 'Disease', 'MESH:D014456', (116, 122))	('associated', 'Reg', (92, 102))
10139	26354049	In addition to genetic or epigenetic changes in the gastric mucin molecule, the HLA-DQA1*0102 allele was associated with increased risk of IPUD.	('IPUD', 'Chemical', '-', (139, 143))	('epigenetic changes', 'Var', (26, 44))	('IPUD', 'Disease', (139, 143))	('gastric mucin molecule', 'Protein', (52, 74))	('HLA-DQA1', 'Gene', (80, 88))	('associated', 'Reg', (105, 115))
10155	26354049	After a bleeding episode, the risk of recurrent ulcer complications within 12 months was higher in patients with H. pylori-negative PUD than in those with H. pylori-related PUD after eradication therapy (13.4% vs. 2.5%, p < 0.001).	('bleeding', 'Disease', (8, 16))	('H. pylori', 'Species', '210', (113, 122))	('H. pylori-negative', 'Var', (113, 131))	('patients', 'Species', '9606', (99, 107))	('H. pylori', 'Species', '210', (155, 164))	('bleeding episode', 'Phenotype', 'HP:0001892', (8, 24))	('ulcer complications', 'Disease', (48, 67))	('ulcer complications', 'Disease', 'MESH:D014456', (48, 67))	('bleeding', 'Disease', 'MESH:D006470', (8, 16))
10158	26354049	The rates of recurrent ulcer or ulcer that has not healed (35% vs. 26%), and relapse of dyspepsia symptoms (16% vs. 7%) were higher in those with H. pylori-negative ulcers than in those with H. pylori-positive ulcers.	('ulcers', 'Disease', 'MESH:D014456', (165, 171))	('ulcers', 'Disease', 'MESH:D014456', (210, 216))	('dyspepsia', 'Phenotype', 'HP:0410281', (88, 97))	('ulcers', 'Disease', (210, 216))	('ulcer', 'Disease', (165, 170))	('dyspepsia symptoms', 'Disease', 'MESH:D004415', (88, 106))	('ulcer', 'Disease', 'MESH:D014456', (210, 215))	('ulcer', 'Disease', (210, 215))	('H. pylori', 'Species', '210', (191, 200))	('ulcer', 'Disease', 'MESH:D014456', (23, 28))	('ulcer', 'Disease', 'MESH:D014456', (32, 37))	('ulcer', 'Disease', 'MESH:D014456', (165, 170))	('H. pylori', 'Species', '210', (146, 155))	('ulcers', 'Disease', (165, 171))	('ulcer', 'Disease', (23, 28))	('dyspepsia symptoms', 'Disease', (88, 106))	('ulcer', 'Disease', (32, 37))	('H. pylori-negative', 'Var', (146, 164))
10181	25932391	The prevalence of HP seropositive was 65.9% versus 50.5% in diabetic and nondiabetics, respectively, and the difference was statistically significant (P = 0.001).	('diabetic', 'Disease', (60, 68))	('diabetics', 'Disease', 'MESH:D003920', (76, 85))	('seropositive', 'Var', (21, 33))	('diabetic', 'Disease', 'MESH:D003920', (76, 84))	('diabetic', 'Disease', 'MESH:D003920', (60, 68))	('diabetic', 'Disease', (76, 84))	('HP', 'Species', '210', (18, 20))	('diabetics', 'Disease', (76, 85))
10206	25932391	Regarding the relationship between variables affecting diabetes, after entering the variables including HDL, LDL, FBS, TG, IR and insulin in the model, LDL and TG increased the chance of developing diabetes up to 0.016 and 0.004, respectively (R2 coefficient = 0.83).	('LDL', 'molecular_function', 'GO:0005322', ('109', '112'))	('TG', 'Chemical', 'MESH:D014280', (119, 121))	('LDL', 'molecular_function', 'GO:0005322', ('152', '155'))	('insulin', 'Gene', (130, 137))	('diabetes', 'Disease', (55, 63))	('HDL', 'molecular_function', 'GO:0005321', ('104', '107'))	('FBS', 'Disease', (114, 117))	('diabetes', 'Disease', 'MESH:D003920', (55, 63))	('insulin', 'Gene', '3630', (130, 137))	('insulin', 'molecular_function', 'GO:0016088', ('130', '137'))	('FBS', 'Disease', 'MESH:D005198', (114, 117))	('diabetes', 'Disease', (198, 206))	('diabetes', 'Disease', 'MESH:D003920', (198, 206))	('TG', 'Chemical', 'MESH:D014280', (160, 162))	('LDL', 'Var', (152, 155))
10246	25932391	In a previous study on diabetic patients, we found that serum insulin (HP- = 6.97 +- 5.64 vs. HP+ = 10.12 +- 7.72, P = 0.002) and insulin resistance degree (HP- = 3.16 +- 3.32 vs. HP+ = 4.48 +- 3.78, P = 0.013) are significantly higher in HP+ group.	('patients', 'Species', '9606', (32, 40))	('insulin', 'Gene', (130, 137))	('higher', 'PosReg', (229, 235))	('HP', 'Species', '210', (71, 73))	('diabetic', 'Disease', (23, 31))	('insulin', 'Gene', '3630', (130, 137))	('HP+', 'Var', (239, 242))	('HP', 'Species', '210', (239, 241))	('HP', 'Species', '210', (157, 159))	('insulin resistance', 'Phenotype', 'HP:0000855', (130, 148))	('insulin', 'molecular_function', 'GO:0016088', ('62', '69'))	('insulin', 'molecular_function', 'GO:0016088', ('130', '137'))	('insulin', 'Gene', (62, 69))	('HP', 'Species', '210', (94, 96))	('insulin', 'Gene', '3630', (62, 69))	('diabetic', 'Disease', 'MESH:D003920', (23, 31))	('HP', 'Species', '210', (180, 182))
10269	24527072	The abnormal expression of miRNAs is key in the progression of human cancer and may act as a biomarker that is used for a clinical diagnosis of early GC.	('human', 'Species', '9606', (63, 68))	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('GC', 'Phenotype', 'HP:0012126', (150, 152))	('clinical', 'Species', '191496', (122, 130))	('cancer', 'Disease', (69, 75))
10324	24527072	These multiple signal pathway alterations, particularly those that include the Wnt and TGF-beta pathways, may reasonably affect the progress of GC carcinogenesis.	('GC', 'Phenotype', 'HP:0012126', (144, 146))	('affect', 'Reg', (121, 127))	('TGF-beta', 'Gene', (87, 95))	('carcinogenesis', 'Disease', 'MESH:D063646', (147, 161))	('carcinogenesis', 'Disease', (147, 161))	('alterations', 'Var', (30, 41))	('TGF-beta', 'Gene', '7040', (87, 95))
10334	33824282	Functional assays such as EdU, colony formation, JC-1 and transwell assays displayed that silencing LINC01559 inhibited cell proliferation and migration while promoted cell apoptosis in GC.	('cell proliferation', 'CPA', (120, 138))	('cell proliferation', 'biological_process', 'GO:0008283', ('120', '138'))	('EdU', 'Chemical', 'MESH:C031086', (26, 29))	('silencing', 'Var', (90, 99))	('LINC01559', 'Gene', '283422', (100, 109))	('LINC01559', 'Gene', (100, 109))	('GC', 'Phenotype', 'HP:0012126', (186, 188))	('formation', 'biological_process', 'GO:0009058', ('38', '47'))	('apoptosis', 'biological_process', 'GO:0097194', ('173', '182'))	('apoptosis', 'biological_process', 'GO:0006915', ('173', '182'))	('promoted', 'PosReg', (159, 167))	('inhibited', 'NegReg', (110, 119))
10335	33824282	Besides, western blot analysis and immunofluorescence assays examined the expression of factors related to epithelial-mesenchymal transition (EMT) and indicated that EMT process was blocked by LINC01559 knockdown in GC cells.	('expression', 'MPA', (74, 84))	('EMT', 'biological_process', 'GO:0001837', ('142', '145'))	('EMT', 'biological_process', 'GO:0001837', ('166', '169'))	('GC', 'Phenotype', 'HP:0012126', (216, 218))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('107', '140'))	('blocked', 'NegReg', (182, 189))	('LINC01559', 'Gene', '283422', (193, 202))	('LINC01559', 'Gene', (193, 202))	('knockdown', 'Var', (203, 212))	('EMT process', 'CPA', (166, 177))
10336	33824282	Besides, LINC01559 silencing inhibited tumor growth in vivo.	('inhibited', 'NegReg', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('silencing', 'Var', (19, 28))	('LINC01559', 'Gene', '283422', (9, 18))	('LINC01559', 'Gene', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))
10344	33824282	Abnormally expressed lncRNAs can serves as oncogenes or tumor suppressors to affect the progression and metastasis of cancers.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('progression', 'CPA', (88, 99))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('tumor', 'Disease', (56, 61))	('metastasis of cancers', 'Disease', (104, 125))	('lncRNAs', 'Protein', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('affect', 'Reg', (77, 83))	('metastasis of cancers', 'Disease', 'MESH:D009362', (104, 125))	('Abnormally expressed', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
10379	33824282	The latter was incubated with blocking buffer and followed by further processing with primary antibodies against GAPDH (1/10000, ab181602), E-cadherin (1:2000-1:8000, 60335-1-Ig), N-cadherin (1 microg/ml, ab18203), Slug (1:1000, 9585S), Twist (1/5000, ab187008), ZEB1 (1:500-1:2000, 21544-1-AP), IGF2BP2 (1:1000, 14672S), MAFK (1/4000-1/8000, ab50322), JUND (1:1000, 5000S), JUN (1:1000-1:8000, 66313-1-Ig), ESR1 (1:500-1:2000, 21244-1-AP) and RFX5 (1/500-1/5000, ab9255) as well as secondary antibodies.	('1/4000-1/8000', 'Var', (328, 341))	('E-cadherin', 'Gene', (140, 150))	('E-cadherin', 'Gene', '999', (140, 150))	('cadherin', 'molecular_function', 'GO:0008014', ('142', '150'))	('P', 'Chemical', 'MESH:D010758', (115, 116))	('GAPDH', 'Gene', '2597', (113, 118))	('S', 'Chemical', 'MESH:D013455', (409, 410))	('S', 'Chemical', 'MESH:D013455', (371, 372))	('MAFK', 'Gene', (322, 326))	('Twist', 'Gene', '7291', (237, 242))	('RFX5', 'Gene', (444, 448))	('ZEB1', 'Gene', '6935', (263, 267))	('RFX5', 'Gene', '5993', (444, 448))	('IGF2BP2', 'Gene', (296, 303))	('Slug', 'Gene', '6591', (215, 219))	('ESR1', 'Gene', '2099', (408, 412))	('S', 'Chemical', 'MESH:D013455', (233, 234))	('GAPDH', 'Gene', (113, 118))	('ESR1', 'Gene', (408, 412))	('JUND', 'Gene', (353, 357))	('S', 'Chemical', 'MESH:D013455', (318, 319))	('P', 'Chemical', 'MESH:D010758', (437, 438))	('P', 'Chemical', 'MESH:D010758', (301, 302))	('MAFK', 'Gene', '7975', (322, 326))	('JUND', 'Gene', '3727', (353, 357))	('ZEB1', 'Gene', (263, 267))	('P', 'Chemical', 'MESH:D010758', (292, 293))	('IGF2BP2', 'Gene', '10644', (296, 303))	('N-cadherin', 'Gene', (180, 190))	('Twist', 'Gene', (237, 242))	('S', 'Chemical', 'MESH:D013455', (215, 216))	('N-cadherin', 'Gene', '1000', (180, 190))	('cadherin', 'molecular_function', 'GO:0008014', ('182', '190'))	('Slug', 'Gene', (215, 219))
10380	33824282	SNU-1 and AGS cells were fixed with 4% paraformaldehyde, followed by the incubation with primary antibodies against E-cadherin (1:2000-1:8000, 60335-1-Ig) and N-cadherin (1 microg/ml, ab18203) overnight at 4  C. Then cells were hatched with Cy3-conjugated secondary antibody for 30 min at room temperature.	('cadherin', 'molecular_function', 'GO:0008014', ('118', '126'))	('60335-1-Ig', 'Var', (143, 153))	('cadherin', 'molecular_function', 'GO:0008014', ('161', '169'))	('antibody', 'cellular_component', 'GO:0042571', ('266', '274'))	('E-cadherin', 'Gene', (116, 126))	('E-cadherin', 'Gene', '999', (116, 126))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (39, 55))	('antibody', 'cellular_component', 'GO:0019815', ('266', '274'))	('AGS', 'Disease', (10, 13))	('N-cadherin', 'Gene', (159, 169))	('S', 'Chemical', 'MESH:D013455', (12, 13))	('Cy3', 'Chemical', '-', (241, 244))	('AGS', 'Disease', 'MESH:C535607', (10, 13))	('N-cadherin', 'Gene', '1000', (159, 169))	('antibody', 'cellular_component', 'GO:0019814', ('266', '274'))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('antibody', 'molecular_function', 'GO:0003823', ('266', '274'))
10405	33824282	Biotin-labeled full-length and antisense LINC01559 or ZEB1 sequences were obtained by the use of Transcript Aid T7 High Yield Transcription Kit (Thermo Scientific).	('Biotin', 'Chemical', 'MESH:D001710', (0, 6))	('LINC01559', 'Gene', (41, 50))	('Kit', 'Gene', '3815', (140, 143))	('ZEB1', 'Gene', (54, 58))	('LINC01559', 'Gene', '283422', (41, 50))	('S', 'Chemical', 'MESH:D013455', (152, 153))	('Aid', 'Gene', '57379', (108, 111))	('ZEB1', 'Gene', '6935', (54, 58))	('Aid', 'Gene', (108, 111))	('Kit', 'Gene', (140, 143))	('antisense', 'Var', (31, 40))
10409	33824282	The different bands between sense and antisense LINC01559 were identified using mass spectrometry and determined through western blot analysis.	('LINC01559', 'Gene', '283422', (48, 57))	('LINC01559', 'Gene', (48, 57))	('antisense', 'Var', (38, 47))
10425	33824282	Then the data from EdU and colony formation experiments showed that after silencing LINC01559, the proliferation capacity of two cancer cells was significantly reduced (Fig.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('EdU', 'Chemical', 'MESH:C031086', (19, 22))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('silencing', 'Var', (74, 83))	('reduced', 'NegReg', (160, 167))	('LINC01559', 'Gene', '283422', (84, 93))	('LINC01559', 'Gene', (84, 93))	('formation', 'biological_process', 'GO:0009058', ('34', '43'))
10427	33824282	The data of following JC-1 assay further verified that silencing of LINC01559 had a promoting effect on the apoptosis of GC cells (Fig.	('silencing', 'Var', (55, 64))	('GC', 'Phenotype', 'HP:0012126', (121, 123))	('apoptosis', 'biological_process', 'GO:0097194', ('108', '117'))	('apoptosis', 'biological_process', 'GO:0006915', ('108', '117'))	('promoting', 'PosReg', (84, 93))	('apoptosis', 'CPA', (108, 117))	('LINC01559', 'Gene', '283422', (68, 77))	('LINC01559', 'Gene', (68, 77))
10428	33824282	In short, knockdown of LINC01559 restrains the growth of GC cells.	('growth of GC cells', 'CPA', (47, 65))	('restrains', 'NegReg', (33, 42))	('LINC01559', 'Gene', '283422', (23, 32))	('LINC01559', 'Gene', (23, 32))	('GC', 'Phenotype', 'HP:0012126', (57, 59))	('knockdown', 'Var', (10, 19))
10432	33824282	The data from western blot analysis indicated that the expression of E-cadherin (epithelial marker) was increased while the levels of N-cadherin (mesenchymal marker) and EMT-related proteins including Slug, Twist and ZEB1 were decreased after the depletion of LINC01559 in GC cells (Figs.	('cadherin', 'molecular_function', 'GO:0008014', ('71', '79'))	('Slug', 'Gene', '6591', (201, 205))	('ZEB1', 'Gene', '6935', (217, 221))	('Twist', 'Gene', '7291', (207, 212))	('E-cadherin', 'Gene', (69, 79))	('E-cadherin', 'Gene', '999', (69, 79))	('EMT', 'biological_process', 'GO:0001837', ('170', '173'))	('cadherin', 'molecular_function', 'GO:0008014', ('136', '144'))	('levels', 'MPA', (124, 130))	('depletion', 'Var', (247, 256))	('expression', 'MPA', (55, 65))	('GC', 'Phenotype', 'HP:0012126', (273, 275))	('Slug', 'Gene', (201, 205))	('ZEB1', 'Gene', (217, 221))	('Twist', 'Gene', (207, 212))	('N-cadherin', 'Gene', (134, 144))	('N-cadherin', 'Gene', '1000', (134, 144))	('increased', 'PosReg', (104, 113))	('decreased', 'NegReg', (227, 236))	('LINC01559', 'Gene', '283422', (260, 269))	('LINC01559', 'Gene', (260, 269))
10436	33824282	As expected, silencing of LINC01559 effectively interfered the tumor growth, resulting in lighter tumor weight (Fig.	('tumor', 'Disease', (63, 68))	('interfered', 'NegReg', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('lighter', 'NegReg', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('LINC01559', 'Gene', (26, 35))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('LINC01559', 'Gene', '283422', (26, 35))	('silencing', 'Var', (13, 22))
10438	33824282	In sum, silencing of LINC01559 inhibits the metastasis and growth of GC cells.	('LINC01559', 'Gene', '283422', (21, 30))	('LINC01559', 'Gene', (21, 30))	('inhibits', 'NegReg', (31, 39))	('silencing', 'Var', (8, 17))	('GC', 'Phenotype', 'HP:0012126', (69, 71))	('metastasis', 'CPA', (44, 54))	('growth of GC cells', 'CPA', (59, 77))
10442	33824282	Thereafter, RT-qPCR data revealed that the expression level of LINC01559 was significantly up-regulated only by ZEB1 overexpression, while no obvious changes affected by the up-regulation of other transcription factors (Figs.	('LINC01559', 'Gene', '283422', (63, 72))	('LINC01559', 'Gene', (63, 72))	('overexpression', 'Var', (117, 131))	('transcription', 'biological_process', 'GO:0006351', ('197', '210'))	('ZEB1', 'Gene', (112, 116))	('expression level', 'MPA', (43, 59))	('up-regulated', 'PosReg', (91, 103))	('ZEB1', 'Gene', '6935', (112, 116))	('regulation', 'biological_process', 'GO:0065007', ('177', '187'))	('P', 'Chemical', 'MESH:D010758', (16, 17))
10445	33824282	The results displayed that ZEB1 overexpression led to an increase in the luciferase activity of LINC01559 promoter that was wild-type or with site 2/3/4/5 mutations in SNU-1 and AGS cells, while no alteration was observed in that of LINC01559 promoter with Site 1 or all five sites mutated (Fig.	('luciferase', 'Enzyme', (73, 83))	('luciferase activity', 'molecular_function', 'GO:0047077', ('73', '92'))	('S', 'Chemical', 'MESH:D013455', (180, 181))	('luciferase activity', 'molecular_function', 'GO:0045289', ('73', '92'))	('luciferase activity', 'molecular_function', 'GO:0047712', ('73', '92'))	('LINC01559', 'Gene', '283422', (233, 242))	('LINC01559', 'Gene', (233, 242))	('AGS', 'Disease', (178, 181))	('luciferase activity', 'molecular_function', 'GO:0050397', ('73', '92'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('73', '92'))	('ZEB1', 'Gene', (27, 31))	('S', 'Chemical', 'MESH:D013455', (257, 258))	('LINC01559', 'Gene', (96, 105))	('LINC01559', 'Gene', '283422', (96, 105))	('activity', 'MPA', (84, 92))	('AGS', 'Disease', 'MESH:C535607', (178, 181))	('S', 'Chemical', 'MESH:D013455', (168, 169))	('mutations', 'Var', (155, 164))	('increase', 'PosReg', (57, 65))	('ZEB1', 'Gene', '6935', (27, 31))
10453	33824282	Interestingly, we detected that the level of ZEB1 was in return decreased by LINC01559 silencing in SNU-1 and AGS cells (Fig.	('silencing', 'Var', (87, 96))	('S', 'Chemical', 'MESH:D013455', (100, 101))	('LINC01559', 'Gene', '283422', (77, 86))	('ZEB1', 'Gene', '6935', (45, 49))	('S', 'Chemical', 'MESH:D013455', (112, 113))	('ZEB1', 'Gene', (45, 49))	('AGS', 'Disease', (110, 113))	('LINC01559', 'Gene', (77, 86))	('AGS', 'Disease', 'MESH:C535607', (110, 113))	('level', 'MPA', (36, 41))	('decreased', 'NegReg', (64, 73))
10468	33824282	It was found that both the mRNA level and protein level of ZEB1 were obviously declined after the intervene of IGF2BP2 (Fig.	('protein level', 'MPA', (42, 55))	('intervene', 'Var', (98, 107))	('IGF2BP2', 'Gene', (111, 118))	('mRNA level', 'MPA', (27, 37))	('ZEB1', 'Gene', (59, 63))	('declined', 'NegReg', (79, 87))	('ZEB1', 'Gene', '6935', (59, 63))	('IGF2BP2', 'Gene', '10644', (111, 118))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))
10474	33824282	The data from following flow cytometry analysis and JC-1 experiments showed that the increased apoptotic rate of GC cells induced by LINC01559 silencing could be totally abolished after ZEB1 up-regulation (Figs.	('GC', 'Phenotype', 'HP:0012126', (113, 115))	('ZEB1', 'Gene', '6935', (186, 190))	('ZEB1', 'Gene', (186, 190))	('up-regulation', 'PosReg', (191, 204))	('LINC01559', 'Gene', '283422', (133, 142))	('LINC01559', 'Gene', (133, 142))	('silencing', 'Var', (143, 152))	('apoptotic rate', 'CPA', (95, 109))	('regulation', 'biological_process', 'GO:0065007', ('194', '204'))
10476	33824282	Moreover, the results from transwell assays revealed that the lessened number of migrated cells owing to LINC01559 knockdown could be completely rescued by ZEB1 overexpression (Figs.	('ZEB1', 'Gene', (156, 160))	('ZEB1', 'Gene', '6935', (156, 160))	('knockdown', 'Var', (115, 124))	('LINC01559', 'Gene', (105, 114))	('lessened', 'NegReg', (62, 70))	('LINC01559', 'Gene', '283422', (105, 114))
10484	33824282	Moreover, LINC02163 contributes to GC cell growth and EMT by targeting miR-593-3p to regulate FOXK1 expression.	('targeting', 'Reg', (61, 70))	('FOXK1', 'Gene', '221937', (94, 99))	('LINC02163', 'Chemical', '-', (10, 19))	('GC', 'Phenotype', 'HP:0012126', (35, 37))	('regulate', 'Reg', (85, 93))	('expression', 'MPA', (100, 110))	('cell growth', 'biological_process', 'GO:0016049', ('38', '49'))	('EMT', 'CPA', (54, 57))	('EMT', 'biological_process', 'GO:0001837', ('54', '57'))	('FOXK1', 'Gene', (94, 99))	('LINC02163', 'Var', (10, 19))	('GC cell growth', 'CPA', (35, 49))
10487	33824282	Moreover, we conducted loss-of function assays and found that silencing of LINC01559 obviously inhibited the growth and migration of GC cells, which suggested that LINC01559 could play a tumor promoting role in GC progression.	('LINC01559', 'Gene', '283422', (164, 173))	('LINC01559', 'Gene', (164, 173))	('silencing', 'Var', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('GC', 'Phenotype', 'HP:0012126', (133, 135))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('inhibited', 'NegReg', (95, 104))	('tumor', 'Disease', (187, 192))	('GC', 'Phenotype', 'HP:0012126', (211, 213))	('LINC01559', 'Gene', '283422', (75, 84))	('LINC01559', 'Gene', (75, 84))
10490	33824282	Besides, silencing of FoxM1 leads to the suppression of EMT in GC cells via regulating ZEB1.	('FoxM1', 'Gene', '2305', (22, 27))	('ZEB1', 'Gene', '6935', (87, 91))	('EMT in GC cells', 'CPA', (56, 71))	('silencing', 'Var', (9, 18))	('FoxM1', 'Gene', (22, 27))	('GC', 'Phenotype', 'HP:0012126', (63, 65))	('EMT', 'biological_process', 'GO:0001837', ('56', '59'))	('regulating', 'Reg', (76, 86))	('ZEB1', 'Gene', (87, 91))	('suppression', 'NegReg', (41, 52))
10502	33824282	It has been reported that HOTAIR silencing impedes the invasion and proliferation of human colon cancer cells through regulating IGF2BP2.	('impedes', 'NegReg', (43, 50))	('colon cancer', 'Disease', 'MESH:D015179', (91, 103))	('IGF2BP2', 'Gene', '10644', (129, 136))	('silencing', 'Var', (33, 42))	('HOTAIR', 'Gene', (26, 32))	('colon cancer', 'Disease', (91, 103))	('IGF2BP2', 'Gene', (129, 136))	('HOTAIR', 'Gene', '100124700', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('colon cancer', 'Phenotype', 'HP:0003003', (91, 103))	('regulating', 'Reg', (118, 128))	('human', 'Species', '9606', (85, 90))
10559	32823876	Aberrant regulation of the molecular pathways involved in inflammation displays a close association with cancer.	('inflammation', 'biological_process', 'GO:0006954', ('58', '70'))	('regulation', 'biological_process', 'GO:0065007', ('9', '19'))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('inflammation', 'Disease', 'MESH:D007249', (58, 70))	('inflammation', 'Disease', (58, 70))
10571	32823876	Oxidative stress, resulting from an imbalance between ROS production and elimination by enzymatic/non-enzymatic antioxidants including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH), promotes tumor cell proliferation, angiogenesis, and metastasis.	('superoxide dismutase', 'Gene', '6647', (135, 155))	('glutathione', 'Chemical', 'MESH:D005978', (179, 190))	('imbalance', 'Var', (36, 45))	('CAT', 'molecular_function', 'GO:0004096', ('173', '176'))	('metastasis', 'CPA', (285, 295))	('CAT', 'Gene', '847', (173, 176))	('cell proliferation', 'biological_process', 'GO:0008283', ('247', '265'))	('tumor', 'Disease', (241, 246))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('catalase', 'Gene', (163, 171))	('catalase', 'Gene', '847', (163, 171))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('ROS', 'Chemical', 'MESH:D017382', (54, 57))	('GSH', 'Chemical', 'MESH:D005978', (226, 229))	('glutathione', 'Chemical', 'MESH:D005978', (213, 224))	('rat', 'Species', '10116', (259, 262))	('superoxide dismutase', 'Gene', (135, 155))	('SOD', 'Gene', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('CAT', 'Gene', (173, 176))	('promotes', 'PosReg', (232, 240))	('SOD', 'Gene', '6647', (157, 160))	('angiogenesis', 'biological_process', 'GO:0001525', ('267', '279'))	('angiogenesis', 'CPA', (267, 279))	('imbalance', 'Phenotype', 'HP:0002172', (36, 45))	('SOD', 'molecular_function', 'GO:0004784', ('157', '160'))
10576	32823876	As a hallmark of cancer, apoptosis resistance leads to uncontrolled proliferation, cancer cells survival under hypoxic conditions, and resistance to chemotherapeutic drugs.	('hypoxic conditions', 'Disease', 'MESH:D000071069', (111, 129))	('apoptosis', 'Var', (25, 34))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('uncontrolled', 'MPA', (55, 67))	('rat', 'Species', '10116', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('hypoxic conditions', 'Disease', (111, 129))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('apoptosis', 'biological_process', 'GO:0097194', ('25', '34'))	('apoptosis', 'biological_process', 'GO:0006915', ('25', '34'))	('cancer', 'Disease', (17, 23))	('leads to', 'Reg', (46, 54))	('cancer', 'Disease', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
10589	32823876	PARP inhibitors expedite ROS production, DNA damage, and programmed cell death.	('expedite', 'PosReg', (16, 24))	('ROS', 'Chemical', 'MESH:D017382', (25, 28))	('PARP', 'Gene', (0, 4))	('DNA damage', 'CPA', (41, 51))	('programmed cell death', 'CPA', (57, 78))	('inhibitors', 'Var', (5, 15))	('ROS production', 'MPA', (25, 39))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('programmed cell death', 'biological_process', 'GO:0012501', ('57', '78'))	('PARP', 'Gene', '142', (0, 4))
10593	32823876	Aberrant regulation of autophagy contributes toward tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('regulation', 'MPA', (9, 19))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', (52, 57))	('autophagy', 'CPA', (23, 32))	('regulation of autophagy', 'biological_process', 'GO:0010506', ('9', '32'))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
10627	32823876	Rutin has been found to counteract several types of cancer through various mechanisms, e.g., inhibition of malignant cell growth, induction of cell cycle arrest and apoptosis, and modulation of angiogenesis, inflammation, and oxidative stress, all of which are mediated by regulating multiple cellular signaling pathways.	('apoptosis', 'biological_process', 'GO:0097194', ('165', '174'))	('apoptosis', 'biological_process', 'GO:0006915', ('165', '174'))	('angiogenesis', 'CPA', (194, 206))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('143', '160'))	('apoptosis', 'CPA', (165, 174))	('angiogenesis', 'biological_process', 'GO:0001525', ('194', '206'))	('inflammation', 'biological_process', 'GO:0006954', ('208', '220'))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('malignant cell growth', 'CPA', (107, 128))	('cell growth', 'biological_process', 'GO:0016049', ('117', '128'))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (143, 160))	('inhibition', 'NegReg', (93, 103))	('arrest', 'Disease', (154, 160))	('oxidative stress', 'Phenotype', 'HP:0025464', (226, 242))	('inflammation', 'Disease', 'MESH:D007249', (208, 220))	('cancer', 'Disease', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('signaling', 'biological_process', 'GO:0023052', ('302', '311'))	('modulation', 'Var', (180, 190))	('Rutin', 'Chemical', 'MESH:D012431', (0, 5))	('inflammation', 'Disease', (208, 220))	('arrest', 'Disease', 'MESH:D006323', (154, 160))
10651	32823876	Therefore, abrogation of chemoresistance can mitigate the relapsed tumor.	('mitigate', 'NegReg', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('abrogation', 'Var', (11, 21))	('chemoresistance', 'CPA', (25, 40))
10694	32823876	Therapeutic intervention involving the inhibition of VEGF has become an innovative strategy for abrogating tumor metastasis.	('inhibition', 'Var', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('rat', 'Species', '10116', (85, 88))	('tumor metastasis', 'Disease', 'MESH:D009362', (107, 123))	('tumor metastasis', 'Disease', (107, 123))	('VEGF', 'Protein', (53, 57))
10724	32823876	ERK plays a key role in TNF-induced autophagy, inhibition of which enhances cellular sensitivity to TNF-induced apoptosis.	('TNF', 'Gene', (24, 27))	('apoptosis', 'biological_process', 'GO:0097194', ('112', '121'))	('TNF', 'Gene', (100, 103))	('apoptosis', 'biological_process', 'GO:0006915', ('112', '121'))	('inhibition', 'Var', (47, 57))	('autophagy', 'biological_process', 'GO:0006914', ('36', '45'))	('enhances', 'PosReg', (67, 75))	('TNF', 'Gene', '7124', (24, 27))	('TNF', 'Gene', '7124', (100, 103))	('autophagy', 'biological_process', 'GO:0016236', ('36', '45'))	('ERK', 'Gene', '5594', (0, 3))	('ERK', 'Gene', (0, 3))	('ERK', 'molecular_function', 'GO:0004707', ('0', '3'))	('cellular sensitivity', 'CPA', (76, 96))
10749	32823876	In another in vivo study, rutin reduces liver/spleen weight, abolishes proliferation, and augments the activity of macrophage phagocytosis, thereby inducing an immune response in WEHI-3-induced leukemia model in BALB/c mice.	('rutin', 'Var', (26, 31))	('immune response', 'CPA', (160, 175))	('rutin', 'Chemical', 'MESH:D012431', (26, 31))	('men', 'Species', '9606', (93, 96))	('abolishes', 'NegReg', (61, 70))	('mice', 'Species', '10090', (219, 223))	('activity of macrophage phagocytosis', 'CPA', (103, 138))	('phagocytosis', 'biological_process', 'GO:0006909', ('126', '138'))	('immune response', 'biological_process', 'GO:0006955', ('160', '175'))	('rat', 'Species', '10116', (78, 81))	('inducing', 'Reg', (148, 156))	('reduces', 'NegReg', (32, 39))	('augments', 'NegReg', (90, 98))	('proliferation', 'CPA', (71, 84))	('liver/spleen weight', 'MPA', (40, 59))	('leukemia', 'Disease', 'MESH:D007938', (194, 202))	('leukemia', 'Phenotype', 'HP:0001909', (194, 202))	('leukemia', 'Disease', (194, 202))
10782	32823876	Na+/K+, Ca2+, and Mg2+ ATPases play a key role in the transportation of the electrolytes sodium, potassium, calcium, and magnesium across membranes.	('sodium', 'Chemical', 'MESH:D012964', (89, 95))	('Mg2+', 'Chemical', '-', (18, 22))	('transportation of the electrolytes sodium', 'MPA', (54, 95))	('magnesium', 'Chemical', 'MESH:D008274', (121, 130))	('Ca2+', 'Chemical', 'MESH:D000069285', (8, 12))	('potassium', 'Chemical', 'MESH:D011188', (97, 106))	('Mg2+', 'Var', (18, 22))	('Na+/K+', 'Var', (0, 6))	('calcium', 'Chemical', 'MESH:D002118', (108, 115))
10786	32823876	Modulation of these parameters is a promising way of controlling cancer.	('Modulation', 'Var', (0, 10))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))
10803	32823876	Overactivation of Bcl-2 proto-oncogene plays a critical role in abrogating cell apoptosis and tumor suppressor protein p53 activity.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('94', '110'))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('Bcl-2', 'Gene', (18, 23))	('cell apoptosis', 'CPA', (75, 89))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor suppressor', 'biological_process', 'GO:0051726', ('94', '110'))	('apoptosis', 'biological_process', 'GO:0097194', ('80', '89'))	('tumor', 'Disease', (94, 99))	('abrogating', 'NegReg', (64, 74))	('apoptosis', 'biological_process', 'GO:0006915', ('80', '89'))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('18', '23'))	('activity', 'MPA', (123, 131))	('Overactivation', 'Var', (0, 14))
10815	32823876	Rutin also demonstrated antiangiogenic effects against B16F-10 melanoma cell-induced capillary formation in an animal model.	('rat', 'Species', '10116', (18, 21))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('B16F', 'SUBSTITUTION', 'None', (55, 59))	('Rutin', 'Chemical', 'MESH:D012431', (0, 5))	('formation', 'biological_process', 'GO:0009058', ('95', '104'))	('antiangiogenic effects', 'CPA', (24, 46))	('B16F', 'Var', (55, 59))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
10960	31468594	RNA pull-down, RIP, ChIP and luciferase reporter assays were carried out to investigate the molecular mechanism of LOXL1-AS1 in gastric carcinoma.	('gastric carcinoma', 'Phenotype', 'HP:0012126', (128, 145))	('gastric carcinoma', 'Disease', 'MESH:D013274', (128, 145))	('gastric carcinoma', 'Disease', (128, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('LOXL1-AS1', 'Var', (115, 124))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
10963	31468594	Our findings demonstrated that LOXL1-AS1 accelerated the deterioration of gastric cancer by inducing cell proliferation, migration, EMT and stemness.	('migration', 'CPA', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('gastric cancer', 'Phenotype', 'HP:0012126', (74, 88))	('gastric cancer', 'Disease', (74, 88))	('EMT', 'biological_process', 'GO:0001837', ('132', '135'))	('EMT', 'Gene', (132, 135))	('gastric cancer', 'Disease', 'MESH:D013274', (74, 88))	('inducing', 'PosReg', (92, 100))	('EMT', 'Gene', '3702', (132, 135))	('cell proliferation', 'biological_process', 'GO:0008283', ('101', '119'))	('accelerated', 'PosReg', (41, 52))	('LOXL1-AS1', 'Var', (31, 40))	('cell proliferation', 'CPA', (101, 119))
10966	31468594	It was also validated that LOXL1-AS1 facilitated cell growth of gastric carcinoma in vivo.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('gastric carcinoma', 'Disease', (64, 81))	('cell growth', 'biological_process', 'GO:0016049', ('49', '60'))	('cell growth', 'CPA', (49, 60))	('facilitated', 'PosReg', (37, 48))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (64, 81))	('LOXL1-AS1', 'Var', (27, 36))	('gastric carcinoma', 'Disease', 'MESH:D013274', (64, 81))
10971	31468594	A multitude of investigations have validated the oncogenic role of LOXL1-AS1 in diverse human cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('LOXL1-AS1', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (88, 93))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
10974	31468594	Our results unveiled that LOXL1-AS1 acted as an oncogene in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('LOXL1-AS1', 'Var', (26, 35))	('gastric cancer', 'Disease', (60, 74))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))
10975	31468594	Mechanically, LOXL1-AS1 exerted its performance through modulation of miR-708-5p/USF1, which provided a better understanding of LOXL1-AS1-mediated gastric cancer progression.	('gastric cancer', 'Phenotype', 'HP:0012126', (147, 161))	('modulation', 'Var', (56, 66))	('miR-708-5p/USF1', 'Gene', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('gastric cancer', 'Disease', (147, 161))	('gastric cancer', 'Disease', 'MESH:D013274', (147, 161))
10990	31468594	The following primary antibodies were applied: anti-USF1 ((ab125020; Abcam), anti-E-cadherin (sc-8426; Santa Cruz), anti-vimentin (sc-6260; Santa Cruz), beta-actin (sc-7963; Santa Cruz), anti-Nanog (ab109250; Abcam), anti-SOX2 (ab137385; Abcam) and anti-OCT4 (ab184665; Abcam).	('beta-actin', 'Gene', '728378', (153, 163))	('ab184665', 'Var', (260, 268))	('beta-actin', 'Gene', (153, 163))	('vimentin', 'cellular_component', 'GO:0045098', ('121', '129'))	('cadherin', 'molecular_function', 'GO:0008014', ('84', '92'))	('vimentin', 'cellular_component', 'GO:0045099', ('121', '129'))	('E-cadherin', 'Gene', (82, 92))	('E-cadherin', 'Gene', '999', (82, 92))	('Nanog', 'Gene', '79923', (192, 197))	('OCT4', 'Gene', '5460', (254, 258))	('OCT4', 'Gene', (254, 258))	('Nanog', 'Gene', (192, 197))
10997	31468594	Extracted RNAs were subjected to RT-qPCR analysis to verify the cellular localization of LOXL1-AS1 with GAPDH as the cytoplasm control and U6 as the nucleus control.	('nucleus', 'cellular_component', 'GO:0005634', ('149', '156'))	('GAPDH', 'Gene', '2597', (104, 109))	('GAPDH', 'Gene', (104, 109))	('cytoplasm', 'cellular_component', 'GO:0005737', ('117', '126'))	('LOXL1-AS1', 'Var', (89, 98))	('cellular localization', 'biological_process', 'GO:0051641', ('64', '85'))
11004	31468594	The wild-type and mutant fragments of LOXL1-AS1 were subcloned into pGL3 plasmids (Promega) to construct LOXL1-AS1-WT and LOXL1-AS1-Mut.	('pGL3', 'Gene', '6391', (68, 72))	('mutant', 'Var', (18, 24))	('pGL3', 'Gene', (68, 72))	('pGL', 'molecular_function', 'GO:0004598', ('68', '71'))
11012	31468594	Furthermore, in contrast with patients at early stages, LOXL1-AS1 expression was prominently upregulated in patients with advanced gastric cancer (Figure 1B).	('gastric cancer', 'Disease', 'MESH:D013274', (131, 145))	('patients', 'Species', '9606', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('gastric cancer', 'Phenotype', 'HP:0012126', (131, 145))	('patients', 'Species', '9606', (30, 38))	('LOXL1-AS1', 'Var', (56, 65))	('upregulated', 'PosReg', (93, 104))	('gastric cancer', 'Disease', (131, 145))
11013	31468594	Consistently, our findings confirmed that LOXL1-AS1 was highly expressed in gastric cancer cells compared to normal cells (Figure 1C).	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('LOXL1-AS1', 'Var', (42, 51))	('highly', 'PosReg', (56, 62))	('gastric cancer', 'Disease', (76, 90))
11015	31468594	Kaplan-Meier analysis exposed the negative association between LOXL1-AS1 level and the overall survival rate of gastric cancer patients (Figure 1D).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('gastric cancer', 'Disease', 'MESH:D013274', (112, 126))	('negative', 'NegReg', (34, 42))	('gastric cancer', 'Disease', (112, 126))	('patients', 'Species', '9606', (127, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (112, 126))	('LOXL1-AS1 level', 'Var', (63, 78))
11018	31468594	EdU assay validated that the proportion of EdU-positive cells was dropped by silencing of LOXL1-AS1 whereas increased by upregulation of LOXL1-AS1 (Figure 2C).	('upregulation', 'PosReg', (121, 133))	('EdU', 'Chemical', 'MESH:C031086', (43, 46))	('increased', 'PosReg', (108, 117))	('silencing', 'Var', (77, 86))	('dropped', 'NegReg', (66, 73))	('EdU', 'Chemical', 'MESH:C031086', (0, 3))	('LOXL1-AS1', 'Gene', (90, 99))
11020	31468594	By the large, we concluded that LOXL1-AS1 induced gastric cancer cell proliferation and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('LOXL1-AS1', 'Var', (32, 41))	('gastric cancer', 'Disease', (50, 64))	('metastasis', 'CPA', (88, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('cell proliferation', 'biological_process', 'GO:0008283', ('65', '83'))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))
11022	31468594	Consistently, it was viewed that the expression of stem factors Nanog, SOX2 and OCT4 was weakened by knockdown of LOXL1-AS1 and enhanced by upregulation of LOXL1-AS1 (Figure 3C).	('LOXL1-AS1', 'Var', (114, 123))	('upregulation', 'PosReg', (140, 152))	('OCT4', 'Gene', '5460', (80, 84))	('OCT4', 'Gene', (80, 84))	('weakened', 'NegReg', (89, 97))	('enhanced', 'PosReg', (128, 136))	('SOX2', 'Gene', (71, 75))	('expression', 'MPA', (37, 47))	('Nanog', 'Gene', '79923', (64, 69))	('Nanog', 'Gene', (64, 69))	('LOXL1-AS1', 'Var', (156, 165))	('knockdown', 'Var', (101, 110))
11024	31468594	We observed that MKN-45 cells with low level of LOXL1-AS1 were more sensitive to cisplatin treatment, whereas forced expression of LOXL1-AS1 increased the cisplatin resistance of AGS cells (Figure 3D).	('increased', 'PosReg', (141, 150))	('sensitive to cisplatin treatment', 'MPA', (68, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('AGS', 'Disease', (179, 182))	('cisplatin resistance', 'MPA', (155, 175))	('LOXL1-AS1', 'Var', (48, 57))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('AGS', 'Disease', 'MESH:C535607', (179, 182))	('LOXL1-AS1', 'Var', (131, 140))
11025	31468594	Taken together, these data provided strong evidence that LOXL1-AS1 facilitated the acquisition of CSC characteristics in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('LOXL1-AS1', 'Var', (57, 66))	('facilitated', 'PosReg', (67, 78))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('acquisition of CSC characteristics', 'CPA', (83, 117))	('gastric cancer', 'Disease', (121, 135))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))
11032	31468594	Correlation analysis disclosed the positive association between USF1 and LOXL1-AS1 as well as the negative correlation between USF1 and miR-708-5p in clinical tumour tissues (Figure 4J).	('tumour', 'Disease', (159, 165))	('negative', 'NegReg', (98, 106))	('USF1', 'Gene', (64, 68))	('USF1', 'Gene', (127, 131))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumour', 'Disease', 'MESH:D009369', (159, 165))	('miR-708-5p', 'Var', (136, 146))
11033	31468594	RIP experiments illuminated that LOXL1-AS1, miR-708-5p and USF1 were abundant in Ago2 precipitates (Figure 5D), further confirming the interaction between LOXL1-AS1, miR-708-5p and USF1.	('Ago2', 'Gene', (81, 85))	('interaction', 'Interaction', (135, 146))	('miR-708-5p', 'Var', (44, 54))	('Ago2', 'Gene', '27161', (81, 85))
11035	31468594	To justify the role of LOXL1-AS1/miR-708-5p/USF1 in the progression of gastric carcinoma, rescue assays were conducted.	('gastric carcinoma', 'Disease', (71, 88))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (71, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('gastric carcinoma', 'Disease', 'MESH:D013274', (71, 88))	('LOXL1-AS1/miR-708-5p/USF1', 'Var', (23, 48))
11036	31468594	CCK-8 and EdU assays manifested that the inhibition of cell proliferation caused by miR-708-5p knockdown was abrogated owing to silencing of USF1 (Figure 7A,B).	('USF1', 'Gene', (141, 145))	('silencing', 'Var', (128, 137))	('miR-708-5p', 'Var', (84, 94))	('cell proliferation', 'CPA', (55, 73))	('inhibition of cell proliferation', 'biological_process', 'GO:0008285', ('41', '73'))	('abrogated', 'NegReg', (109, 118))	('EdU', 'Chemical', 'MESH:C031086', (10, 13))	('inhibition', 'NegReg', (41, 51))
11037	31468594	As anticipated, Western blot exposed that knockdown of miR-708-5p resulted in the reduced E-cadherin expression and the elevated level of vimentin; simultaneously, the impacts of miR-708-5p inhibitor were counteracted by silencing of USF1 (Figure 7D).	('miR-708-5p', 'Var', (55, 65))	('vimentin', 'cellular_component', 'GO:0045099', ('138', '146'))	('vimentin', 'cellular_component', 'GO:0045098', ('138', '146'))	('cadherin', 'molecular_function', 'GO:0008014', ('92', '100'))	('elevated', 'PosReg', (120, 128))	('level of vimentin', 'MPA', (129, 146))	('reduced', 'NegReg', (82, 89))	('E-cadherin', 'Gene', (90, 100))	('E-cadherin', 'Gene', '999', (90, 100))
11038	31468594	In agreement with the foregoing, the expression of Nanog, SOX2 and OCT4 increased by miR-708-5p inhibitor was diminished on account of USF1 knockdown (Figure 7F).	('SOX2', 'Gene', (58, 62))	('increased', 'PosReg', (72, 81))	('Nanog', 'Gene', (51, 56))	('USF1', 'Gene', (135, 139))	('OCT4', 'Gene', '5460', (67, 71))	('OCT4', 'Gene', (67, 71))	('expression', 'MPA', (37, 47))	('miR-708-5p', 'Var', (85, 95))	('diminished', 'NegReg', (110, 120))	('knockdown', 'Var', (140, 149))	('Nanog', 'Gene', '79923', (51, 56))
11039	31468594	Besides, the sensitization of transfected MKN-45 cells to cisplatin was suppressed by miR-708-5p inhibitor and subsequently recovered by depletion of USF1 (Figure 7G).	('sensitization', 'biological_process', 'GO:0046960', ('13', '26'))	('depletion', 'Var', (137, 146))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('suppressed', 'NegReg', (72, 82))	('sensitization', 'MPA', (13, 26))
11040	31468594	Namely, described results affirmed that LOXL1-AS1 maintained stemness and accelerated gastric cancer deterioration via miR-708-5p/USF1.	('gastric cancer', 'Disease', 'MESH:D013274', (86, 100))	('LOXL1-AS1', 'Var', (40, 49))	('accelerated', 'PosReg', (74, 85))	('stemness', 'CPA', (61, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gastric cancer', 'Disease', (86, 100))	('miR-708-5p/USF1', 'Var', (119, 134))
11041	31468594	To further validate the carcinogenic function of LOXL1-AS1 in vivo, we implemented animal experiments.	('LOXL1-AS1', 'Var', (49, 58))	('carcinogenic', 'Disease', 'MESH:D063646', (24, 36))	('carcinogenic', 'Disease', (24, 36))
11044	31468594	In addition, RT-qPCR analysis demonstrated that knockdown of LOXL1-AS1 contributed to the decrease of LOXL1-AS1 and USF1 expression and the enhancement of miR-708-5p level in neoplasms from mice (Figure 8D).	('neoplasms', 'Disease', (175, 184))	('LOXL1-AS1', 'Gene', (61, 70))	('neoplasms', 'Disease', 'MESH:D009369', (175, 184))	('expression', 'MPA', (121, 131))	('USF1', 'Gene', (116, 120))	('neoplasms', 'Phenotype', 'HP:0002664', (175, 184))	('enhancement', 'PosReg', (140, 151))	('knockdown', 'Var', (48, 57))	('mice', 'Species', '10090', (190, 194))	('decrease', 'NegReg', (90, 98))	('miR-708-5p level', 'MPA', (155, 171))	('LOXL1-AS1', 'MPA', (102, 111))
11045	31468594	IHC assay illustrated that silencing of LOXL1-AS1 prominently inhibited the expression of Ki-67, vimentin and SOX2 while fortified E-cadherin level (Figure 8E), further unveiling the stimulative role of LOXL1-AS1 in cell proliferation, EMT and stemness in vivo.	('SOX2', 'Gene', (110, 114))	('E-cadherin', 'Gene', '999', (131, 141))	('LOXL1-AS1', 'Gene', (40, 49))	('silencing', 'Var', (27, 36))	('vimentin', 'Protein', (97, 105))	('fortified', 'PosReg', (121, 130))	('EMT', 'biological_process', 'GO:0001837', ('236', '239'))	('cell proliferation', 'biological_process', 'GO:0008283', ('216', '234'))	('Ki-67', 'Gene', (90, 95))	('EMT', 'Gene', (236, 239))	('cadherin', 'molecular_function', 'GO:0008014', ('133', '141'))	('inhibited', 'NegReg', (62, 71))	('expression', 'MPA', (76, 86))	('EMT', 'Gene', '3702', (236, 239))	('vimentin', 'cellular_component', 'GO:0045099', ('97', '105'))	('E-cadherin', 'Gene', (131, 141))	('vimentin', 'cellular_component', 'GO:0045098', ('97', '105'))
11046	31468594	In short, we proved that LOXL1-AS1 promoted gastric cancer development in vivo.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('gastric cancer', 'Disease', (44, 58))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('promoted', 'PosReg', (35, 43))	('LOXL1-AS1', 'Var', (25, 34))	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))
11049	31468594	In the present study, we found that LOXL1-AS1 expression was overtly upregulated in gastric cancer tissues and cells.	('gastric cancer', 'Disease', (84, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (84, 98))	('LOXL1-AS1', 'Var', (36, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (84, 98))	('upregulated', 'PosReg', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('expression', 'MPA', (46, 56))
11050	31468594	In addition, high expression of LOXL1-AS1 was closely correlated with poor prognosis of gastric cancer.	('LOXL1-AS1', 'Var', (32, 41))	('gastric cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('correlated', 'Reg', (54, 64))	('expression', 'MPA', (18, 28))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))
11051	31468594	Functional experiments demonstrated that LOXL1-AS1 promoted cell proliferation, migration, EMT and the maintenance of CSC characteristics in gastric carcinoma.	('cell proliferation', 'CPA', (60, 78))	('cell proliferation', 'biological_process', 'GO:0008283', ('60', '78'))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (141, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('migration', 'CPA', (80, 89))	('gastric carcinoma', 'Disease', 'MESH:D013274', (141, 158))	('EMT', 'biological_process', 'GO:0001837', ('91', '94'))	('promoted', 'PosReg', (51, 59))	('LOXL1-AS1', 'Var', (41, 50))	('EMT', 'Gene', (91, 94))	('EMT', 'Gene', '3702', (91, 94))	('CSC characteristics', 'CPA', (118, 137))	('gastric carcinoma', 'Disease', (141, 158))
11053	31468594	Further assays testified that LOXL1-AS1 maintained CSC properties and induced gastric cancer tumorigenesis by targeting miR-708-5p/USF1 pathway.	('CSC', 'MPA', (51, 54))	('miR-708-5p/USF1', 'Gene', (120, 135))	('induced', 'PosReg', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('LOXL1-AS1', 'Var', (30, 39))	('gastric cancer', 'Disease', (78, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (78, 92))	('targeting', 'Reg', (110, 119))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))
11055	31468594	To summarize, this study was the first to elucidate the function and regulatory mechanism of LOXL1-AS1 in gastric carcinoma.	('gastric carcinoma', 'Disease', 'MESH:D013274', (106, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('gastric carcinoma', 'Disease', (106, 123))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (106, 123))	('LOXL1-AS1', 'Var', (93, 102))
11084	30952022	A 69 year old female patient, G2P2 with a clear medical history presented to our department suffering from epigastric pain, burning after food intake, nausea, vomiting and weight loss during the last two months.	('nausea', 'Phenotype', 'HP:0002018', (151, 157))	('patient', 'Species', '9606', (21, 28))	('nausea', 'Disease', (151, 157))	('weight loss', 'Disease', (172, 183))	('epigastric pain', 'Disease', (107, 122))	('epigastric pain', 'Phenotype', 'HP:0410019', (107, 122))	('weight loss', 'Phenotype', 'HP:0001824', (172, 183))	('pain', 'Phenotype', 'HP:0012531', (118, 122))	('nausea', 'Disease', 'MESH:D009325', (151, 157))	('vomiting', 'Phenotype', 'HP:0002013', (159, 167))	('burning', 'Disease', (124, 131))	('G2P2', 'Var', (30, 34))	('vomiting', 'Disease', (159, 167))	('vomiting', 'Disease', 'MESH:D014839', (159, 167))	('epigastric pain', 'Disease', 'MESH:D010146', (107, 122))	('weight loss', 'Disease', 'MESH:D015431', (172, 183))
11153	30246718	XB130 Knockdown Inhibits the Proliferation, Invasiveness, and Metastasis of Hepatocellular Carcinoma Cells and Sensitizes them to TRAIL-Induced Apoptosis XB130 is a recently discovered adaptor protein that is highly expressed in many malignant tumors, but few studies have investigated its role in hepatocellular carcinoma (HCC).	('Knockdown', 'Var', (6, 15))	('malignant tumors', 'Disease', 'MESH:D018198', (234, 250))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (298, 322))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('TRAIL', 'Gene', (130, 135))	('Hepatocellular Carcinoma', 'Phenotype', 'HP:0001402', (76, 100))	('Proliferation', 'CPA', (29, 42))	('XB130', 'Gene', '84632', (154, 159))	('malignant tumors', 'Disease', (234, 250))	('Metastasis of Hepatocellular Carcinoma Cells', 'Disease', 'MESH:D009362', (62, 106))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (298, 322))	('XB130', 'Gene', (154, 159))	('Carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('protein', 'cellular_component', 'GO:0003675', ('193', '200'))	('Metastasis of Hepatocellular Carcinoma Cells', 'Disease', (62, 106))	('Inhibits', 'NegReg', (16, 24))	('XB130', 'Gene', '84632', (0, 5))	('Invasiveness', 'CPA', (44, 56))	('hepatocellular carcinoma', 'Disease', (298, 322))	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('XB130', 'Gene', (0, 5))	('TRAIL', 'Gene', '8743', (130, 135))
11156	30246718	XB130 silencing was performed using small hairpin RNA.	('XB130', 'Gene', (0, 5))	('XB130', 'Gene', '84632', (0, 5))	('silencing', 'Var', (6, 15))	('RNA', 'cellular_component', 'GO:0005562', ('50', '53'))
11157	30246718	The effect of silencing XB130 was examined using Cell Counting Kit-8, colony assay, wound healing assay, and cell cycle analysis.	('silencing', 'Var', (14, 23))	('XB130', 'Gene', (24, 29))	('XB130', 'Gene', '84632', (24, 29))	('cell cycle', 'biological_process', 'GO:0007049', ('109', '119'))	('wound healing', 'biological_process', 'GO:0042060', ('84', '97'))
11159	30246718	The Cell Counting Kit-8 assay, colony formation assay, and xenograft model in nude mice showed that silencing XB130 inhibited cell proliferative ability both in vivo and in vitro, with flow cytometry demonstrating that the cells were arrested in the G0/G1 phase in HepG2 (HepG2 XB130-silenced group [shA] vs. HepG2 scramble group [NA]: 74.32 +- 5.86% vs. 60.21 +- 3.07%, P < 0.05) and that the number of G2/M phase cells was decreased (HepG2 shA vs. HepG2 NA: 8.06 +- 2.41% vs. 18.36 +- 4.42%, P < 0.05).	('XB130', 'Gene', '84632', (110, 115))	('decreased', 'NegReg', (425, 434))	('silencing', 'Var', (100, 109))	('G2/M phase cells', 'CPA', (404, 420))	('M phase', 'biological_process', 'GO:0000279', ('407', '414'))	('inhibited', 'NegReg', (116, 125))	('nude mice', 'Species', '10090', (78, 87))	('XB130', 'Gene', (278, 283))	('formation', 'biological_process', 'GO:0009058', ('38', '47'))	('XB130', 'Gene', (110, 115))	('cell proliferative ability', 'CPA', (126, 152))	('HepG2', 'CellLine', 'CVCL:0027', (309, 314))	('G1 phase', 'biological_process', 'GO:0051318', ('253', '261'))	('XB130', 'Gene', '84632', (278, 283))	('HepG2', 'CellLine', 'CVCL:0027', (450, 455))	('HepG2', 'CellLine', 'CVCL:0027', (436, 441))	('HepG2', 'CellLine', 'CVCL:0027', (272, 277))	('HepG2', 'CellLine', 'CVCL:0027', (265, 270))
11160	30246718	Furthermore, the cell invasion and migration abilities were impaired, and the levels of the epithelial-mesenchymal transition-related indicators vimentin and N-cadherin were decreased, although the level of E-cadherin was increased after silencing XB130.	('cadherin', 'molecular_function', 'GO:0008014', ('160', '168'))	('decreased', 'NegReg', (174, 183))	('N-cadherin', 'Gene', (158, 168))	('vimentin', 'Gene', '7431', (145, 153))	('XB130', 'Gene', (248, 253))	('E-cadherin', 'Gene', (207, 217))	('E-cadherin', 'Gene', '999', (207, 217))	('vimentin', 'Gene', (145, 153))	('impaired', 'NegReg', (60, 68))	('silencing', 'Var', (238, 247))	('N-cadherin', 'Gene', '1000', (158, 168))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('92', '125'))	('vimentin', 'cellular_component', 'GO:0045099', ('145', '153'))	('increased', 'PosReg', (222, 231))	('XB130', 'Gene', '84632', (248, 253))	('cadherin', 'molecular_function', 'GO:0008014', ('209', '217'))	('vimentin', 'cellular_component', 'GO:0045098', ('145', '153'))
11203	30246718	The membrane was then blocked in Tris-buffered saline and Tween 20 (TBST: 25 mmol/L Tris-HCl [pH 7.5], 125 mmol/L NaCl, and 0.1% Tween 20) containing 5% bovine serum albumin (BSA) and incubated with antibodies targeting XB130, E-cadherin, N-cadherin, vimentin, Akt, Ser473, Thr308, PTEN, p-PTEN, phos-PI3K (p-PI3K), PI3K, or GAPHD in TBST containing 1% BSA at 4 C overnight.	('Akt', 'Gene', (261, 264))	('cadherin', 'molecular_function', 'GO:0008014', ('229', '237'))	('Ser473', 'Chemical', '-', (266, 272))	('Ser', 'cellular_component', 'GO:0005790', ('266', '269'))	('PTEN', 'Gene', (290, 294))	('phos-PI3K', 'Var', (296, 305))	('GAPHD', 'Gene', '2597', (325, 330))	('bovine', 'Species', '9913', (153, 159))	('Akt', 'Gene', '207', (261, 264))	('XB130', 'Gene', '84632', (220, 225))	('E-cadherin', 'Gene', (227, 237))	('E-cadherin', 'Gene', '999', (227, 237))	('PI3K', 'molecular_function', 'GO:0016303', ('301', '305'))	('Thr308', 'Chemical', '-', (274, 280))	('PI3K', 'molecular_function', 'GO:0016303', ('316', '320'))	('PTEN', 'Gene', (282, 286))	('XB130', 'Gene', (220, 225))	('vimentin', 'cellular_component', 'GO:0045098', ('251', '259'))	('PTEN', 'Gene', '5728', (290, 294))	('cadherin', 'molecular_function', 'GO:0008014', ('241', '249'))	('GAPHD', 'Gene', (325, 330))	('PI3K', 'molecular_function', 'GO:0016303', ('309', '313'))	('membrane', 'cellular_component', 'GO:0016020', ('4', '12'))	('PTEN', 'Gene', '5728', (282, 286))	('vimentin', 'Gene', '7431', (251, 259))	('vimentin', 'Gene', (251, 259))	('N-cadherin', 'Gene', (239, 249))	('vimentin', 'cellular_component', 'GO:0045099', ('251', '259'))	('N-cadherin', 'Gene', '1000', (239, 249))	('PI3K', 'Var', (316, 320))
11228	30246718	Furthermore, the number of clones formed was significantly reduced after silencing XB130 (HepG2 shA vs. HepG2 NC: 1.26 +- 0.14 vs. 2.09 +- 0.14, P < 0.05; MHCC97H shA vs. MHCC97H NC: 1.35 +- 0.12 vs. 1.99 +- 0.10, P < 0.05).	('silencing', 'Var', (73, 82))	('reduced', 'NegReg', (59, 66))	('HepG2', 'CellLine', 'CVCL:0027', (90, 95))	('HepG2', 'CellLine', 'CVCL:0027', (104, 109))	('HepG2 NC', 'CellLine', 'CVCL:0027', (104, 112))	('XB130', 'Gene', (83, 88))	('XB130', 'Gene', '84632', (83, 88))
11229	30246718	Flow cytometry showed that the number of G0/G1 phase cells increased in HepG2 shA compared with those in HepG2 NC (HepG2 shA vs. HepG2 NA: 74.32 +- 5.86% vs. 60.21 +- 3.07%, P < 0.05) and that the number of G2/M phase cells decreased following a reduction in XB130 both in HepG2 shA and MHCC97H shA groups (HepG2 shA vs. HepG2 NA: 8.06 +- 2.41% vs. 18.36 +- 4.42%, P < 0.05; Figures 2f and 2g].	('G2/M phase cells', 'CPA', (207, 223))	('HepG2', 'CellLine', 'CVCL:0027', (307, 312))	('XB130', 'Gene', '84632', (259, 264))	('decreased', 'NegReg', (224, 233))	('HepG2', 'CellLine', 'CVCL:0027', (321, 326))	('HepG2', 'CellLine', 'CVCL:0027', (129, 134))	('HepG2 NC', 'CellLine', 'CVCL:0027', (105, 113))	('HepG2', 'CellLine', 'CVCL:0027', (105, 110))	('G1 phase', 'biological_process', 'GO:0051318', ('44', '52'))	('reduction', 'NegReg', (246, 255))	('HepG2', 'CellLine', 'CVCL:0027', (273, 278))	('HepG2', 'CellLine', 'CVCL:0027', (72, 77))	('G0/G1 phase cells', 'CPA', (41, 58))	('M phase', 'biological_process', 'GO:0000279', ('210', '217'))	('HepG2', 'CellLine', 'CVCL:0027', (115, 120))	('increased', 'PosReg', (59, 68))	('XB130', 'Gene', (259, 264))	('HepG2', 'Var', (72, 77))
11230	30246718	Thus, the proliferation of MHCC97H and HepG2 cells decreased after silencing XB130.	('proliferation', 'CPA', (10, 23))	('HepG2', 'CellLine', 'CVCL:0027', (39, 44))	('XB130', 'Gene', '84632', (77, 82))	('decreased', 'NegReg', (51, 60))	('silencing', 'Var', (67, 76))	('XB130', 'Gene', (77, 82))
11231	30246718	Next, we evaluated the effect of silencing XB130 on the invasiveness and metastasis of HCC cell lines using a Transwell assay and wound healing assay [Figure 3a-3d], which showed that HepG2 shA and MHCC97H shA groups had significantly lower invasion and metastasis abilities than the NC groups (Transwell assay: HepG2 shA vs. HepG2 NC: 33.3 +- 5.2 vs. 207.0 +- 22.7, P < 0.05; Transwell assay: MHCC97H shA vs. MHCC97H NC: 112.3 +- 11.5 vs. 285.3 +- 11.3, P < 0.05; wound assay: HepG2 shA vs. HepG2 NC: 22.83 +- 4.93 vs. 46.31 +- 2.21 mum, P < 0.05; wound assay: MHCC97H shA vs. MHCC97H NC: 25.27 +- 0.78 vs. 50.08 +- 3.85 mum, P < 0.05).	('HepG2', 'CellLine', 'CVCL:0027', (184, 189))	('wound healing', 'biological_process', 'GO:0042060', ('130', '143'))	('XB130', 'Gene', '84632', (43, 48))	('HepG2', 'CellLine', 'CVCL:0027', (312, 317))	('HepG2', 'CellLine', 'CVCL:0027', (326, 331))	('silencing', 'Var', (33, 42))	('HepG2 NC', 'CellLine', 'CVCL:0027', (492, 500))	('HepG2', 'CellLine', 'CVCL:0027', (492, 497))	('lower', 'NegReg', (235, 240))	('HepG2', 'CellLine', 'CVCL:0027', (478, 483))	('HepG2 NC', 'CellLine', 'CVCL:0027', (326, 334))	('XB130', 'Gene', (43, 48))
11232	30246718	We then analyzed the epithelial-mesenchymal transition (EMT)-associated proteins by Western blotting, which showed that the expressions of vimentin and N-cadherin were decreased in the shA groups than those in the NC groups, although the expressions of E-cadherin were increased [all P < 0.05; Figure 3e and 3f].	('N-cadherin', 'Gene', '1000', (152, 162))	('decreased', 'NegReg', (168, 177))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('21', '54'))	('increased', 'PosReg', (269, 278))	('cadherin', 'molecular_function', 'GO:0008014', ('255', '263'))	('E-cadherin', 'Gene', (253, 263))	('vimentin', 'Gene', '7431', (139, 147))	('shA', 'Var', (185, 188))	('E-cadherin', 'Gene', '999', (253, 263))	('EMT', 'biological_process', 'GO:0001837', ('56', '59'))	('vimentin', 'cellular_component', 'GO:0045099', ('139', '147'))	('vimentin', 'Gene', (139, 147))	('expressions', 'MPA', (238, 249))	('expressions', 'MPA', (124, 135))	('cadherin', 'molecular_function', 'GO:0008014', ('154', '162'))	('vimentin', 'cellular_component', 'GO:0045098', ('139', '147'))	('N-cadherin', 'Gene', (152, 162))
11233	30246718	To evaluate the effect of silencing XB130 on tumorigenesis in vitro, we established a nude mouse model of tumor formation and injected the shA and NC groups subcutaneously.	('XB130', 'Gene', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('formation', 'biological_process', 'GO:0009058', ('112', '121'))	('tumor', 'Disease', (45, 50))	('XB130', 'Gene', '84632', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('silencing', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mouse', 'Species', '10090', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Disease', (106, 111))
11235	30246718	These findings suggest that XB130 knockdown inhibits the growth of HCC.	('XB130', 'Gene', (28, 33))	('HCC', 'CPA', (67, 70))	('knockdown', 'Var', (34, 43))	('growth', 'CPA', (57, 63))	('XB130', 'Gene', '84632', (28, 33))	('inhibits', 'NegReg', (44, 52))
11237	30246718	We found that Ser473 (HepG2 shA vs. HepG2 NC: 0.31 +- 0.01 vs. 0.9 +- 0.02, P < 0.05 and MHCC97H shA vs. MHCC97H NC: 0.17 +- 0.02 vs. 0.69 +- 0.02, P < 0.05), threonine 308 (Thr308; HepG2 shA vs. HepG2 NC: 0.12 +- 0.01 vs. 0.43 +- 0.04, P < 0.05 and MHCC97H shA vs. MHCC97H NC: 0.21 +- 0.05 vs. 0.52 +- 0.03, P < 0.05), and p-PI3K were significantly lower in HepG2 shA and MHCC97H shA groups (HepG2 shA vs. HepG2 NC: 0.26 +- 0.04 vs. 0.85 +- 0.03, P < 0.05 and MHCC97H shA vs. MHCC97H NC: 0.19 +- 0.02 vs. 0.86 +- 0.03, P < 0.05), and the level of p-PTEN, which is an inhibitor of p-Akt, was upregulated (HepG2 shA vs. HepG2 NC: 0.42 +- 0.04 vs. 0.25 +- 0.05, P < 0.05 and MHCC97H shA vs. MHCC97H NC: 0.26 +- 0.02 vs. 0.14 +- 0.01, P < 0.05), whereas there was no change in the levels of Akt, PTEN, and PI3K.	('HepG2', 'CellLine', 'CVCL:0027', (359, 364))	('Ser473', 'Chemical', '-', (14, 20))	('HepG2', 'CellLine', 'CVCL:0027', (605, 610))	('HepG2', 'CellLine', 'CVCL:0027', (407, 412))	('HepG2 NC', 'CellLine', 'CVCL:0027', (619, 627))	('upregulated', 'PosReg', (592, 603))	('PTEN', 'Gene', '5728', (793, 797))	('HepG2', 'CellLine', 'CVCL:0027', (619, 624))	('HepG2 NC', 'CellLine', 'CVCL:0027', (196, 204))	('HepG2 NC', 'CellLine', 'CVCL:0027', (36, 44))	('Akt', 'Gene', (583, 586))	('HepG2', 'CellLine', 'CVCL:0027', (182, 187))	('Akt', 'Gene', (788, 791))	('PTEN', 'Gene', (550, 554))	('MHCC97H shA vs.', 'Var', (673, 688))	('HepG2', 'CellLine', 'CVCL:0027', (22, 27))	('Akt', 'Gene', '207', (583, 586))	('Ser', 'cellular_component', 'GO:0005790', ('14', '17'))	('Akt', 'Gene', '207', (788, 791))	('HepG2', 'CellLine', 'CVCL:0027', (196, 201))	('HepG2', 'CellLine', 'CVCL:0027', (393, 398))	('Thr308', 'Chemical', '-', (174, 180))	('PI3K', 'molecular_function', 'GO:0016303', ('326', '330'))	('PTEN', 'Gene', '5728', (550, 554))	('HepG2', 'CellLine', 'CVCL:0027', (36, 41))	('PTEN', 'Gene', (793, 797))	('PI3K', 'molecular_function', 'GO:0016303', ('803', '807'))	('HepG2 NC', 'CellLine', 'CVCL:0027', (407, 415))
11239	30246718	Then, we explored the effect of silencing XB130 on the apoptosis of HCC cell lines using flow cytometry assay and caspase assay.	('apoptosis', 'biological_process', 'GO:0097194', ('55', '64'))	('XB130', 'Gene', (42, 47))	('apoptosis', 'biological_process', 'GO:0006915', ('55', '64'))	('silencing', 'Var', (32, 41))	('caspase', 'Gene', '841;842', (114, 121))	('XB130', 'Gene', '84632', (42, 47))	('caspase', 'Gene', (114, 121))
11258	30246718	found that silencing XB130 arrested thyroid cancer WRO cells in the G0/G1 phase, although the number of S phase cells and levels of the proliferation-associated proteins Ki-67 and proliferating cell nuclear antigen decreased, as did the tumorigenicity of tumor cells in vitro.	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('thyroid cancer', 'Disease', (36, 50))	('XB130', 'Gene', '84632', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('proliferating', 'MPA', (180, 193))	('XB130', 'Gene', (21, 26))	('decreased', 'NegReg', (215, 224))	('thyroid cancer', 'Disease', 'MESH:D013964', (36, 50))	('tumor', 'Disease', (255, 260))	('thyroid cancer', 'Phenotype', 'HP:0002890', (36, 50))	('levels', 'MPA', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('silencing', 'Var', (11, 20))	('proliferating cell nuclear antigen', 'molecular_function', 'GO:0003892', ('180', '214'))	('G1 phase', 'biological_process', 'GO:0051318', ('71', '79'))	('tumor', 'Disease', (237, 242))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('S phase', 'biological_process', 'GO:0051320', ('104', '111'))
11260	30246718	also found similar results in gastric cancer, wherein the knockdown of XB130 in SGC7901 and MNK45 cells led to a decrease in cell proliferation, an increase in G0/G1 phase, and a decrease in S phase cells.	('decrease', 'NegReg', (113, 121))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('increase', 'PosReg', (148, 156))	('G1 phase', 'biological_process', 'GO:0051318', ('163', '171'))	('XB130', 'Gene', '84632', (71, 76))	('cell proliferation', 'biological_process', 'GO:0008283', ('125', '143'))	('S phase cells', 'CPA', (191, 204))	('G0/G1 phase', 'CPA', (160, 171))	('gastric cancer', 'Disease', 'MESH:D013274', (30, 44))	('decrease', 'NegReg', (179, 187))	('gastric cancer', 'Disease', (30, 44))	('cell proliferation', 'CPA', (125, 143))	('S phase', 'biological_process', 'GO:0051320', ('191', '198'))	('SGC7901', 'CellLine', 'CVCL:0520', (80, 87))	('knockdown', 'Var', (58, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (30, 44))	('XB130', 'Gene', (71, 76))
11269	30246718	Akt is a serine/threonine kinase, also known as protein kinase B, which is highly homologous to protein kinase A and protein kinase C, is one of the major downstream effector molecules of PI3K, and can directly phosphorylate many transcriptional factors; its activation requires the activation of Thr308 and Ser473.	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('PI3K', 'molecular_function', 'GO:0016303', ('188', '192'))	('protein kinase B', 'Gene', (48, 64))	('activation', 'PosReg', (259, 269))	('Ser', 'cellular_component', 'GO:0005790', ('308', '311'))	('Thr308', 'Var', (297, 303))	('protein', 'cellular_component', 'GO:0003675', ('96', '103'))	('protein kinase B', 'Gene', '2185', (48, 64))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('Ser473', 'Var', (308, 314))	('Akt', 'Gene', '207', (0, 3))	('Ser473', 'Chemical', '-', (308, 314))	('Thr308', 'Chemical', '-', (297, 303))	('Akt', 'Gene', (0, 3))
11270	30246718	Consistent with this, in the present study, we found that a reduction in XB130 can regulate the expression of the Akt-related phosphorylation markers Ser473 and Thr308 and inhibit the phosphorylation of PI3K but had no effect on the total levels of Akt and PI3K.	('Ser', 'cellular_component', 'GO:0005790', ('150', '153'))	('Ser473', 'MPA', (150, 156))	('Thr308', 'Var', (161, 167))	('phosphorylation', 'MPA', (184, 199))	('expression', 'MPA', (96, 106))	('reduction', 'NegReg', (60, 69))	('regulate', 'Reg', (83, 91))	('inhibit', 'NegReg', (172, 179))	('Thr308', 'Chemical', '-', (161, 167))	('Akt', 'Gene', (114, 117))	('phosphorylation', 'biological_process', 'GO:0016310', ('126', '141'))	('Akt', 'Gene', (249, 252))	('Ser473', 'Chemical', '-', (150, 156))	('PI3K', 'molecular_function', 'GO:0016303', ('203', '207'))	('Akt', 'Gene', '207', (114, 117))	('PI3K', 'Pathway', (203, 207))	('XB130', 'Gene', '84632', (73, 78))	('Akt', 'Gene', '207', (249, 252))	('XB130', 'Gene', (73, 78))	('phosphorylation', 'biological_process', 'GO:0016310', ('184', '199'))	('PI3K', 'molecular_function', 'GO:0016303', ('257', '261'))
11273	30246718	In contrast, the mutations or deletions of PTEN will lose normal inhibition of PIP2 conversion to PIP3, increasing intracellular PIP3 accumulation and Akt activation, thereby inhibiting apoptosis, promoting cell growth, and stimulating tumor angiogenesis.	('PIP3', 'Chemical', '-', (129, 133))	('PIP2', 'Chemical', 'MESH:D019269', (79, 83))	('PIP3', 'Chemical', '-', (98, 102))	('deletions', 'Var', (30, 39))	('Akt', 'Gene', '207', (151, 154))	('inhibition', 'MPA', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('promoting', 'PosReg', (197, 206))	('angiogenesis', 'biological_process', 'GO:0001525', ('242', '254'))	('mutations', 'Var', (17, 26))	('cell growth', 'CPA', (207, 218))	('PTEN', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('cell growth', 'biological_process', 'GO:0016049', ('207', '218'))	('apoptosis', 'CPA', (186, 195))	('inhibiting', 'NegReg', (175, 185))	('PTEN', 'Gene', '5728', (43, 47))	('stimulating', 'Reg', (224, 235))	('apoptosis', 'biological_process', 'GO:0097194', ('186', '195'))	('apoptosis', 'biological_process', 'GO:0006915', ('186', '195'))	('intracellular PIP3 accumulation', 'MPA', (115, 146))	('lose', 'NegReg', (53, 57))	('intracellular', 'cellular_component', 'GO:0005622', ('115', '128'))	('increasing', 'PosReg', (104, 114))	('tumor', 'Disease', (236, 241))	('Akt', 'Gene', (151, 154))	('activation', 'PosReg', (155, 165))
11278	30246718	We used Western blotting to detect EMT-related markers, which showed that downregulation of XB130 upregulated E-cadherin expression, although downregulation of N-cadherin and vimentin could inhibit the progression of EMT and affect the invasion and metastasis of HCC.	('XB130', 'Gene', '84632', (92, 97))	('HCC', 'Disease', (263, 266))	('expression', 'MPA', (121, 131))	('vimentin', 'cellular_component', 'GO:0045099', ('175', '183'))	('XB130', 'Gene', (92, 97))	('downregulation', 'NegReg', (142, 156))	('downregulation', 'Var', (74, 88))	('inhibit', 'NegReg', (190, 197))	('cadherin', 'molecular_function', 'GO:0008014', ('112', '120'))	('EMT', 'biological_process', 'GO:0001837', ('35', '38'))	('vimentin', 'Gene', '7431', (175, 183))	('vimentin', 'Gene', (175, 183))	('upregulated', 'PosReg', (98, 109))	('cadherin', 'molecular_function', 'GO:0008014', ('162', '170'))	('affect', 'Reg', (225, 231))	('vimentin', 'cellular_component', 'GO:0045098', ('175', '183'))	('N-cadherin', 'Gene', (160, 170))	('N-cadherin', 'Gene', '1000', (160, 170))	('EMT', 'biological_process', 'GO:0001837', ('217', '220'))	('metastasis', 'CPA', (249, 259))	('progression of EMT', 'CPA', (202, 220))	('E-cadherin', 'Gene', (110, 120))	('E-cadherin', 'Gene', '999', (110, 120))
11294	30061673	Further, GNL1 induced cell proliferation was altered upon knockdown of RPS20 suggesting its critical role in GNL1 function.	('RPS20', 'Gene', (71, 76))	('altered', 'Reg', (45, 52))	('GNL1', 'Gene', '2794', (109, 113))	('GNL1', 'Gene', (109, 113))	('GNL1', 'Gene', (9, 13))	('cell proliferation', 'biological_process', 'GO:0008283', ('22', '40'))	('GNL1', 'Gene', '2794', (9, 13))	('knockdown', 'Var', (58, 67))	('cell proliferation', 'CPA', (22, 40))
11295	30061673	Interestingly, cell proliferation was significantly impaired upon expression of RPS20 interaction deficient GNL1 mutant suggest that GNL1 interaction with RPS20 is critical for cell growth.	('impaired', 'NegReg', (52, 60))	('GNL1', 'Gene', '2794', (133, 137))	('GNL1', 'Gene', (108, 112))	('interaction', 'Interaction', (86, 97))	('cell proliferation', 'biological_process', 'GO:0008283', ('15', '33'))	('GNL1', 'Gene', '2794', (108, 112))	('GNL1', 'Gene', (133, 137))	('cell proliferation', 'CPA', (15, 33))	('cell growth', 'biological_process', 'GO:0016049', ('177', '188'))	('mutant', 'Var', (113, 119))
11297	30061673	Collectively, our data provided evidence that cross-talk between GNL1 and RPS20 is critical to promote cell proliferation.	('cross-talk', 'Var', (46, 56))	('GNL1', 'Gene', (65, 69))	('promote', 'PosReg', (95, 102))	('cell proliferation', 'CPA', (103, 121))	('GNL1', 'Gene', '2794', (65, 69))	('cell proliferation', 'biological_process', 'GO:0008283', ('103', '121'))	('RPS20', 'Gene', (74, 79))
11299	30061673	The members of this family have shown to be involved in ribosomal assembly and ribosomal RNA processing and are characterized by the presence of circular permutation of guanine nucleotide binding motifs.	('involved', 'Reg', (44, 52))	('ribosomal assembly', 'CPA', (56, 74))	('ribosomal RNA', 'molecular_function', 'GO:0005566', ('79', '92'))	('ribosomal RNA', 'molecular_function', 'GO:0003735', ('79', '92'))	('ribosomal RNA', 'cellular_component', 'GO:0005840', ('79', '92'))	('nucleotide binding', 'molecular_function', 'GO:0000166', ('177', '195'))	('ribosomal RNA processing', 'MPA', (79, 103))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (169, 187))	('RNA processing', 'biological_process', 'GO:0006396', ('89', '103'))	('circular permutation', 'Var', (145, 165))
11300	30061673	The guanine nucleotide motifs G1-G5 of YawG/YIqF GTPases are arranged in G5-G4-G1-G2-G3 order whereas G1-G2-G3-G4-G5 order in classical GTPases.	('G5-G4-G1-G2-G3', 'Var', (73, 87))	('GTP', 'Chemical', 'MESH:D006160', (136, 139))	('GTPases', 'Gene', (49, 56))	('GTP', 'Chemical', 'MESH:D006160', (49, 52))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (4, 22))
11303	30061673	Depletion of GNL2, GNL3 and GNL3L has shown to alter G1/S and G2/M cell cycle transition indicates their role in cell cycle regulation but the molecular mechanism yet to be defined.	('GNL2', 'Gene', (13, 17))	('G1/S', 'CPA', (53, 57))	('GNL3', 'Gene', '26354', (19, 23))	('GNL3', 'Gene', (28, 32))	('GNL3L', 'Gene', (28, 33))	('cell cycle transition', 'biological_process', 'GO:0044770', ('67', '88'))	('alter', 'Reg', (47, 52))	('GNL2', 'Gene', '29889', (13, 17))	('cell cycle transition', 'biological_process', 'GO:0044771', ('67', '88'))	('Depletion', 'Var', (0, 9))	('GNL3', 'Gene', (19, 23))	('GNL3', 'Gene', '26354', (28, 32))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('113', '134'))	('GNL3L', 'Gene', '54552', (28, 33))	('G2/M cell cycle transition', 'CPA', (62, 88))
11337	30061673	Interestingly, the level of pRbS780 was increased in GNL1 expressing cells compared to vector transfected cells without altering total Rb protein levels (Fig.	('protein', 'cellular_component', 'GO:0003675', ('138', '145'))	('expressing', 'Var', (58, 68))	('GNL1', 'Gene', '2794', (53, 57))	('pRbS780', 'Var', (28, 35))	('GNL1', 'Gene', (53, 57))	('increased', 'PosReg', (40, 49))	('level', 'MPA', (19, 24))
11343	30061673	The observed cell cycle arrest at G2/M phase under GNL1 knockdown condition may be due to the changes in cyclins and CDKs levels.	('cell cycle arrest at G2/M phase', 'CPA', (13, 44))	('cyclins', 'Gene', (105, 112))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (13, 30))	('GNL1', 'Gene', '2794', (51, 55))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('13', '30'))	('changes', 'Reg', (94, 101))	('M phase', 'biological_process', 'GO:0000279', ('37', '44'))	('cyclins', 'Gene', '891', (105, 112))	('CDKs levels', 'MPA', (117, 128))	('GNL1', 'Gene', (51, 55))	('knockdown', 'Var', (56, 65))
11344	30061673	Western blot analysis indicated that the levels of cyclin D1, cyclin B1, CDK4 and CDK1 were significantly downregulated upon GNL1 knockdown (Fig.	('cyclin D1', 'Gene', (51, 60))	('downregulated', 'NegReg', (106, 119))	('CDK4', 'MPA', (73, 77))	('cyclin B1', 'Gene', (62, 71))	('GNL1', 'Gene', (125, 129))	('cyclin B1', 'Gene', '891', (62, 71))	('CDK1', 'Gene', (82, 86))	('knockdown', 'Var', (130, 139))	('CDK', 'molecular_function', 'GO:0004693', ('82', '85'))	('cyclin', 'molecular_function', 'GO:0016538', ('62', '68'))	('CDK', 'molecular_function', 'GO:0004693', ('73', '76'))	('cyclin', 'molecular_function', 'GO:0016538', ('51', '57'))	('GNL1', 'Gene', '2794', (125, 129))	('cyclin D1', 'Gene', '595', (51, 60))	('levels', 'MPA', (41, 47))
11362	30061673	Glutathione-Sepharose beads bound GST-RPS20 were incubated with HEK293T cell lysates containing equal amounts of GFP, full length or indicated variants of GNL11-607 (Supplementary Fig.	('Glutathione', 'Chemical', 'MESH:D005978', (0, 11))	('GNL1', 'Gene', (155, 159))	('HEK293T', 'CellLine', 'CVCL:0063', (64, 71))	('GNL1', 'Gene', '2794', (155, 159))	('Sepharose', 'Chemical', 'MESH:D012685', (12, 21))	('variants', 'Var', (143, 151))
11365	30061673	3b indicate that GNL1 mutant containing amino acids 1 to 50 interacted with RPS20 like GNL11-607.	('GNL1', 'Gene', (87, 91))	('GNL1', 'Gene', '2794', (17, 21))	('GNL1', 'Gene', (17, 21))	('GNL1', 'Gene', '2794', (87, 91))	('mutant', 'Var', (22, 28))	('interacted', 'Interaction', (60, 70))
11368	30061673	Lack of interaction between GFP with GST-RPS20 and GST with variants of GNL11-607 indicated the specificity of interaction between GNL1 and RPS20.	('GNL1', 'Gene', '2794', (131, 135))	('GNL1', 'Gene', (72, 76))	('GNL1', 'Gene', (131, 135))	('interaction', 'Interaction', (111, 122))	('interaction', 'Interaction', (8, 19))	('GNL1', 'Gene', '2794', (72, 76))	('variants', 'Var', (60, 68))
11370	30061673	GST pull down assay was carried out with full length or indicated deletion constructs of GST-RPS20 and HEK293T cell lysates containing GFP or GNL11-607 as described in Materials and Methods.	('GNL1', 'Gene', (142, 146))	('GST-RPS20', 'Gene', (89, 98))	('GNL1', 'Gene', '2794', (142, 146))	('HEK293T', 'CellLine', 'CVCL:0063', (103, 110))	('deletion', 'Var', (66, 74))
11371	30061673	S2c suggest that GNL11-607 interacted with RPS20 full length and the deletion constructs of GST-RPS20 containing amino acids 41 to 60 suggest that amino acids between 41-60 is the minimal domain in RPS20 required for its interaction with GNL1.	('GNL1', 'Gene', '2794', (238, 242))	('GNL1', 'Gene', '2794', (17, 21))	('GNL1', 'Gene', (238, 242))	('amino acids between 41-60', 'Var', (147, 172))	('GNL1', 'Gene', (17, 21))
11378	30061673	As noted from the amino acid sequences, GNL11-50 is rich in lysines and arginines and to identify the amino acids that are critical for GNL1 interaction with RPS20, GNL11-607_R22K23A was generated by exchanging the conserved Arg22 and Lys23 with alanine (Supplementary Fig.	('GNL1', 'Gene', '2794', (40, 44))	('GNL1', 'Gene', '2794', (136, 140))	('Arg22', 'Var', (225, 230))	('Arg22 and Lys23 with alanine', 'Mutation', 'p.R,K22,23A', (225, 253))	('GNL1', 'Gene', '2794', (165, 169))	('GNL1', 'Gene', (40, 44))	('Lys23 with alanine', 'SUBSTITUTION', 'None', (235, 253))	('exchanging', 'Var', (200, 210))	('arginine', 'Chemical', 'MESH:D001120', (72, 80))	('lysine', 'Chemical', 'MESH:D008239', (60, 66))	('GNL1', 'Gene', (136, 140))	('Lys23 with alanine', 'Var', (235, 253))	('GNL1', 'Gene', (165, 169))
11379	30061673	Interestingly, results from the co-immunoprecipitation assay indicate that replacement of Arg22 and Lys23 abrogated GNL1 interaction with RPS20 (Fig.	('Lys23', 'Chemical', '-', (100, 105))	('Arg22', 'Var', (90, 95))	('interaction', 'Interaction', (121, 132))	('GNL1', 'Gene', '2794', (116, 120))	('abrogated', 'NegReg', (106, 115))	('RPS20', 'Protein', (138, 143))	('Arg22', 'Chemical', '-', (90, 95))	('GNL1', 'Gene', (116, 120))	('replacement', 'Var', (75, 86))	('Lys23', 'Var', (100, 105))
11380	30061673	Collectively, data suggests that Arg22 and Lys23 residues within GNL11-50 is critical for its interaction with RPS20.	('GNL1', 'Gene', (65, 69))	('interaction', 'Interaction', (94, 105))	('GNL1', 'Gene', '2794', (65, 69))	('Arg22', 'Var', (33, 38))	('Lys23 residues', 'Var', (43, 57))	('Lys23', 'Chemical', '-', (43, 48))	('Arg22', 'Chemical', '-', (33, 38))	('RPS20', 'Protein', (111, 116))
11381	30061673	To confirm the conservation of GNL1 and RPS20 interaction, a panel of cell lines (HCT116p53+/+, AGS and HEK293T) were selected and tested.	('GNL1', 'Gene', (31, 35))	('GNL1', 'Gene', '2794', (31, 35))	('HEK293T', 'CellLine', 'CVCL:0063', (104, 111))	('HCT116p53+/+', 'Var', (82, 94))
11382	30061673	GNL1 and RPS20 complexes from cells lysates were co-immunoprecipitated with anti-RPS20 antibodies followed by western blot with anti-GNL1 (HCT116p53+/+ and AGS) or anti-GFP (HEK 293T) antibodies.	('HCT116p53+/+', 'Var', (139, 151))	('GNL1', 'Gene', '2794', (133, 137))	('GNL1', 'Gene', '2794', (0, 4))	('HEK 293T', 'CellLine', 'CVCL:0063', (174, 182))	('GNL1', 'Gene', (133, 137))	('GNL1', 'Gene', (0, 4))
11389	30061673	In addition, endogenous GNL1 protein level was significantly increased upon ectopic expression of RPS20-FLAG (here after referred as RPS20) in HCT116p53+/+ and AGS cell lines (Fig.	('RPS20-FLAG', 'Var', (98, 108))	('GNL1', 'Gene', '2794', (24, 28))	('increased', 'PosReg', (61, 70))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('GNL1', 'Gene', (24, 28))
11391	30061673	Furthermore, GNL1 knockdown resulted in reduction of RPS20 protein levels in both HCT116p53+/+ and AGS cell lines (Figs 4f and S3b) and the RPS20 depletion downregulated GNL1 levels in HCT116p53+/+ cells (Fig.	('depletion downregulated', 'NegReg', (146, 169))	('knockdown', 'Var', (18, 27))	('RPS20', 'Var', (140, 145))	('RPS20', 'Protein', (53, 58))	('GNL1', 'Gene', (170, 174))	('GNL1', 'Gene', '2794', (13, 17))	('reduction', 'NegReg', (40, 49))	('GNL1', 'Gene', (13, 17))	('GNL1', 'Gene', '2794', (170, 174))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
11393	30061673	The above data lead to the hypothesis that RPS20 increasing GNL1 protein levels by altering its stability.	('GNL1', 'Gene', '2794', (60, 64))	('stability', 'MPA', (96, 105))	('RPS20', 'Var', (43, 48))	('altering', 'Reg', (83, 91))	('GNL1', 'Gene', (60, 64))	('protein', 'cellular_component', 'GO:0003675', ('65', '72'))	('increasing', 'PosReg', (49, 59))
11398	30061673	To further confirm, cell proliferation was measured by MTT and BrdU incorporation assays in RPS20 expressing HCT116p53+/+ cells.	('HCT116p53+/+', 'Var', (109, 121))	('cell proliferation', 'CPA', (20, 38))	('BrdU', 'Chemical', 'MESH:D001973', (63, 67))	('MTT', 'Chemical', 'MESH:C070243', (55, 58))	('cell proliferation', 'biological_process', 'GO:0008283', ('20', '38'))	('RPS20', 'Gene', (92, 97))	('BrdU incorporation assays', 'CPA', (63, 88))
11401	30061673	Western blot analysis indicated that the levels of cyclin D1, cyclinB1, CDK1 and CDK4 were significantly upregulated upon ectopic expression of RPS20 (Fig.	('upregulated', 'PosReg', (105, 116))	('cyclin D1', 'Gene', (51, 60))	('CDK', 'molecular_function', 'GO:0004693', ('72', '75'))	('cyclinB1', 'Gene', (62, 70))	('cyclinB1', 'Gene', '891', (62, 70))	('ectopic expression', 'Var', (122, 140))	('CDK', 'molecular_function', 'GO:0004693', ('81', '84'))	('CDK4', 'Gene', (81, 85))	('RPS20', 'Var', (144, 149))	('cyclin', 'molecular_function', 'GO:0016538', ('51', '57'))	('cyclin D1', 'Gene', '595', (51, 60))	('CDK1', 'Gene', (72, 76))	('levels', 'MPA', (41, 47))
11403	30061673	5e indicate that the RPS20 significantly altered the expression of cyclin A2, cyclin E1, cyclin B1 and CDK1.	('cyclin E1', 'Gene', '898', (78, 87))	('cyclin', 'molecular_function', 'GO:0016538', ('89', '95'))	('altered', 'Reg', (41, 48))	('cyclin', 'molecular_function', 'GO:0016538', ('78', '84'))	('cyclin E1', 'Gene', (78, 87))	('RPS20', 'Var', (21, 26))	('cyclin A2', 'Gene', (67, 76))	('CDK', 'molecular_function', 'GO:0004693', ('103', '106'))	('cyclin', 'molecular_function', 'GO:0016538', ('67', '73'))	('CDK1', 'Gene', (103, 107))	('expression', 'MPA', (53, 63))	('cyclin A2', 'Gene', '890', (67, 76))	('cyclin B1', 'Gene', '891', (89, 98))	('cyclin B1', 'Gene', (89, 98))
11404	30061673	To further define whether RPS20 knockdown alters cell viability/proliferation, MTT and BrdU incorporation assays were performed.	('RPS20', 'Gene', (26, 31))	('cell viability/proliferation', 'CPA', (49, 77))	('knockdown', 'Var', (32, 41))	('alters', 'Reg', (42, 48))	('MTT', 'Chemical', 'MESH:C070243', (79, 82))	('BrdU', 'Chemical', 'MESH:D001973', (87, 91))	('BrdU incorporation', 'CPA', (87, 105))
11405	30061673	Interestingly, RPS20 knockdown significantly decreased the levels of CDK4 and CDK1 without altering cyclin B1 and cyclin D1 expression (Fig.	('RPS20', 'Gene', (15, 20))	('levels', 'MPA', (59, 65))	('CDK', 'molecular_function', 'GO:0004693', ('69', '72'))	('cyclin', 'molecular_function', 'GO:0016538', ('114', '120'))	('CDK4', 'MPA', (69, 73))	('cyclin D1', 'Gene', '595', (114, 123))	('CDK1', 'Gene', (78, 82))	('cyclin B1', 'Gene', (100, 109))	('cyclin D1', 'Gene', (114, 123))	('decreased', 'NegReg', (45, 54))	('cyclin B1', 'Gene', '891', (100, 109))	('cyclin', 'molecular_function', 'GO:0016538', ('100', '106'))	('CDK', 'molecular_function', 'GO:0004693', ('78', '81'))	('knockdown', 'Var', (21, 30))
11407	30061673	Results from MTT assay clearly indicated that expression of GNL11-607 alone or in combination with RPS20 resulted in increased viability of both HCT116p53+/+ and AGS cells (Fig.	('MTT', 'Chemical', 'MESH:C070243', (13, 16))	('GNL1', 'Gene', '2794', (60, 64))	('increased', 'PosReg', (117, 126))	('viability', 'CPA', (127, 136))	('GNL1', 'Gene', (60, 64))	('HCT116p53+/+', 'Var', (145, 157))
11415	30061673	6c suggest that knockdown of both GNL1 and RPS20 resulted in significant reduction of HCT116p53+/+ cell viability.	('RPS20', 'Gene', (43, 48))	('HCT116p53+/+', 'MPA', (86, 98))	('knockdown', 'Var', (16, 25))	('GNL1', 'Gene', '2794', (34, 38))	('reduction', 'NegReg', (73, 82))	('GNL1', 'Gene', (34, 38))
11424	30061673	To understand the physiological importance of GNL1 and RPS20 interaction during tumorigenesis, the colony formation ability of HCT116p53+/+ or AGS cells were checked upon ectopic expression or knockdown of GNL1 with or without RPS20.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('GNL1', 'Gene', (206, 210))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('GNL1', 'Gene', (46, 50))	('knockdown', 'Var', (193, 202))	('GNL1', 'Gene', '2794', (206, 210))	('tumor', 'Disease', (80, 85))	('formation', 'biological_process', 'GO:0009058', ('106', '115'))	('GNL1', 'Gene', '2794', (46, 50))
11426	30061673	Results indicate that the number of colonies were significantly increased upon the expression of GNL11-607 or RPS20 alone or in combination (Figs 7a and S4b).	('GNL1', 'Gene', (97, 101))	('GNL1', 'Gene', '2794', (97, 101))	('increased', 'PosReg', (64, 73))	('RPS20', 'Gene', (110, 115))	('expression', 'Var', (83, 93))
11427	30061673	In contrast, the colony numbers were significantly reduced when HCT116p53+/+ or AGS cells were co-expressed with GNL11-607_R22K23A and RPS20 (Figs 7a and S4b).	('HCT116p53+/+', 'Var', (64, 76))	('reduced', 'NegReg', (51, 58))	('GNL1', 'Gene', '2794', (113, 117))	('GNL1', 'Gene', (113, 117))	('colony numbers', 'CPA', (17, 31))	('RPS20', 'Var', (135, 140))
11439	30061673	Kaplan-Meier analysis showed that high mRNA expression of GNL1 and RPS20 was strongly associated with decreased overall survival of gastric cancer patients (Fig.	('GNL1', 'Gene', (58, 62))	('RPS20', 'Gene', (67, 72))	('gastric cancer', 'Disease', (132, 146))	('mRNA expression', 'MPA', (39, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (132, 146))	('high', 'Var', (34, 38))	('GNL1', 'Gene', '2794', (58, 62))	('patients', 'Species', '9606', (147, 155))	('gastric cancer', 'Phenotype', 'HP:0012126', (132, 146))	('overall survival', 'MPA', (112, 128))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('decreased', 'NegReg', (102, 111))
11456	30061673	Results from the current investigation clearly indicates that ectopic expression of GNL1 upregulates RPS20 expression and promotes cell proliferation.	('GNL1', 'Gene', '2794', (84, 88))	('cell proliferation', 'biological_process', 'GO:0008283', ('131', '149'))	('promotes', 'PosReg', (122, 130))	('expression', 'MPA', (107, 117))	('GNL1', 'Gene', (84, 88))	('upregulates', 'PosReg', (89, 100))	('cell proliferation', 'CPA', (131, 149))	('RPS20', 'Protein', (101, 106))	('ectopic expression', 'Var', (62, 80))
11457	30061673	GNL1 function is severely impaired upon RPS20 knockdown which shows the critical role played by RPS20 in GNL1 function.	('RPS20', 'Gene', (40, 45))	('knockdown', 'Var', (46, 55))	('GNL1', 'Gene', '2794', (0, 4))	('GNL1', 'Gene', (105, 109))	('impaired', 'NegReg', (26, 34))	('GNL1', 'Gene', (0, 4))	('function', 'MPA', (5, 13))	('GNL1', 'Gene', '2794', (105, 109))
11464	30061673	The deregulation of G1/S restriction point leads to uncontrolled cell proliferation and contributes to tumorigenesis.	('G1/S', 'Gene', (20, 24))	('deregulation', 'Var', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('uncontrolled', 'MPA', (52, 64))	('contributes to', 'Reg', (88, 102))	('cell proliferation', 'biological_process', 'GO:0008283', ('65', '83'))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('leads to', 'Reg', (43, 51))
11469	30061673	The observed high expression levels of GNL1 and RPS20 in various cancer tissues together with our results from the current study suggests the possibility that the co-operation of GNL1 and RPS20 may favor faster cell proliferation during cancer progression and may be an ideal target for cancer therapeutic intervention.	('favor faster', 'PosReg', (198, 210))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('GNL1', 'Gene', '2794', (39, 43))	('GNL1', 'Gene', '2794', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('RPS20', 'Gene', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('GNL1', 'Gene', (39, 43))	('cell proliferation', 'biological_process', 'GO:0008283', ('211', '229'))	('co-operation', 'Var', (163, 175))	('cancer', 'Disease', (237, 243))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('GNL1', 'Gene', (179, 183))
11474	30061673	HCT116p53+/+, HCT116p53-/-, AGS and HEK293T cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) (Thermo Fisher Scientific Inc., USA) with 10% Fetal Bovine Serum (FBS) and 1% antibiotics-antimycotics (Thermo Fisher Scientific Inc., USA).	('Bovine', 'Species', '9913', (161, 167))	('DMEM', 'Chemical', '-', (103, 107))	('HEK293T', 'CellLine', 'CVCL:0063', (36, 43))	('HCT116p53+/+', 'Var', (0, 12))	('FBS', 'Disease', 'MESH:D005198', (175, 178))	('HCT116p53-/-', 'Var', (14, 26))	('FBS', 'Disease', (175, 178))
11481	30061673	Full length and variants of RPS20 were transformed into E. coli BL21DE3 cells and grown overnight at 37  C. Single colony containing GST-RPS20 was inoculated into LB medium and the protein expression was induced with 1 mM IPTG at 18  C for 12-14 hours.	('protein', 'Protein', (181, 188))	('IPTG', 'Chemical', 'MESH:D007544', (222, 226))	('GST-RPS20', 'Gene', (133, 142))	('LB medium', 'Chemical', '-', (163, 172))	('RPS20', 'Gene', (28, 33))	('variants', 'Var', (16, 24))	('protein', 'cellular_component', 'GO:0003675', ('181', '188'))	('E. coli BL21DE3', 'Species', '469008', (56, 71))
11482	30061673	Equal amounts of HCT116p53+/+ and AGS cell lysates were incubated with anti-RPS20 antibodies for 6 hours at 4  C and the antibody-protein complexes were eluted and resolved on SDS-12%PAGE followed by western blotting with anti-GNL1 antibody.	('protein', 'cellular_component', 'GO:0003675', ('130', '137'))	('SDS', 'Chemical', 'MESH:D012967', (176, 179))	('GNL1', 'Gene', (227, 231))	('antibody', 'cellular_component', 'GO:0019814', ('121', '129'))	('antibody', 'cellular_component', 'GO:0042571', ('121', '129'))	('antibody', 'cellular_component', 'GO:0042571', ('232', '240'))	('HCT116p53+/+', 'Var', (17, 29))	('antibody', 'molecular_function', 'GO:0003823', ('121', '129'))	('antibody', 'cellular_component', 'GO:0019815', ('232', '240'))	('GNL1', 'Gene', '2794', (227, 231))	('antibody', 'molecular_function', 'GO:0003823', ('232', '240'))	('antibody', 'cellular_component', 'GO:0019814', ('232', '240'))	('antibody', 'cellular_component', 'GO:0019815', ('121', '129'))
11486	30061673	HCT116p53+/+ cells were transfected with GNL11-607, GNL1-shRNA, RPS20-FLAG, RPS20-shRNA, control vectors alone or in combination.	('GNL1', 'Gene', (41, 45))	('GNL1', 'Gene', (52, 56))	('GNL1', 'Gene', '2794', (41, 45))	('RPS20-FLAG', 'Var', (64, 74))	('GNL1', 'Gene', '2794', (52, 56))
11487	30061673	HCT116p53+/+ or AGS cells were transfected with GNL11-607, GNL11-607_R22K23A, RPS20-FLAG, GNL1 shRNA, RPS20 shRNA alone or in combination.	('GNL1', 'Gene', (48, 52))	('GNL1', 'Gene', (59, 63))	('GNL1', 'Gene', (90, 94))	('RPS20-FLAG', 'Var', (78, 88))	('GNL1', 'Gene', '2794', (59, 63))	('GNL1', 'Gene', '2794', (48, 52))	('GNL1', 'Gene', '2794', (90, 94))
11489	30061673	HCT116p53+/+ cells were transfected with GNL11-607, RPS20-FLAG, GNL1 shRNA, RPS20 shRNA alone or in combination.	('GNL1', 'Gene', (41, 45))	('GNL1', 'Gene', '2794', (64, 68))	('GNL1', 'Gene', '2794', (41, 45))	('GNL1', 'Gene', (64, 68))	('RPS20-FLAG', 'Var', (52, 62))	('RPS20', 'Var', (76, 81))
11492	30061673	HCT116p53+/+ and AGS cells were transfected with GNL11-607, GNL11-607_R22K23A, RPS20-FLAG, GNL1 shRNA, RPS20 shRNA alone or in combination.	('GNL1', 'Gene', '2794', (60, 64))	('GNL1', 'Gene', '2794', (91, 95))	('RPS20-FLAG', 'Var', (79, 89))	('GNL1', 'Gene', '2794', (49, 53))	('GNL1', 'Gene', (60, 64))	('GNL1', 'Gene', (91, 95))	('GNL1', 'Gene', (49, 53))
11494	30061673	The surviving fraction of cells was determined by dividing the plating efficiency of cells transfected with GNL11-607, GNL11-607_R22K23A, RPS20-FLAG, GNL1 shRNA, RPS20 shRNA alone or in combination by plating efficiency of control cells.	('GNL1', 'Gene', '2794', (119, 123))	('GNL1', 'Gene', (108, 112))	('GNL1', 'Gene', '2794', (150, 154))	('GNL1', 'Gene', '2794', (108, 112))	('GNL1', 'Gene', (119, 123))	('GNL1', 'Gene', (150, 154))	('RPS20-FLAG', 'Var', (138, 148))
11513	29928545	For the treatment of gastric cancer, there are three accepted approaches, all of which include chemotherapy and resection: Surgery followed by postoperative (adjuvant) chemotherapy with fluorouracil (5-FU) and radiotherapy, primarily for patients in whom resection was less than level D1 (i.e., a suboptimal number of nodes were resected); Preoperative and postoperative chemotherapy with epirubicin, cisplatin, and 5-FU (ECF), for patients with D1-2 resection; Postoperative chemotherapy with capecit-abine and oxaliplatin (XELOX) for patients with D2 resection.	('D1-2', 'Var', (446, 450))	('fluorouracil', 'Chemical', 'MESH:D005472', (186, 198))	('epirubicin', 'Chemical', 'MESH:D015251', (389, 399))	('gastric cancer', 'Phenotype', 'HP:0012126', (21, 35))	('capecit-abine', 'Chemical', 'MESH:D000069287', (494, 507))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (512, 523))	('5-FU', 'Chemical', 'MESH:D005472', (416, 420))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('patients', 'Species', '9606', (536, 544))	('gastric cancer', 'Disease', (21, 35))	('XELOX', 'Chemical', 'MESH:C519688', (525, 530))	('patients', 'Species', '9606', (432, 440))	('5-FU', 'Chemical', 'MESH:D005472', (200, 204))	('gastric cancer', 'Disease', 'MESH:D013274', (21, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (401, 410))	('patients', 'Species', '9606', (238, 246))
11580	29928545	Among 149 esophageal adenocarcinomas, 26 significant genes with mutations or genomic loss have been identified.	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (10, 36))	('esophageal adenocarcinomas', 'Disease', (10, 36))	('mutations', 'Var', (64, 73))
11583	29928545	However, inhibition of EGFR and of MET has universally failed to improve outcomes, and results are mixed for the targeting of ERBB2.	('ERBB2', 'Gene', '2064', (126, 131))	('EGFR', 'molecular_function', 'GO:0005006', ('23', '27'))	('ERBB2', 'Gene', (126, 131))	('MET', 'Gene', (35, 38))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (23, 27))	('inhibition', 'Var', (9, 19))
11593	29805304	In addition, PARI knockdown blocked the effect of FOXM1 on GC cell migration.	('knockdown', 'Var', (18, 27))	('GC cell migration', 'CPA', (59, 76))	('cell migration', 'biological_process', 'GO:0016477', ('62', '76'))	('GC', 'Phenotype', 'HP:0012126', (59, 61))	('PARI', 'Gene', (13, 17))	('FOXM1', 'Gene', (50, 55))	('FOXM1', 'Gene', '2305', (50, 55))	('blocked', 'NegReg', (28, 35))
11601	29805304	Downregulation of PARI in some cancer cells could improve homologous recombination and preserve genomic stability.	('homologous recombination', 'MPA', (58, 82))	('genomic stability', 'CPA', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('preserve', 'Reg', (87, 95))	('Downregulation', 'Var', (0, 14))	('homologous recombination', 'biological_process', 'GO:0035825', ('58', '82'))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('PARI', 'Gene', (18, 22))	('cancer', 'Disease', (31, 37))	('improve', 'PosReg', (50, 57))
11606	29805304	We further demonstrated that knockdown of PARI suppressed GC cell proliferation, migration and invasion in vitro, and inhibited the xenograft tumor growth and lung metastasis in vivo.	('inhibited', 'NegReg', (118, 127))	('suppressed', 'NegReg', (47, 57))	('invasion', 'CPA', (95, 103))	('lung metastasis', 'Disease', 'MESH:D009362', (159, 174))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('knockdown', 'Var', (29, 38))	('GC', 'Phenotype', 'HP:0012126', (58, 60))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('PARI', 'Gene', (42, 46))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('GC cell proliferation', 'CPA', (58, 79))	('lung metastasis', 'Disease', (159, 174))
11626	29805304	The membrane was blocked in 5% blocking buffer (5% non-fat milk and 0.1% Tween-20 in phosphate-buffered saline [PBS]) for 2 h at room temperature, and then incubated with the primary antibody, anti-PARI (1:500, ABGENT, USA), anti-FOXM1 (1:200, Santa Cruz Biotechnology, USA) and anti-GAPDH (1:20000, Proteintech, China), in 0.1% Tween-20 in PBS overnight at 4 C. Incubation with the secondary antibody was performed for 1 h at room temperature.	('antibody', 'cellular_component', 'GO:0019814', ('393', '401'))	('antibody', 'molecular_function', 'GO:0003823', ('393', '401'))	('antibody', 'cellular_component', 'GO:0019815', ('183', '191'))	('PBS', 'Chemical', '-', (341, 344))	('antibody', 'cellular_component', 'GO:0019814', ('183', '191'))	('antibody', 'molecular_function', 'GO:0003823', ('183', '191'))	('antibody', 'cellular_component', 'GO:0042571', ('393', '401'))	('PBS', 'Chemical', '-', (112, 115))	('FOXM1', 'Gene', (230, 235))	('1:20000', 'Var', (291, 298))	('FOXM1', 'Gene', '2305', (230, 235))	('membrane', 'cellular_component', 'GO:0016020', ('4', '12'))	('antibody', 'cellular_component', 'GO:0019815', ('393', '401'))	('antibody', 'cellular_component', 'GO:0042571', ('183', '191'))
11634	29805304	For lung metastasis assay (n=6 for each group), the mice at the age of 6 weeks old were injected with 1x106 cells of SGC7901-Lv-shNC, SGC7901-Lv-shPARI through tail vein, respectively.	('SGC7901-Lv-shPARI', 'Var', (134, 151))	('SGC7901-Lv-shNC', 'Var', (117, 132))	('mice', 'Species', '10090', (52, 56))	('GC', 'Phenotype', 'HP:0012126', (118, 120))	('GC', 'Phenotype', 'HP:0012126', (135, 137))	('lung metastasis', 'Disease', 'MESH:D009362', (4, 19))	('lung metastasis', 'Disease', (4, 19))
11644	29805304	The staining level of PARI was significantly higher in GC tissue group compared with the adjacent noncancerous mucosa control group (Figure 1B).	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('GC tissue', 'Var', (55, 64))	('cancer', 'Disease', (101, 107))	('GC', 'Phenotype', 'HP:0012126', (55, 57))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('staining level', 'MPA', (4, 18))	('higher', 'PosReg', (45, 51))
11649	29805304	As shown in Figure 2B, both MGC803 and AGS cells transfected with siPARIs slowed cell growth compared with the negative control group, indicating PARI knockdown inhibited GC cell growth.	('slowed', 'NegReg', (74, 80))	('inhibited', 'NegReg', (161, 170))	('cell growth', 'biological_process', 'GO:0016049', ('174', '185'))	('cell growth', 'CPA', (81, 92))	('MGC803', 'CellLine', 'CVCL:5334', (28, 34))	('GC cell growth', 'CPA', (171, 185))	('GC', 'Phenotype', 'HP:0012126', (29, 31))	('slowed cell growth', 'Phenotype', 'HP:0001510', (74, 92))	('cell growth', 'biological_process', 'GO:0016049', ('81', '92'))	('siPARIs', 'Gene', (66, 73))	('GC', 'Phenotype', 'HP:0012126', (171, 173))	('knockdown', 'Var', (151, 160))
11654	29805304	As a result, no visible tumors were observed in the PARI silencing group after 4 weeks, whereas tumors were markedly generated in the control group (Figure 3A), implicating that knockdown of PARI abolished tumor formation ability of SGC7901 cells in nude mice.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', (96, 102))	('PARI', 'Gene', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('knockdown', 'Var', (178, 187))	('tumor', 'Disease', (24, 29))	('silencing', 'NegReg', (57, 66))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('formation', 'biological_process', 'GO:0009058', ('212', '221'))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('abolished', 'NegReg', (196, 205))	('GC', 'Phenotype', 'HP:0012126', (234, 236))	('tumor', 'Disease', (206, 211))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('nude mice', 'Species', '10090', (250, 259))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
11656	29805304	Consistently, the tumors formed from PARI silenced MGC803 cells were significantly smaller in size and lower in weight than those formed from the control cells (Figure 3B).	('GC', 'Phenotype', 'HP:0012126', (52, 54))	('lower', 'NegReg', (103, 108))	('PARI silenced', 'Var', (37, 50))	('smaller', 'NegReg', (83, 90))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('MGC803', 'CellLine', 'CVCL:5334', (51, 57))	('MGC803', 'Gene', (51, 57))	('lower in weight', 'Phenotype', 'HP:0004325', (103, 118))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
11660	29805304	The results showed that cell migration and invasion of MGC803 and AGS cells were significantly attenuated by PARI knockdown in the Transwell assay (Figure 4A and 4B).	('cell migration', 'CPA', (24, 38))	('invasion', 'CPA', (43, 51))	('PARI', 'Gene', (109, 113))	('knockdown', 'Var', (114, 123))	('GC', 'Phenotype', 'HP:0012126', (56, 58))	('cell migration', 'biological_process', 'GO:0016477', ('24', '38'))	('attenuated', 'NegReg', (95, 105))	('MGC803', 'CellLine', 'CVCL:5334', (55, 61))
11661	29805304	Consistent with the in vitro assay, the in vivo pulmonary metastasis model result also demonstrated that PARI downregulation suppressed GC cell metastasis, since fewer and smaller tumors formed in the lungs of those mice injected with SGC7901-LV-shPARI cells than those of mice infected with SGC7901-LV-shNC cells.	('SGC7901-LV-shPARI', 'Var', (235, 252))	('PARI', 'Gene', (105, 109))	('downregulation suppressed', 'NegReg', (110, 135))	('GC cell metastasis', 'CPA', (136, 154))	('fewer', 'NegReg', (162, 167))	('mice', 'Species', '10090', (216, 220))	('smaller', 'NegReg', (172, 179))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('pulmonary metastasis', 'Disease', (48, 68))	('GC', 'Phenotype', 'HP:0012126', (293, 295))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('GC', 'Phenotype', 'HP:0012126', (236, 238))	('pulmonary metastasis', 'Disease', 'MESH:D009362', (48, 68))	('mice', 'Species', '10090', (273, 277))	('GC', 'Phenotype', 'HP:0012126', (136, 138))
11666	29805304	The results indicated that the mRNA level of PARI was significantly decreased with FOXM1 knockdown (Figure 5A).	('mRNA level of', 'MPA', (31, 44))	('decreased', 'NegReg', (68, 77))	('knockdown', 'Var', (89, 98))	('FOXM1', 'Gene', (83, 88))	('FOXM1', 'Gene', '2305', (83, 88))
11668	29805304	Furthermore, PARI was also upregulated in protein level with FOXM1 overexpression in SGC7901 cells (Figure 5C).	('protein level', 'MPA', (42, 55))	('GC', 'Phenotype', 'HP:0012126', (86, 88))	('PARI', 'Gene', (13, 17))	('FOXM1', 'Gene', (61, 66))	('FOXM1', 'Gene', '2305', (61, 66))	('upregulated', 'PosReg', (27, 38))	('overexpression', 'Var', (67, 81))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))
11674	29805304	As shown in Figure 6A, the luciferase activity was higher in FOXM1 overexpressed cells than the control cells.	('luciferase activity', 'molecular_function', 'GO:0047712', ('27', '46'))	('activity', 'MPA', (38, 46))	('luciferase activity', 'molecular_function', 'GO:0050397', ('27', '46'))	('luciferase activity', 'molecular_function', 'GO:0050248', ('27', '46'))	('FOXM1', 'Gene', (61, 66))	('overexpressed', 'Var', (67, 80))	('FOXM1', 'Gene', '2305', (61, 66))	('luciferase', 'Enzyme', (27, 37))	('higher', 'PosReg', (51, 57))	('luciferase activity', 'molecular_function', 'GO:0047077', ('27', '46'))	('luciferase activity', 'molecular_function', 'GO:0045289', ('27', '46'))
11678	29805304	As expected, disruption of the FOXM1 binding site significantly attenuated the effect of FOXM1 expression on PARI promoter activity (Figure 6D).	('binding', 'molecular_function', 'GO:0005488', ('37', '44'))	('FOXM1', 'Gene', '2305', (31, 36))	('attenuated', 'NegReg', (64, 74))	('FOXM1', 'Gene', (31, 36))	('disruption', 'Var', (13, 23))	('FOXM1', 'Gene', '2305', (89, 94))	('FOXM1', 'Gene', (89, 94))	('PARI promoter activity', 'MPA', (109, 131))	('expression', 'MPA', (95, 105))	('effect', 'MPA', (79, 85))
11683	29805304	The resulting data indicated that PARI knockdown suppressed the effect of FOXM1 on cell migration (Figure 7), suggesting that PARI may act as a functional downstream effector of FOXM1.	('FOXM1', 'Gene', (74, 79))	('cell migration', 'CPA', (83, 97))	('knockdown', 'Var', (39, 48))	('FOXM1', 'Gene', '2305', (74, 79))	('suppressed', 'NegReg', (49, 59))	('FOXM1', 'Gene', (178, 183))	('PARI', 'Gene', (34, 38))	('FOXM1', 'Gene', '2305', (178, 183))	('cell migration', 'biological_process', 'GO:0016477', ('83', '97'))
11687	29805304	As known, tumorigenesis may originate from the dysregulation of normal developmental genes.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('dysregulation', 'Var', (47, 60))	('tumor', 'Disease', (10, 15))	('originate from', 'Reg', (28, 42))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
11688	29805304	Inappropriate homologous recombination often causes genomic instability and cancer.	('Inappropriate homologous recombination', 'Var', (0, 38))	('homologous recombination', 'biological_process', 'GO:0035825', ('14', '38'))	('causes', 'Reg', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('genomic', 'Disease', (52, 59))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
11691	29805304	Furthermore, knockdown of PARI significantly suppresses human HeLa cell growth in another study.	('PARI', 'Gene', (26, 30))	('human HeLa cell growth', 'CPA', (56, 78))	('human', 'Species', '9606', (56, 61))	('suppresses', 'NegReg', (45, 55))	('HeLa', 'CellLine', 'CVCL:0030', (62, 66))	('knockdown', 'Var', (13, 22))	('cell growth', 'biological_process', 'GO:0016049', ('67', '78'))
11695	29805304	Our present data demonstrate that knockdown of PARI decreases the proliferation and metastasis of human gastric cancer cells in vitro and in vivo.	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('decreases', 'NegReg', (52, 61))	('proliferation', 'CPA', (66, 79))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('PARI', 'Gene', (47, 51))	('metastasis of human', 'CPA', (84, 103))	('knockdown', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('human', 'Species', '9606', (98, 103))	('gastric cancer', 'Disease', (104, 118))
11704	29805304	Therefore, abnormal expression of FOXM1 during the initiation and development of gastric cancer contributes to abnormal PARI expression and activation; the latter may be a novel molecular marker for poor prognosis and contribute to gastric cancer pathogenesis.	('FOXM1', 'Gene', '2305', (34, 39))	('activation', 'MPA', (140, 150))	('gastric cancer', 'Disease', (232, 246))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('contribute', 'Reg', (218, 228))	('abnormal', 'Var', (11, 19))	('gastric cancer', 'Disease', 'MESH:D013274', (232, 246))	('pathogenesis', 'biological_process', 'GO:0009405', ('247', '259'))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('gastric cancer', 'Disease', (81, 95))	('gastric cancer', 'Phenotype', 'HP:0012126', (232, 246))	('FOXM1', 'Gene', (34, 39))	('PARI', 'Protein', (120, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))
11777	29190954	Studies have reported that inhibition of COX-2 reverses the resistance of several types of cancer cells to PTX.	('COX-2', 'Enzyme', (41, 46))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('resistance', 'MPA', (60, 70))	('inhibition', 'Var', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('reverses', 'NegReg', (47, 55))	('PTX', 'Chemical', 'MESH:D017239', (107, 110))
11778	29190954	Additionally, studies have shown that inhibition of COX-2 expression leads to apoptosis in cancer cells by stimulating pro-apoptotic proteins.	('apoptosis', 'biological_process', 'GO:0006915', ('78', '87'))	('apoptosis', 'biological_process', 'GO:0097194', ('78', '87'))	('COX-2', 'Gene', (52, 57))	('apoptosis', 'CPA', (78, 87))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('inhibition', 'Var', (38, 48))	('pro-apoptotic proteins', 'MPA', (119, 141))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('stimulating', 'PosReg', (107, 118))
11793	29190954	From this analysis, the combined effects of UA and PTX can be summarized as follows: CI < 1, CI = 1, and CI >1 indicates synergistic, additive, and antagonistic effects, respectively.	('CI < 1', 'Var', (85, 91))	('UA', 'Chemical', 'MESH:C005466', (44, 46))	('CI = 1', 'Var', (93, 99))	('PTX', 'Chemical', 'MESH:D017239', (51, 54))	('CI >1', 'Var', (105, 110))
11803	28963512	Global network random walk for predicting potential human lncRNA-disease associations There is more and more evidence that the mutation and dysregulation of long non-coding RNA (lncRNA) are associated with numerous diseases, including cancers.	('numerous diseases', 'Disease', (206, 223))	('dysregulation', 'Var', (140, 153))	('mutation', 'Var', (127, 135))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('human', 'Species', '9606', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('RNA', 'cellular_component', 'GO:0005562', ('173', '176'))	('cancers', 'Disease', (235, 242))	('numerous diseases', 'Disease', 'MESH:D004194', (206, 223))	('associated', 'Reg', (190, 200))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
11810	28963512	It is reported that mutations and dysregulations of lncRNAs are associated with a broad range of human diseases, such as breast cancer, colon cancer, cardiovascular diseases, and neurodegenerative diseases.	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (150, 173))	('human', 'Species', '9606', (97, 102))	('dysregulations', 'Var', (34, 48))	('associated', 'Reg', (64, 74))	('colon cancer', 'Phenotype', 'HP:0003003', (136, 148))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (179, 205))	('lncRNAs', 'Gene', (52, 59))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (150, 173))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (179, 205))	('colon cancer', 'Disease', 'MESH:D015179', (136, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('mutations', 'Var', (20, 29))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('breast cancer', 'Disease', (121, 134))	('colon cancer', 'Disease', (136, 148))	('neurodegenerative diseases', 'Disease', (179, 205))	('cardiovascular diseases', 'Disease', (150, 173))
11839	28963512	showed that ablation of PVT1 (ranked fourth) from the MYC-driven colon cancer line HCT116 diminishes tumorigenic potency.	('colon cancer', 'Disease', (65, 77))	('MYC', 'Gene', '4609', (54, 57))	('ablation', 'Var', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('PVT1', 'Gene', (24, 28))	('diminishes', 'NegReg', (90, 100))	('tumor', 'Disease', (101, 106))	('colon cancer', 'Phenotype', 'HP:0003003', (65, 77))	('HCT116', 'CellLine', 'CVCL:0291', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('PVT1', 'Gene', '5820', (24, 28))	('MYC', 'Gene', (54, 57))	('colon cancer', 'Disease', 'MESH:D015179', (65, 77))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
11908	28558708	The infection of the gastric mucosa by Helicobacter pylori represents the major risk factor in over 65% of all distal GC, and recent evidence suggests that it might also play a role in proximal GC.	('infection of the gastric mucosa', 'Disease', 'MESH:D013274', (4, 35))	('infection of the gastric mucosa', 'Disease', (4, 35))	('distal GC', 'Disease', (111, 120))	('GC', 'Phenotype', 'HP:0012126', (118, 120))	('infection of the gastric mucosa', 'Phenotype', 'HP:0004295', (4, 35))	('Helicobacter', 'Var', (39, 51))	('GC', 'Phenotype', 'HP:0012126', (194, 196))	('proximal GC', 'Disease', (185, 196))	('Helicobacter pylori', 'Species', '210', (39, 58))
11914	28558708	H. pylori also induces gastric mucosal infiltration by dendritic cells and T and B cells, and stimulates secretion of macrophage chemotactic protein (MCP)-1, tumor necrosis factor (TNF)-alpha, IL-12, IL-10, transforming growth factor (TGF)-beta, and interferon (IFN)-gamma.	('IL-10', 'Gene', (200, 205))	('H. pylori', 'Species', '210', (0, 9))	('gastric mucosal', 'Disease', (23, 38))	('secretion', 'MPA', (105, 114))	('tumor necrosis', 'Disease', (158, 172))	('protein', 'cellular_component', 'GO:0003675', ('141', '148'))	('MCP', 'Gene', (150, 153))	('secretion', 'biological_process', 'GO:0046903', ('105', '114'))	('H. pylori', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('MCP', 'Gene', '822', (150, 153))	('tumor necrosis factor', 'molecular_function', 'GO:0005164', ('158', '179'))	('induces', 'Reg', (15, 22))	('IFN', 'Gene', '3439', (262, 265))	('MCP', 'molecular_function', 'GO:0004298', ('150', '153'))	('necrosis', 'biological_process', 'GO:0008219', ('164', '172'))	('IFN', 'Gene', (262, 265))	('stimulates', 'PosReg', (94, 104))	('gastric mucosal', 'Disease', 'MESH:D013274', (23, 38))	('necrosis', 'biological_process', 'GO:0008220', ('164', '172'))	('IL-12', 'molecular_function', 'GO:0005143', ('193', '198'))	('IL-10', 'Gene', '3586', (200, 205))	('IL-10', 'molecular_function', 'GO:0005141', ('200', '205'))	('necrosis', 'biological_process', 'GO:0070265', ('164', '172'))	('tumor necrosis', 'Disease', 'MESH:D009336', (158, 172))	('necrosis', 'biological_process', 'GO:0019835', ('164', '172'))	('necrosis', 'biological_process', 'GO:0001906', ('164', '172'))
11961	28558708	In addition, the overexpression of IL-1beta in the stomach of mice led to spontaneous gastric inflammation and cancer, even in the absence of H. pylori infection, and IL-1beta is a potent inhibitor of gastric acid secretion, which may also favor the appearance of preneoplastic lesions because of hypochloridia.	('hypochloridia', 'Disease', 'None', (297, 310))	('mice', 'Species', '10090', (62, 66))	('infection', 'Disease', (152, 161))	('gastric inflammation', 'Disease', (86, 106))	('hypochloridia', 'Disease', (297, 310))	('infection', 'Disease', 'MESH:D007239', (152, 161))	('H. pylori', 'Species', '210', (142, 151))	('cancer', 'Disease', (111, 117))	('gastric inflammation', 'Disease', 'MESH:D007249', (86, 106))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('IL-1', 'molecular_function', 'GO:0005149', ('35', '39'))	('IL-1beta', 'Gene', (35, 43))	('gastric acid secretion', 'biological_process', 'GO:0001696', ('201', '223'))	('preneoplastic lesions', 'CPA', (264, 285))	('IL-1', 'molecular_function', 'GO:0005149', ('167', '171'))	('overexpression', 'PosReg', (17, 31))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('favor', 'PosReg', (240, 245))	('gastric inflammation', 'Phenotype', 'HP:0005263', (86, 106))	('H. pylori infection', 'Phenotype', 'HP:0005202', (142, 161))	('inflammation', 'biological_process', 'GO:0006954', ('94', '106'))	('gastric acid secretion', 'MPA', (201, 223))	('IL-1beta', 'Var', (167, 175))
11969	28558708	Previous studies have shown that specific T cell responses play a critical role in inducing gastric mucosal inflammation, and suggested that IFN-gamma may exacerbate gastric inflammation and favor progression to GC.	('GC', 'Phenotype', 'HP:0012126', (212, 214))	('inducing', 'PosReg', (83, 91))	('progression', 'CPA', (197, 208))	('gastric inflammation', 'Disease', 'MESH:D007249', (166, 186))	('inflammation', 'biological_process', 'GO:0006954', ('108', '120'))	('IFN-gamma', 'Var', (141, 150))	('exacerbate', 'PosReg', (155, 165))	('favor', 'PosReg', (191, 196))	('inflammation', 'biological_process', 'GO:0006954', ('174', '186'))	('gastric mucosal inflammation', 'Phenotype', 'HP:0005263', (92, 120))	('gastric inflammation', 'Disease', (166, 186))	('gastric mucosal inflammation', 'Disease', 'MESH:D007249', (92, 120))	('gastric inflammation', 'Phenotype', 'HP:0005263', (166, 186))	('gastric mucosal inflammation', 'Disease', (92, 120))
11977	28558708	This chemokine plays an important role in the progress of H. pylori-related gastric diseases, and patients infected with H. pylori have significantly higher expression of mcp-1 mRNA in the gastric mucosa than patients without H. pylori infection.	('mcp', 'molecular_function', 'GO:0004298', ('171', '174'))	('expression', 'MPA', (157, 167))	('H. pylori infection', 'Phenotype', 'HP:0005202', (226, 245))	('H. pylori', 'Species', '210', (226, 235))	('higher', 'PosReg', (150, 156))	('H. pylori', 'Species', '210', (58, 67))	('gastric diseases', 'Disease', (76, 92))	('infection', 'Disease', 'MESH:D007239', (236, 245))	('patients', 'Species', '9606', (98, 106))	('H. pylori', 'Species', '210', (121, 130))	('patients', 'Species', '9606', (209, 217))	('gastric diseases', 'Disease', 'MESH:D013274', (76, 92))	('mcp-1', 'Gene', (171, 176))	('infection', 'Disease', (236, 245))	('mcp-1', 'Gene', '6347', (171, 176))	('H. pylori', 'Var', (121, 130))
11985	28558708	These results are consistent with studies showing that IL-8 is also produced by cancer cells and may promote angiogenesis, tumor growth, tissue invasion, and metastatic spread, and that high IL-8 expression directly correlates with a poor prognosis in GC.	('angiogenesis', 'biological_process', 'GO:0001525', ('109', '121'))	('cancer', 'Disease', (80, 86))	('IL-8', 'Gene', (191, 195))	('tumor', 'Disease', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('GC', 'Phenotype', 'HP:0012126', (252, 254))	('metastatic spread', 'CPA', (158, 175))	('IL-8', 'Gene', (55, 59))	('angiogenesis', 'CPA', (109, 121))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('IL-8', 'Gene', '3576', (191, 195))	('high', 'Var', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tissue invasion', 'biological_process', 'GO:0001404', ('137', '152'))	('promote', 'PosReg', (101, 108))	('IL-8', 'molecular_function', 'GO:0005153', ('191', '195'))	('IL-8', 'molecular_function', 'GO:0005153', ('55', '59'))	('expression', 'MPA', (196, 206))	('tissue invasion', 'CPA', (137, 152))	('IL-8', 'Gene', '3576', (55, 59))
12041	28430637	There was no significant difference in the overall survival (OS) and recurrence-free survival (RFS) between the plasma EBV-positive and plasma EBV-negative patients (Figure 1B), although OS rates were significantly higher in patients with EBVaGC in GC tissue (Supplementary Figure 3).	('EBVaGC', 'Var', (239, 245))	('patients', 'Species', '9606', (156, 164))	('higher', 'PosReg', (215, 221))	('patients', 'Species', '9606', (225, 233))	('EBVaGC', 'Chemical', '-', (239, 245))	('EBV', 'Species', '10376', (119, 122))	('EBV', 'Species', '10376', (239, 242))	('EBV', 'Species', '10376', (143, 146))	('GC', 'Phenotype', 'HP:0012126', (249, 251))	('GC', 'Phenotype', 'HP:0012126', (243, 245))
12136	28503090	As a matter of fact, PG490-88, a derivative of triptolide, is part of a phase I clinical trial for treatment of prostate cancer in the USA.	('triptolide', 'Chemical', 'MESH:C001899', (47, 57))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('PG490-88', 'Var', (21, 29))	('prostate cancer', 'Disease', (112, 127))	('prostate cancer', 'Disease', 'MESH:D011471', (112, 127))
12151	28503090	Pristimerin was found to induce apoptosis in hormone-sensitive (LNCaP) and hormone-refractory (PC-3) prostate cancer cell lines.	('Pristimerin', 'Chemical', 'MESH:C009043', (0, 11))	('apoptosis', 'biological_process', 'GO:0097194', ('32', '41'))	('apoptosis', 'CPA', (32, 41))	('prostate cancer', 'Disease', (101, 116))	('induce', 'PosReg', (25, 31))	('apoptosis', 'biological_process', 'GO:0006915', ('32', '41'))	('Pristimerin', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('LNCaP', 'CellLine', 'CVCL:0395', (64, 69))	('PC-3', 'CellLine', 'CVCL:0035', (95, 99))	('prostate cancer', 'Disease', 'MESH:D011471', (101, 116))	('prostate cancer', 'Phenotype', 'HP:0012125', (101, 116))
12152	28503090	Pristimerin increased annexin V-binding and cleavage of PARP-1, procaspases-3 and -9-induced mitochondrial depolarization, cytochrome c release from mitochondria, generation of reactive oxygen species (ROS), and downregulation of BCL-2 and survivin expression via proteasome-dependent degradation.	('cleavage', 'MPA', (44, 52))	('degradation', 'biological_process', 'GO:0009056', ('285', '296'))	('degradation', 'MPA', (285, 296))	('depolarization', 'NegReg', (107, 121))	('Pristimerin', 'Chemical', 'MESH:C009043', (0, 11))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (177, 200))	('generation', 'MPA', (163, 173))	('cytochrome c', 'Gene', (123, 135))	('proteasome', 'cellular_component', 'GO:0000502', ('264', '274'))	('cytochrome c', 'molecular_function', 'GO:0009461', ('123', '135'))	('expression', 'MPA', (249, 259))	('BCL-2', 'Gene', '596', (230, 235))	('BCL-2', 'Gene', (230, 235))	('Pristimerin', 'Var', (0, 11))	('increased', 'PosReg', (12, 21))	('mitochondria', 'cellular_component', 'GO:0005739', ('149', '161'))	('downregulation', 'NegReg', (212, 226))	('BCL-2', 'molecular_function', 'GO:0015283', ('230', '235'))	('annexin V', 'Gene', (22, 31))	('PARP-1, procaspases-3 and -9', 'Gene', '142;836', (56, 84))	('mitochondrial', 'MPA', (93, 106))	('annexin V', 'Gene', '308', (22, 31))	('binding', 'molecular_function', 'GO:0005488', ('32', '39'))	('mitochondrial depolarization', 'biological_process', 'GO:0051882', ('93', '121'))	('survivin', 'Protein', (240, 248))	('cytochrome c', 'Gene', '54205', (123, 135))	('ROS', 'Chemical', 'MESH:D017382', (202, 205))	('cytochrome c', 'molecular_function', 'GO:0045155', ('123', '135'))	('proteasome', 'molecular_function', 'GO:0004299', ('264', '274'))
12160	28503090	The work reported that treatment of pancreatic cancer cells with pristimerin resulted in G1-phase arrest associated with a marked decrease in the level of cyclins CCND1 and CCNE, and cyclin-dependent kinases (CDK-2, -4 and -6) with concomitant induction of CDK inhibitors, CDKN1A (p21WAF1) and CDKN1B (p27KIP1).	('CCND1', 'Gene', (163, 168))	('CDKN1A', 'Gene', (273, 279))	('CCNE', 'Gene', '898', (173, 177))	('CDKN1A', 'Gene', '1026', (273, 279))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (36, 53))	('level', 'MPA', (146, 151))	('CDKN1B', 'Gene', '1027', (294, 300))	('pristimerin', 'Chemical', 'MESH:C009043', (65, 76))	('p27KIP1', 'Gene', '1027', (302, 309))	('cyclin', 'Gene', (183, 189))	('G1-phase', 'biological_process', 'GO:0051318', ('89', '97'))	('p27KIP1', 'Gene', (302, 309))	('G1-phase arrest', 'CPA', (89, 104))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('pancreatic cancer', 'Disease', 'MESH:D010190', (36, 53))	('p21', 'Gene', '1026', (281, 284))	('cyclin', 'Gene', '5111', (155, 161))	('cyclin', 'molecular_function', 'GO:0016538', ('183', '189'))	('CCNE', 'Gene', (173, 177))	('induction', 'PosReg', (244, 253))	('decrease', 'NegReg', (130, 138))	('CDK-2, -4 and -6', 'Gene', '1017;1019;1021', (209, 225))	('pancreatic cancer', 'Disease', (36, 53))	('CDKN1B', 'Gene', (294, 300))	('cyclin', 'Gene', (155, 161))	('CDK', 'molecular_function', 'GO:0004693', ('257', '260'))	('CDK', 'molecular_function', 'GO:0004693', ('209', '212'))	('CCND1', 'Gene', '595', (163, 168))	('pristimerin', 'Var', (65, 76))	('cyclin', 'Gene', '5111', (183, 189))	('p21', 'Gene', (281, 284))
12162	28503090	In human pancreatic ductal adenocarcinoma cells (MiaPaCa-2 and Panc-1) pristimerin inhibited the proliferation and induced apoptosis.	('pancreatic ductal adenocarcinoma', 'Disease', (9, 41))	('human', 'Species', '9606', (3, 8))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (9, 41))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (9, 41))	('proliferation', 'CPA', (97, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('inhibited', 'NegReg', (83, 92))	('Panc-1', 'CellLine', 'CVCL:0480', (63, 69))	('apoptosis', 'CPA', (123, 132))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (49, 58))	('apoptosis', 'biological_process', 'GO:0097194', ('123', '132'))	('pristimerin', 'Var', (71, 82))	('pristimerin', 'Chemical', 'MESH:C009043', (71, 82))	('apoptosis', 'biological_process', 'GO:0006915', ('123', '132'))	('induced', 'Reg', (115, 122))
12164	28503090	The induction of apoptosis was associated with the inhibition of the pro-survival AKT, NF-kappaB and mTOR proteins and downstream targets, such as FOXO3A, CCND1, COX-2, VEGF, p-70S6K1, p-4E-BP1, and protein kinase C-epsilon (PKCepsilon), as well as of anti-apoptotic BCL-2 and survivin (also known as BIRC5) but not BCL-xL.	('mTOR', 'Gene', '2475', (101, 105))	('AKT', 'Gene', '207', (82, 85))	('pro-survival', 'biological_process', 'GO:0043066', ('69', '81'))	('survivin', 'Protein', (277, 285))	('induction of apoptosis', 'biological_process', 'GO:0006915', ('4', '26'))	('NF-kappaB', 'Gene', (87, 96))	('PKCepsilon', 'molecular_function', 'GO:0004697', ('225', '235'))	('protein kinase C-epsilon', 'Gene', '5581', (199, 223))	('BCL-xL', 'Gene', '598', (316, 322))	('NF-kappaB', 'Gene', '4790', (87, 96))	('protein kinase C-epsilon', 'Gene', (199, 223))	('PKCepsilon', 'Gene', '5581', (225, 235))	('FOXO3A', 'Gene', (147, 153))	('apoptosis', 'Disease', (17, 26))	('4E-BP1', 'Gene', '1978', (187, 193))	('COX-2', 'Gene', (162, 167))	('protein', 'cellular_component', 'GO:0003675', ('199', '206'))	('BCL-xL', 'Gene', (316, 322))	('CCND1', 'Gene', (155, 160))	('p-70S6K1', 'Var', (175, 183))	('BCL-2', 'Gene', '596', (267, 272))	('AKT', 'Gene', (82, 85))	('COX-2', 'Gene', '4513', (162, 167))	('BCL-2', 'Gene', (267, 272))	('inhibition', 'NegReg', (51, 61))	('BCL-2', 'molecular_function', 'GO:0015283', ('267', '272'))	('anti-apoptotic', 'CPA', (252, 266))	('4E-BP1', 'Gene', (187, 193))	('mTOR', 'Gene', (101, 105))	('BIRC5', 'Gene', '332', (301, 306))	('BIRC5', 'Gene', (301, 306))	('CCND1', 'Gene', '595', (155, 160))	('PKCepsilon', 'Gene', (225, 235))	('FOXO3A', 'Gene', '2309', (147, 153))
12166	28503090	Pristimerin was found to possess potent cytotoxic effects, inducing apoptosis and inhibiting proliferation in U87 human glioma cells.	('U87', 'Gene', (110, 113))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('Pristimerin', 'Chemical', 'MESH:C009043', (0, 11))	('inducing', 'NegReg', (59, 67))	('inhibiting', 'NegReg', (82, 92))	('proliferation', 'CPA', (93, 106))	('apoptosis', 'CPA', (68, 77))	('Pristimerin', 'Var', (0, 11))	('U87', 'Gene', '677775', (110, 113))	('apoptosis', 'biological_process', 'GO:0097194', ('68', '77'))	('human', 'Species', '9606', (114, 119))	('glioma', 'Disease', (120, 126))	('apoptosis', 'biological_process', 'GO:0006915', ('68', '77'))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
12169	28503090	In ovarian cancer cells, pristimerin also induced apoptosis through cleavage of PARP-1, procaspases-3, -8 and -9 activity and enhanced mitochondrial depolarization.	('PARP-1, procaspases-3, -8 and -9', 'Gene', '142;836', (80, 112))	('mitochondrial depolarization', 'biological_process', 'GO:0051882', ('135', '163'))	('apoptosis', 'biological_process', 'GO:0006915', ('50', '59'))	('cleavage', 'MPA', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('enhanced', 'PosReg', (126, 134))	('pristimerin', 'Var', (25, 36))	('pristimerin', 'Chemical', 'MESH:C009043', (25, 36))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('mitochondrial depolarization', 'MPA', (135, 163))	('ovarian cancer', 'Disease', (3, 17))	('activity', 'MPA', (113, 121))	('apoptosis', 'biological_process', 'GO:0097194', ('50', '59'))	('apoptosis', 'CPA', (50, 59))
12171	28503090	In a somewhat different approach, pristimerin was shown to inhibit human telomerase reverse transcriptase (hTERT) expression and activity in human pancreatic cancer cells.	('hTERT', 'Gene', '7015', (107, 112))	('pancreatic cancer', 'Disease', 'MESH:D010190', (147, 164))	('transcriptase', 'molecular_function', 'GO:0003899', ('92', '105'))	('pristimerin', 'Var', (34, 45))	('pristimerin', 'Chemical', 'MESH:C009043', (34, 45))	('transcriptase', 'molecular_function', 'GO:0003968', ('92', '105'))	('transcriptase', 'molecular_function', 'GO:0034062', ('92', '105'))	('hTERT', 'Gene', (107, 112))	('telomerase reverse transcriptase', 'Gene', (73, 105))	('telomerase reverse transcriptase', 'Gene', '7015', (73, 105))	('human', 'Species', '9606', (141, 146))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (147, 164))	('activity', 'MPA', (129, 137))	('expression', 'MPA', (114, 124))	('inhibit', 'NegReg', (59, 66))	('human', 'Species', '9606', (67, 72))	('pancreatic cancer', 'Disease', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
12177	28503090	On the one hand, silencing of SENP1 or c-JUN in PC-3 prostate cancer cells decreased cellular viability, suggesting that the cytotoxicity of triptolide could result from triptolide-induced downregulation of SENP1, or c-JUN.	('triptolide', 'Chemical', 'MESH:C001899', (170, 180))	('SENP1', 'Gene', (30, 35))	('downregulation', 'NegReg', (189, 203))	('c-JUN', 'Gene', '3725', (39, 44))	('c-JUN', 'Gene', (39, 44))	('triptolide', 'Chemical', 'MESH:C001899', (141, 151))	('PC-3', 'CellLine', 'CVCL:0035', (48, 52))	('cellular viability', 'CPA', (85, 103))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('SENP1', 'Gene', '29843', (207, 212))	('prostate cancer', 'Disease', 'MESH:D011471', (53, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (53, 68))	('cytotoxicity', 'Disease', (125, 137))	('prostate cancer', 'Disease', (53, 68))	('SENP1', 'Gene', (207, 212))	('cytotoxicity', 'Disease', 'MESH:D064420', (125, 137))	('c-JUN', 'Gene', '3725', (217, 222))	('c-JUN', 'Gene', (217, 222))	('SENP1', 'Gene', '29843', (30, 35))	('silencing', 'Var', (17, 26))	('decreased', 'NegReg', (75, 84))
12178	28503090	On the other hand, ectopic expression of SENP1, or c-JUN significantly increased the viability of prostate cancer cells upon triptolide exposure, indicating that rescuing these triptolide downregulated proteins could inhibit cell toxicity induced by triptolide.	('toxicity', 'Disease', 'MESH:D064420', (230, 238))	('prostate cancer', 'Disease', 'MESH:D011471', (98, 113))	('proteins', 'Protein', (202, 210))	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('ectopic expression', 'Var', (19, 37))	('toxicity', 'Disease', (230, 238))	('prostate cancer', 'Disease', (98, 113))	('triptolide', 'Chemical', 'MESH:C001899', (125, 135))	('viability', 'CPA', (85, 94))	('downregulated', 'NegReg', (188, 201))	('SENP1', 'Gene', '29843', (41, 46))	('inhibit', 'NegReg', (217, 224))	('SENP1', 'Gene', (41, 46))	('triptolide', 'Chemical', 'MESH:C001899', (250, 260))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('c-JUN', 'Gene', '3725', (51, 56))	('increased', 'PosReg', (71, 80))	('c-JUN', 'Gene', (51, 56))	('triptolide', 'Chemical', 'MESH:C001899', (177, 187))
12187	28503090	After low-dose combined treatments with triptolide and cisplatin, a decrease in viability with a concomitant increase in apoptosis was observed in SC-M1 cells but not in normal cells.	('triptolide', 'Chemical', 'MESH:C001899', (40, 50))	('decrease', 'NegReg', (68, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('SC-M1', 'CellLine', 'CVCL:G299', (147, 152))	('viability', 'CPA', (80, 89))	('apoptosis', 'biological_process', 'GO:0097194', ('121', '130'))	('apoptosis', 'CPA', (121, 130))	('cisplatin', 'Var', (55, 64))	('apoptosis', 'biological_process', 'GO:0006915', ('121', '130'))
12230	28503090	HNSCC arises from premalignant progenitor cells that progress to invasive malignancy due to cumulative genetic alterations.	('genetic alterations', 'Var', (103, 122))	('invasive malignancy', 'Disease', (65, 84))	('HNSCC', 'Disease', (0, 5))	('HNSCC', 'Phenotype', 'HP:0012288', (0, 5))	('invasive malignancy', 'Disease', 'MESH:D009369', (65, 84))	('progress', 'PosReg', (53, 61))
12237	28503090	However, despite the abundant expression in HNSCC, only a subset of patients responds to EGFR inhibitors since alternative downstream signaling pathways may remain activated.	('responds to', 'MPA', (77, 88))	('EGFR', 'Gene', (89, 93))	('HNSCC', 'Gene', (44, 49))	('signaling', 'biological_process', 'GO:0023052', ('134', '143'))	('patients', 'Species', '9606', (68, 76))	('EGFR', 'molecular_function', 'GO:0005006', ('89', '93'))	('HNSCC', 'Phenotype', 'HP:0012288', (44, 49))	('EGFR', 'Gene', '1956', (89, 93))	('inhibitors', 'Var', (94, 104))
12239	28503090	Loss of heterozygosity at the chromosomal region 9p21 is found in 70-80% of HNSCC cases, representing the most common genetic alteration in this type of cancer and in early pre-invasive lesions.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('chromosomal region', 'cellular_component', 'GO:0098687', ('30', '48'))	('Loss of heterozygosity', 'Var', (0, 22))	('HNSCC', 'Disease', (76, 81))	('cancer', 'Disease', (153, 159))	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('p21', 'Gene', '1026', (50, 53))	('pre', 'molecular_function', 'GO:0003904', ('173', '176'))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('p21', 'Gene', (50, 53))
12264	28503090	Thus, crosstalk by TGF-beta via TAK1 and NF-kappaB promotes the malignant phenotype of HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (87, 92))	('malignant phenotype of', 'CPA', (64, 86))	('TAK1', 'Gene', '6885', (32, 36))	('NF-kappaB', 'Gene', '4790', (41, 50))	('promotes', 'PosReg', (51, 59))	('NF-kappaB', 'Gene', (41, 50))	('TAK1', 'Gene', (32, 36))	('TGF-beta', 'Gene', (19, 27))	('crosstalk', 'Var', (6, 15))	('HNSCC', 'Disease', (87, 92))
12273	26788143	The patients who remained in or switched to the low NLR level subgroup subsequent to first-line chemotherapy had an improved response and improved OS ratios, compared to the patients remaining in or switching to the high NLR level group.	('OS', 'Chemical', '-', (147, 149))	('improved', 'PosReg', (138, 146))	('OS ratios', 'MPA', (147, 156))	('patients', 'Species', '9606', (174, 182))	('patients', 'Species', '9606', (4, 12))	('low', 'Var', (48, 51))	('improved', 'PosReg', (116, 124))	('response', 'MPA', (125, 133))
12290	26788143	The inclusion criteria were: i) patients with histologically or cytologically confirmed recurrent or metastatic GC; ii) age >18 years; iii) Karnofsky performance status (KPS) score of >=70; iv) patients with a predicted survival of >=3 months; v) naive to antitumor treatment or the post-operative adjuvant chemotherapy was performed >=6 months after the previous dose of chemotherapy; vi) in the case of patients scheduled for radiotherapy on the target lesion, radiotherapy was required to have been terminated for at >=3 months; vii) patients with at least one measurable lesion (at least 10x10 mm on CT or MRI); and viii) patients who met the following laboratory criteria: white blood cells (WBC) >=4.0x109/l, absolute neutrophil count (ANC) >=1.5x109/l, platelet (PLT) >=100x109/l, serum bilirubin <= upper limit of normal (ULN), ALT, AST and ALP <= ULN x2.5 (if without liver metastasis) or <= ULN x5 (if with liver metastasis), urea nitrogen <= ULN x1.25, and creatinine <= ULN x1.25.	('tumor', 'Disease', (260, 265))	('platelet', 'MPA', (760, 768))	('urea nitrogen', 'MPA', (936, 949))	('absolute', 'MPA', (715, 723))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('ALP', 'Gene', (849, 852))	('AST', 'Gene', '26503', (841, 844))	('<= ULN x5', 'Var', (898, 907))	('liver metastasis', 'Disease', (877, 893))	('patients', 'Species', '9606', (537, 545))	('men', 'Species', '9606', (271, 274))	('serum bilirubin', 'MPA', (788, 803))	('liver metastasis', 'Disease', (917, 933))	('ALT', 'molecular_function', 'GO:0004021', ('836', '839'))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('AST', 'Gene', (841, 844))	('patients', 'Species', '9606', (194, 202))	('liver metastasis', 'Disease', 'MESH:D009362', (877, 893))	('creatinine', 'MPA', (968, 978))	('patients', 'Species', '9606', (32, 40))	('ALP', 'Gene', '470', (849, 852))	('liver metastasis', 'Disease', 'MESH:D009362', (917, 933))	('patients', 'Species', '9606', (405, 413))	('ALT', 'MPA', (836, 839))	('>=100x109/l', 'Var', (775, 786))	('patients', 'Species', '9606', (626, 634))
12373	26589831	To determine the influence of humoral immune responses against H. pylori infection on gastric carcinoma, we assessed the presence of anti-H. pylori IgG and IgA levels in gastric adenocarcinoma patients and non-cancer patients by ELISA.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('H. pylori', 'Species', '210', (63, 72))	('anti-H.', 'Var', (133, 140))	('IgA', 'Gene', (156, 159))	('gastric adenocarcinoma', 'Disease', (170, 192))	('non-cancer', 'Disease', (206, 216))	('infection on gastric carcinoma', 'Disease', (73, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('patients', 'Species', '9606', (193, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (86, 103))	('H. pylori', 'Species', '210', (138, 147))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (170, 192))	('patients', 'Species', '9606', (217, 225))	('IgG', 'MPA', (148, 151))	('infection on gastric carcinoma', 'Disease', 'MESH:D013274', (73, 103))	('H. pylori infection', 'Phenotype', 'HP:0005202', (63, 82))	('non-cancer', 'Disease', 'MESH:D009369', (206, 216))	('IgA', 'Gene', '973', (156, 159))
12384	26589831	The H. pylori strains 26695 and J99 (ATCC 700392 and 700824, respectively) were growth on Casman agar (DIFCO) supplemented with 10 % defibrinated horse serum (Horse serum ATCC; Manassas, Va) and incubated at 36 +- 1  C during 72 h in microaerophilic conditions.	('horse', 'Species', '9796', (146, 151))	('H. pylori', 'Species', '210', (4, 13))	('700824', 'Var', (53, 59))	('Horse', 'Species', '9796', (159, 164))	('H. pylori', 'Gene', (4, 13))
12389	26589831	We compared anti-H. pylori IgG and IgA levels, as measured by ELISA, in each region between cases and controls and in early (I and II) and advanced (III and IV) stages of gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('anti-H.', 'Var', (12, 19))	('gastric cancer', 'Disease', (171, 185))	('H. pylori', 'Species', '210', (17, 26))	('IgA', 'Gene', (35, 38))	('IgG', 'MPA', (27, 30))	('gastric cancer', 'Disease', 'MESH:D013274', (171, 185))	('IgA', 'Gene', '973', (35, 38))	('gastric cancer', 'Phenotype', 'HP:0012126', (171, 185))
12445	26509158	Aberrant protein glycosylation is well known hallmark of cancer and represents a promising source of potential biomarkers.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('protein glycosylation', 'biological_process', 'GO:0006486', ('9', '30'))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (57, 63))	('protein', 'Protein', (9, 16))	('protein', 'cellular_component', 'GO:0003675', ('9', '16'))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
12460	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))	('glycosylation', 'biological_process', 'GO:0070085', ('9', '22'))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('proteins', 'Protein', (26, 34))	('glycosylation', 'MPA', (9, 22))	('cancer', 'Disease', (63, 69))
12494	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))
12496	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.	('inflammation', 'biological_process', 'GO:0006954', ('42', '54'))	('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))
12508	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))
12556	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))
12570	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))
12571	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))
12575	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))	('colorectal', 'Disease', (81, 91))	('gastric', 'Disease', (93, 100))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('tumour', 'Disease', (62, 68))	('CA19-9', 'Var', (0, 6))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (106, 127))
12599	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))
12606	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))
12668	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))
12673	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))
12681	24899581	In turn, FBW7 is regulated by multiple upstream factors including p53, C/EBP-delta, EBP2, Pin1, Hes-5 and Numb4 as well as by microRNAs such as miR-223, miR-27a, miR-25, and miR-129-5p.	('miR-27a', 'Gene', '407018', (153, 160))	('Hes-5', 'Gene', '388585', (96, 101))	('p53', 'Var', (66, 69))	('miR-25', 'Var', (162, 168))	('Pin1', 'Gene', '5300', (90, 94))	('FBW7', 'Gene', (9, 13))	('Numb', 'Gene', '8650', (106, 110))	('regulated', 'Reg', (17, 26))	('miR-223', 'Var', (144, 151))	('miR-27a', 'Gene', (153, 160))	('EBP2', 'Gene', '10969', (84, 88))	('Hes-5', 'Gene', (96, 101))	('miR-129-5p', 'Gene', (174, 184))	('EBP2', 'Gene', (84, 88))	('C/EBP-delta', 'Gene', (71, 82))	('Numb', 'Gene', (106, 110))	('C/EBP-delta', 'Gene', '1052', (71, 82))	('Pin1', 'Gene', (90, 94))	('miR-129-5p', 'Gene', '100302178', (174, 184))
12686	24899581	Consistent with the notion that FBW7 exerts its anti-tumor activity in various human malignancies, FBW7 mutation and/or deletion are frequently identified in a variety of human neoplasms; for example, FBW7 mutation rate in T-cell acute lymphoblastic leukemia is approximately 30%.	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (230, 258))	('FBW7', 'Gene', (201, 205))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('deletion', 'Var', (120, 128))	('tumor', 'Disease', (53, 58))	('neoplasms', 'Disease', (177, 186))	('FBW7', 'Gene', (99, 103))	('human', 'Species', '9606', (79, 84))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (236, 258))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutation', 'Var', (104, 112))	('neoplasms', 'Phenotype', 'HP:0002664', (177, 186))	('mutation', 'Var', (206, 214))	('human', 'Species', '9606', (171, 176))	('leukemia', 'Phenotype', 'HP:0001909', (250, 258))	('malignancies', 'Disease', 'MESH:D009369', (85, 97))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (236, 258))	('malignancies', 'Disease', (85, 97))	('neoplasms', 'Disease', 'MESH:D009369', (177, 186))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (223, 258))	('lymphoblastic leukemia', 'Disease', (236, 258))
12708	24899581	More importantly, MED13 and MED13L are phosphorylated at T326, which was shown to be required for FBW7-mediated degradation function.	('MED13', 'Gene', '9969', (18, 23))	('MED13', 'Gene', '9969', (28, 33))	('MED13L', 'Gene', (28, 34))	('MED13', 'Gene', (28, 33))	('MED13L', 'Gene', '23389', (28, 34))	('MED13', 'Gene', (18, 23))	('T326', 'Var', (57, 61))	('degradation', 'biological_process', 'GO:0009056', ('112', '123'))
12716	24899581	Consistently, prostate or breast cancer patients with low expression of KLF2 and high levels of EZH2 have a shorter overall survival.	('breast cancer', 'Disease', (26, 39))	('high levels', 'Var', (81, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('low', 'NegReg', (54, 57))	('KLF2', 'Gene', '10365', (72, 76))	('EZH2', 'Gene', '2146', (96, 100))	('expression', 'MPA', (58, 68))	('patients', 'Species', '9606', (40, 48))	('EZH2', 'Gene', (96, 100))	('shorter', 'NegReg', (108, 115))	('KLF2', 'Gene', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('prostate', 'Disease', (14, 22))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('overall', 'MPA', (116, 123))
12723	24899581	Consistently, inhibition of GSK3beta increased the basal levels of KLF2 and extended KLF2 protein half-life.	('extended', 'PosReg', (76, 84))	('KLF2', 'Gene', (85, 89))	('GSK', 'molecular_function', 'GO:0050321', ('28', '31'))	('GSK3beta', 'Gene', '2932', (28, 36))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('KLF2', 'Gene', '10365', (67, 71))	('increased', 'PosReg', (37, 46))	('KLF2', 'Gene', (67, 71))	('GSK3beta', 'Gene', (28, 36))	('inhibition', 'Var', (14, 24))	('inhibition of GSK', 'biological_process', 'GO:1902948', ('14', '31'))	('KLF2', 'Gene', '10365', (85, 89))
12735	24899581	Consistently, FBW7 inactivation up-regulated p100 levels, which subsequently suppressed the canonical NF-kappaB1 signaling as p100 precursor could suppress NF-kappaB1 transcriptional activities in an IkappaB-like manner.	('suppressed', 'NegReg', (77, 87))	('signaling', 'biological_process', 'GO:0023052', ('113', '122'))	('NF-kappaB', 'Gene', '4790', (102, 111))	('NF-kappaB', 'Gene', (102, 111))	('up-regulated', 'PosReg', (32, 44))	('p100 levels', 'MPA', (45, 56))	('NF-kappaB', 'Gene', '4790', (156, 165))	('suppress', 'NegReg', (147, 155))	('inactivation', 'Var', (19, 31))	('FBW7', 'Gene', (14, 18))	('NF-kappaB', 'Gene', (156, 165))
12743	24899581	observed that truncated G-CSFR cooperated with the PML-RARalpha (promyelocytic leukemia-retinoic acid receptor alpha) oncogene to induce acute myeloid leukemia (AML) in mice.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (137, 159))	('induce', 'PosReg', (130, 136))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (137, 159))	('truncated', 'Var', (14, 23))	('leukemia', 'Phenotype', 'HP:0001909', (79, 87))	('leukemia', 'Phenotype', 'HP:0001909', (151, 159))	('PML', 'Gene', '5371', (51, 54))	('AML', 'Disease', 'MESH:D015470', (161, 164))	('leukemia-retinoic', 'Disease', 'MESH:D007938', (79, 96))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (143, 159))	('mice', 'Species', '10090', (169, 173))	('leukemia-retinoic', 'Disease', (79, 96))	('G-CSFR', 'Gene', (24, 30))	('acute myeloid leukemia', 'Disease', (137, 159))	('AML', 'Phenotype', 'HP:0004808', (161, 164))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (65, 87))	('AML', 'Disease', (161, 164))	('PML', 'Gene', (51, 54))
12744	24899581	G-CSFR mutations could disrupt its ubiquitination and subsequently cause aberrant receptor signaling, leading to leukemic transformation.	('cause', 'Reg', (67, 72))	('leukemic transformation', 'Disease', 'MESH:D007938', (113, 136))	('aberrant receptor signaling', 'MPA', (73, 100))	('ubiquitination', 'MPA', (35, 49))	('leading to', 'Reg', (102, 112))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('disrupt', 'NegReg', (23, 30))	('G-CSFR', 'Gene', (0, 6))	('leukemic transformation', 'Disease', (113, 136))	('mutations', 'Var', (7, 16))
12746	24899581	More importantly, FBW7-mediated destruction of G-CSFR suppressed STAT3 (signal transducer and activator of transcription 3) phosphorylation and activation.	('signal transducer and activator of transcription 3', 'Gene', '6774', (72, 122))	('suppressed', 'NegReg', (54, 64))	('activation', 'MPA', (144, 154))	('phosphorylation', 'biological_process', 'GO:0016310', ('124', '139'))	('transcription', 'biological_process', 'GO:0006351', ('107', '120'))	('G-CSFR', 'Gene', (47, 53))	('STAT3', 'Gene', '6774', (65, 70))	('destruction', 'Var', (32, 43))	('STAT3', 'Gene', (65, 70))
12747	24899581	In line with this finding, inhibition of FBW7 restored G-CSFR signaling and subsequently increased STAT3 transcriptional activity.	('restored', 'PosReg', (46, 54))	('STAT3', 'Gene', '6774', (99, 104))	('signaling', 'biological_process', 'GO:0023052', ('62', '71'))	('G-CSFR signaling', 'MPA', (55, 71))	('inhibition', 'Var', (27, 37))	('STAT3', 'Gene', (99, 104))	('increased', 'PosReg', (89, 98))	('FBW7', 'Gene', (41, 45))
12749	24899581	Overall, these reports suggest that G-CSFR could be a substrate of FBW7 and aberrant upregulation of G-CSFR due to impairments in FBW7-mediated destruction could contribute to the development of AML.	('AML', 'Phenotype', 'HP:0004808', (195, 198))	('aberrant', 'Var', (76, 84))	('FBW7-mediated', 'Gene', (130, 143))	('AML', 'Disease', 'MESH:D015470', (195, 198))	('impairments', 'Var', (115, 126))	('contribute', 'Reg', (162, 172))	('upregulation', 'PosReg', (85, 97))	('AML', 'Disease', (195, 198))
12754	24899581	Since p53 mutation/deletion has been identified in, at least, 50% of all human cancers, cancers with a p53 mutation/deletion generally have bad prognosis due to poor response to therapeutics.	('cancers', 'Disease', (79, 86))	('p53', 'Gene', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('human', 'Species', '9606', (73, 78))	('cancers', 'Disease', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('mutation/deletion', 'Var', (107, 124))
12766	24899581	Furthermore, reduced C/EBP-delta gene expression due to promoter methylation has been found in breast cancer cell lines and primary breast tumors.	('breast tumors', 'Disease', 'MESH:D001943', (132, 145))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('expression', 'MPA', (38, 48))	('breast tumors', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('promoter methylation', 'Var', (56, 76))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))	('gene expression', 'biological_process', 'GO:0010467', ('33', '48'))	('breast tumors', 'Phenotype', 'HP:0100013', (132, 145))	('reduced', 'NegReg', (13, 20))	('C/EBP-delta', 'Gene', '1052', (21, 32))	('breast tumor', 'Phenotype', 'HP:0100013', (132, 144))	('C/EBP-delta', 'Gene', (21, 32))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
12780	24899581	Fourth, inactivation of FBW7 did not cause any noticeable changes to neither endogenous EBP2 abundance nor EBP2 stability.	('EBP2', 'Gene', (88, 92))	('EBP2', 'Gene', (107, 111))	('abundance', 'MPA', (93, 102))	('EBP2', 'Gene', '10969', (88, 92))	('inactivation', 'Var', (8, 20))	('FBW7', 'Gene', (24, 28))	('EBP2', 'Gene', '10969', (107, 111))
12783	24899581	These Pin1-induced conformational changes could regulate protein stability, catalytic activity, phosphorylation status, protein-protein interactions, and subcellular localization to further impact a wide range of cellular processes.	('impact', 'Reg', (190, 196))	('catalytic activity', 'molecular_function', 'GO:0003824', ('76', '94'))	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('Pin1', 'Gene', (6, 10))	('protein-protein interactions', 'MPA', (120, 148))	('localization', 'biological_process', 'GO:0051179', ('166', '178'))	('phosphorylation status', 'MPA', (96, 118))	('phosphorylation', 'biological_process', 'GO:0016310', ('96', '111'))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('Pin1', 'Gene', '5300', (6, 10))	('regulate', 'Reg', (48, 56))	('subcellular', 'MPA', (154, 165))	('catalytic activity', 'MPA', (76, 94))	('protein stability', 'MPA', (57, 74))	('conformational changes', 'Var', (19, 41))
12784	24899581	Because regulating these protein functions by Pin1 is involved in diverse physiological and pathological processes, Pin1 deregulation is implicated in a number of diseases, including aging and age-related diseases, such as Alzheimer disease and cancer.	('Pin1', 'Gene', '5300', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', (245, 251))	('Alzheimer disease', 'Disease', 'MESH:D000544', (223, 240))	('deregulation', 'Var', (121, 133))	('Alzheimer disease', 'Disease', (223, 240))	('aging', 'biological_process', 'GO:0007568', ('183', '188'))	('Alzheimer disease', 'Phenotype', 'HP:0002511', (223, 240))	('implicated', 'Reg', (137, 147))	('Pin1', 'Gene', '5300', (116, 120))	('Pin1', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('Pin1', 'Gene', (116, 120))	('involved', 'Reg', (54, 62))
12787	24899581	Accumulated evidence has demonstrated that Pin1 exerts its oncogenic functions in large through activation of numerous oncogenes including Neu, Ras, c-Jun, Mcl-1, Notch-1, c-Myb, and inactivation of a large number of tumor suppressors such as p53, PML, and Foxos.	('Ras', 'Protein', (144, 147))	('Pin1', 'Gene', '5300', (43, 47))	('Foxos', 'Gene', (257, 262))	('oncogenic functions', 'CPA', (59, 78))	('Notch-1', 'Gene', '4851', (163, 170))	('PML', 'Gene', (248, 251))	('c-Myb', 'Gene', '4602', (172, 177))	('c-Myb', 'Gene', (172, 177))	('tumor', 'Disease', (217, 222))	('Neu', 'Gene', (139, 142))	('Neu', 'Gene', '2064', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('Notch-1', 'Gene', (163, 170))	('c-Jun', 'Gene', '3725', (149, 154))	('activation', 'PosReg', (96, 106))	('c-Jun', 'Gene', (149, 154))	('PML', 'Gene', '5371', (248, 251))	('inactivation', 'Var', (183, 195))	('oncogenes', 'Gene', (119, 128))	('Pin1', 'Gene', (43, 47))	('Mcl-1', 'Gene', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('p53', 'Gene', (243, 246))
12794	24899581	Consistently, depletion of Pin1 caused higher expression of FBW7, subsequently decreased Mcl-1 abundance, leading to enhanced Taxol sensitivity in cancer cells.	('decreased Mcl', 'Phenotype', 'HP:0025066', (79, 92))	('Pin1', 'Gene', (27, 31))	('higher', 'PosReg', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('decreased', 'NegReg', (79, 88))	('FBW7', 'Gene', (60, 64))	('Taxol', 'Chemical', 'MESH:D017239', (126, 131))	('depletion', 'Var', (14, 23))	('enhanced', 'PosReg', (117, 125))	('Taxol sensitivity', 'MPA', (126, 143))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('expression', 'MPA', (46, 56))	('Pin1', 'Gene', '5300', (27, 31))	('Mcl-1 abundance', 'MPA', (89, 104))
12799	24899581	Notch intracellular domain (NICD) is produced by the cleavage of membrane-bound Notch by multiple enzymes and released into the cytoplasm, subsequently translocates to the nucleus and activates its target genes including Hes-1, Hes-5, Hey-1, etc.	('Hey-1', 'Gene', (235, 240))	('NICD', 'Disease', (28, 32))	('Hes-1', 'Gene', (221, 226))	('cleavage', 'Var', (53, 61))	('activates', 'PosReg', (184, 193))	('Hes-5', 'Gene', '388585', (228, 233))	('nucleus', 'cellular_component', 'GO:0005634', ('172', '179'))	('Hes-1', 'Gene', '3280', (221, 226))	('Notch', 'Gene', (80, 85))	('NICD', 'Disease', 'None', (28, 32))	('Hes-5', 'Gene', (228, 233))	('Hey-1', 'Gene', '23462', (235, 240))	('membrane', 'cellular_component', 'GO:0016020', ('65', '73'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('128', '137'))	('intracellular', 'cellular_component', 'GO:0005622', ('6', '19'))
12803	24899581	Notably, Hes-1 high expression could be a potential poor prognostic factor for ovarian cancer patients.	('Hes-1', 'Gene', (9, 14))	('high expression', 'Var', (15, 30))	('patients', 'Species', '9606', (94, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ovarian cancer', 'Disease', 'MESH:D010051', (79, 93))	('ovarian cancer', 'Disease', (79, 93))	('Hes-1', 'Gene', '3280', (9, 14))
12813	24899581	Consistently, Numb deletions and low Numb expression have also been observed in pro-neural glioblastomas.	('glioblastomas', 'Phenotype', 'HP:0012174', (91, 104))	('Numb', 'Gene', (37, 41))	('Numb', 'Gene', '8650', (37, 41))	('expression', 'MPA', (42, 52))	('observed', 'Reg', (68, 76))	('glioblastomas', 'Disease', 'MESH:D005909', (91, 104))	('Numb', 'Gene', '8650', (14, 18))	('glioblastomas', 'Disease', (91, 104))	('Numb', 'Gene', (14, 18))	('deletions', 'Var', (19, 28))
12842	24899581	Notably, miR-27a knockdown increased FBW7 levels and subsequently decreased the expression of FBW7 substrates such as c-Myc, c-Jun and Notch-1 in colon cancer.	('FBW7 levels', 'MPA', (37, 48))	('Notch-1', 'Gene', '4851', (135, 142))	('increased', 'PosReg', (27, 36))	('c-Jun', 'Gene', (125, 130))	('miR-27a', 'Gene', (9, 16))	('FBW7', 'Gene', (94, 98))	('colon cancer', 'Disease', (146, 158))	('decreased', 'NegReg', (66, 75))	('c-Myc', 'Gene', '4609', (118, 123))	('miR-27a', 'Gene', '407018', (9, 16))	('c-Myc', 'Gene', (118, 123))	('expression', 'MPA', (80, 90))	('knockdown', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('c-Jun', 'Gene', '3725', (125, 130))	('colon cancer', 'Phenotype', 'HP:0003003', (146, 158))	('colon cancer', 'Disease', 'MESH:D015179', (146, 158))	('Notch-1', 'Gene', (135, 142))
12848	24899581	High expression of miR-223 was also found to be associated with poor survival in gastric carcinomas, ovarian cancer, and esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('High', 'Var', (0, 4))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (121, 155))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('ovarian cancer', 'Disease', (101, 115))	('gastric carcinomas', 'Disease', 'MESH:D013274', (81, 99))	('gastric carcinomas', 'Disease', (81, 99))	('poor', 'NegReg', (64, 68))	('ovarian cancer', 'Disease', 'MESH:D010051', (101, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('esophageal squamous cell carcinoma', 'Disease', (121, 155))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (81, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))	('miR-223', 'Gene', (19, 26))
12907	23610717	All the subjects, who participated in the study were the ones diagnosed with T2NI or less in preoperative endoscopy, abdominal computed tomography, and endoscopic ultrasonography, and had tumor positioned at the mid 1/2 or lower, which enabled subtotal gastrectomy after resection.	('tumor', 'Disease', (188, 193))	('mid 1/2', 'Gene', '4281;11043', (212, 219))	('less', 'NegReg', (85, 89))	('mid 1/2', 'Gene', (212, 219))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('T2NI', 'Var', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))
12909	23610717	The resection range of the lymph node (LN) of D1+beta or more was basically employed, but the resection range of the LN decreased to D1+alpha if tumor restricted to the mucosa was found in patients with concurrent diseases or elderly patients via endoscopic ultrasonography.	('decreased', 'NegReg', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('D1+alpha', 'Var', (133, 141))	('patients', 'Species', '9606', (234, 242))	('patients', 'Species', '9606', (189, 197))
12929	23610717	If this kind of small incision is used, pulling out the stomach from the abdomen causes excessive retraction, which eventually leads to bleeding caused by tissue injury by forcing tension to the nearby tissues, as well as additional problems such as bleeding caused by rectus muscle injury or postoperative pain.	('small incision', 'Phenotype', 'HP:0005486', (16, 30))	('retraction', 'MPA', (98, 108))	('leads to', 'Reg', (127, 135))	('pain', 'Phenotype', 'HP:0012531', (307, 311))	('pulling out', 'Phenotype', 'HP:0001061', (40, 51))	('postoperative pain', 'Disease', 'MESH:D010149', (293, 311))	('tension', 'MPA', (180, 187))	('bleeding', 'Disease', (250, 258))	('muscle injury', 'Disease', 'MESH:D009135', (276, 289))	('pulling out', 'Var', (40, 51))	('postoperative pain', 'Disease', (293, 311))	('muscle injury', 'Disease', (276, 289))	('bleeding', 'MPA', (136, 144))
12946	22195236	CD44 splice variants play roles in carcinogenesis, differentiation, and lymph node metastasis and are predictive of the prognosis for various carcinomas, including gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (164, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('predictive of', 'Reg', (102, 115))	('differentiation', 'CPA', (51, 66))	('roles', 'Reg', (26, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('carcinomas', 'Disease', 'MESH:D002277', (142, 152))	('carcinogenesis', 'Disease', 'MESH:D063646', (35, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (164, 178))	('carcinomas', 'Disease', (142, 152))	('gastric cancer', 'Disease', (164, 178))	('CD44', 'Gene', (0, 4))	('splice variants', 'Var', (5, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('carcinogenesis', 'Disease', (35, 49))	('lymph node metastasis', 'CPA', (72, 93))
12947	22195236	Current data suggest that gastric tissue stem cells and gastric cancer stem cells both express the splice variant, CD44v9.	('gastric cancer', 'Phenotype', 'HP:0012126', (56, 70))	('CD44v9', 'Var', (115, 121))	('gastric cancer', 'Disease', (56, 70))	('gastric cancer', 'Disease', 'MESH:D013274', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
12960	22195236	Factors associated with a more robust inflammatory response such as an infecting strain containing the cag pathogenicity island, or polymorphisms in host genes governing the response to inflammation, both increase the risk of gastric cancer for an individual patient.	('inflammation', 'Disease', 'MESH:D007249', (186, 198))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('increase', 'PosReg', (205, 213))	('inflammation', 'Disease', (186, 198))	('increase the risk of gastric cancer', 'Phenotype', 'HP:0006753', (205, 240))	('gastric cancer', 'Disease', 'MESH:D013274', (226, 240))	('inflammatory response', 'biological_process', 'GO:0006954', ('38', '59'))	('gastric cancer', 'Disease', (226, 240))	('inflammation', 'biological_process', 'GO:0006954', ('186', '198'))	('polymorphisms', 'Var', (132, 145))	('patient', 'Species', '9606', (259, 266))	('gastric cancer', 'Phenotype', 'HP:0012126', (226, 240))
12964	22195236	However, after the development of atrophic gastritis, H. pylori eradication can only reduce the risk of cancer but not completely prevent it.	('H. pylori', 'Species', '210', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('atrophic gastritis', 'Disease', (34, 52))	('reduce', 'NegReg', (85, 91))	('atrophic gastritis', 'Disease', 'MESH:D005757', (34, 52))	('atrophic gastritis', 'Phenotype', 'HP:0002582', (34, 52))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('eradication', 'Var', (64, 75))	('gastritis', 'Phenotype', 'HP:0005263', (43, 52))
12980	22195236	One study that specifically examined H. pylori infected and uninfected stomachs used nested RT-PCR to identify CD44 splice variants V2 to V10 in H. pylori infected and uninfected gastric mucosal biopsies and in relation to the presence of inflammation.	('CD44', 'Gene', (111, 115))	('infected and uninfected stomachs', 'Disease', 'MESH:D013272', (47, 79))	('inflammation', 'biological_process', 'GO:0006954', ('239', '251'))	('inflammation', 'Disease', 'MESH:D007249', (239, 251))	('infected and uninfected gastric mucosal', 'Disease', 'MESH:D013274', (155, 194))	('inflammation', 'Disease', (239, 251))	('V2 to V10', 'Var', (132, 141))	('H. pylori', 'Species', '210', (145, 154))	('H. pylori', 'Species', '210', (37, 46))	('H. pylori', 'Disease', (145, 154))
12982	22195236	With those caveats, they reported expression of CD44v8, v9, and v10 in approximately 40% of those with H. pylori gastritis, 15% to 20% of those with H. pylori-negative noninflamed gastric mucosa, and 18% to 24% of those with H. pylori-negative biopsies with chronic gastritis.	('gastritis', 'Disease', 'MESH:D005756', (113, 122))	('gastritis', 'Disease', 'MESH:D005756', (266, 275))	('v10', 'Var', (64, 67))	('gastritis', 'Phenotype', 'HP:0005263', (113, 122))	('gastritis', 'Disease', (266, 275))	('H. pylori', 'Species', '210', (103, 112))	('gastritis', 'Phenotype', 'HP:0005263', (266, 275))	('gastritis', 'Disease', (113, 122))	('H. pylori', 'Species', '210', (149, 158))	('CD44v8', 'Var', (48, 54))	('H. pylori', 'Species', '210', (225, 234))	('chronic gastritis', 'Phenotype', 'HP:0005231', (258, 275))	('H. pylori gastritis', 'Phenotype', 'HP:0005202', (103, 122))
12984	22195236	used CD44s, CD44v6, and CD44v9 antibodies to study gastric epithelial cells and intraepithelial lymphocytes in H. pylori infected and uninfected individuals.	('H. pylori', 'Species', '210', (111, 120))	('CD44v9', 'Var', (24, 30))	('H. pylori', 'Disease', (111, 120))
12985	22195236	Cd44v9 was not expressed on the gastric epithelium of H. pylori negative individual but was present in H. pylori infection (Table 1).	('infection', 'Disease', (113, 122))	('infection', 'Disease', 'MESH:D007239', (113, 122))	('H. pylori', 'Species', '210', (103, 112))	('Cd44v9', 'Var', (0, 6))	('H. pylori infection', 'Phenotype', 'HP:0005202', (103, 122))	('H. pylori', 'Species', '210', (54, 63))
12987	22195236	studied presumably H. pylori infected gastric mucosa with CD44v9 specific antibodies and reported expression of CD44v9 in the basolateral membranes of pyloric gland cells, in gastric adenomas, and in gastric carcinomas.	('gastric adenomas', 'Disease', (175, 191))	('infected gastric mucosa', 'Disease', 'MESH:D013274', (29, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('carcinomas', 'Phenotype', 'HP:0030731', (208, 218))	('gastric adenomas', 'Disease', 'MESH:D000236', (175, 191))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (200, 217))	('CD44v9', 'Var', (112, 118))	('H. pylori', 'Species', '210', (19, 28))	('infected gastric mucosa', 'Disease', (29, 52))	('CD44v9', 'Gene', (58, 64))	('gastric carcinomas', 'Disease', 'MESH:D013274', (200, 218))	('gastric carcinomas', 'Disease', (200, 218))
12989	22195236	H. pylori infection has also been reported to increase the proportion with CD44v6 (i.e., in 63% of those with H. pylori infection vs 45% in those without).	('infection', 'Disease', 'MESH:D007239', (120, 129))	('increase', 'PosReg', (46, 54))	('infection', 'Disease', (10, 19))	('H. pylori', 'Disease', (0, 9))	('H. pylori', 'Species', '210', (0, 9))	('infection', 'Disease', 'MESH:D007239', (10, 19))	('H. pylori infection', 'Phenotype', 'HP:0005202', (0, 19))	('CD44v6', 'Var', (75, 81))	('H. pylori infection', 'Phenotype', 'HP:0005202', (110, 129))	('H. pylori', 'Species', '210', (110, 119))	('infection', 'Disease', (120, 129))
12993	22195236	They concluded CD44v6 is expressed de novo in premalignant, as well as in sporadic and hereditary malignant lesions of the stomach and suggested that the presence of CD44v6 was potentially a biomarker signaling early transformation of the gastric mucosa.	('CD44v6', 'Var', (166, 172))	('lesions of the stomach', 'Phenotype', 'HP:0006753', (108, 130))	('hereditary malignant lesions of the stomach', 'Disease', 'MESH:D030342', (87, 130))	('presence', 'Var', (154, 162))	('signaling', 'biological_process', 'GO:0023052', ('201', '210'))	('hereditary malignant lesions of the stomach', 'Disease', (87, 130))
12994	22195236	The proportion of cases of diffuse vs intestinal type gastric carcinoma expressing CD44v5 and/or CD44v6 varies among studies and no definitive statement can be made at this time.	('CD44v5', 'Var', (83, 89))	('CD44v6', 'Var', (97, 103))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (54, 71))	('intestinal type gastric carcinoma', 'Disease', 'MESH:D013274', (38, 71))	('intestinal type gastric carcinoma', 'Disease', (38, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
12998	22195236	Most signet ring carcinomas seem to express CD44v5 whether evaluated in terms of RNA or protein expression whereas intestinal-type carcinomas often express both CD44v5 and CD44v6.	('carcinomas', 'Phenotype', 'HP:0030731', (17, 27))	('carcinomas', 'Disease', (17, 27))	('carcinomas', 'Disease', 'MESH:D002277', (17, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('protein', 'cellular_component', 'GO:0003675', ('88', '95'))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('carcinomas', 'Disease', 'MESH:D002277', (131, 141))	('CD44v5', 'Var', (44, 50))	('carcinomas', 'Disease', (131, 141))	('CD44v5', 'Var', (161, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('CD44v6', 'Var', (172, 178))	('RNA', 'cellular_component', 'GO:0005562', ('81', '84'))
13000	22195236	Intestinal metaplasia, a precancerous lesion, expresses CD44v5 and CD44v6 which is similar to the pattern in intestinal-type tumors.	('precancerous lesion', 'Disease', 'MESH:D011230', (25, 44))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('Intestinal metaplasia', 'Disease', (0, 21))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('CD44v6', 'Var', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('intestinal-type tumors', 'Disease', 'MESH:D007414', (109, 131))	('intestinal-type tumors', 'Disease', (109, 131))	('Intestinal metaplasia', 'Disease', 'MESH:D008679', (0, 21))	('metaplasia', 'biological_process', 'GO:0036074', ('11', '21'))	('precancerous lesion', 'Disease', (25, 44))	('CD44v5', 'Var', (56, 62))
13001	22195236	suggested that the difference in CD44 variant expression between diffuse-type and intestinal-type tumors by RT-PCR and immunochemistry would allow the two types to be discriminated on the basis of these molecular markers and that the expression of CD44v6 within precancerous tissue allowed it to be easily and rapidly distinguished from normal gastric mucosa.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('CD44', 'Gene', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('intestinal-type tumors', 'Disease', 'MESH:D007414', (82, 104))	('variant', 'Var', (38, 45))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('intestinal-type tumors', 'Disease', (82, 104))
13002	22195236	provided the first example of cell adhesion molecules playing a role in the metastatic process when they transfected plasmids expressing CD44s or CD44 isoforms into nonmetastatic rat pancreatic carcinoma cells and showed a significant relationship between CD44v6 expression and lymph node metastasis, lymphatic invasion, depth of invasion and tumor stage.	('playing', 'Reg', (54, 61))	('pancreatic carcinoma', 'Disease', (183, 203))	('CD44', 'Gene', (146, 150))	('cell adhesion', 'biological_process', 'GO:0007155', ('30', '43'))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('lymphatic invasion', 'CPA', (301, 319))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (183, 203))	('tumor', 'Disease', 'MESH:D009369', (343, 348))	('CD44s', 'Var', (137, 142))	('CD44v6', 'Gene', (256, 262))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('rat', 'Species', '10116', (179, 182))	('expression', 'MPA', (263, 273))	('depth of invasion', 'CPA', (321, 338))	('tumor', 'Disease', (343, 348))	('lymph node metastasis', 'CPA', (278, 299))
13004	22195236	In gastric cancer CD44v6 expression has also been implicated in the development of lymph node metastasis, hematogenous metastasis, invasion and the pathological grade of the tumor (Tables 2 and 3).	('tumor', 'Disease', (174, 179))	('invasion', 'CPA', (131, 139))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('implicated', 'Reg', (50, 60))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('gastric cancer', 'Disease', (3, 17))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('CD44v6 expression', 'Var', (18, 35))	('hematogenous metastasis', 'CPA', (106, 129))	('lymph node metastasis', 'CPA', (83, 104))
13005	22195236	In one study of submucosal gastric carcinoma CD44v6 was found to be the only indicator of lymph node metastasis.	('gastric carcinoma', 'Phenotype', 'HP:0012126', (27, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('submucosal gastric carcinoma', 'Disease', 'MESH:D013274', (16, 44))	('submucosal gastric carcinoma', 'Phenotype', 'HP:0031498', (16, 44))	('submucosal gastric carcinoma', 'Disease', (16, 44))	('CD44v6', 'Var', (45, 51))
13012	22195236	SCID mice given CD44 positive cells developed tumors within 8 to 12 weeks and CD44 knockdown by short hairpin RNA resulted in a decrease in tumorigenic ability.	('mice', 'Species', '10090', (5, 9))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CD44', 'Gene', (78, 82))	('RNA', 'cellular_component', 'GO:0005562', ('110', '113'))	('tumor', 'Disease', (46, 51))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('SCID', 'Disease', 'MESH:D053632', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('SCID', 'Disease', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumors', 'Disease', (46, 52))	('decrease', 'NegReg', (128, 136))	('knockdown', 'Var', (83, 92))	('tumor', 'Disease', (140, 145))
13014	22195236	CD44v9 expression in the gastric mucosa was previously shown to be positively correlated with proliferative activity as assessed by Ki-67 expression and, in addition, CD44v9 was found to be co-expressed with Ki-67.	('CD44v9', 'Gene', (0, 6))	('rat', 'Species', '10116', (101, 104))	('CD44v9', 'Var', (167, 173))	('correlated', 'Reg', (78, 88))	('proliferative activity', 'CPA', (94, 116))
13015	22195236	CD44v6 was also reported to be associated with expression of p53 but the expression was in different cells and in colorectal carcinoma, variant CD44 expression was found to precede p53 gene mutation in the adenoma-carcinoma sequence.	('colorectal carcinoma', 'Disease', (114, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (114, 134))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (206, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('variant', 'Var', (136, 143))	('CD44', 'Gene', (144, 148))	('adenoma-carcinoma', 'Disease', (206, 223))
13018	22195236	showed that what appeared to be gastric cancer stem cells in mice expressed CD44v9 (the antibody was to CD44V8-V10).	('mice', 'Species', '10090', (61, 65))	('gastric cancer', 'Disease', (32, 46))	('CD44v9', 'Var', (76, 82))	('gastric cancer', 'Disease', 'MESH:D013274', (32, 46))	('antibody', 'cellular_component', 'GO:0019815', ('88', '96'))	('antibody', 'cellular_component', 'GO:0019814', ('88', '96'))	('antibody', 'molecular_function', 'GO:0003823', ('88', '96'))	('gastric cancer', 'Phenotype', 'HP:0012126', (32, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('antibody', 'cellular_component', 'GO:0042571', ('88', '96'))
13030	22195236	reported that germline polymorphism in the CD44 gene, at least one G allele (GG; AG) at the CD44 +4883G>A gene locus (rs187116) associated with clinical outcome in patients with localized gastric adenocarcinoma.	('rs187116', 'Var', (118, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (188, 210))	('gastric adenocarcinoma', 'Disease', (188, 210))	('CD44', 'Gene', (43, 47))	('rs187116', 'Mutation', 'rs187116', (118, 126))	('associated with', 'Reg', (128, 143))	('+4883G>A', 'Mutation', 'g.+4883G>A', (97, 105))	('patients', 'Species', '9606', (164, 172))
13031	22195236	They found that patients having at least one G allele of CD44 rs187116 remained significantly associated with time to recurrence and overall survival and that patients harboring CD44 T-A haplotype were at the lowest risk of developing tumor recurrence and death.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('death', 'Disease', 'MESH:D003643', (256, 261))	('death', 'Disease', (256, 261))	('rs187116', 'Mutation', 'rs187116', (62, 70))	('CD44', 'Gene', (57, 61))	('patients', 'Species', '9606', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('CD44', 'Var', (178, 182))	('associated', 'Reg', (94, 104))	('tumor', 'Disease', (235, 240))	('rs187116', 'Var', (62, 70))	('patients', 'Species', '9606', (159, 167))
13032	22195236	These results suggest that assessment of CD44 polymorphisms may assist in identifying patients with localized gastric cancer who are at high risk for tumor recurrence.	('localized gastric cancer', 'Disease', (100, 124))	('localized gastric cancer', 'Disease', 'MESH:D013274', (100, 124))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('CD44', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('polymorphisms', 'Var', (46, 59))	('tumor', 'Disease', (150, 155))	('patients', 'Species', '9606', (86, 94))
13034	22195236	However, gastric cancer stem cells also co-express Ki-67 whereas tissue stem cells cycle slowly and frequently do not.	('gastric cancer', 'Disease', (9, 23))	('gastric cancer', 'Disease', 'MESH:D013274', (9, 23))	('Ki-67', 'Var', (51, 56))	('slowly', 'NegReg', (89, 95))	('co-express', 'Var', (40, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (9, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
13035	22195236	Prior studies showed that CD44v9 was also co-expressed with Ki-67 in nonmetaplastic gastric mucosa not associated with gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('gastric cancer', 'Disease', (119, 133))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('CD44v9', 'Var', (26, 32))	('nonmetaplastic gastric mucosa', 'Disease', (69, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))
13039	22195236	intravenously injected pSico-CD44v6 shRNA plus a intestine-specific pFabpl promoterdriven-Cre-recombinase plasmid packaged in transferringcoated nanoparticles into a mouse model of intestinal adenoma and silenced CD44v6-v9mRNA expression, inhibited protein expression of CD44v6 variants (v6-9) and reduced tumor number with only a limited effect on CD44s-normal tissue.	('adenoma', 'Disease', 'MESH:D000236', (192, 199))	('protein', 'cellular_component', 'GO:0003675', ('249', '256'))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('inhibited', 'NegReg', (239, 248))	('CD44v6', 'Gene', (271, 277))	('variants', 'Var', (278, 286))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('adenoma', 'Disease', (192, 199))	('mouse', 'Species', '10090', (166, 171))	('tumor', 'Disease', (306, 311))	('protein expression', 'MPA', (249, 267))	('reduced', 'NegReg', (298, 305))
13047	22195236	Finally, an anti-CD44v6 antibody linked to the cytotoxic agent mertansine was used to stabilized the disease in patients with breast cancer refractory to conventional chemotherapy.	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('antibody', 'cellular_component', 'GO:0019815', ('24', '32'))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('mertansine', 'Chemical', 'MESH:D008453', (63, 73))	('breast cancer', 'Disease', (126, 139))	('patients', 'Species', '9606', (112, 120))	('antibody', 'molecular_function', 'GO:0003823', ('24', '32'))	('antibody', 'cellular_component', 'GO:0019814', ('24', '32'))	('anti-CD44v6', 'Var', (12, 23))	('antibody', 'cellular_component', 'GO:0042571', ('24', '32'))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
13050	22195236	RT-PCR amplification and hybridization have shown that tumor cells exhibit a complex pattern of variant CD44 transcripts and that different CD44v patterns occur in different primary gastric tumors and in the lymph node metastasis derived from those tumors.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (249, 254))	('CD44', 'Gene', (104, 108))	('tumors', 'Disease', (190, 196))	('variant', 'Var', (96, 103))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('gastric tumors', 'Disease', 'MESH:D013274', (182, 196))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('gastric tumors', 'Phenotype', 'HP:0006753', (182, 196))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumor', 'Disease', (190, 195))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('gastric tumors', 'Disease', (182, 196))	('tumor', 'Disease', (55, 60))	('occur', 'Reg', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('tumors', 'Disease', (249, 255))
13056	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))
13059	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))
13060	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))
13061	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))
13075	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))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('124', '140'))	('tumor', 'Disease', (124, 129))	('oncogenes', 'Protein', (53, 62))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('124', '140'))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('methylation', 'biological_process', 'GO:0032259', ('79', '90'))	('hypo methylation', 'Var', (4, 20))
13076	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))	('methylation', 'biological_process', 'GO:0032259', ('259', '270'))	('DNA repair', 'biological_process', 'GO:0006281', ('145', '155'))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('MLH1', 'Gene', (60, 64))	('cell cycle', 'biological_process', 'GO:0007049', ('157', '167'))	('apoptosis', 'biological_process', 'GO:0097194', ('188', '197'))	('apoptosis', 'biological_process', 'GO:0006915', ('188', '197'))	('silencing', 'NegReg', (240, 249))	('cell adhesion', 'biological_process', 'GO:0007155', ('169', '182'))	('MLH1', 'Gene', '4292', (60, 64))	('DNA', 'cellular_component', 'GO:0005574', ('145', '148'))	('breast cancer type 1 susceptibility protein', 'Gene', (71, 114))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('MutL homolog 1', 'Gene', '4292', (44, 58))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('8', '24'))	('hyper methylation', 'Var', (253, 270))	('tumor', 'Disease', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('p16', 'Gene', (39, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('8', '24'))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('p16', 'Gene', '1029', (39, 42))	('BRCA1', 'Gene', '672', (116, 121))
13077	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'))
13079	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))
13080	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))
13083	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))
13096	33883026	There was a significant correlation between BRCA1 hyper methylation and poor survival.	('BRCA1', 'Gene', '672', (44, 49))	('BRCA1', 'Gene', (44, 49))	('hyper methylation', 'Var', (50, 67))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('poor survival', 'CPA', (72, 85))
13104	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))	('posttranslational modification', 'biological_process', 'GO:0043687', ('21', '51'))	('P53', 'Gene', (0, 3))	('posttranslational modification', 'Var', (21, 51))	('P53', 'Gene', '7157', (0, 3))
13105	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'))
13113	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))	('signaling', 'biological_process', 'GO:0023052', ('158', '167'))	('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))	('regulation', 'biological_process', 'GO:0065007', ('138', '148'))
13123	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))	('RASSF10', 'Gene', (193, 200))	('ALL', 'Phenotype', 'HP:0006721', (104, 107))	('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))
13124	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))	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('pre', 'molecular_function', 'GO:0003904', ('101', '104'))	('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))
13126	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))	('patients', 'Species', '9606', (191, 199))	('HIC1', 'Gene', '3090', (126, 130))	('tumor', 'Disease', (70, 75))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('methylation', 'biological_process', 'GO:0032259', ('131', '142'))	('correlations', 'Interaction', (49, 61))	('men', 'Species', '9606', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))	('methylation', 'Var', (131, 142))
13128	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))
13129	33883026	Similarly, the RASSF1A methylation has been shown as an efficient prognostic marker in a sample of Saudi breast cancer patients.	('methylation', 'Var', (23, 34))	('RASSF1A', 'Gene', '11186', (15, 22))	('Saudi breast cancer', 'Disease', (99, 118))	('patients', 'Species', '9606', (119, 127))	('Saudi breast cancer', 'Disease', 'MESH:D001943', (99, 118))	('methylation', 'biological_process', 'GO:0032259', ('23', '34'))	('RASSF1A', 'Gene', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
13132	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))	('RASSF1A', 'Gene', '11186', (68, 75))	('benign tumors', 'Disease', 'MESH:D009369', (167, 180))	('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))
13135	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))
13138	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))	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('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))
13146	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))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('oral squamous cell carcinoma', 'Disease', (94, 122))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
13147	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))	('p14ARF', 'Gene', '1029', (76, 82))	('hyper methylation', 'Var', (83, 100))	('methylation', 'biological_process', 'GO:0032259', ('89', '100'))	('p14ARF', 'Gene', (76, 82))	('lymph node involvement', 'CPA', (123, 145))	('patients', 'Species', '9606', (166, 174))
13149	33883026	MDM2 is an oncogene that inactivates p53 during tumorigenesis.	('tumor', 'Disease', (48, 53))	('inactivates', 'Var', (25, 36))	('MDM2', 'Gene', '4193', (0, 4))	('p53', 'Gene', (37, 40))	('MDM2', 'Gene', (0, 4))	('p53', 'Gene', '7157', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
13154	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))
13157	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))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('higher', 'PosReg', (41, 47))	('p16', 'Gene', '1029', (57, 60))	('methylation', 'biological_process', 'GO:0032259', ('136', '147'))	('p16', 'Gene', (132, 135))
13159	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))	('p16', 'Gene', '1029', (76, 79))	('HP infection', 'Disease', 'MESH:C537262', (112, 124))	('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))
13160	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))
13161	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))	('patients', 'Species', '9606', (107, 115))	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('reported', 'Reg', (59, 67))	('aberrant', 'Var', (4, 12))	('OSCC progression', 'Disease', (75, 91))	('p16', 'Gene', '1029', (40, 43))	('p15', 'Gene', (32, 35))	('p15', 'Gene', '1030', (32, 35))
13165	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))	('methylation', 'biological_process', 'GO:0032259', ('75', '86'))	('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))
13175	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))
13176	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'))	('tumor', 'Disease', (53, 58))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('methylation', 'MPA', (9, 20))	('patients', 'Species', '9606', (86, 94))
13184	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))
13185	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))
13187	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', 'molecular_function', 'GO:0005131', ('160', '174'))	('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))	('lipid metabolism', 'biological_process', 'GO:0006629', ('53', '69'))	('AKT signaling', 'biological_process', 'GO:0043491', ('98', '111'))	('Ghrelin', 'Gene', (0, 7))	('secretion', 'biological_process', 'GO:0046903', ('147', '156'))	('regulation', 'biological_process', 'GO:0065007', ('27', '37'))	('AKT', 'Gene', (98, 101))	('P13K', 'SUBSTITUTION', 'None', (93, 97))
13193	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))
13194	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))	('methylation', 'biological_process', 'GO:0032259', ('107', '118'))	('EDNRB', 'Gene', (86, 91))	('higher', 'PosReg', (66, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (23, 40))	('colorectal cancer tumors', 'Disease', (23, 47))
13196	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))
13197	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))
13198	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))
13199	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))
13208	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))
13209	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))	('AKT', 'Gene', '207', (177, 180))	('IGFR growth factor receptors', 'Protein', (131, 159))	('Phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('0', '30'))	('HER1', 'Gene', (115, 119))	('P13K', 'Var', (172, 176))	('Phosphatase', 'molecular_function', 'GO:0016791', ('0', '11'))	('AKT', 'Gene', '207', (62, 65))	('HER2', 'Gene', (121, 125))	('PTEN', 'Gene', (32, 36))	('AKT', 'Gene', (177, 180))	('HER1', 'Gene', '1956', (115, 119))	('AKT signaling', 'biological_process', 'GO:0043491', ('177', '190'))	('PI3K', 'molecular_function', 'GO:0016303', ('57', '61'))	('Phosphatase and tensin homolog', 'Gene', '5728', (0, 30))	('signal transduction', 'MPA', (90, 109))	('PTEN', 'Gene', '5728', (32, 36))	('P13K', 'SUBSTITUTION', 'None', (172, 176))	('signal transduction', 'biological_process', 'GO:0007165', ('90', '109'))
13217	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))	('methylation', 'biological_process', 'GO:0032259', ('112', '123'))	('hyper methylation', 'Var', (106, 123))	('sporadic breast cancer', 'Disease', (25, 47))	('men', 'Species', '9606', (164, 167))
13219	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))
13220	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))
13226	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))
13232	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))	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('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))
13234	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'))
13238	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))
13239	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))	('methylation', 'biological_process', 'GO:0032259', ('8', '19'))	('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))
13241	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))	('methylation', 'biological_process', 'GO:0032259', ('51', '62'))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('methylation', 'Var', (51, 62))	('tumors', 'Disease', (73, 79))	('higher', 'PosReg', (27, 33))	('ER5', 'Protein', (47, 50))	('Her-2', 'Gene', '2064', (66, 71))
13242	33883026	ER-alpha hyper methylation was frequently observed in invasive ductal cell carcinoma patients.	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('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))
13245	33883026	There was a correlation between ER-alpha methylation and poor prognosis in basal and Her2+ tumors.	('tumors', 'Disease', (91, 97))	('ER-alpha', 'Gene', (32, 40))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('correlation', 'Reg', (12, 23))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('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))
13247	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))
13249	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))	('methylation', 'biological_process', 'GO:0032259', ('67', '78'))	('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))
13251	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))
13255	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))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Disease', (100, 105))	('gastric cancer', 'Disease', (170, 184))	('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))	('APAF1', 'Gene', '317', (81, 86))
13261	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))	('mitochondria', 'cellular_component', 'GO:0005739', ('71', '83'))
13262	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))	('methylation', 'biological_process', 'GO:0032259', ('170', '181'))	('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))	('methylation', 'biological_process', 'GO:0032259', ('58', '69'))	('aberrant', 'Var', (36, 44))	('FAS promoter', 'Protein', (45, 57))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 133))
13263	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))
13264	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.	('transcription', 'biological_process', 'GO:0006351', ('31', '44'))	('E2F1', 'Gene', (26, 30))	('CHK1', 'Gene', (169, 173))	('ATM', 'Gene', (65, 68))	('phosphorylation', 'MPA', (150, 165))	('CDC25', 'Gene', (190, 195))	('Deregulated', 'Var', (0, 11))	('DNA', 'cellular_component', 'GO:0005574', ('135', '138'))	('CHK2', 'Gene', (175, 179))	('up regulates', 'PosReg', (52, 64))	('P53', 'Gene', (181, 184))	('E2F1', 'Gene', '1869', (26, 30))	('CDC25', 'Gene', '995', (190, 195))	('transcription factor', 'molecular_function', 'GO:0000981', ('31', '51'))	('CHK1', 'Gene', '1111', (169, 173))	('apoptosis', 'biological_process', 'GO:0097194', ('87', '96'))	('CHK2', 'Gene', '11200', (175, 179))	('P53', 'Gene', '7157', (181, 184))	('cell cycle regulation', 'CPA', (108, 129))	('apoptosis', 'biological_process', 'GO:0006915', ('87', '96'))	('ATM', 'Gene', '472', (65, 68))	('phosphorylation', 'biological_process', 'GO:0016310', ('150', '165'))	('DNA repair', 'biological_process', 'GO:0006281', ('135', '145'))	('DNA repair', 'CPA', (135, 145))	('apoptosis induction', 'CPA', (87, 106))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('108', '129'))
13268	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))
13273	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))	('methylation', 'biological_process', 'GO:0032259', ('85', '96'))	('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))
13275	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))
13278	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))
13279	33883026	The MGMT promoter hyper methylation was also frequently reported in CRC, GB, BC, and OSCC.	('MGMT', 'Gene', '4255', (4, 8))	('CRC', 'Disease', 'MESH:D015179', (68, 71))	('CRC', 'Phenotype', 'HP:0003003', (68, 71))	('hyper methylation', 'Var', (18, 35))	('reported', 'Reg', (56, 64))	('CRC', 'Disease', (68, 71))	('OSCC', 'Disease', (85, 89))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('MGMT', 'Gene', (4, 8))	('MGMT', 'molecular_function', 'GO:0003908', ('4', '8'))
13281	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))
13300	33321820	The switch from the EBNA Cp and Wp:hypermethylated during latency:to the Qp promoter leads to the exclusive expression of the EBNA1 antigen.	('hypermethylated', 'Var', (35, 50))	('EBNA1', 'Gene', (126, 131))	('expression', 'MPA', (108, 118))	('EBNA1', 'Gene', '17494214', (126, 131))
13317	33321820	In addition to these classifications, some molecular markers have a useful impact in GC subtype characterization to lead to more personalized medicine: the presence of HER2 overexpression, which has been associated with a poor prognosis but good response to trastuzumab; MSI-H, and EBV-positive tumors as promising candidates for PD-L1/PD-1 immune checkpoint inhibitors; and CDH1 mutations as a marker for the identification and prophylaxis of the hereditary form.	('PD-L1', 'Gene', (330, 335))	('tumors', 'Disease', (295, 301))	('HER2', 'Gene', '2064', (168, 172))	('EBV', 'Species', '10376', (282, 285))	('PD-1', 'Gene', (336, 340))	('MSI-H', 'Chemical', '-', (271, 276))	('tumors', 'Disease', 'MESH:D009369', (295, 301))	('PD-1', 'Gene', '5133', (336, 340))	('PD-L1', 'Gene', '29126', (330, 335))	('CDH1', 'Gene', (375, 379))	('trastuzumab', 'Chemical', 'MESH:D000068878', (258, 269))	('CDH1', 'Gene', '999', (375, 379))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('hereditary form', 'Disease', (448, 463))	('mutations', 'Var', (380, 389))	('GC', 'Phenotype', 'HP:0012126', (85, 87))	('tumors', 'Phenotype', 'HP:0002664', (295, 301))	('HER2', 'Gene', (168, 172))
13322	33321820	In addition, MSI-H and cytotoxic treatment may lead to an increased tumor neoantigen production, resulting from a greater rate of mutated gene, and subsequent tumor CD8-positive T-cell infiltration that, however, can be exhausted and inhibited by tumor PD-L1 expression.	('tumor', 'Disease', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('men', 'Species', '9606', (38, 41))	('increased', 'PosReg', (58, 67))	('tumor', 'Disease', (247, 252))	('PD-L1', 'Gene', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('PD-L1', 'Gene', '29126', (253, 258))	('CD8', 'Gene', (165, 168))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('CD8', 'Gene', '925', (165, 168))	('mutated', 'Var', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('MSI-H', 'Chemical', '-', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('greater rate', 'PosReg', (114, 126))
13325	33321820	The question of the prognostic impact of EBVaGC was recently investigated in a meta-analysis where the authors concluded that EBVaGC is associated with a lower mortality rate than the other GC subtypes.	('EBVaGC', 'Var', (126, 132))	('lower', 'NegReg', (154, 159))	('mortality', 'Disease', (160, 169))	('EBVaGC', 'Chemical', '-', (126, 132))	('GC', 'Phenotype', 'HP:0012126', (45, 47))	('GC', 'Phenotype', 'HP:0012126', (190, 192))	('EBVaGC', 'Chemical', '-', (41, 47))	('GC', 'Phenotype', 'HP:0012126', (130, 132))	('mortality', 'Disease', 'MESH:D003643', (160, 169))
13331	33321820	Of note, authors highlighted no difference regarding familiarity with GC, HER2, or MSI-H expression between the two groups of patients but a significant positive association between PD-L1 immunostaining with EBVaGC (50% of cases) and the good clinical prognosis.	('EBVaGC', 'Chemical', '-', (208, 214))	('immunostaining', 'Var', (188, 202))	('MSI-H', 'Chemical', '-', (83, 88))	('positive', 'PosReg', (153, 161))	('PD-L1', 'Gene', '29126', (182, 187))	('GC', 'Phenotype', 'HP:0012126', (212, 214))	('GC', 'Phenotype', 'HP:0012126', (70, 72))	('HER2', 'Gene', (74, 78))	('HER2', 'Gene', '2064', (74, 78))	('patients', 'Species', '9606', (126, 134))	('PD-L1', 'Gene', (182, 187))	('EBVaGC', 'Disease', (208, 214))
13334	33321820	The concordance in molecular data taken from several studies indicates an increased expression of phosphoinositide phosphatidylinositol 3-kinase (PIK3CA), a decreased level of AT-rich interactive domain 1A (ARID1A), promoter hypermethylation of the CDKN2A coding for the p16 protein, and amplification of 9p24.1 chromosome harboring the Programmed Death ligand genes (PDCD1L 1-2), and Janus-kinase 2 (JAK2).	('PIK3CA', 'Gene', '5290', (146, 152))	('Janus-kinase 2', 'Gene', '3717', (385, 399))	('Death', 'Disease', 'MESH:D003643', (348, 353))	('Death', 'Disease', (348, 353))	('amplification', 'Var', (288, 301))	('JAK', 'molecular_function', 'GO:0004713', ('401', '404'))	('p16', 'Gene', (271, 274))	('CDKN2A', 'Gene', (249, 255))	('increased', 'PosReg', (74, 83))	('PIK3CA', 'Gene', (146, 152))	('ARID1A', 'Gene', (207, 213))	('p16', 'Gene', '1029', (271, 274))	('decreased', 'NegReg', (157, 166))	('JAK2', 'Gene', '3717', (401, 405))	('Janus-kinase 2', 'Gene', (385, 399))	('CDKN2A', 'Gene', '1029', (249, 255))	('ARID1A', 'Gene', '8289', (207, 213))	('expression', 'MPA', (84, 94))	('protein', 'cellular_component', 'GO:0003675', ('275', '282'))	('ligand', 'molecular_function', 'GO:0005488', ('354', '360'))	('JAK2', 'Gene', (401, 405))	('chromosome', 'cellular_component', 'GO:0005694', ('312', '322'))
13337	33321820	ARID1A and PI3KCA are the most frequently mutated genes in EBVa GC (5-55% and 80%, respectively).	('ARID1A', 'Gene', '8289', (0, 6))	('EBVa GC', 'Gene', (59, 66))	('ARID1A', 'Gene', (0, 6))	('EBVa', 'Chemical', '-', (59, 63))	('GC', 'Phenotype', 'HP:0012126', (64, 66))	('PI3KCA', 'Var', (11, 17))
13338	33321820	Amplification mostly occurs for JAK2 and PDCD1L1/2 genes (about 11% of cases), and the receptor tyrosine kinase pathway, including MET gene amplification, which is also frequent (33% of cases).	('Amplification', 'Var', (0, 13))	('PDCD1L1/2', 'Gene', (41, 50))	('JAK2', 'Gene', (32, 36))	('receptor tyrosine kinase', 'Gene', (87, 111))	('MET', 'Gene', '79811', (131, 134))	('occurs', 'Reg', (21, 27))	('receptor tyrosine kinase', 'Gene', '5979', (87, 111))	('JAK', 'molecular_function', 'GO:0004713', ('32', '35'))	('MET', 'Gene', (131, 134))	('JAK2', 'Gene', '3717', (32, 36))
13346	33321820	Traditionally, EBV types were classified based on variations in a few genes such as EBNA2 (the most frequently used), EBNA3, EBNA1, and LMP1 corresponding to two EBV strains: EBV-1 (B95-8 as prototype 1) and EBV-2 (AG876 as prototype 2).	('EBNA1', 'Gene', '17494214', (125, 130))	('EBNA3', 'Gene', (118, 123))	('EBNA2', 'Gene', '17494192', (84, 89))	('EBNA2', 'Gene', (84, 89))	('EBV', 'Species', '10376', (162, 165))	('EBV', 'Species', '10376', (15, 18))	('LMP1', 'Gene', '9260', (136, 140))	('EBV', 'Species', '10376', (208, 211))	('EBV', 'Species', '10376', (175, 178))	('LMP1', 'Gene', (136, 140))	('variations', 'Var', (50, 60))	('EBNA1', 'Gene', (125, 130))
13349	33321820	With advances in genomic and bioinformatic technologies, the entire 175 kb EBV genome has been sequenced, producing evidence of vast EBV variations as the basis of numerous classification studies, e.g.,.	('EBV', 'Species', '10376', (75, 78))	('variations', 'Var', (137, 147))	('EBV', 'Species', '10376', (133, 136))	('EBV', 'Gene', (133, 136))
13350	33321820	Zanella and collaborators, though combined analysis of EBV genetic structural recombination with that of EBV phylogenetic mutations, proposed 12 distinct EBV phylopopulations (EBV-p) based on geographic location and tumor type.	('tumor', 'Disease', (216, 221))	('EBV', 'Species', '10376', (55, 58))	('EBV', 'Species', '10376', (176, 179))	('EBV', 'Species', '10376', (105, 108))	('EBV', 'Species', '10376', (154, 157))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('mutations', 'Var', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('EBV', 'Gene', (105, 108))
13355	33321820	These shared mutations mapped to antigen epitopes, which suggests EBV immune evasion may be involved in the development of EBVaGC.	('GC', 'Phenotype', 'HP:0012126', (127, 129))	('EBV', 'Species', '10376', (66, 69))	('involved', 'Reg', (92, 100))	('immune evasion', 'biological_process', 'GO:0042783', ('70', '84'))	('EBVaGC', 'Chemical', '-', (123, 129))	('men', 'Species', '9606', (115, 118))	('immune evasion', 'biological_process', 'GO:0051842', ('70', '84'))	('EBV', 'Species', '10376', (123, 126))	('mutations', 'Var', (13, 22))
13360	33321820	Taken together, the data suggest the role of specific EBV variants which are associated with an increased risk of GC.	('variants', 'Var', (58, 66))	('GC', 'Phenotype', 'HP:0012126', (114, 116))	('EBV', 'Species', '10376', (54, 57))	('EBV', 'Gene', (54, 57))	('associated', 'Reg', (77, 87))
13361	33321820	Additional studies should be performed to determine the biological significance of the EBV sequence variations for clinical applications and to study the potential attenuation of antiviral T-cell immunity caused by these viral strain variations.	('variations', 'Var', (234, 244))	('EBV', 'Species', '10376', (87, 90))	('EBV', 'Gene', (87, 90))	('variations', 'Var', (100, 110))
13370	33321820	A recent study identified a mutation in the promoter of BART that could increase the production of miRNAs in EBVa NPC but the same single polymorphism (SNP) was scarcely found in EBVaGC.	('NPC', 'Phenotype', 'HP:0100630', (114, 117))	('increase', 'PosReg', (72, 80))	('miR', 'Gene', '220972', (99, 102))	('miR', 'Gene', (99, 102))	('NPC', 'cellular_component', 'GO:0005643', ('114', '117'))	('GC', 'Phenotype', 'HP:0012126', (183, 185))	('EBVa', 'Chemical', '-', (109, 113))	('BART', 'Gene', (56, 60))	('mutation', 'Var', (28, 36))	('EBVaGC', 'Chemical', '-', (179, 185))	('EBVa', 'Chemical', '-', (179, 183))
13376	33321820	For example, BART15-3p was found to promote apoptosis and immune responses, and BART6-3p was found to reverse the epithelial-mesenchymal phenotype and inhibit tumor invasion and migration.	('apoptosis', 'biological_process', 'GO:0097194', ('44', '53'))	('BART6-3p', 'Var', (80, 88))	('promote', 'PosReg', (36, 43))	('apoptosis', 'CPA', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('immune responses', 'CPA', (58, 74))	('apoptosis', 'biological_process', 'GO:0006915', ('44', '53'))	('tumor', 'Disease', (159, 164))	('BART1', 'Gene', (13, 18))	('reverse', 'PosReg', (102, 109))	('inhibit', 'NegReg', (151, 158))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('BART1', 'Gene', '23568', (13, 18))	('epithelial-mesenchymal phenotype', 'CPA', (114, 146))
13381	33321820	Hypermethylation is another hallmark of EBVaGC, but this mechanism does not involve the MHLH1 gene:a component of the mismatch repair system strongly associated with the GC MSI-H subtype.	('associated', 'Reg', (150, 160))	('EBVaGC', 'Chemical', '-', (40, 46))	('Hypermethylation', 'Var', (0, 16))	('MSI-H', 'Chemical', '-', (173, 178))	('GC MSI-H subtype', 'Disease', (170, 186))	('GC', 'Phenotype', 'HP:0012126', (170, 172))	('mismatch repair', 'biological_process', 'GO:0006298', ('118', '133'))	('GC', 'Phenotype', 'HP:0012126', (44, 46))
13384	33321820	The methylation of the CDKN2A promoter region is also frequent, resulting in the downregulation of CDKN2A (p16) cyclin-dependent kinase inhibitor.	('kinase inhibitor', 'biological_process', 'GO:0033673', ('129', '145'))	('CDKN2A', 'Gene', (99, 105))	('p16', 'Gene', '1029', (107, 110))	('CDKN2A', 'Gene', (23, 29))	('downregulation', 'NegReg', (81, 95))	('methylation', 'Var', (4, 15))	('CDKN2A', 'Gene', '1029', (99, 105))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('112', '145'))	('p16', 'Gene', (107, 110))	('CDKN2A', 'Gene', '1029', (23, 29))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))
13402	33321820	The data also indicate that EBV may infect the well-differentiated epithelial cells of the stomach.	('EBV', 'Var', (28, 31))	('well-differentiated epithelial cells of the', 'CPA', (47, 90))	('EBV', 'Species', '10376', (28, 31))	('infect', 'Reg', (36, 42))
13410	33321820	Alteration in the B-cell immune response might influence the adaptive immune response against infected cells including EBVaGC, though this is today a hypothesis that remains to be demonstrated.	('immune response', 'biological_process', 'GO:0006955', ('25', '40'))	('GC', 'Phenotype', 'HP:0012126', (123, 125))	('B-cell immune response', 'CPA', (18, 40))	('Alteration', 'Var', (0, 10))	('influence', 'Reg', (47, 56))	('EBVaGC', 'Chemical', '-', (119, 125))	('adaptive immune response against', 'CPA', (61, 93))	('infected', 'Disease', 'MESH:D007239', (94, 102))	('adaptive immune response', 'biological_process', 'GO:0002250', ('61', '85'))	('infected', 'Disease', (94, 102))
13415	33321820	Another important mechanism by which EBV reduces host immunity is to alter the metabolism of infected cells, thus modifying the T-cell immune response.	('immune response', 'biological_process', 'GO:0006955', ('135', '150'))	('T-cell immune response', 'CPA', (128, 150))	('reduces', 'NegReg', (41, 48))	('metabolism', 'biological_process', 'GO:0008152', ('79', '89'))	('infected', 'Disease', 'MESH:D007239', (93, 101))	('modifying', 'Reg', (114, 123))	('EBV', 'Species', '10376', (37, 40))	('alter', 'Reg', (69, 74))	('EBV', 'Var', (37, 40))	('infected', 'Disease', (93, 101))	('host immunity', 'CPA', (49, 62))	('metabolism', 'MPA', (79, 89))
13422	33321820	EBV positivity is now well accepted as a consolidated marker for the diagnostic classification of GC.	('EBV', 'Species', '10376', (0, 3))	('positivity', 'Var', (4, 14))	('GC', 'Phenotype', 'HP:0012126', (98, 100))	('EBV', 'Gene', (0, 3))
13431	33321820	The most frequent inhibitory signal found in EBV-positive gastric cancer is high PD-L1 expression resulting from 9p24.1 amplification (about 11% of cases), which leads to immune resistance and reduced survival of patients.	('gastric cancer', 'Phenotype', 'HP:0012126', (58, 72))	('survival', 'CPA', (201, 209))	('PD-L1', 'Gene', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('leads to', 'Reg', (162, 170))	('amplification', 'Var', (120, 133))	('reduced', 'NegReg', (193, 200))	('expression', 'MPA', (87, 97))	('gastric cancer', 'Disease', (58, 72))	('patients', 'Species', '9606', (213, 221))	('9p24.1', 'Gene', (113, 119))	('PD-L1', 'Gene', '29126', (81, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (58, 72))	('immune resistance', 'MPA', (171, 188))	('EBV', 'Species', '10376', (45, 48))
13444	33321820	Mutations in exons 9 and 20 in PI3K catalytic subunit alpha (PIK3CA) as well as mutations in phosphatase and tensin homolog (PTEN), AKT1, AKT2, and AKT3 lead to deregulation of the PI3K-Akt-mTOR pathway; they have been proposed as biomarkers to test novel compounds and dosing schedules.	('PIK3CA', 'Gene', (61, 67))	('AKT2', 'Gene', '208', (138, 142))	('PTEN', 'Gene', (125, 129))	('AKT3', 'Gene', '10000', (148, 152))	('AKT1', 'Gene', '207', (132, 136))	('AKT2', 'Gene', (138, 142))	('AKT3', 'Gene', (148, 152))	('mutations', 'Var', (80, 89))	('PTEN', 'Gene', '5728', (125, 129))	('AKT1', 'Gene', (132, 136))	('Mutations', 'Var', (0, 9))	('deregulation', 'MPA', (161, 173))	('PI3K', 'molecular_function', 'GO:0016303', ('31', '35'))	('PIK3CA', 'Gene', '5290', (61, 67))	('mTOR', 'Gene', (190, 194))	('Akt', 'Gene', (186, 189))	('phosphatase', 'molecular_function', 'GO:0016791', ('93', '104'))	('phosphatase and tensin homolog', 'Gene', '5728', (93, 123))	('PI3K', 'molecular_function', 'GO:0016303', ('181', '185'))	('Akt', 'Gene', '207', (186, 189))	('mTOR', 'Gene', '2475', (190, 194))	('phosphatase and tensin homolog', 'cellular_component', 'GO:1990455', ('93', '123'))
13450	33321820	Some clinical trials of PI3K inhibitors (BKM120, BYL719, and GSK2636771) and Akt inhibitors (MK2206, GSK2110183, and GDC-0068; Table 3) have been performed in patients with advanced and metastatic stage GC.	('BKM120', 'Var', (41, 47))	('Akt', 'Gene', '207', (77, 80))	('GC', 'Phenotype', 'HP:0012126', (203, 205))	('GDC-0068', 'Chemical', 'MESH:C583616', (117, 125))	('GSK', 'molecular_function', 'GO:0050321', ('101', '104'))	('GSK', 'molecular_function', 'GO:0050321', ('61', '64'))	('Akt', 'Gene', (77, 80))	('GSK2110183', 'Chemical', 'MESH:C000595148', (101, 111))	('BKM120', 'Chemical', 'MESH:C571178', (41, 47))	('GSK2636771', 'Chemical', 'MESH:C000627739', (61, 71))	('PI3K', 'molecular_function', 'GO:0016303', ('24', '28'))	('PI3K', 'Gene', (24, 28))	('MK2206', 'Chemical', 'MESH:C548887', (93, 99))	('patients', 'Species', '9606', (159, 167))	('metastatic stage GC', 'Disease', (186, 205))
13453	33321820	Moreover, an association was reported between a high frequency of ARIDIA mutations and overexpression of the PD-L1/L2 and modulation of TP53, which is rarely mutated in EBVaGC compared with the other GC subtypes.	('EBVaGC', 'Chemical', '-', (169, 175))	('ARIDIA', 'Gene', (66, 72))	('TP53', 'Gene', '7157', (136, 140))	('GC', 'Phenotype', 'HP:0012126', (200, 202))	('PD-L1', 'Gene', (109, 114))	('PD-L1', 'Gene', '29126', (109, 114))	('GC', 'Phenotype', 'HP:0012126', (173, 175))	('overexpression', 'MPA', (87, 101))	('modulation', 'Var', (122, 132))	('mutations', 'Var', (73, 82))	('TP53', 'Gene', (136, 140))
13464	33321820	Based on these results, silencing of miRNA (via siRNA) has been proposed as a potential new therapeutic approach in human diseases, but most studies are still at the preclinical stages.	('miR', 'Gene', '220972', (37, 40))	('miR', 'Gene', (37, 40))	('silencing', 'Var', (24, 33))	('human', 'Species', '9606', (116, 121))
13467	33321820	A similar approach involves using antisense oligonucleotides which are complementary to messenger RNA (mRNA), instead of miRNA for intracellular genes overexpressed in cancers, to mediate change in the behavior of malignancies.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('malignancies', 'Disease', 'MESH:D009369', (214, 226))	('malignancies', 'Disease', (214, 226))	('oligonucleotides', 'Chemical', 'MESH:D009841', (44, 60))	('RNA', 'cellular_component', 'GO:0005562', ('98', '101'))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('change', 'Reg', (188, 194))	('men', 'Species', '9606', (77, 80))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('miR', 'Gene', '220972', (121, 124))	('antisense', 'Var', (34, 43))	('miR', 'Gene', (121, 124))	('intracellular', 'cellular_component', 'GO:0005622', ('131', '144'))	('behavior', 'MPA', (202, 210))
13472	33321820	Patients with GC who carry heterogeneous and rare mutations that can benefit from targeted therapies may also benefit from treatment choice guided by liquid biopsy, which is a promising noninvasive and repeatable approach used to obtain tumor genotyping information.	('tumor', 'Disease', (237, 242))	('mutations', 'Var', (50, 59))	('GC', 'Phenotype', 'HP:0012126', (14, 16))	('men', 'Species', '9606', (128, 131))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
13478	33321820	Concerning EBVaGC, the related targeted next-generation sequencing tumor profiling of ctDNA identified the enrichment of PIK3CA mutations in these tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumors', 'Disease', (147, 153))	('mutations', 'Var', (128, 137))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('GC', 'Phenotype', 'HP:0012126', (15, 17))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('PIK3CA', 'Gene', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('men', 'Species', '9606', (113, 116))	('PIK3CA', 'Gene', '5290', (121, 127))	('tumor', 'Disease', (67, 72))	('EBVaGC', 'Chemical', '-', (11, 17))
13479	33321820	These results were in line with the heterogeneity of PIK3CA mutations found both in the primary tumor and in the matched lymph node and/or metastatic biopsies from the same patients, in agreement with the TCGA classification of EBVaGC.	('EBVaGC', 'Chemical', '-', (228, 234))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('patients', 'Species', '9606', (173, 181))	('PIK3CA', 'Gene', '5290', (53, 59))	('tumor', 'Disease', (96, 101))	('men', 'Species', '9606', (191, 194))	('GC', 'Phenotype', 'HP:0012126', (232, 234))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('mutations', 'Var', (60, 69))	('PIK3CA', 'Gene', (53, 59))
13522	32708696	The purification of HpUreG and its mutants was performed using a protocol previously reported.	('HpUreG', 'Gene', (20, 26))	('HpUreG', 'Chemical', '-', (20, 26))	('mutants', 'Var', (35, 42))
13525	32708696	Ni(II) binding titrations of wild-type and C66A mutant HpUreG were performed at 25  C using a high-sensitivity VP-ITC microcalorimeter (MicroCal, Norcross, GA, USA).	('binding', 'molecular_function', 'GO:0005488', ('7', '14'))	('HpUreG', 'Gene', (55, 61))	('C66A', 'Var', (43, 47))	('HpUreG', 'Chemical', '-', (55, 61))	('C66A', 'SUBSTITUTION', 'None', (43, 47))	('Ni(II)', 'Chemical', '-', (0, 6))
13531	32708696	The cysteine mutations were introduced into HpUreG gene from Hp26695 strain urease operon (NCBI code NC000915) cloned into the pET15b expression vector (Novagen, Madison, WI, USA) in a previous work.	('cysteine', 'Chemical', 'MESH:D003545', (4, 12))	('Hp', 'Species', '210', (61, 63))	('urea', 'Chemical', 'MESH:D014508', (76, 80))	('Hp', 'Species', '210', (44, 46))	('cysteine', 'Gene', (4, 12))	('HpUreG', 'Gene', (44, 50))	('mutations', 'Var', (13, 22))	('HpUreG', 'Chemical', '-', (44, 50))
13533	32708696	We decided to perform a Cysteine-Serine mutation for position 48 to preserve the surface charge of the protein, and a Cysteine-Alanine mutation in position 7 which is more buried in the crystal structure.	('mutation', 'Var', (40, 48))	('Serine', 'Chemical', 'MESH:D012694', (33, 39))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('surface charge of the', 'MPA', (81, 102))	('Cysteine', 'Chemical', 'MESH:D003545', (24, 32))	('Cysteine-Alanine', 'Chemical', '-', (118, 134))	('Cysteine', 'Chemical', 'MESH:D003545', (118, 126))
13535	32708696	They were named as following: HpUreG-C7A-C48S: C66proxyl; HpUreG-C7A-C66A: C48proxyl; HpUreG-C66A-C48S: C7proxyl.	('C66A', 'SUBSTITUTION', 'None', (69, 73))	('C48S', 'Mutation', 'p.C48S', (98, 102))	('C66A', 'Var', (93, 97))	('C7proxyl', 'Chemical', '-', (104, 112))	('C66A', 'SUBSTITUTION', 'None', (93, 97))	('HpUreG', 'Chemical', '-', (58, 64))	('HpUreG', 'Chemical', '-', (86, 92))	('C66proxyl', 'Chemical', '-', (47, 56))	('C48S', 'Mutation', 'p.C48S', (41, 45))	('C48proxyl', 'Chemical', '-', (75, 84))	('C48proxyl', 'Var', (75, 84))	('C66A', 'Var', (69, 73))	('HpUreG', 'Chemical', '-', (30, 36))
13536	32708696	Variants containing two labeling sites and thus needing only one cysteine mutated were designed to perform distances measurements by DEER-EPR ("Site-directed mutagenesis" in Supplementary Materials Section S3) were named as following: HpUreG-C7A: C48proxyl /C66proxyl; HpUreG-C66A: C7proxyl/C48proxyl; HpUreG-C48S: C7proxyl/C66proxyl.	('C66proxyl', 'Chemical', '-', (258, 267))	('C7proxyl/C66proxyl', 'Var', (315, 333))	('C66proxyl', 'Chemical', '-', (324, 333))	('C66A', 'Var', (276, 280))	('C48S', 'Mutation', 'p.C48S', (309, 313))	('C7proxyl', 'Chemical', '-', (282, 290))	('C48proxyl', 'Chemical', '-', (291, 300))	('C66A', 'SUBSTITUTION', 'None', (276, 280))	('HpUreG', 'Chemical', '-', (302, 308))	('HpUreG', 'Chemical', '-', (269, 275))	('HpUreG', 'Chemical', '-', (235, 241))	('C48proxyl', 'Chemical', '-', (247, 256))	('C7proxyl', 'Chemical', '-', (315, 323))	('C48proxyl', 'Var', (247, 256))	('cysteine', 'Chemical', 'MESH:D003545', (65, 73))
13557	32708696	HpUreG has three naturally occurring Cys, located in different regions of the protein (Figure 1A): (i) the conserved P-loop-motif, involved in GTP binding, accommodates Cys7; (ii) Helix 2, involved in GTP-dependent conformational changes, contains Cys48; (iii) the fully conserved CPH motif, involved in Ni(II) binding, includes Cys66.	('Cys', 'Chemical', 'MESH:D003545', (169, 172))	('GTP', 'Chemical', 'MESH:D006160', (143, 146))	('GTP binding', 'molecular_function', 'GO:0005525', ('143', '154'))	('CPH', 'Chemical', '-', (281, 284))	('Cys', 'Chemical', 'MESH:D003545', (37, 40))	('Cys48', 'Var', (248, 253))	('HpUreG', 'Chemical', '-', (0, 6))	('Ni(II)', 'Chemical', '-', (304, 310))	('GTP', 'Chemical', 'MESH:D006160', (201, 204))	('Cys', 'Chemical', 'MESH:D003545', (329, 332))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('binding', 'molecular_function', 'GO:0005488', ('311', '318'))	('Cys66', 'Chemical', '-', (329, 334))	('Cys48', 'Chemical', '-', (248, 253))	('Cys66', 'Var', (329, 334))	('Cys7', 'Chemical', 'MESH:C082474', (169, 173))	('Cys', 'Chemical', 'MESH:D003545', (248, 251))
13558	32708696	Consequently, six mutants containing one or two Cys residues were designed and labeled with the MA-Proxyl nitroxide to dissect the protein conformational landscape (Figure 1B): three double variants feature a unique position available for labeling (C7prox, corresponding to the Cys48Ser/Cys66Ala labeled mutant; C48prox corresponding to the Cys7Ala/Cys66Ala labeled mutant; C66prox, corresponding to the Cys7Ala/Cys48Ser labeled mutant), while three single variants possess two positions available for labeling for distance measurements (C7prox/C48prox, corresponding to the Cys66Ala labeled mutant; C7prox/C66prox, corresponding to the Cys48Ser labeled mutant; C48prox/C66prox, corresponding to the Cys7Ala labeled mutant).	('C48prox/C66prox', 'Var', (662, 677))	('Cys66Ala', 'Var', (349, 357))	('Cys66Ala', 'Var', (287, 295))	('Cys48Ser', 'Var', (637, 645))	('Cys7Ala', 'Mutation', 'p.C7A', (700, 707))	('Cys48Ser', 'Var', (278, 286))	('Cys7Ala', 'SUBSTITUTION', 'None', (700, 707))	('Cys', 'Chemical', 'MESH:D003545', (575, 578))	('Ser', 'cellular_component', 'GO:0005790', ('642', '645'))	('Cys', 'Chemical', 'MESH:D003545', (637, 640))	('Cys66Ala', 'SUBSTITUTION', 'None', (575, 583))	('Ser', 'cellular_component', 'GO:0005790', ('283', '286'))	('Cys48Ser', 'Mutation', 'p.C48S', (637, 645))	('Cys7Ala', 'Var', (700, 707))	('C66prox', 'Chemical', '-', (374, 381))	('Cys48Ser', 'Mutation', 'p.C48S', (278, 286))	('Cys48Ser', 'Var', (412, 420))	('Cys', 'Chemical', 'MESH:D003545', (700, 703))	('C7prox/C66prox', 'Var', (600, 614))	('MA-Proxyl nitroxide', 'Chemical', '-', (96, 115))	('Cys7Ala', 'Mutation', 'p.C7A', (341, 348))	('Cys48Ser', 'SUBSTITUTION', 'None', (637, 645))	('Cys66Ala', 'SUBSTITUTION', 'None', (349, 357))	('Cys7Ala', 'SUBSTITUTION', 'None', (341, 348))	('Cys', 'Chemical', 'MESH:D003545', (287, 290))	('Cys7Ala', 'Mutation', 'p.C7A', (404, 411))	('Cys', 'Chemical', 'MESH:D003545', (349, 352))	('Cys7Ala', 'SUBSTITUTION', 'None', (404, 411))	('Cys66Ala', 'SUBSTITUTION', 'None', (287, 295))	('Cys', 'Chemical', 'MESH:D003545', (412, 415))	('Cys7Ala', 'Var', (341, 348))	('Cys48Ser', 'SUBSTITUTION', 'None', (278, 286))	('Cys66Ala', 'Var', (575, 583))	('Cys48Ser', 'Mutation', 'p.C48S', (412, 420))	('Cys7Ala', 'Var', (404, 411))	('Cys', 'Chemical', 'MESH:D003545', (278, 281))	('Cys', 'Chemical', 'MESH:D003545', (48, 51))	('Cys', 'Chemical', 'MESH:D003545', (341, 344))	('Cys', 'Chemical', 'MESH:D003545', (404, 407))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('C66prox', 'Chemical', '-', (607, 614))	('C66prox', 'Chemical', '-', (670, 677))	('Cys48Ser', 'SUBSTITUTION', 'None', (412, 420))	('Ser', 'cellular_component', 'GO:0005790', ('417', '420'))
13560	32708696	Any possible perturbation of the global structure and of the folding of HpUreG mutations was excluded by controlling the global folding by circular dichroism (CD, see Figure S2).	('HpUreG', 'Gene', (72, 78))	('controlling', 'Reg', (105, 116))	('HpUreG', 'Chemical', '-', (72, 78))	('global', 'MPA', (121, 127))	('mutations', 'Var', (79, 88))
13570	32708696	Mutation of the Ni(II) binding residue Cys66 to Ala was previously reported to fully abolish Ni(II) binding capability of the protein.	('Ni(II)', 'Chemical', '-', (93, 99))	('Ni(II)', 'Chemical', '-', (16, 22))	('Cys66', 'Var', (39, 44))	('binding', 'molecular_function', 'GO:0005488', ('23', '30'))	('binding', 'molecular_function', 'GO:0005488', ('100', '107'))	('abolish', 'NegReg', (85, 92))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))	('Cys66 to Ala', 'Mutation', 'p.C66A', (39, 51))
13571	32708696	Here, the ITC titration instead revealed that the Cys66Ala-HpUreG mutant is still able to bind one Ni(II) ion per protein monomer, with an exothermic reaction (Figure 2B, left panel) and one order of magnitude lower affinity (Kd = 236 microM), with substantially invariant enthalpic and entropic contributions (Figure 2B, right panel and Table 1).	('Cys66Ala', 'Var', (50, 58))	('bind', 'Interaction', (90, 94))	('Ni(II)', 'Chemical', '-', (99, 105))	('Cys66Ala', 'SUBSTITUTION', 'None', (50, 58))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('lower', 'NegReg', (210, 215))
13572	32708696	This observation suggests that the two Ni(II) binding sites per monomer, observed in wild-type HpUreG, are distinct, with one site, involving Cys66 in the CPH motif, that is abrogated by the Cys66-to-Ala mutation, while the second is maintained.	('HpUreG', 'Chemical', '-', (95, 101))	('Cys66-to-Ala', 'Mutation', 'p.C66A', (191, 203))	('Cys66', 'Chemical', '-', (142, 147))	('Ni(II)', 'Chemical', '-', (39, 45))	('Cys66', 'Var', (142, 147))	('binding', 'molecular_function', 'GO:0005488', ('46', '53'))	('Cys66', 'Chemical', '-', (191, 196))	('CPH', 'Chemical', '-', (155, 158))	('abrogated', 'NegReg', (174, 183))	('Cys66-to-Ala', 'Var', (191, 203))
13574	32708696	The triply labeled WTprox, while showing the same exothermic effect (Figure 2C, left panel) and the same stoichiometry as the Cys66Ala mutant, features an higher affinity for Ni(II) (Kd = 23 microM), a similar enthalpic value and positive entropic contribution (right panel of Figure 2C and Table 1), as compared to the Cys66Ala mutant (Kd = 236 microM), indicating that the Cys labeling with the nitroxide moiety still abolishes one of the two Ni(II) binding sites observed for the unlabeled WT protein, but, differently from the Cys66Ala mutation, maintains a similar affinity for the second Ni(II) binding event, supporting the idea of cooperativity between the two Ni-binding sites in the WT protein.	('nitroxide', 'Chemical', '-', (397, 406))	('binding', 'molecular_function', 'GO:0005488', ('672', '679'))	('Cys', 'Chemical', 'MESH:D003545', (320, 323))	('Cys', 'Chemical', 'MESH:D003545', (375, 378))	('Cys66Ala', 'Var', (531, 539))	('Cys66Ala', 'Var', (126, 134))	('mutant', 'Var', (135, 141))	('Cys66Ala', 'SUBSTITUTION', 'None', (320, 328))	('Cys', 'Chemical', 'MESH:D003545', (531, 534))	('Ni(II)', 'Chemical', '-', (175, 181))	('protein', 'cellular_component', 'GO:0003675', ('496', '503'))	('binding', 'molecular_function', 'GO:0005488', ('601', '608'))	('protein', 'cellular_component', 'GO:0003675', ('696', '703'))	('Ni(II)', 'Chemical', '-', (445, 451))	('Cys66Ala', 'SUBSTITUTION', 'None', (531, 539))	('Cys66Ala', 'SUBSTITUTION', 'None', (126, 134))	('Ni(II)', 'Chemical', '-', (594, 600))	('Cys66Ala', 'Var', (320, 328))	('Cys', 'Chemical', 'MESH:D003545', (126, 129))	('binding', 'molecular_function', 'GO:0005488', ('452', '459'))
13585	32708696	The apparent decrease in affinity at lower pH is consistent with a proton dissociation event occurring upon metal binding, which possibly involves a cysteine residue (Cys66 in this case), as previously observed in the case of the nickel-dependent transcription factor HpNikR.	('transcription', 'biological_process', 'GO:0006351', ('247', '260'))	('proton dissociation', 'MPA', (67, 86))	('nickel', 'Chemical', 'MESH:D009532', (230, 236))	('decrease', 'NegReg', (13, 21))	('cysteine', 'Chemical', 'MESH:D003545', (149, 157))	('affinity', 'MPA', (25, 33))	('metal', 'Chemical', 'MESH:D008670', (108, 113))	('Cys66', 'Var', (167, 172))	('metal binding', 'molecular_function', 'GO:0046872', ('108', '121'))	('transcription factor', 'molecular_function', 'GO:0000981', ('247', '267'))	('Cys66', 'Chemical', '-', (167, 172))	('Hp', 'Species', '210', (268, 270))
13587	32708696	According to the fit, the first event of Ni(II) binding occurs with one order of magnitude lower affinity (Kd = 160 microM) as observed for the Cys66Ala mutant in the absence of GTPgammaS (Figure 2A), while the second equilibrium shows a similar constant (Kd = 22 microM).	('lower', 'NegReg', (91, 96))	('binding', 'molecular_function', 'GO:0005488', ('48', '55'))	('binding', 'Interaction', (48, 55))	('Cys66Ala', 'Var', (144, 152))	('GTPgammaS', 'Chemical', 'MESH:D016244', (178, 187))	('Cys66Ala', 'SUBSTITUTION', 'None', (144, 152))	('Ni(II)', 'Chemical', '-', (41, 47))	('affinity', 'MPA', (97, 105))
13589	32708696	It is worth noticing that, during sample manipulation, the Cys66Ala mutant was prone to precipitation, especially in the presence of Ni(II), suggesting that at least part of the protein sample undergoes aggregation upon Ni(II) titration, which might be the second process evidenced in the binding isotherm.	('binding', 'molecular_function', 'GO:0005488', ('289', '296'))	('Ni(II)', 'Chemical', '-', (133, 139))	('Cys66Ala', 'Var', (59, 67))	('Cys66Ala', 'SUBSTITUTION', 'None', (59, 67))	('undergoes', 'Reg', (193, 202))	('aggregation', 'MPA', (203, 214))	('protein', 'cellular_component', 'GO:0003675', ('178', '185'))	('Ni(II)', 'Chemical', '-', (220, 226))
13593	32708696	To separately dissect the conformational flexibility of different regions of HpUreG, the EPR spectrum of the nitroxide-labeled HpUreG variants that contain a single labeled cysteine (C7prox, C48prox, and C66prox) were performed in solution and at room temperature (Figure 1C).	('C66prox', 'Chemical', '-', (204, 211))	('HpUreG', 'Gene', (127, 133))	('C48prox', 'Var', (191, 198))	('HpUreG', 'Chemical', '-', (127, 133))	('C7prox', 'Var', (183, 189))	('cysteine', 'Chemical', 'MESH:D003545', (173, 181))	('C66prox', 'Var', (204, 211))	('nitroxide', 'Chemical', '-', (109, 118))	('HpUreG', 'Chemical', '-', (77, 83))
13595	32708696	For the single labelled HpUreG variants, the spectra show different mobility: the line shape becomes sharper going from C7prox to C48prox and then to C66prox, reflecting an increased mobility of the nitroxide moiety and, consequently, of the protein structural motif to which the label is attached (Figure 1C).	('mobility', 'MPA', (183, 191))	('nitroxide', 'Chemical', '-', (199, 208))	('variants', 'Var', (31, 39))	('HpUreG', 'Chemical', '-', (24, 30))	('C66prox', 'Chemical', '-', (150, 157))	('protein', 'cellular_component', 'GO:0003675', ('242', '249'))	('C48prox', 'Var', (130, 137))	('increased', 'PosReg', (173, 182))	('C7prox', 'Var', (120, 126))	('HpUreG', 'Gene', (24, 30))	('C66prox', 'Var', (150, 157))
13600	32708696	This conclusion is consistent with similar phenomena reported for SpUreG, and is further supported by the observation that the HpUreG EPR spectrum of C66prox is modified by the addition of glycerol, a protective osmolyte: in this case, the spectrum can be simulated by increasing the contribution of the slower component, which changes from 44 to 70% (Table 2 and Figure S4).	('C66prox', 'Chemical', '-', (150, 157))	('HpUreG', 'Chemical', '-', (127, 133))	('glycerol', 'Chemical', 'MESH:D005990', (189, 197))	('increasing', 'PosReg', (269, 279))	('C66prox', 'Var', (150, 157))
13609	32708696	Three double-Cys variants were constructed and labeled (C7prox/C48prox, C7prox/C66prox, C48prox/C66prox) and their CW EPR spectra are reported in Supplementary Materials Figure S7.	('C7prox/C48prox', 'Var', (56, 70))	('C66prox', 'Chemical', '-', (96, 103))	('C7prox/C66prox', 'Var', (72, 86))	('Cys', 'Chemical', 'MESH:D003545', (13, 16))	('C66prox', 'Chemical', '-', (79, 86))	('C48prox/C66prox', 'Var', (88, 103))
13616	32708696	To investigate the source of this spectral modifications, and in particular to sort out which of the three nitroxide labels bound to the protein contributes to the Ni(II) and GTP-driven line broadening, the experiment was repeated using the single-Cys variants of HpUreG.	('GTP', 'Chemical', 'MESH:D006160', (175, 178))	('HpUreG', 'Gene', (264, 270))	('nitroxide', 'Chemical', '-', (107, 116))	('GTP-driven', 'MPA', (175, 185))	('HpUreG', 'Chemical', '-', (264, 270))	('Ni(II)', 'Chemical', '-', (164, 170))	('protein', 'cellular_component', 'GO:0003675', ('137', '144'))	('single-Cys variants', 'Var', (241, 260))	('Cys', 'Chemical', 'MESH:D003545', (248, 251))
13617	32708696	Addition of Ni(II) did not produce significant changes of the EPR line shapes for C7prox (Figure 6A) and C48prox (Figure 6B), while for the C66prox spectrum induced a line broadening (Figure 6C), suggesting a reduction of the spin label mobility (Table 2 and Figure 3).	('spin', 'Gene', (226, 230))	('C66prox', 'Var', (140, 147))	('Ni(II)', 'Chemical', '-', (12, 18))	('C66prox', 'Chemical', '-', (140, 147))	('C48prox', 'Var', (105, 112))	('line broadening', 'MPA', (167, 182))	('reduction', 'NegReg', (209, 218))	('spin', 'Gene', '10927', (226, 230))
13625	32708696	The observed spectral changes indicate that Ni(II) and GTP induce structural and dynamics modifications in the Ni(II)-binding region of the protein where C66 is located, and in the region around Helix 2, containing C48.	('protein', 'cellular_component', 'GO:0003675', ('140', '147'))	('dynamics', 'MPA', (81, 89))	('structural', 'MPA', (66, 76))	('modifications', 'Reg', (90, 103))	('Ni(II)', 'Chemical', '-', (44, 50))	('C66', 'Var', (154, 157))	('GTP', 'Chemical', 'MESH:D006160', (55, 58))	('Ni(II)', 'Chemical', '-', (111, 117))	('binding', 'molecular_function', 'GO:0005488', ('118', '125'))
13628	32708696	However, the decrease in the Tm (phase memory time) value (Figure S13A) associated with the field sweep (FS) intensity loss (Figure S13B) in the presence of Ni(II) prevented from obtaining properly exploitable DEER traces.	('decrease', 'NegReg', (13, 21))	('S13A', 'SUBSTITUTION', 'None', (66, 70))	('S13B', 'Var', (132, 136))	('FS', 'Disease', 'MESH:D018223', (105, 107))	('Ni(II)', 'Chemical', '-', (157, 163))	('loss', 'NegReg', (119, 123))	('S13B', 'SUBSTITUTION', 'None', (132, 136))	('S13A', 'Var', (66, 70))	('memory', 'biological_process', 'GO:0007613', ('39', '45'))	('field sweep', 'MPA', (92, 103))
13642	32547314	Genotypic distributions of two GAS5 genetic variants rs145204276 and rs55829688 were detected in 208 patients including 111 patients with invasive cancer, 97 with precancerous lesions as well as 307 control women using real-time polymerase chain reaction.	('precancerous lesions', 'Disease', (163, 183))	('rs55829688', 'Mutation', 'rs55829688', (69, 79))	('rs55829688', 'Var', (69, 79))	('patients', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('invasive cancer', 'Disease', 'MESH:D009362', (138, 153))	('rs145204276', 'Mutation', 'rs145204276', (53, 64))	('women', 'Species', '9606', (207, 212))	('GAS', 'molecular_function', 'GO:0034005', ('31', '34'))	('invasive cancer', 'Disease', (138, 153))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('GAS5', 'Gene', (31, 35))	('precancerous lesions', 'Disease', 'MESH:D011230', (163, 183))	('rs145204276', 'Var', (53, 64))	('patients', 'Species', '9606', (124, 132))
13643	32547314	It explored that patients with cervical precancerous lesion had lower rate of AGGCA deletion (Del) in both alleles (Del/Del) of GAS5 rs145204276 as compared with control women.	('women', 'Species', '9606', (170, 175))	('deletion', 'Var', (84, 92))	('rs145204276', 'Var', (133, 144))	('lower', 'NegReg', (64, 69))	('precancerous lesion', 'Disease', (40, 59))	('AGGCA', 'Gene', (78, 83))	('precancerous lesion', 'Disease', 'MESH:D011230', (40, 59))	('patients', 'Species', '9606', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('GAS5', 'Gene', (128, 132))	('rs145204276', 'Mutation', 'rs145204276', (133, 144))	('GAS', 'molecular_function', 'GO:0034005', ('128', '131'))	('lower rate of AGGCA', 'Phenotype', 'HP:0004315', (64, 83))
13645	32547314	Meanwhile, there were no different genotypic distributions in rs55829688 among patients with cervical invasive cancer and those with precancerous lesions as well as control women.	('women', 'Species', '9606', (173, 178))	('precancerous lesions', 'Disease', 'MESH:D011230', (133, 153))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('precancerous lesions', 'Disease', (133, 153))	('patients', 'Species', '9606', (79, 87))	('cervical invasive cancer', 'Disease', 'MESH:D002583', (93, 117))	('cervical invasive cancer', 'Disease', (93, 117))	('rs55829688', 'Mutation', 'rs55829688', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('rs55829688', 'Var', (62, 72))
13646	32547314	Moreover, cervical cancer patients with Ins (insertion, AGGCA)/Del and Del/Del (-/-) in GAS5 rs55829688 tended to have poorer hazard ratio (HR) of 5 years survival.	('GAS5', 'Gene', (88, 92))	('poorer', 'NegReg', (119, 125))	('rs55829688', 'Mutation', 'rs55829688', (93, 103))	('rs55829688', 'Var', (93, 103))	('patients', 'Species', '9606', (26, 34))	('cervical cancer', 'Disease', (10, 25))	('cervical cancer', 'Disease', 'MESH:D002583', (10, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('GAS', 'molecular_function', 'GO:0034005', ('88', '91'))
13647	32547314	Conclusively, GAS5 polymorphism rs145204276 is probably applicable to predict 5 years survival HR of cervical cancer patients.	('cervical cancer', 'Disease', 'MESH:D002583', (101, 116))	('cervical cancer', 'Disease', (101, 116))	('rs145204276', 'Mutation', 'rs145204276', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('GAS5', 'Gene', (14, 18))	('GAS', 'molecular_function', 'GO:0034005', ('14', '17'))	('patients', 'Species', '9606', (117, 125))	('rs145204276', 'Var', (32, 43))
13648	32547314	However, the mechanism elucidating the methylation status and transcription function of rs145204276 in uterine cervical cancer needs to be delineated for its unique implication in uterine cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cervical cancer', 'Disease', (111, 126))	('cervical cancer', 'Disease', 'MESH:D002583', (111, 126))	('rs145204276', 'Var', (88, 99))	('cervical cancer', 'Disease', (188, 203))	('rs145204276', 'Mutation', 'rs145204276', (88, 99))	('cervical cancer', 'Disease', 'MESH:D002583', (188, 203))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('transcription', 'biological_process', 'GO:0006351', ('62', '75'))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))
13650	32547314	Accumulating evidence has revealed lncRNAs are concerned with various biological roles, including gene expression, cell proliferation and migratory behavior, and are involved in cancer development because of their displaying oncogene or tumor suppressor function.	('tumor', 'Disease', (237, 242))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('gene expression', 'biological_process', 'GO:0010467', ('98', '113'))	('cell proliferation', 'biological_process', 'GO:0008283', ('115', '133'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('237', '253'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('237', '253'))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('migratory behavior', 'CPA', (138, 156))	('cancer', 'Disease', (178, 184))	('oncogene', 'CPA', (225, 233))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cell proliferation', 'CPA', (115, 133))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('involved', 'Reg', (166, 174))	('lncRNAs', 'Var', (35, 42))
13651	32547314	LncRNA Hox transcript antisense intergenic RNA (HOTAIR) is regarded as an oncogenic lncRNA, whereas GAS5 a tumor suppressor lncRNA.	('GAS', 'molecular_function', 'GO:0034005', ('100', '103'))	('HOTAIR', 'Gene', '100124700', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('RNA', 'cellular_component', 'GO:0005562', ('43', '46'))	('antisense', 'Var', (22, 31))	('tumor suppressor', 'biological_process', 'GO:0051726', ('107', '123'))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('HOTAIR', 'Gene', (48, 54))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('107', '123'))
13659	32547314	Some SNPs within lncRNA genes have been demonstrated to affect the expression and action of lncRNAs, which are identified as regulatory RNAs without protein-coding potential, and then affect individual cancer susceptibility and patient survival.	('affect', 'Reg', (56, 62))	('SNPs', 'Var', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('protein', 'cellular_component', 'GO:0003675', ('149', '156'))	('action', 'MPA', (82, 88))	('affect', 'Reg', (184, 190))	('lncRNA genes', 'Gene', (17, 29))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('lncRNAs', 'Gene', (92, 99))	('cancer', 'Disease', (202, 208))	('expression', 'MPA', (67, 77))	('patient survival', 'CPA', (228, 244))	('patient', 'Species', '9606', (228, 235))
13661	32547314	To our knowledge, no investigation has associated GAS5 genetic variants with cervical cancer in Taiwanese women.	('cervical cancer', 'Disease', (77, 92))	('cervical cancer', 'Disease', 'MESH:D002583', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('women', 'Species', '9606', (106, 111))	('genetic variants', 'Var', (55, 71))	('GAS5', 'Gene', (50, 54))	('GAS', 'molecular_function', 'GO:0034005', ('50', '53'))
13662	32547314	Therefore, we designed this study to explore the relationships of GAS5 genetic variants with the development of cervical cancer and patient survival.	('GAS', 'molecular_function', 'GO:0034005', ('66', '69'))	('genetic variants', 'Var', (71, 87))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cervical cancer', 'Disease', (112, 127))	('cervical cancer', 'Disease', 'MESH:D002583', (112, 127))	('GAS5', 'Gene', (66, 70))	('patient', 'Species', '9606', (132, 139))
13663	32547314	The study was designed to explore the relationships of GAS5 genetic variants to the development of uterine cervical cancer and patient survival retrospectively.	('cervical cancer', 'Disease', (107, 122))	('variants', 'Var', (68, 76))	('patient', 'Species', '9606', (127, 134))	('GAS', 'molecular_function', 'GO:0034005', ('55', '58'))	('GAS5', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cervical cancer', 'Disease', 'MESH:D002583', (107, 122))
13670	32547314	Two GAS5 genetic variants rs145204276 and rs55829688 were detected in compliance with the data of International HapMap Project and previous study.	('rs145204276', 'Var', (26, 37))	('rs145204276', 'Mutation', 'rs145204276', (26, 37))	('GAS', 'molecular_function', 'GO:0034005', ('4', '7'))	('GAS5', 'Gene', (4, 8))	('rs55829688', 'Var', (42, 52))	('rs55829688', 'Mutation', 'rs55829688', (42, 52))
13671	32547314	The polymorphism rs145204276 AGGCA/- was demonstrated to be located at the promoter region of lncRNA GAS5 and was associated with the progression of several cancers.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('GAS', 'molecular_function', 'GO:0034005', ('101', '104'))	('rs145204276', 'Var', (17, 28))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('associated with', 'Reg', (114, 129))	('AGGCA/-', 'Gene', (29, 36))	('cancers', 'Disease', (157, 164))	('rs145204276', 'Mutation', 'rs145204276', (17, 28))
13672	32547314	GAS5 genetic polymorphisms rs145204276 and rs55829688 were examined by ABI StepOne Real-Time PCR System (Applied Biosystems, Foster City, CA, USA) as well as delineated with SDS vers.	('rs55829688', 'Mutation', 'rs55829688', (43, 53))	('rs55829688', 'Var', (43, 53))	('GAS5', 'Gene', (0, 4))	('SDS', 'Chemical', 'MESH:D012967', (174, 177))	('rs145204276', 'Var', (27, 38))	('GAS', 'molecular_function', 'GO:0034005', ('0', '3'))	('rs145204276', 'Mutation', 'rs145204276', (27, 38))
13673	32547314	Genotypes of lncRNAs GAS5 genetic variants rs145204276 and rs55829688 were determined by ABI StepOne Real-Time PCR System (Applied Biosystems, Foster City, CA, USA), and analyzed with SDS vers.	('SDS', 'Chemical', 'MESH:D012967', (184, 187))	('rs145204276', 'Var', (43, 54))	('GAS', 'molecular_function', 'GO:0034005', ('21', '24'))	('rs145204276', 'Mutation', 'rs145204276', (43, 54))	('lncRNAs GAS5', 'Gene', (13, 25))	('rs55829688', 'Mutation', 'rs55829688', (59, 69))	('rs55829688', 'Var', (59, 69))
13675	32547314	Hardy-Weinberg equilibrium was applied to check the genotypic distributions of rs145204276 and rs55829688 in control women [degree of freedom (d.f.)=2].	('rs145204276', 'Mutation', 'rs145204276', (79, 90))	('rs55829688', 'Mutation', 'rs55829688', (95, 105))	('rs55829688', 'Var', (95, 105))	('rs145204276', 'Var', (79, 90))	('women', 'Species', '9606', (117, 122))
13676	32547314	Chi-square or Fisher exact tests were applied to examine the relationships of two GAS5 genetic variants with the cervical tumorigenesis.	('GAS', 'molecular_function', 'GO:0034005', ('82', '85'))	('GAS5', 'Gene', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('variants', 'Var', (95, 103))	('tumor', 'Disease', (122, 127))
13682	32547314	The minor allele frequency (MAF) of GAS5 genetic variant rs145204276 accorded with the Hardy-Weinberg equilibrium [chi2 value, 1.172, p=0.556; d.f.=2].	('GAS5', 'Gene', (36, 40))	('GAS', 'molecular_function', 'GO:0034005', ('36', '39'))	('rs145204276', 'Mutation', 'rs145204276', (57, 68))	('rs145204276', 'Var', (57, 68))
13683	32547314	The MAF of GAS5 rs55829688 was also in line with the Hardy-Weinberg equilibrium [chi2 value, 0.0389, p=0.981; d.f.=2].	('GAS', 'molecular_function', 'GO:0034005', ('11', '14'))	('rs55829688', 'Mutation', 'rs55829688', (16, 26))	('GAS5', 'Gene', (11, 15))	('rs55829688', 'Var', (16, 26))
13684	32547314	The genetic distribution of GAS5 rs145204276 polymorphism exerted no significance difference between patients with cervical neoplasia and control women (p=0.241; Table 1).	('rs145204276', 'Var', (33, 44))	('patients', 'Species', '9606', (101, 109))	('neoplasia', 'Disease', (124, 133))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (115, 133))	('neoplasia', 'Disease', 'MESH:D009369', (124, 133))	('neoplasia', 'Phenotype', 'HP:0002664', (124, 133))	('rs145204276', 'Mutation', 'rs145204276', (33, 44))	('GAS5', 'Gene', (28, 32))	('GAS', 'molecular_function', 'GO:0034005', ('28', '31'))	('women', 'Species', '9606', (146, 151))
13686	32547314	Meanwhile, neither was significant differences demonstrated in GAS5 rs55829688 between the patients with cervical neoplasia and the normal controls, nor was statistical difference noted after age adjustment in this genetic polymorphism (Table 1).	('patients', 'Species', '9606', (91, 99))	('neoplasia', 'Disease', (114, 123))	('GAS', 'molecular_function', 'GO:0034005', ('63', '66'))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (105, 123))	('neoplasia', 'Disease', 'MESH:D009369', (114, 123))	('neoplasia', 'Phenotype', 'HP:0002664', (114, 123))	('GAS5', 'Gene', (63, 67))	('rs55829688', 'Mutation', 'rs55829688', (68, 78))	('rs55829688', 'Var', (68, 78))
13687	32547314	If patients having cervical neoplasia group was subdivided into those with invasive cancer and precancerous subgroups, it revealed no significant difference in the genotypic frequencies of Ins/Ins, Ins/Del and Del/Del in GAS5 rs145204276 among patients with invasive cancer and those with precancerous lesions of uterine cervix as well as control women (p = 0.144; Table 2).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('precancerous lesions', 'Disease', (289, 309))	('neoplasia', 'Phenotype', 'HP:0002664', (28, 37))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('rs145204276', 'Var', (226, 237))	('invasive cancer', 'Disease', 'MESH:D009362', (75, 90))	('cancer', 'Disease', (98, 104))	('invasive cancer', 'Disease', (258, 273))	('patients', 'Species', '9606', (244, 252))	('invasive cancer', 'Disease', 'MESH:D009362', (258, 273))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Ins/Del', 'Var', (198, 205))	('cancer', 'Disease', (292, 298))	('GAS5', 'Gene', (221, 225))	('women', 'Species', '9606', (347, 352))	('rs145204276', 'Mutation', 'rs145204276', (226, 237))	('uterine cervix', 'Phenotype', 'HP:0030160', (313, 327))	('precancerous lesions', 'Disease', 'MESH:D011230', (289, 309))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('cancer', 'Disease', (267, 273))	('neoplasia', 'Disease', 'MESH:D009369', (28, 37))	('cancer', 'Disease', (84, 90))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (19, 37))	('GAS', 'molecular_function', 'GO:0034005', ('221', '224'))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('patients', 'Species', '9606', (3, 11))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('neoplasia', 'Disease', (28, 37))	('Del/Del', 'Var', (210, 217))	('Ins/Ins', 'Var', (189, 196))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('invasive cancer', 'Disease', (75, 90))
13688	32547314	While Ins/Inn and Ins/Del were used as references, Taiwanese women with precancerous lesions had significantly lower rate of genotype Del/Del (p= 0.030, AOR=0.40, 95% CI=0.18-0.92; Table 2).	('precancerous lesions', 'Disease', (72, 92))	('AOR', 'molecular_function', 'GO:0033726', ('153', '156'))	('women', 'Species', '9606', (61, 66))	('lower', 'NegReg', (111, 116))	('genotype Del/Del', 'Var', (125, 141))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('precancerous lesions', 'Disease', 'MESH:D011230', (72, 92))
13690	32547314	Meanwhile, there were no different genotypic frequencies between patients with cervical invasive cancer and normal controls as well as between patients with precancerous lesions and normal controls after age adjustment in GAS5 rs55829688 (Table 2).	('GAS', 'molecular_function', 'GO:0034005', ('222', '225'))	('precancerous lesions', 'Disease', 'MESH:D011230', (157, 177))	('patients', 'Species', '9606', (143, 151))	('cervical invasive cancer', 'Disease', 'MESH:D002583', (79, 103))	('cervical invasive cancer', 'Disease', (79, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('patients', 'Species', '9606', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('rs55829688', 'Mutation', 'rs55829688', (227, 237))	('precancerous lesions', 'Disease', (157, 177))	('rs55829688', 'Var', (227, 237))
13691	32547314	While associating GAS5 genetic variants with clinicopathological factors of cervical cancer, it revealed no significant associations of rs145204276 with these factors (Table 3).	('rs145204276', 'Var', (136, 147))	('GAS', 'molecular_function', 'GO:0034005', ('18', '21'))	('rs145204276', 'Mutation', 'rs145204276', (136, 147))	('GAS5', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cervical cancer', 'Disease', (76, 91))	('cervical cancer', 'Disease', 'MESH:D002583', (76, 91))	('associations', 'Interaction', (120, 132))
13692	32547314	In addition, GAS5 rs55829688 also could not exerted significant associations with clinicopathological characteristics (data not shown).	('GAS', 'molecular_function', 'GO:0034005', ('13', '16'))	('GAS5', 'Gene', (13, 17))	('rs55829688', 'Mutation', 'rs55829688', (18, 28))	('rs55829688', 'Var', (18, 28))
13693	32547314	When the distributions of GAS5 genetic polymorphism were analyzed among all cancer stage subdivisions (stage I, II, III and IV) in patients with uterine cervical cancer, we found that patients with genotype TC in GAS5 rs55829688 had more risk to have stage II (OR: 2.69, 95% CI: 1.08-6.70; p=0.033) and stage III (OR: 15.56, 95% CI: 1.80-134.24; p=0.013) using TT as a reference (Supplement Table 1).	('patients', 'Species', '9606', (131, 139))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('TC', 'Chemical', 'MESH:D013667', (207, 209))	('cervical cancer', 'Disease', (153, 168))	('cancer', 'Disease', (162, 168))	('patients', 'Species', '9606', (184, 192))	('rs55829688', 'Mutation', 'rs55829688', (218, 228))	('stage II', 'Disease', (251, 259))	('rs55829688', 'Var', (218, 228))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('GAS', 'molecular_function', 'GO:0034005', ('213', '216'))	('GAS5', 'Gene', (213, 217))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('GAS', 'molecular_function', 'GO:0034005', ('26', '29'))	('cervical cancer', 'Disease', 'MESH:D002583', (153, 168))
13694	32547314	In addition, cervical cancer patients with genotypes TC/CC in rs55829688 had more risk to have stage III (OR: 12.73, 95% CI: 1.49-108.84; p=0.020).	('TC/CC', 'Var', (53, 58))	('TC', 'Chemical', 'MESH:D013667', (53, 55))	('patients', 'Species', '9606', (29, 37))	('cervical cancer', 'Disease', (13, 28))	('cervical cancer', 'Disease', 'MESH:D002583', (13, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('stage III', 'Disease', (95, 104))	('rs55829688', 'Mutation', 'rs55829688', (62, 72))	('rs55829688', 'Var', (62, 72))
13695	32547314	Cervical cancer patients with Ins/Del and Del/Del presented 5 years survival rate 0.79 (95% CI=0.68-0.89), as compared to those with Ins/Ins 0.86 (95% CI=0.76-0.97) in GAS5 rs145204276 (Table 4).	('Del/Del', 'Var', (42, 49))	('cancer', 'Disease', (9, 15))	('GAS', 'molecular_function', 'GO:0034005', ('168', '171'))	('patients', 'Species', '9606', (16, 24))	('rs145204276', 'Mutation', 'rs145204276', (173, 184))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('Ins/Del', 'Var', (30, 37))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
13700	32547314	Genotypic distribution of GAS5 rs145204276 for cervical cancer patients revealed that patients with Ins/Del and Del/Del tended to have poorer 5 years survival HR, compared to those with Ins/Ins after adjusting GAS5 polymorphisms and various clinicopathological factors (p=0.049, HR=3.45, 95% CI=1.01-11.82; Table 5, Figure 1).	('GAS5', 'Gene', (26, 30))	('Ins/Del', 'Var', (100, 107))	('rs145204276', 'Mutation', 'rs145204276', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cervical cancer', 'Disease', (47, 62))	('rs145204276', 'Var', (31, 42))	('cervical cancer', 'Disease', 'MESH:D002583', (47, 62))	('5 years survival HR', 'CPA', (142, 161))	('poorer', 'NegReg', (135, 141))	('Del/Del', 'Var', (112, 119))	('patients', 'Species', '9606', (63, 71))	('GAS', 'molecular_function', 'GO:0034005', ('210', '213'))	('GAS', 'molecular_function', 'GO:0034005', ('26', '29'))	('patients', 'Species', '9606', (86, 94))
13701	32547314	However, patients with Del/Del could not present this tendency as compared to those with Ins/Ins and Ins/Del in GAS5 rs145204276.	('patients', 'Species', '9606', (9, 17))	('GAS', 'molecular_function', 'GO:0034005', ('112', '115'))	('rs145204276', 'Var', (117, 128))	('Del/Del', 'Var', (23, 30))	('rs145204276', 'Mutation', 'rs145204276', (117, 128))
13704	32547314	The study explores that Taiwanese women with precancerous lesions had significantly lower rate of genotype Del/Del in GAS 5 rs145204276.	('genotype Del/Del', 'Var', (98, 114))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('rs145204276', 'Mutation', 'rs145204276', (124, 135))	('GAS 5', 'Gene', (118, 123))	('precancerous lesions', 'Disease', 'MESH:D011230', (45, 65))	('GAS', 'molecular_function', 'GO:0034005', ('118', '121'))	('lower', 'NegReg', (84, 89))	('women', 'Species', '9606', (34, 39))	('rs145204276', 'Var', (124, 135))	('precancerous lesions', 'Disease', (45, 65))
13707	32547314	The patients with precancerous lesions had higher rate of Ins/Ins and Ins/Del in GAS5 rs145204276.	('precancerous lesions', 'Disease', (18, 38))	('Ins/Del', 'Var', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('GAS', 'molecular_function', 'GO:0034005', ('81', '84'))	('rs145204276', 'Mutation', 'rs145204276', (86, 97))	('GAS5', 'Gene', (81, 85))	('Ins/Ins', 'Disease', (58, 65))	('rs145204276', 'Var', (86, 97))	('patients', 'Species', '9606', (4, 12))	('precancerous lesions', 'Disease', 'MESH:D011230', (18, 38))
13708	32547314	The function of GAS5 may be affected by the genetic variants but still preserves tumor suppression function.	('function', 'MPA', (4, 12))	('GAS5', 'Gene', (16, 20))	('variants', 'Var', (52, 60))	('preserves', 'NegReg', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('affected', 'Reg', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('GAS', 'molecular_function', 'GO:0034005', ('16', '19'))	('tumor', 'Disease', (81, 86))
13709	32547314	Therefore, it is suggested that the effect of association of Del/Del with precancerous lesions is not strong enough to destroy the basement membrane of cervical epithelium and induce invasiveness of cervical cancer cells.	('invasiveness', 'CPA', (183, 195))	('precancerous lesions', 'Disease', 'MESH:D011230', (74, 94))	('precancerous lesions', 'Disease', (74, 94))	('induce', 'Reg', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('basement membrane', 'cellular_component', 'GO:0005604', ('131', '148'))	('Del/Del', 'Var', (61, 68))	('cervical cancer', 'Disease', 'MESH:D002583', (199, 214))	('destroy', 'NegReg', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cervical cancer', 'Disease', (199, 214))	('basement membrane', 'CPA', (131, 148))
13710	32547314	There were no significant genotypic distributions among patients with cervical invasive cancer and those with precancerous lesions as well as normal controls in GAS5 rs55829688.	('precancerous lesions', 'Disease', (110, 130))	('patients', 'Species', '9606', (56, 64))	('GAS', 'molecular_function', 'GO:0034005', ('161', '164'))	('rs55829688', 'Mutation', 'rs55829688', (166, 176))	('rs55829688', 'Var', (166, 176))	('GAS5', 'Gene', (161, 165))	('cervical invasive cancer', 'Disease', 'MESH:D002583', (70, 94))	('cervical invasive cancer', 'Disease', (70, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('precancerous lesions', 'Disease', 'MESH:D011230', (110, 130))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
13711	32547314	To the best of our knowledge, few investigations reported the implication of GAS5 polymorphisms in cervical cancer.	('GAS5', 'Gene', (77, 81))	('polymorphisms', 'Var', (82, 95))	('cervical cancer', 'Disease', 'MESH:D002583', (99, 114))	('cervical cancer', 'Disease', (99, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('GAS', 'molecular_function', 'GO:0034005', ('77', '80'))
13713	32547314	As compared to controls, osteosarcoma patients were demonstrated to display significantly lower frequency of genotype Del/Del in GAS5 rs145204276 by Xu et al..	('GAS5', 'Gene', (129, 133))	('osteosarcoma', 'Phenotype', 'HP:0002669', (25, 37))	('GAS', 'molecular_function', 'GO:0034005', ('129', '132'))	('osteosarcoma', 'Disease', (25, 37))	('osteosarcoma', 'Disease', 'MESH:D012516', (25, 37))	('rs145204276', 'Var', (134, 145))	('lower', 'NegReg', (90, 95))	('rs145204276', 'Mutation', 'rs145204276', (134, 145))	('patients', 'Species', '9606', (38, 46))
13714	32547314	Patients with Del/Del exhibited significantly elevated expression of GAS5 as compared to those with Ins/Ins.	('Del/Del', 'Var', (14, 21))	('elevated', 'PosReg', (46, 54))	('expression', 'MPA', (55, 65))	('GAS5', 'Protein', (69, 73))	('Patients', 'Species', '9606', (0, 8))	('GAS', 'molecular_function', 'GO:0034005', ('69', '72'))
13715	32547314	GAS5 rs145204276 is located at promoter area and may modulate GAS5 expression by affecting methylation status at the 7th CpG site.	('rs145204276', 'Var', (5, 16))	('affecting', 'Reg', (81, 90))	('methylation status', 'MPA', (91, 109))	('modulate', 'Reg', (53, 61))	('GAS5', 'Gene', (0, 4))	('rs145204276', 'Mutation', 'rs145204276', (5, 16))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('expression', 'MPA', (67, 77))	('GAS5', 'Gene', (62, 66))	('GAS', 'molecular_function', 'GO:0034005', ('0', '3'))	('GAS', 'molecular_function', 'GO:0034005', ('62', '65'))
13717	32547314	It was also revealed that the rate of genotype Del/Del in GAS5 rs145204276 was statistically lower in patients with gastric cancer than in the controls by Li et al..	('rs145204276', 'Mutation', 'rs145204276', (63, 74))	('GAS', 'molecular_function', 'GO:0034005', ('58', '61'))	('patients', 'Species', '9606', (102, 110))	('gastric cancer', 'Disease', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lower', 'NegReg', (93, 98))	('rs145204276', 'Var', (63, 74))	('gastric cancer', 'Disease', 'MESH:D013274', (116, 130))	('GAS5', 'Gene', (58, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (116, 130))
13718	32547314	They demonstrated if gastric cancer patients had allele deletion they displayed higher GAS5 expression in their cancer tissue samples.	('gastric cancer', 'Phenotype', 'HP:0012126', (21, 35))	('cancer', 'Disease', (29, 35))	('patients', 'Species', '9606', (36, 44))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('GAS5', 'Protein', (87, 91))	('allele deletion', 'Var', (49, 64))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('GAS', 'molecular_function', 'GO:0034005', ('87', '90'))	('gastric cancer', 'Disease', (21, 35))	('gastric cancer', 'Disease', 'MESH:D013274', (21, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('higher', 'PosReg', (80, 86))
13719	32547314	They further found that patients with Del/Del exhibited higher methylation percentage in the 7th CpG.	('methylation percentage', 'MPA', (63, 85))	('methylation', 'biological_process', 'GO:0032259', ('63', '74'))	('patients', 'Species', '9606', (24, 32))	('higher', 'PosReg', (56, 62))	('Del/Del', 'Var', (38, 45))
13721	32547314	demonstrated that deletion allele in GAS5 rs145204276 might protect against the susceptibility to breast cancer via the induction of promoter activity by binding to transcriptional factor specificity protein 1, and subsequently led to elevated GAS5 expression.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('binding', 'Interaction', (154, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('specificity protein 1', 'Gene', '6667', (188, 209))	('GAS5', 'Gene', (37, 41))	('breast cancer', 'Disease', (98, 111))	('specificity protein 1', 'Gene', (188, 209))	('rs145204276', 'Mutation', 'rs145204276', (42, 53))	('GAS', 'molecular_function', 'GO:0034005', ('244', '247'))	('elevated', 'PosReg', (235, 243))	('GAS', 'molecular_function', 'GO:0034005', ('37', '40'))	('promoter activity', 'MPA', (133, 150))	('binding', 'molecular_function', 'GO:0005488', ('154', '161'))	('protein', 'cellular_component', 'GO:0003675', ('200', '207'))	('GAS5 expression', 'MPA', (244, 259))	('rs145204276', 'Var', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('deletion', 'Var', (18, 26))
13722	32547314	revealed that both the genotypes Ins/Del and Del/Del exhibited reduced susceptibility to colorectal cancer.	('Del/Del', 'Var', (45, 52))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('reduced', 'NegReg', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Disease', (89, 106))	('Ins/Del', 'Var', (33, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))
13723	32547314	demonstrated that the allele deletion in rs145204276, which is 5-bp indel polymorphism shown as -/AGGCA as well as -/- and is situated at the promoter area, is correlated with methylation, and then exhibited higher GAS5 expression in hepatocellular carcinoma (HCC).	('GAS5 expression', 'MPA', (215, 230))	('higher', 'PosReg', (208, 214))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (234, 258))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (234, 258))	('hepatocellular carcinoma', 'Disease', (234, 258))	('rs145204276', 'Var', (41, 52))	('correlated', 'Reg', (160, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('methylation', 'MPA', (176, 187))	('HCC', 'Phenotype', 'HP:0001402', (260, 263))	('methylation', 'biological_process', 'GO:0032259', ('176', '187'))	('GAS', 'molecular_function', 'GO:0034005', ('215', '218'))	('rs145204276', 'Mutation', 'rs145204276', (41, 52))
13724	32547314	Elevated GAS5 might present as a proto-oncogene in HCC, in contrast with its inhibitory role in other cancers, and subsequently could elevate the susceptibility to HCC.	('HCC', 'Phenotype', 'HP:0001402', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('GAS', 'molecular_function', 'GO:0034005', ('9', '12'))	('HCC', 'Disease', (164, 167))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('HCC', 'Disease', (51, 54))	('cancers', 'Disease', (102, 109))	('elevate', 'Reg', (134, 141))	('HCC', 'Phenotype', 'HP:0001402', (164, 167))	('Elevated', 'Var', (0, 8))	('GAS5', 'Gene', (9, 13))
13725	32547314	Thereafter, we investigated the associations of GAS5 genetic variants with various clinicopathological factors of uterine cervical cancer.	('associations', 'Interaction', (32, 44))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cervical cancer', 'Disease', 'MESH:D002583', (122, 137))	('cervical cancer', 'Disease', (122, 137))	('GAS5', 'Gene', (48, 52))	('investigated', 'Reg', (15, 27))	('variants', 'Var', (61, 69))	('GAS', 'molecular_function', 'GO:0034005', ('48', '51'))
13726	32547314	The statistical analysis could not reveal significant association among GAS5 polymorphisms rs145204276 and rs55829688 and these parameters.	('rs55829688', 'Var', (107, 117))	('rs145204276', 'Var', (91, 102))	('rs145204276', 'Mutation', 'rs145204276', (91, 102))	('GAS', 'molecular_function', 'GO:0034005', ('72', '75'))	('GAS5', 'Gene', (72, 76))	('rs55829688', 'Mutation', 'rs55829688', (107, 117))
13727	32547314	As we know, no study reported the association of GAS5 genetic variants with clinicopathological factors of cervical cancer in Taiwan.	('cervical cancer', 'Disease', (107, 122))	('genetic variants', 'Var', (54, 70))	('association', 'Interaction', (34, 45))	('GAS', 'molecular_function', 'GO:0034005', ('49', '52'))	('GAS5', 'Gene', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cervical cancer', 'Disease', 'MESH:D002583', (107, 122))
13728	32547314	When the distributions of GAS5 genetic polymorphism were analyzed among all cancer stage subdivisions (stage I, II, III and IV) in patients with uterine cervical cancer, we found that patients with genotype TC or TC/CC in GAS5 rs55829688 have more risk to have stage II or stage III using TT as a reference.	('GAS', 'molecular_function', 'GO:0034005', ('222', '225'))	('TC', 'Chemical', 'MESH:D013667', (207, 209))	('cancer', 'Disease', (162, 168))	('TC', 'Chemical', 'MESH:D013667', (213, 215))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('stage II', 'Disease', (261, 269))	('rs55829688', 'Mutation', 'rs55829688', (227, 237))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('stage III', 'Disease', (273, 282))	('rs55829688', 'Var', (227, 237))	('GAS', 'molecular_function', 'GO:0034005', ('26', '29'))	('patients', 'Species', '9606', (131, 139))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('GAS5', 'Gene', (222, 226))	('cancer', 'Disease', (76, 82))	('cervical cancer', 'Disease', 'MESH:D002583', (153, 168))	('cervical cancer', 'Disease', (153, 168))	('patients', 'Species', '9606', (184, 192))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('TC/CC', 'Var', (213, 218))
13732	32547314	revealed that gastric cancer patients with late tumor stage were found to exhibit a significantly lower rate of Del/Del in GAS5 rs145204276 than those with early tumor stage.	('tumor', 'Disease', (162, 167))	('gastric cancer', 'Phenotype', 'HP:0012126', (14, 28))	('Del/Del', 'Var', (112, 119))	('late tumor', 'Disease', 'MESH:D009369', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('lower', 'NegReg', (98, 103))	('patients', 'Species', '9606', (29, 37))	('rs145204276', 'Var', (128, 139))	('gastric cancer', 'Disease', (14, 28))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (48, 53))	('late tumor', 'Disease', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('GAS', 'molecular_function', 'GO:0034005', ('123', '126'))	('gastric cancer', 'Disease', 'MESH:D013274', (14, 28))	('rs145204276', 'Mutation', 'rs145204276', (128, 139))	('GAS5', 'Gene', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
13733	32547314	revealed that colorectal cancer patients with allele deletion in GAS5 rs145204276 had less risk to develop lymph node metastasis.	('patients', 'Species', '9606', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('GAS', 'molecular_function', 'GO:0034005', ('65', '68'))	('colorectal cancer', 'Phenotype', 'HP:0003003', (14, 31))	('GAS5', 'Gene', (65, 69))	('colorectal cancer', 'Disease', (14, 31))	('rs145204276', 'Var', (70, 81))	('colorectal cancer', 'Disease', 'MESH:D015179', (14, 31))	('rs145204276', 'Mutation', 'rs145204276', (70, 81))
13734	32547314	This study revealed that cervical patients with Ins/Del and Del/Del in rs145204276 tended to have poorer 5 years survival HR, compared to those with Ins/Ins after adjusting GAS5 polymorphisms and various clinicopathological factors.	('cervical', 'Disease', (25, 33))	('poorer', 'NegReg', (98, 104))	('Ins/Del', 'Var', (48, 55))	('rs145204276', 'Gene', (71, 82))	('rs145204276', 'Mutation', 'rs145204276', (71, 82))	('GAS', 'molecular_function', 'GO:0034005', ('173', '176'))	('Del/Del', 'Var', (60, 67))	('patients', 'Species', '9606', (34, 42))	('5 years survival HR', 'CPA', (105, 124))
13736	32547314	It was however revealed that gastric cancer patients with genotype Del/Del had displayed better overall survival rate.	('better', 'PosReg', (89, 95))	('patients', 'Species', '9606', (44, 52))	('gastric cancer', 'Disease', (29, 43))	('overall survival rate', 'CPA', (96, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (29, 43))	('Del/Del', 'Var', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('gastric cancer', 'Phenotype', 'HP:0012126', (29, 43))
13738	32547314	This proposed that allele deletion in GAS5 rs145204276 exerted a protective action in patients with gastric cancer through the modulation of GAS5 transcript.	('gastric cancer', 'Disease', 'MESH:D013274', (100, 114))	('rs145204276', 'Var', (43, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (100, 114))	('protective action', 'CPA', (65, 82))	('GAS5', 'Gene', (38, 42))	('GAS', 'molecular_function', 'GO:0034005', ('38', '41'))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('modulation', 'Reg', (127, 137))	('GAS5', 'Protein', (141, 145))	('rs145204276', 'Mutation', 'rs145204276', (43, 54))	('GAS', 'molecular_function', 'GO:0034005', ('141', '144'))	('gastric cancer', 'Disease', (100, 114))	('patients', 'Species', '9606', (86, 94))
13742	32547314	Therefore, statistical analysis of the implication of GAS5 polymorphism in patient survival was not significant enough to draw a definite association.	('polymorphism', 'Var', (59, 71))	('GAS', 'molecular_function', 'GO:0034005', ('54', '57'))	('patient', 'Species', '9606', (75, 82))	('GAS5', 'Gene', (54, 58))
13743	32547314	Concerned with the relationships of allele deletion in GAS5 rs145204276 with cancer development and progression, there were diverse results in previous studies.	('rs145204276', 'Var', (60, 71))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('GAS', 'molecular_function', 'GO:0034005', ('55', '58'))	('GAS5', 'Gene', (55, 59))	('rs145204276', 'Mutation', 'rs145204276', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
13744	32547314	The mechanism delineating the impact of rs145204276 on methylation status of the GAS5 promoter and transcription activity as well as subsequent GAS5 expression needs further investigation to clarify the exact role of GAS5 polymorphisms in uterine cervical cancer.	('GAS', 'molecular_function', 'GO:0034005', ('81', '84'))	('GAS', 'molecular_function', 'GO:0034005', ('144', '147'))	('rs145204276', 'Mutation', 'rs145204276', (40, 51))	('transcription', 'biological_process', 'GO:0006351', ('99', '112'))	('cervical cancer', 'Disease', 'MESH:D002583', (247, 262))	('cervical cancer', 'Disease', (247, 262))	('GAS', 'molecular_function', 'GO:0034005', ('217', '220'))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('rs145204276', 'Var', (40, 51))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))
13745	32547314	In conclusion, patients with precancerous lesion of uterine cervix exhibited lower rate of Del/Del in GAS5 rs145204276 but those with invasive cancer could not present the finding.	('lower', 'NegReg', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('patients', 'Species', '9606', (15, 23))	('precancerous lesion', 'Disease', (29, 48))	('invasive cancer', 'Disease', (134, 149))	('GAS5', 'Gene', (102, 106))	('rs145204276', 'Mutation', 'rs145204276', (107, 118))	('Del/Del', 'Var', (91, 98))	('precancerous lesion', 'Disease', 'MESH:D011230', (29, 48))	('invasive cancer', 'Disease', 'MESH:D009362', (134, 149))	('GAS', 'molecular_function', 'GO:0034005', ('102', '105'))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('rs145204276', 'Var', (107, 118))	('uterine cervix', 'Phenotype', 'HP:0030160', (52, 66))
13746	32547314	Cervical cancer patients with allele deletion in rs145204276 had the tendency to present poorer HR of 5 years survival rate.	('cancer', 'Disease', (9, 15))	('rs145204276', 'Mutation', 'rs145204276', (49, 60))	('poorer', 'NegReg', (89, 95))	('patients', 'Species', '9606', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('rs145204276', 'Var', (49, 60))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
13747	32547314	There were no associations of GAS5 rs55829688 with development of cervical cancer and patient survival.	('rs55829688', 'Var', (35, 45))	('associations', 'Interaction', (14, 26))	('GAS5', 'Gene', (30, 34))	('patient', 'Species', '9606', (86, 93))	('cervical cancer', 'Disease', (66, 81))	('cervical cancer', 'Disease', 'MESH:D002583', (66, 81))	('GAS', 'molecular_function', 'GO:0034005', ('30', '33'))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('rs55829688', 'Mutation', 'rs55829688', (35, 45))
13748	32547314	However, mechanism delineating the influence of allele deletion in rs145204276 on GAS5 promoter methylation and thereafter on transcription action as well as subsequent GAS5 expression needs further investigation to elucidate the exact role of GAS5 genetic variant in uterine cervical cancer in the near future.	('cervical cancer', 'Disease', (276, 291))	('cervical cancer', 'Disease', 'MESH:D002583', (276, 291))	('GAS', 'molecular_function', 'GO:0034005', ('82', '85'))	('GAS', 'molecular_function', 'GO:0034005', ('244', '247'))	('GAS', 'molecular_function', 'GO:0034005', ('169', '172'))	('transcription', 'biological_process', 'GO:0006351', ('126', '139'))	('rs145204276', 'Mutation', 'rs145204276', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('GAS5', 'Gene', (244, 248))	('methylation', 'biological_process', 'GO:0032259', ('96', '107'))	('rs145204276', 'Var', (67, 78))
13770	32268297	The dysregulated expression of MAZ was recently associated with malignant tumors, such as breast cancer, thyroid cancer, hepatocellular carcinoma and urothelial carcinoma.	('associated', 'Reg', (48, 58))	('urothelial carcinoma', 'Disease', (150, 170))	('hepatocellular carcinoma', 'Disease', (121, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('dysregulated', 'Var', (4, 16))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('expression', 'MPA', (17, 27))	('thyroid cancer', 'Disease', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (121, 145))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('thyroid cancer', 'Disease', 'MESH:D013964', (105, 119))	('malignant tumors', 'Disease', (64, 80))	('expression', 'Species', '29278', (17, 27))	('MAZ', 'Gene', (31, 34))	('malignant tumors', 'Disease', 'MESH:D009369', (64, 80))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (121, 145))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('breast cancer', 'Disease', (90, 103))	('thyroid cancer', 'Phenotype', 'HP:0002890', (105, 119))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (150, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))
13783	32268297	To further determine the role of FOXK1 in GC tissues, we assessed whether the silencing of FOXK1 inhibits the lung partialization of diffuse GC cells in vivo and established a mouse tumor model via tail vein injection.	('GC', 'Phenotype', 'HP:0012126', (42, 44))	('lung partialization of', 'CPA', (110, 132))	('tumor', 'Disease', (182, 187))	('inhibits', 'NegReg', (97, 105))	('mouse', 'Species', '10090', (176, 181))	('GC', 'Phenotype', 'HP:0012126', (141, 143))	('silencing', 'Var', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('FOXK1', 'Gene', (91, 96))
13790	32268297	In addition, IHC measurements of these metastatic nodules excised from the two groups of mice showed that the silencing of FOXK1 increased the expression of LC3-II and E-cadherin and decreased the expression of P62 and MMP9 compared with the expression levels observed in the control nodules (Figure 2E).	('expression', 'Species', '29278', (143, 153))	('MMP9', 'Protein', (219, 223))	('expression', 'Species', '29278', (197, 207))	('MMP9', 'molecular_function', 'GO:0004229', ('219', '223'))	('FOXK1', 'Gene', (123, 128))	('silencing', 'Var', (110, 119))	('P62', 'Gene', (211, 214))	('increased', 'PosReg', (129, 138))	('decreased', 'NegReg', (183, 192))	('expression', 'Species', '29278', (242, 252))	('LC3-II', 'Protein', (157, 163))	('expression', 'MPA', (143, 153))	('E-cadherin', 'Gene', (168, 178))	('E-cadherin', 'Gene', '999', (168, 178))	('expression', 'MPA', (197, 207))	('LC3-II', 'Chemical', '-', (157, 163))	('mice', 'Species', '10090', (89, 93))	('cadherin', 'molecular_function', 'GO:0008014', ('170', '178'))	('P62', 'Gene', '23636', (211, 214))
13791	32268297	Furthermore, we orthotopically transplanted MGC803 cells infected with LV-ctrl, LV-shFOXK1-1 and shFOXK1-2 into the gastric wall of nude mice.	('nude mice', 'Species', '10090', (132, 141))	('MGC803', 'CellLine', 'CVCL:5334', (44, 50))	('LV-ctrl', 'Var', (71, 78))	('infected', 'Disease', (57, 65))	('GC', 'Phenotype', 'HP:0012126', (45, 47))	('infected', 'Disease', 'MESH:D007239', (57, 65))
13792	32268297	Twenty-eight days after orthotopic transplantation, we found that the inhibition of FOXK1 reduced the number of metastases and tumor weight in the gastric wall (Figure 2F-2H).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('reduced', 'NegReg', (90, 97))	('tumor', 'Disease', (127, 132))	('metastases', 'Disease', (112, 122))	('inhibition', 'Var', (70, 80))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('FOXK1', 'Gene', (84, 89))
13793	32268297	The inhibition of FOXK1 has also been shown to decrease the number of diffuse liver metastases (Figure 2I, 2J).	('liver metastases', 'Disease', 'MESH:D009362', (78, 94))	('FOXK1', 'Gene', (18, 23))	('decrease', 'NegReg', (47, 55))	('inhibition', 'Var', (4, 14))	('liver metastases', 'Disease', (78, 94))
13794	32268297	As shown in Supplementary Figure 3, compared with the control group, the inhibition of FOXK1 in a normal environment resulted in increased LC3-II expression and decreased P62 expression, which indicated that the inhibition of FOXK1 under normal conditions can induce autophagy.	('P62', 'Gene', '23636', (171, 174))	('decreased', 'NegReg', (161, 170))	('FOXK1', 'Gene', (226, 231))	('expression', 'MPA', (146, 156))	('expression', 'MPA', (175, 185))	('increased', 'PosReg', (129, 138))	('autophagy', 'CPA', (267, 276))	('P62', 'Gene', (171, 174))	('autophagy', 'biological_process', 'GO:0016236', ('267', '276'))	('inhibition', 'Var', (73, 83))	('LC3-II', 'Protein', (139, 145))	('FOXK1', 'Gene', (87, 92))	('expression', 'Species', '29278', (146, 156))	('induce', 'Reg', (260, 266))	('expression', 'Species', '29278', (175, 185))	('autophagy', 'biological_process', 'GO:0006914', ('267', '276'))	('inhibition', 'Var', (212, 222))	('LC3-II', 'Chemical', '-', (139, 145))	('increased LC3', 'Phenotype', 'HP:0003141', (129, 142))
13795	32268297	In addition, the inhibition of FOXK1 under normal circumstances can increase the expression level of E-cadherin and suppress the expression of N-cadherin and Vimentin compared with that found in the control group.	('expression', 'Species', '29278', (129, 139))	('cadherin', 'molecular_function', 'GO:0008014', ('103', '111'))	('E-cadherin', 'Gene', (101, 111))	('Vimentin', 'cellular_component', 'GO:0045098', ('158', '166'))	('expression', 'MPA', (129, 139))	('Vimentin', 'Protein', (158, 166))	('expression level', 'MPA', (81, 97))	('E-cadherin', 'Gene', '999', (101, 111))	('inhibition', 'Var', (17, 27))	('Vimentin', 'cellular_component', 'GO:0045099', ('158', '166'))	('cadherin', 'molecular_function', 'GO:0008014', ('145', '153'))	('increase', 'PosReg', (68, 76))	('FOXK1', 'Gene', (31, 36))	('suppress', 'NegReg', (116, 124))	('expression', 'Species', '29278', (81, 91))
13798	32268297	Further transwell experiments confirmed that FOXK1 inhibition effectively reduced the invasion of MGC803 and AGS cells under both Matrigel and Matrigel-free conditions (Figure 3B, 3C).	('MGC803', 'CellLine', 'CVCL:5334', (98, 104))	('MGC803', 'Gene', (98, 104))	('FOXK1', 'Gene', (45, 50))	('AGS cells', 'CPA', (109, 118))	('inhibition', 'Var', (51, 61))	('GC', 'Phenotype', 'HP:0012126', (99, 101))	('reduced', 'NegReg', (74, 81))	('invasion', 'CPA', (86, 94))
13801	32268297	As shown in Figure 4A, the MGC803 cells belonging to the control group and transfected with mRFP-GFP-LC3 exhibited the basal levels of autophagy, and the knockout of FOXK1 expression significantly increased the number of red-only LC3 puncta, which indicates an increase in autophagic flux (Figure 4A, 4B).	('LC3', 'Gene', '84557', (230, 233))	('LC3', 'Gene', (230, 233))	('GC', 'Phenotype', 'HP:0012126', (28, 30))	('expression', 'Species', '29278', (172, 182))	('autophagy', 'biological_process', 'GO:0016236', ('135', '144'))	('autophagic flux', 'CPA', (273, 288))	('LC3', 'Gene', '84557', (101, 104))	('knockout', 'Var', (154, 162))	('increased', 'PosReg', (197, 206))	('FOXK1', 'Gene', (166, 171))	('MGC803', 'CellLine', 'CVCL:5334', (27, 33))	('autophagy', 'biological_process', 'GO:0006914', ('135', '144'))	('LC3', 'Gene', (101, 104))	('increase', 'PosReg', (261, 269))
13802	32268297	By transmission electron microscopy, we found that autophagosomes infected with shFOXK1-1 and shFOXK1-2 were significantly more autophagic than those belonging to the control group (Figure 4C, 4D).	('autophagic', 'CPA', (128, 138))	('more', 'PosReg', (123, 127))	('shFOXK1-1', 'Var', (80, 89))	('autophagosomes', 'CPA', (51, 65))	('infected', 'Disease', 'MESH:D007239', (66, 74))	('shFOXK1-2', 'Var', (94, 103))	('infected', 'Disease', (66, 74))
13803	32268297	Western blotting further confirmed that the silencing of FOXK1 in MGC803 and AGS cells increased the levels of LC3-II and Beclin1 proteins and decreased the levels of P62 proteins (Figure 4E).	('increased', 'PosReg', (87, 96))	('levels of LC3-II', 'MPA', (101, 117))	('Beclin1', 'Gene', (122, 129))	('decreased', 'NegReg', (143, 152))	('P62', 'Gene', '23636', (167, 170))	('LC3-II', 'Chemical', '-', (111, 117))	('MGC803', 'CellLine', 'CVCL:5334', (66, 72))	('P62', 'Gene', (167, 170))	('GC', 'Phenotype', 'HP:0012126', (67, 69))	('Beclin1', 'Gene', '8678', (122, 129))	('silencing', 'Var', (44, 53))	('FOXK1', 'Gene', (57, 62))
13806	32268297	In addition, cell scratch and transwell experiments confirmed that the inhibition of autophagy by 3-MA antagonized the inhibitory effect of the knockout of FOXK1 on the migration and invasion of GC cells (Figure 4F-4H).	('FOXK1', 'Gene', (156, 161))	('autophagy', 'biological_process', 'GO:0016236', ('85', '94'))	('migration', 'CPA', (169, 178))	('autophagy', 'biological_process', 'GO:0006914', ('85', '94'))	('inhibition', 'NegReg', (71, 81))	('knockout', 'Var', (144, 152))	('3-MA', 'Chemical', 'MESH:C025946', (98, 102))	('invasion', 'CPA', (183, 191))	('GC', 'Phenotype', 'HP:0012126', (195, 197))	('autophagy', 'CPA', (85, 94))
13808	32268297	Together, these results indicate that the inhibition of FOXK1 expression induces autophagy to inhibit migration and invasion.	('autophagy', 'biological_process', 'GO:0016236', ('81', '90'))	('expression', 'Species', '29278', (62, 72))	('inhibition', 'Var', (42, 52))	('FOXK1', 'Gene', (56, 61))	('autophagy', 'biological_process', 'GO:0006914', ('81', '90'))	('induces', 'Reg', (73, 80))	('autophagy', 'CPA', (81, 90))	('inhibit', 'NegReg', (94, 101))
13817	32268297	Western blotting assays showed that the knockdown of MAZ significantly increased the expression level of LC3-II and decreased the expression level of P62 (Figure 6B).	('P62', 'Gene', '23636', (150, 153))	('knockdown', 'Var', (40, 49))	('P62', 'Gene', (150, 153))	('increased', 'PosReg', (71, 80))	('expression', 'Species', '29278', (85, 95))	('LC3-II', 'Protein', (105, 111))	('expression level', 'MPA', (85, 101))	('MAZ', 'Gene', (53, 56))	('expression', 'Species', '29278', (130, 140))	('decreased', 'NegReg', (116, 125))	('LC3-II', 'Chemical', '-', (105, 111))
13821	32268297	Increasing the expression of MAZ eliminated the sudden increase in red-only LC3 puncta caused by FOXK1 knockdown (Supplementary Figure 4B), which demonstrates that the knockout of FOXK1 induces autophagy and suppresses EMT, at least in part by downregulating MAZ.	('EMT', 'biological_process', 'GO:0001837', ('219', '222'))	('suppresses', 'NegReg', (208, 218))	('EMT', 'CPA', (219, 222))	('downregulating', 'NegReg', (244, 258))	('autophagy', 'biological_process', 'GO:0016236', ('194', '203'))	('expression', 'Species', '29278', (15, 25))	('autophagy', 'biological_process', 'GO:0006914', ('194', '203'))	('LC3', 'Gene', '84557', (76, 79))	('autophagy', 'CPA', (194, 203))	('FOXK1', 'Gene', (180, 185))	('induces', 'PosReg', (186, 193))	('MAZ', 'MPA', (259, 262))	('FOXK1', 'Gene', (97, 102))	('LC3', 'Gene', (76, 79))	('knockout', 'Var', (168, 176))
13822	32268297	As expected, the stable knockdown of FOXK1 increased the E-cadherin protein levels and significantly reduced the expression of N-cadherin and Vimentin (Figure 6G).	('expression', 'MPA', (113, 123))	('Vimentin', 'cellular_component', 'GO:0045098', ('142', '150'))	('E-cadherin', 'Gene', (57, 67))	('E-cadherin', 'Gene', '999', (57, 67))	('cadherin', 'molecular_function', 'GO:0008014', ('129', '137'))	('Vimentin', 'Protein', (142, 150))	('N-cadherin', 'Protein', (127, 137))	('reduced', 'NegReg', (101, 108))	('expression', 'Species', '29278', (113, 123))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('increased', 'PosReg', (43, 52))	('cadherin', 'molecular_function', 'GO:0008014', ('59', '67'))	('Vimentin', 'cellular_component', 'GO:0045099', ('142', '150'))	('knockdown', 'Var', (24, 33))	('FOXK1', 'Gene', (37, 42))
13827	32268297	As shown in Figure 7A, treatment with rapamycin or the silencing of FOXK1 resulted in a significant increase in the number of red-only LC3 puncta compared with that of the control group, and their combination exerted a synergistic effect (Figure 7A, 7B).	('FOXK1', 'Gene', (68, 73))	('silencing', 'Var', (55, 64))	('LC3', 'Gene', '84557', (135, 138))	('rapamycin', 'Chemical', 'MESH:D020123', (38, 47))	('LC3', 'Gene', (135, 138))	('increase', 'PosReg', (100, 108))
13839	32268297	Our results indicate that the inhibition of FOXK1 increases E-cadherin expression, reduces N-cadherin and Vimentin expression in an acidic microenvironment and also decrease the expression levels of MMP9.	('cadherin', 'molecular_function', 'GO:0008014', ('62', '70'))	('reduces', 'NegReg', (83, 90))	('decrease', 'NegReg', (165, 173))	('Vimentin', 'cellular_component', 'GO:0045098', ('106', '114'))	('increases', 'PosReg', (50, 59))	('FOXK1', 'Gene', (44, 49))	('E-cadherin', 'Gene', (60, 70))	('E-cadherin', 'Gene', '999', (60, 70))	('expression', 'Species', '29278', (115, 125))	('cadherin', 'molecular_function', 'GO:0008014', ('93', '101'))	('expression', 'MPA', (71, 81))	('Vimentin', 'Protein', (106, 114))	('expression', 'Species', '29278', (178, 188))	('Vimentin', 'cellular_component', 'GO:0045099', ('106', '114'))	('MMP9', 'molecular_function', 'GO:0004229', ('199', '203'))	('expression levels', 'MPA', (178, 195))	('N-cadherin', 'Protein', (91, 101))	('inhibition', 'Var', (30, 40))	('expression', 'MPA', (115, 125))	('expression', 'Species', '29278', (71, 81))
13840	32268297	Previous studies have also revealed that the coexpression of FOXK1 and Vimentin can upregulate Snail to promote EMT in GC and thereby promotes the metastasis of GC cells in vitro and in vivo.	('FOXK1', 'Gene', (61, 66))	('GC', 'Phenotype', 'HP:0012126', (119, 121))	('upregulate', 'PosReg', (84, 94))	('Vimentin', 'cellular_component', 'GO:0045098', ('71', '79'))	('EMT in GC', 'CPA', (112, 121))	('GC', 'Phenotype', 'HP:0012126', (161, 163))	('promotes', 'PosReg', (134, 142))	('Vimentin', 'cellular_component', 'GO:0045099', ('71', '79'))	('Snail', 'MPA', (95, 100))	('promote', 'PosReg', (104, 111))	('coexpression', 'Var', (45, 57))	('expression', 'Species', '29278', (47, 57))	('EMT', 'biological_process', 'GO:0001837', ('112', '115'))	('metastasis', 'CPA', (147, 157))
13842	32268297	The silencing of FOXK1 promoted the conversion of LC3-I to LC3-II and increased the expression of E-cadherin, which indicated that the inhibition of FOXK1 induces autophagy and inhibits EMT in acidic GC.	('EMT in acidic GC', 'CPA', (186, 202))	('increased', 'PosReg', (70, 79))	('LC3', 'Gene', '84557', (59, 62))	('autophagy', 'biological_process', 'GO:0016236', ('163', '172'))	('LC3-II', 'Chemical', '-', (59, 65))	('conversion', 'MPA', (36, 46))	('expression', 'Species', '29278', (84, 94))	('LC3', 'Gene', '84557', (50, 53))	('promoted', 'PosReg', (23, 31))	('E-cadherin', 'Gene', (98, 108))	('E-cadherin', 'Gene', '999', (98, 108))	('autophagy', 'biological_process', 'GO:0006914', ('163', '172'))	('inhibition', 'Var', (135, 145))	('silencing', 'Var', (4, 13))	('induces', 'PosReg', (155, 162))	('cadherin', 'molecular_function', 'GO:0008014', ('100', '108'))	('LC3', 'Gene', (59, 62))	('FOXK1', 'Gene', (17, 22))	('autophagy', 'CPA', (163, 172))	('expression', 'MPA', (84, 94))	('LC3', 'Gene', (50, 53))	('EMT', 'biological_process', 'GO:0001837', ('186', '189'))	('GC', 'Phenotype', 'HP:0012126', (200, 202))	('inhibits', 'NegReg', (177, 185))	('FOXK1', 'Gene', (149, 154))
13843	32268297	Interestingly, the inhibition of 3-MA-mediated autophagy significantly antagonized the inhibitory effect of the silencing of FOXK1 on acidic GC cell migration and invasion and extensively inhibited silent FOXK1-mediated EMT.	('EMT', 'biological_process', 'GO:0001837', ('220', '223'))	('acidic GC cell migration', 'CPA', (134, 158))	('GC', 'Phenotype', 'HP:0012126', (141, 143))	('inhibited', 'NegReg', (188, 197))	('inhibition', 'NegReg', (19, 29))	('autophagy', 'biological_process', 'GO:0016236', ('47', '56'))	('3-MA-mediated', 'Protein', (33, 46))	('FOXK1', 'Gene', (125, 130))	('antagonized', 'NegReg', (71, 82))	('silencing', 'Var', (112, 121))	('3-MA', 'Chemical', 'MESH:C025946', (33, 37))	('autophagy', 'biological_process', 'GO:0006914', ('47', '56'))	('cell migration', 'biological_process', 'GO:0016477', ('144', '158'))	('invasion', 'CPA', (163, 171))
13846	32268297	Interestingly, the overexpression of MAZ partially eliminated the induction of autophagy by FOXK1 knockdown in acidic GC cells.	('FOXK1', 'Gene', (92, 97))	('autophagy', 'CPA', (79, 88))	('knockdown', 'Var', (98, 107))	('autophagy', 'biological_process', 'GO:0016236', ('79', '88'))	('GC', 'Phenotype', 'HP:0012126', (118, 120))	('eliminated', 'NegReg', (51, 61))	('autophagy', 'biological_process', 'GO:0006914', ('79', '88'))	('expression', 'Species', '29278', (23, 33))
13848	32268297	Our study found that the combination of mTOR inhibition with FOXK1 inhibition induces autophagy in an acidic environment and that this combination is more effective than the antimetastatic effects observed in cells treated with acidic GC alone.	('FOXK1', 'Gene', (61, 66))	('inhibition', 'NegReg', (67, 77))	('induces', 'Reg', (78, 85))	('autophagy', 'CPA', (86, 95))	('mTOR', 'Gene', (40, 44))	('autophagy', 'biological_process', 'GO:0016236', ('86', '95'))	('mTOR', 'Gene', '2475', (40, 44))	('inhibition', 'Var', (45, 55))	('GC', 'Phenotype', 'HP:0012126', (235, 237))	('autophagy', 'biological_process', 'GO:0006914', ('86', '95'))
13850	32268297	This result suggests that the targeting of mTOR and FOXK1 can prevent GC metastasis by reversing EMT.	('EMT', 'biological_process', 'GO:0001837', ('97', '100'))	('GC metastasis', 'Disease', (70, 83))	('GC', 'Phenotype', 'HP:0012126', (70, 72))	('EMT', 'CPA', (97, 100))	('targeting', 'Var', (30, 39))	('reversing', 'NegReg', (87, 96))	('prevent', 'NegReg', (62, 69))	('FOXK1', 'Gene', (52, 57))	('mTOR', 'Gene', (43, 47))	('mTOR', 'Gene', '2475', (43, 47))
13862	32268297	Autophagy double-labeled adenovirus (mRFP-GFP-LC3) was purchased from Hanbio Biotechnology Co., Ltd., and antibodies against E-cadherin (#14472), N-cadherin (#13116), Vimentin (#5741), LC3-I/II (#3868), beta-actin (#4970) and Beclin1 (#3495S) were purchased from Cell Signaling Technology (Beverly, MA, USA).	('E-cadherin', 'Gene', '999', (125, 135))	('Beclin1', 'Gene', (226, 233))	('Vimentin', 'cellular_component', 'GO:0045098', ('167', '175'))	('#4970', 'Var', (215, 220))	('LC3', 'Gene', (46, 49))	('Signaling', 'biological_process', 'GO:0023052', ('268', '277'))	('adenovirus', 'Species', '10508', (25, 35))	('LC3', 'Gene', '84557', (185, 188))	('Autophagy', 'biological_process', 'GO:0016236', ('0', '9'))	('#5741', 'Var', (177, 182))	('#3868', 'Var', (195, 200))	('#13116', 'Var', (158, 164))	('#14472', 'Var', (137, 143))	('LC3', 'Gene', '84557', (46, 49))	('cadherin', 'molecular_function', 'GO:0008014', ('127', '135'))	('Vimentin', 'cellular_component', 'GO:0045099', ('167', '175'))	('Beclin1', 'Gene', '8678', (226, 233))	('Autophagy', 'biological_process', 'GO:0006914', ('0', '9'))	('cadherin', 'molecular_function', 'GO:0008014', ('148', '156'))	('LC3', 'Gene', (185, 188))	('#3495S', 'Var', (235, 241))	('E-cadherin', 'Gene', (125, 135))
13908	30541591	GRINA knockdown decreased PI3K/Akt/mTOR signaling and glycolytic metabolism in gastric cancer cells.	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))	('Akt', 'Gene', (31, 34))	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('mTOR', 'Gene', (35, 39))	('mTOR', 'Gene', '2475', (35, 39))	('PI3K', 'molecular_function', 'GO:0016303', ('26', '30'))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('metabolism', 'biological_process', 'GO:0008152', ('65', '75'))	('Akt', 'Gene', '207', (31, 34))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('knockdown', 'Var', (6, 15))	('gastric cancer', 'Disease', (79, 93))	('glycolytic metabolism', 'MPA', (54, 75))	('decreased', 'NegReg', (16, 25))
13909	30541591	The apoptosis rate was significantly increased in gastric cancer cell lines after knockdown of GRINA.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('gastric cancer', 'Disease', (50, 64))	('apoptosis', 'biological_process', 'GO:0006915', ('4', '13'))	('knockdown', 'Var', (82, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (50, 64))	('apoptosis', 'biological_process', 'GO:0097194', ('4', '13'))	('increased', 'PosReg', (37, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (50, 64))	('apoptosis rate', 'CPA', (4, 18))
13920	30541591	In gastric cancer, copy number alteration (CNA) on Chromosome 8q24.3 is the main mechanism underlying tumorigenesis.	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('tumor', 'Disease', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('copy number alteration', 'Var', (19, 41))	('Chromosome', 'cellular_component', 'GO:0005694', ('51', '61'))	('gastric cancer', 'Disease', (3, 17))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
13922	30541591	Blockade of the NMDA receptor in breast cancer or small cell lung cancer can promote apoptosis of tumour cells, and NMDA receptor is also regarded as a potential therapeutic target in ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('NMDA receptor', 'molecular_function', 'GO:0004972', ('116', '129'))	('NMDA receptor', 'Gene', (16, 29))	('apoptosis', 'biological_process', 'GO:0097194', ('85', '94'))	('apoptosis', 'biological_process', 'GO:0006915', ('85', '94'))	('ovarian cancer', 'Disease', 'MESH:D010051', (184, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('NMDA', 'Chemical', 'MESH:D016202', (16, 20))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (50, 72))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ovarian cancer', 'Disease', (184, 198))	('promote', 'PosReg', (77, 84))	('NMDA', 'Chemical', 'MESH:D016202', (116, 120))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('Blockade', 'Var', (0, 8))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Disease', (98, 104))	('small cell lung cancer', 'Disease', (50, 72))	('ovarian cancer', 'Phenotype', 'HP:0100615', (184, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('small cell lung cancer', 'Disease', 'MESH:D055752', (50, 72))	('NMDA receptor', 'molecular_function', 'GO:0004972', ('16', '29'))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('breast cancer', 'Disease', (33, 46))
13923	30541591	In primary encephaloma, NMDA2B phosphorylation can prevent the epileptic seizures caused by tumours.	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('NMDA', 'Chemical', 'MESH:D016202', (24, 28))	('primary encephaloma', 'Disease', 'MESH:D009378', (3, 22))	('epileptic seizures', 'Disease', (63, 81))	('primary encephaloma', 'Disease', (3, 22))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('tumours', 'Disease', (92, 99))	('prevent', 'NegReg', (51, 58))	('epileptic seizures', 'Disease', 'MESH:D004827', (63, 81))	('NMDA2B', 'Gene', (24, 30))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('phosphorylation', 'Var', (31, 46))	('seizures', 'Phenotype', 'HP:0001250', (73, 81))	('phosphorylation', 'biological_process', 'GO:0016310', ('31', '46'))
13924	30541591	In gastric cancer, knockdown of NR2A, which also belongs to NMDA receptor family, induced cell cycle to arrest in the G1 phase and suppressed the proliferation of MKN45 cells.	('cell cycle to arrest in the G1 phase', 'CPA', (90, 126))	('NR2A', 'Gene', '2903', (32, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('proliferation', 'CPA', (146, 159))	('knockdown', 'Var', (19, 28))	('cell cycle', 'biological_process', 'GO:0007049', ('90', '100'))	('induced', 'Reg', (82, 89))	('G1 phase', 'biological_process', 'GO:0051318', ('118', '126'))	('suppressed', 'NegReg', (131, 141))	('gastric cancer', 'Disease', (3, 17))	('NMDA receptor', 'molecular_function', 'GO:0004972', ('60', '73'))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('NMDA', 'Chemical', 'MESH:D016202', (60, 64))	('NR2A', 'Gene', (32, 36))
13934	30541591	Early research demonstrated that GRINA knockdown in AGS and BGC-823 cell lines resulted in downregulation of Bcl-2 and Bcl-xl but upregulation of Bax and Bak, which suggest that GRINA could regulate gastric cancer cell apoptosis through Bcl-2 family members.	('Bcl-2', 'Gene', (237, 242))	('Bax', 'Gene', (146, 149))	('Bcl-xl', 'Gene', '598', (119, 125))	('Bcl-xl', 'Gene', (119, 125))	('Bax', 'Gene', '581', (146, 149))	('Bak', 'Gene', '578', (154, 157))	('gastric cancer', 'Disease', 'MESH:D013274', (199, 213))	('Bcl-2', 'Gene', (109, 114))	('Bcl-2', 'molecular_function', 'GO:0015283', ('109', '114'))	('Bcl-2', 'Gene', '596', (237, 242))	('Bcl-2', 'molecular_function', 'GO:0015283', ('237', '242'))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('apoptosis', 'biological_process', 'GO:0097194', ('219', '228'))	('apoptosis', 'biological_process', 'GO:0006915', ('219', '228'))	('AGS', 'Disease', (52, 55))	('Bcl-2', 'Gene', '596', (109, 114))	('gastric cancer', 'Phenotype', 'HP:0012126', (199, 213))	('downregulation', 'NegReg', (91, 105))	('Bak', 'Gene', (154, 157))	('AGS', 'Disease', 'MESH:C535607', (52, 55))	('knockdown', 'Var', (39, 48))	('gastric cancer', 'Disease', (199, 213))	('upregulation', 'PosReg', (130, 142))	('regulate', 'Reg', (190, 198))
13995	30541591	Analysis of 876 gastric cancer patients with 33 months of follow-up data in KMplotter database demonstrated that patients with high GRINA expression had worse overall survival (OS) than those with low GRINA expression (Additional file 10: Figure S2), suggesting that GRINA indicates poor prognosis in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('overall survival', 'MPA', (159, 175))	('gastric cancer', 'Disease', (16, 30))	('gastric cancer', 'Disease', (301, 315))	('patients', 'Species', '9606', (113, 121))	('high GRINA', 'Var', (127, 137))	('OS', 'Chemical', '-', (177, 179))	('gastric cancer', 'Disease', 'MESH:D013274', (16, 30))	('gastric cancer', 'Disease', 'MESH:D013274', (301, 315))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('patients', 'Species', '9606', (31, 39))	('worse', 'NegReg', (153, 158))	('gastric cancer', 'Phenotype', 'HP:0012126', (16, 30))	('gastric cancer', 'Phenotype', 'HP:0012126', (301, 315))
14009	30541591	After 4 weeks, we found that tumour weights and sizes were significantly smaller in the shRNA group than in the control group (P < 0.01) (Figs.	('tumour weights', 'Disease', 'MESH:D015431', (29, 43))	('tumour weights', 'Disease', (29, 43))	('smaller', 'NegReg', (73, 80))	('shRNA', 'Var', (88, 93))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))
14011	30541591	Instead, tumour weights and sizes were markedly larger in the GRINA-OE group than in the control group 4 weeks later (P < 0.01) (Figs.	('tumour weights', 'Disease', 'MESH:D015431', (9, 23))	('tumour weights', 'Disease', (9, 23))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('GRINA-OE', 'Var', (62, 70))	('larger', 'PosReg', (48, 54))
14013	30541591	In both AGS and BGC-823 cells, cell migration distances were shorter in the shRNA groups than that in the control groups.	('shorter', 'NegReg', (61, 68))	('cell migration', 'biological_process', 'GO:0016477', ('31', '45'))	('cell migration distances', 'CPA', (31, 55))	('shRNA', 'Var', (76, 81))	('AGS', 'Disease', (8, 11))	('AGS', 'Disease', 'MESH:C535607', (8, 11))
14014	30541591	Next, the results of transwell experiments showed that the number of migrated cells was significantly reduced after GRINA was knocked down in AGS and BGC-823 cell lines (Figs.	('AGS', 'Disease', 'MESH:C535607', (142, 145))	('GRINA', 'Gene', (116, 121))	('knocked down', 'Var', (126, 138))	('reduced', 'NegReg', (102, 109))	('AGS', 'Disease', (142, 145))
14028	30541591	S4A), which indicated a correlation between GRINA expression and enhanced glycolytic metabolism in gastric cancer.	('GRINA', 'Gene', (44, 49))	('glycolytic metabolism', 'MPA', (74, 95))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('gastric cancer', 'Disease', (99, 113))	('expression', 'Var', (50, 60))	('enhanced', 'PosReg', (65, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (99, 113))	('metabolism', 'biological_process', 'GO:0008152', ('85', '95'))	('gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))
14034	30541591	S4P); on the contrary, GRINA knockdown inhibited the phosphorylation of Akt and the downstream effectors of mTOR, P70S6K and 4EBP1, indicating that the mTOR pathway could be activated by GRINA (Fig.	('Akt', 'Gene', '207', (72, 75))	('mTOR', 'Gene', (108, 112))	('inhibited', 'NegReg', (39, 48))	('knockdown', 'Var', (29, 38))	('Akt', 'Gene', (72, 75))	('mTOR', 'Gene', (152, 156))	('mTOR', 'Gene', '2475', (108, 112))	('mTOR', 'Gene', '2475', (152, 156))	('P70S6K and 4EBP1', 'Gene', '6198', (114, 130))	('phosphorylation', 'MPA', (53, 68))	('phosphorylation', 'biological_process', 'GO:0016310', ('53', '68'))
14038	30541591	The percentages of apoptotic cells were obviously augmented in shRNA groups compared with those in control groups after cells were cultured in medium without foetal bovine serum (FBS) for 48 h (Figs 7A-7B).	('shRNA', 'Var', (63, 68))	('bovine', 'Species', '9913', (165, 171))	('FBS', 'Disease', 'MESH:D005198', (179, 182))	('augmented', 'PosReg', (50, 59))	('apoptotic cells', 'CPA', (19, 34))	('FBS', 'Disease', (179, 182))
14039	30541591	TUNEL staining also reaveled that mice tumor tissues in the shRNA group showed higher apoptosis rate than those in the control group (Fig.	('apoptosis', 'biological_process', 'GO:0097194', ('86', '95'))	('mice', 'Species', '10090', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('apoptosis', 'biological_process', 'GO:0006915', ('86', '95'))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('higher', 'PosReg', (79, 85))	('apoptosis rate', 'CPA', (86, 100))	('shRNA', 'Var', (60, 65))
14040	30541591	Then we assessed Bcl-2 and Bax expression after GIRNA knockdown in AGS and BGC-823 cells.	('Bcl-2', 'Gene', (17, 22))	('Bcl-2', 'Gene', '596', (17, 22))	('Bax', 'Gene', '581', (27, 30))	('knockdown', 'Var', (54, 63))	('AGS', 'Disease', 'MESH:C535607', (67, 70))	('Bcl-2', 'molecular_function', 'GO:0015283', ('17', '22'))	('Bax', 'Gene', (27, 30))	('AGS', 'Disease', (67, 70))
14050	30541591	Currently, it is widely recognized that activation of oncogenes and subsequent dysregulation of the related signalling pathways are the main causes of tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('oncogenes', 'Protein', (54, 63))	('tumor', 'Disease', (151, 156))	('causes', 'Reg', (141, 147))	('activation', 'PosReg', (40, 50))	('dysregulation', 'Var', (79, 92))	('signalling', 'biological_process', 'GO:0023052', ('108', '118'))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
14062	30541591	In the KM-plotter database we found that high GRINA expression indicated a poor prognosis in gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('high', 'Var', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gastric cancer', 'Disease', (93, 107))
14073	30541591	G1/S phase disruption was found to impact cell proliferation and resulted in carcinogenesis.	('S phase', 'biological_process', 'GO:0051320', ('3', '10'))	('carcinogenesis', 'Disease', 'MESH:D063646', (77, 91))	('carcinogenesis', 'Disease', (77, 91))	('cell proliferation', 'CPA', (42, 60))	('disruption', 'Var', (11, 21))	('resulted in', 'Reg', (65, 76))	('cell proliferation', 'biological_process', 'GO:0008283', ('42', '60'))	('impact', 'Reg', (35, 41))
14080	30541591	Mutation, overexpression, rearrangement, or translocation of c-Myc are closely related to hematopoietic tumours, including leukaemia, lymphoma, Burkitt's lymphoma, etc..	('rearrangement', 'Var', (26, 39))	('translocation', 'Var', (44, 57))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (144, 162))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (144, 162))	('hematopoietic tumours', 'Disease', 'MESH:D019337', (90, 111))	('Mutation', 'Var', (0, 8))	("Burkitt's lymphoma", 'Disease', (144, 162))	('lymphoma', 'Phenotype', 'HP:0002665', (154, 162))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('c-Myc', 'Gene', '4609', (61, 66))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('lymphoma', 'Phenotype', 'HP:0002665', (134, 142))	('leukaemia, lymphoma', 'Disease', 'MESH:D007938', (123, 142))	('overexpression', 'PosReg', (10, 24))	('related', 'Reg', (79, 86))	('hematopoietic tumours', 'Disease', (90, 111))	('c-Myc', 'Gene', (61, 66))
14082	30541591	MicroRNA-561 can downregulate c-Myc expression to inhibit tumour cell proliferation and migration.	('downregulate', 'NegReg', (17, 29))	('inhibit', 'NegReg', (50, 57))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('c-Myc', 'Gene', '4609', (30, 35))	('tumour', 'Disease', (58, 64))	('cell proliferation', 'biological_process', 'GO:0008283', ('65', '83'))	('MicroRNA-561', 'Var', (0, 12))	('c-Myc', 'Gene', (30, 35))
14083	30541591	Amplification and expression of c-Myc is significantly correlated with clinicopathological parameters in gastric cancer.	('correlated', 'Reg', (55, 65))	('Amplification', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('gastric cancer', 'Disease', (105, 119))	('c-Myc', 'Gene', '4609', (32, 37))	('gastric cancer', 'Disease', 'MESH:D013274', (105, 119))	('expression', 'MPA', (18, 28))	('c-Myc', 'Gene', (32, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (105, 119))
14093	30541591	We found that GRINA knockdown promoted apoptosis in BGC-823 and AGS cells, which suggested that GRINA could inhibit apoptosis.	('apoptosis', 'CPA', (39, 48))	('apoptosis', 'biological_process', 'GO:0097194', ('39', '48'))	('AGS', 'Disease', (64, 67))	('apoptosis', 'biological_process', 'GO:0097194', ('116', '125'))	('apoptosis', 'biological_process', 'GO:0006915', ('39', '48'))	('AGS', 'Disease', 'MESH:C535607', (64, 67))	('apoptosis', 'biological_process', 'GO:0006915', ('116', '125'))	('knockdown', 'Var', (20, 29))
14096	30541591	One type inhibits apoptosis and includes Bcl-XL, Bcl-W, Mcl-1, and A1 in mammals, Ced-9 in nematodes, E1B119kD in vaccinia virus, etc.	('vaccinia virus', 'Species', '10245', (114, 128))	('Mcl-1', 'Gene', '4170', (56, 61))	('apoptosis', 'biological_process', 'GO:0006915', ('18', '27'))	('Bcl-W', 'Gene', '599', (49, 54))	('Bcl-W', 'Gene', (49, 54))	('Bcl-XL', 'Gene', '598', (41, 47))	('inhibits', 'NegReg', (9, 17))	('apoptosis', 'CPA', (18, 27))	('Mcl-1', 'Gene', (56, 61))	('E1B119kD', 'Var', (102, 110))	('Bcl-XL', 'Gene', (41, 47))	('apoptosis', 'biological_process', 'GO:0097194', ('18', '27'))
14103	30541591	In our work, GRINA knockdown in gastric cancer cells promoted cell apoptosis, and induced downregulation of Bcl-2 and upregulation of Bax, which indicates that GRINA inhibits apoptosis through Bcl-2 family members.	('gastric cancer', 'Disease', (32, 46))	('inhibits', 'NegReg', (166, 174))	('upregulation', 'PosReg', (118, 130))	('knockdown', 'Var', (19, 28))	('gastric cancer', 'Disease', 'MESH:D013274', (32, 46))	('Bcl-2', 'Gene', (108, 113))	('apoptosis', 'biological_process', 'GO:0097194', ('67', '76'))	('apoptosis', 'biological_process', 'GO:0006915', ('67', '76'))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('promoted', 'PosReg', (53, 61))	('Bcl-2', 'Gene', '596', (108, 113))	('Bax', 'Gene', (134, 137))	('cell apoptosis', 'CPA', (62, 76))	('Bcl-2', 'Gene', (193, 198))	('gastric cancer', 'Phenotype', 'HP:0012126', (32, 46))	('Bcl-2', 'molecular_function', 'GO:0015283', ('193', '198'))	('Bcl-2', 'molecular_function', 'GO:0015283', ('108', '113'))	('downregulation', 'NegReg', (90, 104))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))	('Bax', 'Gene', '581', (134, 137))	('apoptosis', 'CPA', (175, 184))	('Bcl-2', 'Gene', '596', (193, 198))
14138	30406021	However, the toxicity of PAMAM G3.0 > G4.0; cationic amine surface of PAMAM G4.0 binds with glucose by stable bonding, so, it has the ability to scavenge the glucose excess to cut the protein glycation and glycoxidation (treating severe hyperglycemia).	('glycoxidation', 'MPA', (206, 219))	('glycoxidation', 'Chemical', '-', (206, 219))	('protein', 'cellular_component', 'GO:0003675', ('184', '191'))	('PAMAM G4.0', 'Var', (70, 80))	('glucose excess', 'MPA', (158, 172))	('hyperglycemia', 'Disease', 'MESH:D006943', (237, 250))	('protein', 'Protein', (184, 191))	('cut', 'NegReg', (176, 179))	('PAMAM', 'Chemical', 'MESH:C531249', (70, 75))	('toxicity', 'Disease', 'MESH:D064420', (13, 21))	('glucose', 'Chemical', 'MESH:D005947', (92, 99))	('binds', 'Interaction', (81, 86))	('toxicity', 'Disease', (13, 21))	('hyperglycemia', 'Phenotype', 'HP:0003074', (237, 250))	('scavenge', 'MPA', (145, 153))	('amine', 'Chemical', 'MESH:D000588', (53, 58))	('glucose excess', 'Phenotype', 'HP:0003074', (158, 172))	('glucose', 'Chemical', 'MESH:D005947', (158, 165))	('PAMAM', 'Chemical', 'MESH:C531249', (25, 30))	('hyperglycemia', 'Disease', (237, 250))
14156	30406021	Here, we have tested multiple modified variants of PAMAM on the human gastric cells in-vitro, mice in-vivo, addressing all the three toxicity challenges mentioned above, i.e.	('PAMAM', 'Gene', (51, 56))	('toxicity', 'Disease', 'MESH:D064420', (133, 141))	('human', 'Species', '9606', (64, 69))	('toxicity', 'Disease', (133, 141))	('mice', 'Species', '10090', (94, 98))	('modified variants', 'Var', (30, 47))	('PAMAM', 'Chemical', 'MESH:C531249', (51, 56))	('tested', 'Reg', (14, 20))	('variants', 'Var', (39, 47))
14205	30406021	2), a treatment with the different forms of modified dendrimer demonstrated an increased rate of cell division from the PC to PCM to PCMS using equal concentration of the molecules.	('PCM', 'Gene', '53945', (133, 136))	('PCM', 'Gene', (126, 129))	('increased', 'PosReg', (79, 88))	('cell division', 'CPA', (97, 110))	('C', 'Chemical', 'MESH:D002244', (121, 122))	('modified', 'Var', (44, 52))	('PCM', 'Gene', '53945', (126, 129))	('PCMS', 'Chemical', 'MESH:C045667', (133, 137))	('cell division', 'biological_process', 'GO:0051301', ('97', '110'))	('C', 'Chemical', 'MESH:D002244', (134, 135))	('C', 'Chemical', 'MESH:D002244', (127, 128))	('PCM', 'Gene', (133, 136))
14252	30406021	While comparing stomach of ethanol vs. PCMS + ethanol group, the level of active MMP-9 significantly reversed by PCMS treatment (Fig.	('PCMS', 'Var', (113, 117))	('MMP-9', 'molecular_function', 'GO:0004229', ('81', '86'))	('PCMS', 'Chemical', 'MESH:C045667', (113, 117))	('PCMS', 'Chemical', 'MESH:C045667', (39, 43))	('ethanol', 'Chemical', 'MESH:D000431', (46, 53))	('MMP-9', 'Gene', '17395', (81, 86))	('MMP-9', 'Gene', (81, 86))	('ethanol', 'Chemical', 'MESH:D000431', (27, 34))
14257	30406021	In addition, PCMS, in a particular dose window, prevented this change of both pro and active MMP-9 while preventing the inflammation.	('pro', 'MPA', (78, 81))	('MMP-9', 'Gene', '17395', (93, 98))	('MMP-9', 'Gene', (93, 98))	('PCMS', 'Var', (13, 17))	('prevented', 'NegReg', (48, 57))	('preventing', 'NegReg', (105, 115))	('PCMS', 'Chemical', 'MESH:C045667', (13, 17))	('MMP-9', 'molecular_function', 'GO:0004229', ('93', '98'))	('inflammation', 'Disease', 'MESH:D007249', (120, 132))	('inflammation', 'biological_process', 'GO:0006954', ('120', '132'))	('inflammation', 'Disease', (120, 132))
14275	29631196	Multiple factors contribute to tumorigenesis, including EBV driven hypermethylation of tumor suppressor genes, inflammatory changes in gastric mucosa, host immune evasion by EBV and changes in cell cycle pathways.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('EBV', 'Species', '10376', (56, 59))	('host immune evasion', 'MPA', (151, 170))	('cell cycle pathways', 'Pathway', (193, 212))	('changes', 'Reg', (182, 189))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('inflammatory changes in gastric mucosa', 'Phenotype', 'HP:0004295', (111, 149))	('tumor', 'Disease', (87, 92))	('hypermethylation', 'Var', (67, 83))	('contribute', 'Reg', (17, 27))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('87', '103'))	('cell cycle', 'biological_process', 'GO:0007049', ('193', '203'))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('immune evasion', 'biological_process', 'GO:0042783', ('156', '170'))	('tumor', 'Disease', (31, 36))	('tumor suppressor', 'biological_process', 'GO:0051726', ('87', '103'))	('immune evasion', 'biological_process', 'GO:0051842', ('156', '170'))	('EBV', 'Species', '10376', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
14287	29631196	In 2015, the Asian Cancer Research Group (ACRG) conducted gene expression data on 300 gastric cancers, leading to four different subtypes with prognostic data: MSI, microsatellite stable/epithelial-to-mesenchymal transition (MSS/EMT), MSS/TP53+ and MSS/Tp53-.	('microsatellite', 'Var', (165, 179))	('epithelial-to-mesenchymal transition', 'biological_process', 'GO:0001837', ('187', '223'))	('TP53', 'Gene', '7157', (239, 243))	('gene expression', 'biological_process', 'GO:0010467', ('58', '73'))	('Cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Tp53', 'Gene', (253, 257))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('Cancer', 'Disease', (19, 25))	('gastric cancers', 'Disease', 'MESH:D013274', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gastric cancers', 'Disease', (86, 101))	('EMT', 'Gene', (229, 232))	('gastric cancers', 'Phenotype', 'HP:0012126', (86, 101))	('EMT', 'biological_process', 'GO:0001837', ('229', '232'))	('EMT', 'Gene', '3702', (229, 232))	('TP53', 'Gene', (239, 243))	('MSI', 'Disease', (160, 163))	('Tp53', 'Gene', '7157', (253, 257))	('Cancer', 'Disease', 'MESH:D009369', (19, 25))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))
14291	29631196	Although the ACRG analysis did not identify hypermutation among EBV-positive gastric cancers, it did find EBV to be more frequent in the MSS/TP53+ subtype, with significant enrichment of PIK3CA and ARID1A mutations, and increased immune infiltrates.	('PIK3CA', 'Gene', '5290', (187, 193))	('gastric cancers', 'Disease', (77, 92))	('gastric cancers', 'Phenotype', 'HP:0012126', (77, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('mutations', 'Var', (205, 214))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('immune infiltrates', 'CPA', (230, 248))	('PIK3CA', 'Gene', (187, 193))	('EBV', 'Species', '10376', (64, 67))	('ARID1A', 'Gene', '8289', (198, 204))	('ARID1A', 'Gene', (198, 204))	('gastric cancers', 'Disease', 'MESH:D013274', (77, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('EBV', 'Species', '10376', (106, 109))	('frequent', 'Reg', (121, 129))
14295	29631196	Recent meta-analyses have shown that gastric cancers with EBV positivity and microsatellite instability are most likely to overexpress PDL-1.	('gastric cancers', 'Disease', (37, 52))	('gastric cancers', 'Disease', 'MESH:D013274', (37, 52))	('gastric cancers', 'Phenotype', 'HP:0012126', (37, 52))	('EBV', 'Gene', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('overexpress', 'PosReg', (123, 134))	('EBV', 'Species', '10376', (58, 61))	('positivity', 'Var', (62, 72))	('microsatellite instability', 'Var', (77, 103))	('gastric cancer', 'Phenotype', 'HP:0012126', (37, 51))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('PDL-1', 'Gene', '29126', (135, 140))	('PDL-1', 'Gene', (135, 140))
14308	29631196	EBVaGC was first reported by Burke et al in 1990 using polymerase chain reaction (PCR) in gastric carcinoma cells resembling lymphoepithelioma.	('lymphoepithelioma', 'Disease', 'None', (125, 142))	('lymphoepithelioma', 'Disease', (125, 142))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (90, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('gastric carcinoma', 'Disease', 'MESH:D013274', (90, 107))	('polymerase', 'Var', (55, 65))	('EBV', 'Species', '10376', (0, 3))	('gastric carcinoma', 'Disease', (90, 107))
14321	29631196	A comprehensive analysis of promoter methylation status of 51 gastric carcinoma cases was conducted by Shinozaki et al, who subsequently classified gastric carcinoma into three epigenotypes characterized by different sets of methylation genes: EBV+/extensively high-methylation, EBV-/high-methylation and EBV-/low-methylation.	('EBV+/extensively high-methylation', 'Var', (244, 277))	('EBV-/low-methylation', 'Var', (305, 325))	('EBV', 'Species', '10376', (244, 247))	('gastric carcinoma', 'Disease', 'MESH:D013274', (62, 79))	('EBV', 'Species', '10376', (305, 308))	('EBV-/high-methylation', 'Var', (279, 300))	('gastric carcinoma', 'Disease', 'MESH:D013274', (148, 165))	('gastric carcinoma', 'Disease', (62, 79))	('gastric carcinoma', 'Disease', (148, 165))	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (62, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('methylation', 'biological_process', 'GO:0032259', ('225', '236'))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (148, 165))	('EBV', 'Species', '10376', (279, 282))	('methylation', 'biological_process', 'GO:0032259', ('314', '325'))	('methylation', 'biological_process', 'GO:0032259', ('289', '300'))	('methylation', 'biological_process', 'GO:0032259', ('266', '277'))
14325	29631196	Interestingly, MLH1 was frequently methylated (46%) in the EBV-/high-methylation type, whereas none of the EBVaGC cases showed MLH1 methylation.	('EBV-/high-methylation', 'Disease', (59, 80))	('EBV', 'Species', '10376', (107, 110))	('methylation', 'biological_process', 'GO:0032259', ('69', '80'))	('methylated', 'Var', (35, 45))	('methylation', 'biological_process', 'GO:0032259', ('132', '143'))	('EBV', 'Species', '10376', (59, 62))	('MLH1', 'Gene', (15, 19))
14337	29631196	Chronic inflammation is a risk factor for EBVaGC as it sets the optimal conditions necessary for tumorigenesis, and therefore, certain injuries may condition the gastric mucosa to develop EBV associated carcinomas, a process known as field cancerization.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('EBV', 'Species', '10376', (42, 45))	('carcinomas', 'Disease', 'MESH:D002277', (203, 213))	('Chronic inflammation', 'Disease', (0, 20))	('Chronic inflammation', 'Disease', 'MESH:D007249', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('carcinomas', 'Disease', (203, 213))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('injuries', 'Var', (135, 143))	('develop', 'PosReg', (180, 187))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('inflammation', 'biological_process', 'GO:0006954', ('8', '20'))	('EBV', 'Species', '10376', (188, 191))	('cancer', 'Disease', (240, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('condition', 'Reg', (148, 157))	('carcinomas', 'Phenotype', 'HP:0030731', (203, 213))
14342	29631196	Tumor infiltrating lymphocytes (TILs) create an immune-active tumor microenvironment and their presence improves patient survival.	('patient', 'Species', '9606', (113, 120))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('presence', 'Var', (95, 103))	('improves', 'PosReg', (104, 112))	('patient survival', 'CPA', (113, 129))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
14347	29631196	EBV can also activate several important cellular pathways which promote gastric cancer development.	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('EBV', 'Var', (0, 3))	('activate', 'PosReg', (13, 21))	('promote', 'PosReg', (64, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cellular pathways', 'Pathway', (40, 57))	('EBV', 'Species', '10376', (0, 3))	('gastric cancer', 'Disease', (72, 86))
14356	29631196	The genes targeted by EBV miRNAs are associated with oncogenesis, cell adhesion, signal transduction and apoptosis, all of which contribute to carcinogenesis.	('oncogenesis', 'biological_process', 'GO:0007048', ('53', '64'))	('oncogenesis', 'CPA', (53, 64))	('signal transduction', 'CPA', (81, 100))	('cell adhesion', 'biological_process', 'GO:0007155', ('66', '79'))	('apoptosis', 'biological_process', 'GO:0097194', ('105', '114'))	('signal transduction', 'biological_process', 'GO:0007165', ('81', '100'))	('apoptosis', 'CPA', (105, 114))	('carcinogenesis', 'Disease', 'MESH:D063646', (143, 157))	('contribute', 'Reg', (129, 139))	('cell adhesion', 'CPA', (66, 79))	('miRNAs', 'Var', (26, 32))	('EBV', 'Species', '10376', (22, 25))	('apoptosis', 'biological_process', 'GO:0006915', ('105', '114'))	('associated', 'Reg', (37, 47))	('carcinogenesis', 'Disease', (143, 157))	('EBV', 'Gene', (22, 25))
14360	29631196	IncRNAs are associated with larger tumors, greater invasion and reduced survival rates in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('survival rates', 'CPA', (72, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('IncRNAs', 'Var', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('reduced', 'NegReg', (64, 71))	('invasion', 'CPA', (51, 59))	('gastric cancer', 'Disease', (90, 104))
14386	29631196	Lifestyle factors, such as cigarette smoke, have been shown to reactivate EBV in gastric cell lines.	('EBV', 'Species', '10376', (74, 77))	('reactivate', 'Var', (63, 73))	('EBV', 'Gene', (74, 77))
14396	29631196	Several studies have shown EBVaGC to be associated with a lower T stage (depth of tumor invasion), and N stage (nodal status).	('T stage', 'CPA', (64, 71))	('lower', 'NegReg', (58, 63))	('EBV', 'Species', '10376', (27, 30))	('N stage', 'CPA', (103, 110))	('EBVaGC', 'Var', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
14400	29631196	Whether HER2 positivity predicts a poor or better prognosis is currently controversial, and data regarding its relationship with EBVaGC is scarce.	('positivity', 'Var', (13, 23))	('EBV', 'Species', '10376', (129, 132))	('HER2', 'Gene', '2064', (8, 12))	('HER2', 'Gene', (8, 12))
14418	29631196	Recently, gene expression data from the TCGA cohort was used to identify subgroups with the highest survival advantage from adjuvant chemotherapy, and EBVaGC was associated with the best prognosis for both recurrence-free survival (p=0.006) and OS (p=0.004).	('gene expression', 'biological_process', 'GO:0010467', ('10', '25'))	('EBVaGC', 'Var', (151, 157))	('recurrence-free survival', 'CPA', (206, 230))	('OS', 'Chemical', 'MESH:D009992', (245, 247))	('EBV', 'Species', '10376', (151, 154))
14426	29631196	Mutations in EBVaGC leading to amplification of PIK3CA also lead to poor survival.	('EBVaGC', 'Gene', (13, 19))	('poor', 'NegReg', (68, 72))	('PIK3CA', 'Gene', (48, 54))	('Mutations', 'Var', (0, 9))	('EBV', 'Species', '10376', (13, 16))	('amplification', 'MPA', (31, 44))	('PIK3CA', 'Gene', '5290', (48, 54))
14427	29631196	Ongoing trials testing the efficacy of targeted treatments against PD-L1 and PIK3CA mutations in EBVaGC are further discussed in potential treatments below.	('PIK3CA', 'Gene', (77, 83))	('EBV', 'Species', '10376', (97, 100))	('PD-L1', 'Gene', (67, 72))	('PIK3CA', 'Gene', '5290', (77, 83))	('mutations', 'Var', (84, 93))	('PD-L1', 'Gene', '29126', (67, 72))
14428	29631196	Approximately 50% of the world's population is infected with Helicobacter pylori, which induces gastric inflammation and may set the conditions necessary for EBV related epigenetic changes and tumorigenesis.	('induces', 'Reg', (88, 95))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('gastric inflammation', 'Disease', (96, 116))	('Helicobacter pylori', 'Var', (61, 80))	('gastric inflammation', 'Phenotype', 'HP:0005263', (96, 116))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('EBV', 'Species', '10376', (158, 161))	('Helicobacter pylori', 'Species', '210', (61, 80))	('tumor', 'Disease', (193, 198))	('epigenetic changes', 'Var', (170, 188))	('inflammation', 'biological_process', 'GO:0006954', ('104', '116'))	('gastric inflammation', 'Disease', 'MESH:D007249', (96, 116))
14429	29631196	Hypermethylation and upregulation of inflammatory markers (TNFalpha, IL-1beta) associated with EBVaGC has been linked to H. pylori.	('TNFalpha', 'Gene', (59, 67))	('Hypermethylation', 'Var', (0, 16))	('EBV', 'Species', '10376', (95, 98))	('H. pylori', 'Species', '210', (121, 130))	('H. pylori', 'Disease', (121, 130))	('IL-1', 'molecular_function', 'GO:0005149', ('69', '73'))	('upregulation', 'PosReg', (21, 33))
14432	29631196	They also showed that without EBV, H. pylori did not trigger severe gastritis, and concluded that both pathogens synergistically contribute to inflammation and damage to the gastric mucosa.	('H. pylori', 'Var', (35, 44))	('gastritis', 'Disease', 'MESH:D005756', (68, 77))	('damage to the gastric mucosa', 'Disease', 'MESH:D013272', (160, 188))	('gastritis', 'Phenotype', 'HP:0005263', (68, 77))	('contribute', 'Reg', (129, 139))	('EBV', 'Species', '10376', (30, 33))	('damage to the gastric mucosa', 'Disease', (160, 188))	('H. pylori', 'Species', '210', (35, 44))	('inflammation', 'Disease', 'MESH:D007249', (143, 155))	('gastritis', 'Disease', (68, 77))	('inflammation', 'Disease', (143, 155))	('inflammation', 'biological_process', 'GO:0006954', ('143', '155'))
14433	29631196	Camargo et al also suggested that H. pylori catalase could dampen host oxidative stress response, and allow EBV to remain in latent phase for a longer duration, thereby enabling EBVaGC development.	('EBV', 'Species', '10376', (108, 111))	('host oxidative stress response', 'MPA', (66, 96))	('oxidative stress', 'Phenotype', 'HP:0025464', (71, 87))	('H. pylori', 'Species', '210', (34, 43))	('EBV', 'Species', '10376', (178, 181))	('enabling', 'PosReg', (169, 177))	('H. pylori catalase', 'Var', (34, 52))	('dampen', 'NegReg', (59, 65))	('EBVaGC development', 'CPA', (178, 196))
14435	29631196	Interestingly, presence of EBV has been shown to increase the oncogenic potential of the H. pylori protein, CagA.	('increase', 'PosReg', (49, 57))	('H. pylori', 'Species', '210', (89, 98))	('presence', 'Var', (15, 23))	('EBV', 'Gene', (27, 30))	('oncogenic', 'MPA', (62, 71))	('EBV', 'Species', '10376', (27, 30))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))
14436	29631196	Conversely, a study by Shukla et al suggested that H. pylori might prevent EBVaGC by attenuating TGF-beta expression, which is required for EBV reactivation.	('EBVaGC', 'Disease', (75, 81))	('expression', 'MPA', (106, 116))	('TGF-beta', 'Gene', (97, 105))	('attenuating', 'NegReg', (85, 96))	('EBV', 'Species', '10376', (75, 78))	('H. pylori', 'Species', '210', (51, 60))	('EBV', 'Species', '10376', (140, 143))	('prevent', 'NegReg', (67, 74))	('H. pylori', 'Var', (51, 60))
14459	29631196	A phase I trial (NCT03044743) is evaluating the safety of CRISPR-Cas9 mediated PD-1 knockout EBV-CTL cells (cytotoxic-T cells) in stage IV GCs.	('Cas', 'cellular_component', 'GO:0005650', ('65', '68'))	('EBV', 'Species', '10376', (93, 96))	('knockout', 'Var', (84, 92))	('PD-1', 'Gene', (79, 83))	('cytotoxic-', 'Disease', (108, 118))	('cytotoxic-', 'Disease', 'MESH:D064420', (108, 118))
14460	29631196	EBVaGC also shows an enrichment of PIK3CA mutations, which is part of the PI3K-AKT-mTOR pathway leading to increased cell proliferation.	('mTOR', 'Gene', (83, 87))	('increased', 'PosReg', (107, 116))	('cell proliferation', 'CPA', (117, 135))	('PIK3CA', 'Gene', (35, 41))	('EBV', 'Species', '10376', (0, 3))	('cell proliferation', 'biological_process', 'GO:0008283', ('117', '135'))	('PI3K', 'molecular_function', 'GO:0016303', ('74', '78'))	('PIK3CA', 'Gene', '5290', (35, 41))	('mutations', 'Var', (42, 51))	('mTOR', 'Gene', '2475', (83, 87))
14467	29631196	In preclinical studies, 5-Aza has been shown to restore expression of all methylated genes, activate lytic infection and lead to cell lysis.	('lytic infection', 'CPA', (101, 116))	('5-Aza', 'Chemical', 'MESH:D001374', (24, 29))	('5-Aza', 'Var', (24, 29))	('lysis', 'biological_process', 'GO:0019835', ('134', '139'))	('expression', 'MPA', (56, 66))	('restore', 'PosReg', (48, 55))	('lead to', 'Reg', (121, 128))	('cell lysis', 'CPA', (129, 139))	('activate', 'PosReg', (92, 100))	('methylated genes', 'Gene', (74, 90))
14476	29631196	Approximately 10% of all gastric cancers are related to EBV infection EBV associated gastric cancers have a distinct molecular and clinical profile These tumors have higher PDL-1 expression, PIK3CA mutations and hypermethylation The role of immunotherapy in EBV associated gastric cancer is currently unknown EBV is a promising biomarker in gastric cancer	('gastric cancer', 'Disease', (341, 355))	('EBV', 'Species', '10376', (309, 312))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('EBV', 'Species', '10376', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('EBV infection', 'Disease', 'MESH:D020031', (56, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (273, 287))	('gastric cancer', 'Disease', 'MESH:D013274', (25, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (341, 355))	('higher', 'PosReg', (166, 172))	('EBV', 'Species', '10376', (70, 73))	('PIK3CA', 'Gene', '5290', (191, 197))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('gastric cancers', 'Disease', (25, 40))	('gastric cancers', 'Disease', 'MESH:D013274', (25, 40))	('gastric cancers', 'Phenotype', 'HP:0012126', (25, 40))	('EBV infection', 'Disease', (56, 69))	('hypermethylation', 'Var', (212, 228))	('PDL-1', 'Gene', (173, 178))	('EBV', 'Species', '10376', (258, 261))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('gastric cancer', 'Disease', (273, 287))	('gastric cancer', 'Phenotype', 'HP:0012126', (25, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (341, 355))	('gastric cancer', 'Disease', 'MESH:D013274', (85, 99))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('PIK3CA', 'Gene', (191, 197))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('tumors', 'Disease', (154, 160))	('gastric cancers', 'Disease', 'MESH:D013274', (85, 100))	('expression', 'MPA', (179, 189))	('gastric cancers', 'Disease', (85, 100))	('gastric cancers', 'Phenotype', 'HP:0012126', (85, 100))	('gastric cancer', 'Disease', 'MESH:D013274', (273, 287))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('PDL-1', 'Gene', '29126', (173, 178))	('gastric cancer', 'Phenotype', 'HP:0012126', (85, 99))
14531	29291033	PAR-1 silencing and inhibiting thrombin decrease dissemination of metastatic melanoma cells.	('decrease', 'NegReg', (40, 48))	('thrombin', 'Gene', '2147', (31, 39))	('inhibiting', 'NegReg', (20, 30))	('PAR-1', 'Gene', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('inhibiting thrombin decrease', 'Phenotype', 'HP:0001976', (20, 48))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('silencing', 'Var', (6, 15))	('thrombin', 'Gene', (31, 39))
14532	29291033	PAR-1 siRNA mediated inhibition decreased MMP-2, IL-8 and VEGF, expression levels, subsequently vascular density.	('VEGF', 'Gene', (58, 62))	('MMP-2', 'Gene', (42, 47))	('IL-8', 'molecular_function', 'GO:0005153', ('49', '53'))	('PAR-1', 'Gene', (0, 5))	('VEGF', 'Gene', '7422', (58, 62))	('MMP-2', 'molecular_function', 'GO:0004228', ('42', '47'))	('inhibition', 'Var', (21, 31))	('vascular density', 'CPA', (96, 112))	('IL-8', 'Gene', '3576', (49, 53))	('MMP-2', 'Gene', '4313', (42, 47))	('expression levels', 'MPA', (64, 81))	('IL-8', 'Gene', (49, 53))	('decreased', 'NegReg', (32, 41))
14535	29291033	AA genotype of PAR-1 gene variant IVSn-14A> T was associated with an increased risk of RCC metastasis and a poorer prognosis.	('PAR-1', 'Gene', (15, 20))	('RCC metastasis', 'Disease', 'MESH:C538614', (87, 101))	('-14A> T', 'Mutation', 'rs168753', (38, 45))	('RCC metastasis', 'Disease', (87, 101))	('variant IVSn-14A> T', 'Var', (26, 45))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
14553	29291033	Activated PAR-1 also promotes colon cancer cell proliferation EGFR transactivation.	('EGFR', 'Gene', '1956', (62, 66))	('transactivation', 'biological_process', 'GO:2000144', ('67', '82'))	('cell proliferation', 'biological_process', 'GO:0008283', ('43', '61'))	('colon cancer', 'Phenotype', 'HP:0003003', (30, 42))	('colon cancer', 'Disease', 'MESH:D015179', (30, 42))	('EGFR', 'Gene', (62, 66))	('promotes', 'PosReg', (21, 29))	('Activated', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('EGFR', 'molecular_function', 'GO:0005006', ('62', '66'))	('colon cancer', 'Disease', (30, 42))	('PAR-1', 'Gene', (10, 15))	('rat', 'Species', '10116', (55, 58))
14556	29291033	According to a survey of 209 patients, PAR-1 polymorphism was associated with tumor stage and median OS (overall survival) of squamous cell lung cancer patients.	('squamous cell lung cancer', 'Disease', (126, 151))	('patients', 'Species', '9606', (29, 37))	('polymorphism', 'Var', (45, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('PAR-1', 'Gene', (39, 44))	('associated', 'Reg', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (126, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (126, 151))	('median', 'CPA', (94, 100))	('tumor', 'Disease', (78, 83))	('patients', 'Species', '9606', (152, 160))
14560	29291033	Galphaq and Galpha13, coupled with PAR-1 as well as constitutively active GalphaqQL and Galpha12/13QL mutants to stimulate SCLC (small cell lung cancer) to connect autocrine bombesin (BBS).	('mutants', 'Var', (102, 109))	('small cell lung cancer', 'Disease', (129, 151))	('stimulate', 'PosReg', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('SCLC', 'Disease', (123, 127))	('Galphaq', 'Gene', '2776', (74, 81))	('bombesin', 'Gene', (174, 182))	('Galphaq', 'Gene', (0, 7))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (129, 151))	('Galphaq', 'Gene', '2776', (0, 7))	('SCLC', 'Disease', 'MESH:D018288', (123, 127))	('Galpha13', 'Gene', '10672', (12, 20))	('Galpha12/13QL', 'Gene', (88, 101))	('Galpha13', 'Gene', (12, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('bombesin', 'Gene', '2922', (174, 182))	('small cell lung cancer', 'Disease', 'MESH:D055752', (129, 151))	('Galpha12/13QL', 'Gene', '2768', (88, 101))	('Galphaq', 'Gene', (74, 81))
14566	29291033	Unregulated PAR-1 expression in peritumoral stroma of prostate cancer patient is associated with biochemical recurrence.	('Unregulated', 'Var', (0, 11))	('stroma of prostate cancer', 'Disease', (44, 69))	('PAR-1', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('patient', 'Species', '9606', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('expression', 'MPA', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('stroma of prostate cancer', 'Disease', 'MESH:D011471', (44, 69))	('associated', 'Reg', (81, 91))	('biochemical recurrence', 'Disease', (97, 119))	('tumor', 'Disease', (36, 41))	('prostate cancer', 'Phenotype', 'HP:0012125', (54, 69))
14568	29291033	Tissue kallikrein (TK) promotes keratinocyte migration through activation of PAR-1 and transactivation of EGFR.	('TK', 'Gene', '3816', (19, 21))	('rat', 'Species', '10116', (48, 51))	('kallikrein', 'molecular_function', 'GO:0004293', ('7', '17'))	('promotes', 'PosReg', (23, 31))	('EGFR', 'molecular_function', 'GO:0005006', ('106', '110'))	('PAR-1', 'Gene', (77, 82))	('transactivation', 'biological_process', 'GO:2000144', ('87', '102'))	('transactivation', 'Var', (87, 102))	('Tissue kallikrein', 'Gene', (0, 17))	('EGFR', 'Gene', '1956', (106, 110))	('Tissue kallikrein', 'Gene', '3816', (0, 17))	('kallikrein', 'molecular_function', 'GO:0003807', ('7', '17'))	('keratinocyte migration', 'biological_process', 'GO:0051546', ('32', '54'))	('rat', 'Species', '10116', (34, 37))	('keratinocyte migration', 'CPA', (32, 54))	('activation', 'PosReg', (63, 73))	('EGFR', 'Gene', (106, 110))
14575	29291033	Per HIF-alpha/VEGF pathway, PAR-1 maintains self-renewal and tumorigenicity of tumor-initiating progenitor cells (TPC) in gliomas, whilst inhibition of PAR-1 signaling slows down tumor progression.	('signaling', 'biological_process', 'GO:0023052', ('158', '167'))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('PAR-1', 'Gene', (28, 33))	('inhibition', 'Var', (138, 148))	('self-renewal', 'CPA', (44, 56))	('VEGF', 'Gene', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('gliomas', 'Disease', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('maintains', 'PosReg', (34, 43))	('VEGF', 'Gene', '7422', (14, 18))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))	('tumor', 'Disease', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (179, 184))
14579	29291033	According to the experimental research mentioned above, PAR-1 inhibitors may have the effect of inhibiting tumor cell proliferation, reducing invasion and metastasis, and anti-tumor angiogenesis.	('rat', 'Species', '10116', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cell proliferation', 'biological_process', 'GO:0008283', ('113', '131'))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (176, 181))	('angiogenesis', 'biological_process', 'GO:0001525', ('182', '194'))	('inhibiting', 'NegReg', (96, 106))	('inhibitors', 'Var', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('PAR-1', 'Gene', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('reducing', 'NegReg', (133, 141))
14580	29291033	Currently, vorapaxar (SCH530348) and atopaxar (E5555) are the two clinical formulations of PAR-1 inhibitors,which have undergone extensive clinical development.	('E5555', 'Var', (47, 52))	('PAR-1', 'Gene', (91, 96))	('SCH530348', 'Var', (22, 31))	('vorapaxar', 'Chemical', 'MESH:C530299', (11, 20))	('SCH530348', 'Chemical', 'MESH:C530299', (22, 31))
14602	29291033	Although PAR-1 antagonists are known to be potent antiplatelet agents that are also complementary to other antiplatelet therapies, its role in clinical cancer treatment is still a mystery.	('PAR-1', 'Gene', (9, 14))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('antagonists', 'Var', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
14605	29147648	ncRNAs are associated to higher eukaryotes complexity; accordingly, their dysfunction results in pathological phenotypes, including cancer.	('dysfunction', 'Var', (74, 85))	('cancer', 'Disease', (132, 138))	('ncRNA', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('ncRNA', 'Gene', '220202', (0, 5))	('results in', 'Reg', (86, 96))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
14621	29147648	These observations strongly suggest that ncRNAs are closely related to the complexity of higher eukaryotes and that their dysfunction may result in pathological phenotypes.	('ncRNA', 'Gene', (41, 46))	('dysfunction', 'Var', (122, 133))	('result in', 'Reg', (138, 147))	('ncRNA', 'Gene', '220202', (41, 46))
14636	29147648	In the last two decades, their mutations and altered expression were reported to be causally related to the neoplastic features of the cells, thus providing new perspectives for the understanding of the complex regulatory networks that rule tumor biology.	('mutations', 'Var', (31, 40))	('expression', 'MPA', (53, 63))	('related', 'Reg', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('rule tumor', 'Disease', 'MESH:D009369', (236, 246))	('rule tumor', 'Disease', (236, 246))	('neoplastic features of the cells', 'CPA', (108, 140))
14637	29147648	miRNA dysfunctions exert a pleiotropic effect on the expression of their mRNA targets impairing the functioning of biological networks.	('impairing', 'NegReg', (86, 95))	('dysfunctions', 'Var', (6, 18))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('functioning', 'MPA', (100, 111))	('expression', 'MPA', (53, 63))
14642	29147648	They include transcripts that may be classified as (a) intergenic lncRNAs, (b) intronic lncRNAs, (c) sense or antisense transcripts, (d) pseudogenes, and (e) retrotransposons.	('pseudogenes', 'Var', (137, 148))	('ncRNA', 'Gene', (67, 72))	('ncRNA', 'Gene', (89, 94))	('ncRNA', 'Gene', '220202', (67, 72))	('ncRNA', 'Gene', '220202', (89, 94))
14650	29147648	Dysregulation of lncRNA activity has been frequently reported in association to diseases, including several types of cancer.	('ncRNA', 'Gene', '220202', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('ncRNA', 'Gene', (18, 23))	('cancer', 'Disease', (117, 123))	('reported', 'Reg', (53, 61))
14657	29147648	circRNAs are a circularized isoform of linear protein-coding genes generated through backsplicing, a molecular process that is different from the canonical splicing of linear RNAs.	('cir', 'Gene', (15, 18))	('protein', 'cellular_component', 'GO:0003675', ('46', '53'))	('cir', 'Gene', '9541', (15, 18))	('cir', 'Gene', (0, 3))	('cir', 'Gene', '9541', (0, 3))	('backsplicing', 'Var', (85, 97))	('splicing', 'biological_process', 'GO:0045292', ('156', '164'))
14667	29147648	Just few of these studies attempted to functionally explain how abnormal expression of circRNAs could impair physiological cell homeostasis and thus promote cancer phenotypes.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('abnormal expression', 'Var', (64, 83))	('promote', 'PosReg', (149, 156))	('cir', 'Gene', '9541', (87, 90))	('impair', 'NegReg', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('physiological cell homeostasis', 'MPA', (109, 139))	('cir', 'Gene', (87, 90))	('homeostasis', 'biological_process', 'GO:0042592', ('128', '139'))
14698	29147648	Interestingly, HuR and let-7b/AGO2 complex also decreased the stability of lincRNA-p21, an oncogenic lncRNA that reduced translation of beta-catenin and JUNB (JunB proto-oncogene, subunit of transcription factor AP-1) mRNAs in human cervical carcinoma HeLa cells; even if in other experiments HuR was not able to transfer let-7b to AGO2.	('let-7b', 'Gene', (322, 328))	('AGO2', 'Gene', (30, 34))	('lincRNA-p21', 'Gene', (75, 86))	('let-7b', 'Gene', (23, 29))	('ncRNA', 'Gene', (77, 82))	('ncRNA', 'Gene', '220202', (77, 82))	('translation', 'MPA', (121, 132))	('JUNB', 'Gene', '3726', (153, 157))	('reduced', 'NegReg', (113, 120))	('beta-catenin', 'Gene', (136, 148))	('beta-catenin', 'Gene', '1499', (136, 148))	('decreased', 'NegReg', (48, 57))	('AGO2', 'Gene', '27161', (332, 336))	('carcinoma HeLa', 'Disease', (242, 256))	('transcription factor', 'molecular_function', 'GO:0000981', ('191', '211'))	('JUNB', 'Gene', (153, 157))	('carcinoma HeLa', 'Disease', 'MESH:D002277', (242, 256))	('HuR', 'Gene', (293, 296))	('HuR', 'Gene', (15, 18))	('transcription', 'biological_process', 'GO:0006351', ('191', '204'))	('complex', 'Var', (35, 42))	('AGO2', 'Gene', '27161', (30, 34))	('translation', 'biological_process', 'GO:0006412', ('121', '132'))	('let-7b', 'Gene', '406884', (322, 328))	('let-7b', 'Gene', '406884', (23, 29))	('AP-1', 'cellular_component', 'GO:0005907', ('212', '216'))	('stability', 'MPA', (62, 71))	('AGO2', 'Gene', (332, 336))	('HuR', 'Gene', '1994', (293, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('ncRNA', 'Gene', (102, 107))	('JunB', 'Gene', (159, 163))	('human', 'Species', '9606', (227, 232))	('HuR', 'Gene', '1994', (15, 18))	('lincRNA-p21', 'Gene', '102800311', (75, 86))	('ncRNA', 'Gene', '220202', (102, 107))	('JunB', 'Gene', '3726', (159, 163))
14732	29147648	Dysregulation of FER1L4-miR-106a-5p-PTEN axis increased cell proliferation by promoting the G0/G1 to S phase transition.	('S phase', 'biological_process', 'GO:0051320', ('101', '108'))	('Dysregulation', 'Var', (0, 13))	('increased', 'PosReg', (46, 55))	('FER1L4', 'Gene', '80307', (17, 23))	('PTEN', 'Gene', (36, 40))	('PTEN', 'Gene', '5728', (36, 40))	('promoting', 'PosReg', (78, 87))	('miR-106a', 'Gene', '406899', (24, 32))	('cell proliferation', 'CPA', (56, 74))	('miR-106a', 'Gene', (24, 32))	('FER1L4', 'Gene', (17, 23))	('G0/G1 to S phase transition', 'CPA', (92, 119))	('cell proliferation', 'biological_process', 'GO:0008283', ('56', '74'))
14745	29147648	Upregulation of lncRNA CCAT1 (colon cancer associated transcript 1) in HCC tissues was associated with increased cell proliferation and migration; these oncogenic activities were mediated by its molecular sponge function for let-7: inhibition of let-7 caused upregulated expression of let-7 targets: HMGA2 (high mobility group AT-hook 2) and MYC (MYC proto-oncogene, bHLH transcription factor).	('HCC', 'Phenotype', 'HP:0001402', (71, 74))	('transcription', 'biological_process', 'GO:0006351', ('372', '385'))	('transcription factor', 'molecular_function', 'GO:0000981', ('372', '392'))	('MYC', 'Gene', '4609', (347, 350))	('HMGA2', 'Gene', (300, 305))	('cell proliferation', 'biological_process', 'GO:0008283', ('113', '131'))	('upregulated', 'PosReg', (259, 270))	('inhibition', 'Var', (232, 242))	('CCAT1', 'Gene', '100507056', (23, 28))	('expression', 'MPA', (271, 281))	('CCAT1', 'Gene', (23, 28))	('MYC', 'Gene', (342, 345))	('colon cancer associated transcript 1', 'Gene', '100507056', (30, 66))	('colon cancer associated transcript 1', 'Gene', (30, 66))	('let-7', 'Gene', (246, 251))	('high mobility group AT-hook 2', 'Gene', (307, 336))	('ncRNA', 'Gene', (17, 22))	('HMGA2', 'Gene', '8091', (300, 305))	('ncRNA', 'Gene', '220202', (17, 22))	('MYC', 'Gene', (347, 350))	('colon cancer', 'Phenotype', 'HP:0003003', (30, 42))	('MYC', 'Gene', '4609', (342, 345))	('high mobility group AT-hook 2', 'Gene', '8091', (307, 336))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
14776	29147648	Overexpression of TUG1 was involved in glioblastoma angiogenesis by modulation of endothelial cell proliferation, migration, and tube formation.	('glioblastoma', 'Disease', (39, 51))	('glioblastoma', 'Disease', 'MESH:D005909', (39, 51))	('endothelial cell proliferation', 'biological_process', 'GO:0001935', ('82', '112'))	('TUG1', 'Gene', (18, 22))	('angiogenesis', 'biological_process', 'GO:0001525', ('52', '64'))	('tube formation', 'biological_process', 'GO:0035148', ('129', '143'))	('migration', 'CPA', (114, 123))	('involved', 'Reg', (27, 35))	('modulation', 'Reg', (68, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (39, 51))	('endothelial cell proliferation', 'CPA', (82, 112))	('Overexpression', 'Var', (0, 14))	('tube formation', 'CPA', (129, 143))	('TUG1', 'Gene', '55000', (18, 22))
14778	29147648	In fact, knockdown of TUG1-induced upregulation of miR-299 and concomitant decrease of VEGFA (vascular endothelial growth factor A), target of miR-299.	('miR-299', 'Gene', '407023', (51, 58))	('vascular endothelial growth factor A', 'Gene', '7422', (94, 130))	('knockdown', 'Var', (9, 18))	('decrease', 'NegReg', (75, 83))	('VEGFA', 'Gene', (87, 92))	('vascular endothelial growth factor A', 'Gene', (94, 130))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('94', '128'))	('miR-299', 'Gene', (143, 150))	('TUG1', 'Gene', '55000', (22, 26))	('VEGFA', 'Gene', '7422', (87, 92))	('miR-299', 'Gene', (51, 58))	('upregulation', 'PosReg', (35, 47))	('miR-299', 'Gene', '407023', (143, 150))	('TUG1', 'Gene', (22, 26))
14783	29147648	Because POU2F1 is a target of miR-9-5p, silencing of TUG1-inhibited cell proliferation and colony formation, while inducing G0/G1 cell cycle arrest and apoptosis.	('apoptosis', 'biological_process', 'GO:0097194', ('152', '161'))	('miR-9-5p', 'Gene', (30, 38))	('miR-9-5p', 'Gene', '407052', (30, 38))	('apoptosis', 'biological_process', 'GO:0006915', ('152', '161'))	('cell proliferation', 'CPA', (68, 86))	('colony formation', 'CPA', (91, 107))	('inducing', 'NegReg', (115, 123))	('TUG1', 'Gene', '55000', (53, 57))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (130, 147))	('POU2F1', 'Gene', (8, 14))	('silencing', 'Var', (40, 49))	('POU2F1', 'Gene', '5451', (8, 14))	('formation', 'biological_process', 'GO:0009058', ('98', '107'))	('TUG1', 'Gene', (53, 57))	('apoptosis', 'CPA', (152, 161))	('G0/G1 cell cycle arrest', 'CPA', (124, 147))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('130', '147'))	('cell proliferation', 'biological_process', 'GO:0008283', ('68', '86'))
14788	29147648	They found that ectopic expression of TUSC7 inhibited cell metastasis, invasion, and EMT, by functioning as a competitive sponge for miR-10a.	('TUSC7', 'Gene', (38, 43))	('EMT', 'biological_process', 'GO:0001837', ('85', '88'))	('TUSC7', 'Gene', '285194', (38, 43))	('inhibited', 'NegReg', (44, 53))	('invasion', 'CPA', (71, 79))	('miR-10a', 'Gene', (133, 140))	('ectopic expression', 'Var', (16, 34))	('cell metastasis', 'CPA', (54, 69))	('EMT', 'CPA', (85, 88))	('miR-10a', 'Gene', '406902', (133, 140))
14793	29147648	TUSC7, downregulated in gastric cancer, was an independent prognostic marker of disease-free survival in patients, and its ectopic expression suppressed cancer cell growth both in in vitro and in vivo models, in part by negatively regulating the expression of miR-23.	('regulating', 'Reg', (231, 241))	('negatively', 'NegReg', (220, 230))	('miR', 'Gene', (260, 263))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('gastric cancer', 'Disease', 'MESH:D013274', (24, 38))	('cell growth', 'biological_process', 'GO:0016049', ('160', '171'))	('TUSC7', 'Gene', (0, 5))	('TUSC7', 'Gene', '285194', (0, 5))	('cancer', 'Disease', (32, 38))	('ectopic expression', 'Var', (123, 141))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('expression', 'MPA', (246, 256))	('suppressed', 'NegReg', (142, 152))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('gastric cancer', 'Phenotype', 'HP:0012126', (24, 38))	('patients', 'Species', '9606', (105, 113))	('downregulated', 'NegReg', (7, 20))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('miR', 'Gene', '220972', (260, 263))	('gastric cancer', 'Disease', (24, 38))
14797	29147648	Silencing of UCA1 decreased ROS production and promoted mitochondrial glutaminolysis in bladder cancer cells.	('bladder cancer', 'Disease', 'MESH:D001749', (88, 102))	('bladder cancer', 'Disease', (88, 102))	('decreased', 'NegReg', (18, 27))	('promoted', 'PosReg', (47, 55))	('ROS production', 'MPA', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('ROS', 'Chemical', 'MESH:D017382', (28, 31))	('mitochondrial glutaminolysis', 'MPA', (56, 84))	('UCA1', 'Gene', '652995', (13, 17))	('UCA1', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (88, 102))
14822	29147648	Circ-TTBK2 harbors MREs for miR-217, which has a tumor-suppressive role in glioma cells.	('miR-217', 'Gene', '406999', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('miR-217', 'Gene', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('TTBK2', 'Gene', (5, 10))	('TTBK2', 'Gene', '146057', (5, 10))	('tumor', 'Disease', (49, 54))	('glioma', 'Disease', (75, 81))	('Cir', 'Gene', '9541', (0, 3))	('glioma', 'Disease', 'MESH:D005910', (75, 81))	('Cir', 'Gene', (0, 3))	('MREs', 'Var', (19, 23))
14826	29147648	Moreover, restoration of miR-217 expression reversed the circ-TTBK2-induced promotion of cancer progression, suggesting a reciprocal negative feedback between circ-TTBK2 and miR-217.	('miR-217', 'Gene', '406999', (25, 32))	('TTBK2', 'Gene', '146057', (164, 169))	('TTBK2', 'Gene', '146057', (62, 67))	('restoration', 'Var', (10, 21))	('cir', 'Gene', (57, 60))	('promotion', 'PosReg', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('TTBK2', 'Gene', (164, 169))	('cir', 'Gene', '9541', (57, 60))	('TTBK2', 'Gene', (62, 67))	('miR-217', 'Gene', '406999', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('miR-217', 'Gene', (174, 181))	('cir', 'Gene', (159, 162))	('miR-217', 'Gene', (25, 32))	('cir', 'Gene', '9541', (159, 162))
14832	29147648	Cir-ITCH was downregulated in CRC tissues and its ectopic expression led to decreased cell proliferation.	('ITCH', 'Phenotype', 'HP:0000989', (4, 8))	('ITCH', 'Gene', '83737', (4, 8))	('-ITCH', 'Phenotype', 'HP:0000989', (3, 8))	('downregulated', 'NegReg', (13, 26))	('ectopic expression', 'Var', (50, 68))	('decreased', 'NegReg', (76, 85))	('cell proliferation', 'biological_process', 'GO:0008283', ('86', '104'))	('Cir', 'Gene', '9541', (0, 3))	('ITCH', 'Gene', (4, 8))	('cell proliferation', 'CPA', (86, 104))	('Cir', 'Gene', (0, 3))
14845	29147648	Initially, Sry circRNA was considered an artifact of aberrant RNA splicing and no specific function was attributed to it.	('Sry', 'Gene', '6736', (11, 14))	('cir', 'Gene', (15, 18))	('Sry', 'Gene', (11, 14))	('RNA splicing', 'biological_process', 'GO:0008380', ('62', '74'))	('cir', 'Gene', '9541', (15, 18))	('aberrant', 'Var', (53, 61))	('RNA', 'cellular_component', 'GO:0005562', ('62', '65'))
14870	29147648	In spite of unclear stoichiometric relationships among ncRNAs in cancer, multiple experimental evidence shows that in vitro and in vivo modulation of ncRNAs strongly impair aggressive properties of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('ncRNA', 'Gene', '220202', (55, 60))	('cancer', 'Disease', (198, 204))	('ncRNA', 'Gene', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('ncRNA', 'Gene', '220202', (150